Comprehensive Genetic Analysis of Druze Provides Insights into Carrier Screening.

BACKGROUND: Druze individuals, like many genetically homogeneous and isolated populations, harbor recurring pathogenic variants (PV) in autosomal recessive (AR) disorders. METHODS: Variant calling of whole-genome sequencing (WGS) of 40 Druze from the Human Genome Diversity Project (HGDP) was performed (HGDP-cohort). Additionally, we performed whole exome sequencing (WES) of 118 Druze individuals: 38 trios and 2 couples, representing geographically distinct clans (WES-cohort). Rates of validated PV were compared with rates in worldwide and Middle Eastern populations, from the gnomAD and dbSNP datasets. RESULTS: Overall, 34 PVs were identified: 30 PVs in genes underlying AR disorders, 3 additional PVs were associated with autosomal dominant (AD) disorders, and 1 PV with X-linked-dominant inherited disorder in the WES cohort. CONCLUSIONS: The newly identified PVs associated with AR conditions should be considered for incorporation into prenatal-screening options offered to Druze individuals after an extension and validation of the results in a larger study.

Oncology Treatments during the COVID-19 Pandemic in Israel: the ONCOR Study.

BACKGROUND: The increased susceptibility of cancer patients to coronavirus disease-2019 (COVID-19) infections and complications calls for special precautions while treating cancer patients during COVID-19 pandemics. Thus, oncology departments have had to implement a wide array of prevention measures. OBJECTIVES: To address issues associated with cancer care during the COVID-19 pandemic and to assess the implementation of measures aimed at containment of COVID-19 diffusion while allowing continuation of quality cancer care. METHODS: A national survey among oncology departments in Israel was conducted between 12 April 2020 and 14 April 2020. Eighteen heads of hospital-based oncology departments completed a self-report questionnaire regarding their institute's preparedness for treatment of cancer patients during the COVID-19 pandemic. RESULTS: In this national survey, prevention measures against COVID-19 spread were taken prior to patients' arrival and at arrival or while staying in the departments. Most participants (78-89%) reported using a quick triage of patients and caregivers prior to their entrance to the oncology units, limiting the entrance of caregivers, and reducing unnecessary visits to the clinic. Switching to oral therapies rather than intravenous ones when possible was considered by 82% and shortage in personal protective equipment was reported by five (28%) heads of oncology departments. Some differences between large and small/medium sized medical centers were observed regarding issues related to COVID-19 containment measures and changes in treatment. CONCLUSIONS: Oncology departments in Israel were able to prepare and adapt their services to guidelines and requirements related to the COVID-19 pandemic with little harm to their treatment capacity.

The yield of targeted genotyping for the recurring mutations in BRCA1/2 in Israel.

BACKGROUND: Hereditary breast cancer is predominantly associated with germline mutations in the BRCA1 or BRCA2 genes. A few recurring mutations in these genes were reported in ethnically diverse Jewish populations. Since 2013, most oncogenetic laboratories in Israel adopted a two-step approach for BRCA1/2 genotyping, where the first step is genotyping for 14 seemingly recurring mutations-first-pass genotyping. The aim of this study was to assess the yield of this targeted BRCA sequencing. METHODS: Clinical and genotyping data of all individuals who underwent oncogenetic counseling and first-pass BRCA genotyping at the Oncogenetic Service Sheba and Assaf Harofeh Medical Centers from 1 February 2013 to 30 June 2017 were reviewed. All study participants were unrelated to each other. RESULTS: Overall, 5152 oncogenetic tests were reviewed in the present study, of which 4452 had no a priori known familial mutation. The majority of participants (68.6%) were genotyped because of personal history of cancer; 20.6% were tested because of family history of cancer, and details for the remaining 10.7% were missing. Overall, 256/4452 (5.8%) carriers were detected, 141 BRCA1 and 115 BRCA2 mutation carriers. In 54% of cancer-free carriers, no clinically suspicious family history of cancer was ascertained. CONCLUSIONS: The currently used scheme of first-pass genotyping in Israel seems to have a high yield of mutation detection even in the absence of a significant family history of cancer. The challenge is to optimize the currently used targeted panel of common mutations and adjust it to the accumulating new data in the Israeli population.

Clinical outcomes in patients with node-negative breast cancer treated based on the recurrence score results: evidence from a large prospectively designed registry.

The 21-gene Recurrence Score® (RS) assay is a validated prognostic/predictive tool in ER + early-stage breast cancer. However, clinical outcome data from prospective studies in RS ≥ 11 patients are lacking, as are relevant real-life clinical practice data. In this retrospective analysis of a prospectively designed registry, we evaluated treatments/clinical outcomes in patients undergoing RS-testing through Clalit Health Services. The analysis included N0 ER + HER2-negative breast cancer patients who were RS-tested from 1/2006 through 12/2010. Medical records were reviewed to verify treatments/recurrences/survival. The cohort included 1801 patients (median follow-up, 6.2 years). Median age was 60 years, 50.4% were grade 2 and 81.1% had invasive ductal carcinoma; 48.9% had RS < 18, 40.7% RS 18-30, and 10.4% RS ≥ 31, with chemotherapy use of 1.4, 23.7, and 87.2%, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 0.8, 3.0, and 8.6%, for patients with RS < 18, RS 18-30 and RS ≥ 31, respectively; the corresponding 5-year Kaplan-Meier estimates for breast cancer death were 0.0, 0.9, and 6.2%. Chemotherapy-untreated patients with RS < 11 (n = 304) and 11-25 (n = 1037) (TAILORx categorization) had 5-year Kaplan-Meier estimates for distant recurrence risk/breast cancer death of 1.0%/0.0% and 1.3%/0.4%, respectively. Our results extend those of the prospective TAILORx trial: the 5-year Kaplan-Meier estimates for distant recurrence and breast cancer death rate for the RS < 18 patients were very low supporting the use of endocrine therapy alone. Furthermore, in chemotherapy-untreated patients with RS 11-25 (where TAILORx patients were randomized to chemoendocrine or endocrine therapy alone), 5-year distant recurrence rates were also very low, suggesting that chemotherapy would not have conferred clinically meaningful benefit.

Inherited predisposition to breast and ovarian cancer in non-Jewish populations in Israel.

PURPOSE: The contribution of genetic factors to cancer in non-Jewish populations in Israel is understudied. Yet the early, mostly premenopausal age at breast cancer diagnosis is suggestive of an inherited predisposition. METHODS: High-risk cancer cases of non-Jewish origin who were counseled at the Oncogenetics unit, Sheba Medical Center and the oncology institute at the Ziv medical center from January 1, 2000 to December 31 2016 were eligible. DNA extracted from leukocytes was subjected to massive parallel, next-generation sequencing using the Color Genomics platform. Data were analyzed for pathogenic and likely pathogenic mutations using existing pipelines. RESULTS: Overall, 68 cases, each representing a unique high-risk breast/ovarian family, were genotyped: 32 Druze, 26 Muslim Arabs, and 10 Christian Arabs. Fifty-nine had breast cancer (mean age at diagnosis 42.7 ± 7.6 years), and 9 had ovarian cancer (51.6 ± 9.7 years). Overall three pathogenic mutations one each in BRCA1, PALB2, and BRIP1 genes were detected mostly in Druze families. In addition, 29 variants of unknown significance were also detected, and in 36 cases no sequence variants were noted in any of the genotyped genes. CONCLUSION: The contribution of the known cancer susceptibility genes to the burden of inherited breast/ovarian cancer predisposition in non-Jews in Israel is modest. Other genes or molecular mechanisms account for the familial breast/ovarian cancer clustering in this population.

Complications of dysgerminoma: meeting the health needs of patients in conflict zones.

A symptom of prolonged conflict is the destruction of infrastructure and healthcare systems. While the need for acute trauma services is obvious in conflict zones, patients with chronic diseases also require care. This report describes the clinical course of a young teenage girl with a large mid pelvic tumour originating from the left ovary and reaching the umbilicus. She presented with acute abdominal pain and underwent surgery in a healthcare facility within a conflict zone. She was then transferred to a neighbouring country for continuing care. The tumour is malignant. After further surgery, she required chemotherapy and will need ongoing surveillance. She has since returned to her home country. It is doubtful that she will be able to access all the care she needs. We describe her healthcare needs and discuss the disastrous effects of conflict on meeting the health needs of civilian populations in war zones.

[EFFECT OF YOUNG AGE ON CLINICAL, PATHOLOGICAL FEATURES AND SURVIVAL OF PATIENTS WITH COLORECTAL CANCER].

BACKGROUND: Colorectal cancer is one of the most common malignancies in the Western World and in Israel. Most patients with colon cancer are older than 50 years of age. There is no consensus in the literature regarding the behavior of this disease in young patients. AIM: The aim of the present study is to compare clinical and ic pathological features of colon cancer between young and sold patients. METHODS: All clinical and pathological characteristics of 200 patients with colon cancer treated at our center during the period 2001-2006 were retrospectively reviewed. RESULTS: Twenty five patients (12.5%) were <50 years age (young patients) at diagnosis (mean age 41 years) and 175 were >50 years (mean age 68 years). Males were 56% of the young group and 60.1% of the old one. Arab patients were 52% of the young group, although their total number was 35 of the 200 patients. No significant difference was found in the stage of tumor at diagnosis between the two groups. Histopathological grade 3 tumors were found in 33.3% of young versus 7.7% in old patients. Surgery and chemotherapy were performed in 96% and 88% versus 95.4% and 69.7% in the two groups respectively. In a median follow-up period of 96 months, 35% of young patients died of their disease compared to 33.1% of the old patients. CONCLUSIONS: Other than histological grade, no difference was found in colon cancer features and survival of young compared to old patients. Further studies with higher numbers of patients are suggested to clarify our findings.

Anti-atherogenic properties of high-density lipoproteins in psychiatric patients before and after two months of atypical anti-psychotic therapy.

Some of the medications used for the management of schizophrenia are associated with clinically significant increases in weight and adverse alterations in serum lipid levels. The aim of the study was to investigate the effect of short-term (two months) treatment with atypical anti-psychotics on coronary heart disease risk factors, including the functional properties of high-density lipoprotein (HDL), in psychiatric patients. Nineteen patients diagnosed with schizophrenia, schizoaffective, and bipolar disorder and ten healthy volunteers were enrolled in the study. In the present study blood was drawn at baseline and after two months of atypical anti-psychotic treatment. Wilcoxon non-parametric-test was used to examine differences in the psychotic group before and two months after treatment.Waist circumference and oxidative stress in psychiatric patients were higher compared with the control group. Serum-mediated cholesterol efflux capacity was lower in psychotic patients compared to controls. Two months of anti-psychotic therapy was associated with increased abdominal obesity, decreased paraoxonase lactonase activity, but with no further change in serum-mediated cholesterol efflux from macrophages. Psychotic patients have low serum-mediated cholesterol efflux from macrophages as a parameter of HDL functionality. Atypical anti-psychotic treatment for two months increased metabolic derangements in these patients but without further decrement in serum-mediated cholesterol efflux.

Bleomycin-induced pneumonitis in three patients treated with chemotherapy for primary advanced seminoma.

PURPOSE: Bleomycin, etoposide and cisplatinum (BEP) comprise the most common regimen in the treatment of advanced testicular tumors, including seminoma. Common side effects are of hematologic, renal, and cardiovascular origin. One of the most prominent side effects is pulmonary toxicity attributed to bleomycin. We describe three patients who developed bleomycin-induced pneumonitis (BIP) with full recovery. METHODS: Pre-and post-treatment clinical, biochemical (including specific tumor markers) and radiological response assessment of 26 patients with primary advanced seminoma (AS) who were referred to our hospital for platinum-based chemotherapy between 1989-2010 are described. RESULTS: All patients were assessable for evaluation and all achieved long-term complete remission. Side effects were mild and manageable. Three patients developed bleomycin pulmonary toxicity after reaching cumulative doses of 180-240 units. All three patients presented with classical symptoms of non-productive cough, exertional dyspnea, and low-grade fever. Radiologically, the patients presented in the first months following completion of chemotherapy with initial bilateral interstitial and alveolar infiltrates, which worsened and progressed into consolidation and then regressed until total disappearance. All patients were treated with high-dose steroids and broad-spectrum antibiotics. CONCLUSION: AS is a very chemotherapy-responsive and sensitive disease, and approximately 90% of the patients enjoy complete regression of tumor masses and durable and sustained long-term survival with no evidence of disease. BIP may be a dangerous acute and chronic side effect, even in doses lower than 360 units. Considering the favorable clinical outcome of our patients, prompt diagnosis should be made and rapid medical intervention should be implemented.

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Genotyping of geographically diverse Druze trios reveals substructure and a recent bottleneck.

Druze individuals rarely marry outside their faith (often practicing consanguinity) and are thus believed to form a genetic isolate. To comprehensively characterize the genetic structure of the Druze population, we recruited and genotyped 40 parent-offspring trios from the Upper Galilee in Israel and the Golan Heights, attempting to capture different extended families (clans) across various geographical locations. Principal component (PC) and ADMIXTURE analyses demonstrated that Druze are close to, yet distinct from, other Middle-Eastern groups (Bedouins and Palestinians), supporting the Druze's Middle-Eastern origin and their recent genetic isolation. Reconstruction of the Druze demographic history using identical-by-descent (IBD) segments suggested an ≈15-fold reduction in population size taking place ≈22-47 generations ago, close to the documented time of the foundation of the Druze faith at the 11th century. Combining the Galilee and Golan Druze genotypes with previously published data on Druze from the Carmel (Israel) and Lebanon demonstrated that all four Druze communities are genetically distinct. The Lebanese group shared less IBD segments (within the group and with other groups) compared with the Israeli Druze and showed higher heterozygosity (suggesting less consanguinity), but was less diverse in PC space. These findings suggest complex recent and ancient demographic history of the Druze population.

Lack of HER-2 gene amplification and association with pathological and clinical characteristics of differentiated thyroid cancer.

Human epidermal growth factor receptor 2 (HER-2) is a well recognized prognostic and predictive factor in breast cancer. However, the role of HER-2 in thyroid cancer remains controversial. The aim of this study was to evaluate HER-2 expression in differentiated thyroid cancer (DTC) and determine whether there is an association with other clinical and pathological characteristics. A total of 69 patients with DTC were investigated, 58 of whom had papillary and 11 follicular carcinomas. HER-2 was detected by immunohistochemical examination on sections from formalin-fixed, paraffin-embedded tumor tissues. Tumors with HER-2 expression classed as +1 and +2 were retested with chromogenic in situ hybridization. Clinicopathological data were retrieved from the hospital records of the patients. HER-2 overexpression was found in 4 (6.9%) of the 58 patients with papillary carcinoma, whereas there was no HER-2 overexpression in any of the 11 cases of follicular carcinoma. There was no association of HER-2 expression with tumor size, pathological grade and cervical lymph node metastasis. In conclusion, there were no HER-2 positive cases of follicular carcinoma and the incidence of HER-2 overexpression in papillary carcinoma was very low. Thus, HER-2 cannot be used routinely as a prognostic or predictive factor in DTC. The expression of other epidermal growth factor receptors in DTC merits further investigation.

Radiotherapy for Stage IIA seminoma: The Northern Israel Oncology Center Experience, 1971-2010.

AIM: To evaluate treatment details, outcome, relapse rate and side-effects in Stage IIA seminoma irradiated and followed for a period of 39 years. BACKGROUND: Seminoma is a very radiosensitive disease and radiation therapy alone is able to achieve long-term disease-free survival, even in advanced Stage disease. Due to the lack of long-term prospective studies, it is of value to follow patients and try to determine the appropriate volume to be irradiated and the dose which can achieve total cure with minimal acute and chronic side-effects. PATIENTS AND METHODS: A retrospective review of 24 Stage IIA seminoma patients irradiated between 1971 and 2010 was performed. All patients underwent orchiectomy and meticulous clinical, biochemical and radiological staging. RESULTS: Median age at diagnosis was 36 years and median follow-up was 84 months. A majority of patients received the "hockey-stick" irradiation schedule (para-aortic lymph nodes and hemi-pelvis) to a total dose of 2250-2500 cGy and a boost to radiologically involved nodes of 500-1000 cGy. Treatment was well-tolerated. Twenty-one (88%) patients are alive with no evidence of disease. Two patients died due to unknown causes, while one patient died due to head of the pancreas carcinoma, most probably radiation-induced. CONCLUSIONS: In Stage II seminoma, radiotherapy can provide excellent results with low rates of toxicity. Reduction of total dose and size of fields without affecting the good results should be considered. Due to prolonged survival, awareness of second primary tumor is indicated.

Anaplastic variant of classical seminoma of the testis: northern Israel oncology center experience and brief review of literature.

OBJECTIVES: There are only sporadic reports on the clinical behavior and appropriate treatment of anaplastic seminoma. This retrospective study summarizes our experience with the anaplastic variant of classical (typical) seminoma. METHODS: Between 1986 and 2006, seven anaplastic seminoma patients were staged and treated at the Northern Israel Oncology Center. Staging procedures included meticulous physical and neurological examinations, complete blood count, full biochemistry profile, specific tumor markers, testicular ultrasound, and other radiological measures. All patients underwent inguinal orchiectomy and were staged properly. Six patients had stage I disease, and one patient had stage IIA disease. Patients were irradiated with doses ranging from 2,500 to 3,000 cGy, and the stage IIA patient received an additional 1,000 cGy boost to radiographically involved lymph nodes. RESULTS: After a mean follow-up of 11 years, six patients are alive with no evidence of disease. One patient died due to an unknown, non-oncological, cause, unrelated to his previous testicular tumor, while in complete remission. CONCLUSIONS: Despite the low patient numbers and the retrospective nature of our study, it can be concluded that radiotherapy treatment for early-stage anaplastic seminoma patients might achieve the same excellent survival as for classical seminoma. However, the general consensus achieved through large-scale studies suggests that active surveillance should be offered to all stage I seminoma patients, regardless of the pathologic variant.

Is salivary pH a marker of depression among older spousal caregivers for cancer patients?

The pH in saliva, which decreases due to the activation of the sympathetic nervous system, may serve as a biomarker of psychological distress in caregivers but has rarely been studied in this context. The aims are to examine the levels of salivary pH as a possible biomarker of depression among caregivers and whether depression mediates the association between caregiving status (cancer caregivers vs. non-cancer caregivers) and pH levels. Cross-sectional data were collected from 68 consecutive-sampled spouses of cancer patients, and 42 age-matched individuals. Lower levels of pH saliva were found among caregivers of cancer patients than in the comparison group. Being a caregiver, poor subjective health, higher depression, and lower mastery predicted lower pH levels. In addition, depression mediated the associations of mastery with pH levels. The study provides preliminary evidence that salivary pH may serve as an easily tested indicator of the stress of caregiving and its related depression.

Arterial elasticity in obese subjects with coronary slow flow phenomenon.

BACKGROUND: Coronary slow flow phenomenon (CSFP) is a functional and structural disease that is diagnosed by coronary angiogram. OBJECTIVES: To evaluate the possible association between CSFP and small artery elasticity in an effort to understand the pathogenesis of CSFP. METHODS: The study population comprised 12 patients with normal coronary arteries and CSFP and 12 with normal coronary arteries without CSFP. We measured conjugated diene formation at 234 nm during low density lipoprotein (LDL) oxidation, as well as platelet aggregation. We estimated, noninvasively, arterial elasticity parameters. Mann-Whitney nonparametric test was used to compare differences between the groups. Data are presented as mean +/- standard deviation. RESULTS: Waist circumference was 99.2 +/- 8.8 cm and 114.9 +/- 10.5 cm in the normal flow and CSFP groups, respectively (P = 0.003). Four patients in the CSFP group and one in the normal flow group had type 2 diabetes. Area under the curve in the oral glucose tolerance test was 22% higher in the CSFP than in the normal group (P = 0.04). There was no difference in systolic and diastolic blood pressure, plasma concentrations of total cholesterol, triglycerides, high density lipoprotein, LDL and platelet aggregation parameters between the groups. Lag time required until initiation of LDL oxidation in the presence of CuSO4 was 17% longer (P = 0.02) and homocysteine fasting plasma concentration was 81% lower (P = 0.05) in the normal flow group. Large artery elasticity was the same in both groups. Small artery elasticity was 5 +/- 1.5 ml/mmHg x 100 in normal flow subjects and 6.1 +/- 1.9 ml/mmHg x 100 in the CSFP patients (P = 0.02). CONCLUSIONS: Patients with CSFP had more metabolic derangements. Arterial stiffness was not increased in CSFP.

Cisplatin based chemotherapy in patients with advanced differentiated thyroid carcinoma refractory to I131 treatment.

PURPOSE: The purpose of the study was to evaluate the activity and toxicity of cisplatin based chemotherapy in patients with advanced differentiated thyroid cancer refractory to radioactive iodine (I131). PATIENTS AND METHODS: We retrospectively reviewed the records of 20 patients with advanced thyroid cancer treated with cyclophosphamide 500 mg/m(2) on day 1, doxorubicin 50 mg/m(2) day 1 and cisplatin 50 mg/m(2) day 1 of a 21 days cycle community-acquired pneumonia (CAP) or the same regimens without cyclophosphamide adriamycin and Platinum (AP). RESULTS: Median age of patients was 65 years (range 54-80). The majority of patients had lung metastases (60%). 4 (20%) patients achieved a partial response. Stable disease was achieved in 6 (30%) patients. Overall clinical response was 50%. Mean follow-up time was 8 months (range 4-17). Mean progression free survival was 6 months (range 3-12). Mean overall survival was 9 months (range 4-17). Patients with partial remission had a mean time to disease progression of 9 months. 4 (20%) patients had Grade 3 or 4 neutropenia. One patient had febrile neutropenia. Mild neuropathy was recorded in 5 (25%) of patients. There were no treatment related deaths. CONCLUSION: The combination of CAP is active in the treatment of advanced thyroid cancer with tolerable toxicity. This regimen may still be used in patients who could not be treated with targeted therapy or combined with antiangiogenic drugs in future studies.

Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations.

The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ~2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ~5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ~650 years ago, and into the Iraqi-Jewish community ~450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.

First-line treatment with capecitabine combined with irinotecan in patients with advanced colorectal carcinoma: a phase II study.

GOALS: To evaluate the efficacy and toxicity of capecitabine with irinotecan as first-line treatment in metastatic colorectal cancer. BACKGROUND: The addition of irinotecan to infusional 5 fluorouracil and leucovorin significantly improves the response rate and survival compared with 5 fluorouracil/leucovorin alone in metastatic colorectal cancer. Capecitabine with irinoteacan was reported to yield comparable results in phase II studies. STUDY: Patients older than 75 years, Eastern Cooperative Oncology Group ≤0 to 3, with measurable disease, no previous treatment for advanced disease, previous adjuvant chemotherapy >6 months, and adequate hepatic, renal, and hematological function were included. The treatment protocol included capecitabine 1000 mg/m twice daily given for 14 days (days 1 to 14) and irinotecan (100 mg/m) given on days 1 and 8. Treatment was repeated on day 21. RESULTS: Thirty patients were included. All were assessable for response and toxicity. Average age was 64 years, male/female ratio 20/10. Fifteen had liver metastases; 9 had abdominal metastases; 5 had liver and lymph nodes metastases; and 1 had lung metastases. The median number of cycles was 8. Grades III and IV diarrheas were observed in 20%, mild vomiting in 20%, grades III and IV leukopenia in 23%, and hand and foot syndrome grade III in 1 patient (3%). A complete response was achieved in 3 (10%) patients, a partial response in 16 (53%), disease stabilization in 6 (20%), and tumor progression in 5 (17%). Progression-free survival was 8.4 months. Overall survival was 19.3 months. CONCLUSIONS: This regimen was provided on an outpatient basis with significant antitumor activity and without the need for indwelling catheters and seems to be feasible for patients of all ages, with acceptable toxicity.

Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel.

The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations, respectively.