Novel high dose rate lip brachytherapy technique to improve dose homogeneity and reduce toxicity by customized mold

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Feldman, Jon; Appelbaum, Limor; Sela, Mordechay; Voskoboinik, Ninel; Kadouri, Sarit; Weinberger, Jeffrey; Orion, Itzhak; Meirovitz, Amichay

2014-01-01

The purpose of this study is to describe a novel brachytherapy technique for lip Squamous Cell Carcinoma, utilizing a customized mold with embedded brachytherapy sleeves, which separates the lip from the mandible, and improves dose homogeneity. Seven patients with T2 lip cancer treated with a “sandwich” technique of High Dose Rate (HDR) brachytherapy to the lip, consisting of interstitial catheters and a customized mold with embedded catheters, were reviewed for dosimetry and outcome using 3D planning. Dosimetric comparison was made between the “sandwich” technique to “classic” – interstitial catheters only plan. We compared dose volume histograms for Clinical Tumor Volume (CTV), normal tissue “hot spots” and mandible dose. We are reporting according to the ICRU 58 and calculated the Conformal Index (COIN) to show the advantage of our technique. The seven patients (ages 36–81 years, male) had median follow-up of 47 months. Four patients received Brachytherapy and External Beam Radiation Therapy, 3 patients received brachytherapy alone. All achieved local control, with excellent esthetic and functional results. All patients are disease free. The Customized Mold Sandwich technique (CMS) reduced the high dose region receiving 150% (V150) by an average of 20% (range 1–47%), The low dose region (les then 90% of the prescribed dose) improved by 73% in average by using the CMS technique. The COIN value for the CMS was in average 0.92 as opposed to 0.88 for the interstitial catheter only. All differences (excluding the low dose region) were statistically significant. The CMS technique significantly reduces the high dose volume and increases treatment homogeneity. This may reduce the potential toxicity to the lip and adjacent mandible, and results in excellent tumor control, cosmetic and functionality

Impact of Bone Marrow Radiation Dose on Acute Hematologic Toxicity in Cervical Cancer: Principal Component Analysis on High Dimensional Data

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Yun Liang; Messer, Karen; Rose, Brent S.; Lewis, John H.; Jiang, Steve B.; Yashar, Catheryn M.; Mundt, Arno J.; Mell, Loren K.

2010-01-01

Purpose: To study the effects of increasing pelvic bone marrow (BM) radiation dose on acute hematologic toxicity in patients undergoing chemoradiotherapy, using a novel modeling approach to preserve the local spatial dose information. Methods and Materials: The study included 37 cervical cancer patients treated with concurrent weekly cisplatin and pelvic radiation therapy. The white blood cell count nadir during treatment was used as the indicator for acute hematologic toxicity. Pelvic BM radiation dose distributions were standardized across patients by registering the pelvic BM volumes to a common template, followed by dose remapping using deformable image registration, resulting in a dose array. Principal component (PC) analysis was applied to the dose array, and the significant eigenvectors were identified by linear regression on the PCs. The coefficients for PC regression and significant eigenvectors were represented in three dimensions to identify critical BM subregions where dose accumulation is associated with hematologic toxicity. Results: We identified five PCs associated with acute hematologic toxicity. PC analysis regression modeling explained a high proportion of the variation in acute hematologicity (adjusted R 2 , 0.49). Three-dimensional rendering of a linear combination of the significant eigenvectors revealed patterns consistent with anatomical distributions of hematopoietically active BM. Conclusions: We have developed a novel approach that preserves spatial dose information to model effects of radiation dose on toxicity, which may be useful in optimizing radiation techniques to avoid critical subregions of normal tissues. Further validation of this approach in a large cohort is ongoing.

High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients

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Zelefsky, Michael J.; Fuks, Zvi; Hunt, Margie; Yamada, Yoshiya; Marion, Christine; Ling, C. Clifton; Amols, Howard; Venkatraman, E.S.; Leibel, Steven A.

2002-01-01

Purpose: To report the acute and late toxicity and preliminary biochemical outcomes in 772 patients with clinically localized prostate cancer treated with high-dose intensity-modulated radiotherapy (IMRT). Methods and Materials: Between April 1996 and January 2001, 772 patients with clinically localized prostate cancer were treated with IMRT. Treatment was planned using an inverse-planning approach, and the desired beam intensity profiles were delivered by dynamic multileaf collimation. A total of 698 patients (90%) were treated to 81.0 Gy, and 74 patients (10%) were treated to 86.4 Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined according to The American Society of Therapeutic Radiation Oncology Consensus Statement. The median follow-up time was 24 months (range: 6-60 months). Results: Thirty-five patients (4.5%) developed acute Grade 2 rectal toxicity, and no patient experienced acute Grade 3 or higher rectal symptoms. Two hundred seventeen patients (28%) developed acute Grade 2 urinary symptoms, and one experienced urinary retention (Grade 3). Eleven patients (1.5%) developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced Grade 3 rectal toxicity requiring either one or more transfusions or a laser cauterization procedure. No Grade 4 rectal complications have been observed. The 3-year actuarial likelihood of ≥ late Grade 2 rectal toxicity was 4%. Seventy-two patients (9%) experienced late Grade 2 urinary toxicity, and five (0.5%) developed Grade 3 urinary toxicity (urethral stricture). The 3-year actuarial likelihood of ≥ late Grade 2 urinary toxicity was 15%. The 3-year actuarial PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk group patients were 92%, 86%, and 81%, respectively. Conclusions: These data demonstrate the feasibility of high-dose IMRT in a large number of patients. Acute and late rectal toxicities seem to be

High-dose intensity-modulated radiotherapy for prostate cancer using daily fiducial marker-based position verification: acute and late toxicity in 331 patients

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Lips, Irene M; Dehnad, Homan; Gils, Carla H van; Boeken Kruger, Arto E; Heide, Uulke A van der; Vulpen, Marco van

2008-01-01

We evaluated the acute and late toxicity after high-dose intensity-modulated radiotherapy (IMRT) with fiducial marker-based position verification for prostate cancer. Between 2001 and 2004, 331 patients with prostate cancer received 76 Gy in 35 fractions using IMRT combined with fiducial marker-based position verification. The symptoms before treatment (pre-treatment) and weekly during treatment (acute toxicity) were scored using the Common Toxicity Criteria (CTC). The goal was to score late toxicity according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale with a follow-up time of at least three years. Twenty-two percent of the patients experienced pre-treatment grade ≥ 2 genitourinary (GU) complaints and 2% experienced grade 2 gastrointestinal (GI) complaints. Acute grade 2 GU and GI toxicity occurred in 47% and 30%, respectively. Only 3% of the patients developed acute grade 3 GU and no grade ≥ 3 GI toxicity occurred. After a mean follow-up time of 47 months with a minimum of 31 months for all patients, the incidence of late grade 2 GU and GI toxicity was 21% and 9%, respectively. Grade ≥ 3 GU and GI toxicity rates were 4% and 1%, respectively, including one patient with a rectal fistula and one patient with a severe hemorrhagic cystitis (both grade 4). In conclusion, high-dose intensity-modulated radiotherapy with fiducial marker-based position verification is well tolerated. The low grade ≥ 3 toxicity allows further dose escalation if the same dose constraints for the organs at risk will be used

High-dose intensity-modulated radiotherapy for prostate cancer using daily fiducial marker-based position verification: acute and late toxicity in 331 patients

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Boeken Kruger Arto E

2008-05-01

Full Text Available Abstract We evaluated the acute and late toxicity after high-dose intensity-modulated radiotherapy (IMRT with fiducial marker-based position verification for prostate cancer. Between 2001 and 2004, 331 patients with prostate cancer received 76 Gy in 35 fractions using IMRT combined with fiducial marker-based position verification. The symptoms before treatment (pre-treatment and weekly during treatment (acute toxicity were scored using the Common Toxicity Criteria (CTC. The goal was to score late toxicity according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC scale with a follow-up time of at least three years. Twenty-two percent of the patients experienced pre-treatment grade ≥ 2 genitourinary (GU complaints and 2% experienced grade 2 gastrointestinal (GI complaints. Acute grade 2 GU and GI toxicity occurred in 47% and 30%, respectively. Only 3% of the patients developed acute grade 3 GU and no grade ≥ 3 GI toxicity occurred. After a mean follow-up time of 47 months with a minimum of 31 months for all patients, the incidence of late grade 2 GU and GI toxicity was 21% and 9%, respectively. Grade ≥ 3 GU and GI toxicity rates were 4% and 1%, respectively, including one patient with a rectal fistula and one patient with a severe hemorrhagic cystitis (both grade 4. In conclusion, high-dose intensity-modulated radiotherapy with fiducial marker-based position verification is well tolerated. The low grade ≥ 3 toxicity allows further dose escalation if the same dose constraints for the organs at risk will be used.

The CpG island methylator phenotype may confer a survival benefit in patients with stage II or III colorectal carcinomas receiving fluoropyrimidine-based adjuvant chemotherapy

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Min, Byung-Hoon; Kim, Kyoung-Mee; Kang, Gyeong Hoon; Bae, Jeong Mo; Lee, Eui Jin; Yu, Hong Suk; Kim, Young-Ho; Chang, Dong Kyung; Kim, Hee Cheol; Park, Cheol Keun; Lee, Suk-Hee

2011-01-01

Colorectal carcinoma (CRC) with CpG island methylator phenotype (CIMP) is recognized as a distinct subgroup of CRC, and CIMP status affects prognosis and response to chemotherapy. Identification of CIMP status in CRC is important for proper patient management. In Eastern countries, however, the clinicopathologic and molecular characteristics and prognosis of CRCs with CIMP are still unclear. A total of 245 patients who underwent their first surgical resection for sporadic CRC were enrolled and CIMP status of the CRCs was determined using the quantitative MethyLight assay. The clinicopathologic and molecular characteristics were reviewed and compared according to CIMP status. In addition, the three-year recurrence-free survival (RFS) of 124 patients with stage II or stage III CRC was analyzed in order to assess the effectiveness of fluoropyrimidine-based adjuvant chemotherapy with respect to CIMP status. CIMP-high CRCs were identified in 34 cases (13.9%), and were significantly associated with proximal tumor location, poorly differentiated carcinoma, mucinous histology, and high frequencies of BRAF mutation, MGMT methylation, and MSI-high compared to CIMP-low/negative carcinomas. For patients with stage II or III CIMP-low/negative CRCs, no significant difference was found in RFS between those undergoing surgery alone and those receiving surgery with fluoropyrimidine-based adjuvant chemotherapy. However, for patients with CIMP-high CRCs, patients undergoing surgery with fluoropyrimidine-based adjuvant chemotherapy (n = 17; three-year RFS: 100%) showed significantly better RFS than patients treated with surgery alone (n = 7; three-year RFS: 71.4%) (P = 0.022). Our results suggest that selected patients with CIMP-high CRC may benefit from fluoropyrimidine-based adjuvant chemotherapy with longer RFS. Further large scale-studies are required to confirm our results

The CpG island methylator phenotype may confer a survival benefit in patients with stage II or III colorectal carcinomas receiving fluoropyrimidine-based adjuvant chemotherapy

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Park Cheol

2011-08-01

Full Text Available Abstract Background Colorectal carcinoma (CRC with CpG island methylator phenotype (CIMP is recognized as a distinct subgroup of CRC, and CIMP status affects prognosis and response to chemotherapy. Identification of CIMP status in CRC is important for proper patient management. In Eastern countries, however, the clinicopathologic and molecular characteristics and prognosis of CRCs with CIMP are still unclear. Methods A total of 245 patients who underwent their first surgical resection for sporadic CRC were enrolled and CIMP status of the CRCs was determined using the quantitative MethyLight assay. The clinicopathologic and molecular characteristics were reviewed and compared according to CIMP status. In addition, the three-year recurrence-free survival (RFS of 124 patients with stage II or stage III CRC was analyzed in order to assess the effectiveness of fluoropyrimidine-based adjuvant chemotherapy with respect to CIMP status. Results CIMP-high CRCs were identified in 34 cases (13.9%, and were significantly associated with proximal tumor location, poorly differentiated carcinoma, mucinous histology, and high frequencies of BRAF mutation, MGMT methylation, and MSI-high compared to CIMP-low/negative carcinomas. For patients with stage II or III CIMP-low/negative CRCs, no significant difference was found in RFS between those undergoing surgery alone and those receiving surgery with fluoropyrimidine-based adjuvant chemotherapy. However, for patients with CIMP-high CRCs, patients undergoing surgery with fluoropyrimidine-based adjuvant chemotherapy (n = 17; three-year RFS: 100% showed significantly better RFS than patients treated with surgery alone (n = 7; three-year RFS: 71.4% (P = 0.022. Conclusions Our results suggest that selected patients with CIMP-high CRC may benefit from fluoropyrimidine-based adjuvant chemotherapy with longer RFS. Further large scale-studies are required to confirm our results.

The CpG island methylator phenotype may confer a survival benefit in patients with stage II or III colorectal carcinomas receiving fluoropyrimidine-based adjuvant chemotherapy

Science.gov (United States)

2011-01-01

Background Colorectal carcinoma (CRC) with CpG island methylator phenotype (CIMP) is recognized as a distinct subgroup of CRC, and CIMP status affects prognosis and response to chemotherapy. Identification of CIMP status in CRC is important for proper patient management. In Eastern countries, however, the clinicopathologic and molecular characteristics and prognosis of CRCs with CIMP are still unclear. Methods A total of 245 patients who underwent their first surgical resection for sporadic CRC were enrolled and CIMP status of the CRCs was determined using the quantitative MethyLight assay. The clinicopathologic and molecular characteristics were reviewed and compared according to CIMP status. In addition, the three-year recurrence-free survival (RFS) of 124 patients with stage II or stage III CRC was analyzed in order to assess the effectiveness of fluoropyrimidine-based adjuvant chemotherapy with respect to CIMP status. Results CIMP-high CRCs were identified in 34 cases (13.9%), and were significantly associated with proximal tumor location, poorly differentiated carcinoma, mucinous histology, and high frequencies of BRAF mutation, MGMT methylation, and MSI-high compared to CIMP-low/negative carcinomas. For patients with stage II or III CIMP-low/negative CRCs, no significant difference was found in RFS between those undergoing surgery alone and those receiving surgery with fluoropyrimidine-based adjuvant chemotherapy. However, for patients with CIMP-high CRCs, patients undergoing surgery with fluoropyrimidine-based adjuvant chemotherapy (n = 17; three-year RFS: 100%) showed significantly better RFS than patients treated with surgery alone (n = 7; three-year RFS: 71.4%) (P = 0.022). Conclusions Our results suggest that selected patients with CIMP-high CRC may benefit from fluoropyrimidine-based adjuvant chemotherapy with longer RFS. Further large scale-studies are required to confirm our results. PMID:21827707

Herbal medicine for hand-foot syndrome induced by fluoropyrimidines: A systematic review and meta-analysis.

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Deng, Bo; Sun, Wei

2018-04-16

The aims of this study were to evaluate the efficacy of herbal medicine for the prevention and management of hand-foot syndrome (HFS) induced by fluoropyrimidines and to identify herbs associated with HFS alleviation for further research. The PubMed, Cochrane, Springer, China National Knowledge Infrastructure, and Wanfang databases were searched up to May 2017 for randomized controlled trials (RCTs) that evaluated herbal medicine for relieving HFS in patients undergoing fluoropyrimidine-based chemotherapy. Study evaluation and synthesis methods were in accordance with the Cochrane Handbook, and data were analyzed using RevMan 5.3. In total, 35 RCTs (2,668 participants) were included. Meta-analysis showed that the addition of herbal medicine significantly reduced the incidences of all-grade and high-grade HFS. The total effective rate and complete remission rate of HFS patients increased significantly with herbal medicine arm. Further sensitivity analysis identified Paeoniae Radix Alba, Carthami Flos, Cinnamomi Ramulus, and Glycyrrhizae Radix et Rhizoma as being consistently associated with significant reductions in HFS incidence without important heterogeneity. However, the lack of blinding in most studies may have led to overestimation of these effects. More high-quality RCTs and experimental research are needed to confirm and investigate the efficacy of the herbs identified in this study. Copyright © 2018 John Wiley & Sons, Ltd.

Acute genitourinary toxicity after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiation therapy for localized prostate cancer: Correlation between the urethral dose in HDR brachytherapy and the severity of acute genitourinary toxicity

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Akimoto, Tetsuo; Ito, Kazuto; Saitoh, Jun-ichi; Noda, Shin-ei; Harashima, Koichi; Sakurai, Hideyuki; Nakayama, Yuko; Yamamoto, Takumi; Suzuki, Kazuhiro; Nakano, Takashi; Niibe, Hideo

2005-01-01

Purpose: Several investigations have revealed that the α/β ratio for prostate cancer is atypically low, and that hypofractionation or high-dose-rate (HDR) brachytherapy regimens using appropriate radiation doses may be expected to yield tumor control and late sequelae rates that are better or at least as favorable as those achieved with conventional radiation therapy. In this setting, we attempted treating localized prostate cancer patients with HDR brachytherapy combined with hypofractionated external beam radiation therapy (EBRT). The purpose of this study was to evaluate the feasibility of using this approach, with special emphasis on the relationship between the severity of acute genitourinary (GU) toxicity and the urethral dose calculated from the dose-volume histogram (DVH) of HDR brachytherapy. Methods and Materials: Between September 2000 and December 2003, 70 patients with localized prostate cancer were treated by iridium-192 HDR brachytherapy combined with hypofractionated EBRT at the Gunma University Hospital. Hypofractionated EBRT was administered in fraction doses of 3 Gy, three times per week; a total dose of 51 Gy was delivered to the prostate gland and the seminal vesicles using the four-field technique. No elective pelvic irradiation was performed. After the completion of EBRT, all the patients additionally received transrectal ultrasonography (TRUS)-guided HDR brachytherapy. The fraction size and the number of fractions in HDR brachytherapy were prospectively changed, whereas the total radiation dose for EBRT was fixed at 51 Gy. The fractionation in HDR brachytherapy was as follows: 5 Gy x 5, 7 Gy x 3, 9 Gy x 2, administered twice per day, although the biologic effective dose (BED) for HDR brachytherapy combined with EBRT, assuming that the α/β ratio is 3, was almost equal to 138 in each fractionation group. The planning target volume was defined as the prostate gland with 5-mm margin all around, and the planning was conducted based on

Concurrent radiotherapy with oral fluoropyrimidine versus gemcitabine in locally advanced pancreatic cancer: a systematic review and meta-analysis

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Yang YF

2015-11-01

Full Text Available Yong-Feng Yang,1 Xiao-Hui Cao,1 Chao-En Bao,1 Xin Wan2 1Department of Radiation Oncology, Third Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China Background: Gemcitabine (GEM is the most widely utilized systemic agent in combination with radiation therapy (RT for treating locally advanced pancreatic cancer (LAPC in the concurrent setting. Despite recent interest in using two novel oral fluoropyrimidines (FUs, capecitabine and S-1, in this setting, there is a lack of randomized controlled trials (RCTs to support this approach.Methods: Trials published between 1994 and 2014 were identified by an electronic search of public databases (Medline, Embase, and the Cochrane Library. All prospective studies were independently identified by two authors for inclusion. Demographic data, treatment response, objective response rate (ORR, progression-free and overall survival (PFS and OS, respectively, and toxicities were extracted and analyzed using comprehensive meta-analysis software (version 2.0.Results: Twenty-three cohorts with 843 patients were included: 497 patients were treated with GEM and 346 patients were treated with oral FU. Pooled OS was significantly higher at 1 and 2 years for S-1 plus RT than for GEM plus RT (relative risk [RR] 1.27; 95% confidence interval [CI], 1.00–1.65; P=0.03; and RR 1.75; 95% CI, 1.18–2.60, P=0.002, respectively, while 1-year PFS and ORR were not significantly different between S-1 and GEM-based chemoradiotherapy (P=0.37 and P=0.06, respectively. Additionally, comparable efficacy was found between capecitabine and GEM-based chemoradiotherapy in terms of OS, PFS, and ORR. As for grade 3 and 4 acute toxicity, oral FU plus RT significantly reduced the risk of developing hematologic toxicities, nausea, and vomiting when compared to GEM plus RT (P<0.001.Conclusions

Fluoropyrimidine-HAI (hepatic arterial infusion) versus systemic chemotherapy (SCT) for unresectable liver metastases from colorectal cancer.

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Mocellin, Simone; Pasquali, Sandro; Nitti, Donato

2009-07-08

Although locoregional treatments such as hepatic arterial infusion (HAI) claim the advantage of delivering higher doses of anticancer agents directly into the metastatic organ as compared to systemic chemotherapy (SCT), the benefit in terms of overall survival (OS) is unclear. We quantitatively summarized the results of randomised controlled trials (RCT) comparing HAI to SCT for the treatment of unresectable liver metastatic disease from colorectal cancer (CRC). The aim of this work is to quantitatively summarize the results of RCT comparing HAI to SCT for the treatment of unresectable hepatic metastases from CRC. A systematic review of reports published until September 2008 on the findings of RCT that compared HAI to SCT for the treatment of unresectable CRC liver metastases was performed by searching the MEDLINE, Embase, Cancerlit, Cochrane and GoogleScholar electronic databases as well as other databanks collecting information on clinical trials. Inclusion criteria were patients with unresectable CRC liver metastases enrolled in RCT comparing HAI to SCT. The outcome measures were tumor response rate and overall survival. Two authors independently carried out study selection and assessment of methodological quality. A third author performed a concordance analysis in order to unravel potential systematic biases. Ten RCT were identified that met the eligibility criteria. HAI regimens were based on floxuridine (FUDR), 5-fluorouracil or either one of these two fluoropyrimidines in eight and one RCT, respectively. SCT consisted of FUDR or 5-fluorouracil in three and seven RCT, respectively. By pooling the summary data, tumor response rate resulted 42.9% and 18.4% for HAI and SCT, respectively (RR = 2.26; 95% CI, 1.80 to 2.84; P < 0.0001). Mean weighted median OS times were 15.9 and 12.4 months for HAI and SCT, respectively: the meta-risk of death was not statistically different between the two treatment groups (HR = 0.90; 95% CI, 0.76 to 1.07; P = 0.24). Currently

Dose-Escalated Hypofractionated Intensity-Modulated Radiotherapy in High-Risk Carcinoma of the Prostate: Outcome and Late Toxicity

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David Thomson

2012-01-01

Results. Median followup was 84 months. Five-year overall survival (OS was 83% and biochemical progression-free survival (bPFS was 50% for 57 Gy. Five-year OS was 75% and bPFS 58% for 60 Gy. At 7 years, toxicity by RTOG criteria was acceptable with no grade 3 or above toxicity. Compared with baseline, there was no significant change in urinary symptoms at 2 or 7 years. Bowel symptoms were stable between 2 and 7 years. All patients continued to have significant sexual dysfunction. Conclusion. In high-risk prostate cancer, dose-escalated hypofractionated radiotherapy using IMRT results in encouraging outcomes and acceptable late toxicity.

Small bowel toxicity after high dose spot scanning-based proton beam therapy for paraspinal/retroperitoneal neoplasms

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Schneider, R.A.; Albertini, F.; Koch, T.; Ares, C.; Lomax, A.; Goitein, G. [Paul Scherrer Institute PSI, Villigen (Switzerland). Center for Proton Therapy; Vitolo, V. [Fondazione CNAO, Pavia (Italy); Hug, E.B. [Paul Scherrer Institute PSI, Villigen (Switzerland). Center for Proton Therapy; ProCure Proton Therapy Centers, New York, NY (United States)

2013-12-15

Purpose: Mesenchymal tumours require high-dose radiation therapy (RT). Small bowel (SB) dose constraints have historically limited dose delivery to paraspinal and retroperitoneal targets. This retrospective study correlated SB dose-volume histograms with side-effects after proton radiation therapy (PT). Patients and methods: Between 1997 and 2008, 31 patients (mean age 52.1 years) underwent spot scanning-based PT for paraspinal/retroperitoneal chordomas (81 %), sarcomas (16 %) and meningiom (3 %). Mean total prescribed dose was 72.3 Gy (relative biologic effectiveness, RBE) delivered in 1.8-2 Gy (RBE) fractions. Mean follow-up was 3.8 years. Based on the pretreatment planning CT, SB dose distributions were reanalysed. Results: Planning target volume (PTV) was defined as gross tumour volume (GTV) plus 5-7 mm margins. Mean PTV was 560.22 cm{sup 3}. A mean of 93.2 % of the PTV was covered by at least 90 % of the prescribed dose. SB volumes (cm{sup 3}) receiving doses of 5, 20, 30, 40, 50, 60, 70, 75 and 80 Gy (RBE) were calculated to give V5, V20, V30, V40, V50, V60, V70, V75 and V80 respectively. In 7/31 patients, PT was accomplished without any significant SB irradiation (V5 = 0). In 24/31 patients, mean maximum dose (Dmax) to SB was 64.1 Gy (RBE). Despite target doses of > 70 Gy (RBE), SB received > 50 and > 60 Gy (RBE) in only 61 and 54 % of patients, respectively. Mean SB volumes (cm{sup 3}) covered by different dose levels (Gy, RBE) were: V20 (n = 24): 45.1, V50 (n = 19): 17.7, V60 (n = 17): 7.6 and V70 (n = 12): 2.4. No acute toxicity {>=} grade 2 or late SB sequelae were observed. Conclusion: Small noncircumferential volumes of SB tolerated doses in excess of 60 Gy (RBE) without any clinically-significant late adverse effects. This small retrospective study has limited statistical power but encourages further efforts with higher patient numbers to define and establish high-dose threshold models for SB toxicity in modern radiation oncology. (orig.)

Single dose toxicity and biodistribution studies of [18F] fluorocholine

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Campos, Danielle C.; Santos, Priscilla F.; Silveira, Marina B.; Ferreira, Soraya Z.; Malamut, Carlos; Silva, Juliana B. da; Souza, Cristina M.; Campos, Liliane C.; Ferreira, Enio; Araujo, Marina R.; Cassali, Geovanni D.

2013-01-01

[ 18 F]Fluorocholine ( 18 FCH) is a valuable tool for non-invasive diagnosis using positron emission tomography (PET). This radiotracer has been proven to be highly effective in detecting recurrences and staging prostate cancer, diagnoses brain, breast, and esophageal tumors and also hepatocellular carcinoma. The higher uptake of fluorocholine by malignant tumors results from increased choline kinase activity due to accelerated cell multiplication and membrane formation. According to the Brazilian Health Surveillance Agency (ANVISA), radiopharmaceuticals have to be registered before commercialization. The aim of this work was to evaluate single dose toxicity and biodistribution of 18 FCH in mice, since preclinical safety studies are required for register. Experimental procedures were approved by the Ethics Committee on Animal Use (CEUA-IPEN/SP). Single dose toxicity and biodistribution studies were conducted in Swiss mice. No signs of toxicity were observed during clinical trial. No changes in the parameters which were examined, such as: body weight, food consumption, clinical pathology parameters or lesions microscopic were noted. Biodistribution results indicated high physiological tracer uptake in kidney, liver and heart 30 min after injection. Lower activities were recorded in other organs/tissues: pancreas, intestine, spleen, bone, bladder, muscle, brain and blood. Initial preclinical investigations showed no toxic effects of 18 FCH at investigated doses and a biodistribution profile very similar to other reports in literature. This information is essential to support future human trials. (author)

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines.

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Barbara A Jennings

Full Text Available The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic and drug metabolising (pharmacokinetic enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479 and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively. There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively. We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.

Development of new promising antimetabolite, DFP-11207 with self-controlled toxicity in rodents

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Fukushima M

2017-06-01

Full Text Available Masakazu Fukushima, Kenzo Iizuka, Cheng Jin, Chun Zhang, Mei Hong, Kiyoshi Eshima Division of Oncology Research and Development, Delta-Fly Pharma Inc., Kawauchi-cho, Tokushima, Japan Abstract: To reduce 5-fluorouracil (5-FU-induced serious toxicities without loss of antitumor activity, we have developed DFP-11207, a novel fluoropyrimidine, which consists of 1-ethoxymethyl-5-fluorouracil (EM-FU; a precursor form of 5-FU, 5-chloro-2,4-dihydroxypyridine (CDHP; an inhibitor of 5-FU degradation, and citrazinic acid (CTA; an inhibitor of 5-FU phosphorylation. In vitro studies of DFP-11207 indicated that it strongly inhibited the degradation of 5-FU by dihydropyrimidine dehydrogenase (DPD in homogenates of the rat liver, and also inhibited the phosphorylation of 5-FU by orotate phosphoribosyltransferase (OPRT in tumor tissues in a similar magnitude of potency by CDHP and CTA, respectively. Especially, DFP-11207 inhibited the intracellular phosphorylation of 5-FU in tumor cells in a dose-dependent manner whereas CTA alone did not protect intracellular 5-FU phosphorylation. These results postulate that DFP-11207 rapidly entered into the cell and the free CTA produced from DFP-11207 inhibited the phosphorylation of 5-FU in the cell. Furthermore, following oral administration of DFP-11207, CTA was found to be highly retained in the gastrointestinal (GI tract compared to other tissues in rats. Interestingly, EM-FU, the prodrug of 5-FU was found to specifically produce 5-FU by various species of liver microsomes. When DFP-11207 was administered to rats, the plasma level of 5-FU was persisted for a long-time with lower Cmax and longer half-life than that from other 5-FU prodrugs. The antitumor activity of DFP-11207 was evaluated in human tumor xenografts in nude rats and found that DFP-11207 showed an antitumor activity in a dose-dependent fashion and its efficacy is equivalent to reference 5-FU drugs. In striking contrast, DFP-11207 manifested no or less 5

Dosimetric Coverage of the Prostate, Normal Tissue Sparing, and Acute Toxicity with High-Dose-Rate Brachytherapy for Large Prostate Volumes

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George Yang

2015-06-01

Full Text Available ABSTRACTPurposeTo evaluate dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with HDR brachytherapy for large prostate volumes.Materials and MethodsOne hundred and two prostate cancer patients with prostate volumes >50 mL (range: 5-29 mL were treated with high-dose-rate (HDR brachytherapy ± intensity modulated radiation therapy (IMRT to 4,500 cGy in 25 daily fractions between 2009 and 2013. HDR brachytherapy monotherapy doses consisted of two 1,350-1,400 cGy fractions separated by 2-3 weeks, and HDR brachytherapy boost doses consisted of two 950-1,150 cGy fractions separated by 4 weeks. Twelve of 32 (38% unfavorable intermediate risk, high risk, and very high risk patients received androgen deprivation therapy. Acute toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.ResultsMedian follow-up was 14 months. Dosimetric goals were achieved in over 90% of cases. Three of 102 (3% patients developed Grade 2 acute proctitis. No variables were significantly associated with Grade 2 acute proctitis. Seventeen of 102 (17% patients developed Grade 2 acute urinary retention. American Urological Association (AUA symptom score was the only variable significantly associated with Grade 2 acute urinary retention (p=0.04. There was no ≥ Grade 3 acute toxicity.ConclusionsDosimetric coverage of the prostate and normal tissue sparing were adequate in patients with prostate volumes >50 mL. Higher pre-treatment AUA symptom scores increased the relative risk of Grade 2 acute urinary retention. However, the overall incidence of acute toxicity was acceptable in patients with large prostate volumes.

Dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with high-dose-rate brachytherapy for large prostate volumes

Energy Technology Data Exchange (ETDEWEB)

Yang, George; Strom, Tobin J.; Shrinath, Kushagra; Mellon, Eric A.; Fernandez, Daniel C.; Biagioli, Matthew C. [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Wilder, Richard B., E-mail: mcbiagioli@yahoo.com [Cancer Treatment Centers of America, Newnan, GA (United States)

2015-05-15

Purpose: to evaluate dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with HDR brachytherapy for large prostate volumes. Materials and methods: one hundred and two prostate cancer patients with prostate volumes >50 mL (range: 5-29 mL) were treated with high-dose-rate (HDR) brachytherapy ± intensity modulated radiation therapy (IMRT) to 4,500 cGy in 25 daily fractions between 2009 and 2013. HDR brachytherapy monotherapy doses consisted of two 1,350-1,400 cGy fractions separated by 2-3 weeks, and HDR brachytherapy boost doses consisted of two 950-1,150 cGy fractions separated by 4 weeks. Twelve of 32 (38%) unfavorable intermediate risk, high risk, and very high risk patients received androgen deprivation therapy. Acute toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Results: median follow-up was 14 months. Dosimetric goals were achieved in over 90% of cases. Three of 102 (3%) patients developed Grade 2 acute proctitis. No variables were significantly associated with Grade 2 acute proctitis. Seventeen of 102 (17%) patients developed Grade 2 acute urinary retention. American Urological Association (AUA) symptom score was the only variable significantly associated with Grade 2 acute urinary retention (p-0.04). There was no ≥ Grade 3 acute toxicity. Conclusions: dosimetric coverage of the prostate and normal tissue sparing were adequate in patients with prostate volumes >50 mL. Higher pre-treatment AUA symptom scores increased the relative risk of Grade 2 acute urinary retention. However, the overall incidence of acute toxicity was acceptable in patients with large prostate volumes. (author)

Individualized toxicity-titrated 6-mercaptopurine increments during high-dose methotrexate consolidation treatment of lower risk childhood acute lymphoblastic leukaemia. A Nordic Society of Paediatric Haematology and Oncology (NOPHO) pilot study

DEFF Research Database (Denmark)

Frandsen, Thomas L; Abrahamsson, Jonas; Lausen, Birgitte

2011-01-01

This study explored the feasibility and toxicity of individualized toxicity-titrated 6-mercaptopurine (6MP) dose increments during post-remission treatment with High-dose methotrexate (HDM) (5000 mg/m(2), ×3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25 mg 6MP/m(2...... the remaining patients (P = 0·03). This study shows individualized toxicity-titrated 6MP dosing during consolidation is feasible without increased risk of toxicity....

Near fatal 5-FU gut toxicity post surgery--remarkable effect of high-dose sucralfate.

Science.gov (United States)

Toh, James Wei Tatt; Morris, David; Chen, Zhuoran; Chen, Cindy

2015-06-01

The objective of this review article and case report was to investigate the effectiveness of high-dose sucralfate on severe life-threatening 5-fluorouracil (5-FU) gut toxicity, with reference to, but not limited to dihydropyrimidine dehydrogenase (DPD) deficiency. A search was conducted on PubMed from 1950 to July 2013 for original studies on 5-FU gut toxicity and sucralfate. Studies were limited to human trials and English language and all articles included in this study were assessed with the application of predetermined selection criteria. Each article was then reviewed independently by two reviewers. A case report from our own centre was included in this review. From 33 results, 6 manuscripts were identified including 4 randomized controlled trial. One trial evaluated the use of sucralfate to alleviate stomatitis in patients with 5-FU-based chemotherapy. The other three trials evaluated the role of sucralfate in radiation toxicity. There was one case report which showed gastroscopy confirmed normalization of severe dysplastic erosive gastroduodenitis attributed to hepatic arterial infusion of 5-FU following a 2-month course of sucralfate and cimetidine and one case series showing clinical and sigmoidoscopically demonstrated improvement in ulcerative colitis in majority of patients receiving sucralfate enemas. There was no current literature specifically focussed on the role of sucralfate in 5-FU gut toxicity. Our case report describes the clinical course and successful treatment with sucralfate of a patient with Pseudomyxoma peritonei (PMP) who experienced 5-FU gut toxicity resulting in life-threatening bleeding due to presumed DPD deficiency post intraperitoneal 5-FU administration. This review article showed a lack of literature concerning the use of sucralfate in 5-FU gut toxicity. In our patient's case, sucralfate had a crucial role in the management of near fatal 5-FU gut toxicity, and further evaluation is required.

Acute genitourinary toxicity after high dose rate (HDR) brachytherapy combined with hypofractionated external-beam radiation therapy for localized prostate cancer: Second analysis to determine the correlation between the urethral dose in HDR brachytherapy and the severity of acute genitourinary toxicity

International Nuclear Information System (INIS)

Akimoto, Tetsuo; Katoh, Hiroyuki; Noda, Shin-ei; Ito, Kazuto; Yamamoto, Takumi; Kashiwagi, Bunzo; Nakano, Takashi

2005-01-01

Purpose: We have been treating localized prostate cancer with high-dose-rate (HDR) brachytherapy combined with hypofractionated external beam radiation therapy (EBRT) at our institution. We recently reported the existence of a correlation between the severity of acute genitourinary (GU) toxicity and the urethral radiation dose in HDR brachytherapy by using different fractionation schema. The purpose of this study was to evaluate the role of the urethral dose in the development of acute GU toxicity more closely than in previous studies. For this purpose, we conducted an analysis of patients who had undergone HDR brachytherapy with a fixed fractionation schema combined with hypofractionated EBRT. Methods and Materials: Among the patients with localized prostate cancer who were treated by 192-iridium HDR brachytherapy combined with hypofractionated EBRT at Gunma University Hospital between August 2000 and November 2004, we analyzed 67 patients who were treated by HDR brachytherapy with the fractionation schema of 9 Gy x two times combined with hypofractionated EBRT. Hypofractionated EBRT was administered at a fraction dose of 3 Gy three times weekly, and a total dose of 51 Gy was delivered to the prostate gland and seminal vesicles using the four-field technique. No elective pelvic irradiation was performed. After the completion of EBRT, all the patients additionally received transrectal ultrasonography-guided HDR brachytherapy. The planning target volume was defined as the prostate gland with a 5-mm margin all around, and the planning was conducted based on computed tomography images. The tumor stage was T1c in 13 patients, T2 in 31 patients, and T3 in 23 patients. The Gleason score was 2-6 in 12 patients, 7 in 34 patients, and 8-10 in 21 patients. Androgen ablation was performed in all the patients. The median follow-up duration was 11 months (range 3-24 months). The toxicities were graded based on the Radiation Therapy Oncology Group and the European Organization

Late toxicity and five year outcomes after high-dose-rate brachytherapy as a monotherapy for localized prostate cancer

International Nuclear Information System (INIS)

Ghadjar, Pirus; Oesch, Sebastian L; Rentsch, Cyrill A; Isaak, Bernhard; Cihoric, Nikola; Manser, Peter; Thalmann, George N; Aebersold, Daniel M

2014-01-01

To determine the 5-year outcome after high-dose-rate brachytherapy (HDR-BT) as a monotherapy. Between 10/2003 and 06/2006, 36 patients with low (28) and intermediate (8) risk prostate cancer were treated by HDR-BT monotherapy. All patients received one implant and 4 fractions of 9.5 Gy within 48 hours for a total prescribed dose (PD) of 38 Gy. Five patients received concomitant androgen deprivation therapy (ADT). Toxicity was scored according to the common terminology criteria for adverse events from the National Cancer Institute (CTCAE) version 3.0. Biochemical recurrence was defined according to the Phoenix criteria and analyzed using the Kaplan Meier method. Predictors for late grade 3 GU toxicity were analyzed using univariate and multivariate Cox regression analyses. The median follow-up was 6.9 years (range, 1.5-8.0 years). Late grade 2 and 3 genitourinary (GU) toxicity was observed in 10 (28%) and 7 (19%) patients, respectively. The actuarial proportion of patients with late grade 3 GU toxicity at 5 years was 17.7%. Late grade 2 and 3 gastrointestinal (GI) toxicities were not observed. The crude erectile function preservation rate in patients without ADT was 75%. The 5 year biochemical recurrence-free survival (bRFS) rate was 97%. Late grade 3 GU toxicity was associated with the urethral volume (p = 0.001) and the urethral V 120 (urethral volume receiving ≥120% of the PD; p = 0.0005) after multivariate Cox regression. After HDR-BT monotherapy late grade 3 GU was observed relatively frequently and was associated with the urethral V 120 . GI toxicity was negligible, the erectile function preservation rate and the bRFS rate was excellent

Dose-dependent transitions in mechanisms of toxicity

International Nuclear Information System (INIS)

Slikker, William; Andersen, Melvin E.; Bogdanffy, Matthew S.; Bus, James S.; Cohen, Steven D.; Conolly, Rory B.; David, Raymond M.; Doerrer, Nancy G.; Dorman, David C.; Gaylor, David W.; Hattis, Dale; Rogers, John M.; Woodrow Setzer, R.; Swenberg, James A.; Wallace, Kendall

2004-01-01

Scientists and decision makers from all sectors agree that risk assessments should be based on the best available science. Several years ago, the Health and Environmental Sciences Institute (HESI), a global branch of the International Life Sciences Institute (ILSI), identified the need for better scientific understanding of dose-dependent transitions in mechanisms of toxicity as one avenue by which the best and latest science can be integrated into the decision making process. In July 2001, the HESI Project Committee on Dose-Dependent Transitions in Mechanisms of Toxicity established a group of academic, government, and industry scientists to engage in active technical discourse on the issue of dose-dependent transitions in mechanisms of toxicity. Over the next 18 months, case studies were examined. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, the peroxisome proliferator-activated receptor, progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc (Slikker, W., Jr., Andersen, M.E., Bogdanffy, M.S., Bus, J.S., Cohen, S.D., Conolly, R.B., David, R.M., Doerrer, N.G., Dorman, D.C., Gaylor, D.W., Hattis, D., Rogers, J.M., Setzer, R.W., Swenberg, J.A., Wallace, K., 2004. Dose-dependent transitions in mechanisms of toxicity: case studies. Toxicol. Appl. Pharmacol. 201(3), 226-294 (this issue)). The HESI Project Committee sponsored two technical workshops in 2003. The first of these workshops took place on February 12-13, 2003, and was co-sponsored by the Agency for Toxic Substances and Disease Registry, the American Chemistry Council, the National Institute of Environmental Health Sciences, the Society of Toxicology, and the U.S. Environmental Protection Agency. Additional support was provided by Health Canada. Invited experts from government, academia, and industry provided scientific perspectives and recommendations at the workshop. The purpose of

The impact of an ionizing radiation on fluoropyrimidine metabolism; a study in vitro

Czech Academy of Sciences Publication Activity Database

Kahle, Michal; Taltynov, O.; Jarolímová, Lenka; Hozák, Pavel; Vítek, P.

2008-01-01

Roč. 275, č. 1 (2008), s. 437-437 E-ISSN 1742-4658. [FEBS Congress /33rd/, IUBMB conference /11th/. 28.06.2008-03.07.2008, Athens] R&D Projects: GA MŠk LC545 Grant - others:Mšk LC06063 Program:LC Institutional research plan: CEZ:AV0Z50520514 Keywords : radiotherapy * fluoropyrimidine * metabolism Subject RIV: EB - Genetics ; Molecular Biology

Single dose toxicity and biodistribution studies of [{sup 18}F] fluorocholine

Energy Technology Data Exchange (ETDEWEB)

Campos, Danielle C.; Santos, Priscilla F., E-mail: dcc@cdtn.br [Universidade Federal de Minas Gereais (INCT-MM/UFMG), Belo Horizonte, MG (Brazil). Faculdade de Medicina. Instituto Nacional de Ciencia e Tecnologia de Medicina Molecular; Silveira, Marina B.; Ferreira, Soraya Z.; Malamut, Carlos; Silva, Juliana B. da, E-mail: radiofarmacoscdtn@cdtn.br [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil). Unidade de Pesquisa e Producao de Radiofarmacos; Souza, Cristina M.; Campos, Liliane C.; Ferreira, Enio; Araujo, Marina R.; Cassali, Geovanni D., E-mail: cassalig@icb.ufmg.br [Universidade Federal de Minas Gerais (LPC/UFMG), Belo Horizonte, MG (Brazil). Lab. de Patologia Comparada

2013-07-01

[{sup 18}F]Fluorocholine ({sup 18}FCH) is a valuable tool for non-invasive diagnosis using positron emission tomography (PET). This radiotracer has been proven to be highly effective in detecting recurrences and staging prostate cancer, diagnoses brain, breast, and esophageal tumors and also hepatocellular carcinoma. The higher uptake of fluorocholine by malignant tumors results from increased choline kinase activity due to accelerated cell multiplication and membrane formation. According to the Brazilian Health Surveillance Agency (ANVISA), radiopharmaceuticals have to be registered before commercialization. The aim of this work was to evaluate single dose toxicity and biodistribution of {sup 18}FCH in mice, since preclinical safety studies are required for register. Experimental procedures were approved by the Ethics Committee on Animal Use (CEUA-IPEN/SP). Single dose toxicity and biodistribution studies were conducted in Swiss mice. No signs of toxicity were observed during clinical trial. No changes in the parameters which were examined, such as: body weight, food consumption, clinical pathology parameters or lesions microscopic were noted. Biodistribution results indicated high physiological tracer uptake in kidney, liver and heart 30 min after injection. Lower activities were recorded in other organs/tissues: pancreas, intestine, spleen, bone, bladder, muscle, brain and blood. Initial preclinical investigations showed no toxic effects of {sup 18}FCH at investigated doses and a biodistribution profile very similar to other reports in literature. This information is essential to support future human trials. (author)

Novel 5-Fluorouracil Derivatives: Synthesis and Cytotoxic Activity of 2-Butoxy-4-Substituted 5-Fluoropyrimidines

International Nuclear Information System (INIS)

Sun, Jian; Zhou, Wei; Hu, Weixiao; Shan, Shang; Zhang, Shijie; Li, Haibo

2013-01-01

Twenty two new 5-fluorouracil (5-FU) derivatives, 2-butoxy-4-substituted 5-fluoropyrimidines, were synthesized and characterized by IR, 1 H NMR, MS, HRMS. All compounds were preliminarily evaluated by MTT assay on human liver BEL-7402 cancer cell line in vitro. Ten compounds were selected to test their cytotoxic activity against A549, HL-60 and MCF-7 cancer cell lines in vitro. These compounds were more sensitive to BEL-7402 than other cell lines, particularly, cytotoxic activity of compounds 6b, 6d-f, 6p, 6s-u were in sub-micromolar scale. The highest cytotoxic potency against A549, HL-60 and MCF-7 was shown by 2-butoxy-4-chloro-5-fluoropyrimidine (5) with IC 50 values of 0.10, 1.66 and 0.59 μM, respectively. Compounds 6d and 6e were effective against MCF-7 with IC 50 9.73 μM and HL-60 with IC 50 8.83 μM, respectively

Predictors for Rectal and Intestinal Acute Toxicities During Prostate Cancer High-Dose 3D-CRT: Results of a Prospective Multicenter Study

International Nuclear Information System (INIS)

Vavassori, Vittorio; Fiorino, Claudio; Rancati, Tiziana; Magli, Alessandro; Fellin, Gianni; Baccolini, Michela; Bianchi, Carla; Cagna, Emanuela; Mauro, Flora A.; Monti, Angelo F.; Munoz, Fernando; Stasi, Michele; Franzone, Paola; Valdagni, Riccardo

2007-01-01

Purpose: To find predictors for rectal and intestinal acute toxicity in patients with prostate cancer treated with ≥70 Gy conformal radiotherapy. Methods and Materials: Between July 2002 and March 2004, 1,132 patients were entered into a cooperative study (AIROPROS01-02). Toxicity was scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale and by considering the changes (before and after treatment) of the scores of a self-administered questionnaire on rectal/intestinal toxicity. The correlation with a number of parameters was assessed by univariate and multivariate analyses. Concerning the questionnaire, only moderate/severe complications were considered. Results: Of 1,132 patients, 1,123 were evaluable. Of these patients, 375, 265, and 28 had Grade 1, 2, and 3 Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity, respectively. The mean rectal dose was the most predictive parameter (p = 0.0004; odds ratio, 1.035) for Grade 2 or worse toxicity, and the use of anticoagulants/antiaggregants (p 0.02; odds ratio, 0.63) and hormonal therapy (p = 0.04, odds ratio, 0.65) were protective. The questionnaire-based scoring revealed that a greater mean rectal dose was associated with a greater risk of bleeding; larger irradiated volumes were associated with frequency, tenesmus, incontinence, and bleeding; hormonal therapy was protective against frequency and tenesmus; hemorrhoids were associated with a greater risk of tenesmus and bleeding; and diabetes associated highly with diarrhea. Conclusion: The mean rectal dose correlated with acute rectal/intestinal toxicity in three-dimensional conformal radiotherapy for prostate cancer, and hormonal therapy and the use of anticoagulants/antiaggregants were protective. According to the moderate/severe injury scores on the self-assessed questionnaire, several clinical and dose-volume parameters were independently predictive for

High-dose-rate brachytherapy as monotherapy delivered in two fractions within one day for favorable/intermediate-risk prostate cancer: preliminary toxicity data.

Science.gov (United States)

Ghilezan, Michel; Martinez, Alvaro; Gustason, Gary; Krauss, Daniel; Antonucci, J Vito; Chen, Peter; Fontanesi, James; Wallace, Michelle; Ye, Hong; Casey, Alyse; Sebastian, Evelyn; Kim, Leonard; Limbacher, Amy

2012-07-01

To report the toxicity profile of high-dose-rate (HDR)-brachytherapy (BT) as monotherapy in a Human Investigation Committee-approved study consisting of a single implant and two fractions (12 Gy × 2) for a total dose of 24 Gy, delivered within 1 day. The dose was subsequently increased to 27 Gy (13.5 Gy × 2) delivered in 1 day. We report the acute and early chronic genitourinary and gastrointestinal toxicity. A total of 173 patients were treated between December 2005 and July 2010. However, only the first 100 were part of the IRB-approved study and out of these, only 94 had a minimal follow-up of 6 months, representing the study population for this preliminary report. All patients had clinical Stage T2b or less (American Joint Committee on Cancer, 5th edition), Gleason score 6-7 (3+4), and prostate-specific antigen level of ≤12 ng/mL. Ultrasound-guided HDR-BT with real-time dosimetry was used. The prescription dose was 24 Gy for the first 50 patients and 27 Gy thereafter. The dosimetric goals and constraints were the same for the two dose groups. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. The highest toxicity scores encountered at any point during follow-up are reported. The median follow-up was 17 months (range, 6-40.5). Most patients had Grade 0-1 acute toxicity. The Grade 2 acute genitourinary toxicity was mainly frequency/urgency (13%), dysuria (5%), hematuria, and dribbling/hesitancy (2%). None of the patients required a Foley catheter at any time; however, 8% of the patients experienced transient Grade 1 diarrhea. No other acute gastrointestinal toxicities were found. The most common chronic toxicity was Grade 2 urinary frequency/urgency in 16% of patients followed by dysuria in 4% of patients; 2 patients had Grade 2 rectal bleeding and 1 had Grade 4, requiring laser treatment. Favorable-risk prostate cancer patients treated with a single implant HDR-BT to 24-27 Gy in two fractions

High-Dose-Rate Brachytherapy as Monotherapy Delivered in Two Fractions Within One Day for Favorable/Intermediate-Risk Prostate Cancer: Preliminary Toxicity Data

Energy Technology Data Exchange (ETDEWEB)

Ghilezan, Michel, E-mail: mghilezan@beaumont.edu [Department of Radiation Oncology, William Beaumont Hospital and Rose Cancer Institute, Royal Oak, Michigan (United States); Martinez, Alvaro; Gustason, Gary; Krauss, Daniel; Antonucci, J. Vito; Chen, Peter; Fontanesi, James; Wallace, Michelle; Ye Hong; Casey, Alyse; Sebastian, Evelyn; Kim, Leonard; Limbacher, Amy [Department of Radiation Oncology, William Beaumont Hospital and Rose Cancer Institute, Royal Oak, Michigan (United States)

2012-07-01

Purpose: To report the toxicity profile of high-dose-rate (HDR)-brachytherapy (BT) as monotherapy in a Human Investigation Committee-approved study consisting of a single implant and two fractions (12 Gy Multiplication-Sign 2) for a total dose of 24 Gy, delivered within 1 day. The dose was subsequently increased to 27 Gy (13.5 Gy Multiplication-Sign 2) delivered in 1 day. We report the acute and early chronic genitourinary and gastrointestinal toxicity. Methods and Materials: A total of 173 patients were treated between December 2005 and July 2010. However, only the first 100 were part of the IRB-approved study and out of these, only 94 had a minimal follow-up of 6 months, representing the study population for this preliminary report. All patients had clinical Stage T2b or less (American Joint Committee on Cancer, 5th edition), Gleason score 6-7 (3+4), and prostate-specific antigen level of {<=}12 ng/mL. Ultrasound-guided HDR-BT with real-time dosimetry was used. The prescription dose was 24 Gy for the first 50 patients and 27 Gy thereafter. The dosimetric goals and constraints were the same for the two dose groups. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. The highest toxicity scores encountered at any point during follow-up are reported. Results: The median follow-up was 17 months (range, 6-40.5). Most patients had Grade 0-1 acute toxicity. The Grade 2 acute genitourinary toxicity was mainly frequency/urgency (13%), dysuria (5%), hematuria, and dribbling/hesitancy (2%). None of the patients required a Foley catheter at any time; however, 8% of the patients experienced transient Grade 1 diarrhea. No other acute gastrointestinal toxicities were found. The most common chronic toxicity was Grade 2 urinary frequency/urgency in 16% of patients followed by dysuria in 4% of patients; 2 patients had Grade 2 rectal bleeding and 1 had Grade 4, requiring laser treatment. Conclusions: Favorable

High-Dose-Rate Brachytherapy as Monotherapy Delivered in Two Fractions Within One Day for Favorable/Intermediate-Risk Prostate Cancer: Preliminary Toxicity Data

International Nuclear Information System (INIS)

Ghilezan, Michel; Martinez, Alvaro; Gustason, Gary; Krauss, Daniel; Antonucci, J. Vito; Chen, Peter; Fontanesi, James; Wallace, Michelle; Ye Hong; Casey, Alyse; Sebastian, Evelyn; Kim, Leonard; Limbacher, Amy

2012-01-01

Purpose: To report the toxicity profile of high-dose-rate (HDR)-brachytherapy (BT) as monotherapy in a Human Investigation Committee-approved study consisting of a single implant and two fractions (12 Gy × 2) for a total dose of 24 Gy, delivered within 1 day. The dose was subsequently increased to 27 Gy (13.5 Gy × 2) delivered in 1 day. We report the acute and early chronic genitourinary and gastrointestinal toxicity. Methods and Materials: A total of 173 patients were treated between December 2005 and July 2010. However, only the first 100 were part of the IRB-approved study and out of these, only 94 had a minimal follow-up of 6 months, representing the study population for this preliminary report. All patients had clinical Stage T2b or less (American Joint Committee on Cancer, 5th edition), Gleason score 6-7 (3+4), and prostate-specific antigen level of ≤12 ng/mL. Ultrasound-guided HDR-BT with real-time dosimetry was used. The prescription dose was 24 Gy for the first 50 patients and 27 Gy thereafter. The dosimetric goals and constraints were the same for the two dose groups. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. The highest toxicity scores encountered at any point during follow-up are reported. Results: The median follow-up was 17 months (range, 6–40.5). Most patients had Grade 0-1 acute toxicity. The Grade 2 acute genitourinary toxicity was mainly frequency/urgency (13%), dysuria (5%), hematuria, and dribbling/hesitancy (2%). None of the patients required a Foley catheter at any time; however, 8% of the patients experienced transient Grade 1 diarrhea. No other acute gastrointestinal toxicities were found. The most common chronic toxicity was Grade 2 urinary frequency/urgency in 16% of patients followed by dysuria in 4% of patients; 2 patients had Grade 2 rectal bleeding and 1 had Grade 4, requiring laser treatment. Conclusions: Favorable-risk prostate cancer patients treated with

The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma

Directory of Open Access Journals (Sweden)

Erculj Nina

2014-09-01

Full Text Available Background. We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL. Patients and methods. In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms.

Constitutive gene expression profile segregates toxicity in locally advanced breast cancer patients treated with high-dose hyperfractionated radical radiotherapy

International Nuclear Information System (INIS)

Henríquez Hernández, Luis Alberto; Lara, Pedro Carlos; Pinar, Beatriz; Bordón, Elisa; Gallego, Carlos Rodríguez; Bilbao, Cristina; Pérez, Leandro Fernández; Morales, Amílcar Flores

2009-01-01

Breast cancer patients show a wide variation in normal tissue reactions after radiotherapy. The individual sensitivity to x-rays limits the efficiency of the therapy. Prediction of individual sensitivity to radiotherapy could help to select the radiation protocol and to improve treatment results. The aim of this study was to assess the relationship between gene expression profiles of ex vivo un-irradiated and irradiated lymphocytes and the development of toxicity due to high-dose hyperfractionated radiotherapy in patients with locally advanced breast cancer. Raw data from microarray experiments were uploaded to the Gene Expression Omnibus Database http://www.ncbi.nlm.nih.gov/geo/ (GEO accession GSE15341). We obtained a small group of 81 genes significantly regulated by radiotherapy, lumped in 50 relevant pathways. Using ANOVA and t-test statistical tools we found 20 and 26 constitutive genes (0 Gy) that segregate patients with and without acute and late toxicity, respectively. Non-supervised hierarchical clustering was used for the visualization of results. Six and 9 pathways were significantly regulated respectively. Concerning to irradiated lymphocytes (2 Gy), we founded 29 genes that separate patients with acute toxicity and without it. Those genes were gathered in 4 significant pathways. We could not identify a set of genes that segregates patients with and without late toxicity. In conclusion, we have found an association between the constitutive gene expression profile of peripheral blood lymphocytes and the development of acute and late toxicity in consecutive, unselected patients. These observations suggest the possibility of predicting normal tissue response to irradiation in high-dose non-conventional radiation therapy regimens. Prospective studies with higher number of patients are needed to validate these preliminary results

Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity

Energy Technology Data Exchange (ETDEWEB)

Li, Jun; Sun, Kang [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Ni, Lijuan; Wang, Xufang [School of Chemistry and Materials of Science, University of Science and Technology of China, Hefei 230052, Anhui (China); Wang, Dongxu [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Zhang, Jinsong, E-mail: zjs@ahau.edu.cn [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China)

2012-02-01

Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p < 0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. -- Highlights: ►Cisplatin resulted in diarrhea in mice by 88%. ►i.p. selenosulfate at 9.5 μmol/kg daily for 11 days reduced diarrhea to 6%. ►i.p. selenosulfate at 19 μmol/kg daily for 55 days was not toxic. ►i.p. selenite at 19 μmol/kg daily for 55 days was lethal. ►Innocuous dose of selenosulfate greatly prevents cisplatin-induced diarrhea.

Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity

International Nuclear Information System (INIS)

Li, Jun; Sun, Kang; Ni, Lijuan; Wang, Xufang; Wang, Dongxu; Zhang, Jinsong

2012-01-01

Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p < 0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. -- Highlights: ►Cisplatin resulted in diarrhea in mice by 88%. ►i.p. selenosulfate at 9.5 μmol/kg daily for 11 days reduced diarrhea to 6%. ►i.p. selenosulfate at 19 μmol/kg daily for 55 days was not toxic. ►i.p. selenite at 19 μmol/kg daily for 55 days was lethal. ►Innocuous dose of selenosulfate greatly prevents cisplatin-induced diarrhea.

Application of a New Established System for Toxic Doses in Children With 4-Hydroxycoumarin Rodenticide Intoxication

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Li Ye

2018-05-01

Full Text Available The toxic dose of rodenticides in children is extremely difficult to be determined because of the uncertain exposure history. We established and validated a method to identify the toxic dose in children of 4-hydroxycoumarin (TDCH. Items were selected by Delphi method and weighted by analytic hierarchy process. Toxic doses were classified into three categories: high dose (>24 points, medium (15-24 and low (<15. Sixty-five children with 4-hydroxycoumarin rodenticide intoxication were included in the study. There were 29(44.6%, 8(12.3%, 28(43.1% cases in high, medium, and low dose respectively. Patients in high-dose were more likely to have intentionally attempted suicide (5/29, 17.2% or had no definite history of ingestion (17/29, 58.6%, arrived at the hospital later than 24 h (26/29, 90%, been misdiagnosed initially (25/29, 86.2%, not treated by gastric lavage (27/29, 93.1%, and developed severe hemorrhage. While most patients in low-dose were younger than 6 years (26/28, 92.9%, all have experienced accidental exposure, arrived at the hospital, and received gastric lavage within 24 h, obtained a definite diagnosis, and be asymptomatic. Of 38 patients arrived at hospital within 48 h, patients a score48h ≥ 15 had higher incidence of coagulopathy (6/8, 75.0% than patients with a score48h < 15 (3/30, 10.0%. Of all patients, 37 in the high and medium dose with a score ≥ 15 has higher incidence (35/37, 94.6% of prolonged administration with vitamin K1 (≥1 month than other 28 patients with a score < 15 (0/28, 0%. The TDCH system could not only be used in evaluating toxic doses and predicting coagulopathy in the early stage, but also helps to guide appropriate treatment. Patients with a score48h ≥ 15 were in the high bleeding risk category. And patients with a scores ≥ 15 required treatment with vitamin K1 for more than a month.

Safety and Feasibility of Carboplatin and Paclitaxel followed by Fluoropyrimidine Analogs and Radiation as Adjuvant Therapy for Gastric Cancer

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Mohammad Mobayed

2009-11-01

Full Text Available Background: Adjuvant 5-fluorouracil (5FU-based chemo-radiotherapy is currently considered a standard of care for the treatment of gastric cancer. The impact of 5FU-based adjuvant therapy on the rate of distant recurrence has been modest. In order to improve the systemic effects of adjuvant therapy, we have been treating patients with resected gastric cancer with carboplatin and paclitaxel followed by fluoropyrimidine analogue and radiation. Methods: We report on the outcomes of 21 consecutive gastric cancer patients treated off protocol with adjuvant carboplatin (area under the curve 5 mg/ml × min and paclitaxel (175–200 mg/m2 every 3 weeks, followed by concurrent pyrimidine analogs (either capecitabine 1,600–2,000 mg/m2/day in 17 patients, or 5FU 200 mg/m2/day in 4 patients and radiation (45–50.4 Gy. Patients received a total of 4–6 cycles of carboplatin and paclitaxel. Results: The median age at diagnosis was 60 years. Sixteen patients had stage 3 disease and 7 of them had positive surgical margins (6 with R1 and 1 with R2 resection, 3 patients were stage 2, and 2 patients were stage 1 (all had R0 resection. All patients had D1/D2 (4 had D2 and 17 had D1 lymph node dissection. The incidence of grade 3 or higher overall, hematologic, or gastrointestinal toxicity in the patients receiving carboplatin and paclitaxel was 57, 48 and 10%, respectively. No treatment-related deaths were observed. After adjuvant treatment 15 patients developed recurrent disease, 10 of whom had distant metastases. The median recurrence-free survival (RFS was 12.3 months. The median overall survival (OS was 16.0 months. Patients with R0 resection had significantly longer OS than did those with positive surgical margins (log-rank p = 0.0060. Median OS for the R0 resection group was 28.8 months. Conclusions: Carboplatin and paclitaxel added to radiation plus fluoropyrimidine analogs is a well-tolerated regimen in the adjuvant setting. The activity of this regimen

Postimplantation Analysis Enables Improvement of Dose-Volume Histograms and Reduction of Toxicity for Permanent Seed Implantation

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Wust, Peter; Postrach, Johanna; Kahmann, Frank; Henkel, Thomas; Graf, Reinhold; Cho, Chie Hee; Budach, Volker; Boehmer, Dirk

2008-01-01

Purpose: To demonstrate how postimplantation analysis is useful for improving permanent seed implantation and reducing toxicity. Patients and Methods: We evaluated 197 questionnaires completed by patients after permanent seed implantation (monotherapy between 1999 and 2003). For 70% of these patients, a computed tomography was available to perform postimplantation analysis. The index doses and volumes of the dose-volume histograms (DVHs) were determined and categorized with respect to the date of implantation. Differences in symptom scores relative to pretherapeutic status were analyzed with regard to follow-up times and DVH descriptors. Acute and subacute toxicities in a control group of 117 patients from an earlier study (June 1999 to September 2001) by Wust et al. (2004) were compared with a matched subgroup from this study equaling 110 patients treated between October 2001 and August 2003. Results: Improved performance, identifying a characteristic time dependency of DVH parameters (after implantation) and toxicity scores, was demonstrated. Although coverage (volume covered by 100% of the prescription dose of the prostate) increased slightly, high-dose regions decreased with the growing experience of the users. Improvement in the DVH and a reduction of toxicities were found in the patient group implanted in the later period. A decline in symptoms with follow-up time counteracts this gain of experience and must be considered. Urinary and sexual discomfort was enhanced by dose heterogeneities (e.g., dose covering 10% of the prostate volume, volume covered by 200% of prescription dose). In contrast, rectal toxicities correlated with exposed rectal volumes, especially the rectal volume covered by 100% of the prescription dose. Conclusion: The typical side effects occurring after permanent seed implantation can be reduced by improving the dose distributions. An improvement in dose distributions and a reduction of toxicities were identified with elapsed time between

High Dose-Rate Versus Low Dose-Rate Brachytherapy for Lip Cancer

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Ghadjar, Pirus, E-mail: pirus.ghadjar@insel.ch [Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern (Switzerland); Bojaxhiu, Beat [Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern (Switzerland); Simcock, Mathew [Swiss Group for Clinical Cancer Research Coordinating Center, Bern (Switzerland); Terribilini, Dario; Isaak, Bernhard [Division of Medical Radiation Physics, Inselspital, Bern University Hospital, and University of Bern, Bern (Switzerland); Gut, Philipp; Wolfensberger, Patrick; Broemme, Jens O.; Geretschlaeger, Andreas; Behrensmeier, Frank; Pica, Alessia; Aebersold, Daniel M. [Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern (Switzerland)

2012-07-15

Purpose: To analyze the outcome after low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy for lip cancer. Methods and Materials: One hundred and three patients with newly diagnosed squamous cell carcinoma of the lip were treated between March 1985 and June 2009 either by HDR (n = 33) or LDR brachytherapy (n = 70). Sixty-eight patients received brachytherapy alone, and 35 received tumor excision followed by brachytherapy because of positive resection margins. Acute and late toxicity was assessed according to the Common Terminology Criteria for Adverse Events 3.0. Results: Median follow-up was 3.1 years (range, 0.3-23 years). Clinical and pathological variables did not differ significantly between groups. At 5 years, local recurrence-free survival, regional recurrence-free survival, and overall survival rates were 93%, 90%, and 77%. There was no significant difference for these endpoints when HDR was compared with LDR brachytherapy. Forty-two of 103 patients (41%) experienced acute Grade 2 and 57 of 103 patients (55%) experienced acute Grade 3 toxicity. Late Grade 1 toxicity was experienced by 34 of 103 patients (33%), and 5 of 103 patients (5%) experienced late Grade 2 toxicity; no Grade 3 late toxicity was observed. Acute and late toxicity rates were not significantly different between HDR and LDR brachytherapy. Conclusions: As treatment for lip cancer, HDR and LDR brachytherapy have comparable locoregional control and acute and late toxicity rates. HDR brachytherapy for lip cancer seems to be an effective treatment with acceptable toxicity.

Modulation of toxicity following external beam irradiation preceded by high-dose rate brachytherapy in inoperable oesophageal cancer

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Taal, B.G.; Aleman, B.M.P.; Koning, C.C.E.; Boot, H. [Nederlands Kanker Inst. `Antoni van Leeuwenhoekhuis`, Amsterdam (Netherlands)

1996-09-01

To induce fast relief of dysphagia in inoperable oesephageal cancer, we applied high-dose rate (HDR) intraluminal irradiation followed by external irradiation (EBRT) in a phase II study. 15 patients (group A: n = 15; 10 men, 5 women; median age 66 years) were treated with 10 Gy HDR brachytherapy plus 40 Gy EBRT (15 fractions of 2.67 Gy). Severe side-effects were encountered in 60% of patients: 3 late ulceration, 2 pending fistula and 2 patients with fatal haemorrhage after an interval of 6 months. Overall response was excellent: 9 complete remissions (60%) and 6 partial responses (40%). Because of the high toxicity rate, in a subsequent study (group B: n = 30; 23 mean, 7 women; median age 66 years) the EBRT scheme was changed using smaller fractions (2.0 Gy) to reach the same total dose of 40 Gy. The complication rate (17%) was significantly reduced, while the overall response remained excellent (83%): 17 complete and 8 partial responses. The impressive change in complication rate of HDR brachytherapy and EBRT stresses the impact of the fraction per dose and illustrates the small therapeutic margins. (author).

Modulation of toxicity following external beam irradiation preceded by high-dose rate brachytherapy in inoperable oesophageal cancer

International Nuclear Information System (INIS)

Taal, B.G.; Aleman, B.M.P.; Koning, C.C.E.; Boot, H.

1996-01-01

To induce fast relief of dysphagia in inoperable oesephageal cancer, we applied high-dose rate (HDR) intraluminal irradiation followed by external irradiation (EBRT) in a phase II study. 15 patients (group A: n = 15; 10 men, 5 women; median age 66 years) were treated with 10 Gy HDR brachytherapy plus 40 Gy EBRT (15 fractions of 2.67 Gy). Severe side-effects were encountered in 60% of patients: 3 late ulceration, 2 pending fistula and 2 patients with fatal haemorrhage after an interval of 6 months. Overall response was excellent: 9 complete remissions (60%) and 6 partial responses (40%). Because of the high toxicity rate, in a subsequent study (group B: n = 30; 23 mean, 7 women; median age 66 years) the EBRT scheme was changed using smaller fractions (2.0 Gy) to reach the same total dose of 40 Gy. The complication rate (17%) was significantly reduced, while the overall response remained excellent (83%): 17 complete and 8 partial responses. The impressive change in complication rate of HDR brachytherapy and EBRT stresses the impact of the fraction per dose and illustrates the small therapeutic margins. (author)

High-dose-rate stereotactic body radiation therapy for postradiation therapy locally recurrent prostatic carcinoma: Preliminary prostate-specific antigen response, disease-free survival, and toxicity assessment.

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Fuller, Donald B; Wurzer, James; Shirazi, Reza; Bridge, Stephen S; Law, Jonathan; Mardirossian, George

2015-01-01

Patients with locally recurrent adenocarcinoma of the prostate following radiation therapy (RT) present a challenging problem. We prospectively evaluated the use of "high-dose-rate-like" prostate stereotactic body RT (SBRT) salvage for this circumstance, evaluating prostate-specific antigen response, disease-free survival, and toxicity. Between February 2009 and March 2014, 29 patients with biopsy-proven recurrent locally prostate cancer >2 years post-RT were treated. Median prior RT dose was 73.8 Gy and median interval to SBRT salvage was 88 months. Median recurrence Gleason score was 7 (79% was ≥7). Pre-existing RT toxicity >grade 1 was a reason for exclusion. Magnetic resonance imaging-defined prostate volume including any suspected extraprostatic extension, comprising the planning target volume. A total of 34 Gy/5 fractions was given, delivering a heterogeneous, high-dose-rate-like dose-escalation pattern. Toxicities were assessed using Common Terminology Criteria for Adverse Events, version 3.0, criteria. Twenty-nine treated patients had a median 24-month follow-up (range, 3-60 months). A median pre-SBRT salvage baseline prostate-specific antigen level of 3.1 ng/mL decreased to 0.65 ng/mL and 0.16 ng/mL at 1 and 2 years, respectively. Actuarial 2-year biochemical disease-free survival measured 82%, with no local failures. Toxicity >grade 1 was limited to the genitourinary domain, with 18% grade 2 or higher and 7% grade 3 or higher. No gastrointestinal toxicity >grade 1 occurred. Two-year disease-free survival is encouraging, and the prostate-specific antigen response kinetic appears comparable with that seen in de novo patients treated with SBRT, albeit still a preliminary finding. Grade ≥2 genitourinary toxicity was occasionally seen with no obvious predictive factor. Noting that our only brachytherapy case was 1 of the 2 cases with ≥grade 3 genitourinary toxicity, caution is recommended treating these patients. SBRT salvage of post-RT local recurrence

Assessment of the Toxicity of Sub-chronic Low and High Doses of the Bio-insecticide Spinosad on the Liver, Kidney and the Cerebellum in Male Albino Mice

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Sabry A El-Naggar

2017-06-01

Full Text Available ABSTRACT Spinosad (SPD is a highly selective insect control product. However, it was reported that SPD has toxicity toward other non-target organisms. This study was conducted to address the toxic effect of two sub-chronic low and high doses; 35 and 350 mg/kg SPD on some biochemical, histological and immunohistochemical parameters of the liver, kidney and cerebellum. Thirty-six male Swiss mice were divided into three groups of 12 mice each; first group (G1 served as a control, second group (G2 received a low sub-chronic dose of SPD that is equal to 35 mg/kg, and third group (G3 received a high sub-chronic dose of SPD that is equal to 350 mg/kg. The results showed that mice which were received 350 mg/kg SPD showed a significant decrease in the body weight and a significant increase in their relative kidney and spleen weights. They also showed a significant increase in alanine aminotransferase (ALT, triglycerides and urea levels. Histopathological examination showed cytoplasmic degeneration and cell necrosis in the liver and kidney. Immunohistochemical examination showed that cerebellum illustrated several neurodegenerative changes and a down-regulation of synaptophysin-Syp. In conclusion, exposure to a high dose of SPD that is equal to 350 mg/kg could cause a marked toxicity on the liver, kidney and cerebellum in male albino mice.

Comparison of patient-reported acute urinary and sexual toxicity scores in a 6- versus 2-fraction course of high-dose-rate prostate brachytherapy monotherapy

International Nuclear Information System (INIS)

Ragab, Omar; Park, Sang-June; Zhang, Mingle; Wang, Jason; Velez, Maria; Demanes, David J.; Banerjee, Robyn; Patel, Shyamal; Kamrave, Mitchell

2018-01-01

To identify differences in acute urinary and sexual toxicity between a 6-fraction and 2-fraction high-dose-rate brachytherapy monotherapy regimen and correlate dosimetric constraints to short-term toxicity. A single institution retrospective study of 116 men with prostate cancer treated with HDR monotherapy from 2010 to 2015 was conducted. Eighty-one men had 7.25 Gy × 6-fractions and 35 men had 13.5 Gy × 2-fractions. Patients had two CT-planned implants spaced 1–2 weeks apart. Patient baseline characteristics, International Prostate Symptom Scores (IPSS) and Sexual Health Inventory for Men (SHIM) scores were collected pre-treatment and 3, 6 and 12 months post-implantation. Mixed effect modelling was undertaken to compare baseline, 1–6 month and 7–12 month scores between groups. Poisson regression analysis was performed to correlate dosimetric constraints with acute toxicity. There was no difference between baseline and post-implantation IPSS scores between 6-fraction and 2-fraction groups. SHIM scores for men treated with 6-fractions had a steeper decline at 1–6 months, but resolved at 7–12 months. Pre-treatment alpha-blocker use correlated with worse short-term acute urinary toxicity. Worsened SHIM score correlated with increasing age, diabetes mellitus and androgen-deprivation therapy. In a dosimetric analysis of outcomes, prostate V150 dose and bladder wall (D01.cc, D1cc, D2cc) dose correlated with increased IPSS score. No increased acute genitourinary or sexual dysfunction has been observed in men when transitioning from 6-fraction to 2-fraction HDR monotherapy. A dosimetric correlation was found between the V150 and bladder wall doses for acute urinary toxicity. Future research should continue to standardize and validate dose constraints for prostate HDR monotherapy patients.

Effect of stress at dosing on organophosphate and heavy metal toxicity

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Jortner, Bernard S.

2008-01-01

This paper reviews recent studies assessing the effect of well-defined, severe, transient stress at dosing on two classical models of toxicity. These are the acute (anticholinesterase) toxicity seen following exposure to the organophosphate insecticide chlorpyrifos, and the nephrotoxicity elicited by the heavy metal depleted uranium, in rats. Stress was induced by periods of restraint and forced swimming in days to weeks preceding toxicant exposure. Forced swimming was far more stressful, as measured by marked, if transient, elevation of plasma corticosterone. This form of stress was administered immediately prior to administration of chlorpyrifos or depleted uranium. Chlorpyrifos (single 60 mg/kg subcutaneously) elicited marked inhibition of brain acetylcholinesterase 4-day post-dosing. Depleted uranium (single intramuscular doses of 0.1, 0.3 or 1.0 mg/kg uranium) elicited dose-dependent increase in kidney concentration of the metal, with associated injury to proximal tubular epithelium and increases in serum blood urea nitrogen and creatinine during the 30-day post-dosing period. Stress at dosing had no effect on these toxicologic endpoints

The influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in children with non-Hodgkin malignant lymphoma

International Nuclear Information System (INIS)

Erculj, Nina; Kotnik, Barbara Faganel; Debeljak, Marusa; Jazbec, Janez; Dolzan, Vita

2014-01-01

We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms. Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype. Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTX-related toxicity in children with NHL

Comparison of pharmacokinetics and toxicity after high-dose methotrexate treatments in children with acute lymphoblastic leukemia.

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Csordas, Katalin; Hegyi, Marta; Eipel, Oliver T; Muller, Judit; Erdelyi, Daniel J; Kovacs, Gabor T

2013-02-01

We carried out a detailed comparative study of the pharmacokinetics and toxicity of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) after high-dose intravenous methotrexate (HD-MTX) in children with acute lymphoblastic leukemia (ALL). Overall, 65 children were treated with 5 g/m2/24 h MTX and 88 children were treated with 2 g/m2/24 h MTX according to ALL-BFM 95 and ALL IC-BFM 2002 protocols (mean age: 6.4 years, range 1.0-17.9 years). A total of 583 HD-MTX courses were analyzed. Serum MTX and 7-OH-MTX levels were measured at 24, 36, and 48 h, and cerebrospinal fluid (CSF) MTX levels were determined 24 h after the initiation of the infusion. The area under the concentration-time curve was calculated. Hepatotoxicity, nephrotoxicity, and bone marrow toxicity were estimated by routine laboratory tests. We investigated pharmacokinetics and toxicity in distinct age groups ( 14 years). 5 g/m2/24 h treatments resulted in higher serum and CSF MTX and 7-OH-MTX levels (P treatments did not alter MTX or 7-OH-MTX levels. 7-OH-MTX levels were correlated with nephrotoxicity (r = 0.36, P children aged older than 14 years (P treatments. To predict the development of toxicity, monitoring of the level of the 7-OH-MTX is useful. Monitoring of pharmacokinetics is essential to prevent the development of severe adverse events in adolescents.

Repeated dose 90-day oral toxicity test of G-7% NANA in rats: An application of new criterion for toxicity determination to test article-induced changes.

Science.gov (United States)

Heo, Hye Seon; An, MinJi; Lee, Ji Sun; Kim, Hee Kyong; Park, Yeong-Chul

2018-06-01

G-7% NANA is N-acetylneuraminic acid(NANA) containing 7% sialic acid isolated from glycomacropeptide (GMP), a compound of milk. Since NANA is likely to have immunotoxicity, the need to ensure safety for long-term administration has been raised. In this study, a 90-day repeated oral dose toxicity test was performed in rats using G-7% NANA in the dosages of 0, 1250, 2500 and 5000 mg/kg/day.A toxicity determination criterion based on the significant change caused by the administration of the substancewas developed for estimating NOEL, NOAEL and LOAELapplied to this study. When analyzing the immunological markers, no significant changes were observed, even if other significant changes were observed in the high dose group. In accordance with the toxicity determination criterion developed, the NOEL in male and female has been determined as 2500 mg/kg/day, and the NOAEL in females has been determined as 5000 mg/kg/day. The toxicity determination criterion, applied for the first time in the repeated dose toxicity tests, could provide a basis for distinguishing NOEL and NOAEL more clearly; nevertheless, the toxicity determination criterion needs to be supplemented by adding differentiating adverse effects and non-adverse effects based on more experiences of the repeated dose toxicity tests. Copyright © 2018 Elsevier Inc. All rights reserved.

Diethylene glycol-induced toxicities show marked threshold dose response in rats

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Landry, Greg M., E-mail: Landry.Greg@mayo.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Dunning, Cody L., E-mail: cdunni@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu [Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Latimer, Brian, E-mail: blatim@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Orchard, Elysse, E-mail: eorcha@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA (United States); McMartin, Kenneth E., E-mail: kmcmar@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States)

2015-02-01

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

High Dose-Rate Versus Low Dose-Rate Brachytherapy for Lip Cancer

International Nuclear Information System (INIS)

Ghadjar, Pirus; Bojaxhiu, Beat; Simcock, Mathew; Terribilini, Dario; Isaak, Bernhard; Gut, Philipp; Wolfensberger, Patrick; Brömme, Jens O.; Geretschläger, Andreas; Behrensmeier, Frank; Pica, Alessia; Aebersold, Daniel M.

2012-01-01

Purpose: To analyze the outcome after low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy for lip cancer. Methods and Materials: One hundred and three patients with newly diagnosed squamous cell carcinoma of the lip were treated between March 1985 and June 2009 either by HDR (n = 33) or LDR brachytherapy (n = 70). Sixty-eight patients received brachytherapy alone, and 35 received tumor excision followed by brachytherapy because of positive resection margins. Acute and late toxicity was assessed according to the Common Terminology Criteria for Adverse Events 3.0. Results: Median follow-up was 3.1 years (range, 0.3–23 years). Clinical and pathological variables did not differ significantly between groups. At 5 years, local recurrence-free survival, regional recurrence-free survival, and overall survival rates were 93%, 90%, and 77%. There was no significant difference for these endpoints when HDR was compared with LDR brachytherapy. Forty-two of 103 patients (41%) experienced acute Grade 2 and 57 of 103 patients (55%) experienced acute Grade 3 toxicity. Late Grade 1 toxicity was experienced by 34 of 103 patients (33%), and 5 of 103 patients (5%) experienced late Grade 2 toxicity; no Grade 3 late toxicity was observed. Acute and late toxicity rates were not significantly different between HDR and LDR brachytherapy. Conclusions: As treatment for lip cancer, HDR and LDR brachytherapy have comparable locoregional control and acute and late toxicity rates. HDR brachytherapy for lip cancer seems to be an effective treatment with acceptable toxicity.

Cardiac toxicity and radiation dose to the heart in definitive treated non-small cell lung cancer

International Nuclear Information System (INIS)

Schytte, Tine; Hansen, Olfred; Stolberg-Rohr, Thomine; Brink, Carsten

2010-01-01

In this retrospective analysis of a consecutive series of NSCLC patients treated with definitive radiotherapy, we did not find a correlation between high mean-dose to three different volumes of the heart (left ventricle, both ventricles or whole heart) and cardiac toxicity defined as having an cardiac event after radiotherapy start. This is not as shown in studies with other diseases treated with radiotherapy. Darby et al. recently published a review concerning radiation related heart disease. They reported a significantly worse survival beyond ten years for breast cancer patients receiving radiotherapy. Some studies reported mortality from heart disease increased by 27%. In Hodgkin lymphoma patients an increased risk value of three to five for cardiac morbidity in general compared to general population and relative risk of death from myocardial infarction compared with general population in range 2 to 4. There may be several possible reasons why we did not experience a significant toxicity despite the high doses we delivered to the heart compared with patients receiving RT for breast cancer and lymphoma. Only relative few NSCLC patients live long enough to experience cardiac disease either due to lung cancer itself or comorbidity as a competitive risk factor. In our study the five year survival was 15% leaving very few patients at risk for developing cardiac disease. Without long-term survivors cardiac toxicity does not seem to be a problem, and this suggests that we should aim to increase tumour control by administrating larger doses of radiotherapy to the tumour and/or by adding concurrent chemotherapy. However, the latter may increase the risk of cardiac toxicity by itself, and the results given in present study, may not be extrapolated to this situation. Another reason might be that if NSCLC patients develop dyspnoea, chest pain, etc. it is interpreted as being due to a relapse of lung cancer and not cardiac disease. There are several studies indicating that

N-Acetyl Cysteine does not prevent liver toxicity from chronic low dose plus sub-acute high dose paracetamol exposure in young or old mice

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Kane, Alice-Elizabeth; Huizer-Pajkos, Aniko; Mach, John; McKenzie, Catriona; Mitchell, Sarah-Jayne; de Cabo, Rafael; Jones, Brett; Cogger, Victoria; Le Couteur, David G; Hilmer, Sarah-Nicole

2016-01-01

Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute over-exposures. The risk of hepatotoxicity from non-acute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for non-acute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and sub-acute paracetamol over-exposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33g/kg food) or control diet for 6 weeks. Mice were then dosed orally 8 times over 3 days with additional paracetamol (250mg/kg) or saline, followed by either one or two doses of oral NAC (1200mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Sub-acute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from sub-acute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for sub-acute paracetamol toxicity. PMID:26821200

Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer

International Nuclear Information System (INIS)

Huang, Eugene H.; Pollack, Alan; Levy, Larry; Starkschall, George; Lei Dong; Rosen, Isaac; Kuban, Deborah A.

2002-01-01

Purpose: To identify dosimetric, anatomic, and clinical factors that correlate with late rectal toxicity after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. Methods and Materials: We retrospectively analyzed the dose-volume histograms and clinical records of 163 Stage T1b-T3c prostate cancer patients treated between 1992 and 1999 with 3D-CRT, to a total isocenter dose of 74-78 Gy at The University of Texas M. D. Anderson Cancer Center. The median follow-up was 62 months (range 24-102). All late rectal complications were scored using modified Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. The 6-year toxicity rate was assessed using Kaplan-Meier analysis and the log-rank test. A univariate proportional hazards regression model was used to test the correlation between Grade 2 or higher toxicity and the dosimetric, anatomic, and clinical factors. In a multivariate regression model, clinical factors were added to the dosimetric and anatomic variables to determine whether they significantly altered the risk of developing late toxicity. Results: At 6 years, the rate of developing Grade 2 or higher late rectal toxicity was 25%. A significant volume effect was observed at rectal doses of 60, 70, 75.6, and 78 Gy, and the risk of developing rectal complications increased exponentially as greater volumes were irradiated. Although the percentage of rectal volume treated correlated significantly with the incidence of rectal complications at all dose levels (p 3 of the rectum. Of the clinical variables tested, only a history of hemorrhoids correlated with rectal toxicity (p=0.003). Multivariate analysis showed that the addition of hemorrhoids increased the risk of toxicity for each dosimetric variable found to be significant on univariate analysis (p<0.05 for all comparisons). Conclusion: Dose-volume histogram analyses clearly indicated a volume effect on the probability of developing late rectal complications

Recreating the seawater mixture composition of HOCs in toxicity tests with Artemia franciscana by passive dosing

Energy Technology Data Exchange (ETDEWEB)

Rojo-Nieto, E., E-mail: elisa.rojo@uca.es [Andalusian Centre of Marine Science and Technology (CACYTMAR), Department of Environmental Technologies, University of Cadiz, 11510 Puerto Real (Spain); Smith, K.E.C. [Department of Environmental Science, Aarhus University, DK-4000 Roskilde (Denmark); Perales, J.A. [Andalusian Centre of Marine Science and Technology (CACYTMAR), Department of Environmental Technologies, University of Cadiz, 11510 Puerto Real (Spain); Mayer, P. [Department of Environmental Science, Aarhus University, DK-4000 Roskilde (Denmark)

2012-09-15

The toxicity testing of hydrophobic organic compounds (HOCs) in aquatic media is generally challenging, and this is even more problematic for mixtures. The hydrophobic properties of these compounds make them difficult to dissolve, and subsequently to maintain constant exposure concentrations. Evaporative and sorptive losses are highly compound-specific, which can alter not only total concentrations, but also the proportions between the compounds in the mixture. Therefore, the general aim of this study was to explore the potential of passive dosing for testing the toxicity of a PAH mixture that recreates the mixture composition found in seawater from a coastal area of Spain, the Bay of Algeciras. First, solvent spiking and passive dosing were compared for their suitability to determine the acute toxicity to Artemia franciscana nauplii of several PAHs at their respective solubility limits. Second, passive dosing was applied to recreate the seawater mixture composition of PAHs measured in a Spanish monitoring program, to test the toxicity of this mixture at different levels. HPLC analysis was used to confirm the reproducibility of the dissolved exposure concentrations for the individual PAHs and mixtures. This study shows that passive dosing has some important benefits in comparison with solvent spiking for testing HOCs in aquatic media. These include maintaining constant exposure concentrations, leading to higher reproducibility and a relative increase in toxicity. Passive dosing is also able to faithfully reproduce real mixtures of HOCs such as PAHs, in toxicity tests, reproducing both the levels and proportions of the different compounds. This provides a useful approach for studying the toxicity of environmental mixtures of HOCs, both with a view to investigating their toxicity but also for determining safety factors before such mixtures result in detrimental effects.

Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy

International Nuclear Information System (INIS)

Vargas, Carlos; Martinez, Alvaro; Kestin, Larry L.; Yan Di; Grills, Inga; Brabbins, Donald S.; Lockman, David M.; Liang Jian; Gustafson, Gary S.; Chen, Peter Y.; Vicini, Frank A.; Wong, John W.

2005-01-01

Purpose We analyzed our experience treating localized prostate cancer with image-guided off-line correction with adaptive high-dose radiotherapy (ART) in our Phase II dose escalation study to identify factors predictive of chronic rectal toxicity. Materials and Methods From 1999-2002, 331 patients with clinical stage T1-T3N0M0 prostate cancer were prospectively treated in our Phase II 3D conformal dose escalation ART study to a median dose of 75.6 Gy (range, 63.0-79.2 Gy), minimum dose to confidence limited-planning target volume (cl-PTV) in 1.8 Gy fractions (median isocenter dose = 79.7 Gy). Seventy-four patients (22%) also received neoadjuvant/adjuvant androgen deprivation therapy. A patient-specific cl-PTV was constructed using 5 computed tomography scans and 4 sets of electronic portal images by applying an adaptive process to assure target accuracy and minimize PTV margin. For each case, the rectum (rectal solid) was contoured from the sacroiliac joints or rectosigmoid junction (whichever was higher) to the anal verge or ischial tuberosities (whichever was lower), with a median volume of 81.2 cc. The rectal wall was defined using the rectal solid with an individualized 3-mm wall thickness (median volume = 29.8 cc). Rectal wall dose-volume histogram was used to determine the prescribed dose. Toxicity was quantified using the National Cancer Institute Common Toxicity Criteria 2.0. Multiple dose-volume endpoints were evaluated for their association with chronic rectal toxicity. Results Median follow-up was 1.6 years. Thirty-four patients (crude rate 10.3%) experienced Grade 2 chronic rectal toxicity at a median interval of 1.1 years. Nine patients (crude rate = 2.7%) experienced Grade ≥3 chronic rectal toxicity (1 was Grade 4) at a median interval of 1.2 years. The 3-year rates of Grade ≥2 and Grade ≥3 chronic rectal toxicity were 20% and 4%, respectively. Acute toxicity predicted for chronic: Acute Grade 2-3 rectal toxicity (p 40% respectively. The volume

The influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in children with non-Hodgkin malignant lymphoma

Science.gov (United States)

Erculj, Nina; Kotnik, Barbara Faganel; Debeljak, Marusa; Jazbec, Janez; Dolzan, Vita

2014-01-01

Background We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). Patients and methods In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms. Results Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype. Conclusions Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTX-related toxicity in children with NHL. PMID:25177243

Aquatic toxicity testing of liquid hydrophobic chemicals – Passive dosing exactly at the saturation limit

DEFF Research Database (Denmark)

Stibany, Felix; Nørgaard Schmidt, Stine; Schäffer, Andreas

2017-01-01

The aims of the present study were (1) to develop a passive dosing approach for aquatic toxicity testing of liquid substances with very high Kow values and (2) to apply this approach to the model substance dodecylbenzene (DDB, Log Kow = 8.65). The first step was to design a new passive dosing...... format for testing DDB exactly at its saturation limit. Silicone O-rings were saturated by direct immersion in pure liquid DDB, which resulted in swelling of >14%. These saturated O-rings were used to establish and maintain DDB exposure exactly at the saturation limit throughout 72-h algal growth...... at chemical activity of unity was higher than expected relative to a reported hydrophobicity cut-off in toxicity, but lower than expected relative to a reported chemical activity range for baseline toxicity. The present study introduces a new effective approach for toxicity testing of an important group...

Late Toxicity After Intensity-Modulated Radiation Therapy for Localized Prostate Cancer: An Exploration of Dose-Volume Histogram Parameters to Limit Genitourinary and Gastrointestinal Toxicity

Energy Technology Data Exchange (ETDEWEB)

Pederson, Aaron W.; Fricano, Janine; Correa, David; Pelizzari, Charles A. [Department of Radiation and Cellular Oncology, Pritzker School of Medicine, University of Chicago, Chicago, IL (United States); Liauw, Stanley L., E-mail: sliauw@radonc.uchicago.edu [Department of Radiation and Cellular Oncology, Pritzker School of Medicine, University of Chicago, Chicago, IL (United States)

2012-01-01

Purpose: To characterize the late genitourinary (GU) and gastrointestinal (GI) toxicity for prostate cancer patients treated with intensity-modulated radiation therapy (IMRT) and propose dose-volume histogram (DVH) guidelines to limit late treatment-related toxicity. Methods and Materials: In this study 296 consecutive men were treated with IMRT for adenocarcinoma of the prostate. Most patients received treatment to the prostate with or without proximal seminal vesicles (90%), to a median dose of 76 Gy. Concurrent androgen deprivation therapy was given to 150 men (51%) for a median of 4 months. Late toxicity was defined by Common Toxicity Criteria version 3.0 as greater than 3 months after radiation therapy completion. Four groupings of DVH parameters were defined, based on the percentage of rectal or bladder tissue receiving 70 Gy (V{sub 70}), 65 Gy (V{sub 65}), and 40 Gy (V{sub 40}). These DVH groupings, as well as clinical and treatment characteristics, were correlated to maximal Grade 2+ GU and GI toxicity. Results: With a median follow-up of 41 months, the 4-year freedom from maximal Grade 2+ late toxicity was 81% and 91% for GU and GI systems, respectively, and by last follow-up, the rates of Grade 2+ GU and GI toxicity were 9% and 5%, respectively. On multivariate analysis, whole-pelvic IMRT was associated with Grade 2+ GU toxicity and age was associated with Grade 2+ GI toxicity. Freedom from Grade 2+ GI toxicity at 4 years was 100% for men with rectal V{sub 70} {<=}10%, V{sub 65} {<=}20%, and V{sub 40} {<=}40%; 92% for men with rectal V{sub 70} {<=}20%, V{sub 65} {<=}40%, and V{sub 40} {<=}80%; and 85% for men exceeding these criteria (p = 0.13). These criteria were more highly associated with GI toxicity in men aged {>=}70 years (p = 0.07). No bladder dose-volume relationships were associated with the risk of GU toxicity. Conclusions: IMRT is associated with low rates of severe GU or GI toxicity after treatment for prostate cancer. Rectal dose constraints

Anatomy-based inverse planning dose optimization in HDR prostate implant: A toxicity study

International Nuclear Information System (INIS)

Mahmoudieh, Alireza; Tremblay, Christine; Beaulieu, Luc; Lachance, Bernard; Harel, Francois; Lessard, Etienne; Pouliot, Jean; Vigneault, Eric

2005-01-01

Background and purpose: The aim of this study is to evaluate the acute and late complications in patients who have received HDR implant boost using inverse planning, and to determine dose volume correlations. Patients and methods: Between September 1999 and October 2002, 44 patients with locally advanced prostate cancer (PSA ≥10 ng/ml, and/or Gleason score ≥7, and/or Stage T2c or higher) were treated with 40-45 Gy external pelvic field followed by 2-3 fraction of inverse-planned HDR implant boost (6-9.5 Gy /fraction). Median follow-up time was 1.7 years with 81.8% of patients who had at least 12 months of follow up (range 8.6-42.5. Acute and late morbidity data were collected and graded according to RTOG criteria. Questionnaires were used to collect prostate related measures of quality of life, and international prostate symptom score (IPSS) before and after treatment. Dose-volume histograms for prostate, urethra, bladder, penis bulb and rectum were analyzed. Results: The median patient age was 64 years. Of these, 32% were in the high risk group, and 61% in the intermediate risk group. 3 patients (7%) had no adverse prognostic factors. A single grade 3 GU acute toxicity was reported but no grade 3-4 acute GI toxicity. No grade 3-4 late GU or GI toxicity was reported. Acute (late) grade 2 urinary and rectal symptoms were reported in 31.8 (11.4%) and 4.6% (4.6%) of patients, respectively. A trend for predicting acute GU toxicity is seen for total HDR dose of more than 18 Gy (OR=3.6, 95%CI=[0.96-13.5], P=0.058). The evolution of toxicity is presented for acute and late GU/GI toxicity. Erectile dysfunction occurs in approximately 27% of patients who were not on hormonal deprivation, but may be taking sildenafil. The IPSS peaked on averaged 6 weeks post-implant and returned to the baseline at a median of 6 months. Conclusions: Inverse-planned HDR brachytherapy is a viable option to deliver higher dose to the prostate as a boost without increasing GU or rectal

PAH toxicity at aqueous solubility in the fish embryo test with Danio rerio using passive dosing

DEFF Research Database (Denmark)

Seiler, Thomas-Benjamin; Best, Nina; Fernqvist, Margit Møller

2014-01-01

to animal testing in (eco)toxicology. However, for hydrophobic organic chemicals it remains a technical challenge to ensure constant freely dissolved concentration at the maximum exposure level during such biotests. Passive dosing with PDMS silicone was thus applied to control the freely dissolved...... further data to support the close relationship between the chemical activity and the toxicity of hydrophobic organic compounds. Passive dosing from PDMS silicone enabled reliable toxicity testing of (highly) hydrophobic substances at aqueous solubility, providing a practical way to control toxicity...... exactly at the maximum exposure level. This approach is therefore expected to be useful as a cost-effective initial screening of hydrophobic chemicals for potential adverse effects to freshwater vertebrates....

Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects

Energy Technology Data Exchange (ETDEWEB)

Veen, Sonja J. van der; Faber, Hette; Ghobadi, Ghazaleh [Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Brandenburg, Sytze [KVI Center for Advanced Radiation Research, University of Groningen, Groningen (Netherlands); Langendijk, Johannes A. [Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Coppes, Robert P. [Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Luijk, Peter van, E-mail: p.van.luijk@umcg.nl [Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands)

2016-01-01

Purpose: Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed the dose-limiting toxicity. Methods and Materials: A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects. Results: Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD. Conclusions: In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late

Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity : A systematic review and meta-analysis of individual patient data

NARCIS (Netherlands)

Meulendijks, Didier; Henricks, Linda M.; Sonke, Gabe S.; Deenen, Maarten J.; Froehlich, Tanja K.; Amstutz, Ursula; Largiadèr, Carlo R.; Jennings, Barbara A.; Marinaki, Anthony M.; Sanderson, Jeremy D.; Kleibl, Zdenek; Kleiblova, Petra; Schwab, Matthias; Zanger, Ulrich M.; Palles, Claire; Tomlinson, Ian; Gross, Eva; van Kuilenburg, André B P; Punt, Cornelis J A; Koopman, Miriam; Beijnen, Jos H.|info:eu-repo/dai/nl/071919570; Cats, Annemieke; Schellens, Jan H M|info:eu-repo/dai/nl/073926272

2015-01-01

Background: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including. DPYD*2A and c.2846A>T. Three other variants- DPYD c.1679T>G, c.1236G>A/HapB3, and

Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity : a systematic review and meta-analysis of individual patient data

NARCIS (Netherlands)

Meulendijks, Didier; Henricks, Linda M; Sonke, Gabe S; Deenen, Maarten J; Froehlich, Tanja K; Amstutz, Ursula; Largiadèr, Carlo R; Jennings, Barbara A; Marinaki, Anthony M; Sanderson, Jeremy D; Kleibl, Zdenek; Kleiblova, Petra; Schwab, Matthias; Zanger, Ulrich M; Palles, Claire; Tomlinson, Ian; Gross, Eva; van Kuilenburg, André B P; Punt, Cornelis J A; Koopman, Miriam; Beijnen, Jos H; Cats, Annemieke; Schellens, Jan H M

2015-01-01

BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and

A comparison of dose-volume constraints derived using peak and longitudinal definitions of late rectal toxicity

International Nuclear Information System (INIS)

Gulliford, Sarah L.; Partridge, Mike; Sydes, Matthew R.; Andreyev, Jervoise; Dearnaley, David P.

2010-01-01

Background and purpose: Accurate reporting of complications following radiotherapy is an important part of the feedback loop to improve radiotherapy techniques. The definition of toxicity is normally regarded as the maximum or peak (P) grade of toxicity reported over the follow-up period. An alternative definition (integrated longitudinal toxicity (ILT)) is proposed which takes into account both the severity and the duration of the complication. Methods and materials: In this work, both definitions of toxicity were used to derive dose-volume constraints for six specific endpoints of late rectal toxicity from a cohort of patients who received prostate radiotherapy in the MRC RT01 trial. The dose-volume constraints were derived using ROC analysis for 30, 40, 50, 60, 65 and 70 Gy. Results: Statistically significant dose-volume constraints were not derived for all dose levels tested for each endpoint and toxicity definition. However, where both definitions produced constraints, there was generally good agreement. Variation in the derived dose-volume constraints was observed to be larger between endpoints than between the two definitions of toxicity. For one endpoint (stool frequency (LENT/SOM)) statistically significant dose-volume constraints were only derived using ILT. Conclusions: The longitudinal definition of toxicity (ILT) produced results consistent with those derived using peak toxicity and in some cases provided additional information which was not seen by analysing peak toxicity alone.

Long-Term Results of Fixed High-Dose I-131 Treatment for Toxic Nodular Goiter: Higher Euthyroidism Rates in Geriatric Patients

Directory of Open Access Journals (Sweden)

Gül Ege Aktaş

2015-10-01

Full Text Available Objective: Geriatric patient population has special importance due to particular challenges. In addition to the increase in incidence of toxic nodular goiter (TNG with age, it has a high incidence in the regions of low-medium iodine intake such as in our country. The aim of this study was to evaluate the overall outcome of high fixed dose radioiodine (RAI therapy, and investigate the particular differences in the geriatric patient population. Methods: One hundred and three TNG patients treated with high dose I-131 (370-740 MBq were retrospectively reviewed. The baseline characteristics; age, gender, scintigraphic patterns and thyroid function tests before and after treatment, as well as follow-up, duration of antithyroid drug (ATD medication and achievement of euthyroid or hypothyroid state were evaluated. The patient population was divided into two groups as those=>65 years and those who were younger, in order to assess the effect of age. Results: Treatment success was 90% with single dose RAI therapy. Hyperthyroidism was treated in 7±7, 2 months after RAI administration. At the end of the first year, overall hypothyroidism rate was 30% and euthyroid state was achieved in 70% of patients. Age was found to be the only statistically significant variable effecting outcome. A higher ratio of euthyroidism was achieved in the geriatric patient population. Conclusion: High fixed dose I-131 treatment should be preferred in geriatric TNG patients in order to treat persistent hyperthyroidism rapidly. The result of this study suggests that high fixed dose RAI therapy is a successful modality in treating TNG, and high rates of euthyroidism can be achieved in geriatric patients.

Radiotherapy after high-dose chemotherapy and peripheral blood stem cell support in high-risk breast cancer

International Nuclear Information System (INIS)

Hoeller, Ulrike; Heide, Juergen; Kroeger, Nicolaus; Krueger, William; Jaenicke, Fritz; Alberti, Winfried

2002-01-01

Purpose: To assess the toxicity and efficacy of radiotherapy with respect to locoregional control after adjuvant high-dose chemotherapy for patients with breast cancer. At first, radiotherapy was withheld because of toxicity concerns, but it was introduced in 1995 because of reported high locoregional relapse rates. Methods and Materials: Between 1992 and 1998, 40 patients with Stage II-III high-risk breast cancer received adjuvant high-dose chemotherapy consisting of thiotepa, mitoxantrone, and cyclophosphamide and peripheral blood stem cell support after four cycles of induction chemotherapy. The chest wall or breast, as well as the supraclavicular nodes, were irradiated with electrons and photons to a median dose of 50.4 Gy in 20 patients. Six additional patients received only supraclavicular irradiation to a median dose of 50.4 Gy. Acute toxicity was scored clinically. Pulmonary function tests were performed in 14 irradiated patients before high-dose chemotherapy and 1.1-4.4 years (median 1.6) after irradiation. The median follow-up time of living patients was 33 vs. 67 months in irradiated (n=26) and nonirradiated (n=14) patients, respectively. Results: G2 and G3 hematologic toxicity occurred in 1 patient each. No clinical pneumonitis or clinical impairment of lung function was observed. After 1-2 years, the lung function tests showed only minor changes in 4 patients. The 3-year locoregional control rate was 92% in the irradiated patients vs. 58% in the nonirradiated patients (p=0.049, actuarial analysis). Conclusion: In this series, adjuvant radiotherapy after adjuvant chemotherapy for breast cancer appeared well tolerated, with improved local regional control and without significant side effects. Longer follow-up and more patient accrual, as well as Phase III trials, are necessary for confirmation

Reproductive toxicity in rats after chronic oral exposure to low dose of depleted uranium

International Nuclear Information System (INIS)

Li Rong; Ai Guoping; Xu Hui; Su Yongping; Cheng Tianmin; Leng Yanbing

2007-01-01

Objective: To study the reproductive toxicity in rats induced by low dose of depleted uranium (DU). Methods: Male and female rats(F 0 generation) were exposed to DU in food at doses of 0, 0.4, 4 and 40 mg·kg -1 ·d -1 for 160 days, respectively. Then the activities of enzymes in testis and sexual hormone contents in serum were detected. Mature male rats were mated with female rats exposed to the same doses for 14 days. Pregnant rate and normal labor rate in F 0 rats were detected, as well as the survival rate and weight of F 1 rats within 21 d after birth. Results: No adverse effects of DU on fertility were evident at any dose in F 0 rats. Compared with control group, the rate of pregnancy, normal labor, survival of offspring birth and offspring nurture in F 1 generation of high-dose group reduced to 40.0%, 33.3%, 33.3%, and 33.3%, respectively. The sexual hormone contents in F 0 generation exposed increased, but those in Fl rats decreased significantly. The activities of lactate dehydrogenase-X (LDH-X) decreased in F 1 rats exposed to high-dose of DU, and those of sorbitol dehydrogenase (SDH), LDH and Na + -K + -ATPase decreased in F 1 rats exposed to DU. Conclusions: Reproduction function, growth and development of F 0 rats are not obviously affected after chronic oral exposure to DU, while the toxicity effects in F 1 generation was observed at any dose. (authors)

Accelerated partial breast irradiation: An analysis of variables associated with late toxicity and long-term cosmetic outcome after high-dose-rate interstitial brachytherapy

International Nuclear Information System (INIS)

Wazer, David E.; Kaufman, Seth; Cuttino, Laurie; Di Petrillo, Thomas; Arthur, Douglas W.

2006-01-01

Purpose: To perform a detailed analysis of variables associated with late tissue effects of high-dose-rate (HDR) interstitial brachytherapy accelerated partial breast irradiation (APBI) in a large cohort of patients with prolonged follow-up. Methods and Materials: Beginning in 1995, 75 women with Stage I/II breast cancer were enrolled in identical institutional trials evaluating APBI as monotherapy after lumpectomy. Patients eligible included those with T1-2, N0-1 (≤3 nodes positive), M0 tumors of nonlobular histology with negative surgical margins, no extracapsular nodal extension, and negative results on postexcision mammogram. All patients underwent surgical excision and postoperative irradiation with HDR interstitial brachytherapy. The planning target volume was defined as the excision cavity plus a 2-cm margin. Treatment was delivered with a high-activity Ir-192 source at 3.4 Gy per fraction twice daily for 5 days to a total dose of 34 Gy. Dosimetric analyses were performed with three-dimensional postimplant dose and volume reconstructions. All patients were evaluated at 3-6-month intervals and assessed with a standardized cosmetic rating scale and according to Radiation Therapy Oncology Group late normal tissue toxicity scoring criteria. Clinical and therapy-related features were analyzed for their relationship to cosmetic outcome and toxicity rating. Clinical features analyzed included age, volume of resection, history of diabetes or hypertension, extent of axillary surgery, and systemic therapies. Therapy-related features analyzed included volume of tissue encompassed by the 100%, 150%, and 200% isodose lines (V100, V150, and V200, respectively), the dose homogeneity index (DHI), number of source dwell positions, and planar separation. Results: The median follow-up of all patients was 73 months (range, 43-118 months). The cosmetic outcome at last follow-up was rated as excellent, good, and fair/poor in 67%, 24%, and 9% of patients, respectively

Impact of Drug Therapy, Radiation Dose, and Dose Rate on Renal Toxicity Following Bone Marrow Transplantation

International Nuclear Information System (INIS)

Cheng, Jonathan C.; Schultheiss, Timothy E.; Wong, Jeffrey Y.C.

2008-01-01

Purpose: To demonstrate a radiation dose response and to determine the dosimetric and chemotherapeutic factors that influence the incidence of late renal toxicity following total body irradiation (TBI). Methods and Materials: A comprehensive retrospective review was performed of articles reporting late renal toxicity, along with renal dose, fractionation, dose rate, chemotherapy regimens, and potential nephrotoxic agents. In the final analysis, 12 articles (n = 1,108 patients), consisting of 24 distinct TBI/chemotherapy conditioning regimens were included. Regimens were divided into three subgroups: adults (age ≥18 years), children (age <18 years), and mixed population (both adults and children). Multivariate logistic regression was performed to identify dosimetric and chemotherapeutic factors significantly associated with late renal complications. Results: Individual analysis was performed on each population subgroup. For the purely adult population, the only significant variable was total dose. For the mixed population, the significant variables included total dose, dose rate, and the use of fludarabine. For the pediatric population, only the use of cyclosporin or teniposide was significant; no dose response was noted. A logistic model was generated with the exclusion of the pediatric population because of its lack of dose response. This model yielded the following significant variables: total dose, dose rate, and number of fractions. Conclusion: A dose response for renal damage after TBI was identified. Fractionation and low dose rates are factors to consider when delivering TBI to patients undergoing bone marrow transplantation. Drug therapy also has a major impact on kidney function and can modify the dose-response function

Dose-response of acute urinary toxicity of long-course preoperative chemoradiotherapy for rectal cancer

DEFF Research Database (Denmark)

Appelt, Ane L.; Bentzen, Søren M.; Jakobsen, Anders

2015-01-01

BACKGROUND: Long-course preoperative chemoradiotherapy (chemo-RT) improves outcomes for rectal cancer patients, but acute side effects during treatment may cause considerable patient discomfort and may compromise treatment compliance. We developed a dose-response model for acute urinary toxicity...... based on a large, single-institution series. MATERIAL AND METHODS: In total 345 patients were treated with (chemo-)RT for primary rectal cancer from January 2007 to May 2012. Urinary toxicity during RT was scored prospectively using the CTCAE v 3.0 cystitis score (grade 0-5). Clinical variables...... and radiation dose to the bladder were related to graded toxicity using multivariate ordinal logistic regression. Three models were optimized, each containing all available clinical variables and one of three dose metrics: Mean dose (Dmean), equivalent uniform dose (EUD), or relative volume given x Gy or above...

Multifocal Electroretinography after High Dose Chloroquine Therapy for Malaria

Directory of Open Access Journals (Sweden)

Aline Correa de Carvalho

2013-01-01

Full Text Available Purpose: To investigate changes in multifocal electroretinography (mfERG parameters associated with high dose chloroquine therapy for treatment of malaria in the Amazonia region of Brazil. Methods: Forty-eight subjects who had received chloroquine treatment for single or multiple malaria infections with a cumulative dose ranging from 1,050 to 27,000mg were included. The control group consisted of 37 healthy aged-matched subjects. Data was collected on amplitude and implicit time of the N1, P1 and N2 waves in the central macular hexagon (R1 and in five concentric rings at different retinal eccentricities (R2-R6. Results: No significant difference was observed in any mfERG parameter between chloroquine treated patients and control subjects. A comparison with previous data obtained from patients with rheumatologic disorders in the same region of Brazil who had received larger cumulative doses of chloroquine and had displayed mfERG changes, indicated that retinal toxicity seems to be dependent on cumulative dose. Conclusion: Lack of mfERG changes in the current study suggests that intensive high dose chloroquine therapy for treatment of malaria is not associated with retinal toxicity.

Interstitial high-dose rate brachytherapy as boost for anal canal cancer

International Nuclear Information System (INIS)

Falk, Alexander Tuan; Claren, Audrey; Benezery, Karen; François, Eric; Gautier, Mathieu; Gerard, Jean-Pierre; Hannoun-Levi, Jean-Michel

2014-01-01

To assess clinical outcomes of patients treated with a high-dose rate brachytherapy boost for anal canal cancer (ACC). From August 2005 to February 2013, 28 patients presenting an ACC treated by split-course external beam radiotherapy (EBRT) and HDR brachytherapy with or without chemotherapy in a French regional cancer center in Nice were retrospectively analyzed. Median age was 60.6 years [34 – 83], 25 patients presented a squamous cell carcinoma and 3 an adenocarcinoma; 21 received chemotherapy. Median dose of EBRT was 45 Gy [43.2 – 52]. Median dose of HDR brachytherapy was 12 Gy [10 - 15] with a median duration of 2 days. Median overall treatment time was 63 days and median delay between EBRT and brachytherapy was 20 days. Two-year local relapse free, metastatic free, disease free and overall survivals were 83%, 81.9%, 71.8% and 87.7% respectively. Acute toxicities were frequent but not severe with mostly grade 1 toxicities: 37% of genito-urinary, 40.7% of gastro-intestinal and 3.7% of cutaneous toxicities. Late toxicities were mainly G1 (43.1%) and G2 (22%). Two-year colostomy-free survival was 75.1%, one patient had a definitive sphincter amputation. High-dose rate brachytherapy for anal canal carcinoma as boost represents a feasible technique compared to low or pulsed-dose rate brachytherapy. This technique remains an excellent approach to precisely boost the tumor in reducing the overall treatment time

Low doses of six toxicants change plant size distribution in dense populations of Lactuca sativa.

Science.gov (United States)

Belz, Regina G; Patama, Marjo; Sinkkonen, Aki

2018-08-01

Toxicants are known to have negligible or stimulatory, i.e. hormetic, effects at low doses below those that decrease the mean response of a plant population. Our earlier observations indicated that at such low toxicant doses the growth of very fast- and slow-growing seedlings is selectively altered, even if the population mean remains constant. Currently, it is not known how common these selective low-dose effects are, whether they are similar among fast- and slow-growing seedlings, and whether they occur concurrently with hormetic effects. We tested the response of Lactuca sativa in complete dose-response experiments to six different toxicants at doses that did not decrease population mean and beyond. The tested toxicants were IAA, parthenin, HHCB, 4-tert-octylphenol, glyphosate, and pelargonic acid. Each experiment consisted of 14,400-16,800 seedlings, 12-14 concentrations, 24 replicates per concentration and 50 germinated seeds per replicate. We analyzed the commonness of selective low-dose effects and explored if toxic effects and hormetic stimulation among fast- and slow-growing individuals occurred at the same concentrations as they occur at the population level. Irrespective of the observed response pattern and toxicant, selective low-dose effects were found. Toxin effects among fast-growing individuals usually started at higher doses compared to the population mean, while the opposite was found among slow-growing individuals. Very low toxin exposures tended to homogenize plant populations due to selective effects, while higher, but still hormetic doses tended to heterogenize plant populations. Although the extent of observed size segregation varied with the specific toxin tested, we conclude that a dose-dependent alteration in size distribution of a plant population may generally apply for many toxin exposures. Copyright © 2018 Elsevier B.V. All rights reserved.

Assessment of diurnal systemic dose of agrochemicals in regulatory toxicity testing--an integrated approach without additional animal use.

Science.gov (United States)

Saghir, Shakil A; Bartels, Michael J; Rick, David L; McCoy, Alene T; Rasoulpour, Reza J; Ellis-Hutchings, Robert G; Sue Marty, M; Terry, Claire; Bailey, Jason P; Billington, Richard; Bus, James S

2012-07-01

Integrated toxicokinetics (TK) data provide information on the rate, extent and duration of systemic exposure across doses, species, strains, gender, and life stages within a toxicology program. While routine for pharmaceuticals, TK assessments of non-pharmaceuticals are still relatively rare, and have never before been included in a full range of guideline studies for a new agrochemical. In order to better understand the relationship between diurnal systemic dose (AUC(24h)) and toxicity of agrochemicals, TK analyses in the study animals is now included in all short- (excluding acute), medium- and long-term guideline mammalian toxicity studies including reproduction/developmental tests. This paper describes a detailed procedure for the implementation of TK in short-, medium- and long-term regulatory toxicity studies, without the use of satellite animals, conducted on three agrochemicals (X11422208, 2,4-D and X574175). In these studies, kinetically-derived maximum doses (KMD) from short-term studies instead of, or along with, maximum tolerated doses (MTD) were used for the selection of the high dose in subsequent longer-term studies. In addition to leveraging TK data to guide dose level selection, the integrated program was also used to select the most appropriate method of oral administration (i.e., gavage versus dietary) of test materials for rat and rabbit developmental toxicity studies. The integrated TK data obtained across toxicity studies (without the use of additional/satellite animals) provided data critical to understanding differences in response across doses, species, strains, sexes, and life stages. Such data should also be useful in mode of action studies and to improve human risk assessments. Copyright © 2012 Elsevier Inc. All rights reserved.

Hepatocyte membrane injury and bleb formation following low dose comfrey toxicity in rats.

Science.gov (United States)

Yeong, M L; Wakefield, S J; Ford, H C

1993-04-01

Comfrey, a popular herbal remedy, contains hepatotoxic pyrrolizidine alkaloids and has been implicated in recent human toxicity. Although alkaloids from other plant sources have been extensively researched, studies on the hepatotoxic effects of comfrey alkaloids are scant. The effects of high dose comfrey toxicity have been studied and the present investigation was undertaken to identify changes associated with relatively low dose toxicity. Eight young adult rats were dosed weekly for six weeks with 50 mg/kg of comfrey derived alkaloids. The animals were dissected one week after the last dose and the livers examined by light and electron microscopy. Changes at the light microscopic level showed vascular congestion, mild zone 3 necrosis and loss of definition of hepatocyte cellular membranes. Extensive ultrastructural abnormalities were identified in the form of endothelial sloughing and the loss of hepatocyte microvilli. A striking finding was florid bleb formation on the sinusoidal borders of hepatocytes. Many blebs were shed into the space of Disse and extruded to fill, and sometimes occlude, sinusoidal lumina. Platelets were frequently found in areas of bleb formation. There was evidence of late damage in collagenization of Disse's space. Hepatocyte bleb formation is known to occur under a variety of pathological conditions but there is little to no information in the literature on the effects, if any, of bleb formation on fibrogenesis and the microcirculation and its role in the pathogenesis of liver disease. The pyrrolizidine alkaloids of comfrey may serve as an experimental tool to study the process of bleb formation and the intimate relationship between hepatocyte and sinusoidal injury in the liver.

The dose-volume relationship of acute small bowel toxicity from concurrent 5-FU-based chemotherapy and radiation therapy for rectal cancer

International Nuclear Information System (INIS)

Baglan, Kathy L.; Frazier, Robert C.; Yan Di; Huang, Raywin R.; Martinez, Alvaro A.; Robertson, John M.

2002-01-01

Purpose: A direct relationship between the volume of small bowel irradiated and the degree of acute small bowel toxicity experienced during concurrent 5-fluorouracil (5-FU)-based chemoradiotherapy for rectal carcinoma is well recognized but poorly quantified. This study uses three-dimensional treatment-planning tools to more precisely quantify this dose-volume relationship. Methods and Materials: Forty patients receiving concurrent 5-FU-based chemotherapy and pelvic irradiation for rectal carcinoma had treatment-planning CT scans with small bowel contrast. A median isocentric dose of 50.4 Gy was delivered using a posterior-anterior and opposed lateral field arrangement. Bowel exclusion techniques were routinely used, including prone treatment position on a vacuum bag cradle to allow anterior displacement of the abdominal contents and bladder distension. Individual loops of small bowel were contoured on each slice of the planning CT scan, and a small bowel dose-volume histogram was generated for the initial pelvis field receiving 45 Gy. The volume of small bowel receiving each dose between 5 and 40 Gy was recorded at 5-Gy intervals. Results: Ten patients (25%) experienced Common Toxicity Criteria Grade 3+ acute small bowel toxicity. A highly statistically significant association between the development of Grade 3+ acute small bowel toxicity and the volume of small bowel irradiated was found at each dose level. Specific dose-volume threshold levels were found, below which no Grade 3+ toxicity occurred and above which 50-60% of patients developed Grade 3+ toxicity. The volume of small bowel receiving at least 15 Gy (V 15 ) was strongly associated with the degree of toxicity. Univariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicity. Conclusions: A strong dose-volume relationship exists for the development of Grade 3+ acute small bowel toxicity in patients receiving concurrent 5-FU-based chemoradiotherapy

Evaluation of hematologic toxicity of concurrent chemoradiotherapy using protracted infusion of low-dose cisplatin and 5-FU and radiotherapy for malignant tumors in elderly patients

International Nuclear Information System (INIS)

Itoh, Yoshiyuki; Fuwa, Nobukazu; Matsumoto, Akira; Asano, Akiko; Sasaoka, Masahiro; Ii, Noriko; Kimura, Yasuo

1999-01-01

We evaluated the relationship between hematologic toxicity and the daily dose of CDDP or the field size of radiation in 26 patients with malignant tumors aged>70 years who underwent concurrent chemoradiotherapy consisting of infusion of low-dose CDDP and 5-FU and radiotherapy. None of the 26 patients developed Gr4 toxicity. The incidence of Gr3 toxicity was 23.1% (6/26) for leukocytes, 7.7% (2/26) for platelets, and 3.8% (1/26) for hemoglobin, being high for leukocytes. When the patients were classified into those aged 70-74 years (younger group) and those aged>75 years (older group), the incidence of Gr3 leukocyte and platelet toxicity was low in the former but high in the latter. Concerning the relationship between hematologic toxicity and the field size of radiation, the incidence of Gr3 hemoglobin, leukocyte, and platelet toxicity with a radiation field size 2 was 44% (4/9) in the older group but 0% in the younger group. In the older group, the daily CDDP dose tended to be low, and the field size of radiation tended to be small, but the incidence of hematological toxicity was high. In the younger group, the incidence of Gr2 or Gr3 toxicity increased with the daily dose of CDDP and the field size of radiation. (author)

Chronic toxicity of selected polycyclic aromatic hydrocarbons to algae and crustaceans using passive dosing.

Science.gov (United States)

Bragin, Gail E; Parkerton, Thomas F; Redman, Aaron D; Letinksi, Daniel J; Butler, Josh D; Paumen, Miriam Leon; Sutherland, Cary A; Knarr, Tricia M; Comber, Mike; den Haan, Klaas

2016-12-01

Because of the large number of possible aromatic hydrocarbon structures, predictive toxicity models are needed to support substance hazard and risk assessments. Calibration and evaluation of such models requires toxicity data with well-defined exposures. The present study has applied a passive dosing method to generate reliable chronic effects data for 8 polycyclic aromatic hydrocarbons (PAHs) on the green algae Pseudokirchneriella subcapitata and the crustacean Ceriodaphnia dubia. The observed toxicity of these substances on algal growth rate and neonate production were then compared with available literature toxicity data for these species, as well as target lipid model and chemical activity-based model predictions. The use of passive dosing provided well-controlled exposures that yielded more consistent data sets than attained by past literature studies. Results from the present study, which were designed to exclude the complicating influence of ultraviolet light, were found to be well described by both target lipid model and chemical activity effect models. The present study also found that the lack of chronic effects for high molecular weight PAHs was consistent with the limited chemical activity that could be achieved for these compounds in the aqueous test media. Findings from this analysis highlight that variability in past literature toxicity data for PAHs may be complicated by both poorly controlled exposures and photochemical processes that can modulate both exposure and toxicity. Environ Toxicol Chem 2016;35:2948-2957. © 2016 SETAC. © 2016 SETAC.

Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): Predictors for radiation pneumonitis and fibrosis

International Nuclear Information System (INIS)

Kong, F.-M.; Hayman, James A.; Griffith, Kent A.; Kalemkerian, Gregory P.; Arenberg, Douglas; Lyons, Susan; Turrisi, Andrew; Lichter, Allen; Fraass, Benedick; Eisbruch, Avraham; Lawrence, Theodore S.; Haken, Randall K. ten

2006-01-01

Purpose: We aimed to report the final toxicity results on a radiation-dose escalation trial designed to test a hypothesis that very high doses of radiation could be safely administered to patients with non-small-cell lung cancer (NSCLC) by quantifying the dose-volume toxicity relationship of the lung. Methods and Materials: A total of 109 patients with unresectable or medically inoperable NSCLC were enrolled and treated with radiation-dose escalation (on the basis of predicted normal-lung toxicity) either alone or with neoadjuvant chemotherapy by use of 3D conformal techniques. Eighty-four patients (77%) received more than 69 Gy, the trial was stopped after the dose reached 103 Gy. Estimated median follow-up was 110 months. Results: There were 17 (14.6%) Grade 2 to 3 pneumonitis and 15 (13.8%) Grade 2 to 3 fibrosis and no Grade 4 to 5 lung toxicity. Multivariate analyses showed them to be (1) not associated with the dose prescribed to the tumor, and (2) significantly (p < 0.001) associated with lung-dosimetric parameters such as the mean lung dose (MLD), volume of lung that received at least 20 Gy (V20), and the normal-tissue complication probability (NTCP) of the lung. If cutoffs are 30% for V20, 20 Gy for MLD, and 10% for NTCP, these factors have positive predictive values of 50% to 71% and negative predictive value of 85% to 89%. Conclusions: With long-term follow-up for toxicity, we have demonstrated that much higher doses of radiation than are traditionally administered can be safely delivered to a majority of patients with NSCLC. Quantitative lung dose-volume toxicity-based dose escalation can form the basis for individualized high-dose radiation treatment to maximize the therapeutic ratio in these patients

Vaginal Dose Is Associated With Toxicity in Image Guided Tandem Ring or Ovoid-Based Brachytherapy

International Nuclear Information System (INIS)

Susko, Matthew; Craciunescu, Oana; Meltsner, Sheridan; Yang, Yun; Steffey, Beverly; Cai, Jing; Chino, Junzo

2016-01-01

Purpose: To calculate vaginal doses during image guided brachytherapy with volume-based metrics and correlate with long-term vaginal toxicity. Methods and Materials: In this institutional review board–approved study, institutional databases were searched to identify women undergoing computed tomography and/or magnetic resonance–guided brachytherapy at the Duke Cancer Center from 2009 to 2015. All insertions were contoured to include the vagina as a 3-dimensional structure. All contouring was performed on computed tomography or magnetic resonance imaging and used a 0.4-cm fixed brush to outline the applicator and/or packing, expanded to include any grossly visible vagina. The surface of the cervix was specifically excluded from the contour. High-dose-rate (HDR) and low-dose-rate (LDR) doses were converted to the equivalent dose in 2-Gy fractions using an α/β of 3 for late effects. The parameters D0.1cc, D1cc, and D2cc were calculated for all insertions and summed with prior external beam therapy. Late and subacute toxicity to the vagina were determined by the Common Terminology Criteria for Adverse Events version 4.0 and compared by the median and 4th quartile doses, via the log-rank test. Univariate and multivariate hazard ratios were calculated via Cox regression. Results: A total of 258 insertions in 62 women who underwent definitive radiation therapy including brachytherapy for cervical (n=48) and uterine cancer (n=14) were identified. Twenty HDR tandem and ovoid, 32 HDR tandem and ring, and 10 LDR tandem and ovoid insertions were contoured. The median values (interquartile ranges) for vaginal D0.1cc, D1cc, and D2cc were 157.9 (134.4-196.53) Gy, 112.6 (96.7-124.6) Gy, and 100.5 (86.8-108.4) Gy, respectively. At the 4th quartile cutoff of 108 Gy for D2cc, the rate of late grade 1 toxicity at 2 years was 61.2% (95% confidence interval [CI] 43.0%-79.4%) below 108 Gy and 83.9% (63.9%-100%) above (P=.018); grade 2 or greater toxicity was 36.2% (95% CI 15

Vaginal Dose Is Associated With Toxicity in Image Guided Tandem Ring or Ovoid-Based Brachytherapy

Energy Technology Data Exchange (ETDEWEB)

Susko, Matthew; Craciunescu, Oana; Meltsner, Sheridan; Yang, Yun; Steffey, Beverly; Cai, Jing; Chino, Junzo, E-mail: junzo.chino@duke.edu

2016-04-01

Purpose: To calculate vaginal doses during image guided brachytherapy with volume-based metrics and correlate with long-term vaginal toxicity. Methods and Materials: In this institutional review board–approved study, institutional databases were searched to identify women undergoing computed tomography and/or magnetic resonance–guided brachytherapy at the Duke Cancer Center from 2009 to 2015. All insertions were contoured to include the vagina as a 3-dimensional structure. All contouring was performed on computed tomography or magnetic resonance imaging and used a 0.4-cm fixed brush to outline the applicator and/or packing, expanded to include any grossly visible vagina. The surface of the cervix was specifically excluded from the contour. High-dose-rate (HDR) and low-dose-rate (LDR) doses were converted to the equivalent dose in 2-Gy fractions using an α/β of 3 for late effects. The parameters D0.1cc, D1cc, and D2cc were calculated for all insertions and summed with prior external beam therapy. Late and subacute toxicity to the vagina were determined by the Common Terminology Criteria for Adverse Events version 4.0 and compared by the median and 4th quartile doses, via the log-rank test. Univariate and multivariate hazard ratios were calculated via Cox regression. Results: A total of 258 insertions in 62 women who underwent definitive radiation therapy including brachytherapy for cervical (n=48) and uterine cancer (n=14) were identified. Twenty HDR tandem and ovoid, 32 HDR tandem and ring, and 10 LDR tandem and ovoid insertions were contoured. The median values (interquartile ranges) for vaginal D0.1cc, D1cc, and D2cc were 157.9 (134.4-196.53) Gy, 112.6 (96.7-124.6) Gy, and 100.5 (86.8-108.4) Gy, respectively. At the 4th quartile cutoff of 108 Gy for D2cc, the rate of late grade 1 toxicity at 2 years was 61.2% (95% confidence interval [CI] 43.0%-79.4%) below 108 Gy and 83.9% (63.9%-100%) above (P=.018); grade 2 or greater toxicity was 36.2% (95% CI 15

Vaginal Dose Is Associated With Toxicity in Image Guided Tandem Ring or Ovoid-Based Brachytherapy.

Science.gov (United States)

Susko, Matthew; Craciunescu, Oana; Meltsner, Sheridan; Yang, Yun; Steffey, Beverly; Cai, Jing; Chino, Junzo

2016-04-01

To calculate vaginal doses during image guided brachytherapy with volume-based metrics and correlate with long-term vaginal toxicity. In this institutional review board-approved study, institutional databases were searched to identify women undergoing computed tomography and/or magnetic resonance-guided brachytherapy at the Duke Cancer Center from 2009 to 2015. All insertions were contoured to include the vagina as a 3-dimensional structure. All contouring was performed on computed tomography or magnetic resonance imaging and used a 0.4-cm fixed brush to outline the applicator and/or packing, expanded to include any grossly visible vagina. The surface of the cervix was specifically excluded from the contour. High-dose-rate (HDR) and low-dose-rate (LDR) doses were converted to the equivalent dose in 2-Gy fractions using an α/β of 3 for late effects. The parameters D0.1cc, D1cc, and D2cc were calculated for all insertions and summed with prior external beam therapy. Late and subacute toxicity to the vagina were determined by the Common Terminology Criteria for Adverse Events version 4.0 and compared by the median and 4th quartile doses, via the log-rank test. Univariate and multivariate hazard ratios were calculated via Cox regression. A total of 258 insertions in 62 women who underwent definitive radiation therapy including brachytherapy for cervical (n=48) and uterine cancer (n=14) were identified. Twenty HDR tandem and ovoid, 32 HDR tandem and ring, and 10 LDR tandem and ovoid insertions were contoured. The median values (interquartile ranges) for vaginal D0.1cc, D1cc, and D2cc were 157.9 (134.4-196.53) Gy, 112.6 (96.7-124.6) Gy, and 100.5 (86.8-108.4) Gy, respectively. At the 4th quartile cutoff of 108 Gy for D2cc, the rate of late grade 1 toxicity at 2 years was 61.2% (95% confidence interval [CI] 43.0%-79.4%) below 108 Gy and 83.9% (63.9%-100%) above (P=.018); grade 2 or greater toxicity was 36.2% (95% CI 15.8%-56.6%) below 108 Gy and 70.7% (95% CI 45

Finding dose-volume constraints to reduce late rectal toxicity following 3D-conformal radiotherapy (3D-CRT) of prostate cancer

International Nuclear Information System (INIS)

Greco, Carlo; Mazzetta, Chiara; Cattani, Federica; Tosi, Giampiero; Castiglioni, Simona; Fodor, Andrei; Orecchia, Roberto

2003-01-01

Background and purpose: The rectum is known to display a dose-volume effect following high-dose 3D-conformal radiotherapy (3D-CRT). The aim of the study is to search for significant dose-volume combinations with the specific treatment technique and patient set-up currently used in our institution. Patients and methods: We retrospectively analyzed the dose-volume histograms (DVH) of 135 patients with stage T1b-T3b prostate cancer treated consecutively with 3D-CRT between 1996 and 2000 to a total dose of 76 Gy. The median follow-up was 28 months (range 12-62). All late rectal complications were scored using RTOG criteria. Time to late toxicity was assessed using the Kaplan-Meyer method. The association between variables at baseline and ≥2 rectal toxicity was tested using χ 2 test or Fisher's exact test. A multivariate analysis using logistic regression was performed. Results: Late rectal toxicity grade ≥2 was observed in 24 of the 135 patients (17.8%). A 'grey area' of increased risk has been identified. Average DVHs of the bleeding and non-bleeding patients were generated. The area under the percent volume DVH for the rectum of the bleeding patients was significantly higher than that of patients without late rectal toxicity. On multivariate analysis the correlation between the high risk DVHs and late rectal bleeding was confirmed. Conclusions: The present analysis confirms the role of the rectal DVH as a tool to discriminate patients undergoing high-dose 3D-CRT into a low and a high risk of developing late rectal bleeding. Based on our own results and taking into account the data published in the literature, we have been able to establish new dose-volume constraints for treatment planning: if possible, the percentage of rectal volume exposed to 40, 50, 60, 72 and 76 Gy should be limited to 60, 50, 25, 15 and 5%, respectively

Association between SLC19A1 gene polymorphism and high dose methotrexate toxicity in childhood acute lymphoblastic leukaemia and non Hodgkin malignant lymphoma: introducing a haplotype based approach

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Kotnik Barbara Faganel

2017-09-01

Full Text Available We investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL and non Hodgkin malignant lymphoma (NHML.

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method

International Nuclear Information System (INIS)

Takahashi, Hiro; Kaniwa, Nahoko; Saito, Yoshiro; Sai, Kimie; Hamaguchi, Tetsuya; Shirao, Kuniaki; Shimada, Yasuhiro; Matsumura, Yasuhiro; Ohtsu, Atsushi; Yoshino, Takayuki; Doi, Toshihiko; Takahashi, Anna; Odaka, Yoko; Okuyama, Misuzu; Sawada, Jun-ichi; Sakamoto, Hiromi; Yoshida, Teruhiko

2015-01-01

Variability in drug response between individual patients is a serious concern in medicine. To identify single-nucleotide polymorphisms (SNPs) related to drug response variability, many genome-wide association studies have been conducted. We previously applied a knowledge-based bioinformatic approach to a pharmacogenomics study in which 119 fluoropyrimidine-treated gastric cancer patients were genotyped at 109,365 SNPs using the Illumina Human-1 BeadChip. We identified the SNP rs2293347 in the human epidermal growth factor receptor (EGFR) gene as a novel genetic factor related to chemotherapeutic response. In the present study, we reanalyzed these hypothesis-free genomic data using extended knowledge. We identified rs2867461 in annexin A3 (ANXA3) gene as another candidate. Using logistic regression, we confirmed that the performance of the rs2867461 + rs2293347 model was superior to those of the single factor models. Furthermore, we propose a novel integrated predictive index (iEA) based on these two polymorphisms in EGFR and ANXA3. The p value for iEA was 1.47 × 10 −8 by Fisher’s exact test. Recent studies showed that the mutations in EGFR is associated with high expression of dihydropyrimidine dehydrogenase, which is an inactivating and rate-limiting enzyme for fluoropyrimidine, and suggested that the combination of chemotherapy with fluoropyrimidine and EGFR-targeting agents is effective against EGFR-overexpressing gastric tumors, while ANXA3 overexpression confers resistance to tyrosine kinase inhibitors targeting the EGFR pathway. These results suggest that the iEA index or a combination of polymorphisms in EGFR and ANXA3 may serve as predictive factors of drug response, and therefore could be useful for optimal selection of chemotherapy regimens. The online version of this article (doi:10.1186/s12885-015-1721-z) contains supplementary material, which is available to authorized users

Acute toxicity and the 28-day repeated dose study of a Siddha medicine Nuna Kadugu in rats

Directory of Open Access Journals (Sweden)

Ramaswamy Ramaswamy

2012-10-01

Full Text Available Abstract Background Nuna Kadugu (NK, a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats. Methods Acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed. Results In acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment. Conclusion Acute study reveals that the LD50 of NK is greater than 2000mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats

Critical dose and toxicity index of organs at risk in radiotherapy: Analyzing the calculated effects of modified dose fractionation in non–small cell lung cancer

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Pedicini, Piernicola, E-mail: ppiern@libero.it [Service of Medical Physics, I.R.C.C.S. Regional Cancer Hospital C.R.O.B, Rionero in Vulture (Italy); Strigari, Lidia [Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome (Italy); Benassi, Marcello [Service of Medical Physics, Scientific Institute of Tumours of Romagna I.R.S.T., Meldola (Italy); Caivano, Rocchina [Service of Medical Physics, I.R.C.C.S. Regional Cancer Hospital C.R.O.B, Rionero in Vulture (Italy); Fiorentino, Alba [U.O. of Radiotherapy, I.R.C.C.S. Regional Cancer Hospital C.R.O.B., Rionero in Vulture (Italy); Nappi, Antonio [U.O. of Nuclear Medicine, I.R.C.C.S. Regional Cancer Hospital C.R.O.B., Rionero in Vulture (Italy); Salvatore, Marco [U.O. of Nuclear Medicine, I.R.C.C.S. SDN Foundation, Naples (Italy); Storto, Giovanni [U.O. of Nuclear Medicine, I.R.C.C.S. Regional Cancer Hospital C.R.O.B., Rionero in Vulture (Italy)

2014-04-01

To increase the efficacy of radiotherapy for non–small cell lung cancer (NSCLC), many schemes of dose fractionation were assessed by a new “toxicity index” (I), which allows one to choose the fractionation schedules that produce less toxic treatments. Thirty-two patients affected by non resectable NSCLC were treated by standard 3-dimensional conformal radiotherapy (3DCRT) with a strategy of limited treated volume. Computed tomography datasets were employed to re plan by simultaneous integrated boost intensity-modulated radiotherapy (IMRT). The dose distributions from plans were used to test various schemes of dose fractionation, in 3DCRT as well as in IMRT, by transforming the dose-volume histogram (DVH) into a biological equivalent DVH (BDVH) and by varying the overall treatment time. The BDVHs were obtained through the toxicity index, which was defined for each of the organs at risk (OAR) by a linear quadratic model keeping an equivalent radiobiological effect on the target volume. The less toxic fractionation consisted in a severe/moderate hyper fractionation for the volume including the primary tumor and lymph nodes, followed by a hypofractionation for the reduced volume of the primary tumor. The 3DCRT and IMRT resulted, respectively, in 4.7% and 4.3% of dose sparing for the spinal cord, without significant changes for the combined-lungs toxicity (p < 0.001). Schedules with reduced overall treatment time (accelerated fractionations) led to a 12.5% dose sparing for the spinal cord (7.5% in IMRT), 8.3% dose sparing for V{sub 20} in the combined lungs (5.5% in IMRT), and also significant dose sparing for all the other OARs (p < 0.001). The toxicity index allows to choose fractionation schedules with reduced toxicity for all the OARs and equivalent radiobiological effect for the tumor in 3DCRT, as well as in IMRT, treatments of NSCLC.

Anti-Aging Activity and Non-Toxic Dose of Phytooxyresveratrol from ...

African Journals Online (AJOL)

Erah

, 4Division of Medical Molecular. Biology, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University,. Bangkok 10700, Thailand. Abstract. Purpose: To determine the anti-aging activity and toxicity doses ...

Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial

DEFF Research Database (Denmark)

Møller, Søren; Munck Af Rosenschöld, Per; Costa, Junia

2017-01-01

.1-3.5) and the median overall survival was 7.0 months (95%CI: 3.5-10.5). Early side effects were mild and included headache and fatigue. Seven patients were progression-free beyond 10 weeks and were evaluable for late toxicity. Among these patients, three (43%) suffered late adverse events which included radionecrosis......INTRODUCTION: The purpose of this study was to evaluate the safety and efficacy of PET and MRI guided re-irradiation of recurrent high-grade glioma (HGG) and to assess the impact of radiotherapy dose, fractionation and irradiated volume. MATERIAL AND METHODS: Patients with localized, recurrent HGG...... (grades III-IV) and no other treatment options were eligible for a prospective phase I trial. Gross tumor volumes for radiotherapy were defined using T1-contrast enhanced MRI and (18)F-fluoro-ethyl tyrosine PET. Radiotherapy was delivered using volumetric modulated arc therapy with a 2-mm margin. The dose...

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer.

Science.gov (United States)

Uwagawa, Tadashi; Sakamoto, Taro; Abe, Kyohei; Okui, Norimitsu; Hata, Daigo; Shiba, Hiroaki; Futagawa, Yasuro; Aiba, Keisuke; Yanaga, Katsuhiko

2015-01-01

To date, gemcitabine-based or fluoropyrimidine-based regimens are recommended for unresectable advanced biliary tract cancer. Then, we conducted a phase I study of gemcitabine/cisplatin and S-1 that is an oral fluoropyrimidine. The aim of this study was to determine the dose-limiting toxicity (DLT), maximum-tolerated dose, and a recommended phase II dose of S-1. Response was assessed as a secondary endpoint. Patients who have been diagnosed with unresectable or postoperative recurrent biliary tract cancer received cisplatin (25 mg/m² i.v. for 120 min) followed by gemcitabine (1,000 mg/m² i.v. for 30 min) on days 1 and 8, and oral S-1 on alternate days; this regimen was repeated at 21-day intervals. A standard '3 + 3' phase I dose-escalation design was adopted. This study was registered with University hospital Medical Information Network (UMIN) Center in Japan, number UMIN000008415. Twelve patients were evaluable in this study. No patients developed DLTs. Recommended dose of S-1 was 80 (day. One patient could achieve conversion to curative surgery. This phase I study was performed safely and demonstrated encouraging response.

Dose and batch-dependent hepatobiliary toxicity of 10 nm silver nanoparticles

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Marcella De Maglie

2015-07-01

Full Text Available Silver nanoparticles (AgNPs are widely used because of their antimicrobial properties in medical devices and in a variety of consumer products. The extensive use of AgNPs raises concerns about their potential toxicity, although it is still difficult to draw definite conclusions about their toxicity based on published data. Our preliminary studies performed to compare the effect of the AgNPs size (10-40-100 nm on toxicity, demonstrated that the smallest AgNPs determine the most severe toxicological effects. In order to best investigate the impact of physicochemical characteristics of 10 nm AgNPs on toxicity, we compare three different batches of 10 nm AgNPs slightly different in size distribution (Batch A: 8.8±1.7 nm; Batch B: 9.4±1.7 nm; Batch C: 10.0±1.8 nm. Mice were intravenously treated with two doses (5 and 10 mg/kg of the 3 AgNPs. 24 hours after the treatment, mice were euthanized and underwent complete necropsy. Tissues were collected for histopathological examination and total silver content was determined in tissues by inductively coupled plasma mass spectrometry (ICP-MS. All batches induced severe hepatobiliary lesions, i.e. marked hepatocellular necrosis and massive hemorrhage of the gall bladder. The toxicity was dose-dependent and interestingly, the toxic effects were more severe in mice treated with batches A and B that contained smaller AgNPs. Since the total silver mass concentration was similar, the observed batch-dependent toxicity suggest that even subtle differences in size may contribute to relevant changes in the toxicological outcomes, confirming the fundamental involvement of physicochemical features with respect to toxicity.

Consolidating duodenal and small bowel toxicity data via isoeffective dose calculations based on compiled clinical data.

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Prior, Phillip; Tai, An; Erickson, Beth; Li, X Allen

2014-01-01

To consolidate duodenum and small bowel toxicity data from clinical studies with different dose fractionation schedules using the modified linear quadratic (MLQ) model. A methodology of adjusting the dose-volume (D,v) parameters to different levels of normal tissue complication probability (NTCP) was presented. A set of NTCP model parameters for duodenum toxicity were estimated by the χ(2) fitting method using literature-based tolerance dose and generalized equivalent uniform dose (gEUD) data. These model parameters were then used to convert (D,v) data into the isoeffective dose in 2 Gy per fraction, (D(MLQED2),v) and convert these parameters to an isoeffective dose at another NTCP (D(MLQED2'),v). The literature search yielded 5 reports useful in making estimates of duodenum and small bowel toxicity. The NTCP model parameters were found to be TD50(1)(model) = 60.9 ± 7.9 Gy, m = 0.21 ± 0.05, and δ = 0.09 ± 0.03 Gy(-1). Isoeffective dose calculations and toxicity rates associated with hypofractionated radiation therapy reports were found to be consistent with clinical data having different fractionation schedules. Values of (D(MLQED2'),v) between different NTCP levels remain consistent over a range of 5%-20%. MLQ-based isoeffective calculations of dose-response data corresponding to grade ≥2 duodenum toxicity were found to be consistent with one another within the calculation uncertainty. The (D(MLQED2),v) data could be used to determine duodenum and small bowel dose-volume constraints for new dose escalation strategies. Copyright © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Brachytherapy Partial Breast Irradiation: Analyzing Effect of Source Configurations on Dose Metrics Relevant to Toxicity

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Cormack, Robert A.; Devlin, Phillip M.

2008-01-01

Purpose: Recently, the use of partial breast irradiation (PBI) for patients with early-stage breast cancer with low-risk factors has increased. The volume of the high-dose regions has been correlated with toxicity in interstitial treatment. Although no such associations have been made in applicator-based experience, new applicators are being developed that use complex noncentered source configurations. This work studied the effect of noncentered source placements on the volume of the high-dose regions around a spherical applicator. Methods and Materials: Many applicator configurations were numerically simulated for a range of inflation radii. For each configuration, a dose homogeneity index was used as a dose metric to measure the volume of the high-dose region. Results: All multisource configurations examined resulted in an increase of the high-dose region compared with a single-center source. The resulting decrease in the prescription dose homogeneity index was more pronounced for sources further from the center of the applicator, and the effect was reduced as the number of dwell locations was increased. Conclusion: The geometries of particular applicators were not considered to achieve a more general result. On the basis of the calculations of this work, it would appear that treatment using noncentered dwell locations will lead to an increase in the volume of the high-dose regions

Oral repeated-dose systemic and reproductive toxicity of 6:2 fluorotelomer alcohol in mice

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Pushkor Mukerji

2015-01-01

Full Text Available 6:2 fluorotelomer alcohol (6:2 FTOH was evaluated for potential systemic repeated-dose and reproductive toxicity in mice. 6:2 FTOH was administered by oral gavage to CD-1 mice as a suspension in 0.5% aqueous methylcellulose with 0.1% Tween-80 at dosages of 1, 5, 25, or 100 mg/kg/day. The no-observed-adverse-effect level (NOAEL for systemic toxicity was 25 mg/kg/day (males and 5 mg/kg/day (females, based on effects at higher doses on mortality, clinical observations, body weight, nutritional parameters, hematology (red and white blood cell, clinical chemistry (liver-related, liver weights, and histopathology (liver, teeth, reproductive tract, and mammary gland. However, 6:2 FTOH was not a selective reproductive toxicant. The NOAEL for reproductive toxicity was >100 mg/kg/day; no effects on reproductive outcome were observed at any dosage. The NOAEL for viability and growth of the offspring was 25 mg/kg/day, based on clinical signs of delayed maturation in pups, and reductions in pup survival and pup body weight during lactation at 100 mg/kg/day. While the severity of the effects was generally greater in mice than previously reported in CD rats, the overall NOAELs were identical in both species, 5 mg/kg/day for systemic toxicity and 25 mg/kg/day for offspring viability/growth. 6:2 FTOH was not a selective reproductive toxicant in either species; no effects on reproductive outcome occurred at any dose level, and any effects observed in offspring occurred at dose levels that induced mortality and severe toxicity in maternal animals.

BAYESIAN DATA AUGMENTATION DOSE FINDING WITH CONTINUAL REASSESSMENT METHOD AND DELAYED TOXICITY

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Liu, Suyu; Yin, Guosheng; Yuan, Ying

2014-01-01

A major practical impediment when implementing adaptive dose-finding designs is that the toxicity outcome used by the decision rules may not be observed shortly after the initiation of the treatment. To address this issue, we propose the data augmentation continual re-assessment method (DA-CRM) for dose finding. By naturally treating the unobserved toxicities as missing data, we show that such missing data are nonignorable in the sense that the missingness depends on the unobserved outcomes. The Bayesian data augmentation approach is used to sample both the missing data and model parameters from their posterior full conditional distributions. We evaluate the performance of the DA-CRM through extensive simulation studies, and also compare it with other existing methods. The results show that the proposed design satisfactorily resolves the issues related to late-onset toxicities and possesses desirable operating characteristics: treating patients more safely, and also selecting the maximum tolerated dose with a higher probability. The new DA-CRM is illustrated with two phase I cancer clinical trials. PMID:24707327

Study of single dose toxic test of Sweet Bee Venom in Beagle Dogs

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Hye-Chul, Yoon

2010-12-01

Full Text Available Objectives : This study was performed to analyse single dose toxicity of Sweet Bee Venom(Sweet BV extracted from the bee venom in Beagle dogs. Methods : All experiments were conducted under the regulations of Good Laboratory Practice (GLP at Biotoxtech Company, a non-clinical study authorized institution. Male and female Beagle dogs of 5-6 months old were chosen for the pilot study of single dose toxicity of Sweet BV which was administered at the level of 9.0 ㎎/㎏ body weight which is 1300 times higher than the clinical application dosage as the high dosage, followed by 3.0 and 1.0 ㎎/㎏ as midium and low dosage, respectively. Equal amount of excipient(normal saline to the Sweet BV experiment groups was administered as the control group. Results : 1. No mortality was witnessed in all of the experiment groups. 2. Hyperemia and movement disorder were observed around the area of administration in all the experiment groups, and higher occurrence in the higher dosage treatment. 3. For weight measurement, Neither male nor female groups showed significant changes. 4. To verify abnormalities of organs and tissues, thigh muscle which treated with Sweet BV, brain, liver, lung, kidney, and spinal cords were removed and histologocal observation using H-E staining was conducted. In the histologocal observation of thigh muscle, cell infiltration, inflammation, degeneration, necrosis of muscle fiber, and fibrosis were found in both thigh tissue. And the changes depend on the dose of Sweet BV. But the other organs did not showed in any abnormality. 5. The maximum dose of Sweet BV in Beagle dogs were over 9 ㎎/㎏ in this study. Conclusions : The above findings of this study suggest that Sweet BV is a relatively safe treatment medium. Further studies on the toxicity of Sweet BV should be conducted to yield more concrete evidences.

Determination of Prognostic Factors for Vaginal Mucosal Toxicity Associated With Intravaginal High-Dose Rate Brachytherapy in Patients With Endometrial Cancer

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Bahng, Agnes Y.; Dagan, Avner; Bruner, Deborah W.; Lin, Lilie L.

2012-01-01

Purpose: The objective of this study was to determine the patient- and treatment-related prognostic factors associated with vaginal toxicity in patients who received intravaginal high dose rate (HDR) brachytherapy alone as adjuvant treatment for endometrial cancer. Secondary goals of this study included a quantitative assessment of optimal dilator use frequency and a crude assessment of clinical predictors for compliant dilator use. Methods and Materials: We retrospectively reviewed the charts of 100 patients with histologically confirmed endometrial cancer who underwent total hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection and adjuvant intravaginal brachytherapy between 1995 and 2009 at the Hospital of University of Pennsylvania. The most common treatment regimen used was 21 Gy in three fractions (71 patients). Symptoms of vaginal mucosal toxicity were taken from the history and physical exams noted in the patients’ charts and were graded according to the Common Toxicity Criteria for Adverse Events v. 4.02. Results: The incidence of Grade 1 or asymptomatic vaginal toxicity was 33% and Grade 2–3 or symptomatic vaginal toxicity was 14%. Multivariate analysis of age, active length, and dilator use two to three times a week revealed odds ratios of 0.93 (p = 0.013), 3.96 (p = 0.008), and 0.17 (p = 0.032) respectively. Conclusion: Increasing age, vaginal dilator use of at least two to three times a week, and shorter active length were found to be significantly associated with a decreased risk of vaginal stenosis. Future prospective studies are necessary to validate our findings.

Determination of Prognostic Factors for Vaginal Mucosal Toxicity Associated With Intravaginal High-Dose Rate Brachytherapy in Patients With Endometrial Cancer

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Bahng, Agnes Y.; Dagan, Avner [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Bruner, Deborah W. [University of Pennsylvania School of Nursing, Philadelphia, PA (United States); Lin, Lilie L., E-mail: lin@xrt.upenn.edu [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States)

2012-02-01

Purpose: The objective of this study was to determine the patient- and treatment-related prognostic factors associated with vaginal toxicity in patients who received intravaginal high dose rate (HDR) brachytherapy alone as adjuvant treatment for endometrial cancer. Secondary goals of this study included a quantitative assessment of optimal dilator use frequency and a crude assessment of clinical predictors for compliant dilator use. Methods and Materials: We retrospectively reviewed the charts of 100 patients with histologically confirmed endometrial cancer who underwent total hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection and adjuvant intravaginal brachytherapy between 1995 and 2009 at the Hospital of University of Pennsylvania. The most common treatment regimen used was 21 Gy in three fractions (71 patients). Symptoms of vaginal mucosal toxicity were taken from the history and physical exams noted in the patients' charts and were graded according to the Common Toxicity Criteria for Adverse Events v. 4.02. Results: The incidence of Grade 1 or asymptomatic vaginal toxicity was 33% and Grade 2-3 or symptomatic vaginal toxicity was 14%. Multivariate analysis of age, active length, and dilator use two to three times a week revealed odds ratios of 0.93 (p = 0.013), 3.96 (p = 0.008), and 0.17 (p = 0.032) respectively. Conclusion: Increasing age, vaginal dilator use of at least two to three times a week, and shorter active length were found to be significantly associated with a decreased risk of vaginal stenosis. Future prospective studies are necessary to validate our findings.

Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery

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Moussazadeh, Nelson; Lis, Eric; Katsoulakis, Evangelia; Kahn, Sweena; Svoboda, Marek; DiStefano, Natalie M.; McLaughlin, Lily; Bilsky, Mark H.; Yamada, Yoshiya; Laufer, Ilya

2015-01-01

Purpose: To characterize local tumor control and toxicity risk in very long-term survivors (>5 years) after high-dose spinal image guided, intensity modulated radiation therapy delivered as single-dose stereotactic radiosurgery (SRS). Previously published spinal SRS outcome analyses have included a heterogeneous population of cancer patients, mostly with short survival. This is the first study reporting the long-term tumor control and toxicity profiles after high-dose single-fraction spinal SRS. Methods and Materials: The study population included all patients treated from June 2004 to July 2009 with single-fraction spinal SRS (dose 24 Gy) who had survived at least 5 years after treatment. The endpoints examined included disease progression, surgical or radiation retreatment, in-field fracture development, and radiation-associated toxicity, scored using the Radiation Therapy Oncology Group radiation morbidity scoring criteria and the Common Terminology Criteria for Adverse Events, version 4.0. Local control and fracture development were assessed using Kaplan-Meier analysis. Results: Of 278 patients, 31 (11.1%), with 36 segments treated for spinal tumors, survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 6.1 years (maximum 102 months). The histopathologic findings for the 5-year survivors included radiation-resistant metastases in 58%, radiation-sensitive metastases in 22%, and primary bone tumors in 19%. In this selected cohort, 3 treatment failures occurred at a median of 48.6 months, including 2 recurrences in the radiation field and 1 patient with demonstrated progression at the treatment margins. Ten lesions (27.8%) were associated with acute grade 1 cutaneous or gastrointestinal toxicity. Delayed toxicity ≥3 months after treatment included 8 cases (22.2%) of mild neuropathy, 2 (5.6%) of gastrointestinal discomfort, 8 (22.2%) of dermatitides, and 3 (8.3%) of myalgias/myositis. Thirteen

Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery

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Moussazadeh, Nelson [Division of Neurological Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York (United States); Lis, Eric [Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Katsoulakis, Evangelia [Department of Radiation Oncology, New York Methodist Hospital, Brooklyn, New York (United States); Kahn, Sweena; Svoboda, Marek; DiStefano, Natalie M.; McLaughlin, Lily [Division of Neurological Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Bilsky, Mark H. [Division of Neurological Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York (United States); Yamada, Yoshiya [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Laufer, Ilya, E-mail: lauferi@mskcc.org [Division of Neurological Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York (United States)

2015-10-01

Purpose: To characterize local tumor control and toxicity risk in very long-term survivors (>5 years) after high-dose spinal image guided, intensity modulated radiation therapy delivered as single-dose stereotactic radiosurgery (SRS). Previously published spinal SRS outcome analyses have included a heterogeneous population of cancer patients, mostly with short survival. This is the first study reporting the long-term tumor control and toxicity profiles after high-dose single-fraction spinal SRS. Methods and Materials: The study population included all patients treated from June 2004 to July 2009 with single-fraction spinal SRS (dose 24 Gy) who had survived at least 5 years after treatment. The endpoints examined included disease progression, surgical or radiation retreatment, in-field fracture development, and radiation-associated toxicity, scored using the Radiation Therapy Oncology Group radiation morbidity scoring criteria and the Common Terminology Criteria for Adverse Events, version 4.0. Local control and fracture development were assessed using Kaplan-Meier analysis. Results: Of 278 patients, 31 (11.1%), with 36 segments treated for spinal tumors, survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 6.1 years (maximum 102 months). The histopathologic findings for the 5-year survivors included radiation-resistant metastases in 58%, radiation-sensitive metastases in 22%, and primary bone tumors in 19%. In this selected cohort, 3 treatment failures occurred at a median of 48.6 months, including 2 recurrences in the radiation field and 1 patient with demonstrated progression at the treatment margins. Ten lesions (27.8%) were associated with acute grade 1 cutaneous or gastrointestinal toxicity. Delayed toxicity ≥3 months after treatment included 8 cases (22.2%) of mild neuropathy, 2 (5.6%) of gastrointestinal discomfort, 8 (22.2%) of dermatitides, and 3 (8.3%) of myalgias/myositis. Thirteen

Plumbagin Nanoparticles Induce Dose and pH Dependent Toxicity on Prostate Cancer Cells.

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Nair, Harikrishnan A; Snima, K S; Kamath, Ravindranath C; Nair, Shantikumar V; Lakshmanan, Vinoth-Kumar

2015-01-01

Stable nano-formulation of Plumbagin nanoparticles from Plumbago zeylanica root extract was explored as a potential natural drug against prostate cancer. Size and morphology analysis by DLS, SEM and AFM revealed the average size of nanoparticles prepared was 100±50nm. In vitro cytotoxicity showed concentration and time dependent toxicity on prostate cancer cells. However, plumbagin crude extract found to be highly toxic to normal cells when compared to plumbagin nanoformulation, thus confirming nano plumbagin cytocompatibility with normal cells and dose dependent toxicity to prostate cells. In vitro hemolysis assay confirmed the blood biocompatibility of the plumbagin nanoparticles. In wound healing assay, plumbagin nanoparticles provided clues that it might play an important role in the anti-migration of prostate cancer cells. DNA fragmentation revealed that partial apoptosis induction by plumbagin nanoparticles could be expected as a potent anti-cancer effect towards prostate cancer.

Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis.

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Srivastava, Shashikant; Magombedze, Gesham; Koeuth, Thearith; Sherman, Carleton; Pasipanodya, Jotam G; Raj, Prithvi; Wakeland, Edward; Deshpande, Devyani; Gumbo, Tawanda

2017-08-01

Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC 0-24 ) to MIC. Optimal microbial kill was achieved at an AUC 0-24 /MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87% and >99% of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300-mg/day dose did not achieve AUC 0-24 s associated with linezolid toxicity, while 600 mg/day achieved those AUC 0-24 s in linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials. Copyright © 2017 Srivastava et al.

A dose-escalation trial with the adaptive radiotherapy process as a delivery system in localized prostate cancer: Analysis of chronic toxicity

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Brabbins, Donald; Martinez, Alvaro; Yan Di; Lockman, David; Wallace, Michell; Gustafson, Gary; Chen, Peter; Vicini, Frank; Wong, John

2005-01-01

prostate and seminal vesicles. Chronic genitourinary and/or gastrointestinal categories were incontinence, persistent urinary retention, increased urinary frequency/urgency, urethral stricture, hematuria, diarrhea, rectal pain, bleeding, ulcer, fistula, incontinence, and proctitis. Toxicity at the high dose level was not different from toxicity at the intermediate or lower dose levels. No significant difference was observed in any of the individual toxicity categories. Conclusions: By applying the ART process-namely, developing a patient-specific PTV-to prostate cancer patients, significant dose escalation can be achieved without increases in genitourinary or gastrointestinal toxicity. Our data validate the rectal and bladder dose-volume constraints chosen for our three-dimensional conformal and IMRT prostrate radiotherapy planning

Dose-Escalated Stereotactic Body Radiation Therapy for Patients With Intermediate- and High-Risk Prostate Cancer: Initial Dosimetry Analysis and Patient Outcomes

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Kotecha, Rupesh; Djemil, Toufik; Tendulkar, Rahul D.; Reddy, Chandana A.; Thousand, Richard A.; Vassil, Andrew; Stovsky, Mark; Berglund, Ryan K.; Klein, Eric A.; Stephans, Kevin L.

2016-01-01

Purpose: To report the short-term clinical outcomes and acute and late treatment-related genitourinary (GU) and gastrointestinal (GI) toxicities in patients with intermediate- and high-risk prostate cancer treated with dose-escalated stereotactic body radiation therapy (SBRT). Methods and Materials: Between 2011 and 2014, 24 patients with prostate cancer were treated with SBRT to the prostate gland and proximal seminal vesicles. A high-dose avoidance zone (HDAZ) was created by a 3-mm expansion around the rectum, urethra, and bladder. Patients were treated to a minimum dose of 36.25 Gy in 5 fractions, with a simultaneous dose escalation to a dose of 50 Gy to the target volume away from the HDAZ. Acute and late GU and GI toxicity outcomes were measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 4. Results: The median follow-up was 25 months (range, 18-45 months). Nine patients (38%) experienced an acute grade 2 GU toxicity, which was medically managed, and no patients experienced an acute grade 2 GI toxicity. Two patients (8%) experienced late grade 2 GU toxicity, and 2 patients (8%) experienced late grade 2 GI toxicity. No acute or late grade ≥3 GU or GI toxicities were observed. The 24-month prostate-specific antigen relapse-free survival outcome for all patients was 95.8% (95% confidence interval 75.6%-99.4%), and both biochemical failures occurred in patients with high-risk disease. All patients are currently alive at the time of this analysis and continue to be followed. Conclusions: A heterogeneous prostate SBRT planning technique with differential treatment volumes (low dose: 36.25 Gy; and high dose: 50 Gy) with an HDAZ provides a safe method of dose escalation. Favorable rates of biochemical control and acceptably low rates of acute and long-term GU and GI toxicity can be achieved in patients with intermediate- and high-risk prostate cancer treated with SBRT.

Dose-Escalated Stereotactic Body Radiation Therapy for Patients With Intermediate- and High-Risk Prostate Cancer: Initial Dosimetry Analysis and Patient Outcomes

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Kotecha, Rupesh; Djemil, Toufik; Tendulkar, Rahul D.; Reddy, Chandana A.; Thousand, Richard A.; Vassil, Andrew [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Stovsky, Mark; Berglund, Ryan K.; Klein, Eric A. [Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio (United States); Stephans, Kevin L., E-mail: stephak@ccf.org [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States)

2016-07-01

Purpose: To report the short-term clinical outcomes and acute and late treatment-related genitourinary (GU) and gastrointestinal (GI) toxicities in patients with intermediate- and high-risk prostate cancer treated with dose-escalated stereotactic body radiation therapy (SBRT). Methods and Materials: Between 2011 and 2014, 24 patients with prostate cancer were treated with SBRT to the prostate gland and proximal seminal vesicles. A high-dose avoidance zone (HDAZ) was created by a 3-mm expansion around the rectum, urethra, and bladder. Patients were treated to a minimum dose of 36.25 Gy in 5 fractions, with a simultaneous dose escalation to a dose of 50 Gy to the target volume away from the HDAZ. Acute and late GU and GI toxicity outcomes were measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 4. Results: The median follow-up was 25 months (range, 18-45 months). Nine patients (38%) experienced an acute grade 2 GU toxicity, which was medically managed, and no patients experienced an acute grade 2 GI toxicity. Two patients (8%) experienced late grade 2 GU toxicity, and 2 patients (8%) experienced late grade 2 GI toxicity. No acute or late grade ≥3 GU or GI toxicities were observed. The 24-month prostate-specific antigen relapse-free survival outcome for all patients was 95.8% (95% confidence interval 75.6%-99.4%), and both biochemical failures occurred in patients with high-risk disease. All patients are currently alive at the time of this analysis and continue to be followed. Conclusions: A heterogeneous prostate SBRT planning technique with differential treatment volumes (low dose: 36.25 Gy; and high dose: 50 Gy) with an HDAZ provides a safe method of dose escalation. Favorable rates of biochemical control and acceptably low rates of acute and long-term GU and GI toxicity can be achieved in patients with intermediate- and high-risk prostate cancer treated with SBRT.

Effect of low-dose ionizing radiation on luminous marine bacteria: radiation hormesis and toxicity

International Nuclear Information System (INIS)

Kudryasheva, N.S.; Rozhko, T.V.

2015-01-01

The paper summarizes studies of effects of alpha- and beta-emitting radionuclides (americium-241, uranium-235+238, and tritium) on marine microorganisms under conditions of chronic low-dose irradiation in aqueous media. Luminous marine bacteria were chosen as an example of these microorganisms; bioluminescent intensity was used as a tested physiological parameter. Non-linear dose-effect dependence was demonstrated. Three successive stages in the bioluminescent response to americium-241 and tritium were found: 1 – absence of effects (stress recognition), 2 – activation (adaptive response), and 3 – inhibition (suppression of physiological function, i.e. radiation toxicity). The effects were attributed to radiation hormesis phenomenon. Biological role of reactive oxygen species, secondary products of the radioactive decay, is discussed. The study suggests an approach to evaluation of non-toxic and toxic stages under conditions of chronic radioactive exposure. - Highlights: • Luminous bacteria demonstrate nonlinear dose-effect relation in radioactive solutions. • Response to low-dose radiation includes 3 stages: threshold, activation, inhibition. • ROS are responsible for low-dose effects of alpha-emitting radionuclides. • Luminous marine bacteria are a convenient tool to study radiation hormesis

Effect and toxicity of endoluminal high-dose-rate (HDR) brachytherapy in centrally located tumors of the upper respiratory tract

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Harms, W.; Wannenmacher, M.; Becker, H.; Herth, F.; Fritz, P.

2000-01-01

Aim: To assess effect an toxicity of high-dose-rate afterloading (HDR) alone or in combination with external beam radiotherapy (EBRT) in centrally located tumors of the upper respiratory tract. Patients and Methods: From 1987 to 1996, 55 patients were treated. Twenty-one patients (group A1: 17 non-small-cell lung cancer [NSCLC], A2: 4 metastases from other malignancies) were treated using HDR alone due to a relapse after external beam irradiation. In 34 previously untreated and inoperable patients (group B1: 27 NSCLC, B2: 7 metastases from other malignancies) HDR was given as a boost after EBRT (30 to 60 Gy, median 50). HDR was carried out with a 192 Ir source (370 GBq). The brachytherapy dose (group A: 5 to 27 Gy, median 20; B: 10 to 20 Gy, median 15) was prescribed to 1 cm distance from the source axis. A distanciable applicator was used in 39/55 patients. Results: In group A1, a response rate (CR, PR) of 53% (group B1: 77%) was reached. The median survival (Kaplan-Meier) was 5 months in group A1 (B1: 20 months). The 1-, 3- and 5-year local progression free survival rates (Kaplan-Meier) were 66% (15%), 52% (0%), and 37% (0%) in group B1 (group A1). Prognostic favorable factors in group B1 were a tumor diameter 70. Grade-1 or 2 toxicity (RTOG/EORTC) occurred in 0% in group A and in 6% in group B. We observed no Grad-3 or 4 toxicity. Complications caused by persistent or progressive local disease occurred in 3 patients in goup A (fatal hemorrhage, tracheomediastinal fistula, hemoptysis) and in 2 patients in group B (fatal hemorrhage, hemoptysis). Conclusions: HDR brachytherapy is an effective treatment with moderate side effects. In combination with external beam irradiation long-term remissions can be reached in one third of the patients. (orig.) [de

High-Dose-Rate Monotherapy: Safe and Effective Brachytherapy for Patients With Localized Prostate Cancer

International Nuclear Information System (INIS)

Demanes, D. Jeffrey; Martinez, Alvaro A.; Ghilezan, Michel; Hill, Dennis R.; Schour, Lionel; Brandt, David; Gustafson, Gary

2011-01-01

Purpose: High-dose-rate (HDR) brachytherapy used as the only treatment (monotherapy) for early prostate cancer is consistent with current concepts in prostate radiobiology, and the dose is reliably delivered in a prospectively defined anatomic distribution that meets all the requirements for safe and effective therapy. We report the disease control and toxicity of HDR monotherapy from California Endocurietherapy (CET) and William Beaumont Hospital (WBH) in low- and intermediate-risk prostate cancer patients. Methods and Materials: There were 298 patients with localized prostate cancer treated with HDR monotherapy between 1996 and 2005. Two biologically equivalent hypofractionation protocols were used. At CET the dose was 42 Gy in six fractions (two implantations 1 week apart) delivered to a computed tomography–defined planning treatment volume. At WBH the dose was 38 Gy in four fractions (one implantation) based on intraoperative transrectal ultrasound real-time treatment planning. The bladder, urethral, and rectal dose constraints were similar. Toxicity was scored with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3. Results: The median follow-up time was 5.2 years. The median age of the patients was 63 years, and the median value of the pretreatment prostate-specific antigen was 6.0 ng/mL. The 8-year results were 99% local control, 97% biochemical control (nadir +2), 99% distant metastasis–free survival, 99% cause-specific survival, and 95% overall survival. Toxicity was scored per event, meaning that an individual patient with more than one symptom was represented repeatedly in the morbidity data table. Genitourinary toxicity consisted of 10% transient Grade 2 urinary frequency or urgency and 3% Grade 3 episode of urinary retention. Gastrointestinal toxicity was <1%. Conclusions: High disease control rates and low morbidity demonstrate that HDR monotherapy is safe and effective for patients with localized prostate cancer.

Serum Creatinine Versus Plasma Methotrexate Levels to Predict Toxicities in Children Receiving High-dose Methotrexate.

Science.gov (United States)

Tiwari, Priya; Thomas, M K; Pathania, Subha; Dhawan, Deepa; Gupta, Y K; Vishnubhatla, Sreenivas; Bakhshi, Sameer

2015-01-01

Facilities for measuring methotrexate (MTX) levels are not available everywhere, potentially limiting administration of high-dose methotrexate (HDMTX). We hypothesized that serum creatinine alteration after HDMTX administration predicts MTX clearance. Overall, 122 cycles in 50 patients of non-Hodgkin lymphoma or acute lymphoblastic leukemia aged ≤18 years receiving HDMTX were enrolled prospectively. Plasma MTX levels were measured at 12, 24, 36, 48, 60, and 72 hours; serum creatinine was measured at baseline, 24, 48, and 72 hours. Correlation of plasma MTX levels with creatinine levels and changes in creatinine from baseline (Δ creatinine) were evaluated. Plasma MTX levels at 72 hours showed positive correlation with serum creatinine at 48 hours (P = .011) and 72 hours (P = .013) as also Δ creatinine at 48 hours (P = .042) and 72 hours (P = .045). However, cut-off value of either creatinine or Δ creatinine could not be established to reliably predict delayed MTX clearance. Greater than 50% Δ creatinine at 48 and 72 hours significantly predicted grade 3/4 leucopenia (P = .036 and P = .001, respectively) and thrombocytopenia (P = .012 and P = .009, respectively) but not mucositis (P = .827 and P = .910, respectively). Delayed MTX elimination did not predict any grade 3/4 toxicity. In spite of demonstration of significant correlation between serum creatinine and Δ creatinine with plasma MTX levels at 72 hours, cut-off value of either variable to predict MTX delay could not be established. Thus, either of these cannot be used as a surrogate for plasma MTX estimation. Interestingly, Δ creatinine effectively predicted hematological toxicities, which were not predicted by delayed MTX clearance.

SU-E-J-149: Establishing the Relationship Between Pre-Treatment Lung Ventilation, Dose, and Toxicity Outcome

International Nuclear Information System (INIS)

Mistry, N; D'Souza, W; Sornsen de Koste, J; Senan, S

2014-01-01

Purpose: Recently, there has been an interest in incorporating functional information in treatment planning especially in thoracic tumors. The rationale is that healthy lung regions need to be spared from radiation if possible to help achieve better control on toxicity. However, it is still unclear whether high functioning regions need to be spared or have more capacity to deal with the excessive radiation as compared to the compromised regions of the lung. Our goal with this work is to establish the tools by which we can establish a relationship between pre-treatment lung function, dose, and radiographic outcomes of lung toxicity. Methods: Treatment planning was performed using a single phase of a 4DCT scan, and follow-up anatomical CT scans were performed every 3 months for most patients. In this study, we developed the pipeline of tools needed to analyze such a large dataset, while trying to establish a relationship between function, dose, and outcome. Pre-treatment lung function was evaluated using a recently published technique that evaluates Fractional Regional Ventilation (FRV). All images including the FRV map and the individual follow-up anatomical CT images were all spatially matched to the planning CT using a diffusion based Demons image registration algorithm. Change in HU value was used as a metric to capture the effects of lung toxicity. To validate the findings, a radiologist evaluated the follow-up anatomical CT images and scored lung toxicity. Results: Initial experience in 1 patient shows a relationship between the pre-treatment lung function, dose and toxicity outcome. The results are also correlated to the findings by the radiologist who was blinded to the analysis or dose. Conclusion: The pipeline we have established to study this enables future studies in large retrospective studies. However, the tools are dependent on the fidelity of 4DCT reconstruction for accurate evaluation of regional ventilation. Patent Pending for the technique

Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy

LENUS (Irish Health Repository)

Bratland, Ase

2011-04-08

Abstract Background In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT. Findings Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug. Conclusions When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile. Trial registration ClinicalTrials.gov: NCT00455351

Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy

International Nuclear Information System (INIS)

Bratland, Åse; Dueland, Svein; Hollywood, Donal; Flatmark, Kjersti; Ree, Anne H

2011-01-01

In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT. Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug. When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile.

Acute and late vaginal toxicity after adjuvant high-dose-rate vaginal brachytherapy in patients with intermediate risk endometrial cancer: is local therapy with hyaluronic acid of clinical benefit?

Science.gov (United States)

Delishaj, Durim; Fabrini, Maria Grazia; Gonnelli, Alessandra; Morganti, Riccardo; Perrone, Franco; Tana, Roberta; Paiar, Fabiola; Gadducci, Angiolo

2016-01-01

Purpose The aim of the present study was to evaluate the effectiveness of hyaluronic acid (HA) in the prevention of acute and late vaginal toxicities after high-dose-rate (HDR) vaginal brachytherapy (BT). Material and methods Between January 2011 and January 2015, we retrospectively analyzed 126 patients with endometrial cancer who underwent extrafascial hysterectomy with or without lymphadenectomy and adjuvant HDR-vaginal BT +/– adjuvant chemotherapy. The total dose prescription was 21 Gy in 3 fractions (one fraction for week). Vaginal ovules containing 5 mg of HA were given for whole duration of vaginal BT and for the two following weeks. Acute and late toxicities were evaluated according to CTCAE vs 4.02. Results According to the revised FIGO 2009 classification, most tumors were in stage IA (30.9%) and in stage IB (57.9%). Thirty-three patients (26.2%) received adjuvant chemotherapy before vaginal BT. Five-year disease-free survival (DFS) and five-year overall survival (OS) were 88% and 93%, respectively. The most common grade 1-2 acute toxicities were vaginal inflammation (18 patients, 14.3%) and dyspareunia (7 patients, 5.5%). Two patients (1.6%) had more than one toxicity. Late toxicity occurred in 20 patients (15.9%). Grade 1-2 late toxicities were fibrosis (14 patients, 11.1%) and telangiectasias (7 patients, 5.5%). Six patients (4.8%) had more than one late toxicity. No grade 3 or higher acute or late toxicities were observed. Conclusions These results appear to suggest that the local therapy with HA is of clinical benefit for intermediate risk endometrial cancer patients who receive adjuvant HDR-vaginal BT after surgery. A randomized trial comparing HA treatment vs. no local treatment in this clinical setting is warranted to further evaluate the efficacy of HA in preventing vaginal BT-related vaginal toxicity. PMID:28115957

Phase I Trial of Pelvic Nodal Dose Escalation With Hypofractionated IMRT for High-Risk Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Adkison, Jarrod B.; McHaffie, Derek R.; Bentzen, Soren M.; Patel, Rakesh R.; Khuntia, Deepak [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, WI (United States); Petereit, Daniel G. [Department of Radiation Oncology, John T. Vucurevich Regional Cancer Care Institute, Rapid City Regional Hospital, Rapid City, SD (United States); Hong, Theodore S.; Tome, Wolfgang [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, WI (United States); Ritter, Mark A., E-mail: ritter@humonc.wisc.edu [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, WI (United States)

2012-01-01

Purpose: Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided intensity-modulated radiation therapy (IMRT) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5 Vulgar-Fraction-One-Half weeks. Methods and Materials: Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network (NCCN) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months. Results: The median follow-up time was 25.4 months (range, 4.2-57.2). No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary (GU) or gastrointestinal (GI) toxicities were seen. The cumulative actuarial incidence of Grade 2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Grade 2 early GI toxicity. None of the dose-volume descriptors correlated with GU toxicity, and only the volume of bowel receiving {>=}30 Gy correlated with early GI toxicity (p = 0.029). Maximum late Grades 1, 2, and 3 GU toxicities were seen in 30%, 25%, and 2% of patients, respectively. Maximum late Grades 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery) of patients, respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 {+-} 6.6%. No patient manifested pelvic nodal failure, whereas 2 experienced paraaortic nodal failure outside the field. The six other clinical failures were distant only. Conclusions: Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient, and well-tolerated 28-fraction schedule. Pelvic nodal dose

Low dose iodine-131 therapy in solitary toxic thyroid nodules

International Nuclear Information System (INIS)

Prakash, Rajeev

1999-01-01

Forty patients with solitary hyperfunctioning thyroid nodules were treated with relatively low dose radioiodine therapy, 131 I doses were calculated taking into account thyroid mass and radioiodine kinetics to deliver 100 μCi/g of estimated nodule weight corrected for uptake. Patients remaining persistently hyperthyroid at four months after the initial therapy were retreated with a similarly calculated dose. Cure of the hyperthyroid state was achieved in all patients, total administered dose in individual cases ranging from 3-17 mCi. 28 of the 40 patients required a single therapy dose. 36 patients were euthyroid after a 4.5 year mean follow-up period. Four cases developed post therapy hypothyroidism requiring replacement therapy. Nodules regressed completely in nine cases following 131 I treatment, with partial regression in size in 19 patients. Control of hyperthyroid state in cases of solitary toxic thyroid nodules can be satisfactorily achieved using relatively low dose radioiodine therapy with low incidence of post therapy hypothyroidism. (author)

Lean body mass as an independent determinant of dose-limiting toxicity and neuropathy in patients with colon cancer treated with FOLFOX regimens

International Nuclear Information System (INIS)

Ali, Raafi; Sawyer, Michael B.; Bianchi, Laurent; Roberts, Sarah; Mollevi, Caroline; Senesse, Pierre; Baracos, Vickie E.; Assenat, Eric

2016-01-01

Evidence suggests that lean body mass (LBM) may be useful to normalize chemotherapy doses. Data from one prospective and one retrospective study were used to determine if the highest doses of oxaliplatin/kg LBM within FOLFOX regimens would be associated with dose-limiting toxicity (DLT) in colon cancer patients. Toxicity over four cycles was graded according to NCI Common Toxicity Criteria V2 or V3 (Common Terminology Criteria for Adverse Events, National Cancer Institute, Bethesda, MD). Muscle tissue was measured by computerized tomography (CT) and used to evaluate the LBM compartment of the whole body. In prospective randomized clinical trials conducted in France (n = 58), for patients given FOLFOX-based regimens according to body surface area, values of oxaliplatin/kg LBM were highly variable, ranging from 2.55 to 6.6 mg/kg LBM. A cut point of 3.09 mg oxaliplatin/kg LBM for developing toxicity was determined by Receiver Operating Characteristic (ROC) analysis, below this value 0/17 (0.0%) of patients experienced DLT; in contrast above this value 18/41 (44.0%) of patients were dose reduced or had treatment terminated owing to toxicity (≥Grade 3 or neuropathy ≥Grade 2); for 9/41 the DLT was sensory neuropathy. These findings were validated in an independent cohort of colon cancer patients (n = 80) receiving FOLFOX regimens as part of standard care, in Canada. Low LBM is a significant predictor of toxicity and neuropathy in patients administered FOLFOX-based regimens using conventional body surface area (BSA) dosing

Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

Energy Technology Data Exchange (ETDEWEB)

Hoffman, Karen E., E-mail: khoffman1@mdanderson.org; Voong, K. Ranh; Pugh, Thomas J.; Skinner, Heath; Levy, Lawrence B.; Takiar, Vinita; Choi, Seungtaek; Du, Weiliang; Frank, Steven J.; Johnson, Jennifer; Kanke, James; Kudchadker, Rajat J.; Lee, Andrew K.; Mahmood, Usama; McGuire, Sean E.; Kuban, Deborah A.

2014-04-01

Objective: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. Methods and Materials: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. Results: 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). Conclusions: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this

Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

International Nuclear Information System (INIS)

Hoffman, Karen E.; Voong, K. Ranh; Pugh, Thomas J.; Skinner, Heath; Levy, Lawrence B.; Takiar, Vinita; Choi, Seungtaek; Du, Weiliang; Frank, Steven J.; Johnson, Jennifer; Kanke, James; Kudchadker, Rajat J.; Lee, Andrew K.; Mahmood, Usama; McGuire, Sean E.; Kuban, Deborah A.

2014-01-01

Objective: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. Methods and Materials: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. Results: 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). Conclusions: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this

Repeated-dose toxicological studies of Tithonia diversifolia (Hemsl.) A. gray and identification of the toxic compounds.

Science.gov (United States)

Passoni, Flávia Donaire; Oliveira, Rejane Barbosa; Chagas-Paula, Daniela Aparecida; Gobbo-Neto, Leonardo; Da Costa, Fernando Batista

2013-05-20

Tithonia diversifolia (Hemsl.) A. Gray has been commonly used in folk medicine to treat abscesses, microbiological infections, snake bites, malaria and diabetes. Both anti-inflammatory and anti-malarial properties have been identified using appropriate assays, but the effective doses have demonstrated toxic effects for the experimental animals. Most of the pharmacological activities have been attributed to sesquiterpene lactones (STLs) and some chlorogenic acid derivatives (CAs) in the leaves of this species. This work aimed to evaluate the repeated-dose toxicity of an aqueous extract (AE) from Tithonia diversifolia leaves and to compare the results with an extract rich in STLs (LRE) and a polar extract (PE) without STLs but rich in CAs. The purpose of this work was to provide insights into the identity of the compounds responsible for the toxic effects of Tithonia diversifolia. The major classes of compounds were confirmed in each extract by IR spectra and HPLC-UV-DAD profiling using previously isolated or standard compounds. The toxicity of each extract was evaluated in a repeated-dose toxicity study in Wistar rats for 90 days. The AE is composed of both STLs and CAs, the LRE is rich in STLs, and the PE is rich in CAs. The AE caused alterations in haematological parameters but few alterations in biochemical parameters and was relatively safe at doses lower than 100mg/kg. However, the PE and LRE demonstrated several adverse effects by damaging the liver and kidneys, respectively. STLs and CAs can be toxic in prolonged use at higher doses in extracts prepared from Tithonia diversifolia by affecting the kidneys and liver. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Fluoropyrimidines plus cisplatin versus gemcitabine/gemcitabine plus cisplatin in locally advanced and metastatic biliary tract carcinoma - a retrospective study.

Science.gov (United States)

Croitoru, Adina; Gramaticu, Iulia; Dinu, Ioana; Gheorghe, Liana; Alexandrescu, Sorin; Buica, Florina; Luca, Ioana; Becheanu, Gabriel; Herlea, Vlad; Simionov, Iulia; Hrehoret, Doina; Lupescu, Ioana; Popescu, Irinel; Diculescu, Mircea

2012-09-01

This is a retrospective study of patients with advanced biliary tract carcinoma (BTC), who were treated with different regimens of chemotherapy. We studied patients with advanced BTC registered at the Department of Oncology at the Fundeni Clinical Institute between 2004 and 2008. The following data were analyzed: rate of response, progression free survival (PFS) to first and second line of chemotherapy, overall survival (OS) and drug toxicity. Ninety-six patients were eligible having either advanced intra or extrahepatic cholangiocarcinoma, or gallbladder cancer with no prior chemotherapy. Out of 96 patients, 57 (59.4%) received fluoropyrimidines (FP)+cisplatin and 39 (40.6%) gemcitabine (Gem)+/-cisplatin. The median PFS for FP+cisplatin was 5.9 months (95%CI 5-6.9) and for Gem+/-cisplatin 6.3 months (95%CI 5.4-7.1), p=0.661. Median OS for FP+cisplatin was 10.3 months (95%CI 7.5-13.1) and for Gem+/-cisplatin 9.1 months (95%CI 7.0-11.2), p=0.098. On disease progression, 46 patients received second line CT (Gem or FP+/-platinum compounds). Median OS for patients with FP based first line and Gem+/-cisplatin in second line was 19 months (95%CI 8.9-29) higher than for the reverse sequence: 13.2 months (95%CI 12-14.4), but not statistically significant (p=0.830). All patients were evaluated for toxicities. Most patients (75.5%) reported at least one adverse event. Our results through direct comparison of FP+cisplatin with Gem+/-cisplatin as first line treatment did not show any statistical differences in terms of rate of response, PFS and OS. However, our study showed that FP+cisplatin as first line and Gem based second line therapy gave a better OS rate.

Hematological toxicity in radioimmunotherapy is predicted both by the computed absorbed whole body dose (cGy) and by the administered dose (mCi)

International Nuclear Information System (INIS)

Marquez, Sheri D.; Knox, Susan J.; Trisler, Kirk D.; Goris, Michael L.

1997-01-01

Purpose/Objective: Radioimmunotherapy (RIT) has yielded encouraging response rates in patients with recurrent non-Hodgkin's lymphoma, but myelotoxicity remains the dose limiting factor. Dose optimization is theoretically possible, since a pretreatment biodistribution study with tracer doses allows for a fairly accurate estimate of the whole body (and by implication the bone marrow) dose in patients. It has been shown that the radiation dose as a function of the administered dose varies widely from patient to patient. The pretreatment study could therefore be used to determine the maximum tolerable dose for each individual patient. The purpose of this study was to examine whether the administered dose or the estimated whole body absorbed radiation dose were indeed predictors of bone marrow toxicity. Materials and Methods: We studied two cohorts of patients to determine if the computed integral whole body or marrow dose is predictive of myelotoxicity. The first cohort consisted of 13 patients treated with Yttrium-90 labeled anti-CD20 (2B8) monoclonal antibody. Those patients were treated in a dose escalation protocol, based on the administered dose, without correction for weight or body surface. The computed whole body dose varied from 41 to 129 cGy. The second cohort (6 patients) were treated with Iodine-131 labeled anti-CD20 (B1) antibody. In this group the administered dose was tailored to deliver an estimated 75 cGy whole body dose. The administered dose varied from 54 to 84 mCi of Iodine-131. For each patient, white blood cell count with differential, hemoglobin, hematocrit, and platelet levels were measured before and at regular intervals after RIT was administered. Using linear regression analysis, a relationship between administered dose, absorbed dose and myelotoxicity was determined for each patient cohort. Results: Marrow toxicity was measured by the absolute decrease in white blood cell (DWBC), platelet (DPLAT), and neutrophil (DN) values. In the Yttrium

Escalation to High Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease

Science.gov (United States)

Triplett, Brandon M.; Kuttab, Hani I.; Kang, Guolian; Leung, Wing

2015-01-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those utilized in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial, 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. There was no observed increase in toxicity until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10–100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, while those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (p=0.008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose escalation strategy remains unclear, as outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. PMID:26278046

Dosimetric Factors and Toxicity in Highly Conformal Thoracic Reirradiation

Energy Technology Data Exchange (ETDEWEB)

Binkley, Michael S.; Hiniker, Susan M.; Chaudhuri, Aadel [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Maxim, Peter G. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Diehn, Maximilian [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California (United States); Loo, Billy W., E-mail: BWLoo@Stanford.edu [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Shultz, David Benjamin, E-mail: David.Shultz@rmp.uhn.on.ca [Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario (Canada)

2016-03-15

} range: 207.5-302.2 Gy), brachial plexopathy (n=1; D0.2 cm{sup 3} = 242.5 Gy), and Horner's syndrome (n=1; sympathetic trunk D0.2 cm{sup 3} = 130.8 Gy). No grade ≥4 toxicity was observed. Conclusions: Overlapping courses of reirradiation can be safely delivered with acceptable toxicity. Some toxicities occurred acutely at doses considered safe for a single course of therapy (esophagus). We observed rib fracture, brachial plexopathy, and Horner's syndrome for patients receiving high cumulative doses to corresponding critical structures.

Anatomy-based inverse optimization in high-dose-rate brachytherapy combined with hypofractionated external beam radiotherapy for localized prostate cancer: Comparison of incidence of acute genitourinary toxicity between anatomy-based inverse optimization and geometric optimization

International Nuclear Information System (INIS)

Akimoto, Tetsuo; Katoh, Hiroyuki; Kitamoto, Yoshizumi; Shirai, Katsuyuki; Shioya, Mariko; Nakano, Takashi

2006-01-01

Purpose: To evaluate the advantages of anatomy-based inverse optimization (IO) in planning high-dose-rate (HDR) brachytherapy. Methods and Materials: A total of 114 patients who received HDR brachytherapy (9 Gy in two fractions) combined with hypofractionated external beam radiotherapy (EBRT) were analyzed. The dose distributions of HDR brachytherapy were optimized using geometric optimization (GO) in 70 patients and by anatomy-based IO in the remaining 44 patients. The correlation between the dose-volume histogram parameters, including the urethral dose and the incidence of acute genitourinary (GU) toxicity, was evaluated. Results: The averaged values of the percentage of volume receiving 80-150% of the prescribed minimal peripheral dose (V 8 -V 15 ) of the urethra generated by anatomy-based IO were significantly lower than the corresponding values generated by GO. Similarly, the averaged values of the minimal dose received by 5-50% of the target volume (D 5 -D 5 ) obtained using anatomy-based IO were significantly lower than those obtained using GO. Regarding acute toxicity, Grade 2 or worse acute GU toxicity developed in 23% of all patients, but was significantly lower in patients for whom anatomy-based IO (16%) was used than in those for whom GO was used (37%), consistent with the reduced urethral dose (p <0.01). Conclusion: The results of this study suggest that anatomy-based IO is superior to GO for dose optimization in HDR brachytherapy for prostate cancer

Efficiency of radioiodine therapy with a fix dose of I-131 in toxic thyroid adenoma

International Nuclear Information System (INIS)

Petrovski, Z

2004-01-01

Purpose: The aim of this study was to estimate the results obtained using a fix dose of I-131 in the treatment of the solitary toxic thyroid adenoma. Material and Methods: We have performed radioiodine therapy m 64 patients, 49 female (50+ 1 7 yrs) and 15 male (43+-15 yrs) with solitary toxic thyroid adenoma. 45 patients received fix dose I-131 of 850 MBq, while 19 patients were treated with calculated (MBq/gr) dose 555-1100 MBq Previously 39(64%) patients were clinically hyperthyreotic and received thyreostatic meditication which were interruptecf one week before the administration of I-131. Those patients who were euthyreotic, TSH was suppressed(<0.25 MU/m1). 61(95.3%) patients received a single dose, while 3(4, 7%) patients needed two doses. Resulting thyroid matabolism and volume of nodules were evaluated 6-48 months after treatment. Results: From 45 radioiodine treated patients with fix dose 6(9, 8%) became hypothyroidism, 36(85, 3%) euthyroidism and 3(4, 9%) recurrent hyperthyroidism, in comparison with 19 treated patients with calculated I-131 dose: 2(10, 5%) hypothyroidism, 16(84, 3%) euthyroidism and 1(5, 2%) recurrent hyperthyroidism. The size of the nodules became unpalpable m 17(26, 2%), decreased evidently in 33(52, 5%) and remained unchanged in 14(21, 3%) of the treated patients. Conclusion: A fix dose of I-131 is simple, safe and efficient in the treatment of solitary toxic thyroid adenoma. There was not significant different in incidence of late follow-up results of hypothyroidism and recurrent hyperthyroidism between fix dose and calculated MBq/gr dose. (authors)

Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin.

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Overman, Michael J; Morris, Van; Moinova, Helen; Manyam, Ganiraju; Ensor, Joe; Lee, Michael S; Eng, Cathy; Kee, Bryan; Fogelman, David; Shroff, Rachna T; LaFramboise, Thomas; Mazard, Thibault; Feng, Tian; Hamilton, Stanley; Broom, Bradley; Lutterbaugh, James; Issa, Jean-Pierre; Markowitz, Sanford D; Kopetz, Scott

2016-10-11

Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (PCIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker.

Pharmacogenetics and Metabolism from Science to Implementation in Clinical Practice: The Example of Dihydropyrimidine Dehydrogenase.

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Del Re, Marzia; Restante, Giuliana; Di Paolo, Antonello; Crucitta, Stefania; Rofi, Eleonora; Danesi, Romano

2017-01-01

Fluoropyrimidines are widely used in the treatment of solid tumors and remain the backbone of many combination chemotherapy regimens. Despite their clinical benefit, they are associated with frequent gastrointestinal and hematological toxicities, which often lead to treatment discontinuation. Fluoropyrimidines undergo complex anabolic and catabolic biotransformation. Enzymes involved in this pathway include dihydropyrimidine dehydrogenase (DPD), which breaks down 5-FU and its prodrugs. Candidate gene approaches have demonstrated associations between 5-FU treatment outcomes and germline polymorphisms in DPD. The aim of this review is to report and discuss the latest results on fluoropyrimidine pharmacogenetics. Literature from PubMed databases and bibliography from retrieved publications have been analyzed according to terms such DPD, DPYD, fluoropyrimdines, polymorphisms, toxicity, pharmacogenetics. To date, many sequence variations have been identified within DPYD gene, although the majority of these have no functional consequences on enzymatic activity. Nowadays, there is a general agreement on the clinical significance of the importance of DPD deficiency in patients who suffer from severe, life-threatening drug toxicity although preemptive testing is not applied to all patients. Considering the published literature, clinicians are strongly encouraged to consider testing for DPD poor metabolizer variants as a rational pre-treatment screening for patients candidate to a fluoropyrimidine-based regimens, in order to prevent toxicities and personalise treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Dose rate and dose fractionation studies in total body irradiation of dogs

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Kolb, H.J.; Netzel, B.; Schaffer, E.; Kolb, H.

1979-01-01

Total body irradiation (TBI) with 800-900 rads and allogeneic bone marrow transplantation according to the regimen designated by the Seattle group has induced remissions in patients with otherwise refractory acute leukemias. Relapse of leukemia after bone marrow transplantation remains the major problem, when the Seattle set up of two opposing 60 Co-sources and a low dose rate is used in TBI. Studies in dogs with TBI at various dose rates confirmed observations in mice that gastrointestinal toxicity is unlike toxicity against hemopoietic stem cells and possibly also leukemic stem cells depending on the dose rate. However, following very high single doses (2400 R) and marrow infusion acute gastrointestinal toxicity was not prevented by the lowest dose rate studied (0.5 R/min). Fractionated TBI with fractions of 600 R in addition to 1200 R (1000 rads) permitted the application of total doses up to 300 R followed by marrow infusion without irreversible toxicity. 26 dogs given 2400-3000 R have been observed for presently up to 2 years with regard to delayed radiation toxicity. This toxicity was mild in dogs given single doses at a low dose rate or fractionated TBI. Fractionated TBI is presently evaluated with allogeneic transplants in the dog before being applied to leukemic patients

Simultaneous adjuvant radiation therapy and chemotherapy in high-risk breast cancer--toxicity and dose modification: a trans-tasman radiation oncology group multi-institution study

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Denham, James W.; Hamilton, Christopher S.; Christie, David; O'Brien, Maree; Bonaventura, Antonino; Stewart, John F.; Ackland, Stephen P.; Lamb, David S.; Spry, Nigel A.; Dady, Peter; Atkinson, Christopher H.; Wynne, Christopher; Joseph, David J.

1995-01-01

Purpose: To establish the toxicity profile of simultaneously administered postoperative radiation therapy and CMF chemotherapy as a prelude to a randomized controlled study addressing the sequencing of the two modalities. Methods and Materials: One hundred and thirty eight breast cancer patients at high risk of locoregional, as well as systemic relapse, who were referred to three centers in Australia and New Zealand were treated with postoperative radiation therapy and chemotherapy simultaneously. Acute toxicity and dose modifications in these patients were compared with 83 patients treated over the same time frame with chemotherapy alone. In a separate study the long-term radiation and surgical effects in 24 patients treated simultaneously with radiation therapy and chemotherapy at Newcastle (Australia) following conservative surgery were compared with 23 matched patients treated at Newcastle with radiation therapy alone. Results: Myelotoxicity was increased in patients treated simultaneously with radiation therapy and chemotherapy. The effect was not great, but may have contributed to chemotherapy dose reductions. Lymphopenia was observed to be the largest factor in total white cell depressions caused by the simultaneous administration of radiation therapy. Postsurgical appearances were found to so dominate long-term treatment effects on the treated breast that the effect of radiation therapy dose and additional chemotherapy was difficult to detect. Conclusion: Studies addressing the sequencing of radiation therapy and chemotherapy will necessarily be large because adverse effects from administering the two modalities simultaneously are not great. The present study has endorsed the importance in future studies of stratification according to the extent and type of surgery and adherence to a single strict policy of chemotherapy dose modification

Preliminary Toxicity Analysis of 3-Dimensional Conformal Radiation Therapy Versus Intensity Modulated Radiation Therapy on the High-Dose Arm of the Radiation Therapy Oncology Group 0126 Prostate Cancer Trial

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Michalski, Jeff M., E-mail: jmichalski@radonc.wustl.edu [Department of Radiation Oncology Washington University Medical Center, St. Louis, Missouri (United States); Yan, Yan [Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States); Watkins-Bruner, Deborah [Emory University School of Nursing, Atlanta, Georgia (United States); Bosch, Walter R. [Department of Radiation Oncology Washington University Medical Center, St. Louis, Missouri (United States); Winter, Kathryn [Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States); Galvin, James M. [Department of Radiation Oncology Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (United States); Bahary, Jean-Paul [Department of Radiation Oncology Centre Hospitalier de l' Université de Montréal-Notre Dame, Montreal, QC (Canada); Morton, Gerard C. [Department of Radiation Oncology Toronto-Sunnybrook Regional Cancer Centre, Toronto, ON (Canada); Parliament, Matthew B. [Department of Oncology Cross Cancer Institute, Edmonton, AB (Canada); Sandler, Howard M. [Department of Radiation Oncology Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California (United States)

2013-12-01

Purpose: To give a preliminary report of clinical and treatment factors associated with toxicity in men receiving high-dose radiation therapy (RT) on a phase 3 dose-escalation trial. Methods and Materials: The trial was initiated with 3-dimensional conformal RT (3D-CRT) and amended after 1 year to allow intensity modulated RT (IMRT). Patients treated with 3D-CRT received 55.8 Gy to a planning target volume that included the prostate and seminal vesicles, then 23.4 Gy to prostate only. The IMRT patients were treated to the prostate and proximal seminal vesicles to 79.2 Gy. Common Toxicity Criteria, version 2.0, and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late morbidity scores were used for acute and late effects. Results: Of 763 patients randomized to the 79.2-Gy arm of Radiation Therapy Oncology Group 0126 protocol, 748 were eligible and evaluable: 491 and 257 were treated with 3D-CRT and IMRT, respectively. For both bladder and rectum, the volumes receiving 65, 70, and 75 Gy were significantly lower with IMRT (all P<.0001). For grade (G) 2+ acute gastrointestinal/genitourinary (GI/GU) toxicity, both univariate and multivariate analyses showed a statistically significant decrease in G2+ acute collective GI/GU toxicity for IMRT. There were no significant differences with 3D-CRT or IMRT for acute or late G2+ or 3+ GU toxicities. Univariate analysis showed a statistically significant decrease in late G2+ GI toxicity for IMRT (P=.039). On multivariate analysis, IMRT showed a 26% reduction in G2+ late GI toxicity (P=.099). Acute G2+ toxicity was associated with late G3+ toxicity (P=.005). With dose–volume histogram data in the multivariate analysis, RT modality was not significant, whereas white race (P=.001) and rectal V70 ≥15% were associated with G2+ rectal toxicity (P=.034). Conclusions: Intensity modulated RT is associated with a significant reduction in acute G2+ GI/GU toxicity. There is a trend for a

Escalation to High-Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease.

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Triplett, Brandon M; Kuttab, Hani I; Kang, Guolian; Leung, Wing

2015-12-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

High-dose, hyperfractionated, accelerated radiotherapy using a concurrent boost for the treatment of nonsmall cell lung cancer: unusual toxicity and promising early results

International Nuclear Information System (INIS)

King, Stephen C.; Acker, Jeffrey C.; Kussin, Peter S.; Marks, Lawrence B.; Weeks, Kenneth J.; Leopold, Kenneth A.

1996-01-01

Purpose: The treatment of nonsmall cell lung cancer (NSCLC) with conventional radiotherapy (RT) results in inadequate local tumor control and survival. We report results of a Phase II trial designed to treat patients with a significantly increased total dose administered in a reduced overall treatment time using a hyperfractionated, accelerated treatment schedule with a concurrent boost technique. Methods and Materials: A total of 49 patients with unresectable Stage IIIA/IIIB (38 patients) or medically inoperable Stage I/II (11 patients) NSCLC were prospectively enrolled in this protocol. Radiation therapy was administered twice daily, 5 days/week with > 6 h between each treatment. The primary tumor and adjacent enlarged lymph nodes were treated to a total dose of 73.6 Gy in 46 fractions of 1.6 Gy each. Using a concurrent boost technique, electively irradiated nodal regions were simultaneously treated with a dose of 1.25 Gy/fraction for the first 36 fractions to a total dose of 45 Gy. Results: Median survival for the entire group of 49 patients is 15.3 months. Actuarial survival at 2 years is 46%: 60% for 11 Stage I/II patients, 55% for 21 Stage IIIA patients, and 26% for 17 Stage IIIB patients. The actuarial rate of freedom from local progression at 2 years is 64% for the entire group of 49 patients: 62% for Stage I/II patients, 70% for Stage IIIA patients, and 55% for Stage IIIB patients. Patients who underwent serial bronchoscopic reevaluation (4 Stage I/II, 8 Stage IIIA, and 6 Stage IIIB) have an actuarial rate of local control of 71% at 2 years. The median total treatment time was 32 days. Nine of 49 patients (18%) experienced Grade III acute esophageal toxicity. The 2-year actuarial risk of Grade III or greater late toxicity is 30%. The 2-year actuarial rate of severe-late pulmonary and skin-subcutaneous toxicity is 20% and 15%, respectively. Conclusion: This treatment regimen administers a substantially higher biologically effective dose compared with

Effect of low-dose ionizing radiation on luminous marine bacteria: radiation hormesis and toxicity.

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Kudryasheva, N S; Rozhko, T V

2015-04-01

The paper summarizes studies of effects of alpha- and beta-emitting radionuclides (americium-241, uranium-235+238, and tritium) on marine microorganisms under conditions of chronic low-dose irradiation in aqueous media. Luminous marine bacteria were chosen as an example of these microorganisms; bioluminescent intensity was used as a tested physiological parameter. Non-linear dose-effect dependence was demonstrated. Three successive stages in the bioluminescent response to americium-241 and tritium were found: 1--absence of effects (stress recognition), 2--activation (adaptive response), and 3--inhibition (suppression of physiological function, i.e. radiation toxicity). The effects were attributed to radiation hormesis phenomenon. Biological role of reactive oxygen species, secondary products of the radioactive decay, is discussed. The study suggests an approach to evaluation of non-toxic and toxic stages under conditions of chronic radioactive exposure. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prostate Specific Antigen (PSA) as Predicting Marker for Clinical Outcome and Evaluation of Early Toxicity Rate after High-Dose Rate Brachytherapy (HDR-BT) in Combination with Additional External Beam Radiation Therapy (EBRT) for High Risk Prostate Cancer.

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Ecke, Thorsten H; Huang-Tiel, Hui-Juan; Golka, Klaus; Selinski, Silvia; Geis, Berit Christine; Koswig, Stephan; Bathe, Katrin; Hallmann, Steffen; Gerullis, Holger

2016-11-10

High-dose-rate brachytherapy (HDR-BT) with external beam radiation therapy (EBRT) is a common treatment option for locally advanced prostate cancer (PCa). Seventy-nine male patients (median age 71 years, range 50 to 79) with high-risk PCa underwent HDR-BT following EBRT between December 2009 and January 2016 with a median follow-up of 21 months. HDR-BT was administered in two treatment sessions (one week interval) with 9 Gy per fraction using a planning system and the Ir192 treatment unit GammaMed Plus iX. EBRT was performed with CT-based 3D-conformal treatment planning with a total dose administration of 50.4 Gy with 1.8 Gy per fraction and five fractions per week. Follow-up for all patients was organized one, three, and five years after radiation therapy to evaluate early and late toxicity side effects, metastases, local recurrence, and prostate-specific antigen (PSA) value measured in ng/mL. The evaluated data included age, PSA at time of diagnosis, PSA density, BMI (body mass index), Gleason score, D'Amico risk classification for PCa, digital rectal examination (DRE), PSA value after one/three/five year(s) follow-up (FU), time of follow-up, TNM classification, prostate volume, and early toxicity rates. Early toxicity rates were 8.86% for gastrointestinal, and 6.33% for genitourinary side effects. Of all treated patients, 84.81% had no side effects. All reported complications in early toxicity were grade 1. PSA density at time of diagnosis ( p = 0.009), PSA on date of first HDR-BT ( p = 0.033), and PSA on date of first follow-up after one year ( p = 0.025) have statistical significance on a higher risk to get a local recurrence during follow-up. HDR-BT in combination with additional EBRT in the presented design for high-risk PCa results in high biochemical control rates with minimal side-effects. PSA is a negative predictive biomarker for local recurrence during follow-up. A longer follow-up is needed to assess long-term outcome and toxicities.

Passive dosing of polycyclic aromatic hydrocarbon (PAH) mixtures to terrestrial springtails: linking mixture toxicity to chemical activities, equilibrium lipid concentrations, and toxic units.

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Schmidt, Stine N; Holmstrup, Martin; Smith, Kilian E C; Mayer, Philipp

2013-07-02

A 7-day mixture toxicity experiment with the terrestrial springtail Folsomia candida was conducted, and the effects were linked to three different mixture exposure parameters. Passive dosing from silicone was applied to tightly control exposure levels and compositions of 12 mixture treatments, containing the polycyclic aromatic hydrocarbons (PAHs) naphthalene, phenanthrene, and pyrene. Springtail lethality was then linked to sum chemical activities (∑a), sum equilibrium lipid concentrations (∑C(lipid eq.)), and sum toxic units (∑TU). In each case, the effects of all 12 mixture treatments could be fitted to one sigmoidal exposure-response relationship. The effective lethal chemical activity (La50) of 0.027 was well within the expected range for baseline toxicity of 0.01-0.1. Linking the effects to the lipid-based exposure parameter yielded an effective lethal concentration (LC(lipid eq 50)) of 133 mmol kg(-1) lipid in good correspondence with the lethal membrane burden for baseline toxicity (40-160 mmol kg(-1) lipid). Finally, the effective lethal toxic unit (LTU50) of 1.20 was rather close to the expected value of 1. Altogether, passive dosing provided tightly controlled mixture exposure in terms of both level and composition, while ∑a, ∑C(lipid eq.), and ∑TU allowed baseline toxicity to be linked to mixture exposure.

A 4-Week Repeated-Dose Oral Toxicity Study of Bojungikgi-Tang in Crl:CD Sprague Dawley Rats

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Sae-Rom Yoo

2017-01-01

Full Text Available Traditional herbal medicines have been used for centuries in Asian countries. However, recent studies have led to increasing concerns about the safety and toxicity of herbal prescriptions. Bojungikgi-tang (BJIGT, a herbal decoction, has been used in Korea to improve physical strength. To establish the safety information, BJIGT water extract was evaluated in a 4-week repeated-dose oral toxicity test in Crl:CD Sprague Dawley rats. BJIGT was orally administered in daily doses of 0, 500, 1000, and 2000 mg/kg/day for 4 weeks via oral gavage in male and female rats. We examined the mortality, clinical signs, body weight change, food intake, organ weights, hematology, serum biochemistry, and urinalysis parameters. No significant changes were observed in mortality, clinical sings, body weight, food intake, organ weights, hematology, serum biochemistry, and urinalysis parameters between the control group and the BJIGT-treated groups in the rats of both sexes. The results indicate that BJIGT did not induce toxic effects at a dose level up to 2000 mg/kg in rats. Thus, this concentration is considered the nonobservable effect dose in rats and is appropriate for a 13-week subchronic toxicity study.

Pulmonary Toxicity in Stage III Non-Small Cell Lung Cancer Patients Treated With High-Dose (74 Gy) 3-Dimensional Conformal Thoracic Radiotherapy and Concurrent Chemotherapy Following Induction Chemotherapy: A Secondary Analysis of Cancer and Leukemia Group B (CALGB) Trial 30105

International Nuclear Information System (INIS)

Salama, Joseph K.; Stinchcombe, Thomas E.; Gu Lin; Wang Xiaofei; Morano, Karen; Bogart, Jeffrey A.; Crawford, Jeffrey C.; Socinski, Mark A.; Blackstock, A. William; Vokes, Everett E.

2011-01-01

Purpose: Cancer and Leukemia Group B (CALGB) 30105 tested two different concurrent chemoradiotherapy platforms with high-dose (74 Gy) three-dimensional conformal radiotherapy (3D-CRT) after two cycles of induction chemotherapy for Stage IIIA/IIIB non–small cell lung cancer (NSCLC) patients to determine if either could achieve a primary endpoint of >18-month median survival. Final results of 30105 demonstrated that induction carboplatin and gemcitabine and concurrent gemcitabine 3D-CRT was not feasible because of treatment-related toxicity. However, induction and concurrent carboplatin/paclitaxel with 74 Gy 3D-CRT had a median survival of 24 months, and is the basis for the experimental arm in CALGB 30610/RTOG 0617/N0628. We conducted a secondary analysis of all patients to determine predictors of treatment-related pulmonary toxicity. Methods and Materials: Patient, tumor, and treatment-related variables were analyzed to determine their relation with treatment-related pulmonary toxicity. Results: Older age, higher N stage, larger planning target volume (PTV)1, smaller total lung volume/PTV1 ratio, larger V20, and larger mean lung dose were associated with increasing pulmonary toxicity on univariate analysis. Multivariate analysis confirmed that V20 and nodal stage as well as treatment with concurrent gemcitabine were associated with treatment-related toxicity. A high-risk group comprising patients with N3 disease and V20 >38% was associated with 80% of Grades 3-5 pulmonary toxicity cases. Conclusions: Elevated V20 and N3 disease status are important predictors of treatment related pulmonary toxicity in patients treated with high-dose 3D-CRT and concurrent chemotherapy. Further studies may use these metrics in considering patients for these treatments.

Pulmonary Toxicity in Stage III Non-Small Cell Lung Cancer Patients Treated With High-Dose (74 Gy) 3-Dimensional Conformal Thoracic Radiotherapy and Concurrent Chemotherapy Following Induction Chemotherapy: A Secondary Analysis of Cancer and Leukemia Group B (CALGB) Trial 30105

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Salama, Joseph K., E-mail: joseph.salama@duke.edu [Duke University Medical Center, Durham, NC (United States); Stinchcombe, Thomas E. [University of North Carolina at Chapel Hill, Chapel Hill, NC (United States); Gu Lin; Wang Xiaofei [CALGB Statistical Center, Duke University Medical Center, Durham, NC (United States); Morano, Karen [Quality Assurance Review Center, Lincoln, RI (United States); Bogart, Jeffrey A. [State University of New York Upstate Medical University, Syracuse, NY (United States); Crawford, Jeffrey C. [Duke University Medical Center, Durham, NC (United States); Socinski, Mark A. [University of North Carolina at Chapel Hill, Chapel Hill, NC (United States); Blackstock, A. William [Wake Forest University School of Medicine, Winston-Salem, NC (United States); Vokes, Everett E. [University of Chicago, Chicago, IL (United States)

2011-11-15

Purpose: Cancer and Leukemia Group B (CALGB) 30105 tested two different concurrent chemoradiotherapy platforms with high-dose (74 Gy) three-dimensional conformal radiotherapy (3D-CRT) after two cycles of induction chemotherapy for Stage IIIA/IIIB non-small cell lung cancer (NSCLC) patients to determine if either could achieve a primary endpoint of >18-month median survival. Final results of 30105 demonstrated that induction carboplatin and gemcitabine and concurrent gemcitabine 3D-CRT was not feasible because of treatment-related toxicity. However, induction and concurrent carboplatin/paclitaxel with 74 Gy 3D-CRT had a median survival of 24 months, and is the basis for the experimental arm in CALGB 30610/RTOG 0617/N0628. We conducted a secondary analysis of all patients to determine predictors of treatment-related pulmonary toxicity. Methods and Materials: Patient, tumor, and treatment-related variables were analyzed to determine their relation with treatment-related pulmonary toxicity. Results: Older age, higher N stage, larger planning target volume (PTV)1, smaller total lung volume/PTV1 ratio, larger V20, and larger mean lung dose were associated with increasing pulmonary toxicity on univariate analysis. Multivariate analysis confirmed that V20 and nodal stage as well as treatment with concurrent gemcitabine were associated with treatment-related toxicity. A high-risk group comprising patients with N3 disease and V20 >38% was associated with 80% of Grades 3-5 pulmonary toxicity cases. Conclusions: Elevated V20 and N3 disease status are important predictors of treatment related pulmonary toxicity in patients treated with high-dose 3D-CRT and concurrent chemotherapy. Further studies may use these metrics in considering patients for these treatments.

Dose- dependent ameliorative effects of quercetin and l-Carnitine against atrazine- induced reproductive toxicity in adult male Albino rats.

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Abdel Aziz, Rabie L; Abdel-Wahab, Ahmed; Abo El-Ela, Fatma I; Hassan, Nour El-Houda Y; El-Nahass, El-Shaymaa; Ibrahim, Marwa A; Khalil, Abdel-Tawab A Y

2018-06-01

This study aimed to determine the protective effects of co-administration of Quercetin (QT) or l-Carnitine (LC) against the oxidative stress induced by Atrazine (ATZ) in the reproductive system of intact male Albino rats. 36 rats were divided equally into 6 groups. Rats in the control negative "CNT" group received 1.5 ml distilled water for 21 days. All rats in the other groups received ATZ (120 mg/kg bw) through gavage. Groups 3 and 4 were co-administered with either low or high dose of QT (10 "ATZLQT" and 50 "ATZHQT" mg/kg bw, respectively). Groups 5 and 6 were co-administered with either low or high dose of LC (200 "ATZLLC" and 400 "ATZHLC" mg/kg bw, respectively). At the end of the experiment, animals were sacrificed and all samples were collected. ATZ significantly increased serum level of malondialdehyde (MDA) and decreased total antioxidant capacity (TAC). Also, ATZ increased significantly the sperm cell abnormalities and reduced both testicular IgA and serum testosterone levels. Testicular DNA laddering % and CYP17A1 mRNA expression were significantly reduced in ATZ group. Interestingly, co-administration with low dose QT or different doses of LC succeeded to counteract the negative toxic effects of ATZ on serum oxidative stress indicators, serum testosterone levels, testicular IgA level and improved testicular CYP17A1 mRNA expression. In conclusion, QT in low dose and LC in both low and high doses exerted a significant protective action against the reproductive toxicity of ATZ, while higher dose of QT failed induce immune-stimulant effect against ATZ in adult male Albino rats. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

"Ecstasy" toxicity to adolescent rats following an acute low binge dose.

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Teixeira-Gomes, Armanda; Costa, Vera Marisa; Feio-Azevedo, Rita; Duarte, José Alberto; Duarte-Araújo, Margarida; Fernandes, Eduarda; Bastos, Maria de Lourdes; Carvalho, Félix; Capela, João Paulo

2016-06-28

3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") is a worldwide drug of abuse commonly used by adolescents. Most reports focus on MDMA's neurotoxicity and use high doses in adult animals, meanwhile studies in adolescents are scarce. We aimed to assess in rats the acute MDMA toxicity to the brain and peripheral organs using a binge dose scheme that tries to simulate human adolescent abuse. Adolescent rats (postnatal day 40) received three 5 mg/kg doses of MDMA (estimated equivalent to two/three pills in a 50 kg adolescent), intraperitoneally, every 2 h, while controls received saline. After 24 h animal sacrifice took place and collection of brain areas (cerebellum, hippocampus, frontal cortex and striatum) and peripheral organs (liver, heart and kidneys) occurred. Significant hyperthermia was observed after the second and third MDMA doses, with mean increases of 1 °C as it occurs in the human scenario. MDMA promoted ATP levels fall in the frontal cortex. No brain oxidative stress-related changes were observed after MDMA. MDMA-treated rat organs revealed significant histological tissue alterations including vascular congestion, but no signs of apoptosis or necrosis were found, which was corroborated by the lack of changes in plasma biomarkers and tissue caspases. In peripheral organs, MDMA did not affect significantly protein carbonylation, glutathione, or ATP levels, but liver presented a higher vulnerability as MDMA promoted an increase in quinoprotein levels. Adolescent rats exposed to a moderate MDMA dose, presented hyperthermia and acute tissue damage to peripheral organs without signs of brain oxidative stress.

Polyethylene glycol hydrogel rectal spacer implantation in patients with prostate cancer undergoing combination high-dose-rate brachytherapy and external beam radiotherapy.

Science.gov (United States)

Yeh, Jekwon; Lehrich, Brandon; Tran, Carolyn; Mesa, Albert; Baghdassarian, Ruben; Yoshida, Jeffrey; Torrey, Robert; Gazzaniga, Michael; Weinberg, Alan; Chalfin, Stuart; Ravera, John; Tokita, Kenneth

2016-01-01

To present rectal toxicity rates in patients administered a polyethylene glycol (PEG) hydrogel rectal spacer in conjunction with combination high-dose-rate brachytherapy and external beam radiotherapy. Between February 2010 and April 2015, 326 prostate carcinoma patients underwent combination high-dose-rate brachytherapy of 16 Gy (average dose 15.5 Gy; standard deviation [SD] = 1.6 Gy) and external beam radiotherapy of 59.4 Gy (average dose 60.2 Gy; SD = 2.9 Gy). In conjunction with the radiation therapy regimen, each patient was injected with 10 mL of a PEG hydrogel in the anterior perirectal fat space. The injectable spacer (rectal spacer) creates a gap between the prostate and the rectum. The rectum is displaced from the radiation field, and rectal dose is substantially reduced. The goal is a reduction in rectal radiation toxicity. Clinical efficacy was determined by measuring acute and chronic rectal toxicity using the National Cancer Center Institute Common Terminology Criteria for Adverse Events v4.0 grading scheme. Median followup was 16 months. The mean anterior-posterior separation achieved was 1.6 cm (SD = 0.4 cm). Rates of acute Grade 1 and 2 rectal toxicity were 37.4% and 2.8%, respectively. There were no acute Grade 3/4 toxicities. Rates of late Grade 1, 2, and 3 rectal toxicity were 12.7%, 1.4%, and 0.7%, respectively. There were no late Grade 4 toxicities. PEG rectal spacer implantation is safe and well tolerated. Acute and chronic rectal toxicities are low despite aggressive dose escalation. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Studies on the toxic interaction between monensin and tiamulin in rats: toxicity and pathology.

Science.gov (United States)

Szücs, G; Bajnógel, J; Varga, A; Móra, Z; Laczay, P

2000-01-01

The characteristics of the toxic interaction between monensin and tiamulin were investigated in rats. A three-day comparative oral repeated-dose toxicity study was performed in Phase I, when the effects of monensin and tiamulin were studied separately (monensin 10, 30, and 50 mg/kg or tiamulin 40, 120, and 200 mg/kg body weight, respectively). In Phase II, the two compounds were administered simultaneously to study the toxic interaction (monensin 10 mg/kg and tiamulin 40 mg/kg b.w., respectively). Monensin proved to be toxic to rats at doses of 30 and 50 mg/kg. Tiamulin was well tolerated up to the dose of 200 mg/kg. After combined administration, signs of toxicity were seen (including lethality in females). Monensin caused a dose-dependent cardiotoxic effect and vacuolar degeneration of the skeletal muscles in the animals given 50 mg/kg. Both compounds exerted a toxic effect on the liver in high doses. After simultaneous administration of the two compounds, there was a mild effect on the liver (females only), hydropic degeneration of the myocardium and vacuolar degeneration of the skeletal muscles. The alteration seen in the skeletal muscles was more marked than that seen after the administration of 50 mg/kg monensin alone.

High-dose myeloablative versus conventional low-dose radioimmunotherapy (RIT) of mantle cell lymphoma (MCL) with the chimeric anti-CD20 antibody C2B8

International Nuclear Information System (INIS)

Behr, T.M.; Gotthardt, M.; Schipperm, M.L.; Gratz, S.; Behe, M.P.; Brittinger, G.; Woermann, B.; Becker, W.

2002-01-01

CD20 has been used as target molecule for low-dose as well as high-dose, myeloablative RIT of B-cell NHL. MCL is an especially aggressive, prognostically unfavorable form of B-cell NHL. The aim of this study was to investigate whether high-dose, myeloablative RIT with the 131 I-labeled chimeric anti-CD20 antibody C2B8 (rituxan, Mabthera, Roche) may be therapeutically more effective than conventional low-dose therapy in MCL. A total of twelve patients with chemorefractory or relapsed mantle cell lymphoma were studied so far (all of them having relapsed after high-dose chemotherapy, seven of them combined with 12 Gy TBI). A diagnostic-dosimetric study was performed with 10 mCi of 131 I-C2B8 at a protein dose of 2.5 mg/kg. In case of splenic pooling, the protein dose was increased until a more 'favorable' biodistribution was obtained. Therapy was performed with conventional (30-75 mCi; n=4) or myeloablative activities (261-515 mCi; n=8) of 131 I-C2B8 at the previously optimized protein dose, aiming at whole-body doses of ≤ 0.8 Gy (for low-dose RIT) or lung doses of ≤ 27 Gy (for high-dose RIT). Clinical follow-up was obtained for up to 42 months. Overall, in 11 patients the 2.5 mg/kg protein dose was used, whereas in one patient with marked splenomegaly, 10 mg/kg were necessary to overcome the splenic antigenic sink. In the high-dose patients, non-hematologic toxicity was restricted to mild to moderate nausea, fever, transient bilirubin or liver enzyme elevations. Despite thyroid blocking, 6/8 high-dose (in contrast to 0/4 low-dose) patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. The response rate in the low-dose arm was only 1(PR)/4, whereas 7/8 high-dose patients experienced complete and the remainder a partial remission. 6 high-dose patients are still in CR (one of them relapsed locally at 3 months, one systemically at 26 months after RIT), and 7 are still alive for up to 42+ months. In contrast to low-dose therapy

High-dose-rate brachytherapy alone post-hysterectomy for endometrial cancer

International Nuclear Information System (INIS)

MacLeod, Craig; Fowler, Allan; Duval, Peter; D'Costa, Ieta; Dalrymple, Chris; Firth, Ian; Elliott, Peter; Atkinson, Ken; Carter, Jonathan

1998-01-01

Purpose: To evaluate the outcome of post-hysterectomy adjuvant vaginal high-dose-rate (HDR) brachytherapy. Methods and Materials: A retrospective analysis was performed on a series of 143 patients with endometrial cancer treated with HDR brachytherapy alone post-hysterectomy from 1985 to June 1993. Of these patients, 141 received 34 Gy in four fractions prescribed to the vaginal mucosa in a 2-week period. The median follow-up was 6.9 years. Patients were analyzed for treatment parameters, survival, local recurrence, distant relapse, and toxicity. Results: Five-year relapse free survival and overall survival was 100% and 88% for Stage 1A, 98% and 94% for Stage IB, 100% and 86% for Stage IC, and 92% and 92% for Stage IIA. The overall vaginal recurrence rate was 1.4%. The overall late-toxicity rate was low, and no RTOG grade 3, 4, or 5 complications were recorded. Conclusion: These results are similar to reported international series that have used either low-dose-rate or HDR brachytherapy. The biological effective dose was low for both acute and late responding tissues compared with some of the HDR brachytherapy series, and supports using this lower dose and possibly decreasing late side-effects with no apparent increased risk of vaginal recurrence

Dose-response study of the hematological toxicity induced by vectorized radionuclides in a mouse model

International Nuclear Information System (INIS)

Rousseau-Poivet, J.; Sas, N.; Nguyen, F.; Abadie, J.; Chouin, N.; Barbet, J.

2015-01-01

Full text of publication follows. Aim: in internal radiotherapy, the dose-limiting factor is often the bone marrow (BM) toxicity. In patients, its relationship with the BM absorbed dose seems to be elusive. Most probable reasons are the BM depletion following previous treatments associated to dose assessment complexity. To avoid this and better understand myelotoxicity mechanisms, we investigated hematopoiesis from BM to blood after radionuclide injections in healthy mice associated to individual BM dosimetry. Based on these data, a compartmental model was developed to predict the depletion of each mouse hematopoietic cell in a dose-dependent manner. Materials and methods: C57/Bl6 mice were injected with increasing activities of 18 FNa, an osteo-tropic agent. Mean absorbed doses to the BM were calculated using the MIRD formalism with the mineralized bone considered as the principal source of 18 FNa. Time-integrated activities within the skeleton were derived from dynamic micro PET-CT images. Hematological toxicity was monitored via blood cell counts and myeloid progenitor colony assays over time after injection. The myelotoxicity model consists in compartments for each hematopoietic cell. Its parameters were adjusted to reproduce experimental toxicities. Results: for an absorbed dose to the BM of 0.8 ± 0.1 Gy, myeloid progenitors showed a 84% depletion 84% at day 7 post-injection (D7) and a recovery at D14 for all precursors and D21 for the less differentiated progenitor. In blood, neutrocytopenia was observed at D3 (80% decrease) and recovered at D7. Thrombocytopenia was also noticed between D7 and D17 with a nadir at D7 (26% of depletion). The compartmental model predicted platelets kinetics in a satisfying manner. The nadir value, time to nadir and time to recovery were estimated with errors of 4.9%, 10.2% and 10% respectively. Whereas higher absorbed doses only increased platelets depletion (62% associated to 1.4 Gy), they extended the recovery time for all

Impact of Dose to the Bladder Trigone on Long-Term Urinary Function After High-Dose Intensity Modulated Radiation Therapy for Localized Prostate Cancer

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Ghadjar, Pirus; Zelefsky, Michael J.; Spratt, Daniel E. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Munck af Rosenschöld, Per; Oh, Jung Hun; Hunt, Margie [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Kollmeier, Marisa [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Happersett, Laura; Yorke, Ellen; Deasy, Joseph O. [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Jackson, Andrew, E-mail: jacksona@mskcc.org [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

2014-02-01

Purpose: To determine the potential association between genitourinary (GU) toxicity and planning dose–volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients. Methods and Materials: A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose–volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analyses were done by the Kaplan-Meier method and Cox proportional hazard models, respectively. Results: Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19). Conclusions: The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the

Uncommon toxicity of low-dose methotrexate: case report

Directory of Open Access Journals (Sweden)

Zohreh Yousefi

2015-10-01

Full Text Available Background: Standard treatment of Gestational Trophoblastic Disease (GTD is chemotherapy. Single-agent chemotherapy regime including Methotrexate (MTX or Actinomycin. Single-agent is widely used in treatment of persistent trophoblastic disease. We reported an uncommon toxicity of low-dose single-agent methotrexate in a patient. Case Presentation: A 20-year-old woman, primary gravid after two months missed period and spotting with diagnosis of incomplete abortion with uterine size equivalent of ten weeks pregnancy (8-10 cm underwent evacuation curettage. In serial follow-up, based on rise of beta-hCG titer and absence of metastatic disease, it was categorized as low-risk persistent trophoblastic disease. She was referred to gynecology oncology center of Ghaem Hospital, Mashhad University of Medical Sciences in May 2014. Because of rise of beta-hCG titer, after complete metastatic work-up and lack of disease in other sites, persistent disease was diagnosed and candidate for chemotherapy (single agent low-dose. The patient received first course of therapy with MTX (50 mg/m², intra muscular. Unfortunately, after two days of treatment she developed uncommon severe toxicity, fever, severe nausea and vomiting, tachycardia, and generalized weakness. Also, we found hematologic abnormality (WBC: -14000-15000 µI, platelet- 540 µI and sever neutropenia, and abnormal rising in liver function test (SGOT, SGPT (three to four times and renal function test (BUN and Creatinine (two times. In addition, she had disseminated erosive lesion in all of body especially in face. Due to the fatal side effects of chemotherapy, she was admitted to intensive care unit (ICU. Fortunately, after two to three weeks, she was improved by conservative management. After few weeks beta-hCG titer was in normal limit. However she had normal serial beta-hCG in one year of follow-up. Conclusion: It is important to emphasis unpredictable side effects of chemotherapy with low-dose

Hemolytic uremic syndrome after high dose chemotherapy with autologous stem cell support

NARCIS (Netherlands)

van der Lelie, H.; Baars, J. W.; Rodenhuis, S.; Van Dijk, M. A.; de Glas-Vos, C. W.; Thomas, B. L.; van Oers, R. H.; von dem Borne, A. E.

1995-01-01

BACKGROUND: Chemotherapy intensification may lead to new forms of toxicity such as hemolytic uremic syndrome. METHODS: Three patients are described who developed this complication 4 to 6 months after high dose chemotherapy followed by autologous stem cell support. The literature on this subject is

The Effect of Dose-Volume Parameters and Interfraction Interval on Cosmetic Outcome and Toxicity After 3-Dimensional Conformal Accelerated Partial Breast Irradiation

International Nuclear Information System (INIS)

Leonard, Kara Lynne; Hepel, Jaroslaw T.; Hiatt, Jessica R.; Dipetrillo, Thomas A.; Price, Lori Lyn; Wazer, David E.

2013-01-01

Purpose: To evaluate dose-volume parameters and the interfraction interval (IFI) as they relate to cosmetic outcome and normal tissue effects of 3-dimensional conformal radiation therapy (3D-CRT) for accelerated partial breast irradiation (APBI). Methods and Materials: Eighty patients were treated by the use of 3D-CRT to deliver APBI at our institutions from 2003-2010 in strict accordance with the specified dose-volume constraints outlined in the National Surgical Adjuvant Breast and Bowel Project B39/Radiation Therapy Oncology Group 0413 (NSABP-B39/RTOG 0413) protocol. The prescribed dose was 38.5 Gy in 10 fractions delivered twice daily. Patients underwent follow-up with assessment for recurrence, late toxicity, and overall cosmetic outcome. Tests for association between toxicity endpoints and dosimetric parameters were performed with the chi-square test. Univariate logistic regression was used to evaluate the association of interfraction interval (IFI) with these outcomes. Results: At a median follow-up time of 32 months, grade 2-4 and grade 3-4 subcutaneous fibrosis occurred in 31% and 7.5% of patients, respectively. Subcutaneous fibrosis improved in 5 patients (6%) with extended follow-up. Fat necrosis developed in 11% of women, and cosmetic outcome was fair/poor in 19%. The relative volume of breast tissue receiving 5%, 20%, 50%, 80%, and 100% (V5-V100) of the prescribed dose was associated with risk of subcutaneous fibrosis, and the volume receiving 50%, 80%, and 100% (V50-V100) was associated with fair/poor cosmesis. The mean IFI was 6.9 hours, and the minimum IFI was 6.2 hours. The mean and minimum IFI values were not significantly associated with late toxicity. Conclusions: The incidence of moderate to severe late toxicity, particularly subcutaneous fibrosis and fat necrosis and resulting fair/poor cosmesis, remains high with continued follow-up. These toxicity endpoints are associated with several dose-volume parameters. Minimum and mean IFI values were

Salvage high-dose-rate brachytherapy for local prostate cancer recurrence after radical radiotherapy

Directory of Open Access Journals (Sweden)

V. A. Solodkiy

2016-01-01

Full Text Available Studies salvage interstitial radiation therapy for recurrent prostate cancer, launched at the end of the XX century. In recent years, more and more attention is paid to high-dose-rate brachytherapy (HDR-BT as a method of treating local recurrence.The purpose of research – preliminary clinical results of salvage high-dose-rate brachytherapy applied in cases of suspected local recurrence or of residual tumour after radiotherapy.Preliminary findings indicate the possibility of using HDR-BT, achieving local tumor control with low genitourinary toxicity.

Periodical assessment of genitourinary and gastrointestinal toxicity in patients who underwent prostate low-dose-rate brachytherapy

International Nuclear Information System (INIS)

Tanaka, Nobumichi; Asakawa, Isao; Anai, Satoshi; Hirayama, Akihide; Hasegawa, Masatoshi; Konishi, Noboru; Fujimoto, Kiyohide

2013-01-01

To compare the periodical incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicity in patients who underwent prostate low-dose-rate brachytherapy between the monotherapy group (seed implantation alone) and the boost group (in combination with external beam radiation therapy (EBRT)). A total of 218 patients with a median follow-up of 42.5 months were enrolled. The patients were divided into 2 groups by treatment modality, namely, the monotherapy group (155 patients) and the boost group (63 patients). The periodical incidence rates of GU and GI toxicity were separately evaluated and compared between the monotherapy group and the boost group using the National Cancer Institute - Common Terminology Criteria for Adverse Events, version 3.0. To elucidate an independent factor among clinical and postdosimetric parameters to predict grade 2 or higher GU and GI toxicity in the acute and late phases, univariate and multivariate logistic regression analyses were carried out. Of all patients, 78.0% showed acute GU toxicity, and 7.8% showed acute GI toxicity, while 63.8% showed late GU toxicity, and 21.1% showed late GI toxicity. The incidence rates of late GU and GI toxicity were significantly higher in the boost group. Multivariate analysis showed that the International Prostate Symptom Score (IPSS) before seed implantation was a significant parameter to predict acute GU toxicity, while there were no significant predictive parameters for acute GI toxicity. On the other hand, combination with EBRT was a significant predictive parameter for late GU toxicity, and rectal volume (mL) receiving 100% of the prescribed dose (R100) was a significant predictive parameter for late GI toxicity. The boost group showed higher incidence rates of both GU and GI toxicity. Higher IPSS before seed implantation, combination with EBRT and a higher R100 were significant predictors for acute GU, late GU and late GI toxicity

Toxicity and cosmetic result of partial breast high-dose-rate interstitial brachytherapy for conservatively operated early breast cancer

International Nuclear Information System (INIS)

Xiu Xia; Tripuraneni Prabhakar; Giap Huan; Lin Ray; Chu Colin

2007-01-01

Objective: Objective To study the method, side effects and cosmetic outcome of high- dose-rate (HDR) accelerated partial breast interstitial irradiation (APBI) alone in early stage breast cancer' after conservative surgery. Methods: From February 2002 to June 2003,47 breast cancer lesions from 46 patients suffering from stage I/II breast cancer were treated with HDR 192 Ir APBI after conservative surgery. All patients were over 40 year-old, with T1-2N0-1 (≤3 lymph nodes positive), surgical margin > 1-2 mm, but those having lobular or inflammatory breast cancer were excluded. HDR brachytherapy with 34 Gy, 10 fractions/5 days was used after surgery, toxic reaction and cosmetic outcome were observed in one month, 6 and 12 months respectively. Results: Follow up of 1846 months, 34 months was carried out for the whole group. During the treatment, acute reactions including: erythema, edema, tenderness and infection, all under I-II grade, none of III-IV grade were observed in 21 patients(46%); late toxicity reactions: skin fibrosis, breast tenderness, fat necrosis, and telangiectasia, totally 20 patients (43%) were observed: 2 patients in III grade but one patient received 6 cycle chemotherapy. The result of cosmetic outcome evaluation was excellent or good, at 6 months 95% and 12 months 98%, respectively, but there was no recurfence. Conclusions: Excellent and favorable cosmetic results are noted after APBI by interstitial alone. Acute and late reactions are few. Long term observation is necessary for the rate of' local control. (authors)

Toxicity of titanium dioxide nanoparticles: Effect of dose and time on biochemical disturbance, oxidative stress and genotoxicity in mice.

Science.gov (United States)

Rizk, Maha Z; Ali, Sanaa A; Hamed, Manal A; El-Rigal, Nagy Saba; Aly, Hanan F; Salah, Heba H

2017-06-01

The toxic impact of titanium dioxide nanoparticles (TiO 2 NPs) on human health is of prime importance owing to their wide uses in many commercial industries. In the present study, the effect of different doses and exposure time durations of TiO 2 NPs (21nm) inducing oxidative stress, biochemical disturbance, histological alteration and cytogenetic aberration in mice liver and bone marrow was investigated. Different doses of (TiO 2 NPs) (50, 250 and 500mg/kg body weight) were each daily intrapertioneally injected to mice for 7, 14 and 45days. Aspartate and alanine aminotransferases (AST &ALT), gamma glutamyl transpeptidase (GGT), total protein, total antioxidant capacity (TAC), malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and nitric oxide (NO) levels were measured. The work was extended to evaluate the liver histopathological pattern and the chromosomal aberration in mice spinal cord bone marrow. The results revealed severe TiO 2 NPs toxicity in a dose and time dependent manner with positive correlation (r=0.98) for most investigated biochemical parameters. The same observation was noticed for the histological analysis. In case of cytogenetic study, chromosomal aberrations were demonstrated after injection of TiO 2 NPs with 500mg/kg b. wt. for 45days. In conclusion, the selected biochemical parameters and the liver architectures were influenced with dose and time of TiO 2 NPs toxicity, while the genetic disturbance started at the high dose of exposure and for long duration. Further studies are needed to fulfil the effect of TiO 2 NPs on pharmaceutical and nutritional applications. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Low-dose total skin electron beam therapy for cutaneous lymphoma : Minimal risk of acute toxicities.

Science.gov (United States)

Kroeger, Kai; Elsayad, Khaled; Moustakis, Christos; Haverkamp, Uwe; Eich, Hans Theodor

2017-12-01

Low-dose total skin electron beam therapy (TSEBT) is attracting increased interest for the effective palliative treatment of primary cutaneous T‑cell lymphoma (pCTCL). In this study, we compared toxicity profiles following various radiation doses. We reviewed the records of 60 patients who underwent TSEBT for pCTCL between 2000 and 2016 at the University Hospital of Munster. The treatment characteristics of the radiotherapy (RT) regimens and adverse events (AEs) were then analyzed and compared. In total, 67 courses of TSEBT were administered to 60 patients. Of these patients, 34 (51%) received a standard dose with a median surface dose of 30 Gy and 33 patients (49%) received a low dose with the median surface dose of 12 Gy (7 salvage low-dose TSEBT courses were administered to 5 patients). After a median follow-up of 15 months, the overall AE rate was 100%, including 38 patients (57%) with grade 2 and 7 (10%) with grade 3 AEs. Patients treated with low-dose TSEBT had significantly fewer grade 2 AEs than those with conventional dose regimens (33 vs. 79%, P dose regimen compared to those with the conventional dose regimens (6 vs. 15%, P = 0.78). Multiple/salvage low-dose TSEBT courses were not associated with an increased risk of acute AEs. Low-dose TSEBT regimens are associated with significantly fewer grade 2 acute toxicities compared with conventional doses of TSEBT. Repeated/Salvage low-dose TSEBT, however, appears to be tolerable and can even be applied safely in patients with cutaneous relapses.

Toxicity risk of non-target organs at risk receiving low-dose radiation: case report

International Nuclear Information System (INIS)

Shueng, Pei-Wei; Lin, Shih-Chiang; Chang, Hou-Tai; Chong, Ngot-Swan; Chen, Yu-Jen; Wang, Li-Ying; Hsieh, Yen-Ping; Hsieh, Chen-Hsi

2009-01-01

The spine is the most common site for bone metastases. Radiation therapy is a common treatment for palliation of pain and for prevention or treatment of spinal cord compression. Helical tomotherapy (HT), a new image-guided intensity modulated radiotherapy (IMRT), delivers highly conformal dose distributions and provides an impressive ability to spare adjacent organs at risk, thus increasing the local control of spinal column metastases and decreasing the potential risk of critical organs under treatment. However, there are a lot of non-target organs at risk (OARs) occupied by low dose with underestimate in this modern rotational IMRT treatment. Herein, we report a case of a pathologic compression fracture of the T9 vertebra in a 55-year-old patient with cholangiocarcinoma. The patient underwent HT at a dose of 30 Gy/10 fractions delivered to T8-T10 for symptom relief. Two weeks after the radiotherapy had been completed, the first course of chemotherapy comprising gemcitabine, fluorouracil, and leucovorin was administered. After two weeks of chemotherapy, however, the patient developed progressive dyspnea. A computed tomography scan of the chest revealed an interstitial pattern with traction bronchiectasis, diffuse ground-glass opacities, and cystic change with fibrosis. Acute radiation pneumonitis was diagnosed. Oncologists should be alert to the potential risk of radiation toxicities caused by low dose off-targets and abscopal effects even with highly conformal radiotherapy

High-dose-rate brachytherapy as salvage modality for locally recurrent prostate cancer after definitive radiotherapy. A systematic review

International Nuclear Information System (INIS)

Chatzikonstantinou, Georgios; Zamboglou, Nikolaos; Roedel, Claus; Tselis, Nikolaos; Zoga, Eleni; Strouthos, Iosif; Butt, Saeed Ahmed

2017-01-01

To review the current status of interstitial high-dose-rate brachytherapy as a salvage modality (sHDR BRT) for locally recurrent prostate cancer after definitive radiotherapy (RT). A literature search was performed in PubMed using ''high-dose-rate, brachytherapy, prostate cancer, salvage'' as search terms. In all, 51 search results published between 2000 and 2016 were identified. Data tables were generated and summary descriptions created. The main outcome parameters used were biochemical control (BC) and toxicity scores. Eleven publications reported clinical outcome and toxicity with follow-up ranging from 4-191 months. A variety of dose and fractionation schedules were described, including 19.0 Gy in 2 fractions up to 42.0 Gy in 6 fractions. The 5-year BC ranged from 18-77%. Late grade 3 genitourinary and gastrointestinal toxicity was 0-32% and 0-5.1%, respectively. sHDR BRT appears as safe and effective salvage modality for the reirradiation of locally recurrent prostate cancer after definitive RT. (orig.) [de

A method for comparison of animal and human alveolar dose and toxic effect of inhaled ozone

International Nuclear Information System (INIS)

Hatch, G.E.; Koren, H.; Aissa, M.

1989-01-01

Present models for predicting the pulmonary toxicity of O 3 in humans from the toxic effects observed in animals rely on dosimetric measurements of O 3 mass balance and species comparisons of mechanisms that protect tissue against O 3 . The goal of the study described was to identify a method to directly compare O 3 dose and effect in animals and humans using bronchoalveolar lavage fluid markers. The feasibility of estimating O 3 dose to alveoli of animals and humans was demonstrated through assay of reaction products of 18 O-labeled O 3 in lung surfactant and macrophage pellets of rabbits. The feasibility of using lung lavage fluid protein measurements to quantify the O 3 toxic response in humans was demonstrated by the finding of significantly increased lung lavage protein in 10 subjects exposed to 0.4 ppm O 3 for 2 h with intermittent periods of heavy exercise. The validity of using the lavage protein marker to quantify the response in animals has already been established. The positive results obtained in both the 18 O 3 and the lavage protein studies reported here suggest that it should be possible to obtain a direct comparison of both alveolar dose and toxic effect of O 3 to alveoli of animals or humans

Pretreatment by low-dose fibrates protects against acute free fatty acid-induced renal tubule toxicity by counteracting PPARα deterioration

International Nuclear Information System (INIS)

Takahashi, Kyoko; Kamijo, Yuji; Hora, Kazuhiko; Hashimoto, Koji; Higuchi, Makoto; Nakajima, Takero; Ehara, Takashi; Shigematsu, Hidekazu; Gonzalez, Frank J.; Aoyama, Toshifumi

2011-01-01

Development of a preventive strategy against tubular damage associated with proteinuria is of great importance. Recently, free fatty acid (FFA) toxicities accompanying proteinuria were found to be a main cause of tubular damage, which was aggravated by insufficiency of peroxisome proliferator-activated receptor alpha (PPARα), suggesting the benefit of PPARα activation. However, an earlier study using a murine acute tubular injury model, FFA-overload nephropathy, demonstrated that high-dose treatment of PPARα agonist (0.5% clofibrate diet) aggravated the tubular damage as a consequence of excess serum accumulation of clofibrate metabolites due to decreased kidney elimination. To induce the renoprotective effects of PPARα agonists without drug accumulation, we tried a pretreatment study using low-dose clofibrate (0.1% clofibrate diet) using the same murine model. Low-dose clofibrate pretreatment prevented acute tubular injuries without accumulation of its metabolites. The tubular protective effects appeared to be associated with the counteraction of PPARα deterioration, resulting in the decrease of FFAs influx to the kidney, maintenance of fatty acid oxidation, diminution of intracellular accumulation of undigested FFAs, and attenuation of disease developmental factors including oxidative stress, apoptosis, and NFκB activation. These effects are common to other fibrates and dependent on PPARα function. Interestingly, however, clofibrate pretreatment also exerted PPARα-independent tubular toxicities in PPARα-null mice with FFA-overload nephropathy. The favorable properties of fibrates are evident when PPARα-dependent tubular protective effects outweigh their PPARα-independent tubular toxicities. This delicate balance seems to be easily affected by the drug dose. It will be important to establish the appropriate dosage of fibrates for treatment against kidney disease and to develop a novel PPARα activator that has a steady serum concentration regardless of

Intensity modulated radiotherapy for localized prostate cancer: rigid compliance to dose-volume constraints as a warranty of acceptable toxicity?

International Nuclear Information System (INIS)

Chen, Michael J; Nadalin, Wladmir; Weltman, Eduardo; Hanriot, Rodrigo M; Luz, Fábio P; Cecílio, Paulo J; Cruz, José C da; Moreira, Frederico R; Santos, Adriana S; Martins, Lidiane C

2007-01-01

To report the toxicity after intensity modulated radiotherapy (IMRT) for patients with localized prostate cancer, as a sole treatment or after radical prostatectomy. Between August 2001 and December 2003, 132 patients with prostate cancer were treated with IMRT and 125 were evaluable to acute and late toxicity analysis, after a minimum follow-up time of one year. Clinical and treatment data, including normal tissue dose-volume histogram (DVH) constraints, were reviewed. Gastro-intestinal (GI) and genito-urinary (GU) signs and symptoms were evaluated according to the Radiation Therapy Oncology Group (RTOG) toxicity scales. Median prescribed dose was 76 Gy. Median follow-up time was of 26.1 months. From the 125 patients, 73 (58.4%) presented acute Grade 1 or Grade 2 GI and 97 (77.2%) presented acute Grade 1 or Grade 2 GU toxicity. Grade 3 GI acute toxicity occurred in only 2 patients (1.6%) and Grade 3 GU acute toxicity in only 3 patients (2.4%). Regarding Grade 1 and 2 late toxicity, 26 patients (20.8%) and 21 patients (16.8%) presented GI and GU toxicity, respectively. Grade 2 GI late toxicity occurred in 6 patients (4.8%) and Grade 2 GU late toxicity in 4 patients (3.2%). None patient presented any Grade 3 or higher late toxicity. Non-conformity to DVH constraints occurred in only 11.2% of treatment plans. On univariate analysis, no significant risk factor was identified for Grade 2 GI late toxicity, but mean dose delivered to the PTV was associated to higher Grade 2 GU late toxicity (p = 0.042). IMRT is a well tolerable technique for routine treatment of localized prostate cancer, with short and medium-term acceptable toxicity profiles. According to the data presented here, rigid compliance to DHV constraints might prevent higher incidences of normal tissue complication

Renal function affects absorbed dose to the kidneys and haematological toxicity during {sup 177}Lu-DOTATATE treatment

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Svensson, Johanna; Berg, Gertrud [Sahlgrenska University Hospital, Department of Oncology, Goeteborg (Sweden); Waengberg, Bo [Sahlgrenska University Hospital, Department of Surgery, Goeteborg (Sweden); Larsson, Maria [University of Gothenburg, Department of Radiation Physics, Institute of Clinical Sciences, The Sahlgrenska Academy, Goeteborg (Sweden); Forssell-Aronsson, Eva; Bernhardt, Peter [University of Gothenburg, Department of Radiation Physics, Institute of Clinical Sciences, The Sahlgrenska Academy, Goeteborg (Sweden); Sahlgrenska University Hospital, Department of Medical Physics and Medical Bioengineering, Goeteborg (Sweden)

2015-05-01

Peptide receptor radionuclide therapy (PRRT) has become an important treatment option in the management of advanced neuroendocrine tumours. Long-lasting responses are reported for a majority of treated patients, with good tolerability and a favourable impact on quality of life. The treatment is usually limited by the cumulative absorbed dose to the kidneys, where the radiopharmaceutical is reabsorbed and retained, or by evident haematological toxicity. The aim of this study was to evaluate how renal function affects (1) absorbed dose to the kidneys, and (2) the development of haematological toxicity during PRRT treatment. The study included 51 patients with an advanced neuroendocrine tumour who received {sup 177}Lu-DOTATATE treatment during 2006 - 2011 at Sahlgrenska University Hospital in Gothenburg. An average activity of 7.5 GBq (3.5 - 8.2 GBq) was given at intervals of 6 - 8 weeks on one to five occasions. Patient baseline characteristics according to renal and bone marrow function, tumour burden and medical history including prior treatment were recorded. Renal and bone marrow function were then monitored during treatment. Renal dosimetry was performed according to the conjugate view method, and the residence time for the radiopharmaceutical in the whole body was calculated. A significant correlation between inferior renal function before treatment and higher received renal absorbed dose per administered activity was found (p < 0.01). Patients with inferior renal function also experienced a higher grade of haematological toxicity during treatment (p = 0.01). The residence time of {sup 177}Lu in the whole body (range 0.89 - 3.0 days) was correlated with grade of haematological toxicity (p = 0.04) but not with renal absorbed dose (p = 0.53). Patients with inferior renal function were exposed to higher renal absorbed dose per administered activity and developed a higher grade of haematological toxicity during {sup 177}Lu-DOTATATE treatment. The study confirms the

In vivo assessment of the gastric mucosal tolerance dose after single fraction, small volume irradiation of liver malignancies by computed tomography-guided, high-dose-rate brachytherapy

International Nuclear Information System (INIS)

Streitparth, Florian; Pech, Maciej; Boehmig, Michael; Ruehl, Ricarda; Peters, Nils; Wieners, Gero; Steinberg, Johannes; Lopez-Haenninen, Enrique; Felix, Roland; Wust, Peter; Ricke, Jens

2006-01-01

Purpose: The aim of this study was to assess the tolerance dose of gastric mucosa for single-fraction computed tomography (CT)-guided, high-dose-rate (HDR) brachytherapy of liver malignancies. Methods and Materials: A total of 33 patients treated by CT-guided HDR brachytherapy of liver malignancies in segments II and/or III were included. Dose planning was performed upon a three-dimensional CT data set acquired after percutaneous applicator positioning. All patients received gastric protection post-treatment. For further analysis, the contours of the gastric wall were defined in every CT slice using Brachyvision Software. Dose-volume histograms were calculated for each treatment and correlated with clinical data derived from questionnaires assessing Common Toxicity Criteria (CTC). All patients presenting symptoms of upper GI toxicity were examined endoscopically. Results: Summarizing all patients the minimum dose applied to 1 ml of the gastric wall (D 1ml ) ranged from 6.3 to 34.2 Gy; median, 14.3 Gy. Toxicity was present in 18 patients (55%). We found nausea in 16 (69%), emesis in 9 (27%), cramping in 13 (39%), weight loss in 12 (36%), gastritis in 4 (12%), and ulceration in 5 patients (15%). We found a threshold dose D 1ml of 11 Gy for general gastric toxicity and 15.5 Gy for gastric ulceration verified by an univariate analysis (p = 0.01). Conclusions: For a single fraction, small volume irradiation we found in the upper abdomen a threshold dose D 1ml of 15.5 Gy for the clinical endpoint ulceration of the gastric mucosa. This in vivo assessment is in accordance with previously published tolerance data

SU-E-J-93: Parametrisation of Dose to the Mucosa of the Anterior Rectal Wall in Transrectal Ultrasound Guided High-Dose-Rate Brachytherapy of the Prostate

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Aitkenhead, A; Hamlett, L; Wood, D; Choudhury, A [The Christie Hospital NHS Foundation Trust, Manchester, Greater Manchester (United Kingdom)

2014-06-01

Purpose: In high-dose-rate (HDR) brachytherapy of the prostate, radiation is delivered from a number of radioactive sources which are inserted via catheter into the target volume. The rectal mucosa also receives dose during the treatment, which may lead to late toxicity effects. To allow possible links between rectal dose and toxicity to be investigated, suitable methods of parametrising the rectal dose are needed. Methods: During treatment of a series of 95 patients, anatomy and catheter locations were monitored by transrectal ultrasound, and target volume positions were contoured on the ultrasound scan by the therapist. The anterior rectal mucosal wall was identified by contouring the transrectal ultrasound balloon within the ultrasound scan. Source positions and dwell times, along with the dose delivered to the patient were computed using the Oncentra Prostate treatment planning system (TPS). Data for the series of patients were exported from the TPS in Dicom format, and a series of parametrisation methods were developed in a Matlab environment to assess the rectal dose. Results: Contours of the anterior rectal mucosa were voxelised within Matlab to allow the dose to the rectal mucosa to be analysed directly from the 3D dose grid. Dose parametrisations based on dose-surface (DSH) and dose-line (DLH) histograms were obtained. Both lateral and longitudinal extents of the mucosal dose were parametrised using dose-line histograms in the relevant directions. Conclusion: We have developed a series of dose parametrisations for quantifying the dose to the rectal mucosa during HDR prostate brachytherapy which are suitable for future studies investigating potential associations between mucosal dose and late toxicity effects. The geometry of the transrectal probe standardises the rectal anatomy, making this treatment technique particularly suited to studies of this nature.

SU-E-J-93: Parametrisation of Dose to the Mucosa of the Anterior Rectal Wall in Transrectal Ultrasound Guided High-Dose-Rate Brachytherapy of the Prostate

International Nuclear Information System (INIS)

Aitkenhead, A; Hamlett, L; Wood, D; Choudhury, A

2014-01-01

Purpose: In high-dose-rate (HDR) brachytherapy of the prostate, radiation is delivered from a number of radioactive sources which are inserted via catheter into the target volume. The rectal mucosa also receives dose during the treatment, which may lead to late toxicity effects. To allow possible links between rectal dose and toxicity to be investigated, suitable methods of parametrising the rectal dose are needed. Methods: During treatment of a series of 95 patients, anatomy and catheter locations were monitored by transrectal ultrasound, and target volume positions were contoured on the ultrasound scan by the therapist. The anterior rectal mucosal wall was identified by contouring the transrectal ultrasound balloon within the ultrasound scan. Source positions and dwell times, along with the dose delivered to the patient were computed using the Oncentra Prostate treatment planning system (TPS). Data for the series of patients were exported from the TPS in Dicom format, and a series of parametrisation methods were developed in a Matlab environment to assess the rectal dose. Results: Contours of the anterior rectal mucosa were voxelised within Matlab to allow the dose to the rectal mucosa to be analysed directly from the 3D dose grid. Dose parametrisations based on dose-surface (DSH) and dose-line (DLH) histograms were obtained. Both lateral and longitudinal extents of the mucosal dose were parametrised using dose-line histograms in the relevant directions. Conclusion: We have developed a series of dose parametrisations for quantifying the dose to the rectal mucosa during HDR prostate brachytherapy which are suitable for future studies investigating potential associations between mucosal dose and late toxicity effects. The geometry of the transrectal probe standardises the rectal anatomy, making this treatment technique particularly suited to studies of this nature

Study on a 4-Week Recovery Test of Sweet Bee Venom after a 13-Week, Repeated, Intramuscular Dose Toxicity Test in Sprague-Dawley Rats

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Chungsan Lim

2014-06-01

Full Text Available Objectives:This study was performed to check for reversibility in the changes induced by a 13-week, repeated, dose toxicity test of Sweet Bee Venom (SBV in Sprague-Dawley (SD rats. Methods:Fifteen male and 15 female SD rats were treated with 0.28 mg/kg of SBV (high-dosage group and the same numbers of male and female SD rats were treated with 0.2 mL/kg of normal saline (control group for 13 weeks. We selected five male and five female SD rats from the high-dosage group and the same numbers of male and female SD rats from the control group, and we observed these rats for four weeks. We conducted body-weight measurements, ophthalmic examinations, urinalyses and hematology, biochemistry, histology tests. Results:(1 Hyperemia and movement disorder were observed in the 13-week, repeated, dose toxicity test, but these symptoms were not observed during the recovery period. (2 The rats in the high-dose group showed no significant changes in weight compared to the control group. (3 No significant differences in the ophthalmic parameters, urine analyses, complete blood cell counts (CBCs, and biochemistry were observed among the recovery groups. (4 No changes in organ weights were observed during the recovery period. (5 Histological examination of the thigh muscle indicated cell infiltration, inflammation, degeneration, necrosis of muscle fiber, and fibrosis during the treatment period, but these changes were not observed during the recovery period. The fatty liver change that was observed during the toxicity test was not observed during the recovery period. No other organ abnormalities were observed. Conclusion:The changes that occurred during the 13-week, repeated, dose toxicity test are reversible, and SBV can be safely used as a treatment modality.

[Exposure to toxic dose of adrenaline on the functional state of the liver].

Science.gov (United States)

Kopylova, S V; Vlasova, K M; Anashkina, A A

2017-01-01

The blood biochemical parameters characterizing the functional state of the liver, and the morphological profile of the body after a single exposure to a toxic dose of adrenaline were studied. Studies were conducted on 60 adult rats (female) weighing 0.15-0.2 kg, were divided into groups: intact animals; experience - animals, injected with epinephrine hydrochloride intraperitoneally in a dose of 0.5 mg/kg. All kinds of Biological material (blood, liver) were collected out through one and ten days after the start of the experiment. The degree of influence of high doses of epinephrine were evaluated in terms of lipid peroxidation (LPO) and protein (PSP) in liver homogenates, the concentration of average weight molecules (MSM), the activity of ALT, AST, alkaline phosphatase, LDH, total protein concentration, glucose and lactate in the blood plasma, as well as the determination of the prothrombin time (PTT) with the counting on the basis thereof of international normalized ration (INR). Histology of the liver was studied by light microscopy. It was found that throughout the experiment, there was an increased in the concentration of lipid peroxidation products and protein in liver homogenates, there was an increase in the concentration of MSM 1.7. Twenty-four hours after the administration of a toxic dose of adrenaline observed hyperenzymemia that manifested an increase in the activity of ALT and AST, was an increase in LDH. After 10-day five after the start of the experiment established the presence hyperenzymemia activity decreased ALT and AST, LDH activity remained elevated, total protein level was higher than in the group of animal in which investigations were conducted one day after the start of the experiment, PTV also continued to decline. In histological sections of the development of a pathological condition characterized by circulatory disturbance - plasmatization, both in central and in small vessels. From the hepatocytes both in the center and the periphery

Biological impact of high-dose and dose-rate radiation exposure

International Nuclear Information System (INIS)

Maliev, V.; Popov, D.; Jones, J.; Gonda, S.; Prasad, K.; Viliam, C.; Haase, G.; Kirchin, V.; Rachael, C.

2006-01-01

radiation, a time after radiation, individual and situational conditions of the irradiated object and the environment. A group of essential radiation toxins with antigenic properties expressed significantly and specifically for different forms of the radiation disease represents the group of compounds: glycoproteins and lipoproteins that accumulate in the lymphatic system of mammals at once in the first hours after radiation. The molecular weight of radiation toxins of S.D.R. group constitutes 200-250 k DA. The essential radiation toxins, preparations of S.D.R. (Specific Radiation Determinant), were isolated from the lymphatic system of laboratory and agricultural animals that were irradiated by doses capable to induce development of cerebral (S.D.R. - 1), toxic (S.D.R.-2), gastrointestinal (S.D.R.-3) and typical (S.D.R.-4) forms of the acute radiation disease. Biological properties and reproduction effects of preparations of essential radiation toxins of S.D.R. group depended on a magnitude of radiation doses that animal-donors absorbed being irradiated. The essential radiation toxins of S.D.R. group isolated from the lymphatic system of irradiated animals and injected by the different doses to intact animals can provide the effects which induce development of different forms of the acute radiation disease. Different doses of active biological substance of S.D.R. can provide different effects:1. Optimal doses are necessary for an active immune response and radioprotection effects 2. Toxic doses can induce and stimulate the radiation disease. Optimal doses of S.D.R. preparations applied for active immunization are determined very individually and depend on species of laboratory animals, their weight and gender. Toxic doses of S.D.R. preparations can cause, stimulate and imitate the development of different forms of the acute radiation syndromes and any consequences of the acute radiation disorder. Previously researchers allow making assumption what toxic doses of biological

Biological impact of high-dose and dose-rate radiation exposure

Energy Technology Data Exchange (ETDEWEB)

Maliev, V.; Popov, D. [Russian Academy of Science, Vladicaucas (Russian Federation); Jones, J.; Gonda, S. [NASA -Johnson Space Center, Houston (United States); Prasad, K.; Viliam, C.; Haase, G. [Antioxida nt Research Institute, Premier Micronutrient Corporation, Novato (United States); Kirchin, V. [Moscow State Veterinary and Biotechnology Acade my, Moscow (Russian Federation); Rachael, C. [University Space Research Association, Colorado (United States)

2006-07-01

radiation, a time after radiation, individual and situational conditions of the irradiated object and the environment. A group of essential radiation toxins with antigenic properties expressed significantly and specifically for different forms of the radiation disease represents the group of compounds: glycoproteins and lipoproteins that accumulate in the lymphatic system of mammals at once in the first hours after radiation. The molecular weight of radiation toxins of S.D.R. group constitutes 200-250 k DA. The essential radiation toxins, preparations of S.D.R. (Specific Radiation Determinant), were isolated from the lymphatic system of laboratory and agricultural animals that were irradiated by doses capable to induce development of cerebral (S.D.R. - 1), toxic (S.D.R.-2), gastrointestinal (S.D.R.-3) and typical (S.D.R.-4) forms of the acute radiation disease. Biological properties and reproduction effects of preparations of essential radiation toxins of S.D.R. group depended on a magnitude of radiation doses that animal-donors absorbed being irradiated. The essential radiation toxins of S.D.R. group isolated from the lymphatic system of irradiated animals and injected by the different doses to intact animals can provide the effects which induce development of different forms of the acute radiation disease. Different doses of active biological substance of S.D.R. can provide different effects:1. Optimal doses are necessary for an active immune response and radioprotection effects 2. Toxic doses can induce and stimulate the radiation disease. Optimal doses of S.D.R. preparations applied for active immunization are determined very individually and depend on species of laboratory animals, their weight and gender. Toxic doses of S.D.R. preparations can cause, stimulate and imitate the development of different forms of the acute radiation syndromes and any consequences of the acute radiation disorder. Previously researchers allow making assumption what toxic doses of biological

Optimal dose-response relationships in voice therapy.

Science.gov (United States)

Roy, Nelson

2012-10-01

Like other areas of speech-language pathology, the behavioural management of voice disorders lacks precision regarding optimal dose-response relationships. In voice therapy, dosing can presumably vary from no measurable effect (i.e., no observable benefit or adverse effect), to ideal dose (maximum benefit with no adverse effects), to doses that produce toxic or harmful effects on voice production. Practicing specific vocal exercises will inevitably increase vocal load. At ideal doses, these exercises may be non-toxic and beneficial, while at intermediate or high doses, the same exercises may actually be toxic or damaging to vocal fold tissues. In pharmacology, toxicity is a critical concept, yet it is rarely considered in voice therapy, with little known regarding "effective" concentrations of specific voice therapies vs "toxic" concentrations. The potential for vocal fold tissue damage related to overdosing on specific vocal exercises has been under-studied. In this commentary, the issue of dosing will be explored within the context of voice therapy, with particular emphasis placed on possible "overdosing".

Second salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer

Directory of Open Access Journals (Sweden)

Metha Maenhout

2017-04-01

Full Text Available Purpose : Salvage treatments for localized radiorecurrent prostate cancer can be performed safely when a focal and image guided approach is used. Due to the low toxicity, the opportunity exists to investigate a second salvage treatment when a second locally recurrent prostate cancer occurs. Here, we describe a second salvage treatment procedure of 4 patients. Material and methods : Four patients with a pathologically proven second local recurrence were treated in an outpatient magnetic resonance imaging (MRI-guided setting with a single fraction of 19 Gy focal high-dose-rate brachytherapy (HDR-BT. Delineation was performed using choline-PET-CT or a 68Ga-PSMA PET in combination with multiparametric 3 Tesla MRI in all four patients. Toxicity was measured using common toxicity criteria for adverse events (CTCAE version 4.0. Results : With a median follow-up of 12 months (range, 6-15, there were 2 patients with biochemical recurrence as defined by the Phoenix-definition. There were no patients with grade 3 or more toxicity. In all second salvage HDR-BT treatments, the constraints for rectum, bladder, and urethra were met. Median treatment volume (GTV was 4.8 cc (range, 1.9-6.6 cc. A median of 8 catheters (range, 6-9 were used, and the median dose to the treatment volume (GTV was a D95: 19.3 Gy (SD 15.5-19.4 Gy. Conclusions : Second focal salvage MRI-guided HDR-BT for a select group of patients with a second locally recurrent prostate cancer is feasible. There was no grade 3 or more acute toxicity for these four patients.

Health-Related Quality of Life After Single-Fraction High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy for Prostate Cancer

International Nuclear Information System (INIS)

Morton, Gerard C.; Loblaw, D. Andrew; Chung, Hans; Tsang, Gail; Sankreacha, Raxa; Deabreu, Andrea; Zhang Liying; Mamedov, Alexandre; Cheung, Patrick; Batchelar, Deidre; Danjoux, Cyril; Szumacher, Ewa

2011-01-01

Purpose: To investigate the change in health-related quality of life for men after high-dose-rate brachytherapy and external beam radiotherapy for prostate cancer and the factors associated with this change. Methods and Materials: Eligible patients had clinically localized intermediate-risk prostate cancer. The patients received high-dose-rate brachytherapy as a single 15-Gy implant, followed by external beam radiotherapy to 37.5 Gy in 15 fractions. The patients were monitored prospectively for toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]). The proportion of patients developing a clinically significant difference in the EPIC domain score (minimally important difference of >0.5 standard deviation) was determined and correlated with the baseline clinical and dosimetric factors. The study accrued 125 patients, with a median follow-up of 24 months. Results: By 24 months, 23% had Grade 2 urinary toxicity and only 5% had Grade 2 bowel toxicity, with no Grade 3 toxicity. The proportion of patients reporting a significant decrease in EPIC urinary, bowel, sexual, and hormonal domain scores was 53%, 51%, 45%, and 40% at 12 months and 57%, 65%, 51%, and 30% at 24 months, respectively. The proportion with a >1 standard deviation decrease in the EPIC urinary, bowel, sexual, and hormonal domain scores was 38%, 36%, 24%, and 20% at 12 months and 46%, 48%, 19%, and 8% at 24 months, respectively. On multivariate analysis, the dose to 10% of the urethra was associated with a decreasing EPIC urinary domain score (p = .0089) and, less strongly (p = .0312) with a decreasing hormonal domain score. No association was found between the prostate volume, bladder dose, or high-dose volume and urinary health-related quality of life. A high baseline International Index of Erectile Function score was associated (p = .0019) with a decreasing sexual domain score. The optimal maximal dose

Effect of a High Dose of Three Antibiotics on the Reproduction of a Parthenogenetic Strain of Folsomia candida (Isotomidae: Collembola)

DEFF Research Database (Denmark)

Giordano, R.; Weber, E; Waite, J

2010-01-01

Folsomia candida Willem (Isotomidae: Collembola) is an edaphic parthenogenetic species commonly used in ecotoxicity studies. We exposed F. candida to a high dose of three antibiotics, tylosin, ampicillin, and oxytetracycline, that target different bacterial groups. Possible toxic effects were...... assessed through egg production, hatching, and body size. All three antibiotics caused toxic effects. Treatment with oxytetracycline proved the most toxic. This group showed the smallest body size and lowest number of eggs laid, likely the result of a combination of antibiotic toxicity and avoidance...... of the antibiotic spiked food. Active toxin avoidance by F. candida in toxicological assays may play a role in minimizing their exposure to toxic compounds. Despite the administration of high doses of oxytetracycline, F. candida individuals remained infected with the intracellular bacteria Wolbachia indicating...

Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response

International Nuclear Information System (INIS)

Skwarchuk, Mark W.; Jackson, Andrew; Zelefsky, Michael J.; Venkatraman, Ennapadam S.; Cowen, Didier M.; Levegruen, Sabine; Burman, Chandra M.; Fuks, Zvi; Leibel, Steven A.; Ling, C. Clifton

2000-01-01

Purpose: The purpose of this paper is to use the outcome of a dose escalation protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer to study the dose-response for late rectal toxicity and to identify anatomic, dosimetric, and clinical factors that correlate with late rectal bleeding in multivariate analysis. Methods and Materials: Seven hundred forty-three patients with T1c-T3 prostate cancer were treated with 3D-CRT with prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy (119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within 30 months after treatment (i.e., 70.2 Gy--13 patients, 75.6 Gy--36 patients) or were nonbleeding for at least 30 months (i.e., 70.2 Gy--39 patients, 75.6 Gy--83 patients). Univariate and multivariate logistic regression was performed to correlate late rectal bleeding with several anatomic, dosimetric, and clinical variables. Results: A dose response for ≥ Grade 2 late rectal toxicity was observed. By multivariate analysis, the following factors were significantly correlated with ≥ Grade 2 late rectal bleeding for patients prescribed 70.2 Gy: 1) enclosure of the outer rectal contour by the 50% isodose on the isocenter slice (i.e., Iso50) (p max (p max

Acute hyperammonemic encephalopathy after fluoropyrimidine-based chemotherapy: A case series and review of the literature.

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Mitani, Seiichiro; Kadowaki, Shigenori; Komori, Azusa; Sugiyama, Keiji; Narita, Yukiya; Taniguchi, Hiroya; Ura, Takashi; Ando, Masashi; Sato, Yozo; Yamaura, Hidekazu; Inaba, Yoshitaka; Ishihara, Makoto; Tanaka, Tsutomu; Tajika, Masahiro; Muro, Kei

2017-06-01

Acute hyperammonemic encephalopathy induced by fluoropyrimidines (FPs) is a rare complication. Its pathophysiology remains unclear, especially given the currently used regimens, including intermediate-doses of 5-fluorouracil (5-FU) or oral FP agents. We aimed to characterize the clinical manifestations in cancer patients who developed hyperammonemic encephalopathy after receiving FP-based chemotherapy.We retrospectively reviewed 1786 patients with gastrointestinal or primary-unknown cancer who received FP-based regimens between 2007 and 2012. Eleven patients (0.6%) developed acute hyperammonemic encephalopathy. The incidence according to the administered anticancer drugs were as follows: 5-FU (8 of 1176, 0.7%), S-1 (1 of 679, 0.1%), capecitabine (2 of 225, 0.9%), and tegafur-uracil (UFT) (0 of 39, 0%). Ten patients (90.9%) had at least 1 aggravating factor, including infection, dehydration, constipation, renal dysfunction, and muscle loss. All the 10 patients met the definition of sarcopenia. Median time to the onset of hyperammonemic encephalopathy in the cycle was 3 days (range: 2-21). Three patients (27.3%) developed encephalopathy during the first cycle of the regimen and the remaining 8 patients during the second or more cycles. Seven patients (63.6%) had received at least 1 other FP-containing regimen before without episodes of encephalopathy.All patients recovered soon after immediate discontinuation of chemotherapy and supportive therapies, such as hydration, infusion of branched-chain amino acids, and oral lactulose intake, with a median time to recovery of 2 days (range: encephalopathy due to S-1 monotherapy, received modified FOLFOX-6 therapy without encephalopathy later.FP-associated acute hyperammonemic encephalopathy is extremely rare, but a possible event at any time and even during the administration of oral FP agents. Particular attention is warranted when giving FP-based therapy for patients with aggravating factors, such as sarcopenia. This

Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose (MTD) in Future Studies.

Science.gov (United States)

Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

2015-07-01

High doses in Tg.rasH2 carcinogenicity studies are usually set at the maximum tolerated dose (MTD), although this dose selection strategy has not been critically evaluated. We analyzed the body weight gains (BWGs), mortality, and tumor response in control and treated groups of 29 Tg.rasH2 studies conducted at BioReliance. Based on our analysis, it is evident that the MTD was exceeded at the high and/or mid-doses in several studies. The incidence of tumors in high doses was lower when compared to the low and mid-doses of both sexes. Thus, we recommend that the high dose in male mice should not exceed one-half of the estimated MTD (EMTD), as it is currently chosen, and the next dose should be one-fourth of the EMTD. Because females were less sensitive to decrements in BWG, the high dose in female mice should not exceed two-third of EMTD and the next dose group should be one-third of EMTD. If needed, a third dose group should be set at one-eighth EMTD in males and one-sixth EMTD in females. In addition, for compounds that do not show toxicity in the range finding studies, a limit dose should be applied for the 26-week carcinogenicity studies. © 2014 by The Author(s).

High-dose-rate brachytherapy in uterine cervical carcinoma

International Nuclear Information System (INIS)

Patel, Firuza D.; Rai, Bhavana; Mallick, Indranil; Sharma, Suresh C.

2005-01-01

Purpose: High-dose-rate (HDR) brachytherapy is in wide use for curative treatment of cervical cancer. The American Brachytherapy Society has recommended that the individual fraction size be <7.5 Gy and the range of fractions should be four to eight; however, many fractionation schedules, varying from institution to institution, are in use. We use 9 Gy/fraction of HDR in two to five fractions in patients with carcinoma of the uterine cervix. We found that our results and toxicity were comparable to those reported in the literature and hereby present our experience with this fractionation schedule. Methods and Materials: A total of 121 patients with Stage I-III carcinoma of the uterine cervix were treated with HDR brachytherapy between 1996 and 2000. The total number of patients analyzed was 113. The median patient age was 53 years, and the histopathologic type was squamous cell carcinoma in 93% of patients. The patients were subdivided into Groups 1 and 2. In Group 1, 18 patients with Stage Ib-IIb disease, tumor size <4 cm, and preserved cervical anatomy underwent simultaneous external beam radiotherapy to the pelvis to a dose of 40 Gy in 20 fractions within 4 weeks with central shielding and HDR brachytherapy of 9 Gy/fraction, given weekly, and interdigitated with external beam radiotherapy. The 95 patients in Group 2, who had Stage IIb-IIIb disease underwent external beam radiotherapy to the pelvis to a dose of 46 Gy in 23 fractions within 4.5 weeks followed by two sessions of HDR intracavitary brachytherapy of 9 Gy each given 1 week apart. The follow-up range was 3-7 years (median, 36.4 months). Late toxicity was graded according to the Radiation Therapy Oncology Group criteria. Results: The 5-year actuarial local control and disease-free survival rate was 74.5% and 62.0%, respectively. The actuarial local control rate at 5 years was 100% for Stage I, 80% for Stage II, and 67.2% for Stage III patients. The 5-year actuarial disease-free survival rate was 88.8% for

High-dose Extended-Field Irradiation and High-Dose-Rate Brachytherapy With Concurrent Chemotherapy for Cervical Cancer With Positive Para-Aortic Lymph Nodes

International Nuclear Information System (INIS)

Kim, Young Seok; Kim, Jong Hoon; Ahn, Seung Do; Lee, Sang-wook; Shin, Seong Soo; Nam, Joo-Hyun; Kim, Young-Tak; Kim, Yong-Man; Kim, Jong-Hyeok; Choi, Eun Kyung

2009-01-01

Purpose: To determine the efficacy and toxicity of extended-field radiotherapy (RT) with concurrent platinum-based chemotherapy in patients with uterine cervical carcinoma and positive para-aortic nodes. Methods and Materials: We retrospectively reviewed the results for 33 women with Stage IB-IVB cervical cancer. Each patient had received 59.4 Gy, including a three-dimensional conformal boost to the para-aortic lymph nodes and 41.4-50.4 Gy of external beam radiotherapy to the pelvis. Each patient also underwent six or seven applications of high-dose-rate brachytherapy (median, 5 Gy to point A at each session). Results: The median follow-up period of surviving patients was 39 months. The most common acute toxicity was hematologic, observed in 23 women. Severe acute and late gastrointestinal toxicity was observed in 3 and 4 patients, respectively. More than three-quarters of patients showed a complete response, encompassing the primary mass, metastatic pelvic, and para-aortic lymph nodes. Of the 33 women, 15 had no evidence of disease, 6 had persistent disease, 4 developed in-field failures, and 6 developed distant failures. The 5-year overall and disease-free survival rate was 47% and 42%, respectively. Conclusion: Concurrent chemoradiotherapy with extended-field radiotherapy is feasible in women with uterine cervical carcinoma and positive para-aortic lymph nodes, with acceptable late morbidity and a high survival rate, although it was accompanied by substantial acute toxicity.

Chronic uranium exposure and growth toxicity for phytoplankton. Dose-effect relationship: first comparison of chemical and radiological toxicity

International Nuclear Information System (INIS)

Gilbin, R.; Pradines, C.; Garnier-Laplace, J.

2004-01-01

The bioavailability of uranium for freshwater organisms, as for other dissolved metals, is closely linked to chemical speciation in solution (U aqueous speciation undergoes tremendous changes in the presence of ligands commonly found in natural waters e.g. carbonate, phosphate, hydroxide and natural organic matter). For the studied chemical domain, short-term uranium uptake experiments have already shown that the free uranyl ion concentration [UO 2 2+ ] is a good predictor of uranium uptake by the green algae Chlamydomonas reinhardtii, as predicted by the Free Ion Activity Model. In agreement with these results, acidic pH and low ligands concentrations in water enhance uranium bioavailability and consequently its potential chronic effects on phytoplankton. Moreover, uranium is known to be both radio-toxic and chemo-toxic. The use of different isotopes of uranium allows to expose organisms to different radiological doses for the same molar concentration: e.g. for a given element concentration (chemical dose), replacing depleted U by U-233 obviously leads to an enhanced radiological delivered dose to organisms (x10 4 ). In this work we established relationships between uranium doses (depleted uranium and 233-U ) and effect on the growth rate of the green algae Chlamydomonas reinhardtii. Uranium bioaccumulation was also monitored. Growth rate was measured both in classical batch (0-72 hrs) and continuous (turbidostat) cultures, the latter protocol allowing medium renewal to diminish exudates accumulation and speciation changes in the medium. The differences in effects will be, if possible, related to the development of defence mechanisms against the formation of reactive oxygen species (forms of glutathione) and the production of phyto-chelatins (small peptides rich in cystein that play an important role in the homeostasis and the detoxication of metals in cells). (author)

Split-Course, High-Dose Palliative Pelvic Radiotherapy for Locally Progressive Hormone-Refractory Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Gogna, Nirdosh Kumar, E-mail: kumar_gogna@health.qld.gov.au [Radiation Oncology Services, Mater Centre, Brisbane, Queensland (Australia); Baxi, Siddhartha; Hickey, Brigid; Baumann, Kathryn [Radiation Oncology Services, Mater Centre, Brisbane, Queensland (Australia); Burmeister, Elizabeth [Princess Alexandra Hospital, Brisbane, Queensland (Australia); Holt, Tanya [Radiation Oncology Services, Mater Centre, Brisbane, Queensland (Australia)

2012-06-01

Purpose: Local progression, in patients with hormone-refractory prostate cancer, often causes significant morbidity. Pelvic radiotherapy (RT) provides effective palliation in this setting, with most published studies supporting the use of high-dose regimens. The aim of the present study was to examine the role of split-course hypofractionated RT used at our institution in treating this group of patients. Methods and Materials: A total of 34 men with locoregionally progressive hormone-refractory prostate cancer, treated with a split course of pelvic RT (45-60 Gy in 18-24 fractions) between 2000 and 2008 were analyzed. The primary endpoints were the response rate and actuarial locoregional progression-free survival. Secondary endpoints included overall survival, compliance, and acute and late toxicity. Results: The median age was 71 years (range, 53-88). Treatment resulted in an overall initial response rate of 91%, a median locoregional progression-free survival of 43 months, and median overall survival of 28 months. Compliance was excellent and no significant late toxicity was reported. Conclusions: The split course pelvic RT described has an acceptable toxicity profile, is effective, and compares well with other high-dose palliative regimens that have been previously reported.

Single, 14-Day, and 13-Week Repeated Dose Toxicity Studies of Daily Oral Gelidium elegans Extract Administration to Rats.

Science.gov (United States)

Choi, Jia; Ryu, Su-Jung; Kim, Kui-Jin; Kim, Hyung-Min; Chung, Hee-Chul; Lee, Boo-Yong

2018-01-20

Gelidium elegans extract (GEE) is derived from a red alga from the Asia-Pacific region, which has antioxidant, anti-adipogenic, and anti-hyperglycemic effects. However, detailed studies of the toxicology of GEE have not been performed. We evaluated the single oral dose toxicity of GEE in male and female Sprague-Dawley (CD) rats. GEE did not cause deaths or have toxic effects at dosages of 5000 mg/kg/day, although compound-colored stools and diarrhea were observed in both sexes, which lasted 5000 mg/kg. We next evaluated the repeated oral dose toxicity of GEE in CD rats over 14 days and 13 weeks. GEE did not induce any significant toxicological changes in either sex at 2000 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects, in terms of clinical signs, mortality, body mass, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy, organ masses, or histopathology, at dosages of 500, 1000, or 2000 mg/kg/day. The no observed adverse effect level (NOAEL) for GEE is thus likely to be >2000 mg/kg/day, and no pathology was identified in potential target organs. Therefore, this study indicates that repeated oral dosing with GEE is safe in CD rats.

Correlation of Acute and Late Brainstem Toxicities With Dose-Volume Data for Pediatric Patients With Posterior Fossa Malignancies

Energy Technology Data Exchange (ETDEWEB)

Nanda, Ronica H., E-mail: rhazari@emory.edu [Department of Radiation Oncology, Winship Cancer Institute, Emory University College of Medicine, Atlanta, Georgia (United States); Ganju, Rohit G.; Schreibmann, Edward [Department of Radiation Oncology, Winship Cancer Institute, Emory University College of Medicine, Atlanta, Georgia (United States); Chen, Zhengjia; Zhang, Chao [Department of Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University Rollins School of Public Health, Atlanta, Georgia (United States); Jegadeesh, Naresh; Cassidy, Richard; Deng, Claudia; Eaton, Bree R.; Esiashvili, Natia [Department of Radiation Oncology, Winship Cancer Institute, Emory University College of Medicine, Atlanta, Georgia (United States)

2017-06-01

Purpose: Radiation-induced brainstem toxicity after treatment of pediatric posterior fossa malignancies is incompletely understood, especially in the era of intensity modulated radiation therapy (IMRT). The rates of, and predictive factors for, brainstem toxicity after photon RT for posterior fossa tumors were examined. Methods and Materials: After institutional review board approval, 60 pediatric patients treated at our institution for nonmetastatic infratentorial ependymoma and medulloblastoma with IMRT were included in the present analysis. Dosimetric variables, including the mean and maximum dose to the brainstem, the dose to 10% to 90% of the brainstem (in 10% increments), and the volume of the brainstem receiving 40, 45, 50, and 55 Gy were recorded for each patient. Acute (onset within 3 months) and late (>3 months of RT completion) RT-induced brainstem toxicities with clinical and radiographic correlates were scored using Common Terminology Criteria for Adverse Events, version 4.0. Results: Patients aged 1.4 to 21.8 years underwent IMRT or volumetric arc therapy postoperatively to the posterior fossa or tumor bed. At a median clinical follow-up period of 2.8 years, 14 patients had developed symptomatic brainstem toxicity (crude incidence 23.3%). No correlation was found between the dosimetric variables examined and brainstem toxicity. Vascular injury or ischemia showed a strong trend toward predicting brainstem toxicity (P=.054). Patients with grade 3 to 5 brainstem toxicity had undergone treatment to significant volumes of the posterior fossa. Conclusion: The results of the present series demonstrate a low, but not negligible, risk of brainstem radiation necrosis for pediatric patients with posterior fossa malignancies treated with IMRT. No specific dose-volume correlations were identified; however, modern treatment volumes might help limit the incidence of severe toxicity. Additional work investigating inherent biologic sensitivity might also provide

Transuranium element toxicity: dose-response relationships at low exposure levels. Summary and speculative interpretation relative to exposure limits

International Nuclear Information System (INIS)

Thompson, R.C.

1975-01-01

A summary is given of information on transuranium element toxicity and the correlation of this information with current established exposure limits. It is difficult to calculate a biologically relevant radiation dose from deposited plutonium; it is exposure that must be controlled in order to prevent biological effect, and if the relationship between exposure and effect is known, then radiation dose is of no concern. There are extensive data on the effects of plutonium in bone. Results of studies at the University of Utah indicate that plutonium in beagles may be as much as ten times more toxic than radium. It has been suggested that this toxicity ratio may be even higher in man than in the beagle dog because of differences in surface-to-volume ratios and differences in the rate of burial of surface-deposited plutonium. The present capabilities for extrapolating dose-effect relationships seem to be limited to the setting of upper limits, based on assumptions of linearity and considerations related to natural background

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials.

Science.gov (United States)

Lee, Shing M; Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-04-20

The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. © 2016 by American Society of Clinical Oncology.

Interindividual registration and dose mapping for voxelwise population analysis of rectal toxicity in prostate cancer radiotherapy

Energy Technology Data Exchange (ETDEWEB)

Dréan, Gaël; Acosta, Oscar, E-mail: Oscar.Acosta@univ-rennes1.fr; Simon, Antoine; Haigron, Pascal [INSERM, U1099, Rennes F-35000 (France); Université de Rennes 1, LTSI, Rennes F-35000 (France); Lafond, Caroline; Crevoisier, Renaud de [INSERM, U1099, Rennes F-35000 (France); Université de Rennes 1, LTSI, Rennes F-35000 (France); Département de Radiothérapie, Center Eugène Marquis, Rennes F-35000 (France)

2016-06-15

Purpose: Recent studies revealed a trend toward voxelwise population analysis in order to understand the local dose/toxicity relationships in prostate cancer radiotherapy. Such approaches require, however, an accurate interindividual mapping of the anatomies and 3D dose distributions toward a common coordinate system. This step is challenging due to the high interindividual variability. In this paper, the authors propose a method designed for interindividual nonrigid registration of the rectum and dose mapping for population analysis. Methods: The method is based on the computation of a normalized structural description of the rectum using a Laplacian-based model. This description takes advantage of the tubular structure of the rectum and its centerline to be embedded in a nonrigid registration-based scheme. The performances of the method were evaluated on 30 individuals treated for prostate cancer in a leave-one-out cross validation. Results: Performance was measured using classical metrics (Dice score and Hausdorff distance), along with new metrics devised to better assess dose mapping in relation with structural deformation (dose-organ overlap). Considering these scores, the proposed method outperforms intensity-based and distance maps-based registration methods. Conclusions: The proposed method allows for accurately mapping interindividual 3D dose distributions toward a single anatomical template, opening the way for further voxelwise statistical analysis.

Gastrointestinal Dose-Histogram Effects in the Context of Dose-Volume–Constrained Prostate Radiation Therapy: Analysis of Data From the RADAR Prostate Radiation Therapy Trial

Energy Technology Data Exchange (ETDEWEB)

Ebert, Martin A., E-mail: Martin.Ebert@health.wa.gov.au [Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia (Australia); School of Physics, University of Western Australia, Perth, Western Australia (Australia); Foo, Kerwyn [Sydney Medical School, University of Sydney, Sydney, New South Wales (Australia); Haworth, Annette [Department of Physical Sciences, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria (Australia); Gulliford, Sarah L. [Joint Department of Physics, Institute of Cancer Research and Royal Marsden National Health Service Foundation Trust, Sutton, Surrey (United Kingdom); Kennedy, Angel [Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia (Australia); Joseph, David J. [Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia (Australia); School of Surgery, University of Western Australia, Perth, Western Australia (Australia); Denham, James W. [School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales (Australia)

2015-03-01

Purpose: To use a high-quality multicenter trial dataset to determine dose-volume effects for gastrointestinal (GI) toxicity following radiation therapy for prostate carcinoma. Influential dose-volume histogram regions were to be determined as functions of dose, anatomical location, toxicity, and clinical endpoint. Methods and Materials: Planning datasets for 754 participants in the TROG 03.04 RADAR trial were available, with Late Effects of Normal Tissues (LENT) Subjective, Objective, Management, and Analytic (SOMA) toxicity assessment to a median of 72 months. A rank sum method was used to define dose-volume cut-points as near-continuous functions of dose to 3 GI anatomical regions, together with a comprehensive assessment of significance. Univariate and multivariate ordinal regression was used to assess the importance of cut-points at each dose. Results: Dose ranges providing significant cut-points tended to be consistent with those showing significant univariate regression odds-ratios (representing the probability of a unitary increase in toxicity grade per percent relative volume). Ranges of significant cut-points for rectal bleeding validated previously published results. Separation of the lower GI anatomy into complete anorectum, rectum, and anal canal showed the impact of mid-low doses to the anal canal on urgency and tenesmus, completeness of evacuation and stool frequency, and mid-high doses to the anorectum on bleeding and stool frequency. Derived multivariate models emphasized the importance of the high-dose region of the anorectum and rectum for rectal bleeding and mid- to low-dose regions for diarrhea and urgency and tenesmus, and low-to-mid doses to the anal canal for stool frequency, diarrhea, evacuation, and bleeding. Conclusions: Results confirm anatomical dependence of specific GI toxicities. They provide an atlas summarizing dose-histogram effects and derived constraints as functions of anatomical region, dose, toxicity, and endpoint for

Gastrointestinal Dose-Histogram Effects in the Context of Dose-Volume–Constrained Prostate Radiation Therapy: Analysis of Data From the RADAR Prostate Radiation Therapy Trial

International Nuclear Information System (INIS)

Ebert, Martin A.; Foo, Kerwyn; Haworth, Annette; Gulliford, Sarah L.; Kennedy, Angel; Joseph, David J.; Denham, James W.

2015-01-01

Purpose: To use a high-quality multicenter trial dataset to determine dose-volume effects for gastrointestinal (GI) toxicity following radiation therapy for prostate carcinoma. Influential dose-volume histogram regions were to be determined as functions of dose, anatomical location, toxicity, and clinical endpoint. Methods and Materials: Planning datasets for 754 participants in the TROG 03.04 RADAR trial were available, with Late Effects of Normal Tissues (LENT) Subjective, Objective, Management, and Analytic (SOMA) toxicity assessment to a median of 72 months. A rank sum method was used to define dose-volume cut-points as near-continuous functions of dose to 3 GI anatomical regions, together with a comprehensive assessment of significance. Univariate and multivariate ordinal regression was used to assess the importance of cut-points at each dose. Results: Dose ranges providing significant cut-points tended to be consistent with those showing significant univariate regression odds-ratios (representing the probability of a unitary increase in toxicity grade per percent relative volume). Ranges of significant cut-points for rectal bleeding validated previously published results. Separation of the lower GI anatomy into complete anorectum, rectum, and anal canal showed the impact of mid-low doses to the anal canal on urgency and tenesmus, completeness of evacuation and stool frequency, and mid-high doses to the anorectum on bleeding and stool frequency. Derived multivariate models emphasized the importance of the high-dose region of the anorectum and rectum for rectal bleeding and mid- to low-dose regions for diarrhea and urgency and tenesmus, and low-to-mid doses to the anal canal for stool frequency, diarrhea, evacuation, and bleeding. Conclusions: Results confirm anatomical dependence of specific GI toxicities. They provide an atlas summarizing dose-histogram effects and derived constraints as functions of anatomical region, dose, toxicity, and endpoint for

Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer

Energy Technology Data Exchange (ETDEWEB)

Warren, Samantha, E-mail: Samantha.warren@oncology.ox.ac.uk [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Partridge, Mike [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Carrington, Rhys [Velindre Cancer Centre, Velindre Hospital, Cardiff (United Kingdom); Hurt, Chris [Wales Cancer Trials Unit, School of Medicine, Heath Park, Cardiff (United Kingdom); Crosby, Thomas [Velindre Cancer Centre, Velindre Hospital, Cardiff (United Kingdom); Hawkins, Maria A. [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom)

2014-10-01

Purpose: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm{sup 3}. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA{sub 62.5}) was compared to a standard dose plan of 50 Gy/25 fractions (RA{sub 50}). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA{sub 50}) to 56.3% (RA{sub 62.5}), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA{sub 50}) versus 5.6% (RA{sub 62.5}) P<.001 and median lung NTCP 6.5% (RA{sub 50}) versus 7.5% (RA{sub 62.5}) P<.001. Conclusions: Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials.

Biochemical criteria of toxicity of therapy with high doses of methotrexate in children with osteosarcoma

Directory of Open Access Journals (Sweden)

A. M. Strizhevskaya

2015-01-01

Full Text Available Methotrexate (Mtx is a cytotoxic drug from the group of antimetabolites, folic acid antagonists. High-dose (HD Mtx in pediatric oncology are used for the treatment of osteosarcoma (OS, and other types of tumors. This therapy has allowed to achieve a five-year relapse-free survival rates up to 80 % in patients with OS. However, the high toxicity of Mtx is a serious constraint in achieving the maximum therapeutic effect, which in most cases poses the occurrence of side effects in patients on various organs and systems. Treatment should be under strict laboratory monitoring, primarily therapeutic drug monitoring the concentration of Mtx in serum.246 children (boys – 125, girls – 121 aged 5 to 16 years with osteosarcoma (mean age 12.2 years who were treated in N.N. Blokhin Russian Cancer Research Center from 2006 to 2013. Patients were conducted from 1 to 8 courses HD Mtx at a dose of 8 or 12 g/m2 , administered within 4 h of infusion on the background of alkaline prehydrate. Leucovorin was administered intravenously, every 6 hours, starting 24 h from the start of the Mtx infusion. 1137 courses of HD Mtx were conducted with FPIA method (analyzer TDx/Flx, Abbott, USA. The technique of monitoring of homocysteine (Hcy in the blood serum by analyzer Vitros 5/1FS (Johnson & Johnson, USA during the entire course of high-dose Mtx was tested. In groups calculated pharmacokinetic parameters Mtx were tested: area under the pharmacokinetic curve (MtxAUC, clearance of methotrexate (ClMtx, the elimination half-life (T1/2 and the total time of excretion (Ttotal. Normal excretion of Mtx was revealed at 1050 courses Mtx, corresponding to the following values: 4 h – 1109 ± 283 μmol/l; 24 h – 4,67 ± 0,95 μmol/l; 42 h – 0,38 ± 0.16 µmol/l; 48 h – less than 0,23 ± 0.04 µmol/l; 72 h of 0.07 ± 0,03 µmol/l; 96 h of 0.03 ± 0.01 µmol/l. At 87 courses identified delayed Mtx excretion, accounting for 7.6 % of all courses. In all measured parameters

Evaluation of preclinical single and multiple dose toxicity and efficacy of 213 Bi-labeled plasminogen activator inhibitor 2 for breast and prostate cancer

International Nuclear Information System (INIS)

Rizvi, S.; Li, Y.; Allen, B.; Littlejohn, T.; Ranson, M.; Links, M.; Irving, D.; Andrews, J.

2003-01-01

The aim of the study was to evaluate the single and multiple dose toxicity (maximum tolerated dose or MTD) regimes for 213 Bi-labeled PAI2. Dose range of 2-8 mCi/kg was used for the single dose toxicity studies. It was found that end point (20% weight loss and/or distressed behaviour) was not reached for the highest dose either with single or multiple dose injections. For multiple dose toxicity studies, the dose levels ranged between 0.4 - 2 mCi/kg, and were administered daily for 5 days. The highest level tested (2mCi/kg/day x 5) was the maximum tolerated dose as 3/6 mice succumbed to the endpoints. However, histological examination of major organs showed no adverse morphological changes. From these toxicity studies, we concluded that either a dose of 1.6mCi/kg of 213 Bi-PAI2 per day for 5 days or a single injection of 8 mCi/kg can be administered without reaching the endpoints. These dose levels were used for efficacy trials. The efficacy studies were conducted to examine if the 1.6mCi/kgday x 5 multiple dose schedule (sub-maximum tolerated dose) showed efficacy against established and early stage human breast and prostate tumours in mice. Statistical analyses of the data indicate a significant tumour growth rate delay and increased time to reach tumour size endpoint for alpha-PAI2 treatment compared to control tumours, in both pre-tumour stage and established tumour models

A high throughput passive dosing format for the Fish Embryo Acute Toxicity test

DEFF Research Database (Denmark)

Vergauwen, Lucia; Nørgaard Schmidt, Stine; Stinckens, Evelyn

2015-01-01

(lethal chemical activity) was 0.047. All values were within ranges expected for baseline toxicity. Impaired swim bladder inflation was the most pronounced morphological effect and swimming activity was reduced in all exposure concentrations. Further analysis showed that the effect on swimming activity...... dilution series. We report effect values for both mortality and sublethal morphological effects based on (1) measured exposure concentrations, (2) (lipid normalized) body residues and (3) chemical activity. The LC50 for 120 hpf was 310 μg/L, CBR50 (critical body residue) was 2.72 mmol/kg fresh wt and La50...... for obtaining mechanistic toxicity information, and (3) cause no toxicity, demonstrating its potential as an extension of the FET test when testing hydrophobic chemicals....

The effect of dose, dose rate, route of administration, and species on tissue and blood levels of benzene metabolites

International Nuclear Information System (INIS)

Henderson, R.F.; Sabourin, P.J.; Bechtold, W.E.; Griffith, W.C.; Medinsky, M.A.; Birnbaum, L.S.; Lucier, G.W.

1989-01-01

Studies were completed in F344/N rats and B6C3F 1 mice to determine the effect of dose, dose rate, route of administration, and rodent species on formation of total and individual benzene metabolites. Oral doses of 50 mg/kg or higher saturated the capacity for benzene metabolism in both rats and mice, resulting in an increased proportion of the administered dose being exhaled as benzene. The saturating air concentration for benzene metabolism during 6-hr exposures was between 130 and 900 ppm. At the highest exposure concentration, rats exhaled approximately half of the internal dose retained at the end of the 6-hr exposure as benzene; mice exhaled only 15% as benzene. Mice were able to convert more of the inhaled benzene to metabolites than were rats. In addition, mice metabolized more of the benzene by pathways leading to the putative toxic metabolites, benzoquinone and muconaldehyde, than did rats. In both rats and mice, the effect of increasing dose, administered orally or by inhalation, was to increase the proportion of the total metabolites that were the products of detoxification pathways relative to the products of pathways leading to putative toxic metabolites. This indicates low-affinity, high-capacity pathways for detoxification and high-affinity, low-capacity pathways leading to putative toxic metabolites. If the results of rodent studied performed at high doses were used to assess the health risk at low-dose exposures to benzene, the toxicity of benzene would be underestimated

High-Dose Methylprednisolone for Veno-Occlusive Disease of the Liver in Pediatric Hematopoietic Stem Cell Transplantation Recipients

Science.gov (United States)

Myers, Kasiani C.; Lawrence, Julia; Marsh, Rebecca A.; Davies, Stella M.; Jodele, Sonata

2017-01-01

Veno-occlusive disease (VOD) of the liver is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT), with few successful treatment modalities available for severe disease. Some reports have demonstrated success in adults with the use of high-dose steroid therapy, but experience in the pediatric population is lacking. We retrospectively reviewed HSCT patients treated at our institution since 2003 and identified 15 (2.4%) who developed VOD. Of these, nine (60%) were treated with intravenous high-dose methylprednisolone (500 mg/m2 per dose every 12 hours for six doses). Steroid therapy was initiated at or before first ultrasound evidence of reversal of portal venous flow and before meeting criteria for initiation of defibrotide therapy. Four patients were also treated with defibrotide starting 2 to 5 days after initiation of steroids. Eight of nine patients (88%) with VOD were diagnosed with multiorgan failure. Response to high-dose steroid therapy as defined by decrease in bilirubin by 50% in 10 days from therapy initiation was noted in six of nine patients (67%), occurring within 3 to 6 days of steroid therapy. Two patients died from multiorgan failure due to VOD. Seven survivors of VOD recovered at the median 6 days (range, 5 to 38) from VOD diagnosis. Overall, VOD survival as a group was 78%; however, survival among responders was 100%. No serious toxicities related to high-dose steroid therapy were observed. We conclude that high-dose steroid therapy if initiated early may reverse VOD of the liver in pediatric HSCT patients, abrogating the need for defibrotide therapy with its associated toxicities and regulatory difficulties. PMID:23211838

Computational systems biology and dose-response modeling in relation to new directions in toxicity testing.

Science.gov (United States)

Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E; Conolly, Rory B

2010-02-01

The new paradigm envisioned for toxicity testing in the 21st century advocates shifting from the current animal-based testing process to a combination of in vitro cell-based studies, high-throughput techniques, and in silico modeling. A strategic component of the vision is the adoption of the systems biology approach to acquire, analyze, and interpret toxicity pathway data. As key toxicity pathways are identified and their wiring details elucidated using traditional and high-throughput techniques, there is a pressing need to understand their qualitative and quantitative behaviors in response to perturbation by both physiological signals and exogenous stressors. The complexity of these molecular networks makes the task of understanding cellular responses merely by human intuition challenging, if not impossible. This process can be aided by mathematical modeling and computer simulation of the networks and their dynamic behaviors. A number of theoretical frameworks were developed in the last century for understanding dynamical systems in science and engineering disciplines. These frameworks, which include metabolic control analysis, biochemical systems theory, nonlinear dynamics, and control theory, can greatly facilitate the process of organizing, analyzing, and understanding toxicity pathways. Such analysis will require a comprehensive examination of the dynamic properties of "network motifs"--the basic building blocks of molecular circuits. Network motifs like feedback and feedforward loops appear repeatedly in various molecular circuits across cell types and enable vital cellular functions like homeostasis, all-or-none response, memory, and biological rhythm. These functional motifs and associated qualitative and quantitative properties are the predominant source of nonlinearities observed in cellular dose response data. Complex response behaviors can arise from toxicity pathways built upon combinations of network motifs. While the field of computational cell

Single, 14-Day, and 13-Week Repeated Dose Toxicity Studies of Daily Oral Gelidium elegans Extract Administration to Rats

Directory of Open Access Journals (Sweden)

Jia Choi

2018-01-01

Full Text Available Gelidium elegans extract (GEE is derived from a red alga from the Asia–Pacific region, which has antioxidant, anti-adipogenic, and anti-hyperglycemic effects. However, detailed studies of the toxicology of GEE have not been performed. We evaluated the single oral dose toxicity of GEE in male and female Sprague-Dawley (CD rats. GEE did not cause deaths or have toxic effects at dosages of 5000 mg/kg/day, although compound-colored stools and diarrhea were observed in both sexes, which lasted <2 days. Therefore, the LD50 of GEE is likely to be >5000 mg/kg. We next evaluated the repeated oral dose toxicity of GEE in CD rats over 14 days and 13 weeks. GEE did not induce any significant toxicological changes in either sex at 2000 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects, in terms of clinical signs, mortality, body mass, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy, organ masses, or histopathology, at dosages of 500, 1000, or 2000 mg/kg/day. The no observed adverse effect level (NOAEL for GEE is thus likely to be >2000 mg/kg/day, and no pathology was identified in potential target organs. Therefore, this study indicates that repeated oral dosing with GEE is safe in CD rats.

Acute small bowel toxicity and preoperative chemoradiotherapy for rectal cancer: Investigating dose-volume relationships and role for inverse planning

International Nuclear Information System (INIS)

Tho, Lye Mun; Glegg, Martin; Paterson, Jennifer; Yap, Christina; MacLeod, Alice; McCabe, Marie; McDonald, Alexander C.

2006-01-01

Purpose: The relationship between volume of irradiated small bowel (VSB) and acute toxicity in rectal cancer radiotherapy is poorly quantified, particularly in patients receiving concurrent preoperative chemoradiotherapy. Using treatment planning data, we studied a series of such patients. Methods and Materials: Details of 41 patients with locally advanced rectal cancer were reviewed. All received 45 Gy in 25 fractions over 5 weeks, 3-4 fields three-dimensional conformal radiotherapy with daily 5-fluorouracil and folinic acid during Weeks 1 and 5. Toxicity was assessed prospectively in a weekly clinic. Using computed tomography planning software, the VSB was determined at 5 Gy dose intervals (V 5 , V 1 , etc.). Eight patients with maximal VSB had dosimetry and radiobiological modeling outcomes compared between inverse and conformal three-dimensional planning. Results: VSB correlated strongly with diarrheal severity at every dose level (p 5 and V 15 . Conclusions: A strong dose-volume relationship exists between VSB and acute diarrhea at all dose levels during preoperative chemoradiotherapy. Our constructed model may be useful in predicting toxicity, and this has been derived without the confounding influence of surgical excision on bowel function. Inverse planning can reduce calculated dose to small bowel and late NTCP, and its clinical role warrants further investigation

SU-F-J-217: Accurate Dose Volume Parameters Calculation for Revealing Rectum Dose-Toxicity Effect Using Deformable Registration in Cervical Cancer Brachytherapy: A Pilot Study

Energy Technology Data Exchange (ETDEWEB)

Zhen, X; Chen, H; Liao, Y; Zhou, L [Southern Medical University, Guangzhou, Guangdong (China); Hrycushko, B; Albuquerque, K; Gu, X [UT Southwestern Medical Center, Dallas, TX (United States)

2016-06-15

Purpose: To study the feasibility of employing deformable registration methods for accurate rectum dose volume parameters calculation and their potentials in revealing rectum dose-toxicity between complication and non-complication cervical cancer patients with brachytherapy treatment. Method and Materials: Data from 60 patients treated with BT including planning images, treatment plans, and follow-up clinical exam were retrospectively collected. Among them, 12 patients complained about hematochezia were further examined with colonoscopy and scored as Grade 1–3 complication (CP). Meanwhile, another 12 non-complication (NCP) patients were selected as a reference group. To seek for potential gains in rectum toxicity prediction when fractional anatomical deformations are account for, the rectum dose volume parameters D0.1/1/2cc of the selected patients were retrospectively computed by three different approaches: the simple “worstcase scenario” (WS) addition method, an intensity-based deformable image registration (DIR) algorithm-Demons, and a more accurate, recent developed local topology preserved non-rigid point matching algorithm (TOP). Statistical significance of the differences between rectum doses of the CP group and the NCP group were tested by a two-tailed t-test and results were considered to be statistically significant if p < 0.05. Results: For the D0.1cc, no statistical differences are found between the CP and NCP group in all three methods. For the D1cc, dose difference is not detected by the WS method, however, statistical differences between the two groups are observed by both Demons and TOP, and more evident in TOP. For the D2cc, the CP and NCP cases are statistically significance of the difference for all three methods but more pronounced with TOP. Conclusion: In this study, we calculated the rectum D0.1/1/2cc by simple WS addition and two DIR methods and seek for gains in rectum toxicity prediction. The results favor the claim that accurate dose

Single Oral Dose Toxicity Test of Blue Honeysuckle Concentrate in Mice

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Park, Sang-In; Choi, Seung-Hoon; Song, Chang-Hyun; Park, Soo-Jin; Shin, Yong-Kook; Han, Chang-Hyun; Lee, Young Joon; Ku, Sae-Kwang

2015-01-01

The objective of this study was to obtain single oral dose toxicity information for concentrated and lyophilized powder of blue honeysuckle (Lonicera caerulea L., Caprifoliaceae; BHcL) in female and male ICR mice to aid in the process of developing natural origin medicinal ingredients or foods following proximate analysis and phytochemical profile measurement. The proximate analysis revealed that BHcL had an energy value of 3.80 kcal/g and contained 0.93 g/g of carbohydrate, 0.41 g/g of sugar, 0.02 g/g of protein, and 0.20 mg/g of sodium. BHcL did not contain lipids, including saturated lipids, trans fats, or cholesterols. Further, BHcL contained 4.54% of betaine, 210.63 mg/g of total phenols, 159.30 mg/g of total flavonoids, and 133.57 mg/g of total anthocyanins. Following administration of a single oral BHcL treatment, there were no treatment-related mortalities, changes in body weight (bw) or organ weight, clinical signs, necropsy or histopathological findings up to 2,000 mg/kg bw, the limited dosage for rodents of both sexes. We concluded that BHcL is a practically non-toxic material in toxicity potency. PMID:25874034

Dose and volume effects of gastrointestinal toxicity during neoadjuvant IMRT for rectal cancer

DEFF Research Database (Denmark)

Appelt, A. L.; Vogelius, I. R.; Jakobsen, Anders

2015-01-01

. Materials and Methods: We explored dose metrics correlating with acute diarrhea and chemotherapy compliance for a single-institution cohort of rectal cancer patients (n=115) treated with IMRT. Acute diarrhea during treatment was scored prospectively by trained RT nurses (CTCAE v3.0). The highest toxicity.......03) and patients with diabetes (OR=7.29, 1.21-43.8, p=0.03). Age, brachytherapy boost, prior abdominal surgery, smoking history, or domestic status had no influence on any of the two endpoints, nor had concurrent chemotherapy on the risk of acute diarrhea. Conclusions: We found that dose to the intestinal cavity...

Acute and Subacute Toxicity Evaluation of Corn Silk Extract.

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Ha, Ae Wha; Kang, Hyeon Jung; Kim, Sun Lim; Kim, Myung Hwan; Kim, Woo Kyoung

2018-03-01

Many studies have reported therapeutic efficacy of corn silk extract. However, research on its toxicity and safe dose range is limited. Thus, the objective of this study was to determine the acute and subacute toxicity of corn silk extract in ICR mice. To determine acute toxicity, corn silk extract containing high levels of maysin was orally administered to mice at a dose of 0 or 2,000 mg/kg. Clinical symptoms, mortality, and body weight changes were recorded for 14 days. To determine subacute toxicity, corn silk extract was orally administered to mice over a 4-week period, and then body weight, water and food consumption, and organ weight were determined. In addition, urine and serum analyses were performed. In the acute toxicity study, no death or abnormal symptoms was observed in all treatment groups during the study period. Body weights did not show any significant change compared to those of the control group. Lethal dose of corn silk extract was estimated to be more than 2,000 mg/kg. In the 4-week subacute toxicity study, there was no corn silk extract related toxic effect on body weight, water intake, food consumption, urine parameters, clinical chemistry, or organ weight. Histopathological examination showed no abnormality related to the administration of corn silk extract at 500 mg/kg. The maximum non-toxic dose of corn silk extract containing high levels of maysin was found to be more than 500 mg/kg.

A Case of a Contraband Body Packer Requiring High-Dose Naloxone

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Khusro Shamim

2017-09-01

Full Text Available Background:Body packers occasionally refer to the Emergency Department (ED, after leakage of package contents within intestinal lumen, resulting in life-threatening toxicities, depending upon the nature of the chemical product. Case Presentation: We present a case report of a patient presented with sudden onset of drowsiness while he was on board a flight. He was brought in by the airport security staff. On arrival to the ED, his Glasgow Coma Scale (GCS was 3/15 and pupils were pinpoint bilaterally. He was empirically treated with Naloxone on clinical suspicion of narcotic overdose. He required a cumulative dose of 12 mg of Naloxone for reversal of respiratory depression and coma. On subsequent investigation in the ED, he was identified to be a body packer. Discussion: This case represents a rare clinical example of narcotic overdose which resulted in a life-threatening opioid toxicity due to leakage of the package contents into his bowels. In this case, a dosage greater than 10 mg of the maximum recommended dose of Naloxone is required for reversal of toxicity. Conclusion:It is imperative to have a high level of suspicion for managing possible opioid intoxication as immediate treatment can be diagnostic and lifesaving. Our case required more than the recommended dosage of Naloxone, highlighting the possible suggestion of further studies to look into the maximum threshold of this reversal agent.

Postnatal development of resistance to short-term high-dose toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in TCDD-resistant and -semiresistant rats

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Simanainen, Ulla; Tuomisto, Jouni T.; Pohjanvirta, Raimo; Syrjaelae, Paula; Tuomisto, Jouko; Viluksela, Matti

2004-01-01

Despite great interspecies differences in adult 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) sensitivity, the toxic potency of TCDD is similar across species in fetal mortality. Han/Wistar (Kuopio; H/W) rats are exceptionally resistant to acute toxicity of TCDD, but show sensitivity to embryotoxicity and teratogenicity. The resistance of adult H/W rats to acute TCDD toxicity is based on a point mutation in the transactivation domain of the aryl hydrocarbon receptor (AHR) and to an unknown gene ''B''. This study investigated the time course of postnatal development of resistance to TCDD and the significance of genotypic variation in resistance development. H/W, line A (a new line with the H/W-type mutated AHR), and line B rats (a line with normal AHR but moderately resistant because of gene ''B'') were exposed to a single dose of TCDD 2-56 days after birth. H/W and line A rats received 1000 μg/kg; male and female B rats received 200 and 100 μg/kg, respectively. Survival was monitored for 42 days. Interestingly, although TCDD ceased growth and weight gain in all TCDD groups, the younger dosed animals did not seem to reach the body weight of the older dosed animals even in 100 days. The survival results after 42 days showed that line A rats are fairly resistant to TCDD immediately after birth, and their full TCDD resistance develops during the first week of life. The moderate resistance of line B rats develops approximately at the time of weaning. This difference in the time course of resistance development suggests that there are basic differences in pathways mediating resistance in lines A and B rats

Toxicity after intensity-modulated, image-guided radiotherapy for prostate cancer

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Flentje, Michael; Guckenberger, Matthias; Ok, Sami; Polat, Buelent; Sweeney, Reinhart A.

2010-01-01

Purpose: To evaluate toxicity after dose-escalated radiotherapy for prostate cancer using intensity-modulated treatment planning (IMRT) and image-guided treatment (IGRT) delivery. Patients and Methods: 100 patients were treated with simultaneous integrated boost (SIB) IMRT for prostate cancer: doses of 76.23 Gy and 60 Gy in 33 fractions were prescribed to the prostate and the seminal vesicles, respectively, for intermediate- and high-risk patients (n = 74). The total dose was 73.91 Gy in 32 fractions for low-risk patients and after transurethral resection of the prostate (n = 26). The pelvic lymphatics were treated with 46 Gy in 25 fractions in patients with high risk of lymph node metastases using an SIB to the prostate (n = 25). IGRT was practiced with cone-beam computed tomography. Acute and late gastrointestinal (GI) and genitourinary (GU) toxicity was evaluated prospectively (CTCAE v3.0). Results: Treatment was completed as planned by all patients. Acute GI and GU toxicity grade ≥ 2 was observed in 12% and 42% of the patients, respectively, with 4% suffering from GU toxicity grade 3. 6 weeks after treatment, the incidence of acute toxicity grade ≥ 2 had decreased to 12%. With a median follow-up of 26 months, late GI and GU toxicity grade ≥ 2 was seen in 1.5% and 7.7% of the patients at 24 months. Four patients developed late toxicity grade 3 (GI n = 1; GU n = 3). Presence of acute GI and GU toxicity was significantly associated with late GI (p = 0.0007) and GU toxicity (p = 0.006). Conclusion: High-dose radiotherapy for prostate cancer using IMRT and IGRT resulted in low rates of acute toxicity and preliminary results of late toxicity are promising. (orig.)

Toxicity after intensity-modulated, image-guided radiotherapy for prostate cancer

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Flentje, Michael [Dept. of Radiotherapy, Univ. Hospital Wuerzburg (Germany); Guckenberger, Matthias; Ok, Sami; Polat, Buelent; Sweeney, Reinhart A.

2010-10-15

Purpose: To evaluate toxicity after dose-escalated radiotherapy for prostate cancer using intensity-modulated treatment planning (IMRT) and image-guided treatment (IGRT) delivery. Patients and Methods: 100 patients were treated with simultaneous integrated boost (SIB) IMRT for prostate cancer: doses of 76.23 Gy and 60 Gy in 33 fractions were prescribed to the prostate and the seminal vesicles, respectively, for intermediate- and high-risk patients (n = 74). The total dose was 73.91 Gy in 32 fractions for low-risk patients and after transurethral resection of the prostate (n = 26). The pelvic lymphatics were treated with 46 Gy in 25 fractions in patients with high risk of lymph node metastases using an SIB to the prostate (n = 25). IGRT was practiced with cone-beam computed tomography. Acute and late gastrointestinal (GI) and genitourinary (GU) toxicity was evaluated prospectively (CTCAE v3.0). Results: Treatment was completed as planned by all patients. Acute GI and GU toxicity grade {>=} 2 was observed in 12% and 42% of the patients, respectively, with 4% suffering from GU toxicity grade 3. 6 weeks after treatment, the incidence of acute toxicity grade {>=} 2 had decreased to 12%. With a median follow-up of 26 months, late GI and GU toxicity grade {>=} 2 was seen in 1.5% and 7.7% of the patients at 24 months. Four patients developed late toxicity grade 3 (GI n = 1; GU n = 3). Presence of acute GI and GU toxicity was significantly associated with late GI (p = 0.0007) and GU toxicity (p = 0.006). Conclusion: High-dose radiotherapy for prostate cancer using IMRT and IGRT resulted in low rates of acute toxicity and preliminary results of late toxicity are promising. (orig.)

Maternal and developmental toxicity of ayahuasca in Wistar rats.

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Oliveira, Carolina Dizioli Rodrigues; Moreira, Camila Queiroz; de Sá, Lilian Rose Marques; Spinosa, Helenice de Souza; Yonamine, Mauricio

2010-06-01

Ayahuasca is a psychotropic plant beverage initially used by shamans throughout the Amazon region during traditional religious cult. In recent years, ayahuasca has also been used in ceremonies of a number of modern syncretic religious groups, including pregnant women. However, no documented study has been performed to evaluate the risk of developmental toxicity of ayahuasca. In the present work, maternal and developmental toxicity was evaluated in Wistar rats. Ayahuasca was administered to pregnant rats in three different doses [the equivalent typical dose (TD) administered to humans, five-fold TD and 10-fold TD] during the gestational period (6-20 days). Dams treated with the highest ayahuasca dose showed maternal toxicity with decrease of weight gain and food intake. Visceral fetal findings were observed in all treatment groups. Skeletal findings were observed in the intermediate- and high-dose groups. The fetuses deriving from the highest dose group also presented a decrease in body weight. From these results, it is possible to conclude that there is a risk of maternal and developmental toxicity following ayahuasca exposure and that the level of toxicity appears to be dose-dependent.

Management of pegylated interferon alpha toxicity in adjuvant therapy of melanoma.

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Daud, Adil; Soon, Christopher; Dummer, Reinhard; Eggermont, Alexander M M; Hwu, Wen-Jen; Grob, Jean Jacques; Garbe, Claus; Hauschild, Axel

2012-08-01

Both native IFNα2b and pegylated IFNα2b (PegIFNα2b) are approved for the adjuvant treatment of high-risk melanoma. This review compares the toxicity profiles of high-dose IFNα2b (HDI) and PegIFNα2b, and provides recommendations on the management of common PegIFNα2b-related toxicities, based on available clinical data and published literature. The toxicity profile of PegIFNα2b at the approved dose (6 μg/kg/week for 8 weeks then 3 μg/kg/week for up to 5 years) is qualitatively similar to HDI in melanoma. The most common adverse events (AEs) are fatigue, anorexia, hepatotoxicity, flu-like symptoms, injection site reactions and depression. However, fatigue and flu-like symptoms appear less severe with PegIFNα2b, and toxicity seems to occur earlier, whereas with HDI toxicity may increase with time. Most AEs can be managed effectively by dose modification and aggressive symptom control. Dosing to tolerance using a three-step dose reduction schedule to maintain an ECOG performance status of 0 - 1 may enable patients experiencing toxicity to remain on treatment; this can be applied readily in clinical practice. PegIFNα2b is therefore a valuable alternative option for adjuvant treatment in melanoma, with a toxicity profile similar to that of HDI overall but a more convenient administration schedule.

Bringing in vitro analysis closer to in vivo: Studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling.

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Verheijen, Marcha; Schrooders, Yannick; Gmuender, Hans; Nudischer, Ramona; Clayton, Olivia; Hynes, James; Niederer, Steven; Cordes, Henrik; Kuepfer, Lars; Kleinjans, Jos; Caiment, Florian

2018-05-24

Doxorubicin (DOX) is a chemotherapeutic agent of which the medical use is limited due to cardiotoxicity. While acute cardiotoxicity is reversible, chronic cardiotoxicity is persistent or progressive, dose-dependent and irreversible. While DOX mechanisms of action are not fully understood yet, 3 toxicity processes are known to occur in vivo: cardiomyocyte dysfunction, mitochondrial dysfunction and cell death. We present an in vitro experimental design aimed at detecting DOX-induced cardiotoxicity by obtaining a global view of the induced molecular mechanisms through RNA-sequencing. To better reflect the in vivo situation, human 3D cardiac microtissues were exposed to physiologically-based pharmacokinetic (PBPK) relevant doses of DOX for 2 weeks. We analysed a therapeutic and a toxic dosing profile. Transcriptomics analysis revealed significant gene expression changes in pathways related to "striated muscle contraction" and "respiratory electron transport", thus suggesting mitochondrial dysfunction as an underlying mechanism for cardiotoxicity. Furthermore, expression changes in mitochondrial processes differed significantly between the doses. Therapeutic dose reflects processes resembling the phenotype of delayed chronic cardiotoxicity, while toxic doses resembled acute cardiotoxicity. Overall, these results demonstrate the capability of our innovative in vitro approach to detect the three known mechanisms of DOX leading to toxicity, thus suggesting its potential relevance for reflecting the patient situation. Our study also demonstrated the importance of applying physiologically relevant doses during toxicological research, since mechanisms of acute and chronic toxicity differ. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

High-Dose-Rate Monotherapy for Localized Prostate Cancer: 10-Year Results

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Hauswald, Henrik; Kamrava, Mitchell R.; Fallon, Julia M.; Wang, Pin-Chieh; Park, Sang-June; Van, Thanh; Borja, Lalaine; Steinberg, Michael L.; Demanes, D. Jeffrey, E-mail: JDemanes@mednet.ucla.edu

2016-03-15

Purpose: High-dose-rate (HDR) brachytherapy was originally used with external beam radiation therapy (EBRT) to increase the dose to the prostate without injuring the bladder or rectum. Numerous studies have reported HDR brachytherapy is safe and effective. We adapted it for use without EBRT for cases not requiring lymph node treatment. Patients and Methods: We entered the patient demographics, disease characteristics, and treatment parameters into a prospective registry and serially added follow-up data for 448 men with low-risk (n=288) and intermediate-risk (n=160) prostate cancer treated from 1996 to 2009. Their median age was 64 years (range 42-90). The median prostate-specific antigen (PSA) level was 6.0 ng/mL (range 0.2-18.2). The Gleason score was ≤6 in 76% and 7 in 24%. The median dose was 43.5 Gy in 6 fractions. The clinical and biochemical disease control and survival rates were calculated. Adverse events were graded according to the Common Toxicity Criteria of Adverse Events. Results: The median follow-up period was 6.5 years (range 0.3-15.3). The actuarial 6- and 10-year PSA progression-free survival was 98.6% (95% confidence interval [CI] 96.9%-99.4%) and 97.8% (95% CI 95.5%-98.9%). Overall survival at 10 years was 76.7% (95% CI 69.9%-82.2%). The local control, distant metastasis-free survival, and cause-specific survival were 99.7% (95% CI 97.9%-99.9%), 98.9% (95% CI 96.3%-99.7%), and 99.1% (95% CI 95.8%-99.8%). T stage, initial PSA level, Gleason score, National Comprehensive Cancer Network risk group, patient age, and androgen deprivation therapy did not significantly correlate with disease control or survival. No late grade 3 to 4 rectal toxicities developed. Late grade 3 to 4 genitourinary toxicity occurred in 4.9% (grade 3 in 4.7%). Conclusions: HDR monotherapy is a safe and highly effective treatment of low- and intermediate-risk prostate cancer.

Regorafenib with a fluoropyrimidine for metastatic colorectal cancer after progression on multiple 5-FU-containing combination therapies and regorafenib monotherapy.

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Marks, Eric I; Tan, Carlyn; Zhang, Jun; Zhou, Lanlan; Yang, Zhaohai; Scicchitano, Angelique; El-Deiry, Wafik S

2015-01-01

We present 2 patients with metastatic colorectal cancer who had progressed despite treatment with first-line FOLFOX and second-line FOLFIRI combination chemotherapy regimens. After failing these fluoropyrimidine-based regimens, both patients received additional cytotoxic and targeted therapies with eventual disease progression. These therapies included capecitabine plus dabrafenib and trametinib, regorafenib monotherapy, and regorafenib with panitumumab. After exhausting available options, both patients were offered regorafenib with either 5-fluorouracil (5-FU) or capecitabine. These therapies are individually approved for the treatment of colorectal cancer but have not yet been studied in combination. This regimen produced stable disease in both patients with acceptable toxicity. One patient continued therapy for 17 months. Although these patients previously progressed during treatment with regorafenib, capecitabine or 5-FU, the combination had some activity in both cases of refractory metastatic colorectal cancer and may be considered in the palliative setting. In bedside-to-bench cell culture experiments performed after the clinical observations, we observed sensitivity of human colorectal cancer cell lines (N = 4) to single agent regorafenib or 5-FU and evidence of synergy with the combination therapy. Synergistic effects were noted in colorectal cancer cells with KRAS mutation, BRAF mutation, and p53 mutation, as well as mismatch repair deficient cells. Regorafenib suppressed Mcl-1 and Bcl-XL in treated cancer cells that may have contributed to the anticancer efficacy including in combination with 5-FU. The safety and efficacy of regorafenib with 5-FU or capecitabine in combination should be further investigated as a therapy for patients with refractory metastatic colorectal cancer, including individuals who had progressed on regorafenib monotherapy.

HIGH-DOSE RATE BRACHYTHERAPY IN CARCINOMA CERVIX STAGE IIIB

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Sathya Maruthavanan

2016-07-01

Full Text Available INTRODUCTION Radiotherapy is the standard treatment in locally advanced (IIB-IVA and early inoperable cases. The current standard of practice with curable intent is concurrent chemoradiation in which intracavitary brachytherapy is an integral component of radiotherapy. This study aims at assessing the efficacy of HDR ICBT (High-dose rate intracavitary brachytherapy in terms local response, normal tissue reactions, and feasibility. METHODS AND MATERIALS A total of 20 patients of stage IIIB cancer of the uterine cervix were enrolled in the study and were planned to receive concurrent chemotherapy weekly along with EBRT (external beam radiotherapy to a dose of 50 Gy/25 Fr. Suitability for ICBT was assessed at 40 Gy/20 Fr. 6/20 patients were suitable at 40 Gy and received HDR ICBT with a dose of 5.5 Gy to point A in 4 sessions (5.5 Gy/4 Fr. The remaining 14/20 patients completed 50 Gy and received HDR ICBT with a dose of 6 Gy to point A in 3 sessions (6 Gy/3 Fr. RESULTS A total of 66 intracavitary applications were done and only one application required dose modification due to high bladder dose, the pelvic control rate was 85% (17/20. 10% (2/20 had stable disease and 5% (1/20 had progressive disease at one year of follow up. When toxicity was considered only 15% developed grade I and grade II rectal complications. Patient compliance and acceptability was 100%. Patients were very comfortable with the short treatment time as compared with patients on LDR ICBT (low-dose rate intracavitary brachytherapy treatment interviewed during the same period. CONCLUSION This study proves that HDR brachytherapy is efficacious and feasible in carcinoma of cervix stage IIIB. It also proves that good dose distribution can be achieved with HDR intracavitary facility by the use of dose optimization. The short treatment time in HDR ICBT makes it possible to maintain this optimised dose distribution throughout the treatment providing a gain in the therapeutic ratio and

Early and late toxicity of involved-field radiation therapy in conjunction with high-dose chemotherapy and stem cell rescue

International Nuclear Information System (INIS)

Lubich, L.; Mundt, A.; Sibley, G.; Hallahan, D.; Nautiyal, J.; Weichselbaum, R.

1995-01-01

Purpose: Recent reports have demonstrated a benefit to involved-field radiation therapy (IFRT) in patients with relapsed/metastatic disease undergoing high-dose chemotherapy (HDCT) and stem cell rescue (SCR). We evaluate here the early and late toxicity of this approach. Methods: Eighty-five patients with either metastatic breast cancer (MBC) (31) or relapsed/refractory Hodgkin's disease (HD) (54) underwent HDCT/SCR. HDCT in the MBC patients consisted of cytoxan, thiotepa +/- carmustine and VP-16, cytoxan, BCNU +/- thiotepa in the HD patients. Thirty-four patients (40%) received IFRT either prior to (14) or following (20) HDCT to sites of disease involvement. A total of 18 patients received chest wall/mediastinal (CWMED) RT. Median followup for the MBC and HD patients were 21.3 months and 41 months, respectively. Results: Acute sequelae were similar in the 2 groups. Only one patient (5%) treated with IFRT (HD with 5 nodal sites) required a break from therapy due to low blood counts. Seven patients (0 MBC, 7 HD) (8.2%) suffered a toxic death (TD). No difference in was seen in the rate of TD in the patients as a whole ((1(14)) vs. (6(71))) (p =0.87) nor in the HD patients alone ((1(7)) vs. (6(47))) (p =0.91) with the use of IFRT prior to HDCT. Eleven patients (12.9%) developed late toxicity: 3 myelodysplasia/acute leukemia (MAL), 2 persistent low blood counts (requiring transfusions), 4 pulmonary toxicity (PT) and 2 hypothyroidism. All 4 cases of PT occurred in the HD group of which 3 received CWMED RT. The Table below shows the 5-yr actuarial risk of PT with and without CWMED RT as well as the 5-yr actuarial risk of MAL and any hematologic sequelae with and without RT. Multivariate analysis in the HD patients demonstrated that CWMED RT was the most significant factor for PT (p =0.09). All 3 cases of MAL and the 2 cases of persistent low blood counts occurred in the HD group. The use of IFRT did not increase the incidence of MAL or of any hematologic sequelae

Effect of radiation dose rate and cyclophosphamide on pulmonary toxicity after total body irradiation in a mouse model

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Safwat, Akmal; Nielsen, Ole S.; El-Badawy, Samy; Overgaard, Jens

1996-01-01

Purpose: Interstitial pneumonitis (IP) is still a major complication after total body irradiation (TBI) and bone marrow transplantation (BMT). It is difficult to determine the exact role of radiation in this multifactorial complication, especially because most of the experimental work on lung damage was done using localized lung irradiation and not TBI. We have thus tested the effect of radiation dose rate and combining cyclophosphamide (CTX) with single fraction TBI on lung damage in a mouse model for BMT. Methods and Materials: TBI was given as a single fraction at a high dose rate (HDR, 0.71 Gy/min) or a low dose rate (LDR, 0.08 Gy/min). CTX (250 mg/kg) was given 24 h before TBI. Bone marrow transplantation (BMT) was performed 4-6 h after the last treatment. Lung damage was assessed using ventilation rate (VR) and lethality between 28 and 180 days (LD (50(28))-180 ). Results: The LD 50 for lung damage, ± standard error (SE), increased from 12.0 (± 0.2) Gy using single fraction HDR to 15.8 (± 0.6) Gy using LDR. Adding CTX shifted the dose-response curves towards lower doses. The LD 50 values for the combined treatment were 5.3 (± 0.2) and 3.5 (± 0.2) Gy for HDR and LDR, respectively. This indicates that the combined effect of CTX and LDR was more toxic than that of combined CTX and HDR. Lung damage evaluated by VR demonstrated two waves of VR increase. The first wave of VR increase occurred after 6 weeks using TBI only and after 3 weeks in the combined CTX-TBI treatment, irrespective of total dose or dose rate. The second wave of VR elevation resembled the IP that follows localized thoracic irradiation in its time of occurrence. Conclusions: Lung damage following TBI could be spared using LDR. However, CTX markedly enhances TBI-induced lung damage. The combination of CTX and LDR is more toxic to the lungs than combining CTX and HDR

Acute toxicity study of tilmicosin-loaded hydrogenated castor oil-solid lipid nanoparticles

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Xie Shuyu

2011-11-01

Full Text Available Abstract Background Our previous studies demonstrated that tilmicosin-loaded hydrogenated castor oil solid lipid nanoparticles (Til-HCO-SLN are a promising formulation for enhanced pharmacological activity and therapeutic efficacy in veterinary use. The purpose of this work was to evaluate the acute toxicity of Til-HCO-SLN. Methods Two nanoparticle doses were used for the study in ICR mice. The low dose (766 mg/kg.bw with tilmicosin 7.5 times of the clinic dosage and below the median lethal dose (LD50 was subcutaneously administered twice on the first and 7th day. The single high dose (5 g/kg.bw was the practical upper limit in an acute toxicity study and was administered subcutaneously on the first day. Blank HCO-SLN, native tilmicosin, and saline solution were included as controls. After medication, animals were monitored over 14 days, and then necropsied. Signs of toxicity were evaluated via mortality, symptoms of treatment effect, gross and microscopic pathology, and hematologic and biochemical parameters. Results After administration of native tilmicosin, all mice died within 2 h in the high dose group, in the low dose group 3 died after the first and 2 died after the second injections. The surviving mice in the tilmicosin low dose group showed hypoactivity, accelerated breath, gloomy spirit and lethargy. In contrast, all mice in Til-HCO-SLN and blank HCO-SLN groups survived at both low and high doses. The high nanoparticle dose induced transient clinical symptoms of treatment effect such as transient reversible action retardation, anorexy and gloomy spirit, increased spleen and liver coefficients and decreased heart coefficients, microscopic pathological changes of liver, spleen and heart, and minor changes in hematologic and biochemical parameters, but no adverse effects were observed in the nanoparticle low dose group. Conclusions The results revealed that the LD50 of Til-HCO-SLN and blank HCO-SLN exceeded 5 g/kg.bw and thus the

High-dose proton beam therapy for sinonasal mucosal malignant melanoma

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Fuji, Hiroshi; Yoshikawa, Shusuke; Kasami, Masako; Murayama, Shigeyuki; Onitsuka, Tetsuro; Kashiwagi, Hiroya; Kiyohara, Yoshio

2014-01-01

The significance of definitive radiotherapy for sinonasal mucosal melanoma (SMM) is sill controvertial. This study was to evaluate the role of high-dose proton beam therapy (PBT) in patients with SMM. The cases of 20 patients with SMM localized to the primary site who were treated by PBT between 2006 and 2012 were retrospectively analyzed. The patterns of overall survival and morbidity were assessed. The median follow-up time was 35 months (range, 6–77 months). The 5-year overall and disease-free survival rates were 51% and 38%, respectively. Four patients showed local failure, 2 showed regrowth of the primary tumor, and 2 showed new sinonasal tumors beyond the primary site. The 5-year local control rate after PBT was 62%. Nodal and distant failure was seen in 7 patients. Three grade 4 late toxicities were observed in tumor-involved optic nerve. Our findings suggested that high-dose PBT is an effective local treatment that is less invasive than surgery but with comparable outcomes

Attenuating the toxicity of cisplatin by using selenosulfate with reduced risk of selenium toxicity as compared with selenite

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Zhang Jinsong; Peng Dungeng; Lu Hongjuan; Liu Qingliang

2008-01-01

It has been reported that high doses of sodium selenite can reduce side effects of cisplatin (CDDP) without compromising its antitumor activity, thus substantially enhancing the cure rate in tumor-bearing mice. However, the toxicity of selenite at high doses should be a concern. The present study revealed that selenosulfate had much lower toxicity, but possessed equal efficacy in selenium (Se) utilization, as compared with selenite at similar doses when used for the intervention of CDDP. In addition, Se accumulation in whole blood and kidney of mice treated with selenosulfate was highly correlated with the survival rate of mice treated with CDDP (both r > 0.96 and both p < 0.05), suggesting that whole blood Se is a potential clinical biomarker to predict host tolerance to CDDP. In either Se-deficient or -sufficient mice bearing solid tumors of hepatoma 22 (H22), selenosulfate did not disturb the therapeutic effect of CDDP on tumors but effectively attenuated the toxicity of CDDP. Furthermore, in a highly malignant cancer model, with Se-sufficient mice bearing ascitic H22 cells, 8 or 10 mg/kg CDDP alone only achieved a null or 25% cure rate, whereas coadministration of selenosulfate with the above two doses of CDDP achieved cure rates of 87.5% or 75%. These results together argue for consideration of selenosulfate as an agent to enhance the therapeutic efficacy of CDDP

Long term results of a prospective dose escalation phase-II trial: Interstitial pulsed-dose-rate brachytherapy as boost for intermediate- and high-risk prostate cancer

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Lettmaier, Sebastian; Lotter, Michael; Kreppner, Stephan; Strnad, Annedore; Fietkau, Rainer; Strnad, Vratislav

2012-01-01

Purpose: We reviewed our seven year single institution experience with pulsed dose rate brachytherapy dose escalation study in patients with intermediate and high risk prostate cancer. Materials and methods: We treated a total of 130 patients for intermediate and high risk prostate cancer at our institution between 2000 and 2007 using PDR-brachytherapy as a boost after conformal external beam radiation therapy to 50.4 Gy. The majority of patients had T2 disease (T1c 6%, T2 75%, T3 19%). Seventy three patients had intermediate-risk and 53 patients had high-risk disease according to the D’Amico classification. The dose of the brachytherapy boost was escalated from 25 to 35 Gy – 33 pts. received 25 Gy (total dose 75 Gy), 63 pts. 30 Gy (total dose 80 Gy) and 34 pts. 35 Gy, (total dose 85 Gy) given in one session (dose per pulse was 0.60 Gy or 0.70 Gy/h, 24 h per day, night and day, with a time interval of 1 h between two pulses). PSA-recurrence-free survival according to Kaplan–Meier using the Phoenix definition of biochemical failure was calculated and also late toxicities according to Common Toxicity Criteria scale were assessed. Results: At the time of analysis with a median follow-up of 60 months biochemical control was achieved by 88% of patients – only 16/130 patients (12.3%) developed a biochemical relapse. Biochemical relapse free survival calculated according to Kaplan–Meier for all patients at 5 years was 85.6% (83.9% for intermediate-risk patients and 84.2% for high-risk patients) and at 9 years’ follow up it was 79.0%. Analysing biochemical relapse free survival separately for different boost dose levels, at 5 years it was 97% for the 35 Gy boost dose and 82% for the 25 and 30 Gy dose levels. The side effects of therapy were negligible: There were 18 cases (15%) of grade 1/2 rectal proctitis, one case (0.8%) of grade 3 proctitis, 18 cases (15%) of grade 1/2 cystitis, and no cases (0%) with dysuria grade 3. No patient had a bulbourethral

Interstitial high-dose-rate brachytherapy boost: The feasibility and cosmetic outcome of a fractionated outpatient delivery scheme

International Nuclear Information System (INIS)

Manning, Matthew A.; Arthur, Douglas W.; Schmidt-Ullrich, Rupert K.; Arnfield, Mark R.; Amir, Cyrus; Zwicker, Robert D.

2000-01-01

Purpose: To evaluate the feasibility, potential toxicity, and cosmetic outcome of fractionated interstitial high dose rate (HDR) brachytherapy boost for the management of patients with breast cancer at increased risk for local recurrence. Methods and Materials: From 1994 to 1996, 18 women with early stage breast cancer underwent conventionally fractionated whole breast radiotherapy (50-50.4 Gy) followed by interstitial HDR brachytherapy boost. All were considered to be at high risk for local failure. Seventeen had pathologically confirmed final surgical margins of less than 2 mm or focally positive. Brachytherapy catheter placement and treatment delivery were conducted on an outpatient basis. Preplanning was used to determine optimal catheter positions to enhance dose homogeneity of dose delivery. The total HDR boost dose was 15 Gy delivered in 6 fractions of 2.5 Gy over 3 days. Local control, survival, late toxicities (LENT-SOMA), and cosmetic outcome were recorded in follow-up. In addition, factors potentially influencing cosmesis were analyzed by logistic regression analysis. Results: The minimum follow-up is 40 months with a median 50 months. Sixteen patients were alive without disease at last follow-up. There have been no in-breast failures observed. One patient died with brain metastases, and another died of unrelated causes without evidence of disease. Grade 1-2 late toxicities included 39% with hyperpigmentation, 56% with detectable fibrosis, 28% with occasional discomfort, and 11% with visible telangiectasias. Grade 3 toxicity was reported in one patient as persistent discomfort. Sixty-seven percent of patients were considered to have experienced good/excellent cosmetic outcomes. Factors with a direct relationship to adverse cosmetic outcome were extent of surgical defect (p = 0.00001), primary excision volume (p = 0.017), and total excision volume (p = 0.015). Conclusions: For high risk patients who may benefit from increased doses, interstitial HDR

Rectal balloon use limits vaginal displacement, rectal dose, and rectal toxicity in patients receiving IMRT for postoperative gynecological malignancies.

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Wu, Cheng-Chia; Wuu, Yen-Ruh; Yanagihara, Theodore; Jani, Ashish; Xanthopoulos, Eric P; Tiwari, Akhil; Wright, Jason D; Burke, William M; Hou, June Y; Tergas, Ana I; Deutsch, Israel

2018-01-01

Pelvic radiotherapy for gynecologic malignancies traditionally used a 4-field box technique. Later trials have shown the feasibility of using intensity-modulated radiotherapy (IMRT) instead. But vaginal movement between fractions is concerning when using IMRT due to greater conformality of the isodose curves to the target and the resulting possibility of missing the target while the vagina is displaced. In this study, we showed that the use of a rectal balloon during treatment can decrease vaginal displacement, limit rectal dose, and limit acute and late toxicities. Little is known regarding the use of a rectal balloon (RB) in treating patients with IMRT in the posthysterectomy setting. We hypothesize that the use of an RB during treatment can limit rectal dose and acute and long-term toxicities, as well as decrease vaginal cuff displacement between fractions. We performed a retrospective review of patients with gynecological malignancies who received postoperative IMRT with the use of an RB from January 1, 2012 to January 1, 2015. Rectal dose constraint was examined as per Radiation Therapy Oncology Group (RTOG) 1203 and 0418. Daily cone beam computed tomography (CT) was performed, and the average (avg) displacement, avg magnitude, and avg magnitude of vector were calculated. Toxicity was reported according to RTOG acute radiation morbidity scoring criteria. Acute toxicity was defined as less than 90 days from the end of radiation treatment. Late toxicity was defined as at least 90 days after completing radiation. Twenty-eight patients with postoperative IMRT with the use of an RB were examined and 23 treatment plans were reviewed. The avg rectal V40 was 39.3% ± 9.0%. V30 was65.1% ± 10.0%. V50 was 0%. Separate cone beam computed tomography (CBCT) images (n = 663) were reviewed. The avg displacement was as follows: superior 0.4 + 2.99 mm, left 0.23 ± 4.97 mm, and anterior 0.16 ± 5.18 mm. The avg magnitude of displacement was superior

Alternative methods for the median lethal dose (LD(50)) test: the up-and-down procedure for acute oral toxicity.

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Rispin, Amy; Farrar, David; Margosches, Elizabeth; Gupta, Kailash; Stitzel, Katherine; Carr, Gregory; Greene, Michael; Meyer, William; McCall, Deborah

2002-01-01

The authors have developed an improved version of the up-and-down procedure (UDP) as one of the replacements for the traditional acute oral toxicity test formerly used by the Organisation for Economic Co-operation and Development member nations to characterize industrial chemicals, pesticides, and their mixtures. This method improves the performance of acute testing for applications that use the median lethal dose (classic LD50) test while achieving significant reductions in animal use. It uses sequential dosing, together with sophisticated computer-assisted computational methods during the execution and calculation phases of the test. Staircase design, a form of sequential test design, can be applied to acute toxicity testing with its binary experimental endpoints (yes/no outcomes). The improved UDP provides a point estimate of the LD50 and approximate confidence intervals in addition to observed toxic signs for the substance tested. It does not provide information about the dose-response curve. Computer simulation was used to test performance of the UDP without the need for additional laboratory validation.

Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

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Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

2015-04-01

Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

Association of rectal toxicity with thermal dose parameters in treatment of locally advanced prostate cancer with radiation and hyperthermia

International Nuclear Information System (INIS)

Hurwitz, Mark D.; Kaplan, Irving D.; Hansen, Jorgen L.; Prokopios-Davos, Savina; Topulos, George P.; Wishnow, Kenneth; Manola, Judith; Bornstein, Bruce A.; Hynynen, Kullervo

2002-01-01

Purpose: Although hyperthermia has been used for more than two decades in the treatment of pelvic tumors, little is known about the potential impact of heat on rectal toxicity when combined with other treatment modalities. Because rectal toxicity is a concern with radiation and may be exacerbated by hyperthermia, definition of the association of thermal dose parameters with rectal toxicity is important. In this report, we correlate rectal toxicity with thermal dose parameters for patients treated with hyperthermia and radiation for prostate cancer. Methods and Materials: Thirty patients with T2b-T3b disease (1992 American Joint Committee On Cancer criteria) enrolled in a Phase II study of external beam radiation ± androgen-suppressive therapy with two transrectal ultrasound hyperthermia treatments were assessed for rectal toxicity. Prostatic and anterior rectal wall temperatures were monitored for all treatments. Rectal wall temperatures were limited to 40 deg. C in 19 patients, 41 deg. C in 3 patients, and 42 deg. C in 8 patients. Logistic regression was used to estimate the log hazard of developing National Cancer Institute Common Toxicity Criteria Grade 2 toxicity based on temperature parameters. The following were calculated: hazard ratios, 95% confidence intervals, p values for statistical significance of each parameter, and proportion of variability explained for each parameter. Results: Gastrointestinal toxicity was limited to Grade 2. The rate of acute Grade 2 proctitis was greater for patients with an allowable rectal wall temperature of >40 deg. C. In this group, 7 of 11 patients experienced acute Grade 2 proctitis, as opposed to 3 of 19 patients in the group with rectal wall temperatures limited to 40 deg. C (p=0.004). Preliminary assessment of long-term toxicity revealed no differences in toxicity. Hazard ratios for acute Grade 2 proctitis for allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax were 9.33 (p=0.01), 3

18F-Choline Positron Emission Tomography/Computed Tomography–Driven High-Dose Salvage Radiation Therapy in Patients With Biochemical Progression After Radical Prostatectomy: Feasibility Study in 60 Patients

International Nuclear Information System (INIS)

D'Angelillo, Rolando M.; Sciuto, Rosa; Ramella, Sara; Papalia, Rocco; Jereczek-Fossa, Barbara A.; Trodella, Luca E.; Fiore, Michele; Gallucci, Michele; Maini, Carlo L.; Trodella, Lucio

2014-01-01

Purpose: To retrospectively review data of a cohort of patients with biochemical progression after radical prostatectomy, treated according to a uniform institutional treatment policy, to evaluate toxicity and feasibility of high-dose salvage radiation therapy (80 Gy). Methods and Materials: Data on 60 patients with biochemical progression after radical prostatectomy between January 2009 and September 2011 were reviewed. The median value of prostate-specific antigen before radiation therapy was 0.9 ng/mL. All patients at time of diagnosis of biochemical recurrence underwent dynamic 18 F-choline positron emission tomography/computed tomography (PET/CT), which revealed in all cases a local recurrence. High-dose salvage radiation therapy was delivered up to total dose of 80 Gy to 18F-choline PET/CT-positive area. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events, version 3.0, scale. Results: Treatment was generally well tolerated: 54 patients (90%) completed salvage radiation therapy without any interruption. Gastrointestinal grade ≥2 acute toxicity was recorded in 6 patients (10%), whereas no patient experienced a grade ≥2 genitourinary toxicity. No grade 4 acute toxicity events were recorded. Only 1 patient (1.7%) experienced a grade 2 gastrointestinal late toxicity. With a mean follow-up of 31.2 months, 46 of 60 patients (76.6%) were free of recurrence. The 3-year biochemical progression-free survival rate was 72.5%. Conclusions: At early follow-up, 18 F-choline PET/CT-driven high-dose salvage radiation therapy seems to be feasible and well tolerated, with a low rate of toxicity

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

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Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3-6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.

In vitro chondrocyte toxicity following long-term, high-dose exposure to Gd-DTPA and a novel cartilage-targeted MR contrast agent

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Midura, Sharon; Midura, Ronald J. [Cleveland Clinic, Biomedical Engineering, Lerner Research Institute, Cleveland, OH (United States); Schneider, Erika [Cleveland Clinic, Imaging Institute, A21, Cleveland, OH (United States); NitroSci Pharmaceuticals, New Berlin, WI (United States); Rosen, Gerald M. [University of Maryland School of Pharmacy, Department of Pharmaceutical Sciences, Baltimore, MD (United States); NitroSci Pharmaceuticals, New Berlin, WI (United States); Winalski, Carl S. [Cleveland Clinic, Biomedical Engineering, Lerner Research Institute, Cleveland, OH (United States); Cleveland Clinic, Imaging Institute, A21, Cleveland, OH (United States)

2017-01-15

To determine the concentrations exhibiting toxicity of a cartilage-targeted magnetic resonance imaging contrast agent compared with gadopentetate dimeglumine (Gd-DT-PA) in chondrocyte cultures. A long-term Swarm rat chondrosarcoma chondrocyte-like cell line was exposed for 48 h to 1.0-20 mM concentrations of diaminobutyl-linked nitroxide (DAB4-DLN) citrate, 1.0-20 mM Gd-DTPA, 1.0 μM staurosporine (positive control), or left untreated. Cell appearance, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays of metabolic activity, quantitative PicoGreen assays of DNA content, and calcein-AM viability assays were compared. At 1.0-7.5 mM, minimal decrease in cell proliferation was found for both agents. At all doses of both agents, cell culture appearances were similar after 24 h of treatment. At the higher doses, differences in cell culture appearance were found after 48 h of treatment, with dose-dependent declines in chondrocyte populations for both agents. Concentration-dependent declines in DNA content and calcein fluorescence were found after 48 h of treatment, but beginning at a lower dose of DAB4-DLN citrate than Gd-DTPA. Dose-dependent decreases in MTT staining (cell metabolism) were apparent for both agents, but larger effects were evident at a lower dose for DAB-DLN citrate. Poor MTT staining of cells exposed for 48 h to 20 mM DAB4-DLN citrate probably indicates dead or dying cells. The minimal effect of the long-term exposure of model chondrocyte cell cultures to DAB4-DLN citrate and Gd-DTPA concentrations up to 7.5 mM (3x typical arthrographic administration) is supporting evidence that these doses are acceptable for MR arthrography. The findings are reassuring given that the experimental exposure to the contrast agents at sustained concentrations was much longer than when used clinically. (orig.)

In vitro chondrocyte toxicity following long-term, high-dose exposure to Gd-DTPA and a novel cartilage-targeted MR contrast agent

International Nuclear Information System (INIS)

Midura, Sharon; Midura, Ronald J.; Schneider, Erika; Rosen, Gerald M.; Winalski, Carl S.

2017-01-01

To determine the concentrations exhibiting toxicity of a cartilage-targeted magnetic resonance imaging contrast agent compared with gadopentetate dimeglumine (Gd-DT-PA) in chondrocyte cultures. A long-term Swarm rat chondrosarcoma chondrocyte-like cell line was exposed for 48 h to 1.0-20 mM concentrations of diaminobutyl-linked nitroxide (DAB4-DLN) citrate, 1.0-20 mM Gd-DTPA, 1.0 μM staurosporine (positive control), or left untreated. Cell appearance, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays of metabolic activity, quantitative PicoGreen assays of DNA content, and calcein-AM viability assays were compared. At 1.0-7.5 mM, minimal decrease in cell proliferation was found for both agents. At all doses of both agents, cell culture appearances were similar after 24 h of treatment. At the higher doses, differences in cell culture appearance were found after 48 h of treatment, with dose-dependent declines in chondrocyte populations for both agents. Concentration-dependent declines in DNA content and calcein fluorescence were found after 48 h of treatment, but beginning at a lower dose of DAB4-DLN citrate than Gd-DTPA. Dose-dependent decreases in MTT staining (cell metabolism) were apparent for both agents, but larger effects were evident at a lower dose for DAB-DLN citrate. Poor MTT staining of cells exposed for 48 h to 20 mM DAB4-DLN citrate probably indicates dead or dying cells. The minimal effect of the long-term exposure of model chondrocyte cell cultures to DAB4-DLN citrate and Gd-DTPA concentrations up to 7.5 mM (3x typical arthrographic administration) is supporting evidence that these doses are acceptable for MR arthrography. The findings are reassuring given that the experimental exposure to the contrast agents at sustained concentrations was much longer than when used clinically. (orig.)

Mechanism of action for anti-radiation vaccine in reducing the biological impact of high-dose gamma irradiation

Science.gov (United States)

Maliev, Vladislav; Popov, Dmitri; Jones, Jeffrey A.; Casey, Rachael C.

Ionizing radiation is a major health risk of long-term space travel, the biological consequences of which include genetic and oxidative damage. In this study, we propose an original mechanism by which high doses of ionizing radiation induce acute toxicity. We identified biological components that appear in the lymphatic vessels shortly after high-dose gamma irradiation. These radiation-induced toxins, which we have named specific radiation determinants (SRD), were generated in the irradiated tissues and then circulated throughout the body via the lymph circulation and bloodstream. Depending on the type of SRD elicited, different syndromes of acute radiation sickness (ARS) were expressed. The SRDs were developed into a vaccine used to confer active immunity against acute radiation toxicity in immunologically naïve animals. Animals that were pretreated with SRDs exhibited resistance to lethal doses of gamma radiation, as measured by increased survival times and survival rates. In comparison, untreated animals that were exposed to similar large doses of gamma radiation developed acute radiation sickness and died within days. This phenomenon was observed in a number of mammalian species. Initial analysis of the biochemical characteristics indicated that the SRDs were large molecular weight (200-250 kDa) molecules that were comprised of a mixture of protein, lipid, carbohydrate, and mineral. Further analysis is required to further identify the SRD molecules and the biological mechanism by which they mediate the toxicity associated with acute radiation sickness. By doing so, we may develop an effective specific immunoprophylaxis as a countermeasure against the acute effects of ionizing radiation.

Part of curietherapy at high rate of dose in the treatment of locally advanced esophagus carcinomas: preliminary results

International Nuclear Information System (INIS)

Maingon, P.; Bidault, F.; Barillot, I.; Bone-Lepinoy, M.C.; Coudert, B.; Horiot, J.C.

1994-01-01

The technology of curietherapy for esophagus shows its feasibility and its interest in advanced tumors of esophagus, by association with external radiotherapy and/or association radio-chemotherapy. It allows to deliver a high dose in the heart of the tumor with a tolerable toxicity. Its efficiency and the analysis of toxicity should be reevaluated at long term. Its place should be discussed in randomized protocols proposed to this selection of patients

Relationships Between Rectal Wall Dose-Volume Constraints and Radiobiologic Indices of Toxicity for Patients With Prostate Cancer

International Nuclear Information System (INIS)

Marzi, Simona; Arcangeli, Giorgio; Saracino, Bianca; Petrongari, Maria G.; Bruzzaniti, Vicente; Iaccarino, Giuseppe; Landoni, Valeria; Soriani, Antonella; Benassi, Marcello

2007-01-01

Purpose: The purpose of this article was to investigate how exceeding specified rectal wall dose-volume constraints impacts on the risk of late rectal bleeding by using radiobiologic calculations. Methods and Materials: Dose-volume histograms (DVH) of the rectal wall of 250 patients with prostate cancer were analyzed. All patients were treated by three-dimensional conformal radiation therapy, receiving mean target doses of 80 Gy. To study the main features of the patient population, the average and the standard deviation of the distribution of DVHs were generated. The mean dose , generalized equivalent uniform dose formulation (gEUD), modified equivalent uniform dose formulation (mEUD) 0 , and normal tissue complication probability (NTCP) distributions were also produced. The DVHs set was then binned into eight classes on the basis of the exceeding or the fulfilling of three dose-volume constraints: V 40 = 60%, V 50 = 50%, and V 70 = 25%. Comparisons were made between them by , gEUD, mEUD 0 , and NTCP. Results: The radiobiologic calculations suggest that late rectal toxicity is mostly influenced by V 70 . The gEUD and mEUD 0 are risk factors of toxicity always concordant with NTCP, inside each DVH class. The mean dose, although a reliable index, may be misleading in critical situations. Conclusions: Both in three-dimensional conformal radiation therapy and particularly in intensity-modulated radiation therapy, it should be known what the relative importance of each specified dose-volume constraint is for each organ at risk. This requires a greater awareness of radiobiologic properties of tissues and radiobiologic indices may help to gradually become aware of this issue

Dose-rate effects of ethylene oxide exposure on developmental toxicity.

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Weller, E; Long, N; Smith, A; Williams, P; Ravi, S; Gill, J; Henessey, R; Skornik, W; Brain, J; Kimmel, C; Kimmel, G; Holmes, L; Ryan, L

1999-08-01

In risk assessment, evaluating a health effect at a duration of exposure that is untested involves assuming that equivalent multiples of concentration (C) and duration (T) of exposure have the same effect. The limitations of this approach (attributed to F. Haber, Zur Geschichte des Gaskrieges [On the history of gas warfare], in Funf Vortrage aus den Jahren 1920-1923 [Five lectures from the years 1920-1923], 1924, Springer, Berlin, pp. 76-92), have been noted in several studies. The study presented in this paper was designed to specifically look at dose-rate (C x T) effects, and it forms an ideal case study to implement statistical models and to examine the statistical issues in risk assessment. Pregnant female C57BL/6J mice were exposed, on gestational day 7, to ethylene oxide (EtO) via inhalation for 1.5, 3, or 6 h at exposures that result in C x T multiples of 2100 or 2700 ppm-h. EtO was selected because of its short half-life, documented developmental toxicity, and relevance to exposures that occur in occupational settings. Concurrent experiments were run with animals exposed to air for similar periods. Statistical analysis using models developed to assess dose-rate effects revealed significant effects with respect to fetal death and resorptions, malformations, crown-to-rump length, and fetal weight. Animals exposed to short, high exposures of EtO on day 7 of gestation were found to have more adverse effects than animals exposed to the same C x T multiple but at longer, lower exposures. The implication for risk assessment is that applying Haber's Law could potentially lead to an underestimation of risk at a shorter duration of exposure and an overestimation of risk at a longer duration of exposure. Further research, toxicological and statistical, are required to understand the mechanism of the dose-rate effects, and how to incorporate the mechanistic information into the risk assessment decision process.

Study of four week repeated dose toxic test of Sweet Bee Venom in Beagle Dogs

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Jae-Seuk Park

2010-12-01

Full Text Available Objectives: This study was performed to analyse four week repeated dose toxicity of Sweet Bee Venom(Sweet BV extracted from the bee venom in Beagle dogs. Methods: All experiments were conducted under the regulations of Good Laboratory Practice (GLP at Biotoxtech Company, a non-clinical study authorized institution. Male and female Beagle dogs of 5-6 months old were chosen for the pilot study of four week repeated dose toxicity of Sweet BV which was administered at the level of 0.56㎎/㎏ body weight which is eighty times higher than the clinical application dosage as the high dosage, followed by 0.28 and 0.14㎎/㎏ as midium and low dosage, respectively. Equal amount of excipient(normal saline to the Sweet BV experiment groups was administered as the control group every day for four weeks. Results: 1. No mortality was witnessed in all of the experiment groups. 2. All experiment groups were appealed pain sense in the treating time compared to the control group, and hyperemia and movement disorder were observed around the area of administration in all experiment groups, and higher occurrence in the higher dosage treatment. 3. For weight measurement, Neither male nor female groups showed significant changes. 4. In the urine analysis, CBC and biochemistry didn't show any significant changes in the experiment groups compared with control group. 5. For weight measurement of organs, experiment groups didn't show any significant changes compared with control group. 6. To verify abnormalities of organs and tissues, thigh muscle which treated with Sweet BV, cerebrum, liver, lung, kidney, and spinal cords were removed and conducted histologocal observation with H-E staining. In the histologocal observation of thigh muscle, cell infiltration, inflammatory, degeneration, necrosis of muscle fiber, and fibrosis were found in both thigh tissue. And the changes were depend on the dose of Sweet BV. But another organs were not detected in any abnormalities. 7

Delivery of adjuvant sequential dose-dense FEC-Doc to patients with breast cancer is feasible, but dose reductions and toxicity are dependent on treatment sequence.

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Wildiers, H; Dirix, L; Neven, P; Prové, A; Clement, P; Squifflet, P; Amant, F; Skacel, T; Paridaens, R

2009-03-01

This study prospectively investigates the impact of dose densification and altering sequence of fluorouracil, epirubicin and cyclophosphamide [FEC(100)] and docetaxel [Doc] on dose delivery and tolerability of adjuvant chemotherapy in breast cancer patients. 117 patients with high-risk primary operable breast cancer were randomized (1:1:2:2) to conventional (three cycles of 3-weekly FEC(100) then three cycles of 3-weekly Doc 100 mg/m(2) or reverse sequence) or dose-dense (dd) treatment (four 10- to 11-day cycles of FEC(75) then four 2-weekly cycles of Doc 75 mg/m(2), or the reverse). In the dd arms, pegfilgrastim was given on day 2 of each cycle, but only as secondary prophylaxis in conventional arms. The primary endpoint was the proportion of patients completing intended cycles at relative dose intensity >or=85% and this was achieved by 95% of patients in each group except for the ddDoc-->FEC group (90%). Dose intensity in the dd arms increased by 48% for FEC and 11% for docetaxel, compared with the conventional arms (both P Doc dose reductions were more frequent with dd treatment and when Doc was given after FEC. Grade 3-4 neutropenia was significantly more frequent with conventional treatment, while fatigue and hand-foot syndrome were numerically more common with dd treatment, particularly when Doc was given after FEC. Discussion Delivery of adjuvant sequential ddFEC and Doc is feasible with growth factor support, and chemotherapy sequence appeared to affect delivery of target doses and toxicity.

Single-dose Toxicity of ShinYangHur Herbal Acupuncture

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Eunhye Cha

2015-06-01

Full Text Available Objectives: This study was carried out to analyze the single-dose toxicity of ShinYangHur (SYH herbal acupuncture injected into the muscles of Sprague-Dawley (SD rats. Methods: The SYH herbal acupuncture was made in a clean room at the Korean Pharmacopuncture Institute (KPI, Korea-Good Manufacturing Practice, K-GMP. After the mixing process with sterile distilled water, the pH was controlled to between 7.0 and 7.5. Then, NaCl was added to make a 0.9% isotonic solution by using sterilized equipment. All experiments were conducted at Biotoxtech, an institution authorized to perform non clinical studies under the regulations of Good Laboratory Practice (GLP. SD rats were chosen for the pilot study. Doses of SYH herbal acupuncture, 0.25, 0.5, and 1.0 mL, were administered to the experimental groups, and a dose of normal saline solution, 1.0 mL, was administered to the control group. This study was conducted under the approval of the Institutional Animal Ethics Committee. Results: No deaths or abnormalities occurred in any of the four groups. No significant changes in weight, hematological parameters or clinical chemistry between the control group and the experimental groups were observed. To check for abnormalities in organs and tissues, we used microscopy was used to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs or tissues. Conclusion: The above outcomes suggest that treatment with SYH herbal acupuncture is relatively safe. Further studies on this subject are needed to yield more concrete evidence.

Gamma dosimetry of high doses

International Nuclear Information System (INIS)

Martinez C, T.; Galvan G, A.; Canizal, G.

1991-01-01

The gamma dosimetry of high doses is problematic in almost all the classic dosemeters either based on the thermoluminescence, electric, chemical properties, etc., because they are saturated to very high dose and they are no longer useful. This work carries out an investigation in the interval of high doses. The solid system of heptahydrate ferrous sulfate, can be used as solid dosemeter of routine for high doses of radiation. The proposed method is simple, cheap and it doesn't require sophisticated spectrophotometers or spectrometers but expensive and not common in some laboratories

High-dose-rate brachytherapy as salvage modality for locally recurrent prostate cancer after definitive radiotherapy. A systematic review

Energy Technology Data Exchange (ETDEWEB)

Chatzikonstantinou, Georgios; Zamboglou, Nikolaos; Roedel, Claus; Tselis, Nikolaos [J.W. Goethe University of Frankfurt, Department of Radiotherapy and Oncology, Frankfurt am Main (Germany); Zoga, Eleni [Sana Klinikum Offenbach, Department of Radiotherapy and Oncology, Offenbach am Main (Germany); Strouthos, Iosif [Medical Center - University of Freiburg, Department of Radiotherapy and Oncology, University of Freiburg, Freiburg (Germany); Butt, Saeed Ahmed [Sana Klinikum Offenbach, Department of Medical Physics and Engineering, Offenbach am Main (Germany)

2017-09-15

To review the current status of interstitial high-dose-rate brachytherapy as a salvage modality (sHDR BRT) for locally recurrent prostate cancer after definitive radiotherapy (RT). A literature search was performed in PubMed using ''high-dose-rate, brachytherapy, prostate cancer, salvage'' as search terms. In all, 51 search results published between 2000 and 2016 were identified. Data tables were generated and summary descriptions created. The main outcome parameters used were biochemical control (BC) and toxicity scores. Eleven publications reported clinical outcome and toxicity with follow-up ranging from 4-191 months. A variety of dose and fractionation schedules were described, including 19.0 Gy in 2 fractions up to 42.0 Gy in 6 fractions. The 5-year BC ranged from 18-77%. Late grade 3 genitourinary and gastrointestinal toxicity was 0-32% and 0-5.1%, respectively. sHDR BRT appears as safe and effective salvage modality for the reirradiation of locally recurrent prostate cancer after definitive RT. (orig.) [German] Zusammenfassende Darstellung relevanter Literatur zur interstitiellen High-Dose-Rate-Brachytherapie als Salvage-Modalitaet (sHDR-BRT) bei der Behandlung des lokal rezidivierten Prostatakarzinoms nach vorausgegangener definitiver Radiotherapie (RT). In der PubMed-Datenbank wurde eine Literaturrecherche mit den Suchbegriffen ''high-dose-rate, brachytherapy, prostate cancer, salvage'' durchgefuehrt. Zwischen den Jahren 2000 und 2016 wurden 51 Publikationen identifiziert. Die biochemische Kontrolle (BC) sowie das assoziierte Toxizitaetsprofil waren onkologische Hauptpunkte in der Analyse der beruecksichtigten Literatur. Von onkologischen Ergebnissen und Toxizitaeten berichteten 11 Publikationen bei einer medianen Nachbeobachtungszeit von 4-191 Monaten. Eine Variabilitaet von Dosis- und Fraktionierungsregimen wurde beschrieben mit totalen physikalischen Dosen von 19,0 Gy in 2 Fraktionen bis zu 42,0 Gy in 6 Fraktionen

Extended duration of prehydration does not prevent nephrotoxicity or delayed drug elimination in high-dose methotrexate infusions

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Mikkelsen, Torben Stamm; Mamoudou, Aissata Diop; Tuckuviene, Ruta

2014-01-01

Alkalized hydration is used as supportive care to prevent renal toxicity during infusions with high-dose methotrexate (HDMTX). In children with acute lymphoblastic leukemia (ALL), the hydration is commonly initiated 4 hours before start of the methotrexate (MTX) infusion. To test if longer durati...

Behavioral effects of ketamine and toxic interactions with psychostimulants

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Yamamoto Keiichi

2006-03-01

Full Text Available Abstract Background The anesthetic drug ketamine (KT has been reported to be an abused drug and fatal cases have been observed in polydrug users. In the present study, considering the possibility of KT-enhanced toxic effects of other drugs, and KT-induced promotion of an overdose without making the subject aware of the danger due to the attenuation of several painful subjective symptoms, the intraperitoneal (i.p. KT-induced alterations in behaviors and toxic interactions with popular co-abused drugs, the psychostimulants cocaine (COC and methamphetamine (MA, were examined in ICR mice. Results A single dose of KT caused hyperlocomotion in a low (30 mg/kg, i.p. dose group, and hypolocomotion followed by hyperlocomotion in a high (100 mg/kg, i.p. dose group. However, no behavioral alterations derived from enhanced stress-related depression or anxiety were observed in the forced swimming or the elevated plus-maze test. A single non-fatal dose of COC (30 mg/kg, i.p. or MA (4 mg/kg, i.p. caused hyperlocomotion, stress-related depression in swimming behaviors in the forced swimming test, and anxiety-related behavioral changes (preference for closed arms in the elevated plus-maze test. For the COC (30 mg/kg or MA (4 mg/kg groups of mice simultaneously co-treated with KT, the psychostimulant-induced hyperlocomotion was suppressed by the high dose KT, and the psychostimulant-induced behavioral alterations in the above tests were reversed by both low and high doses of KT. For the toxic dose COC (70 mg/kg, i.p.- or MA (15 mg/kg, i.p.-only group, mortality and severe seizures were observed in some animals. In the toxic dose psychostimulant-KT groups, KT attenuated the severity of seizures dose-dependently. Nevertheless, the mortality rate was significantly increased by co-treatment with the high dose KT. Conclusion Our results demonstrated that, in spite of the absence of stress-related depressive and anxiety-related behavioral alterations following a single

Treatment of diffuse toxic goiter with 131I doses of 80 μCi/g of thyroid tissue

International Nuclear Information System (INIS)

Ochoa Torres, Francisco; Knight Bermudez, Hugh Gregorio; Alavez Martin, Ernesto

2004-01-01

131 I has proved to be the most efficient therapeutics in the treatment of diffuse toxic goiter (DTG). However, there is no consensus on the dose to be administered: fixed dose or according to the functional activity of the thyroid and its size. In order to evaluate the therapeutical results at a dose of 80 μCi/g of thyroid tissue, estimated by palpation and without having into account the functional activity of thyroid and whether they had received propylthiouracil (PTU) previously, 61 patients diagnosed by the clinic, as well as determinations of TSH and total T4, were studied in individuals aged 20-80 of both sexes, with a thyroid size over 30 g. The postoperative follow-up was performed every 2 months for 3 years by the same specialist and with identical procedures. The efficiency of the treatment with the first dose was 85.2 %. The frequency of hypothyroidism at 3 years of evolution was 29.5. The age of the patient, the sex, the goiter size and the treatment with PTU did not influence on the response to it. The advantages showed by the method were: high efficiency, the dose of 131 I may be easily calculated, simple application, decrease of the cost, since it is not necessary to assess the functional state of the gland, and reduction of visits

Short- and Long-Term Effects of Prenatal Exposure to Iron Oxide Nanoparticles: Influence of Surface Charge and Dose on Developmental and Reproductive Toxicity

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Kristin R. Di Bona

2015-12-01

Full Text Available Iron oxide nanoparticles (NPs are commonly utilized for biomedical, industrial, and commercial applications due to their unique properties and potential biocompatibility. However, little is known about how exposure to iron oxide NPs may affect susceptible populations such as pregnant women and developing fetuses. To examine the influence of NP surface-charge and dose on the developmental toxicity of iron oxide NPs, Crl:CD1(ICR (CD-1 mice were exposed to a single, low (10 mg/kg or high (100 mg/kg dose of positively-charged polyethyleneimine-Fe2O3-NPs (PEI-NPs, or negatively-charged poly(acrylic acid-Fe2O3-NPs (PAA-NPs during critical windows of organogenesis (gestation day (GD 8, 9, or 10. A low dose of NPs, regardless of charge, did not induce toxicity. However, a high exposure led to charge-dependent fetal loss as well as morphological alterations of the uteri (both charges and testes (positive only of surviving offspring. Positively-charged PEI-NPs given later in organogenesis resulted in a combination of short-term fetal loss (42% and long-term alterations in reproduction, including increased fetal loss for second generation matings (mice exposed in utero. Alternatively, negatively-charged PAA-NPs induced fetal loss (22% earlier in organogenesis to a lesser degree than PEI-NPs with only mild alterations in offspring uterine histology observed in the long-term.

Association between SLC19A1 Gene Polymorphism and High Dose Methotrexate Toxicity in Childhood Acute Lymphoblastic Leukaemia and Non Hodgkin Malignant Lymphoma: Introducing a Haplotype based Approach

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Kotnik, Barbara Faganel; Jazbec, Janez; Grabar, Petra Bohanec; Rodriguez-Antona, Cristina

2017-01-01

Abstract Background We investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX) related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL) and non Hodgkin malignant lymphoma (NHML). Patients and methods Eighty-eight children and adolescents with ALL/NHML were investigated for the influence of SLC 19A1 single nucleotide polymorphisms (SNPs) and haplotypes on HD-MTX induced toxicities. Results Patients with rs2838958 TT genotype had higher probability for mucositis development as compared to carriers of at least one rs2838958 C allele (OR 0.226 (0.071–0.725), p < 0.009). Haplotype TGTTCCG (H4) statistically significantly reduced the risk for the occurrence of adverse events during treatment with HD-MTX (OR 0.143 (0.023–0.852), p = 0.030). Conclusions SLC 19A1 SNP and haplotype analysis could provide additional information in a personalized HD-MTX therapy for children with ALL/NHML in order to achieve better treatment outcome. However further studies are needed to validate the results. PMID:29333125

Mouse single oral dose toxicity test of bupleuri radix aqueous extracts.

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Kim, Kyung-Hu; Gam, Cheol-Ou; Choi, Seong-Hun; Ku, Sae-Kwang

2012-03-01

The aim of this study was to evaluate the single oral dose toxicity of Bupleuri Radix (BR) aqueous extracts, it has been traditionally used as anti-inflammatory agent, in male and female mice. BR extracts (yield = 16.52%) was administered to female and male ICR mice as an oral dose of 2,000, 1,000 and 500 mg/kg (body weight) according to the recommendation of Korea Food and Drug Administration (KFDA) Guidelines. Animals were monitored for the mortality and changes in body weight, clinical signs and gross observation during 14 days after dosing, upon necropsy; organ weight and histopathology of 14 principal organs were examined. As the results, no BR extracts treatment related mortalities, clinical signs, changes on the body and organ weights, gross and histopathological observations against 14 principal organs were detected up to 2,000 mg/kg in both female and male mice, except for soft feces and related body weight decrease detected in male mice treated with 2,000 mg/kg. Therefore, LD50 (50% lethal dose) and approximate LD of BR aqueous extracts after single oral treatment in female and male mice were considered over 2000 mg/kg, respectively. Although it was also observed that the possibilities of digestive disorders, like soft feces when administered over 2,000 mg/kg of BR extracts in the present study, these possibilities of digestive disorders can be disregard in clinical use because they are transient in the highest dosages male only.

Available evidence on re-irradiation with stereotactic ablative radiotherapy following high-dose previous thoracic radiotherapy for lung malignancies.

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De Bari, Berardino; Filippi, Andrea Riccardo; Mazzola, Rosario; Bonomo, Pierluigi; Trovò, Marco; Livi, Lorenzo; Alongi, Filippo

2015-06-01

Patients affected with intra-thoracic recurrences of primary or secondary lung malignancies after a first course of definitive radiotherapy have limited therapeutic options, and they are often treated with a palliative intent. Re-irradiation with stereotactic ablative radiotherapy (SABR) represents an appealing approach, due to the optimized dose distribution that allows for high-dose delivery with better sparing of organs at risk. This strategy has the goal of long-term control and even cure. Aim of this review is to report and discuss published data on re-irradiation with SABR in terms of efficacy and toxicity. Results indicate that thoracic re-irradiation may offer satisfactory disease control, however the data on outcome and toxicity are derived from low quality retrospective studies, and results should be cautiously interpreted. As SABR may be associated with serious toxicity, attention should be paid for an accurate patients' selection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immunological changes following a combined effect of chromic small dose γ-irradiation and toxic agents

International Nuclear Information System (INIS)

Shubik, V.M.; Zykova, I.A.

1981-01-01

Immunologic changes under conditions of durable effect of low dose γ-radiation on people in the case of combining radiation with the effect of low concentrations of toxic substances, are studied. Under the above effect, the appearance of deviations from the side of immunologic status is possible. Taking into account the important role of the immunity system in homeostasis preservation and the formation of a series of pathological states it is advisable to use figures, and characteristics inherent in the state of the cell immunity to autoallergic processes to estimate a combined effect of radiation and toxic substances on the organism of people [ru

High-dose versus low-dose local anaesthetic for transversus abdominis plane block post-Caesarean delivery analgesia: a meta-analysis.

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Ng, S C; Habib, A S; Sodha, S; Carvalho, B; Sultan, P

2018-02-01

The optimal local-anaesthetic (LA) dose for transversus-abdominis-plane (TAP) block is unclear. In this meta-analysis, we aimed to determine whether TAP blocks for Caesarean delivery (CD) with low-dose (LD) LA demonstrated non-inferiority in terms of analgesic efficacy, compared with high-dose (HD) LA. A literature search was performed for randomised controlled trials examining the analgesic efficacy of TAP blocks vs control after CD. The different dosing used in these studies was classified as HD or LD (bupivacaine equivalents >50 or ≤50 mg per block side, respectively). The pooled results of each dose group vs control were indirectly compared using the Q test. The primary outcome was 24 h opioid consumption. Secondary outcomes included 6 and 24 h postoperative pain scores, time to first analgesia, 6 h opioid consumption, opioid-related side-effects, and maternal satisfaction. Fourteen studies consisting of 770 women (389 TAP and 381 control) were included. Compared with controls, the 24 h opioid consumption (milligram morphine equivalents) was lower in HD [mean difference (MD) 95% confidence interval (CI) -22.41 (-38.56, -6.26); P=0.007; I 2 =93%] and LD [MD 95% CI -16.29 (-29.74, -2.84); P=0.02; I 2 =98%] TAP groups. However, no differences were demonstrated between the HD and LD groups (P=0.57). There were also no differences between the HD and LD groups for the 6 h opioid consumption, time to first analgesia, 6 and 24 h pain scores, postoperative nausea and vomiting, pruritus, and maternal satisfaction. Low-dose TAP blocks for Caesarean delivery provide analgesia and opioid-sparing effects comparable with the high-dose blocks. This suggests that lower doses can be used to reduce local anaesthetic toxicity risk without compromising the analgesic efficacy. Copyright © 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule-Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non-Small-Cell Lung Cancer

International Nuclear Information System (INIS)

Chen, Yuhchyau; Pandya, Kishan J.; Feins, Richard; Johnstone, David W.; Watson, Thomas; Smudzin, Therese; Keng, Peter C.

2008-01-01

Purpose: We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a Phase I study for inoperable non-small-cell lung cancer. Methods and Materials: Paclitaxel at escalating doses of 15 mg/m 2 , 20 mg/m 2 , and 25 mg/m 2 were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by high-performance liquid chromatography. Results: Dose-limiting toxicities included 3 of 18 patients with Grade 3 pneumonitis and 3 of 18 patients with Grade 3 esophagitis. There was no Grade 4 or 5 pneumonitis or esophagitis. There was also no Grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For Dose Levels I (15 mg/m 2 ), II (20 mg/m 2 ), and III (25 mg/m 2 ), the mean peak plasma level was 0.23 ± 0.06 μmol/l, 0.32 ± 0.05 μmol/l, and 0.52 ± 0.14 μmol/l, respectively; AUC was 0.44 ± 0.09 μmol/l, 0.61 ± 0.1 μmol/l, and 0.96 ± 0.23 μmol/l, respectively; and duration of drug concentration >0.05 μmol/l (t > 0.05 μmol/l) was 1.6 ± 0.3 h, 1.9 ± 0.2 h, and 3.0 ± 0.9 h, respectively. Conclusion: Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration >0.05 μmol/l for a minimum of 1.6 h was sufficient for effective radiosensitization

Principal Component Analysis-Based Pattern Analysis of Dose-Volume Histograms and Influence on Rectal Toxicity

International Nuclear Information System (INIS)

Soehn, Matthias; Alber, Markus; Yan Di

2007-01-01

Purpose: The variability of dose-volume histogram (DVH) shapes in a patient population can be quantified using principal component analysis (PCA). We applied this to rectal DVHs of prostate cancer patients and investigated the correlation of the PCA parameters with late bleeding. Methods and Materials: PCA was applied to the rectal wall DVHs of 262 patients, who had been treated with a four-field box, conformal adaptive radiotherapy technique. The correlated changes in the DVH pattern were revealed as 'eigenmodes,' which were ordered by their importance to represent data set variability. Each DVH is uniquely characterized by its principal components (PCs). The correlation of the first three PCs and chronic rectal bleeding of Grade 2 or greater was investigated with uni- and multivariate logistic regression analyses. Results: Rectal wall DVHs in four-field conformal RT can primarily be represented by the first two or three PCs, which describe ∼94% or 96% of the DVH shape variability, respectively. The first eigenmode models the total irradiated rectal volume; thus, PC1 correlates to the mean dose. Mode 2 describes the interpatient differences of the relative rectal volume in the two- or four-field overlap region. Mode 3 reveals correlations of volumes with intermediate doses (∼40-45 Gy) and volumes with doses >70 Gy; thus, PC3 is associated with the maximal dose. According to univariate logistic regression analysis, only PC2 correlated significantly with toxicity. However, multivariate logistic regression analysis with the first two or three PCs revealed an increased probability of bleeding for DVHs with more than one large PC. Conclusions: PCA can reveal the correlation structure of DVHs for a patient population as imposed by the treatment technique and provide information about its relationship to toxicity. It proves useful for augmenting normal tissue complication probability modeling approaches

Literature-based recommendations for treatment planning and execution in high-dose radiotherapy for lung cancer

International Nuclear Information System (INIS)

Senan, Suresh; De Ruysscher, Dirk; Giraud, Philippe; Mirimanoff, Rene; Budach, Volker

2004-01-01

Background and purpose: To review the literature on techniques used in high-dose radiotherapy of lung cancer in order to develop recommendations for clinical practice and for use in research protocols. Patients and methods: A literature search was performed for articles and abstracts that were considered both clinically relevant and practical to use. The relevant information was arbitrarily categorized under the following headings: patient positioning, CT scanning, incorporating tumour mobility, definition of target volumes, radiotherapy planning, treatment delivery, and scoring of response and toxicity. Results: Recommendations were made for each of the above steps from the published literature. Although most of the recommended techniques have yet to be evaluated in multicenter clinical trials, their use in high-dose radiotherapy to the thorax appears to be rational on the basis of current evidence. Conclusions: Recommendations for the clinical implementation of high-dose conformal radiotherapy for lung tumours were identified in the literature. Procedures that are still considered to be investigational were also highlighted

Collaborative work on evaluation of ovarian toxicity. 13) Two- or four-week repeated dose studies and fertility study of PPAR alpha/gamma dual agonist in female rats.

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Sato, Norihiro; Uchida, Keisuke; Nakajima, Mikio; Watanabe, Atsushi; Kohira, Terutomo

2009-01-01

The main focus of this study was to determine the optimal dosing period in a repeated dose toxicity study based on toxic effects as assessed by ovarian morphological changes. To assess morphological and functional changes induced in the ovary by a peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, the compound was administered to female rats at dose levels of 0, 4, 20, and 100 mg/kg/day in a repeated dose toxicity study for 2 or 4 weeks, and from 2 weeks prior to mating to Day 7 of pregnancy in a female fertility study. In the repeated dose toxicity study, an increase in atresia of large follicles, a decrease in corpora lutea, and an increase in stromal cells were observed in the treated groups. In addition, the granulosa cell exfoliations into antrum of large follicles and corpora lutea with retained oocyte are morphological characteristics induced by this compound, and they might be related with abnormal condition of ovulation. In the female fertility study, the pregnancy rate tended to decrease in the 100 mg/kg/day group. At necropsy, decreases in the number of corpora lutea, implantations and live embryos were noted in the 20 and 100 mg/kg/day group. No changes were observed in animals given 4 mg/kg/day. These findings indicated that histopathological changes in the ovary are important endpoints for evaluation of drugs inducing ovarian damage. In conclusion, a 2-week administration period is sufficient to detect ovarian toxicity of this test compound in the repeated dose toxicity study.

Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity

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Levinsen, Mette; Rosthøj, Susanne; Nygaard, Ulrikka

2015-01-01

Purpose: Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine...... methyltransferase (TPMTIA) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Methods: Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1......,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. Results: The degree of myelosuppression following HD-MTX was similar for patients with TPMTIA and patients with high TPMT activity (TPMTHA), when HD-MTX started with same blood counts and 6MP doses. However...

Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia

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Vang, Sophia Ingeborg; Schmiegelow, Kjeld; Frandsen, Thomas

2015-01-01

High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue ...

Factors modifying the toxicity of total body irradiation (TBI) with bone marrow transplant

International Nuclear Information System (INIS)

Fish, B.L.; Moulder, J.E.

1987-01-01

In defined-flora, barrier-maintained rats, radiation nephritis is the principle late toxicity seen after single dose, high dose rate TBI with bone marrow transplant. Shielding the kidneys eliminates this late toxicity. If rats are exposed to a conventional microbiological environment during and after TBI and bone marrow transplant, the principle late toxicity is pneumonitis. Low dose rate TBI gives similar renal toxicity but at doses twice as large. Clinically, TBI and bone marrow transplant is preceded by intensive drug treatment, typically with cyclophosphamide (Cytoxan) and cytosine arabinoside (ara-C). Pretreatment with a standard cytoxan/ara-C regimen, has no effect on the gastrointestinal toxicity of TBI, but results in a decrease in marrow toxicity. Late renal toxicity still occurs when bone marrow transplants are given, but it is to early to determine whether drug treatment has affected late renal tolerance. Experiments are also underway to determine the effects of fractionated TBI (3, 6 and 9 fractions in 60 hours) on acute tolerance and on late tolerance after bone marrow transplantation

[Sarcopenia: a concept of growing importance in the management of colorectal cancer].

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Barret, Maximilien; Berthaud, Constance; Taïeb, Julien

2014-06-01

Malnutrition in digestive oncology affects quality of life, increases postoperative complication rates, and results in increased chemotherapy toxicity and reduced survival. Loss of skeletal muscle or sarcopenia is not correlated to body mass index, and might play a major role in the complications of malnutrition in oncology. The diagnosis of sarcopenia can be made on routinely available CT scanner images using consensual cutoff numbers. Lean body mass may be useful in normalizing the doses of hydrophilic chemotherapy drugs, such as fluoropyrimidines. To date, neither nutritional intervention nor specific drugs have proven useful in preventing or treating sarcopenia in cancer patients. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Standard dose 131I therapy for toxic multinodular goiter in an endemic goiter region

International Nuclear Information System (INIS)

Goncalves, E.; Castro, J.A.S.; Gross, J.L.

1986-01-01

The effect of the standard 15 mCi dose of 131 I on the thyroid function of 25 patients from an endemic goiter region with toxic multinodular goiter of different sizes was determined. The patients were followed for 1 to 5 years and 7 months (mean: 2 years and 10 months). Eighteen patients were treated with the antithyroid drugs propylthiouracil or methimazole before 131 I and seven only received 131 I. All but three patients achieved euthyroidism after a single dose of 131 I. Two patients in the antithyroid treatment group became hypothyroid 2 months and 2 years after the isotope therapy, respectively. Pretreatment with antithyroid drugs did not significantly modify the effectiveness of 131 I treatment. This simplified dose regimen of 131 I was effective in the treatment of hyperthyroidism caused by multinodular goiter in an endemic region, and the efficacy was independent of the size of the goiter. (author)

Single high dose intraoperative electrons for advanced stage pancreatic cancer: Phase I pilot study

International Nuclear Information System (INIS)

Goldson, A.L.; Ashaveri, E.; Espinoza, M.C.

1981-01-01

Phase I toxicity studies with intraoperative radiotherapy proved to be a feasible adjunct to surgery for unresectable malignancies of the pancreas at Howard University Hospital. There have been minimal side effects or complications related to the combination of limited surgical decompression and intraoperative radiotherapy alone. The toxic effects of intraoperative radiotherapy on normal tissues is being assessed on a dose volume basis. Doses of 2000 to 2500 rad in a single exposure to include the pancreas, regional nodes and duodenum are acceptable if the total treatment volume is less than or equal to 100 cm. The tumoricidal effects on the cancer are demonstratable when one reviews the pathological specimens that illustrate massive tumor necrosis and fibros replacement, but in all cases reviewed, viable cancer was noted. Intraoperative radiotherapy, therefore, represents a significant boost dose for resectable, partially resectable or non-resectable tumors when added to conventional external beam irradiation and/or chemotherapy. Preliminary clinical data and minimal toxicity justifies further investigation

Tolerance of the Brachial Plexus to High-Dose Reirradiation

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Chen, Allen M., E-mail: achen5@kumc.edu; Yoshizaki, Taeko; Velez, Maria A.; Mikaeilian, Argin G.; Hsu, Sophia; Cao, Minsong

2017-05-01

Purpose: To study the tolerance of the brachial plexus to high doses of radiation exceeding historically accepted limits by analyzing human subjects treated with reirradiation for recurrent tumors of the head and neck. Methods and Materials: Data from 43 patients who were confirmed to have received overlapping dose to the brachial plexus after review of radiation treatment plans from the initial and reirradiation courses were used to model the tolerance of this normal tissue structure. A standardized instrument for symptoms of neuropathy believed to be related to brachial plexus injury was utilized to screen for toxicity. Cumulative dose was calculated by fusing the initial dose distributions onto the reirradiation plan, thereby creating a composite plan via deformable image registration. The median elapsed time from the initial course of radiation therapy to reirradiation was 24 months (range, 3-144 months). Results: The dominant complaints among patients with symptoms were ipsilateral pain (54%), numbness/tingling (31%), and motor weakness and/or difficulty with manual dexterity (15%). The cumulative maximum dose (Dmax) received by the brachial plexus ranged from 60.5 Gy to 150.1 Gy (median, 95.0 Gy). The cumulative mean (Dmean) dose ranged from 20.2 Gy to 111.5 Gy (median, 63.8 Gy). The 1-year freedom from brachial plexus–related neuropathy was 67% and 86% for subjects with a cumulative Dmax greater than and less than 95.0 Gy, respectively (P=.05). The 1-year complication-free rate was 66% and 87%, for those reirradiated within and after 2 years from the initial course, respectively (P=.06). Conclusion: The development of brachial plexus–related symptoms was less than expected owing to repair kinetics and to the relatively short survival of the subject population. Time-dose factors were demonstrated to be predictive of complications.

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

Directory of Open Access Journals (Sweden)

Shakespeare TP

2016-05-01

Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Rural Clinical School, Faculty of Medicine, University of New South Wales, Coffs Harbour, NSW, Australia Aim: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods: Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results: In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion: There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. Keywords: radiotherapy, IMRT, dose

Post operative high dose rate intravaginal irradiation in endometrial cancer: a safe and effective outpatient treatment

International Nuclear Information System (INIS)

Chen, Peter; Gibbons, Susan; Vicini, Frank; Weiner, Sheldon; Dmuchowski, Carl; Mele, Beth; Brabbins, Donald; Jennings, John; Gustafson, Gary; Martinez, Alvaro

1995-01-01

Purpose: We reviewed our experience with out patient high dose rate (HDR) intravaginal irradiation given post-operatively in endometrial cancer to assess local control, survival, and toxicity when used alone or in combination with external beam irradiation. Methods and Materials: From (12(88)) to (12(92)), 78 patients underwent TAH/BSO and received post-operative HDR intravaginal irradiation for endometrial cancer. Pathologic stage distribution was IB/IC: 56%, II: 22%, III: 22%. Adjuvant therapy was given in one of three schemes: HDR vaginal radiation alone (6 weekly fractions of 500 cGy prescribed 5 mm from the applicator surface treating the upper 4 cm of the vagina), pelvic irradiation with vaginal HDR (500 cGy x 4 weekly fractions) or whole abdomen/pelvic irradiation (WAPI) with vaginal HDR treatment (500 cGy x 3 weekly fractions). Prior to the first HDR vaginal treatment, a simulation with placement of vaginal apex metallic markers was performed to assure proper positioning of the intravaginal cylinders. Pelvic midline blocking was designed from the HDR intravaginal simulation films. The 55 patients who underwent combined external beam irradiation/brachytherapy received a median dose to the pelvis of 5040 cGy (range 25.2-51.6 Gy), and a median total vaginal dose of 5060 cGy (range 30.0-57.6 Gy). Results: Median follow-up is 37 months (range 6-73 months). Local control (vaginally) is 98.7%. The one vaginal failure was in the distal vagina, outside the treatment volume. All other failures (4) were distant with the vagina controlled [3 intra-abdominal and one bone/intra-abdominal]. For stages I and II, the disease free survival is 92.8%. For stage III the disease free survival is 86.5%. Median overall time to failure is 14.3 months (range 8.5-18.6 months). In terms of acute toxicity, no grade 3-4 acute toxicity of the vagina or bladder was seen. However, 9% acute GI toxicity was encountered. Chronic grade 1-2 toxicities included: vaginal 21.8% (foreshortening and

Single Intramuscular-dose Toxicity of Water soluble Carthmi-Flos herbal acupuncture (WCF in Sprague-Dawley Rats

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Lee Hyung-geol

2014-03-01

Full Text Available Objectives: This experiment was conducted to examine the toxicity of WCF (Water soluble Carthmi-Flos herbal acupuncture by administering a single intramuscular dose of WCF in 6-week-old, male and female Sprague-Dawley rats and to find the lethality dose for WCF. Methods: The experiment was conducted at Biotoxtech according to Good Laboratory Practices under a request by the Korean Pharmacopuncture Institute. This experiment was performed based on the testing standards of “Toxicity Test Standards for Drugs” by the Ministry of Food and Drug Safety. Subjects were divided into 4 groups: 1 control group in which normal saline was administered and 3 test groups in which 0.1, 0.5 or 1.0 mL of WCF was administered; a single intramuscular dose was injected into 5 males and 5 females in each group. General symptoms and body weights were observed/measured for 14 days after injection. At the end of the observation period, hematological and clinical chemistry tests were performed, followed by necropsy and histopathological examinations of the injected sections. Results: No mortalities were observed in any group. Also, symptoms, body weight, hematology, clinical chemistry and necropsy were not affected. However, histopathological examination of the injected part in one female in the 1.0-mL group showed infiltration of mononuclear cells and a multi-nucleated giant cell around eosinophilic material. Conclusion: Administration of single intramuscular doses of WCF in 3 groups of rats showed that the approximate lethal dose of WCF for all rats was in excess of 1.0 mL, as no mortalities were observed for injections up to and including 1.0 mL.

Phase I/II trial of single-fraction high-dose-rate brachytherapy-boosted hypofractionated intensity-modulated radiation therapy for localized adenocarcinoma of the prostate.

Science.gov (United States)

Myers, Michael A; Hagan, Michael P; Todor, Dorin; Gilbert, Lynn; Mukhopadhyay, Nitai; Randolf, Jessica; Heimiller, Jeffrey; Anscher, Mitchell S

2012-01-01

A Phase I/II protocol was conducted to examine the toxicity and efficacy of the combination of intensity-modulated radiation therapy (IMRT) with a single-fraction high-dose-rate (HDR) brachytherapy implant. From 2001 through 2006, 26 consecutive patients were treated on the trial. The primary objective was to demonstrate a high rate of completion without experiencing a treatment-limiting toxicity. Eligibility was limited to patients with T stage ≤2b, prostate-specific antigen (PSA) ≤20, and Gleason score ≤7. Treatment began with a single HDR fraction of 6Gy to the entire prostate and 9Gy to the peripheral zone, followed by IMRT optimized to deliver in 28 fractions with a normalized total dose of 70Gy. Patients received 50.4Gy to the pelvic lymph node. The prostate dose (IMRT and HDR) resulted in an average biologic equivalent dose >128Gy (α/β=3). Patients whose pretreatment PSA was ≥10ng/mL, Gleason score 7, or stage ≥T2b received short-term androgen ablation. Median followup was 53 months (9-68 months). There were no biochemical failures by either the American Society of Therapeutic Radiology and Oncology or the Phoenix definitions. The median nadir PSA was 0.32ng/mL. All the 26 patients completed the treatment as prescribed. The rate of Grade 3 late genitourinary toxicity was 3.8% consisting of a urethral stricture. There was no other Grade 3 or 4 genitourinary or gastrointestinal toxicities. Single-fraction HDR-boosted IMRT is a safe effective method of dose escalation for localized prostate cancer. Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

Science.gov (United States)

Aisa, Yoshinobu; Mori, Takehiko; Kudo, Masumi; Yashima, Tomoko; Kondo, Sakiko; Yokoyama, Akihiro; Ikeda, Yasuo; Okamoto, Shinichiro

2005-04-01

The purpose of this study was to evaluate the efficacy of oral cryotherapy to prevent high-dose melphalan-induced stomatitis. Eighteen consecutive recipients of allogeneic hematopoietic stem cell transplant conditioned with high-dose melphalan (140 mg/m2) in combination with fludarabine alone or with fludarabine and additional chemotherapy or radiation were enrolled. The severity of stomatitis was graded according to the National Cancer Institute Common Toxicity Criteria. Patients were kept on oral cryotherapy using ice chips and ice-cold water shortly before, during, and for additional 90 min after completion of melphalan administration. Only two of 18 patients (11.1%) developed grade 2 or 3 stomatitis while six of seven patients in the historical control developed it (85.7%; P=0.001). These results suggested that oral cryotherapy could effectively prevent stomatitis caused by high-dose melphalan, and we recommend that it should be incorporated into the conditioning regimen with high-dose melphalan.

Phasing out of the Universal Mega Dose of Vitamin-A Prophylaxis to Avoid Toxicity

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Sudip Bhattacharya

2017-01-01

Full Text Available Childhood blindness due to corneal ulceration was prevalent among poor Indian children. To tackle this situation, the National Institute of Nutrition (NIN, Hyderabad, India, Vitamin-A (Vit-A prophylaxis programme was launched nationally in 1970 after field testing. Research of Indian Council for Medical Research (ICMR documented that prevalence of Vit-A deficiency signs such as Bitot’s spot decreased among children, over a period of time. However, this decrease cannot be ascertained is due to mass Vit-A prophylaxis programme. This is because coverage was low and patchy. Improved nutrition status, wider vaccination coverage, increased rate in breast feeding and improvement of healthcare services played a crucial role. Rather many studies revealed that (mass prophylaxis to the child who is having adequate Vit-A level it may be harmful to certain group of children as a result of acute toxic symptoms. High dose of Vit-A is capable of loss of bone density-hence retarded growth may be observed in susceptible individuals. To tackle this issue food based approach should be promoted (which includes breast feeding along with timely measles vaccination. The children who have signs of Vit-A deficiency (e.g. night blindness, xeropthalmia, Bitot’s spot or post measles children should receive Vit-A in age specific daily doses for two weeks along with Vit-A rich food, like green leafy vegetables, red palm oil, liver etc. Public spirited citizens, together with scientific community in India, should discourage this “one size fit to all” approach. It will not only avoid the ill effects of high dose of Vit-A but also it will help us optimal utilization of health resources in a resource poor country like India.

Biological dose estimation for accidental supra-high dose gamma-ray exposure

International Nuclear Information System (INIS)

Chen, Y.; Yan, X.K.; Du, J.; Wang, Z.D.; Zhang, X.Q.; Zeng, F.G.; Zhou, P.K.

2011-01-01

To correctly estimate the biological dose of victims accidentally exposed to a very high dose of 60 Co gamma-ray, a new dose-effect curve of chromosomal dicentrics/multicentrics and rings in the supra-high dose range was established. Peripheral blood from two healthy men was irradiated in vitro with doses of 60 Co gamma-rays ranging from 6 to 22 Gy at a dose rate of 2.0 Gy/min. Lymphocytes were concentrated, cultured and harvested at 52 h, 68 h and 72 h. The numbers of dic + r were counted. The dose-effect curves were established and validated using comparisons with doses from the Tokai-mura accident and were then applied to two victims of supra-high dose exposure accident. The results indicated that there were no significant differences in chromosome aberration frequency among the different culture times from 52 h to 72 h. The 6-22 Gy dose-effect curve was fitted to a linear quadratic model Y = -2.269 + 0.776D - 7.868 x l0 -3 D 2 . Using this mathematic model, the dose estimates were similar to data from Tokai-mura which were estimated by PCC ring. Whole body average doses of 9.7 Gy and 18.1 Gy for two victims in the Jining accident were satisfactorily given. We established and successfully applied a new dose-effect curve of chromosomal dicentrics plus ring (dic + r) after 6-22 Gy γ-irradiation from a supra-high dose 60 Co gamma-ray accident.

Treatment of diffuse toxic goiter with 131I. at doses of 80ΜCi/g of thyroid tissue

International Nuclear Information System (INIS)

Ochoa Torres, Francisco; Knight Bermudez, Hugh Gregorio; Alavez Martin, Ernesto

2004-01-01

131 I. has proved to be the most efficient therapeutics in the treatment of diffuse toxic goiter (DTG). However, there is no consensus on the dose to be administered: fixed dose or according to the functional activity of the thyroid and its size. In order to evaluate the therapeutical results at a dose of 80 ΜCi/g of thyroid tissue, estimated by palpation and without having into account the functional activity of thyroid and whether they had received propylthiouracil (PTU) previously , 61 patients diagnosed by the clinic, as well as determinations of TSH and total T4, were studied in individuals aged 20-80 of both sexes, with a thyroid size over 30 g. The postoperative follow-up was performed every 2 months for 3 years by the same specialist and with identical procedures. The efficiency of the treatment with the first dose was 85.2 %. The frequency of hypothyroidism at 3 years of evolution was 29.5. The age of the patient, the sex, the goiter size and the treatment with PTU did not influence on the response to it. The advantages showed by the method were: high efficiency, the dose of 131 I. may be easily calculated, simple application, decrease of the cost, since it is not necessary to assess the functional state of the gland, and reduction of visits

Use of an oiled gravel column dosing system to characterize exposure and toxicity of fish to sunken heavy oil on spawning substrates

International Nuclear Information System (INIS)

Martin, J.; Hodson, P.

2010-01-01

In August 2005, a freight train derailment near the shore of Lake Wabamun near Edmonton, Alberta resulted in the release of nearly 150,000 litres of Bunker C oil on the lakeshore. The purpose of this study was to define the toxic load of oil in sediments to better describe the exposure and toxicity of fish to sunken heavy oil on spawning substrates. Heavy Bunker C fuel contains a complex mixture of polycyclic aromatic hydrocarbons (PAH), particularly the 3-4 ringed alkylated forms that cause sublethal toxic responses in early life stages of rainbow trout (Oncorhynchus mykiss). Oil patches still persist in near-shore sediments where fish spawn. This study evaluated how the behaviour of heavy oil in water interacts with exposure and toxicity to trout embryo. Flow-through oiled gravel columns were used to determine whether the toxic constituents of heavy oil are transferred to water quickly enough to cause toxicity. Embryonic trout exposed to the outflow of these columns showed signs of sublethal toxicity and dose-dependent mortality. In addition, column output of hydrocarbons and CYP1A induction in fish were flow-dependent. The desorption kinetics of the gravel column dosing was characterized in order to evaluate the toxicity of oil on these substrates and relate it back to toxicity of oil in sediments. The time to steady-state desorption of oil constituents in water was first determined, and then the rate at which different classes of oil constituents partition into water were identified.

The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

Science.gov (United States)

Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry

2013-01-01

The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Phase I study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer

International Nuclear Information System (INIS)

Sudo, Kentaro; Yamaguchi, Taketo; Ishihara, Takeshi; Nakamura, Kazuyoshi; Shirai, Yoshihiko; Nakagawa, Akihiko; Kawakami, Hiroyuki; Uno, Takashi; Ito, Hisao; Saisho, Hiromitsu

2007-01-01

Purpose: The primary objective of this study was to determine the maximum-tolerated dose (MTD) of S-1, an oral fluoropyrimidine derivative, with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Methods and Materials: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day from Day 1 to 14 and 22 to 35 at escalating doses from 60 to 80 mg/m 2 /day. Results: Sixteen patients were enrolled in this study. Three patients received S-1 at 60 mg/m 2 /day, 3 at 70 mg/m 2 /day, and 10 at 80 mg/m 2 /day. Though 1 patient at the final dose level (80 mg/m 2 /day) experienced a dose limiting toxicity (biliary infection with Grade 3 neutropenia), the MTD was not reached in this study. The most common toxicities were anorexia and leukocytopenia, with Grade 3 toxicity occurring in 31% and 6.3% of the patients, respectively. Conclusions: The recommended dose of S-1 with concurrent radiotherapy was determined to be 80 mg/m 2 /day from Day 1 to 14 and 22 to 35 in patients with locally advanced pancreatic cancer. Oral S-1 and radiotherapy is well tolerated and feasible and should be further investigated

Low-dose total skin electron beam therapy for cutaneous lymphoma. Minimal risk of acute toxicities

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Kroeger, Kai; Elsayad, Khaled; Moustakis, Christos; Haverkamp, Uwe; Eich, Hans Theodor [University Hospital of Muenster, Department of Radiation Oncology, Muenster (Germany)

2017-12-15

Low-dose total skin electron beam therapy (TSEBT) is attracting increased interest for the effective palliative treatment of primary cutaneous T-cell lymphoma (pCTCL). In this study, we compared toxicity profiles following various radiation doses. We reviewed the records of 60 patients who underwent TSEBT for pCTCL between 2000 and 2016 at the University Hospital of Munster. The treatment characteristics of the radiotherapy (RT) regimens and adverse events (AEs) were then analyzed and compared. In total, 67 courses of TSEBT were administered to 60 patients. Of these patients, 34 (51%) received a standard dose with a median surface dose of 30 Gy and 33 patients (49%) received a low dose with the median surface dose of 12 Gy (7 salvage low-dose TSEBT courses were administered to 5 patients). After a median follow-up of 15 months, the overall AE rate was 100%, including 38 patients (57%) with grade 2 and 7 (10%) with grade 3 AEs. Patients treated with low-dose TSEBT had significantly fewer grade 2 AEs than those with conventional dose regimens (33 vs. 79%, P < 0.001). A lower grade 3 AE rate was also observed in patients who had received the low-dose regimen compared to those with the conventional dose regimens (6 vs. 15%, P = 0.78). Multiple/salvage low-dose TSEBT courses were not associated with an increased risk of acute AEs. Low-dose TSEBT regimens are associated with significantly fewer grade 2 acute toxicities compared with conventional doses of TSEBT. Repeated/Salvage low-dose TSEBT, however, appears to be tolerable and can even be applied safely in patients with cutaneous relapses. (orig.) [German] Eine niedrigdosierte Ganzhautelektronenbestrahlung (TSEBT) wird vermehrt zur effektiven palliativen Behandlung von Patienten mit primaer kutanen T-Zell-Lymphomen (pCTCL) eingesetzt. In dieser Studie vergleichen wir die Toxizitaetsprofile verschiedener Dosiskonzepte. Untersucht wurden 60 zwischen 2000 und 2016 am Universitaetsklinikum Muenster mittels TSEBT

Developing A Directional High-Dose Rate (d-HDR) Brachytherapy Source

Science.gov (United States)

Heredia, Athena Yvonne

Conventional sources used in brachytherapy provide nearly isotropic or radially symmetric dose distributions. Optimizations of dose distributions have been limited to varied dwell times at specified locations within a given treatment volume, or manipulations in source position for seed implantation techniques. In years past, intensity modulated brachytherapy (IMBT) has been used to reduce the amount of radiation to surrounding sensitive structures in select intracavitary cases by adding space or partial shields. Previous work done by Lin et al., at the University of Wisconsin-Madison, has shown potential improvements in conformality for brachytherapy treatments using a directionally shielded low dose rate (LDR) source for treatments in breast and prostate. Directional brachytherapy sources irradiate approximately half of the radial angles around the source, and adequately shield a quarter of the radial angles on the opposite side, with sharp gradient zones between the treated half and shielded quarter. With internally shielded sources, the radiation can be preferentially emitted in such a way as to reduce toxicities in surrounding critical organs. The objective of this work is to present findings obtained in the development of a new directional high dose rate (d-HDR) source. To this goal, 103Pd (Z = 46) is reintroduced as a potential radionuclide for use in HDR brachytherapy. 103Pd has a low average photon energy (21 keV) and relatively short half -life (17 days), which is why it has historically been used in low dose rate applications and implantation techniques. Pd-103 has a carrier-free specific activity of 75000 Ci/g. Using cyclotron produced 103Pd, near carrier-free specific activities can be achieved, providing suitability for high dose rate applications. The evolution of the d-HDR source using Monte Carlo simulations is presented, along with dosimetric parameters used to fully characterize the source. In addition, a discussion on how to obtain elemental

Supraphysiological Doses of Performance Enhancing Anabolic-Androgenic Steroids Exert Direct Toxic Effects on Neuron-like Cells

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John Robert Basile

2013-05-01

Full Text Available Anabolic-androgenic steroids (AAS are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few have been specifically tested for direct neurotoxicity. We evaluated the effects of supraphysiological doses of methandienone and 17-α-methyltestosterone on sympathetic-like neuron cells. Vitality and apoptotic effects were analyzed, and immunofluorescence staining and western blot performed. In this study, we demonstrate that exposure of supraphysiological doses of methandienone and 17-α-methyltestosterone are toxic to the neuron-like differentiated pheochromocytoma cell line PC12, as confirmed by toxicity on neurite networks responding to nerve growth factor and the modulation of the survival and apoptosis-related proteins ERK, caspase-3, poly (ADP-ribose polymerase and heat-shock protein 90. We observe, in contrast to some previous reports but in accordance with others, expression of the androgen receptor (AR in neuron-like cells, which when inhibited mitigated the toxic effects of AAS tested, suggesting that the AR could be binding these steroid hormones to induce genomic effects. We also note elevated transcription of neuritin in treated cells, a neurotropic factor likely expressed in an attempt to resist neurotoxicity. Taken together, these results demonstrate that supraphysiological exposure to the AAS methandienone and 17-α-methyltestosterone exert neurotoxic effects by an increase in the activity of the intrinsic apoptotic pathway and alterations in neurite networks.

A hypothetical model for predicting the toxicity of high aspect ratio nanoparticles (HARN)

Science.gov (United States)

Tran, C. L.; Tantra, R.; Donaldson, K.; Stone, V.; Hankin, S. M.; Ross, B.; Aitken, R. J.; Jones, A. D.

2011-12-01

The ability to predict nanoparticle (dimensional structures which are less than 100 nm in size) toxicity through the use of a suitable model is an important goal if nanoparticles are to be regulated in terms of exposures and toxicological effects. Recently, a model to predict toxicity of nanoparticles with high aspect ratio has been put forward by a consortium of scientists. The High aspect ratio nanoparticles (HARN) model is a platform that relates the physical dimensions of HARN (specifically length and diameter ratio) and biopersistence to their toxicity in biological environments. Potentially, this model is of great public health and economic importance, as it can be used as a tool to not only predict toxicological activity but can be used to classify the toxicity of various fibrous nanoparticles, without the need to carry out time-consuming and expensive toxicology studies. However, this model of toxicity is currently hypothetical in nature and is based solely on drawing similarities in its dimensional geometry with that of asbestos and synthetic vitreous fibres. The aim of this review is two-fold: (a) to present findings from past literature, on the physicochemical property and pathogenicity bioassay testing of HARN (b) to identify some of the challenges and future research steps crucial before the HARN model can be accepted as a predictive model. By presenting what has been done, we are able to identify scientific challenges and research directions that are needed for the HARN model to gain public acceptance. Our recommendations for future research includes the need to: (a) accurately link physicochemical data with corresponding pathogenicity assay data, through the use of suitable reference standards and standardised protocols, (b) develop better tools/techniques for physicochemical characterisation, (c) to develop better ways of monitoring HARN in the workplace, (d) to reliably measure dose exposure levels, in order to support future epidemiological

A hypothetical model for predicting the toxicity of high aspect ratio nanoparticles (HARN)

International Nuclear Information System (INIS)

Tran, C. L.; Tantra, R.; Donaldson, K.; Stone, V.; Hankin, S. M.; Ross, B.; Aitken, R. J.; Jones, A. D.

2011-01-01

The ability to predict nanoparticle (dimensional structures which are less than 100 nm in size) toxicity through the use of a suitable model is an important goal if nanoparticles are to be regulated in terms of exposures and toxicological effects. Recently, a model to predict toxicity of nanoparticles with high aspect ratio has been put forward by a consortium of scientists. The High aspect ratio nanoparticles (HARN) model is a platform that relates the physical dimensions of HARN (specifically length and diameter ratio) and biopersistence to their toxicity in biological environments. Potentially, this model is of great public health and economic importance, as it can be used as a tool to not only predict toxicological activity but can be used to classify the toxicity of various fibrous nanoparticles, without the need to carry out time-consuming and expensive toxicology studies. However, this model of toxicity is currently hypothetical in nature and is based solely on drawing similarities in its dimensional geometry with that of asbestos and synthetic vitreous fibres. The aim of this review is two-fold: (a) to present findings from past literature, on the physicochemical property and pathogenicity bioassay testing of HARN (b) to identify some of the challenges and future research steps crucial before the HARN model can be accepted as a predictive model. By presenting what has been done, we are able to identify scientific challenges and research directions that are needed for the HARN model to gain public acceptance. Our recommendations for future research includes the need to: (a) accurately link physicochemical data with corresponding pathogenicity assay data, through the use of suitable reference standards and standardised protocols, (b) develop better tools/techniques for physicochemical characterisation, (c) to develop better ways of monitoring HARN in the workplace, (d) to reliably measure dose exposure levels, in order to support future epidemiological

Toxicogenomic analysis of the particle dose- and size-response relationship of silica particles-induced toxicity in mice

International Nuclear Information System (INIS)

Lu Xiaoyan; Jin Tingting; Jin Yachao; Wu Leihong; Hu Bin; Tian Yu; Fan Xiaohui

2013-01-01

This study investigated the relationship between particle size and toxicity of silica particles (SP) with diameters of 30, 70, and 300 nm, which is essential to the safe design and application of SP. Data obtained from histopathological examinations suggested that SP of these sizes can all induce acute inflammation in the liver. In vivo imaging showed that intravenously administrated SP are mainly present in the liver, spleen and intestinal tract. Interestingly, in gene expression analysis, the cellular response pathways activated in the liver are predominantly conserved independently of particle dose when the same size SP are administered or are conserved independently of particle size, surface area and particle number when nano- or submicro-sized SP are administered at their toxic doses. Meanwhile, integrated analysis of transcriptomics, previous metabonomics and conventional toxicological results support the view that SP can result in inflammatory and oxidative stress, generate mitochondrial dysfunction, and eventually cause hepatocyte necrosis by neutrophil-mediated liver injury. (paper)

The association of rectal equivalent dose in 2 Gy fractions (EQD2) to late rectal toxicity in locally advanced cervical cancer patients who were evaluated by rectosigmoidoscopy in Faculty of Medicine, Chiang Mai University

Energy Technology Data Exchange (ETDEWEB)

Tharavichtikul, Ekkasit; Chitapanarux, Taned; Chakrabandhu, Somvilai; Klunklin, Pitchayaponne; Onchan, Wimrak; Wanwilairat, Somsak; Chitapanarux, Imjai [Faculty of Medicine, Chiang Mai University, Chiang Mai (Thailand); Meungwong, Pooriwat [Lampang Cancer Hospital, Lampang (Thailand); Traisathit, Patrinee [Faculty of Science, Chiang Mai University, Chiang Mai (Thailand); Galalae, Razvan [aculty of Medicine, Christian-Albrechts University at Kiel, Kiei (Germany)

2014-06-15

To evaluate association between equivalent dose in 2 Gy (EQD2) to rectal point dose and gastrointestinal toxicity from whole pelvic radiotherapy (WPRT) and intracavitary brachytherapy (ICBT) in cervical cancer patients who were evaluated by rectosigmoidoscopy in Faculty of Medicine, Chiang Mai University. Retrospective study was designed for the patients with locally advanced cervical cancer, treated by radical radiotherapy from 2004 to 2009 and were evaluated by rectosigmoidoscopy. The cumulative doses of WPRT and ICBT to the maximally rectal point were calculated to the EQD2 and evaluated the association of toxicities. Thirty-nine patients were evaluated for late rectal toxicity. The mean cumulative dose in term of EQD2 to rectum was 64.2 Gy. Grade 1 toxicities were the most common findings. According to endoscopic exam, the most common toxicities were congested mucosa (36 patients) and telangiectasia (32 patients). In evaluation between rectal dose in EQD2 and toxicities, no association of cumulative rectal dose to rectal toxicity, except the association of cumulative rectal dose in EQD2 >65 Gy to late effects of normal tissue (LENT-SOMA) scale > or = grade 2 (p = 0.022; odds ratio, 5.312; 95% confidence interval, 1.269-22.244). The cumulative rectal dose in EQD2 >65 Gy have association with > or = grade 2 LENT-SOMA scale.

The association of rectal equivalent dose in 2 Gy fractions (EQD2) to late rectal toxicity in locally advanced cervical cancer patients who were evaluated by rectosigmoidoscopy in Faculty of Medicine, Chiang Mai University.

Science.gov (United States)

Tharavichtikul, Ekkasit; Meungwong, Pooriwat; Chitapanarux, Taned; Chakrabandhu, Somvilai; Klunklin, Pitchayaponne; Onchan, Wimrak; Wanwilairat, Somsak; Traisathit, Patrinee; Galalae, Razvan; Chitapanarux, Imjai

2014-06-01

To evaluate association between equivalent dose in 2 Gy (EQD2) to rectal point dose and gastrointestinal toxicity from whole pelvic radiotherapy (WPRT) and intracavitary brachytherapy (ICBT) in cervical cancer patients who were evaluated by rectosigmoidoscopy in Faculty of Medicine, Chiang Mai University. Retrospective study was designed for the patients with locally advanced cervical cancer, treated by radical radiotherapy from 2004 to 2009 and were evaluated by rectosigmoidoscopy. The cumulative doses of WPRT and ICBT to the maximally rectal point were calculated to the EQD2 and evaluated the association of toxicities. Thirty-nine patients were evaluated for late rectal toxicity. The mean cumulative dose in term of EQD2 to rectum was 64.2 Gy. Grade 1 toxicities were the most common findings. According to endoscopic exam, the most common toxicities were congested mucosa (36 patients) and telangiectasia (32 patients). In evaluation between rectal dose in EQD2 and toxicities, no association of cumulative rectal dose to rectal toxicity, except the association of cumulative rectal dose in EQD2 >65 Gy to late effects of normal tissue (LENT-SOMA) scale ≥ grade 2 (p = 0.022; odds ratio, 5.312; 95% confidence interval, 1.269-22.244). The cumulative rectal dose in EQD2 >65 Gy have association with ≥ grade 2 LENT-SOMA scale.

Optimizing bevacizumab dosing in glioblastoma: less is more.

Science.gov (United States)

Ajlan, Abdulrazag; Thomas, Piia; Albakr, Abdulrahman; Nagpal, Seema; Recht, Lawrence

2017-10-01

Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below maximum tolerated dose. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of 10 mg/kg every other week for glioma patients, there has not been much prior work examining whether the relatively high complication rates reported with this agent can be decreased by lowering the dose without impairing efficacy. We assessed charts from 80 patients who received BEV for glioblastoma to survey the incidence of complications relative to BEV dose. All patients were treated with standard upfront chemoradiation. The toxicity was graded based on the NCI CTCAE, version 4.03. The rate of BEV serious related adverse events was 12.5% (n = 10/80). There were no serious adverse events (≥grade 3) when the administered dose was (<3 mg/kg/week), compared to a 21% incidence in those who received higher doses (≥3 mg/kg/week) (P < 0.01). Importantly, the three patient deaths attributable to BEV administration occurred in patients receiving higher doses. Patients who received lower doses also had a better survival rate, although this did not reach statistical significance [median OS 39 for low dose group vs. 17.3 for high dose group (P = 0.07)]. Lower rates of serious BEV related toxicities are noted when lower dosages are used without diminishing positive clinical impact. Further work aimed at optimizing BEV dosage is justified.

Comparison of rectal volume definition techniques and their influence on rectal toxicity in patients with prostate cancer treated with 3D conformal radiotherapy: a dose-volume analysis

International Nuclear Information System (INIS)

Onal, Cem; Topkan, Erkan; Efe, Esma; Yavuz, Melek; Sonmez, Serhat; Yavuz, Aydin

2009-01-01

To evaluate the impact of four different rectum contouring techniques and rectal toxicities in patients with treated with 3D conformal radiotherapy (3DCRT). Clinical and dosimetric data were evaluated for 94 patients who received a total dose 3DCRT of 70 Gy, and rectal doses were compared in four different rectal contouring techniques: the prostate-containing CT sections (method 1); 1 cm above and below the planning target volume (PTV) (method 2); 110 mm starting from the anal verge (method 3); and from the anal verge to the sigmoid flexure (method 4). The percentage of rectal volume receiving RT doses (30–70 Gy) and minimum, mean rectal doses were assessed. Median age was 69 years. Percentage of rectal volume receiving high doses (≥ 70 Gy) were higher with the techniques that contoured smaller rectal volumes. In methods 2 and 3, the percentage of rectal volume receiving ≥ 70 Gy was significantly higher in patients with than without rectal bleeding (method 2: 30.8% vs. 22.5%, respectively (p = 0.03); method 3: 26.9% vs. 18.1%, respectively (p = 0.006)). Mean rectal dose was significant predictor of rectal bleeding only in method 3 (48.8 Gy in patients with bleeding vs. 44.4 Gy in patients without bleeding; p = 0.02). Different techniques of rectal contouring significantly influence the calculation of radiation doses to the rectum and the prediction of rectal toxicity. Rectal volume receiving higher doses (≥ 70 Gy) and mean rectal doses may significantly predict rectal bleeding for techniques contouring larger rectal volumes, as was in method 3

Optimized dose distribution of a high dose rate vaginal cylinder

International Nuclear Information System (INIS)

Li Zuofeng; Liu, Chihray; Palta, Jatinder R.

1998-01-01

Purpose: To present a comparison of optimized dose distributions for a set of high-dose-rate (HDR) vaginal cylinders calculated by a commercial treatment-planning system with benchmark calculations using Monte-Carlo-calculated dosimetry data. Methods and Materials: Optimized dose distributions using both an isotropic and an anisotropic dose calculation model were obtained for a set of HDR vaginal cylinders. Mathematical optimization techniques available in the computer treatment-planning system were used to calculate dwell times and positions. These dose distributions were compared with benchmark calculations with TG43 formalism and using Monte-Carlo-calculated data. The same dwell times and positions were used for a quantitative comparison of dose calculated with three dose models. Results: The isotropic dose calculation model can result in discrepancies as high as 50%. The anisotropic dose calculation model compared better with benchmark calculations. The differences were more significant at the apex of the vaginal cylinder, which is typically used as the prescription point. Conclusion: Dose calculation models available in a computer treatment-planning system must be evaluated carefully to ensure their correct application. It should also be noted that when optimized dose distribution at a distance from the cylinder surface is calculated using an accurate dose calculation model, the vaginal mucosa dose becomes significantly higher, and therefore should be carefully monitored

Toxicity assessment due to sub-chronic exposure to individual and mixtures of four toxic heavy metals

Energy Technology Data Exchange (ETDEWEB)

Cobbina, Samuel J.; Chen, Yao [School of the Environment, Jiangsu University, Xuefu Rd. 301, Zhenjiang 212013, Jiangsu (China); Zhou, Zhaoxiang; Wu, Xueshan; Zhao, Ting [School of Chemistry and Chemical Engineering, Jiangsu University, Xuefu Rd. 301, Zhenjiang 212013 (China); Zhang, Zhen [School of the Environment, Jiangsu University, Xuefu Rd. 301, Zhenjiang 212013, Jiangsu (China); Feng, Weiwei; Wang, Wei [School of Food and Biological Engineering, Jiangsu University, Xuefu Rd. 301, Zhenjiang 212013, Jiangsu (China); Li, Qian [School of Pharmacy, Jiangsu University, Xuefu Rd. 301, Zhenjiang 212013, Jiangsu (China); Wu, Xiangyang, E-mail: wuxy@ujs.edu.cn [School of the Environment, Jiangsu University, Xuefu Rd. 301, Zhenjiang 212013, Jiangsu (China); Yang, Liuqing, E-mail: yangliuqing@ujs.edu.cn [School of Chemistry and Chemical Engineering, Jiangsu University, Xuefu Rd. 301, Zhenjiang 212013 (China)

2015-08-30

Highlights: • Low dose single and mixtures of toxic metals had adverse effect on mice. • Metal mixtures exhibited higher toxicities compared to individual metals. • Mixtures of low dose Pb + Hg + Cd induced neuronal degeneration in brain of mice. • Exposure to Pb + Hg + As + Cd showed renal tubular necrosis in kidney. - Abstract: Humans are exposed to a cocktail of heavy metal toxicants in the environment. Though heavy metals are deleterious, there is a paucity of information on toxicity of low dose mixtures. In this study, lead (Pb) (0.01 mg/L), mercury (Hg) (0.001 mg/L), cadmium (Cd) (0.005 mg/L) and arsenic (As) (0.01 mg/L) were administered individually and as mixtures to 10 groups of 40 three-week old mice (20 males and 20 females), for 120 days. The study established that low dose exposures induced toxicity to the brain, liver, and kidney of mice. Metal mixtures showed higher toxicities compared to individual metals, as exposure to low dose Pb + Hg + Cd reduced brain weight and induced structural lesions, such as neuronal degeneration in 30-days. Pb + Hg + Cd and Pb + Hg + As + Cd exposure induced hepatocellular injury to mice evidenced by decreased antioxidant activities with marginal increases in MDA. These were accentuated by increases in ALT, AST and ALP. Interactions in metal mixtures were basically synergistic in nature and exposure to Pb + Hg + As + Cd induced renal tubular necrosis in kidneys of mice. This study underlines the importance of elucidating the toxicity of low dose metal mixtures so as to protect public health.

Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis.

Science.gov (United States)

Peyro Saint Paul, Laure; Debruyne, Danièle; Bernard, Delphine; Mock, Donald M; Defer, Gilles L

2016-01-01

Multiple sclerosis (MS) is a chronic, potentially highly disabling neurological disorder. No disease-modifying treatments are approved in the progressive and not active forms of the disease. High doses of biotin were tested in an open-label pilot study involving 23 patients with progressive MS and reported positive results. A randomized, double-blind, placebo-controlled trial in 154 progressive MS patients confirmed the beneficial effect of MD1003 (high-dose biotin) on reversing or stabilizing disability progression, with a good safety profile. It is proposed that MD1003 in progressive MS 1) increases energy production in demyelinated axons and/or 2) enhances myelin synthesis in oligodendrocytes. Biotin is highly bioavailable; absorption and excretion are rapid. The major route of elimination is urinary excretion. A high oral dose of biotin seems generally well tolerated but a few important safety concerns were identified: 1) teratogenicity in one species and 2) interference with some biotin-based laboratory immunoassays. The animal toxicity data are limited at such high doses. Further preclinical studies would be useful to address the mechanism of action of MD1003. Assessment of clinical benefit duration in responders will be also very important to set. Results of randomized, placebo-controlled trial are reassuring and provide hope for the treatment of progressive MS.

Nationwide, Multicenter, Retrospective Study on High-Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer

International Nuclear Information System (INIS)

Yoshioka, Yasuo; Kotsuma, Tadayuki; Komiya, Akira; Kariya, Shinji; Konishi, Koji; Nonomura, Norio; Ogawa, Kazuhiko; Tanaka, Eiichi; Nishimura, Kensaku; Fujiuchi, Yasuyoshi; Kitamura, Hiroshi; Yamagami, Takuji; Yamasaki, Ichiro; Nishimura, Kazuo; Teshima, Teruki; Nakamura, Katsumasa; Itami, Jun

2017-01-01

Purpose: To present, analyze, and discuss results of a nationwide, multicenter, retrospective study on high-dose-rate brachytherapy (HDR-BT) as monotherapy for low-, intermediate-, and high-risk prostate cancer. Methods and Materials: From 1995 through 2013, 524 patients, 73 (14%) with low-risk, 207 (40%) with intermediate-risk, and 244 (47%) with high-risk prostate cancer, were treated with HDR-BT as monotherapy at 5 institutions in Japan. Dose fractionations were 27 Gy/2 fractions for 69 patients (13%), 45.5 Gy/7 fractions for 168 (32%), 49 Gy/7 fractions for 149 (28%), 54 Gy/9 fractions for 130 (25%), and others for 8 (2%). Of these patients, 156 (30%) did not receive androgen deprivation therapy, and 202 patients (39%) did receive androgen deprivation therapy 3 years. Median follow-up time was 5.9 years (range, 0.4-18.1 years), with a minimum of 2 years for surviving patients. Results: After 5 years, respective actuarial rates of no biochemical evidence of disease, overall survival, cause-specific survival, and metastasis-free survival for all patients were 92%, 97%, 99%, and 94%. For low/intermediate/high-risk patients, the 5-year no biochemical evidence of disease rates were 95%/94%/89%, the 5-year overall survival rates were 98%/98%/94%, the 5-year cause-specific survival rates were 98%/100%/98%, and the 5-year metastasis-free survival rates were 98%/95%/90%, respectively. The cumulative incidence of late grade 2 to 3 genitourinary toxicity at 5 years was 19%, and that of late grade 3 was 1%. The corresponding incidences of gastrointestinal toxicity were 3% and 0% (0.2%). No grade 4 or 5 of either type of toxicity was detected. Conclusions: The findings of this nationwide, multicenter, retrospective study demonstrate that HDR-BT as monotherapy was safe and effective for all patients with low-, intermediate-, and high-risk prostate cancer.

Nationwide, Multicenter, Retrospective Study on High-Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Yoshioka, Yasuo, E-mail: yoshioka@radonc.med.osaka-u.ac.jp [Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka (Japan); Kotsuma, Tadayuki [Department of Radiation Oncology, Osaka National Hospital, Osaka (Japan); Komiya, Akira [Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama (Japan); Department of Urology, Chiba University Hospital, Chiba (Japan); Kariya, Shinji [Department of Radiology, Kochi Medical School, Kochi (Japan); Konishi, Koji [Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka (Japan); Nonomura, Norio [Department of Urology, Osaka University Graduate School of Medicine, Osaka (Japan); Ogawa, Kazuhiko [Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka (Japan); Tanaka, Eiichi [Department of Radiation Oncology, Osaka National Hospital, Osaka (Japan); Nishimura, Kensaku [Department of Urology, Osaka National Hospital, Osaka (Japan); Fujiuchi, Yasuyoshi; Kitamura, Hiroshi [Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama (Japan); Yamagami, Takuji [Department of Radiology, Kochi Medical School, Kochi (Japan); Yamasaki, Ichiro [Department of Urology, Kochi Medical School, Kochi (Japan); Nishimura, Kazuo [Department of Urology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka (Japan); Teshima, Teruki [Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka (Japan); Nakamura, Katsumasa [Department of Radiation Oncology, Hamamatsu University School of Medicine, Shizuoka (Japan); Itami, Jun [Department of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan)

2017-04-01

Purpose: To present, analyze, and discuss results of a nationwide, multicenter, retrospective study on high-dose-rate brachytherapy (HDR-BT) as monotherapy for low-, intermediate-, and high-risk prostate cancer. Methods and Materials: From 1995 through 2013, 524 patients, 73 (14%) with low-risk, 207 (40%) with intermediate-risk, and 244 (47%) with high-risk prostate cancer, were treated with HDR-BT as monotherapy at 5 institutions in Japan. Dose fractionations were 27 Gy/2 fractions for 69 patients (13%), 45.5 Gy/7 fractions for 168 (32%), 49 Gy/7 fractions for 149 (28%), 54 Gy/9 fractions for 130 (25%), and others for 8 (2%). Of these patients, 156 (30%) did not receive androgen deprivation therapy, and 202 patients (39%) did receive androgen deprivation therapy <1 year, 112 (21%) for 1-3 years, and 54 (10%) for >3 years. Median follow-up time was 5.9 years (range, 0.4-18.1 years), with a minimum of 2 years for surviving patients. Results: After 5 years, respective actuarial rates of no biochemical evidence of disease, overall survival, cause-specific survival, and metastasis-free survival for all patients were 92%, 97%, 99%, and 94%. For low/intermediate/high-risk patients, the 5-year no biochemical evidence of disease rates were 95%/94%/89%, the 5-year overall survival rates were 98%/98%/94%, the 5-year cause-specific survival rates were 98%/100%/98%, and the 5-year metastasis-free survival rates were 98%/95%/90%, respectively. The cumulative incidence of late grade 2 to 3 genitourinary toxicity at 5 years was 19%, and that of late grade 3 was 1%. The corresponding incidences of gastrointestinal toxicity were 3% and 0% (0.2%). No grade 4 or 5 of either type of toxicity was detected. Conclusions: The findings of this nationwide, multicenter, retrospective study demonstrate that HDR-BT as monotherapy was safe and effective for all patients with low-, intermediate-, and high-risk prostate cancer.

Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial

International Nuclear Information System (INIS)

Pollack, Alan; Hanlon, Alexandra L.; Horwitz, Eric M.; Feigenberg, Steven J.; Konski, Andre A.; Movsas, Benjamin; Greenberg, Richard E.; Uzzo, Robert G.; Ma, C.-M. Charlie; McNeeley, Shawn W.; Buyyounouski, Mark K.; Price, Robert A.

2006-01-01

Purpose: The α/β ratio for prostate cancer is postulated to be between 1 and 3, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. The dosimetry and acute toxicity are described in the first 100 men enrolled in a randomized trial. Patients and Methods: The trial compares 76 Gy in 38 fractions (Arm I) to 70.2 Gy in 26 fractions (Arm II) using intensity modulated radiotherapy. The planning target volume (PTV) margins in Arms I and II were 5 mm and 3 mm posteriorly and 8 mm and 7 mm in all other dimensions. The PTV D95% was at least the prescription dose. Results: The mean PTV doses for Arms I and II were 81.1 and 73.8 Gy. There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity acutely. However, there was a slight but significant increase in Arm II GI toxicity during Weeks 2, 3, and 4. In multivariate analyses, only the combined rectal DVH parameter of V65 Gy/V50 Gy was significant for GI toxicity and the bladder volume for GU toxicity. Conclusion: Hypofractionation at 2.7 Gy per fraction to 70.2 Gy was well tolerated acutely using the planning conditions described

Progress in high-dose radiation dosimetry

International Nuclear Information System (INIS)

Ettinger, K.V.; Nam, J.W.; McLaughlin, W.L.; Chadwick, K.H.

1981-01-01

The last decade has witnessed a deluge of new high-dose dosimetry techniques and expanded applications of methods developed earlier. Many of the principal systems are calibrated by means of calorimetry, although production of heat is not always the final radiation effect of interest. Reference systems also include a number of chemical dose meters: ferrous sulphate, ferrous-cupric sulphate, and ceric sulphate acidic aqueous solutions. Requirements for stable and reliable transfer dose meters have led to further developments of several important high-dose systems: amino acids and saccharides analysed by ESR or lyoluminescence, thermoluminescent materials, radiochromic dyes and plastics, ceric-cerous solutions analysed by potentiometry, and ethanol-chlorobenzene solutions analysed by high-frequency oscillometry. A number of other prospective dose meters are also treated in this review. In addition, an IAEA programme of high-dose standardization and intercomparison for industrial radiation processing is described. (author)

Chemo-radiotherapy for localized pancreatic cancer: increased dose intensity and reduced acute toxicity with concomitant radiotherapy and protracted venous infusion 5-fluorouracil

International Nuclear Information System (INIS)

Poen, Joseph C.; Collins, Helen L.; Niederhuber, John E.; Oberhelman, Harry A.; Vierra, Mark A.; Bastidas, Augusto J.; Young, Harvey S.; Slosberg, Edward A.; Jeffrey, Brooke R.; Longacre, Teri A.; Goffinet, Don R.

1996-01-01

Purpose: Although concomitant radiotherapy (RT) and bolus 5-Fluorouracil (5-FU) have been shown to improve survival in patients with resectable or locally advanced pancreatic cancer, most patients will eventually succumb to their disease. Since 1994, we have attempted to improve efficacy by administering 5-FU by protracted venous infusion (PVI). This study compares the dose intensity and acute toxicity of our current regimen utilizing 5-FU by PVI with our prior regimen of radiotherapy and bolus 5-FU. Materials and Methods: Since January, 1986, 77 patients with resectable or locally advanced adenocarcinoma of the pancreas were treated with radiation therapy. Thirteen received radiation therapy alone or a planned split-course treatment and were therefore excluded from this study. The remaining 64 patients were treated with continuous course RT and concurrent 5-FU by bolus injection for 3 days during weeks 1 and 5 (n=44) or by PVI 5-FU throughout the entire course of radiotherapy (n=20). Patients were treated on 6 or 15 MV linear accelerators with 3-4 custom shaped fields to target doses of 40-50 Gy following pancreaticoduodenectomy or 50-60 Gy for locally advanced disease. 5-FU target doses were 500 mg/m 2 for bolus injection and 200-225 mg/m 2 /day for PVI. Dose intensity was assessed for both 5-FU and radiotherapy by calculating total doses (mg/m 2 and Gy, respectively) and dose/week of treatment. The Cooperative Group Common Toxicity Scale was used to score acute hematologic and gastrointestinal toxicity. Only those endpoints which could be reliably and objectively quantified (e.g. blood counts, weight loss, treatment interruption) were evaluated. Patients with resectable and locally advanced disease were jointly and independently evaluated. Results: The patient characteristics and radiotherapy treatment techniques were similar between the two treatment groups. The mean irradiated volume was 1,323 cm 3 (95% CI: 1,210-1,436). Chemotherapy and radiotherapy dose

Establishing locoregional control of malignant pleural mesothelioma using high-dose radiotherapy and 18F-FDG PET/CT scan correlation

International Nuclear Information System (INIS)

Feigen, Malcolm; Lawford, Catherine; Churcher, Katheryn; Zupan, Eddy; Hamilton, Chris; Lee, Sze Ting; Scott, Andrew M.

2011-01-01

The management of malignant pleural mesothelioma represents one of the most challenging issues in oncology, as there is no proven long-term benefit from surgery, radiotherapy or chemotherapy alone or in combination. Locoregional progression remains the major cause of death, but radical surgical resection may produce major postoperative morbidity. While radical or postoperative radiotherapy using conventional techniques has resulted in severe toxicity with no impact on survival, recent advances in radiotherapy delivery may be more effective. We treated patients with locally advanced mesothelioma whose tumours had been sub optimally resected with high-dose three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) to large volumes of one hemithorax, using CT and positron emission tomography (PET) scan-based treatment planning. Clinical outcomes were assessed by determining patterns of failure and metabolic changes in total glycolytic volume (TGV) between pre- and post-irradiation 18 F-FDG PET/CT scans and by recording acute and late toxicity grades. Fourteen patients were analysed with 40 PET scans performed before and up to 4.5 years after radiotherapy. Eleven patients had pleurectomy/decortications, one had an extrapleural pneumonectomy and two had no surgery. Four patients who received chemotherapy had all progressed prior to radiotherapy. After radiotherapy, the in-field local control rate was 71%. No progression occurred in two patients, one was salvaged with further radiotherapy to a new site, four recurred inside the irradiated volume all with concurrent distant metastases and the other seven had distant metastases only. The TGVs were reduced by an average of 67% (range 12–100%) after doses of 45 to 60 Gy to part or all of one hemithorax. There were no serious treatment-related toxicities. Median survival was 25 months from diagnosis and 17 months after starting radiotherapy. We have established that mesothelioma can be

The protein corona protects against size- and dose-dependent toxicity of amorphous silica nanoparticles

Directory of Open Access Journals (Sweden)

Dominic Docter

2014-08-01

Full Text Available Besides the lung and skin, the gastrointestinal (GI tract is one of the main targets for accidental exposure or biomedical applications of nanoparticles (NP. Biological responses to NP, including nanotoxicology, are caused by the interaction of the NP with cellular membranes and/or cellular entry. Here, the physico-chemical characteristics of NP are widely discussed as critical determinants, albeit the exact mechanisms remain to be resolved. Moreover, proteins associate with NP in physiological fluids, forming the protein corona potentially transforming the biological identity of the particle and thus, adding an additional level of complexity for the bio–nano responses.Here, we employed amorphous silica nanoparticles (ASP and epithelial GI tract Caco-2 cells as a model to study the biological impact of particle size as well as of the protein corona. Caco-2 or mucus-producing HT-29 cells were exposed to thoroughly characterized, negatively charged ASP of different size in the absence or presence of proteins. Comprehensive experimental approaches, such as quantifying cellular metabolic activity, microscopic observation of cell morphology, and high-throughput cell analysis revealed a dose- and time-dependent toxicity primarily upon exposure with ASP30 (Ø = 30 nm. Albeit smaller (ASP20, Ø = 20 nm or larger particles (ASP100; Ø = 100 nm showed a similar zeta potential, they both displayed only low toxicity. Importantly, the adverse effects triggered by ASP30/ASP30L were significantly ameliorated upon formation of the protein corona, which we found was efficiently established on all ASP studied. As a potential explanation, corona formation reduced ASP30 cellular uptake, which was however not significantly affected by ASP surface charge in our model. Collectively, our study uncovers an impact of ASP size as well as of the protein corona on cellular toxicity, which might be relevant for processes at the nano–bio interface in general.

Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by 18FDG-PET/CT for esophageal cancer

International Nuclear Information System (INIS)

Yu, Wen; Cai, Xu-Wei; Liu, Qi; Zhu, Zheng-Fei; Feng, Wen; Zhang, Qin; Zhang, Ying-Jian; Yao, Zhi-Feng; Fu, Xiao-Long

2015-01-01

Purpose: To observe the safety of selective dose boost to the pre-treatment high 18 F-deoxyglucose (FDG) uptake areas of the esophageal GTV. Methods: Patients with esophageal squamous cell carcinoma were treated with escalating radiation dose of 4 levels, with a simultaneous integrated boost (SIB) to the pre-treatment 50% SUVmax area of the primary tumor. Patients received 4 monthly cycles of cisplatin and fluorouracil. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher acute toxicities causing continuous interruption of radiation for over 1 week. Results: From April 2012 to February 2014, dose has been escalated up to LEVEL 4 (70 Gy). All of the 25 patients finished the prescribed dose without DLT, and 10 of them developed Grade 3 acute esophagitis. One patient of LEVEL 2 died of esophageal hemorrhage within 1 month after completion of radiotherapy, which was not definitely correlated with treatment yet. Late toxicities remained under observation. With median follow up of 8.9 months, one-year overall survival and local control was 69.2% and 77.4%, respectively. Conclusions: Dose escalation in esophageal cancer based on 18 FDG-PET/CT has been safely achieved up to 70 Gy using the SIB technique. Acute toxicities were well tolerated, whereas late toxicities and long-term outcomes deserved further observation

Allyl nitrile: Toxicity and health effects.

Science.gov (United States)

Tanii, Hideji

2017-03-28

Allyl nitrile (3-butenenitrile) occurs naturally in the environment, in particular, in cruciferous vegetables, indicating a possible daily intake of the compound. There is no report on actual health effects of allyl nitrile in humans, although it is possible that individuals in the environment are at a risk of exposure to allyl nitrile. However, little is known about its quantitative assessment for the environment and bioactivity in the body. This study provides a review of previous accumulated studies on allyl nitrile. Published literature on allyl nitrile was examined for findings on toxicity, metabolism, risk of various cancers, generation, intake estimates, and low-dose effects in the body. High doses of allyl nitrile produce toxicity characterized by behavioral abnormalities, which are considered to be produced by an active metabolite, 3,4-epoxybutyronitrile. Cruciferous vegetables have been shown to have a potential role in reducing various cancers. Hydrolysis of the glucosinolate sinigrin, rich in cruciferous vegetables, results in the generation of allyl nitrile. An intake of allyl nitrile is estimated at 0.12 μmol/kg body weight in Japan. Repeated exposure to low doses of allyl nitrile upregulates antioxidant/phase II enzymes in various tissues; this may contribute to a reduction in neurotoxicity and skin inflammation. These high and low doses are far more than the intake estimate. Allyl nitrile in the environment is a compound with diverse bioactivities in the body, characterized by inducing behavioral abnormalities at high doses and some antioxidant/phase II enzymes at low doses.

Reverse Phase Protein Arrays for High-throughput Toxicity Screening

DEFF Research Database (Denmark)

Pedersen, Marlene Lemvig; Block, Ines; List, Markus

High-throughput screening is extensively applied for identification of drug targets and drug discovery and recently it found entry into toxicity testing. Reverse phase protein arrays (RPPAs) are used widespread for quantification of protein markers. We reasoned that RPPAs also can be utilized...... beneficially in automated high-throughput toxicity testing. An advantage of using RPPAs is that, in addition to the baseline toxicity readout, they allow testing of multiple markers of toxicity, such as inflammatory responses, which do not necessarily cumulate in cell death. We used transfection of si......RNAs with known killing effects as a model system to demonstrate that RPPA-based protein quantification can serve as substitute readout of cell viability, hereby reliably reflecting toxicity. In terms of automation, cell exposure, protein harvest, serial dilution and sample reformatting were performed using...

High-Dose Adjuvant Radiotherapy After Radical Prostatectomy With or Without Androgen Deprivation Therapy

International Nuclear Information System (INIS)

Ost, Piet; Cozzarini, Cesare; De Meerleer, Gert; Fiorino, Claudio; De Potter, Bruno; Briganti, Alberto; Nagler, Evi V.T.; Montorsi, Francesco; Fonteyne, Valérie; Di Muzio, Nadia

2012-01-01

Purpose: To retrospectively evaluate the outcome and toxicity in patients receiving high-dose (>69 Gy) adjuvant radiotherapy (HD-ART) and the impact of androgen deprivation therapy (ADT). Methods and Materials: Between 1999 and 2008, 225 node-negative patients were referred for HD-ART with or without ADT to two large academic institutions. Indications for HD-ART were extracapsular extension, seminal vesicle invasion (SVI), and/or positive surgical margins at radical prostatectomy (RP). A dose of at least 69.1 Gy was prescribed to the prostate bed and seminal vesicle bed. The ADT consisted of a luteinizing hormone–releasing hormone analog. The duration and indication of ADT was left at the discretion of the treating physician. The effect of HD-ART and ADT on biochemical (bRFS) and clinical (cRFS) relapse-free survival was examined through univariate and multivariate analysis, with correction for known patient- and treatment-related variables. Interaction terms were introduced to evaluate effect modification. Results: After a median follow-up time of 5 years, the 7-year bRFS and cRFS were 84% and 88%, respectively. On multivariate analysis, the addition of ADT was independently associated with an improved bRFS (hazard ratio [HR] 0.4, p = 0.02) and cRFS (HR 0.2, p = 0.008). Higher Gleason scores and SVI were associated with decreased bRFS and cRFS. A lymphadenectomy at the time of RP independently improved cRFS (HR 0.09, p = 0.009). The 7-year probability of late Grade 2–3 toxicity was 29% and 5% for genitourinary (GU) and gastrointestinal (GI) symptoms, respectively. The absolute incidence of Grade 3 toxicity was <1% and 10% for GI and GU symptoms, respectively. The study is limited by its retrospective design and the lack of a standardized use of ADT. Conclusions: This retrospective study shows significantly improved bRFS and cRFS rates with the addition of ADT to HD-ART, with low Grade 3 gastrointestinal toxicity and 10% Grade 3 genitourinary toxicity.

Salicylate toxicity model of tinnitus

Directory of Open Access Journals (Sweden)

Daniel eStolzberg

2012-04-01

Full Text Available Salicylate, the active component of the common drug aspirin, has mild analgesic, antipyretic, and anti-inflammatory effects at moderate doses. At higher doses, however, salicylate temporarily induces moderate hearing loss and the perception of a high-pitch ringing in humans and animals. This phantom perception of sound known as tinnitus is qualitatively similar to the persistent subjective tinnitus induced by high-level noise exposure, ototoxic drugs or aging which affects ~14% of the general population. For over a quarter century, auditory scientists have used the salicylate toxicity model to investigate candidate biochemical and neurophysiological mechanisms underlying phantom sound perception. In this review, we summarize some of the intriguing biochemical and physiological effects associated with salicylate-induced tinnitus, some of which occur in the periphery and others in the central nervous system. The relevance and general utility of the salicylate toxicity model in understanding phantom sound perception in general are discussed.

Toxicity attenuation optimization of crotalic venom by gamma radiation and studies of its immunogenic properties

International Nuclear Information System (INIS)

Clissa, Patricia Bianca

1997-01-01

Literature data show that 2.0 kGy dose of gamma radiation, generated by 60 source, reduces the toxic activity of Crotalus durissus terrificus venom, without altering its immunogenic capacity. When crotoxin, main toxin from crotalic venom, was irradiated with the same dose, toxicity was also reduced and the immunogenicity was maintained. This fact was attributed to aggregates (compounds with high molecular weight generated during irradiation), that showed no toxicity but were able to induce the antibodies formation against native venom. Crotalus durissus terrificus venom was irradiated with 2.0, 3.0, 5.0 and 10.0 kGy doses and submitted to molecular exclusion chromatography, in order to find an efficient dose that produces large amounts of non toxic but still immunogenic aggregates. After being isolated, the products of irradiation were evaluated for the amount produced, molecular alteration, and toxic and immunogenic activities. These parameters were also analyzed for the whole venom irradiated. The results from different doses irradiated venom were compared with native one, and 2.0 kGy dose was confirmed to be the most efficient in the association of toxicity attenuation with maintenance of immunogenicity of the crotalic venom, while other doses, in spite of being efficient in the toxicity attenuation, they were not able to keep the immunogenicity property. So, the dose of 2.0 kGy could be used to immunize animals in order to improve anticrotalic sera production. (author)

High-dose chemotherapy for patients with high-risk breast cancer: a clinical and economic assessment using a quality-adjusted survival analysis.

Science.gov (United States)

Marino, Patricia; Roché, Henri; Moatti, Jean-Paul

2008-04-01

The benefit of high-dose chemotherapy (HDC) has not been clearly demonstrated. It may offer disease-free survival improvement at the expense of major toxicity and increasing cost. We evaluated the trade-offs between toxicity, relapse, and costs using a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis. The analysis was conducted in the context of a randomized trial (PEGASE 01) evaluating the benefit of HDC for 314 patients with high-risk breast cancer. A Q-TWiST analysis was first performed to compare HDC with standard chemotherapy. We then used the results of this Q-TWiST analysis to inform a cost per quality-adjusted life-year (QALY) comparison between treatments. Q-TWiST durations were in favor of HDC, whatever the weighting coefficients used for the analysis. This benefit was significant when the weighting coefficient related to the time spent after relapse was low (0.78), HDC offered no benefit. For intermediate values, the results depended on the weighting coefficient attributed to the toxicity period. The incremental cost per QALY ranged from 12,691euro/QALY to 26,439euro/QALY, according to the coefficients used to weight toxicity and relapse. The benefits of HDC outweigh the burdens of treatment for a wide range of utility coefficients. Economic impact is not a barrier to HDC diffusion in this situation. Nevertheless, no significant benefit was demonstrated for a certain range of utility values.

New insights into mycotoxin mixtures: The toxicity of low doses of Type B trichothecenes on intestinal epithelial cells is synergistic

Energy Technology Data Exchange (ETDEWEB)

Alassane-Kpembi, Imourana [INRA, UMR 1331 Toxalim, Research Center in Food Toxicology, F-31027 Toulouse (France); Université de Toulouse, ENVT, INP, UMR 1331 Toxalim, F-31076 Toulouse (France); Institut des Sciences Biomédicales Appliquées, Cotonou, Bénin (Benin); Kolf-Clauw, Martine; Gauthier, Thierry; Abrami, Roberta [INRA, UMR 1331 Toxalim, Research Center in Food Toxicology, F-31027 Toulouse (France); Université de Toulouse, ENVT, INP, UMR 1331 Toxalim, F-31076 Toulouse (France); Abiola, François A. [Institut des Sciences Biomédicales Appliquées, Cotonou, Bénin (Benin); Oswald, Isabelle P., E-mail: Isabelle.Oswald@toulouse.inra.fr [INRA, UMR 1331 Toxalim, Research Center in Food Toxicology, F-31027 Toulouse (France); Université de Toulouse, ENVT, INP, UMR 1331 Toxalim, F-31076 Toulouse (France); Puel, Olivier [INRA, UMR 1331 Toxalim, Research Center in Food Toxicology, F-31027 Toulouse (France); Université de Toulouse, ENVT, INP, UMR 1331 Toxalim, F-31076 Toulouse (France)

2013-10-01

Deoxynivalenol (DON) is the most prevalent trichothecene mycotoxin in crops in Europe and North America. DON is often present with other type B trichothecenes such as 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon-X (FX). Although the cytotoxicity of individual mycotoxins has been widely studied, data on the toxicity of mycotoxin mixtures are limited. The aim of this study was to assess interactions caused by co-exposure to Type B trichothecenes on intestinal epithelial cells. Proliferating Caco-2 cells were exposed to increasing doses of Type B trichothecenes, alone or in binary or ternary mixtures. The MTT test and neutral red uptake, respectively linked to mitochondrial and lysosomal functions, were used to measure intestinal epithelial cytotoxicity. The five tested mycotoxins had a dose-dependent effect on proliferating enterocytes and could be classified in increasing order of toxicity: 3-ADON < 15-ADON ≈ DON < NIV ≪ FX. Binary or ternary mixtures also showed a dose-dependent effect. At low concentrations (cytotoxic effect between 10 and 30–40%), mycotoxin combinations were synergistic; however DON–NIV–FX mixture showed antagonism. At higher concentrations (cytotoxic effect around 50%), the combinations had an additive or nearly additive effect. These results indicate that the simultaneous presence of low doses of mycotoxins in food commodities and diet may be more toxic than predicted from the mycotoxins alone. Considering the frequent co-occurrence of trichothecenes in the diet and the concentrations of toxins to which consumers are exposed, this synergy should be taken into account. - Highlights: • We assessed the individual and combined cytotoxicity of five trichothecenes. • The tested concentrations correspond to the French consumer exposure levels. • The type of interaction in combined cytotoxicity varied with the effect level. • Low doses of Type B trichothecenes induced synergistic

Toxicity of the styrene metabolite, phenylglyoxylic acid, in rats after three months' oral dosing

DEFF Research Database (Denmark)

Ladefoged, Ole; Lam, Henrik Rye; Ostergaard, G.

1998-01-01

Male Wistar rats were dosed with 0, 1250, 3750 or 5000 mg/l of phenylglyoxylic acid (PGA) (CAS no. 611-73-4) in the drinking water ad libitum for 3 months. During the entire treatment period, there were no gross signs of toxicity related to PGA. No changes in neurobehavior were found after using ....... Alternatively, the ototoxicity of styrene, like toluene, may be caused the parent compound itself and not by a metabolite like PGA. (C) 1998 Inter Press, inc....

Transmammary transfer of toxicity to nursing kids from Isocoma pluriflora (rayless goldenrod) dosed to lactating goats.

Science.gov (United States)

Pfister, James A; Stegelmeier, Bryan L; Lee, Stephen T; Davis, T Zane; Green, Ben T

2018-05-01

Rayless goldenrod (RG; Isocoma pluriflora) poisons livestock in the southwestern U.S., west Texas, and northern Mexico. The putative toxin(s) have historically been thought to be benzofuran ketones. Goats have been used successfully as a model of RG poisoning. The transmammary transfer of toxicity to offspring from lactating goats has not been studied, thus the objective of this study was to determine if nursing kids would become poisoned via mother's milk when the dams were dosed with RG. Twelve lactating goats (6 controls and 6 treated; all with twin kids) were dosed via oral gavage with alfalfa or rayless goldenrod at 2% of BW per day for 14 days. Two kids showed overt clinical signs near the end of the study; however, no dams showed clinical signs, and none developed exercise intolerance or muscle weakness. After day 11 of treatment, the RG kids showed increased (P kids declined rapidly over 7 days after transmammary exposure ended. Histopathology revealed that one kid had extensive myonecrosis that involved both myocardium and skeletal muscles. The other kids from RG-treated does had minimal myocyte degeneration and necrosis characterized by individual myofiber swelling, hypereosinophilia and loss of striation. Benzofuran ketones were not detected in the milk of lactating goats; further, dosing with RG did not alter milk composition. In summary, milk ingestion from does dosed with >300 mg/kg BW of benzofuran ketones from RG over 14 days increased mean CK concentrations in treated kids compared to controls; however kids rapidly recovered when exposure ended. Additional work is needed to better define benzofuran ketone metabolism, toxicity, and animal susceptibility. Copyright © 2018 Elsevier Ltd. All rights reserved.

High Dose Rate Brachytherapy in Two 9 Gy Fractions in the Treatment of Locally Advanced Cervical Cancer - a South Indian Institutional Experience.

Science.gov (United States)

Ghosh, Saptarshi; Rao, Pamidimukkala Bramhananda; Kotne, Sivasankar

2015-01-01

Although 3D image based brachytherapy is currently the standard of treatment in cervical cancer, most of the centres in developing countries still practice orthogonal intracavitary brachytherapy due to financial constraints. The quest for optimum dose and fractionation schedule in high dose rate (HDR) intracavitary brachytherapy (ICBT) is still ongoing. While the American Brachytherapy Society recommends four to eight fractions of each less than 7.5 Gy, there are some studies demonstrating similar efficacy and comparable toxicity with higher doses per fraction. To assess the treatment efficacy and late complications of HDR ICBT with 9 Gy per fraction in two fractions. This is a prospective institutional study in Southern India carried on from 1st June 2012 to 31st July 2014. In this period, 76 patients of cervical cancer satisfying our inclusion criteria were treated with concurrent chemo-radiation following ICBT with 9 Gy per fraction in two fractions, five to seven days apart. The median follow-up period in the study was 24 months (range 10.6 - 31.2 months). The 2 year actuarial local control rate, disease-free survival and overall survival were 88.1%, 84.2% and 81.8% respectively. Although 38.2% patients suffered from late toxicity, only 3 patients had grade III late toxicity. In our experience, HDR brachytherapy with 9 Gy per fraction in two fractions is an effective dose fractionation for the treatment of cervical cancer with acceptable toxicity.

Intracranial meningiomas after high-dose irradiation

International Nuclear Information System (INIS)

Soffer, D.; Gomori, J.M.; Siegal, T.; Shalit, M.N.

1989-01-01

Three patients who presented with intracranial meningiomas 12, 15, and 20 years, respectively, after therapeutic high-dose irradiation of a primary brain tumor are described. Analysis of these cases and similar documented cases suggests that meningiomas after high-dose irradiation constitute a recognizable entity. Patients with such tumors received radiation therapy at a young age (mean age, 9.4 years). After a latent period of 2 to 47 years (mean, 19.8 years) they developed meningiomas at the site of irradiation, at a much younger age than patients with ''spontaneous'' meningiomas. Similar to the situation with meningiomas after low-dose irradiation, a relatively high proportion of meningiomas induced by high-dose irradiation tend to be malignant and biologically aggressive. A very young age at the time of irradiation seems to predispose to the induction of malignant meningiomas, rather than benign tumors. These unusual features provide indirect evidence that high-dose radiation may play a role in the pathogenesis of meningiomas.41 references

Definitive intraoperative very high-dose radiotherapy for localized osteosarcoma in the extremities

International Nuclear Information System (INIS)

Oya, Natsuo; Kokubo, Masaki; Mizowaki, Takashi; Shibamoto, Yuta; Nagata, Yasushi; Sasai, Keisuke; Nishimura, Yasumasa; Tsuboyama, Tadao; Toguchida, Junya; Nakamura, Takashi; Hiraoka, Masahiro

2001-01-01

Purpose: To evaluate the outcome and adverse effects in patients with osteosarcoma treated with very high-dose definitive intraoperative radiotherapy (IORT), with the intention of saving the affected limb. Methods and Materials: Thirty-nine patients with osteosarcoma in their extremities were treated with definitive IORT. The irradiation field included the tumor plus an adequate wide margin and excluded the major vessels and nerves. Forty-five to 80 Gy of electrons or X-rays were delivered. The median follow-up of the surviving patients was 124 months. Results: The cause-specific and relapse-free 5-year survival rate was 50% and 43%, respectively. Distant metastasis developed in 23 patients; 19 died and 4 were alive for >10 years. Nine local recurrences were found 4-29 months after IORT in the affected limb. No radiation-induced skin reaction or nerve palsy was observed in the patients treated with X-rays. Experiments using phantoms also confirmed that the scatter dose was below the toxic level in the IORT setting with X-rays. Conclusions: Very high-dose definitive IORT combined with preventive nailing and chemotherapy appeared to be a promising quality-of-life-oriented alternative to treating patients with osteosarcomas in the extremities, although the problem of recurrences from the surrounding unirradiated soft tissue remains to be solved

SU-F-T-133: Uniform Scanning Proton Therapy for Lung Cancer: Toxicity and Its Correlation with Dosimetry

International Nuclear Information System (INIS)

Zheng, Y; Rana, S; Larson, G

2016-01-01

Purpose: To analyze the toxicity of uniform scanning proton therapy for lung cancer patients and its correlation with dose distribution. Methods: In this study, we analyzed the toxicity of 128 lung cancer patients, including 18 small cell lung cancer and 110 non small cell lung cancer patients. Each patient was treated with uniform scanning proton beams at our center using typically 2–4 fields. The prescription was typically 74 Cobalt gray equivalent (CGE) at 2 CGE per fraction. 4D Computerized Tomography (CT) scans were used to evaluate the target motion and contour the internal target volume, and repeated 3 times during the course of treatment to evaluate the need for plan adaptation. Toxicity data for these patients were obtained from the proton collaborative group (PCG) database. For cases of grade 3 toxicities or toxicities of interest such as esophagitis and radiation dermatitis, dose distributions were reviewed and analyzed in attempt to correlate the toxicity with radiation dose. Results: At a median follow up time of about 21 months, none of the patients had experienced Grade 4 or 5 toxicity. The most common adverse effect was dermatitis (81%: 52%-Grade 1, 28%-Grade 2, and 1% Grade 3), followed by fatigue (48%), Cough (46%), and Esophagitis (45%), as shown in Figure 1. Severe toxicities, such as Grade 3 dermatitis or pain of skin, had a clear correlation with high radiation dose. Conclusion: Uniform scanning proton therapy is well tolerated by lung cancer patients. Preliminary analysis indicates there is correlation between severe toxicity and high radiation dose. Understanding of radiation resulted toxicities and careful choice of beam arrangement are critical in minimizing toxicity of skin and other organs.

SU-F-T-133: Uniform Scanning Proton Therapy for Lung Cancer: Toxicity and Its Correlation with Dosimetry

Energy Technology Data Exchange (ETDEWEB)

Zheng, Y; Rana, S; Larson, G [Procure Proton Therapy Center, Oklahoma City, OK (United States)

2016-06-15

Purpose: To analyze the toxicity of uniform scanning proton therapy for lung cancer patients and its correlation with dose distribution. Methods: In this study, we analyzed the toxicity of 128 lung cancer patients, including 18 small cell lung cancer and 110 non small cell lung cancer patients. Each patient was treated with uniform scanning proton beams at our center using typically 2–4 fields. The prescription was typically 74 Cobalt gray equivalent (CGE) at 2 CGE per fraction. 4D Computerized Tomography (CT) scans were used to evaluate the target motion and contour the internal target volume, and repeated 3 times during the course of treatment to evaluate the need for plan adaptation. Toxicity data for these patients were obtained from the proton collaborative group (PCG) database. For cases of grade 3 toxicities or toxicities of interest such as esophagitis and radiation dermatitis, dose distributions were reviewed and analyzed in attempt to correlate the toxicity with radiation dose. Results: At a median follow up time of about 21 months, none of the patients had experienced Grade 4 or 5 toxicity. The most common adverse effect was dermatitis (81%: 52%-Grade 1, 28%-Grade 2, and 1% Grade 3), followed by fatigue (48%), Cough (46%), and Esophagitis (45%), as shown in Figure 1. Severe toxicities, such as Grade 3 dermatitis or pain of skin, had a clear correlation with high radiation dose. Conclusion: Uniform scanning proton therapy is well tolerated by lung cancer patients. Preliminary analysis indicates there is correlation between severe toxicity and high radiation dose. Understanding of radiation resulted toxicities and careful choice of beam arrangement are critical in minimizing toxicity of skin and other organs.

Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 22). Effects of 2- and 4-week administration of theobromine on the testis.

Science.gov (United States)

Funabashi, H; Fujioka, M; Kohchi, M; Tateishi, Y; Matsuoka, N

2000-10-01

The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity. Theobromine was administered orally to male Sprague-Dawley rats at dose levels of 250 and 500 mg/kg for 2 weeks starting at the age of 6 or 8 weeks, and for 4 weeks from the age of 6 weeks. Histopathological examination of reproductive organs revealed toxic findings in the testis at 500 mg/kg after 2 weeks of dosing at both ages, and at 250 and 500 mg/kg after 4 weeks of dosing. The primary findings were degeneration/necrosis and desquamation of spermatids and spermatocytes, vacuolization of seminiferous tubules, and multinucleated giant cell formation. These findings were present mainly in stages I-VI and XII-XIV. From these results, it is concluded that the toxic effects of theobromine on the testis can be detected by repeated dosing for 2 weeks as well as for 4 weeks.

Single and 2-week repeated intravenous dose toxicity studies of disodium mercaptoundecahydro-closo-dodecaborate in rats

Energy Technology Data Exchange (ETDEWEB)

Itoh, Fumio; Yabuuchi, Kazuya; Ohno, Kouji; Muraoka, Yoshihiro [Shionogi and Co. Ltd., Toyonaka, Osaka (Japan). Developmental Research Lab.; Ikeuchi, Isao

1998-10-01

Disodium mercaptoundecahydro-closo-dodecaborate (BSH) is a boron compound used in Boron Neutron Capture Therapy for malignant brain tumors. Intravenous single and 2-week repeated dose toxicity studies of BSH were performed in Sprague-Dawley rats. In the single-dose study, BSH was administered at doses of 100, 300 or 600 mg/kg. Death occurred within 10 min (acute type) or from 5 hr to 2 days (delayed type) after dosing in the 600 mg/kg group. No differences in mortality by sex and dosing speed were observed. Major causes of death were considered to be circulatory disorder in acute death and renal injury in delayed death. The renal injury was observed in the 300 and 600 mg/kg groups. In the 2-week repeated dose study, BSH was administered at doses of 30, 100 or 300 mg/kg/day for 14 days. Body weight gain was suppressed in the 100 and 300 mg/kg groups. One male in the 300 mg/kg group died due to renal and pulmonary lesions at day 8. Slight anemia was observed in the 300 mg/kg group. Pathologically, the kidney showed tubular regeneration with increase of weight in the 300 mg/kg. From these results, the NOAEL of BSH is 30 mg/kg/day. (author)

Tomotherapy for prostate adenocarcinoma: A report on acute toxicity

International Nuclear Information System (INIS)

Keiler, Louis; Dobbins, Donald; Kulasekere, Ravi; Einstein, Douglas

2007-01-01

Background and purpose: To analyze the impact of Tomotherapy (TOMO) intensity modulated radiotherapy (IMRT) on acute gastrointestinal (GI) and genitourinary (GU) toxicity in prostate cancer. Materials and methods: The records of 55 consecutively treated TOMO patients were reviewed. Additionally a well-matched group of 43 patients treated with LINAC-based step and shoot IMRT (LINAC) was identified. Acute toxicity was scored according to Radiation Therapy Oncology Group acute toxicity criterion. Results: The grade 2-3 acute GU toxicity rates for the TOMO vs. LINAC groups were 51% vs. 28% (p = 0.001). Acute grade 2 GI toxicity was 25% vs. 40% (p = 0.024), with no grade 3 GI toxicity in either group. In univariate analysis, androgen deprivation, prostate volume, pre-treatment urinary toxicity, and prostate dose homogeneity correlated with acute GI and GU toxicity. With multivariate analysis use of Tomotherapy, median bladder dose and bladder dose homogeneity remained significantly correlated with GU toxicity. Conclusions: Acute GI toxicity for prostate cancer is improved with Tomotherapy at a cost of increased acute GU toxicity possibly due to differences in bladder and prostate dose distribution

Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: factors associated with liver toxicities.

Science.gov (United States)

Goin, James E; Salem, Riad; Carr, Brian I; Dancey, Janet E; Soulen, Michael C; Geschwind, Jean Francois H; Goin, Kathleen; Van Buskirk, Mark; Thurston, Kenneth

2005-02-01

Intraarterial injection of yttrium 90 microspheres (TheraSpheres) is used in the treatment of hepatocellular carcinoma (HCC). This article presents an analysis of the incidence of liver toxicities (liver-related events) and pretreatment factors associated with liver toxicities after TheraSphere treatment. Eighty-eight TheraSphere-treated patients with low 90-day mortality risk were selected for analysis, with liver toxicities coded with use of standard oncology criteria. Descriptive and inferential statistical methods were applied to estimate the incidence of liver toxicities and to evaluate the influence of liver radiation dose and various pretreatment factors on the risk of their occurrence. Sixty-eight liver toxicities occurred in 37 of the 88 patients (42%). Thirty-two patients (36%) experienced 50 liver toxicities after the first treatment and nine of 23 patients (39%) who received a second treatment experienced 18 liver toxicities. Pretreatment total bilirubin and liver radiation dose were found to be associated with the risk of at least one liver toxicity and with the time to first occurrence of a liver toxicity after first treatment. Pretreatment total bilirubin also was associated with liver toxicities after the second treatment. Most of the toxicities resolved; however, those that did not resolve were attributed to tumor progression or advancing cirrhosis. The risk of liver toxicities in patients with unresectable HCC treated with TheraSpheres increases with increasing pretreatment total bilirubin level and liver radiation dose to a maximum of 150 Gy for a single administration. The toxicities attributed to treatment resolved over time, and none of the patients studied had confirmed radiation-induced liver disease. Consequently, doses as high as 150 Gy on a single administration and as high as 268 Gy on repeated administrations were well tolerated.

Treatment of relapsed or refractory acute leukemia in childhood with bisantrene combined with high dose aracytine.

Science.gov (United States)

Leblanc, T; Deméocq, F; Leverger, G; Baruchel, A; Lemerle, S; Vannier, J P; Nelken, B; Guillot, T; Schaison, G

1994-01-01

Bisantrene is an anthracene derivative which has demonstrated activity in acute myeloblastic leukemia (AML) and in lymphoma. The present study was designed to assess the reinduction rate and toxicity of bisantrene (250 mg/m2/d x 5) associated with aracytine (100 mg/m2 twice a day x 5) in refractory and relapsed acute childhood leukemia. Patients who relapsed after bone marrow transplantation were eligible. Twenty-six children were included. Diagnoses were as follows: 13 AML, 9 acute lymphoblastic leukemia (ALL), and 4 undifferentiated leukemia (AUL). All patients had been very highly pretreated, especially with anthracyclines, and most of them were of poor prognosis. The overall response rate was 46% with a 95% confidence interval ranging from 27-65%. According to diagnosis, complete remission (CR) rates are: AML: 5/13, ALL: 5/9, and AUL: 2/4. Four children died, three from infection and one from acute lysis syndrome. The major toxicity was infection with grade 3 and 4 episodes occurring in 42% of patients. No significant cardiac toxicity was noted. Hepatic and renal toxicity was noted. Hepatic and renal toxicity were limited and transient. Bisantrene in association with aracytine is effective in both AML and ALL of childhood. Bisantrene should be evaluated with a five-day schedule in other pediatric malignancies. In children with acute leukemia previously treated with high dose aracytine, new combination regimen is warranted.

Acute toxicity of injection of 153Sm-EDTMP

International Nuclear Information System (INIS)

Chen Baiwei; Chai Xuehong

2004-01-01

Sm-153 has several distinct advantages as a radiopharmaceutical for the treat of patients with bone to skeletal metastasis. Sm-153 shows high skeletal uptake and rapid blood and nonosseous tissue clearance. Several paper have considered the toxicity of 153Sm-EDTMP. We report the acute toxicity in mice and rats after injection of 153Sm-EDTMP or unlabeled EDTMP. The EDTMP was injected to mice by 9.76, 7.8, 6.25, 5, 4 mg/Kg. The logarithmic dose of EDTMP were given to mice to determine LD50. The LD50 of EDTMP in mice is 7.1 mg/Kg. The decay of 153Sm-EDTMP for 4 months were injected to mice at dose of 225 mg/Kg. 153Sm-EDTMP were given at 4 difference dosage to rats by 74 MBq/Kg, 370 MBq/Kg, 1110 MBq/Kg, 1850 MBq/Kg. The LD50 of 153Sm-EDTMP in rats is more than 370 MBq/Kg. Although the cold EDTMP LD50 was low, chelated with Sm can decrease it's toxicity. The decay 153Sm-EDTMP can be safe at dose of 225 mg/Kg. The clinical dose will be used at 37 MBq/Kg. So there is no need to consider to acute toxicity in clinical used 153Sm-EDTMP in designated regimen because the safe range is wide enough to cover clinical used. (authors)

Toxicity testing in the 21 century: defining new risk assessment approaches based on perturbation of intracellular toxicity pathways.

Directory of Open Access Journals (Sweden)

Sudin Bhattacharya

Full Text Available The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC report Toxicity Testing in the 21(st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a "toxicity pathways" (the innate cellular pathways that may be perturbed by chemicals and (b the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU. EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair.

High-Dose and Extended-Field Intensity Modulated Radiation Therapy for Early-Stage NK/T-Cell Lymphoma of Waldeyer's Ring: Dosimetric Analysis and Clinical Outcome

Energy Technology Data Exchange (ETDEWEB)

Bi, Xi-Wen; Li, Ye-Xiong, E-mail: yexiong@yahoo.com; Fang, Hui; Jin, Jing; Wang, Wei-Hu; Wang, Shu-Lian; Liu, Yue-Ping; Song, Yong-Wen; Ren, Hua; Dai, Jian-Rong

2013-12-01

Purpose: To assess the dosimetric benefit, treatment outcome, and toxicity of high-dose and extended-field intensity modulated radiation therapy (IMRT) in patients with early-stage NK/T-cell lymphoma of Waldeyer's ring (WR-NKTCL). Methods and Materials: Thirty patients with early-stage WR-NKTCL who received extended-field IMRT were retrospectively reviewed. The prescribed dose was 50 Gy to the primary involved regions and positive cervical lymph nodes (planning target volume requiring radical irradiation [PTV{sub 50}]) and 40 Gy to the negative cervical nodes (PTV{sub 40}). Dosimetric parameters for the target volume and critical normal structures were evaluated. Locoregional control (LRC), overall survival (OS), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Results: The median mean doses to the PTV{sub 50} and PTV{sub 40} were 53.2 Gy and 43.0 Gy, respectively. Only 1.4% of the PTV{sub 50} and 0.9% of the PTV{sub 40} received less than 95% of the prescribed dose, indicating excellent target coverage. The average mean doses to the left and right parotid glands were 27.7 and 28.4 Gy, respectively. The 2-year OS, PFS, and LRC rates were 71.2%, 57.4%, and 87.8%. Most acute toxicities were grade 1 to 2, except for grade ≥3 dysphagia and mucositis. The most common late toxicity was grade 1-2 xerostomia, and no patient developed any ≥grade 3 late toxicities. A correlation between the mean dose to the parotid glands and the degree of late xerostomia was observed. Conclusions: IMRT achieves excellent target coverage and dose conformity, as well as favorable survival and locoregional control rates with acceptable toxicities in patients with WR-NKTCL.

A blinded, randomized, controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock.

Science.gov (United States)

Cole, J B; Stellpflug, S J; Ellsworth, H; Anderson, C P; Adams, A B; Engebretsen, K M; Holger, J S

2013-05-01

High dose insulin (HDI) has proven superior to glucagon and catecholamines in the treatment of poison-induced cardiogenic shock (PICS) in previous animal studies. Standard recommendations for dosing of insulin vary and the optimal dose of HDI in PICS has not been established. Our hypothesis was a dose of 10 U/kg/hr of HDI would be superior to 1 U/kg/hr with cardiac output (CO) as our primary outcome measure in pigs with propranolol-induced PICS. This was a blinded, prospective, randomized trial with 4 arms consisting of 4 pigs in each arm. The arms were as follows: placebo (P), 1 U/kg/hr (HDI-1), 5 U/kg/hr (HDI-5), and 10 U/kg/hr (HDI-10). Cardiogenic shock was induced with a bolus of 0.5 mg/kg of propranolol followed by an infusion of 0.25 mg/kg/min until the point of toxicity, defined as 0.75 x (HR x MAP) was reached. At this point the propranolol infusion was decreased to 0.125 mg/kg/min and a 20 mL/kg bolus of normal saline (NS) was administered. The protocol was continued for 6 hours or until the animals died. 2 pigs died in the P arm, 1 pig died each in the HDI-1 and HDI-5 arms, and all pigs lived in the HDI-10 arm. There was a statistically significant difference in dose by time interaction on CO of 1.13 L/min over the 6 hr study period (p = < 0.001). There was also a statistically significant difference in dose by time interaction on MAP, HR, and systemic vascular resistance (SVR). No statistically significant difference was found between any of the arms regarding glucose utilization. HDI was statistically and clinically significantly superior to placebo in this propranolol model of PICS. Furthermore a dose response over time was found where CO increased corresponding to increases in doses of HDI.

High-dose irradiation of food

International Nuclear Information System (INIS)

Diehl, J.F.

1999-01-01

Studies performed on behalf of the International Project on Food Irradiation in the period from 1971 until 1980 resulted in the concluding statement that ''.the irradiation of any food commodity up to an overall average dose of 10 kGy presents no toxicological hazard; hence, toxicological testing of foods so treated is no longer required.'' Since then, licenses for food irradiation have been restricted to this maximum dose in any country applying this technology. Further testing programmes have been carried out investigating the wholesomeness or hazards of high-dose irradiation, but there has been little demand so far by the food industry for licensing of high-dose irradiation, as there is only a small range of products whose irradiation at higher doses offers advantages for given, intended use. These include eg. spices, dried herbs, meat products in flexible pouch packagings for astronauts, or patients with immune deficiencies. (orig./CB) [de

Single oral dose toxicity test of platycodin d, a saponin from platycodin radix in mice.

Science.gov (United States)

Lee, Won-Ho; Gam, Cheol-Ou; Ku, Sae-Kwang; Choi, Seong-Hun

2011-12-01

The object of this study was to evaluate the single oral dose toxicity of platycodin D, a saponin from the root of Platycodon grandiflorum in male and female mice. Platycodin D was administered to female and male mice as an oral dose of 2000, 1000, 500, 250 and 125 mg/kg (body wt.). Animals were monitored for the mortality and changes in body weight, clinical signs and gross observation during 14 days after treatment, upon necropsy, organ weight and histopathology of 14 principle organs were examined. As the results, no platycodin D treatment related mortalities, clinical signs, changes on the body and organ weights, gross and histopathological observations against 14 principle organs were detected up to 2000 mg/kg in both female and male mice. Therefore, LD50 (50% lethal dose) and approximate LD of playtcodin D after single oral treatment in female and male mice were considered over 2000 mg/kg - the limited dosages recommended by KFDA Guidelines [2009-116, 2009], respectively.

Treating chronic arsenic toxicity with high selenium lentil diets

Energy Technology Data Exchange (ETDEWEB)

Sah, Shweta [Department of Ecosystem and Public Health, Faculty of Medicine, University of Calgary, Calgary, AB T2N 4Z6 (Canada); Vandenberg, Albert [Department of Plant Sciences, University of Saskatchewan, Saskatoon, SK S7N 5A8 (Canada); Smits, Judit, E-mail: judit.smits@ucalgary.ca [Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6 (Canada)

2013-10-01

Arsenic (As) toxicity causes serious health problems in humans, especially in the Indo-Gangetic plains and mountainous areas of China. Selenium (Se), an essential micronutrient is a potential mitigator of As toxicity due to its antioxidant and antagonistic properties. Selenium is seriously deficient in soils world-wide but is present at high, yet non-toxic levels in the great plains of North America. We evaluate the potential of dietary Se in counteracting chronic As toxicity in rats through serum biochemistry, blood glutathione levels, immunotoxicity (antibody response), liver peroxidative stress, thyroid response and As levels in tissues and excreta. To achieve this, we compare diets based on high-Se Saskatchewan (SK) lentils versus low-Se lentils from United States. Rats drank control (0 ppm As) or As (40 ppm As) water while consuming SK lentils (0.3 ppm Se) or northwestern USA lentils (< 0.01 ppm Se) diets for 14 weeks. Rats on high Se diets had higher glutathione levels regardless of As exposure, recovered antibody responses in As-exposed group, higher fecal and urinary As excretion and lower renal As residues. Selenium deficiency caused greater hepatic peroxidative damage in the As exposed animals. Thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were not different. After 14 weeks of As exposure, health indicators in rats improved in response to the high Se lentil diets. Our results indicate that high Se lentils have a potential to mitigate As toxicity in laboratory mammals, which we hope will translate into benefits for As exposed humans. - Highlights: • We reduce chronic arsenic toxicity in rats with a whole food solution. • High selenium lentils decrease liver damage and increase blood glutathione levels. • High selenium lentil diets increase urinary and fecal arsenic excretion. • High selenium lentil diets decrease arsenic levels in kidney, the storage organ. • High selenium lentil diets reverse arsenic suppression of the B cell

Treating chronic arsenic toxicity with high selenium lentil diets

International Nuclear Information System (INIS)

Sah, Shweta; Vandenberg, Albert; Smits, Judit

2013-01-01

Arsenic (As) toxicity causes serious health problems in humans, especially in the Indo-Gangetic plains and mountainous areas of China. Selenium (Se), an essential micronutrient is a potential mitigator of As toxicity due to its antioxidant and antagonistic properties. Selenium is seriously deficient in soils world-wide but is present at high, yet non-toxic levels in the great plains of North America. We evaluate the potential of dietary Se in counteracting chronic As toxicity in rats through serum biochemistry, blood glutathione levels, immunotoxicity (antibody response), liver peroxidative stress, thyroid response and As levels in tissues and excreta. To achieve this, we compare diets based on high-Se Saskatchewan (SK) lentils versus low-Se lentils from United States. Rats drank control (0 ppm As) or As (40 ppm As) water while consuming SK lentils (0.3 ppm Se) or northwestern USA lentils (< 0.01 ppm Se) diets for 14 weeks. Rats on high Se diets had higher glutathione levels regardless of As exposure, recovered antibody responses in As-exposed group, higher fecal and urinary As excretion and lower renal As residues. Selenium deficiency caused greater hepatic peroxidative damage in the As exposed animals. Thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were not different. After 14 weeks of As exposure, health indicators in rats improved in response to the high Se lentil diets. Our results indicate that high Se lentils have a potential to mitigate As toxicity in laboratory mammals, which we hope will translate into benefits for As exposed humans. - Highlights: • We reduce chronic arsenic toxicity in rats with a whole food solution. • High selenium lentils decrease liver damage and increase blood glutathione levels. • High selenium lentil diets increase urinary and fecal arsenic excretion. • High selenium lentil diets decrease arsenic levels in kidney, the storage organ. • High selenium lentil diets reverse arsenic suppression of the B cell

''Low dose'' and/or ''high dose'' in radiation protection: A need to setting criteria for dose classification

International Nuclear Information System (INIS)

Sohrabi, M.

1997-01-01

The ''low dose'' and/or ''high dose'' of ionizing radiation are common terms widely used in radiation applications, radiation protection and radiobiology, and natural radiation environment. Reading the title, the papers of this interesting and highly important conference and the related literature, one can simply raise the question; ''What are the levels and/or criteria for defining a low dose or a high dose of ionizing radiation?''. This is due to the fact that the criteria for these terms and for dose levels between these two extreme quantities have not yet been set, so that the terms relatively lower doses or higher doses are usually applied. Therefore, setting criteria for classification of radiation doses in the above mentioned areas seems a vital need. The author while realizing the existing problems to achieve this important task, has made efforts in this paper to justify this need and has proposed some criteria, in particular for the classification of natural radiation areas, based on a system of dose limitation. (author)

Brachytherapy optimization using radiobiological-based planning for high dose rate and permanent implants for prostate cancer treatment

Science.gov (United States)

Seeley, Kaelyn; Cunha, J. Adam; Hong, Tae Min

2017-01-01

We discuss an improvement in brachytherapy--a prostate cancer treatment method that directly places radioactive seeds inside target cancerous regions--by optimizing the current standard for delivering dose. Currently, the seeds' spatiotemporal placement is determined by optimizing the dose based on a set of physical, user-defined constraints. One particular approach is the ``inverse planning'' algorithms that allow for tightly fit isodose lines around the target volumes in order to reduce dose to the patient's organs at risk. However, these dose distributions are typically computed assuming the same biological response to radiation for different types of tissues. In our work, we consider radiobiological parameters to account for the differences in the individual sensitivities and responses to radiation for tissues surrounding the target. Among the benefits are a more accurate toxicity rate and more coverage to target regions for planning high-dose-rate treatments as well as permanent implants.

A survey of the effects of Raha® and Berberin medicine in toxic and sub toxic doses compare with Clonidine medicine on reducing symptoms of morphine withdrawal

Directory of Open Access Journals (Sweden)

Mohammad.J Khoshnood

2010-09-01

Full Text Available Background: Opiate withdrawal refers to the wide range of symptoms that occur after stopping or dramatically reducing opiate drugs after heavy and prolonged use. The aim of the present study was to determine the effects of Raha and Berberin medicine in toxic and sub toxic doses compare with Clonidine medicine on reducing symptoms of morphine withdrawal in Syrian mice.Materials and Method: 140 Syrian mice (weight range 70-90 gr were divided randomly into 2 groups; first group; n1=35(receiving drug =21, control=14 & second group; n2=105 (receiving drug=91, control=14. Animals were treated by injected increasing doses of morphine sulfate for physical dependence. Then withdrawal syndrome was induced by administration of Naloxone. In order to evaluate the effect of Raha Berberin and Clonidine on morphine withdrawal syndrome in Syrian mice and also amount of total alkaloids and Berberin value in the Raha® were measured.Result: Total of average of alkaloid and Berberin value was 120, 5.72 mg, respectively in 5 ml of the Raha®. The rate of alcohol in Raha® was shown by using the USP procedure which was 19.34 percent. Toxic doses of Raha® and Berberin were 4, 40 mg/kg, respectively. Results indicated that, Raha increases significantly the percent of occurrence of ptosis and immobility were compared with control group (distilled water receiver (p=0.016. The occurrence rate of sniffing, grooming and rearing behavior in Raha and Berberin treated groups compared with control group, within 15min period, was not found statistically significant (p=0.089.Conclusion: Based on our study both Raha® and Berberin in any dilution had no effect on reducing signs of opioid withdrawal syndrome. According to the lack of its effect in mice, further studies should be undertaken for prescription of this drug in human

Cost minimization analysis of high-dose-rate versus low-dose-rate brachytherapy in endometrial cancer

International Nuclear Information System (INIS)

Pinilla, James

1998-01-01

Purpose: Endometrial cancer is a common, usually curable malignancy whose treatment frequently involves low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. These treatments involve substantial resource commitments and this is increasingly important. This paper presents a cost minimization analysis of HDR versus LDR brachytherapy in the treatment of endometrial cancer. Methods and Materials: The perspective of the analysis is that of the payor, in this case the Ministry of Health. One course of LDR treatment is compared to two courses of HDR treatment. The two alternatives are considered to be comparable with respect to local control, survival, and toxicities. Labor, overhead, and capital costs are accounted for and carefully measured. A 5% inflation rate is used where applicable. A univariate sensitivity analysis is performed. Results: The HDR regime is 22% less expensive compared to the LDR regime. This is $991.66 per patient or, based on the current workload of this department (30 patients per year) over the useful lifetime of the after loader, $297,498 over 10 years in 1997 dollars. Conclusion: HDR brachytherapy minimizes costs in the treatment of endometrial cancer relative to LDR brachytherapy. These results may be used by other centers to make rational decisions regarding brachytherapy equipment replacement or acquisition

Acute and subacute toxicity of 10B-paraboronophenylalanine

International Nuclear Information System (INIS)

Taniyama, K.; Fujiwara, H.; Kuno, T.; Saito, N.; Shuntoh, H.; Sakaue, M.; Tanaka, C.

1989-01-01

The acute and subacute toxicities of 10B-paraboronophenylalanine (10B-BPA) were investigated in the rat, according to the Good Laboratory Practice Standard for safety studies on drugs in Japan. In the acute toxicity test of 10B-BPA, LD50 values of acidic 10B-BPA for intraperitoneal and subcutaneous injections were 640 mg/kg for male and 710 mg/kg for female rats, and more than 1,000 mg/kg for male and female rats, respectively. The LD50 values of neutral 10B-BPA for intraperitoneal and subcutaneous injections were more than 3,000 mg/kg for male and female rats. The difference in LD50 values between acidic and neutral 10B-BPA may be attributed to the acidity of material. From the subacute toxicity test, in which the rats were injected daily subcutaneously for 28 days, the following toxic effects of 10B-BPA were observed. Increase in ketone level in the urine was induced in all rats treated with 10B-BPA. High dose of 10B-BPA (1,500 mg/kg) induced increase in spleen weight and reticulocyte count, and decrease in hemoglobin count, thereby suggesting that 10B-BPA causes hemolysis. Increases in the leukocyte count and the ratio of neutrophils and lymphocytes were also observed in rats treated with a high dose of 10B-BPA. This may be attributed to local reactions at the injection site. There were no significant differences in the findings between control rats and rats treated with a low dose of 10B-BPA (300 mg/kg). Thus, low doses of neutral 10B-BPA may be available for use as a drug

The integral biologically effective dose to predict brain stem toxicity of hypofractionated stereotactic radiotherapy

International Nuclear Information System (INIS)

Clark, Brenda G.; Souhami, Luis; Pla, Conrado; Al-Amro, Abdullah S.; Bahary, Jean-Paul; Villemure, Jean-Guy; Caron, Jean-Louis; Olivier, Andre; Podgorsak, Ervin B.

1998-01-01

Purpose: The aim of this work was to develop a parameter for use during fractionated stereotactic radiotherapy treatment planning to aid in the determination of the appropriate treatment volume and fractionation regimen that will minimize risk of late damage to normal tissue. Materials and Methods: We have used the linear quadratic model to assess the biologically effective dose at the periphery of stereotactic radiotherapy treatment volumes that impinge on the brain stem. This paper reports a retrospective study of 77 patients with malignant and benign intracranial lesions, treated between 1987 and 1995, with the dynamic rotation technique in 6 fractions over a period of 2 weeks, to a total dose of 42 Gy prescribed at the 90% isodose surface. From differential dose-volume histograms, we evaluated biologically effective dose-volume histograms and obtained an integral biologically-effective dose (IBED) in each case. Results: Of the 77 patients in the study, 36 had target volumes positioned so that the brain stem received more than 1% of the prescribed dose, and 4 of these, all treated for meningioma, developed serious late damage involving the brain stem. Other than type of lesion, the only significant variable was the volume of brain stem exposed. An analysis of the IBEDs received by these 36 patients shows evidence of a threshold value for late damage to the brain stem consistent with similar thresholds that have been determined for external beam radiotherapy. Conclusions: We have introduced a new parameter, the IBED, that may be used to represent the fractional effective dose to structures such as the brain stem that are partially irradiated with stereotactic dose distributions. The IBED is easily calculated prior to treatment and may be used to determine appropriate treatment volumes and fractionation regimens minimizing possible toxicity to normal tissue

Repeated dose oral toxicity of inorganic mercury in wistar rats: biochemical and morphological alterations

Directory of Open Access Journals (Sweden)

M. D. Jegoda

2013-06-01

Full Text Available Aim: The study was conducted to find out the possible toxic effect of mercuric chloride (HgCl2 at the histological, biochemical, and haematological levels in the wistar rats for 28 days. Materials and Methods: The biochemical and hematological alteration were estimated in four groups of rat (each group contain ten animals, which were treated with 0 (control, 2, 4, and 8 mg/kg body weight of HgCl2 through oral gavage. At the end of study all rats were sacrificed and subjected for histopathology. Result: A significantly (P < 0.05 higher level of serum alanine amino transferase (ALT, gamma Glutamyle Transferase, and creatinine were recorded in treatment groups, while the level of alkaline phosphtase (ALP was significantly decreased as compared to the control group. The toxic effect on hematoclogical parameter was characterized by significant decrease in hemoglobin, packed cell volume, total erythrocytes count, and total leukocyte count. Gross morphological changes include congestion, severe haemorrhage, necrosis, degenerative changes in kidneys, depletion of lymphocyte in spleen, decrease in concentration of mature spermatocyte, and edema in testis. It was notable that kidney was the most affected organ. Conclusion: Mercuric chloride (HgCl caused dose-dependent toxic effects on blood parameters and kidney. [Vet World 2013; 6(8.000: 563-567

Dose-reduction techniques for high-dose worker groups in nuclear power plants

International Nuclear Information System (INIS)

Khan, T.A.; Baum, J.W.; Dionne, B.J.

1991-03-01

This report summarizes the main findings of a study of the extent of radiation dose received by special work groups in the nuclear power industry. Work groups which chronically get large doses were investigated, using information provided by the industry. The tasks that give high doses to these work groups were examined and techniques described that were found to be particularly successful in reducing dose. Quantitative information on the extent of radiation doses to various work groups shows that significant numbers of workers in several critical groups receive doses greater than 1 and even 2 rem per year, particularly contract personnel and workers at BWR-type plants. The number of radiation workers whose lifetime dose is greater than their age is much less. Although the techniques presented would go some way in reducing dose, it is likely that a sizeable reduction to the high-dose work groups may require development of new dose-reduction techniques as well as major changes in procedures. 10 refs., 26 tabs

Evaluation of acute toxicity of genabilic acid (menbutone 10% in rabbits

Directory of Open Access Journals (Sweden)

S. O. El Okle

2014-09-01

Full Text Available Normal 0 false false false MicrosoftInternetExplorer4 A complete investigation of the acute toxicity of a choleretic compound, menbutone, was performed in rabbits, including lethal dose for 50% of rabbits determination, clinical signs observation and in vivo and post-mortem examinations. Haematological, biochemical and histopathological changes resulting from intramuscular injection of menbutone were also investigated at dose 400 mg/kg body weight. Acute toxicity of menbutone at dose of 400 mg/kg BW induced interstitial myocarditis and multifocal necrosis, whereas serum creatine phosphokinase, creatinine phosphokinase-MB isoenzyme and aspartate aminotransferase activities were significantly increased. Elevation of serum alanine aminotransferase and alkaline phosphatase activities and total bilirubin level associated with lowered albumin content was consistent with histopathological changes of hepatic tissues; hepatic necrosis and fatty infiltration were pronounced indicators of injuries. Renal tubular necrosis and interstitial nephritis were also observed in intoxicated rabbits. Menbutone also induced variations in some haematological parameters. We concluded that acute toxicity of menbutone in rabbits occurred at accidental high doses, as the lethal dose was about 50 fold over the recommended therapeutic dose for other animals. Cardiac muscle, liver and kidneys are the main target organs for menbutone toxicity. Menbutone is not recommended for use in rabbits suffering from any cardiacand hepatic disorders, especially in overdosing situations.

Performance of thermoluminescent materials for high dose dosimetry

International Nuclear Information System (INIS)

Texeira, Maria I.; Cecatti, Sonia G.P.; Caldas, Linda V.E.

2008-01-01

Cases involving high-doses of ionizing radiation are becoming increasingly common.The objective of this work was to characterize thermoluminescent materials for the dosimetry of workers exposed to high doses. Samples of TLD-200, TLD-400 and TLD-800 pellets from Thermo Electron Corporation were studied in gamma high-doses. Dose-response curves were obtained for doses between 100 mGy and 100 Gy. The reproducibility, the lower detection limits and dose-response curves were obtained for all three materials. The different kinds of detectors show usefulness for dosimetry of workers exposed accidentally to high doses. (author)

A Novel Method for Predicting Late Genitourinary Toxicity After Prostate Radiation Therapy and the Need for Age-Based Risk-Adapted Dose Constraints

International Nuclear Information System (INIS)

Ahmed, Awad A.; Egleston, Brian; Alcantara, Pino; Li, Linna; Pollack, Alan; Horwitz, Eric M.; Buyyounouski, Mark K.

2013-01-01

Background: There are no well-established normal tissue sparing dose–volume histogram (DVH) criteria that limit the risk of urinary toxicity from prostate radiation therapy (RT). The aim of this study was to determine which criteria predict late toxicity among various DVH parameters when contouring the entire solid bladder and its contents versus the bladder wall. The area under the histogram curve (AUHC) was also analyzed. Methods and Materials: From 1993 to 2000, 503 men with prostate cancer received 3-dimensional conformal RT (median follow-up time, 71 months). The whole bladder and the bladder wall were contoured in all patients. The primary endpoint was grade ≥2 genitourinary (GU) toxicity occurring ≥3 months after completion of RT. Cox regressions of time to grade ≥2 toxicity were estimated separately for the entire bladder and bladder wall. Concordance probability estimates (CPE) assessed model discriminative ability. Before training the models, an external random test group of 100 men was set aside for testing. Separate analyses were performed based on the mean age (≤ 68 vs >68 years). Results: Age, pretreatment urinary symptoms, mean dose (entire bladder and bladder wall), and AUHC (entire bladder and bladder wall) were significant (P 68 years. Conclusion: The AUHC method based on bladder wall volumes was superior for predicting late GU toxicity. Age >68 years was associated with late grade ≥2 GU toxicity, which suggests that risk-adapted dose constraints based on age should be explored

Harmonizing human exposure and toxicity characterization

DEFF Research Database (Denmark)

Fantke, Peter; Jolliet, O.; McKone, T.E.

2017-01-01

The UNEP-SETAC Life Cycle Initiative has launched a project to provide global guidance and build consensus on environmental life cycle impact assessment (LCIA) indicators. Human health effects from exposure to toxic chemicals was selected as impact category due to high relevance of human toxicity...... and harmonizing human toxicity characterization in LCIA. Building on initial work for the far-field and indoor air environments, and combining it with latest work on near-field consumer and occupational exposure assessment, dose-response and severity data, we aim at providing revised guidance on the development...... and use of impact factors for toxic chemicals. We propose to couple fate processes in consumer and occupational environments with existing environmental compartments and processes via a consistent and mass balance-based set of transfer fractions to quantify overall aggregated exposure to toxic substances...

Acute toxicity of intravenously administered titanium dioxide nanoparticles in mice.

Directory of Open Access Journals (Sweden)

Jiaying Xu

Full Text Available BACKGROUND: With a wide range of applications, titanium dioxide (TiO₂ nanoparticles (NPs are manufactured worldwide in large quantities. Recently, in the field of nanomedicine, intravenous injection of TiO₂ nanoparticulate carriers directly into the bloodstream has raised public concerns on their toxicity to humans. METHODS: In this study, mice were injected intravenously with a single dose of TiO₂ NPs at varying dose levels (0, 140, 300, 645, or 1387 mg/kg. Animal mortality, blood biochemistry, hematology, genotoxicity and histopathology were investigated 14 days after treatment. RESULTS: Death of mice in the highest dose (1387 mg/kg group was observed at day two after TiO₂ NPs injection. At day 7, acute toxicity symptoms, such as decreased physical activity and decreased intake of food and water, were observed in the highest dose group. Hematological analysis and the micronucleus test showed no significant acute hematological or genetic toxicity except an increase in the white blood cell (WBC count among mice 645 mg/kg dose group. However, the spleen of the mice showed significantly higher tissue weight/body weight (BW coefficients, and lower liver and kidney coefficients in the TiO₂ NPs treated mice compared to control. The biochemical parameters and histological tissue sections indicated that TiO₂ NPs treatment could induce different degrees of damage in the brain, lung, spleen, liver and kidneys. However, no pathological effects were observed in the heart in TiO₂ NPs treated mice. CONCLUSIONS: Intravenous injection of TiO₂ NPs at high doses in mice could cause acute toxicity effects in the brain, lung, spleen, liver, and kidney. No significant hematological or genetic toxicity was observed.

Acute Toxicity Grade 3 and 4 After Irradiation in Children and Adolescents: Results From the IPPARCA Collaboration

Energy Technology Data Exchange (ETDEWEB)

Pixberg, Caroline [Department of Radiation Oncology, University Hospital of Muenster, Muenster (Germany); Koch, Raphael [Institute of Biostatistics and Clinical Research, University of Muenster, Muenster (Germany); Eich, Hans Theodor, E-mail: Hans.Eich@ukmuenster.de [Department of Radiation Oncology, University Hospital of Muenster, Muenster (Germany); Department of Radiation Oncology, University of Koeln, Koeln (Germany); Martinsson, Ulla [Department of Oncology, University Hospital, Uppsala (Sweden); Kristensen, Ingrid [Department of Radiation Physics, Skåne University Hospital, Lund (Sweden); Matuschek, Christiane [Department of Radiation Oncology, University Hospital of Duesseldorf, Duesseldorf (Germany); Kortmann, Rolf-Dieter [Department of Radiation Oncology, University Hospital of Leipzig, Leipzig (Germany); Pohl, Fabian [Department of Radiation Oncology, University of Regensburg, Regensburg (Germany); Elsayad, Khaled [Department of Radiation Oncology, University Hospital of Muenster, Muenster (Germany); Christiansen, Hans [Department of Radiation Oncology, Medical School Hannover, Hannover (Germany); Willich, Normann [Department of Radiation Oncology, University Hospital of Muenster, Muenster (Germany); Lindh, Jack [Department of Radiation Sciences, Umeå University, Umeå (Sweden); Steinmann, Diana [Department of Radiation Oncology, University Hospital of Muenster, Muenster (Germany); Department of Radiation Oncology, Medical School Hannover, Hannover (Germany)

2016-03-15

Purpose: In the context of oncologic therapy for children, radiation therapy is frequently indicated. This study identified the frequency of and reasons for the development of high-grade acute toxicity and possible sequelae. Materials and Methods: Irradiated children have been prospectively documented since 2001 in the Registry for the Evaluation of Side Effects After Radiation in Childhood and Adolescence (RiSK) database in Germany and since 2008 in the registry for radiation therapy toxicity (RADTOX) in Sweden. Data were collected using standardized, published forms. Toxicity classification was based on Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Results: As of June 2013, 1500 children have been recruited into the RiSK database and 485 into the RADTOX registry leading to an analysis population of 1359 patients (age range 0-18). A total of 18.9% (n=257) of all investigated patients developed high-grade acute toxicity (grades 3/4). High-grade toxicity of the bone marrow was documented for 63.8% (n=201) of those patients, oral mucositis for 7.6% (n=24), and dermatitis for 7.6% (n=24). Patients with high-grade acute toxicity received concomitant chemotherapy more frequently (56%) than patients with no or lower acute toxicity (31.5%). In multivariate analyses, concomitant chemotherapy, diagnosis of Ewing sarcoma, and total radiation dose showed a statistically noticeable effect (P≤.05) on acute toxicity, whereas age, concomitant chemotherapy, Hodgkin lymphoma, Ewing sarcoma, total radiation dose, and acute toxicity influenced the time until maximal late toxicity. Conclusions: Generally, high-grade acute toxicity after irradiation in children and adolescence occurs in a moderate proportion of patients (18.9%). As anticipated, the probability of acute toxicity appeared to depend on the prescribed dose as well as concomitant chemotherapy. The occurrence of chronic toxicity correlates with the prior acute

Re-irradiation: Outcome, cumulative dose and toxicity in patients retreated with stereotactic radiotherapy in the abdominal or pelvic region

NARCIS (Netherlands)

H. Abusaris (Huda); M.S. Hoogeman (Mischa); J.J.M.E. Nuyttens (Joost)

2012-01-01

textabstractThe purpose of the present study was to explore the outcome, cumulative dose in tumor and organs at risk and toxicity after extra-cranial stereotactic re-irradiation. Twenty-seven patients were evaluated who had been re-irradiated with stereotactic body radiotherapy (SBRT) after

Prostate cancer treated with image-guided helical TomoTherapy {sup registered} and image-guided LINAC-IMRT. Correlation between high-dose bladder volume, margin reduction, and genitourinary toxicity

Energy Technology Data Exchange (ETDEWEB)

Drozdz, Sonia; Wendt, Thomas G. [University Hospital Jena, Friedrich-Schiller-University Jena, Department of Radiation Oncology, Jena (Germany); Schwedas, Michael; Salz, Henning [University Hospital Jena, Friedrich-Schiller-University Jena, Department of Radiation Oncology, Section of Medical Physics, Jena (Germany); Foller, Susan [University Hospital Jena, Friedrich-Schiller-University Jena, Department of Urology, Jena (Germany)

2016-04-15

We compared different image-guidance (IG) strategies for prostate cancer with high-precision IG intensity-modulated radiation therapy (IMRT) using TomoTherapy {sup registered} (Accuray Inc., Madison, WI, USA) and linear accelerator (LINAC)-IMRT and their impact on planning target volume (PTV) margin reduction. Follow-up data showed reduced bladder toxicity in TomoTherapy patients compared to LINAC-IMRT. The purpose of this study was to quantify whether the treatment delivery technique and decreased margins affect reductions in bladder toxicity. Setup corrections from 30 patients treated with helical TomoTherapy and 30 treated with a LINAC were analyzed. These data were used to simulate three IG protocols based on setup error correction and a limited number of imaging sessions. For all patients, gastrointestinal (GI) and genitourinary (GU) toxicity was documented and correlated with the treatment delivery technique. For fiducial marker (FM)-based RT, a margin reduction of up to 3.1, 3.0, and 4.8 mm in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions, respectively, could be achieved with calculation of a setup correction from the first three fractions and IG every second day. Although the bladder volume was treated with mean doses of 35 Gy in the TomoTherapy group vs. 22 Gy in the LINAC group, we observed less GU toxicity after TomoTherapy. Intraprostate FMs allow for small safety margins, help decrease imaging frequency after setup correction, and minimize the dose to bladder and rectum, resulting in lower GU toxicity. In addition, IMRT delivered with TomoTherapy helps to avoid hotspots in the bladder neck, a critical anatomic structure associated with post-RT urinary toxicity. (orig.) [German] Wir haben im Rahmen der Prostatakarzinombehandlung verschiedene bildgefuehrte (IG) Strategien der hochpraezisen intensitaetsmodulierten Radiotherapie (IMRT) unter Einsatz der Tomotherapie (TomoTherapy {sup registered}, Accuray Inc., Madison

Nucleotide metabolism in Lactococcus lactis: Salvage pathways of exogenous pyrimidines

DEFF Research Database (Denmark)

Martinussen, Jan; Andersen, Paal Skytt; Hammer, Karin

1994-01-01

By measuring enzyme activities in crude extracts and studying the effect of toxic analogs (5-fluoropyrimidines) on cell growth, the metabolism of pyrimidines in Lactococcus lactis was analyzed. Pathways by which uracil, uridine, deoxyuridine, cytidine, and deoxycytidine are metabolized in L. lact...

Acute toxicity of ingested fluoride.

Science.gov (United States)

Whitford, Gary Milton

2011-01-01

This chapter discusses the characteristics and treatment of acute fluoride toxicity as well as the most common sources of overexposure, the doses that cause acute toxicity, and factors that can influence the clinical outcome. Cases of serious systemic toxicity and fatalities due to acute exposures are now rare, but overexposures causing toxic signs and symptoms are not. The clinical course of systemic toxicity from ingested fluoride begins with gastric signs and symptoms, and can develop with alarming rapidity. Treatment involves minimizing absorption by administering a solution containing calcium, monitoring and managing plasma calcium and potassium concentrations, acid-base status, and supporting vital functions. Approximately 30,000 calls to US poison control centers concerning acute exposures in children are made each year, most of which involve temporary gastrointestinal effects, but others require medical treatment. The most common sources of acute overexposures today are dental products - particularly dentifrices because of their relatively high fluoride concentrations, pleasant flavors, and their presence in non-secure locations in most homes. For example, ingestion of only 1.8 ounces of a standard fluoridated dentifrice (900-1,100 mg/kg) by a 10-kg child delivers enough fluoride to reach the 'probably toxic dose' (5 mg/kg body weight). Factors that may influence the clinical course of an overexposure include the chemical compound (e.g. NaF, MFP, etc.), the age and acid-base status of the individual, and the elapsed time between exposure and the initiation of treatment. While fluoride has well-established beneficial dental effects and cases of serious toxicity are now rare, the potential for toxicity requires that fluoride-containing materials be handled and stored with the respect they deserve. Copyright © 2011 S. Karger AG, Basel.

Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer.

Science.gov (United States)

Wilcox, Shea W; Aherne, Noel J; Benjamin, Linus C; Wu, Bosco; de Campos Silva, Thomaz; McLachlan, Craig S; McKay, Michael J; Last, Andrew J; Shakespeare, Thomas P

2014-01-01

Dose-escalated (DE) radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS) in several studies. In the same group of patients, androgen deprivation therapy (ADT) has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT) with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT) and ADT. Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2.1% and 3.4%, respectively. No grade 3 or 4 late toxicities were reported. Pretreatment prostate specific antigen (P=0.001) and Gleason score (P=0.03) were significant in predicting biochemical failure on multivariate analysis. There is a high probability of tumor control with DE IG-IMRT combined with androgen deprivation, and this is a technique with a low probability of significant late toxicity. Our long term results corroborate the safety and efficacy of treating with IG-IMRT to high doses and compares favorably with published series for

Importance of dose metrics for lethal and sublethal sediment metal toxicity in the oligochaete worm Lumbriculus variegatus

Energy Technology Data Exchange (ETDEWEB)

Penttinen, O.P.; Kilpi-Koski, J.; Toivainen, K. [Helsinki Univ., Lahti (Finland). Dept. of Ecology end Environmental Sciences; Jokela, M. [Mikkeli Univ. of Applied Sciences, Mikkeli (Finland); Vaeisaenen, A. [Jyvaeskylae Univ. (Finland). Dept. of Chemistry

2008-02-15

Background, aims, and scope. There is an increasing demand for controlled toxicity tests to predict biological effects related to sediment metal contamination. In this context, questions of metal-specific factors, sensitivity of toxicity endpoints, and variability in exposure duration arise. In addition, the choice of the dose metrics for responses is equally important and is related to the applicability of the concept of critical body residue (CBR) in exposure assessments, as well as being the main focus of this study. Methods. Experiments were conducted to assess toxicity of Cd, Cr, Cu and Pb to the oligochaete worm Lumbriculus variegatus with the aim of determining CBRs for two response metrics. Mortality and feeding activity of worms exposed to sediment-spiked metals were used as end-points in connection with residue analyses from both the organisms and the surrounding media. Results. LC50 values were 0.3, 1.4, 5.2, and 6.7 mg/L (from 4.7 {mu}mol/L to 128.0 {mu}mol/L), and the order of toxicity, from most toxic to least toxic, was Cu > Cd > Pb>Cr. By relating toxicity to body residue, variability in toxicity among the metals decreased and the order of toxicity was altered. The highest lethal residue value was obtained for Cu (10.8 mmol/kg) and the lowest was obtained for Cd (2.3 mmol/kg). In the 10-d sublethal test, both time and metal exposure were an important source of variation in the feeding activity of worms. The significant treatment effects were observed from worms exposed to Cd or Pb, with the controls yielding the highest feeding rate. However, quantitative changes in the measured end-point did not correlate with the exposure concentrations or body residues, which remained an order of magnitude lower than in the acute exposures. (orig.)

Perculiarities of the toxicity and radioprotective activity of aminopropyl aminoethyl thiophosphate

International Nuclear Information System (INIS)

Terekhov, A.V.; Besedina, L.N.; Zherebchenko, P.G.; Znamenskij, V.V.; Suslikov, V.I.; Titov, B.A.

1976-01-01

Toxicity and radioprotective activity of aminopropyl aminoethyl thiophosphate (APAETP) has been compared to those of cystaphos. APAETP has been shown to exceed cystaphos slightly by the value of the radioprotective effect but it is inferior to the latter in the duration of the action after intraperitoneal administration. APAETP, used in toxic doses, does not cause spastic reactions in animals. The range of radioprotective effect of APAETP is almost twice as high as that of cystaphos. Both APAETP and cystaphos have a pronounced radioprotective action not only at high (355 R/min) but also at comparatively low (10.7 R/min) dose-rates of γ-radiation

Impact of Fraction Size on Lung Radiation Toxicity: Hypofractionation may be Beneficial in Dose Escalation of Radiotherapy for Lung Cancers

International Nuclear Information System (INIS)

Jin Jinyue; Kong Fengming; Chetty, Indrin J.; Ajlouni, Munther; Ryu, Samuel; Ten Haken, Randall; Movsas, Benjamin

2010-01-01

Purpose: To assess how fraction size impacts lung radiation toxicity and therapeutic ratio in treatment of lung cancers. Methods and Materials: The relative damaged volume (RDV) of lung was used as the endpoint in the comparison of various fractionation schemes with the same normalized total dose (NTD) to the tumor. The RDV was computed from the biologically corrected lung dose-volume histogram (DVH), with an α/β ratio of 3 and 10 for lung and tumor, respectively. Two different (linear and S-shaped) local dose-effect models that incorporated the concept of a threshold dose effect with a single parameter D L50 (dose at 50% local dose effect) were used to convert the DVH into the RDV. The comparison was conducted using four representative DVHs at different NTD and D L50 values. Results: The RDV decreased with increasing dose/fraction when the NTD was larger than a critical dose (D CR ) and increased when the NTD was less than D CR . The D CR was 32-50 Gy and 58-87 Gy for a small tumor (11 cm 3 ) for the linear and S-shaped local dose-effect models, respectively, when D L50 was 20-30 Gy. The D CR was 66-97 Gy and 66-99 Gy, respectively, for a large tumor (266 cm 3 ). Hypofractionation was preferred for small tumors and higher NTDs, and conventional fractionation was better for large tumors and lower NTDs. Hypofractionation might be beneficial for intermediate-sized tumors when NTD = 80-90 Gy, especially if the D L50 is small (20 Gy). Conclusion: This computational study demonstrated that hypofractionated stereotactic body radiotherapy is a better regimen than conventional fractionation in lung cancer patients with small tumors and high doses, because it generates lower RDV when the tumor NTD is kept unchanged.

Mechanism of Action for Anti-radiation Vaccine in Reducing the Biological Impact of High-dose Gamma Irradiation

Science.gov (United States)

Maliev, Vladislav; Popov, Dmitri; Jones, Jeffrey A.; Casey, Rachael C.

2007-01-01

Ionizing radiation is a major health risk of long-term space travel, the biological consequences of which include genetic and oxidative damage. In this study, we propose an original mechanism by which high doses of ionizing radiation induce acute toxicity. We identified biological components that appear in the lymphatic vessels shortly after gamma irradiation. These radiation-induced toxins, which we have named specific radiation determinants (SRD), were generated in the irradiated tissues and then collected and circulated throughout the body via the lymph circulation and bloodstream. Depending on the type of SRD elicited, different syndromes of acute radiation sickness (ARS) were expressed. The SRDs were developed into a vaccine used to confer active immunity against acute radiation toxicity in immunologically naive animals. Animals that were pretreated with SRDs exhibited resistance to lethal doses of gamma radiation, as measured by increased survival times and survival rates. In comparison, untreated animals that were exposed to similar large doses of gamma radiation developed acute radiation sickness and died within days. This phenomenon was observed in a number of mammalian species. Initial analysis of the biochemical characteristics indicated that the SRDs were large molecular weight (200-250 kDa) molecules that were comprised of a mixture of protein, lipid, carbohydrate, and mineral. Further analysis is required to further identify the SRD molecules and the biological mechanism by which the mediate the toxicity associated with acute radiation sickness. By doing so, we may develop an effective specific immunoprophylaxis as a countermeasure against the acute effects of ionizing radiation.

Fiber optics in high dose radiation fields

International Nuclear Information System (INIS)

Partin, J.K.

1985-01-01

A review of the behavior of state-of-the-art optical fiber waveguides in high dose (greater than or equal to 10 5 rad), steady state radiation fields is presented. The influence on radiation-induced transmission loss due to experimental parameters such as dose rate, total dose, irradiation history, temperature, wavelength, and light intensity, for future work in high dose environments are given

Radiophotoluminescence light scope for high-dose dosimetry

International Nuclear Information System (INIS)

Sato, Fuminobu; Zushi, Naoki; Sakiyama, Tomoki; Kato, Yushi; Murata, Isao; Shimizu, Kikuo; Yamamoto, Takayoshi; Iida, Toshiyuki

2015-01-01

A radiophotoluminescence (RPL) light scope is a remote-sensing technique for measuring in situ the radiation dose in an RPL detector placed at a distance. The RPL light scope is mainly composed of an ultraviolet (UV) pulse laser, telescopic lenses, a photomultiplier tube, and camera modules. In a performance test, some RPL detectors were placed at distances up to 30 m and were illuminated with a pulsed UV laser beam. The photoluminescence responses of the RPL detectors were analyzed using this scope. Their radiation doses were determined from the amplitude of the given component of the photoluminescence responses. The RPL readout could be repeated without fading, and its amplitude exhibited good linearity at a dose ranging from 0.1 to 60 Gy. Furthermore, a two-dimensional distribution of radiation dose was obtained by laser scanning on an RPL detector. It was confirmed that the RPL light scope was a useful remote-sensing tool for high-dose dosimetry. - Highlights: • A radiophotoluminescence (RPL) light scope was developed for high-dose dosimetry. • The RPL light scope has high sensitivity and accuracy in high-dose dosimetry. • Two-dimensional radiation dose distribution was obtained by the RPL light scope.

Effect of radiosterilization of some antihistamines on their toxicity

International Nuclear Information System (INIS)

El-Sayed, M.E.; Roushdy, H.M.; Naiema, M.; Seham, H.M.H.

1985-01-01

The effect of gamma irradiation of pgeniramine maleate and menhydrinate solutions at the radiation levels of 15,25 and 50KGY on their toxicity has been investigated. Irradiation of pheniramine maleate and dimenhydrinate solutions at dose levels of 15,25 and 50KGY resulted in no significant change in neither the gross toxicity of the two drugs nor in their LD 50's on rats. Pheniramine maleate and dimenhydrinate whether irradiated or not, resulted in no significant increase in serum GPT or alkaline phosphatase activities when given at a dose of 15mg/Kg suggesting no significant alteration to liver function in rats. Higher doses of the two antihistaminics, namely, the minimal lethal doses and the LD 50's induced hydropic degeneration of liver cells, lymphocytic infiltration of the portal tract and focal areas of necrosis of hepatic cells mostly in the central lobule. Fatty infiltration was observed with dimenhydrinate. Radiation treatment of those antihistamines up to 50KGY resulting in no alteration in their toxicity projects the high radiation stability of pheniramine maleate and dimenhydrinate and confirms gamma irradiation is a successful method for their sterilization

Repeated Dose 28-Days Oral Toxicity Study of Carica papaya L. Leaf Extract in Sprague Dawley Rats