Adjusting the duration of androgen deprivation therapy (ADT) based on nadir PSA for high risk localized prostate cancer patients treated with definitive external beam radiation therapy and ADT.

BACKGROUND: A nadir Prostate-Specific Antigen (nPSA) of 0.06 ng/mL has been shown to be a strong independent predictor of biochemical recurrence-free survival (bRFS) in patients with intermediate or high-risk (HR) prostate cancer treated with definitive external beam radiation therapy (RT) and androgen deprivation therapy (ADT). We aimed to examine the association between the duration of ADT and bRFS in HR localized prostate cancer, based on nPSA. METHODS: Between 1998 and 2015, 204 patients with HR localized prostate cancer were identified. Of them, 157 patients (77.0%) reached the desired nPSA of < 0.06 ng/mL (favorable group), while 47 (23.0%) did not (unfavorable group). Duration of ADT varied among patients depending on physician preference, patient tolerance, and/or compliance. Survival outcomes were calculated using Kaplan-Meier methods and predictors of outcomes using multi-variable cox regression model. RESULTS: In the favorable group, ADT for at least 12 months lead to superior bRFS compared to ≤ 9 months of ADT (P = 0.036). However, no significant difference was seen when examining the value of receiving ADT beyond 12, 18, or 24 months, respectively. On univariate analysis for bRFS, the use of ADT for at least 12 months was significant (P = 0.012) as well as time to nadir PSA (tnPSA), (≤ 6 vs > 6 months); (P = 0.043). The presenting T stage was borderline significant (HR 3.074; 95% CI 0.972-9.719; P = 0.056), while PSA at presentation, Gleason Score and age were not. On multivariate analysis, the use of ADT for 12 months (P = 0.012) and tnPSA (P = 0.037) remained significant. In the unfavorable group, receiving ADT beyond 9 and 12 months was associated with improved bRFS (P = 0.044 and 0.019, respectively). However, beyond 18 months, there was no significant difference. CONCLUSION: In HR localized prostate cancer patients treated with definitive RT and ADT, the total duration of ADT may be adjusted according to treatment response using nPSA. In patients reaching a nPSA below 0.06 ng/mL, a total of 12 months of ADT may be sufficient, while in those not reaching a nPSA below 0.06 ng/mL, a total duration of 18 months is required.

Low- and middle-income countries can reduce risks of subsequent neoplasms by referring pediatric craniospinal cases to centralized proton treatment centers.

Few children with cancer in low- and middle-income countries (LMICs) have access to proton therapy. Evidence exists to support replacing photon therapy with proton therapy to reduce the incidence of secondary malignant neoplasms (SMNs) in childhood cancer survivors. The purpose of this study was to estimate the potential reduction in SMN incidence and in SMN mortality for pediatric medulloblastoma patients in LMICs if proton therapy were made available to them. For nine children of ages 2 to 14 years, we calculated the equivalent dose in organs or tissues at risk for radiogenic SMNs from therapeutic and stray radiation for photon craniospinal irradiation (CSI) in a LMIC and proton CSI in a high-income country. We projected the lifetime risks of SMN incidence and SMN mortality for every SMN site with a widely-used model from the literature. We found that the average total lifetime attributable risks of incidence and mortality were very high for both photon CSI (168% and 41%, respectively) and proton CSI (88% and 26%, respectively). SMNs having the highest risk of mortality were lung cancer (16%), non-site-specific solid tumors (16%), colon cancer (5.9%), leukemia (5.4%), and for girls breast cancer (5.0%) after photon CSI and non-site-specific solid tumors (12%), lung cancer (11%), and leukemia (4.8%) after proton CSI. The risks were higher for younger children than for older children and higher for girls than for boys. The ratios of proton CSI to photon CSI of total risks of SMN incidence and mortality were 0.56 (95% CI, 0.37 to 0.75) and 0.64 (95% CI, 0.45 to 0.82), respectively, averaged over this sample group. In conclusion, proton therapy has the potential to lessen markedly subsequent SMNs and SMN fatalities in survivors of childhood medulloblastoma in LMICs, for example, through regional centralized care. Additional methods should be explored urgently to reduce therapeutic-field doses in organs and tissues at risk for SMN, especially in the lungs, colon, and breast tissues.

Randomized, Prospective, Open-label Phase III Trial Comparing Mebo Ointment With Biafine Cream for the Management of Acute Dermatitis During Radiotherapy for Breast Cancer.

PURPOSE: Acute radiation dermatitis is a common side-effect of radiotherapy in breast cancer and has a profound impact on patients' quality of life, due to pain and discomfort. The aim of this study is to compare the effect of ß-sitosterol (Mebo) ointment to trolamine (Biafine) cream for the prevention and treatment of radiation dermatitis in breast cancer patients receiving adjuvant radiation therapy. MATERIALS AND METHODS: This is a prospective open-label randomized phase III study developed to assess the efficacy of 2 topical agents used for management of acute radiation dermatitis. Female breast cancer patients who needed a course of radiation therapy in our institution were enrolled and randomized into 2 groups 1 with Mebo ointment and 1 with Biafine cream. Both medications were applied twice per day during the whole period of treatment and skin reactions and related symptoms were assessed weekly during the entire course. Grading of skin reactions was done according to the Radiation Therapy Oncology Group grading system. RESULTS: Between September 2015 and May 2017, a total of 161 patients were recruited for this trial. Mean age was similar for both groups (50.19±12.57 vs. 51.73±11.23, respectively, P=0.41). All other patients and treatment characteristics were similar in both groups, except for the use of boost (82.7% in the Biafine group vs. 36.7% in Mebo group, P=0.012). Analysis was done for reactions recorded before the beginning of the boost and for the entire course including the boost. Using univariate and multivariate analysis, there was no significant difference in grades 2 and 3 dermatitis between the 2 groups. However, the incidence of severe pruritus and severe local skin pain were both significantly reduced in the Mebo group (14.1% in Biafine vs. 2.9% in Mebo, P=0.016 for pruritus and 11.5% vs. 1.4%, respectively, P=0.02 for severe pain). CONCLUSIONS: This study showed no difference between Mebo and Biafine in the incidence and severity of breast skin dermatitis during radiation therapy. However, the use of Mebo ointment was associated with decreased severe pruritus and pain which could positively affect patient comfort and quality of life.

Prophylactic Cranial Irradiation in Patients With Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: We systematically reviewed the literature for trials addressing the efficacy of prophylactic cranial irradiation (PCI) in patients with non-small-cell lung cancer (NSCLC) treated with a curative intent. METHODS: Randomized controlled trials (RCT) comparing PCI to no PCI in patients with NSCLC treated with a curative intent were eligible for inclusion. We searched EMBASE, MEDLINE, PubMed, and CENTRAL between 1946 and July 2016. We also received continual search alerts from PubMed through September 2017. Search terms included "non-small-cell lung carcinoma," "cranial irradiation," and "randomized controlled trials." We conducted meta-analyses using random-effects models for relative measures of treatment effect for the incidence of brain metastasis, overall survival (OS), and disease-free survival (DFS). We used Parmar's methodology to derive hazard ratios (HR) when not explicitly stated in RCTs. We narratively synthesized data for the impact of PCI on quality of life (QoL) and neurocognitive function (NCF). We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. RESULTS: Out of 3,548 citations captured by the search strategy, we retained 8 papers and 1 abstract, reporting on 6 eligible trials. Patients who received PCI had a significant reduction in the risk of developing brain metastases as compared with patients who did not [relative risk (RR) = 0.37; 95% confidence interval (CI): 0.26-0.52; moderate quality evidence]. However, there was no OS benefit (HR = 1.08, 95% CI: 0.90-1.31; moderate quality evidence). Sensitivity analysis excluding older studies did not show substantively different findings. DFS was reported in the two most recent trials that included only stage III patients. There was significant improvement in DFS with PCI (HR = 0.67; 95% CI: 0.46-0.98; high quality evidence). Two studies that reported on QoL reported no statistically significant differences. There was no significant difference in NCF decline in the only study that reported on this outcome, except in immediate and delayed recall, as assessed by the Hopkins Verbal Learning Test. CONCLUSION: There is moderate quality evidence that the use of PCI in patients with NSCLC decreases the risk of brain metastases, but does not provide an OS benefit. However, data limited to stage III patients suggests that PCI improves DFS, with no effect on QoL.

Nadir PSA is a strong predictor of treatment outcome in intermediate and high risk localized prostate cancer patients treated by definitive external beam radiotherapy and androgen deprivation.

BACKGROUND: The aim of this study is to investigate the effect of tumor characteristics and parameters of treatment response in predicting biochemical disease-free survival (BFS) for patients with intermediate or high risk prostate cancer treated by combined definitive external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT). METHODS: Between June 1995 and January 2015, 375 patients with localized prostate cancer and a National Comprehensive Cancer Network (NCCN) intermediate or high risk categories were treated by definitive EBRT and ADT. Median duration of androgen blockade was 10 months (range: 3-36 months); Median radiation dose was 72 Gy (Range: 70-78 Gy). Median follow-up time was 5.8 years (range: 0.8-16.39 years). The main study endpoint was biochemical disease free survival (BFS). RESULTS: Forty seven patients (12.5%) developed biochemical recurrence (BCR) during the observation period. Monovariate analysis identified baseline PSA (bPSA) (p = 0.024), T-stage (p = 0.001), Gleason's score (GS) (p = 0.042), radiation dose (p = 0.045), PSA pre-radiation therapy (p = 0.048), and nadir PSA (nPSA), (p < 0.001) as significant variables affecting BCR. The receiver operating characteristic (ROC) curve identified a nPSA of 0.06 ng/ml as optimal cut-off value significantly predicting the patients' risk of BCR (p < 0.001). Multivariate cox regression analysis revealed T-stage, GS, and nPSA as independent variable affecting BFS, while bPSA, age, and radiation dose were not. CONCLUSION: Nadir PSA at 0.06 is a strong independent predictor of BFS in patients with intermediate or high risk prostate cancer treated by definitive EBRT and ADT.

Inter-Institutional Comparison of Personalized Risk Assessments for Second Malignant Neoplasms for a 13-Year-Old Girl Receiving Proton versus Photon Craniospinal Irradiation.

Children receiving radiotherapy face the probability of a subsequent malignant neoplasm (SMN). In some cases, the predicted SMN risk can be reduced by proton therapy. The purpose of this study was to apply the most comprehensive dose assessment methods to estimate the reduction in SMN risk after proton therapy vs. photon therapy for a 13-year-old girl requiring craniospinal irradiation (CSI). We reconstructed the equivalent dose throughout the patient's body from therapeutic and stray radiation and applied SMN incidence and mortality risk models for each modality. Excluding skin cancer, the risk of incidence after proton CSI was a third of that of photon CSI. The predicted absolute SMN risks were high. For photon CSI, the SMN incidence rates greater than 10% were for thyroid, non-melanoma skin, lung, colon, stomach, and other solid cancers, and for proton CSI they were non-melanoma skin, lung, and other solid cancers. In each setting, lung cancer accounted for half the risk of mortality. In conclusion, the predicted SMN risk for a 13-year-old girl undergoing proton CSI was reduced vs. photon CSI. This study demonstrates the feasibility of inter-institutional whole-body dose and risk assessments and also serves as a model for including risk estimation in personalized cancer care.

Complete response of brain metastases from breast cancer overexpressing Her-2/neu to radiation and concurrent Lapatinib and Capecitabine.

Breast cancers that overexpress the human epidermal growth factor receptor 2 (HER-2) have a predilection to metastasize to the brain. Therapeutic options for brain metastases with systemic therapy remain a challenge in those patients since targeted and chemotherapeutic agents have limited penetration through the blood-brain barrier. Here we report the case of a patient with brain metastases from breast cancer overexpressing HER-2 who achieved a complete radiologic response after treatment by radiation and concurrent Lapatinib and Capecitabine.

A phase II randomized trial comparing radiotherapy with concurrent weekly cisplatin or weekly paclitaxel in patients with advanced cervical cancer.

PURPOSE/OBJECTIVE: This is a prospective comparison of weekly cisplatin to weekly paclitaxel as concurrent chemotherapy with standard radiotherapy for locally advanced cervical carcinoma. MATERIALS/METHODS: Between May 2000 and May 2004, 31 women with FIGO stage IB2-IVA cervical cancer or with postsurgical pelvic recurrence were enrolled into this phase II study and randomized to receive on a weekly basis either 40 mg/m² Cisplatin (group I; 16 patients) or 50 mg/m² paclitaxel (group II; 15 patients) concurrently with radiotherapy. Median total dose to point A was 74 Gy (range: 66-92 Gy) for group I and 66 Gy (range: 40-98 Gy) for group II. Median follow-up time was 46 months. RESULTS: Patient and tumor characteristics were similar in both groups. The mean number of chemotherapy cycles was also comparable with 87% and 80% of patients receiving at least 4 doses in groups I and II, respectively. Seven patients (44%) of group I and 8 patients (53%) of group II developed tumor recurrence. The Median Survival time was not reached for Group I and 53 months for group II. The proportion of patients surviving at 2 and 5 years was 78% and 54% for group I and 73% and 43% for group II respectively. CONCLUSIONS: This small prospective study shows that weekly paclitaxel does not provide any clinical advantage over weekly cisplatin for concurrent chemoradiation for advanced carcinoma of the cervix.

Modification and implementation of NCCN guidelines on non-small cell lung cancer in the Middle East and North Africa region.

A lung cancer committee from the Middle East and North Africa (MENA) region was established to modify the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Non-Small Cell Lung Cancer to create a platform for standard care in the region. The committee comprised different experts in thoracic oncology from the region, including the disciplines of medical and clinical oncology, radiation oncology, thoracic surgery, pulmonary medicine, radiology, and pathology. The committee reviewed version 2 of the 2009 NCCN Guidelines on Non-Small Cell Lung Cancer and identified recommendations requiring modification for the region using published evidence and relevant experience. These suggested modifications were discussed among the group and with a United States-based NCCN expert for approval. The recommended modifications, with justification and references, were categorized based on the NCCN Guidelines flow. This article describes these recommended modifications. The process of adapting the first NCCN-based guidelines in the region is a step toward helping to improve lung cancer care in the region and encouraging networking and collaboration.

Extraneural metastases from cranial meningioma: a case report.

Extracranial metastases from brain meningiomas is a rare, but well-documented entity. Metastases occur mostly in the lungs, pleura and liver, but may also affect lymph nodes and bones. We report here on a patient who was treated for an atypical brain meningioma with multiple surgeries and multiple sessions of stereotactic radiosurgery with good control of his brain disease. Thirteen years after diagnosis, he developed bilateral large sacroiliac and abdominal metastases.

Duodenal mucosa-associated lymphoid tissue lymphoma successfully treated by radiation therapy.

Duodenal mucosa-associated lymphoid tissue (MALT) lymphoma is very rare, and little is known about its clinical characteristics, endoscopic and endosonographic features, and treatment. We hereby report a case of duodenal MALT lymphoma successfully treated by radiation therapy (RT). The patient was referred to us with epigastric pain and positive fecal occult blood testing. His symptoms failed to resolve with eradication therapy for a Helicobacter pylori infection that was diagnosed by a gastric biopsy performed elsewhere. Endoscopy at our institution revealed hypertrophy of the duodenal folds with erosions involving a third of the circumference few centimeters beyond the ampulla of Vater. Histopathologic and immunophenotypic features were consistent with a MALT lymphoma. There was no evidence of a H. pylori infection by gastric biopsy and urea breath test. Computed tomography scan of the abdomen and pelvis was normal. Endoscopic ultrasound showed thickening of the duodenal wall and hypoechoic infiltration into the submucosal layer. The patient was treated with RT with a complete response. Two and a half years later, he remains in complete clinical, endoscopic, and histopathologic remission. This case illustrates the importance of RT in patients with duodenal MALT lymphoma whose disease did not respond to H. pylori eradication.

Breast cancer patients with 10 or more involved axillary lymph nodes treated by multimodality therapy: influence of clinical presentation on outcome.

PURPOSE: To analyze tumor control and survival for breast cancer patients with 10 or more positive lymph nodes without systemic disease, treated by adjuvant radiation alone or combined-modality therapy. METHODS AND MATERIALS: We reviewed the records of 309 consecutive patients with these characteristics who received locoregional radiotherapy (RT) at our institution. The majority of patients had clinical Stage II or IIIA-B disease (43% and 48%, respectively). The median number of positive axillary lymph nodes was 15 (range, 10-78). Adjuvant therapy consisted of RT alone, with or without chemotherapy, tamoxifen, and/or ovarian castration. RESULTS: The overall 5-year and 10-year disease-free survival (DFS) rates were 20% and 7%, respectively. Median DFS was higher for patients with Stage I-II compared with those with Stage IIIABC (28 vs. 19 months; p = 0.006). Median DFS for patients aged

Effects of young age at presentation on survival in breast cancer.

BACKGROUND: Young age remains a controversial issue as a prognostic factor in breast cancer. Debate includes patients from different parts of the world. Almost 50% of patients with breast cancer seen at the American University of Beirut Medical Center (AUBMC) are below age 50. METHODS: We reviewed 1320 patients seen at AUBMC between 1990 and 2001. We divided them in three age groups: Below 35, 35-50, and above 50. Data and survival were analyzed using Chi-square, Cox regression analysis, and Kaplan Meier. RESULTS: Mean age at presentation was 50.8 years. 107 patients were below age 35, 526 between 35-50 and 687 patients above age 50. Disease stages were as follows: stage I: 14.4%, stage II: 59.9%, stage III: 20% and stage IV: 5.7%. Hormone receptors were positive in 71.8% of patients below 35, in 67.6% of patients 35-50 and in 78.3% of patients above 50. Grade of tumor was higher as age at presentation was lower. More young patients received anthracycline-based adjuvant chemotherapy. Of hormone receptor-positive patients, 83.8% of those below age 35 years, 87.76% of those aged 35-50 years, and 91.2% of those aged above 50 years received adjuvant tamoxifen. The mean follow up time was 3.7 +/- 2.9 years. Time to death was the only variable analyzed for survival analysis. Excluding stage IV patients, tumor size, lymph node, tumor grade and negative hormone receptors were inversely proportional to survival. Higher percentage of young patients at presentation developed metastasis (32.4% of patients below 35, as compared to 22.9% of patients 35-50 and 22.8% of patients above 50) and had a worse survival. Young age had a negative impact on survival of patients with positive axillary lymph nodes, and survival of patients with positive hormonal receptors, but not on survival of patients with negative lymph nodes, or patients with negative hormonal receptors. CONCLUSION: Young age at presentation conferred a worse prognosis in spite of a higher than expected positive hormone receptor status, more anthracycline-based adjuvant chemotherapy and equivalent adjuvant tamoxifen hormonal therapy in younger patients. This negative impact on survival was seen in patients with positive lymph nodes and those with positive hormonal receptors.

A clinical phase II study of cisplatinum and vinorelbine (PVn) in advanced breast carcinoma (ABC).

OBJECTIVES: The effectiveness of cisplatinum and vinorelbine (PVn) as a salvage regimen in patients with metastatic breast cancer was reported in previous studies. This report is a pilot study assessing the antitumor efficacy and safety of this regimen as first line therapy for advanced breast cancer patients. METHODS: Thirty-five patients were enrolled: 22 with metastatic breast carcinoma and 13 with locally advanced breast carcinoma (stage III). A total of 4 cycles of PVn were planned. After the 4th cycle, patients with metastatic breast cancer received vinorelbine biweekly until disease progression or for a total of 12 cycles, whereas those with locally advanced breast cancer who showed complete or partial response underwent curative surgery. RESULTS: The overall response rate of our whole population was 74.29%. For the metastatic breast cancer group, the overall response rate was 64%, with a median survival of 19 months (range 2-36). For the locally advanced breast cancer group, the overall response rate was 92.3% with a median time to disease progression of 26 months (range 25-27). Toxicity was acceptable, and no treatment-related mortality was encountered. CONCLUSIONS: PVn is effective as first line treatment of advanced breast cancer with overall response rate of 64% in metastatic breast cancer and 92.3% in locally advanced breast cancer, and acceptable toxicity.

Trauma-associated growth of suspected dormant micrometastasis.

BACKGROUND: Cancer patients may harbor micrometastases that remain dormant, clinically undetectable during a variable period of time. A traumatic event or surgery may trigger the balance towards tumor growth as a result of associated angiogenesis, cytokine and growth factors release. CASE PRESENTATION: We describe a patient with non-small lung cancer who had a rapid tumor growth and recurrence at a minor trauma site of his skull bone. CONCLUSION: This case is an illustration of the phenomenon of tumor growth after trauma or surgery and its associated cellular mechanisms. This phenomenon deserves further investigation and study.

Nasopharyngeal cancer in the Middle East: experience of the American University of Beirut Medical Center.

PURPOSE: To review the data of nasopharyngeal carcinoma (NPC) treated at the American University of Beirut Medical Center and reflect on the characteristics and treatment outcome of NPC in the Middle East compared with those of Western countries and countries in which NPC is endemic. METHODS AND MATERIALS: Between 1966 and 1998, 151 patients with the diagnosis of NPC received definitive radiotherapy at the American University of Beirut Medical Center. Of the 151 patients, 111 were males (gender ratio, 2.78); the median age was 45 years (range, 11-75 years). Most (95%) patients (n = 144) were Lebanese, 4 were Syrians, and 3 were from the Gulf countries. Most (60%) patients (n = 91) had Stage IV disease, 27% had Stage III, and 13% had Stage I or II disease; nodal disease was present in 117 patients (77%). The pathologic type was predominantly lymphoepithelioma or World Health Organization type III (95 patients, 63%). Treatment consisted of definitive radiotherapy alone for 116 patients (77%). All others received induction chemotherapy, primarily with cisplatin-containing regimens. The median radiation dose was 66 Gy (range, 47-73 Gy) to the primary and 67 Gy (range, 49-85 Gy) to involved neck nodes given at 2 Gy/fraction. The average follow-up was 3.02 years (range, 0.1-24.5 years). RESULTS: The 5-year and 10-year disease-free survival (DFS) rate was 46%. Using univariate analyses, the following factors significantly affected DFS: node size (<3 vs. 3-6 vs. >6 cm; p = 0.01), node level (upper vs. mid vs. lower neck; p = 0.004), and duration of radiotherapy (p = 0.002). However, T stage, age, gender, radiation dose, use of chemotherapy, and histologic features had no statistically significant influence on DFS. The actuarial rate of local control at 5 and 10 years was 81% and 73%. T stage, N stage, and histologic features were statistically significant variables for local control in the univariate analyses. Using a Cox regression model, N stage (N1-N2 vs. N3; relative risk 2.09, p = 0.004) was identified as an independent variable for DFS, and N stage and pathologic features were identified as independent variables for local control. The actuarial rate of distant metastases was 32% at both 5 and 10 years. Distant metastases were only affected by N stage (upper-mid vs. lower neck; p = 0.004). Six patients (4%) were reported to have Grade 4 late complications. CONCLUSION: Our results indicate that the characteristics of NPC patients in Lebanon and their parameters of outcome are comparable to those reported in Western series, particularly for the relative frequency and effect of lymphoepithelial histologic type. Because of potential confounding factors, no definite conclusions about induction chemotherapy could be drawn from this retrospective study.

Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation.

Point mutations and deletions in mitochondrial DNA (mtDNA) accumulate as a result of oxidative stress, including ionizing radiation. As a result, dysfunctional mitochondria suffer from a decline in oxidative phosphorylation and increased release of superoxides and other reactive oxygen species (ROS). Through this mechanism, mitochondria have been implicated in a host of degenerative diseases. Associated with this type of damage, and serving as a marker of total mtDNA mutations and deletions, the accumulation of a specific 4977-bp deletion, known as the common deletion (Delta-mtDNA(4977)), takes place. The Delta-mtDNA(4977) has been reported to increase with age and during the progression of mitochondrial degeneration. The purpose of this study was to investigate whether ionizing radiation induces the formation of the common deletion in a variety of human cell lines and to determine if it is associated with cellular radiosensitivity. Cell lines used included eight normal human skin fibroblast lines, a radiosensitive non-transformed and an SV40 transformed ataxia telangiectasia (AT) homozygous fibroblast line, a Kearns Sayre Syndrome (KSS) line known to contain mitochondrial deletions, and five human tumor lines. The Delta-mtDNA(4977) was assessed by polymerase chain reaction (PCR). Significant levels of Delta-mtDNA(4977) accumulated 72 h after irradiation doses of 2, 5, 10 or 20 Gy in all of the normal lines with lower response in tumor cell lines, but the absolute amounts of the induced deletion were variable. There was no consistent dose-response relationship. SV40 transformed and non-transformed AT cell lines both showed significant induction of the deletion. However, the five tumor cell lines showed only a modest induction of the deletion, including the one line that was deficient in DNA damage repair. No relationship was found between sensitivity to radiation-induced deletions and sensitivity to cell killing by radiation.

Chromosomal fragility syndrome and family history of radiosensitivity as indicators for radiotherapy dose modification.

Beside a few known radiosensitive syndromes, a patient's reaction to radiotherapy is difficult to predict. In this report we describe the management of a pediatric cancer patient presented with a family history of radiosensitivity and cancer proneness. Laboratory investigations revealed a chromosomal fragility syndrome and an increased cellular radiosensitivity in vitro. AT gene sequencing revealed no mutations. The patient was treated with reduced radiation doses to avoid the presumed increased risks of toxicity to normal tissues. The patient tolerated well the treatment with no significant acute or late radiation sequelae. Five years later, the patient remains both disease and complications free. While an accurate laboratory test for radiosensitivity is still lacking, assessments of chromosomal fragility, cell survival and clinical medicine will continue to be useful for a small number of patients.

Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2.

The BRCA1 and BRCA2 gene products are thought to play important roles in the processing of DNA damage. To assess whether heterozygous mutations in these genes are associated with cellular radiosensitivity, we performed an in vitro radiation clonogenic survival assay on dermal fibroblasts obtained from 8 sequence-proven BRCA heterozygotes (6 BRCA1, 2 BRCA2). These data were compared to results obtained from a previous set of 17 prospectively studied cancer patients who had a negligible risk for a BRCA mutation. In addition, results from radiation-induced chromatid break assay performed on lymphocytes obtained from 9 BRCA heterozygotes (8 BRCA1, 1 BRCA2) were compared to results from a control group of 18 women with no cancer history. Results from both assays suggested that cells containing a heterozygous mutation in BRCA1 or BRCA2 were more radiosensitive than controls. For the fibroblast studies, the mean surviving fraction at 2 Gy (SF2) for carriers was 0.279 vs. 0.348 for the control set (p = 0.007). For the lymphocyte studies, the mean number of chromatid breaks after 125 cGy of radiation was 0.79 breaks per cell for the carriers vs. 0.45 for the controls (p = 0.0005). There was no apparent difference in the radiosensitivity between cells with BRCA1 vs. BRCA2 mutations (p = 0.769), although the small sample size minimizes the certainty of this observation. These preliminary results are consistent with a relationship between a germline mutation in BRCA1 or BRCA2 and a hypersensitivity to radiation. This phenotype could possibly predispose to an increased risk of radiation-induced mutagenesis and carcinogenesis.