Colorectal and Endometrial Cancer Risk and Age at Diagnosis in BLMAsh Mutation Carriers.

BACKGROUND: Biallelic BLM gene mutation carriers are at an increased risk for cancer, including colorectal cancer (CRC). Whether heterozygous BLM gene mutations confer an increased cancer risk remains controversial. OBJECTIVES: To evaluate CRC and endometrial cancer risk in BLM heterozygous mutation carriers. METHODS: Jewish Ashkenazim at high risk for colon or endometrial cancer and endometrial cancer cases unselected for family history were genotyped for the BLMAsh predominant mutation. RESULTS: Overall, 243 high-risk individuals were included: 97 men CRC patients (55.12 ± 12.3 years at diagnosis), 109 women with CRC (56.5 ± 13.7 years), 32 women with endometrial cancer (58.25 ± 13.4 years) and 5 women with both CRC and endometrial cancer. In addition, 120 unselected Ashkenazi women with endometrial cancer (64.2 ± 11.58 years) were genotyped. The BLMAsh mutation was present in 4/243 (1.65%) high-risk patients; 2 CRC (0.97%) 2 endometrial cancer (5.4%), and 1/120 unselected endometrial cancer patients (0.84%). Notably, in high-risk cases, BLMAsh mutation carriers were diagnosed at a younger age (for CRC 47.5 ± 7.8 years; P = 0.32 ; endometrial cancer 49.5 ± 7.7 years; P = 0.36) compared with non-carriers. CONCLUSIONS: Ashkenazi high risk CRC/endometrial cancer, and women with endometrial cancer have a higher rate of BLMAsh heterozygous mutation compared with the general population. BLMAsh heterozygous mutation carriers are diagnosed with CRC and endometrial cancer at a younger age compared with non-carriers. These observations should be validated and the possible clinical implications assessed.

Where to die? That is the question: A study of cancer patients in Israel.

OBJECTIVE: Most patients prefer to die at home, but barely 30% do so. This study examines the variables contributing to dying at home. METHODS: The participants were 326 cancer patients, of both genders, with a mean age of 63.25 years, who died from 2000 to 2008 and were treated by the palliative care unit of the Barzilai Hospital. Some 65.7% died at home and 33.4% in a hospital. The data were extracted from patient files. The examined variables were demographic (e.g., age, gender, marital status, ethnic background, number of years in Israel until death), medical (e.g., age at diagnosis, diagnosis, nature of last treatment, patient received nursing care, patient given the care of a social worker, patient had care of a psychologist, family received care of a social worker, patient had a special caregiver), and sociological (e.g., having insurance, having worked in Israel, living alone or with family, living with one's children, living in self-owned or rented house, family members working). RESULTS: The findings indicate that the chances of dying at home are higher if the patient is non-Ashkenazi, the family got social worker care, the patient lived in a self-owned house, the patient lived with his family, the family members worked, and the patient's stay in Israel since immigration was longer. Logistic regression showed that all the predictors together yielded a significant model accounting for 10.9-12.3% of the variance. SIGNIFICANCE OF RESULTS: The findings suggest that dying at home requires maintaining continued care for the patient and family in a community context.

Using a simple diary for management of nausea and vomiting during chemotherapy.

To help clinical staff make effective adjustments to patients' antiemetic therapy, the authors gave patients a nausea and vomiting diary to record their experiences. Use of the diary strengthened patients' sense of security, as well as trust between staff and patients, in addition to increasing the staff's sensitivity to cultural differences in their approach to cancer and chemotherapy. Most patients responded favorably to the opportunity to express their fears and anxieties in diary format.

The influence of early diagnosis of endometrioid endometrial cancer on disease stage and survival.

OBJECTIVE: To evaluate whether the presence or duration of uterine bleeding is associated with disease stage, and survival of patients with endometrioid endometrial carcinoma (EEC). METHODS: The records of 220 patients with EEC who underwent surgery were reviewed. The patients were divided into three groups according to the presence and duration of vaginal bleeding at the time of surgery. Group 1, without vaginal bleeding; group 2, vaginal bleeding up to 3 months; group 3, vaginal bleeding exceeding 3 months prior to surgery. Disease stage and survival were between the three groups. RESULTS: Of the 220 patients, 42 (19%) were asymptomatic; 95 (43%) had symptom duration of up to 3 months and 83 (38%) experienced bleeding for >3 months. There were no significant differences between groups 1, 2 and 3 regarding the proportion of patients with deep invasion in stage I (21, 24, 26%, p = 0.84; respectively), with grade 3 tumors (10, 13, 14%, p = 0.42; respectively) or with advanced stage disease (12, 14, 15%, p = 0.92; respectively). Survival analysis demonstrated a non-significant trend toward better survival in asymptomatic patients and in patients with a shorter duration of symptoms (p = 0.172). CONCLUSIONS: Diagnosis of EEC in asymptomatic patients or in patients with a short duration of bleeding is associated with comparable stage and survival.

Weekly topotecan for recurrent ovarian, fallopian tube and primary peritoneal carcinoma: tolerability and efficacy study--the Israeli experience.

OBJECTIVES: The purpose of this study was to assess the clinical activity and toxicity of weekly topotecan in a large cohort of epithelial ovarian (EOC), primary peritoneal (PPC), and tubal cancer patients. METHODS: Records of patients with recurrent EOC, PPC, and tubal cancer who were treated with weekly topotecan (4.0 mg/m on days 1, 8, and 15 on a 28-day cycle) after failure of more than 1 prior regimen were retrospectively reviewed in 8 centers in Israel. RESULTS: Two hundred four patients were evaluated for efficacy and toxicity. Median age was 62 years (range, 27-89 years); 121 (59.3%) were platinum sensitive. Patients were exposed to a median of 2 previous lines (range, 1-9), and 48.5% received only 1 prior chemotherapy regimen. Median follow-up was 15.5 months (range, 2.5-112 months). Overall response rate was 26.5%, of which 11 patients (5.4%) had complete response, and 43 patients (21.1%) had partial response. Clinical benefit rate (complete response + partial response + stable disease) was 65.7%. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.5-4.5 months). There was no significant difference between platinum-sensitive and platinum-resistant patients regarding response rate or progression-free survival. Median overall survival from disease diagnosis was 45.0 months (95% CI, 40.04-49.6 months) and 16.0 months (95% CI, 12.3-19.7 months) from initiation of topotecan therapy. Overall survival was significantly different between patients with platinum-sensitive and platinum-resistant disease (19.9 vs. 10.8 months, respectively, P = 0.003; 95% CI, 8.1-16.3 months). Multivariate analysis showed that only platinum sensitivity and topotecan line were associated with overall survival. Weekly topotecan was well tolerated-with only 16.7% of patients experiencing grade 3 to 4 hematologic toxicities. There were no other grade 4 toxicities, and only 6.9% grade 3 toxicities. CONCLUSIONS: In this large cohort of recurrent EOC, PPC, and tubal cancer, weekly topotecan was well tolerated with good clinical benefit rate, comparable to previous studies.

Adjuvant chemotherapy for breast cancer patients: patients' expectations and physicians' attitudes.

OBJECTIVE: Findings show that there is a certain degree of refusal on the part of breast cancer patients to undergo adjuvant therapy. Accordingly, the major goals of the study were, first, to learn more about the beliefs of breast cancer patients in regard to adjuvant therapy; second, to find out about the sources of the patients' beliefs; and third, to learn about the attitudes of oncologists concerning the same aspects of adjuvant therapy to which the patients' beliefs referred. METHOD: The participants were 92 breast cancer patients (mean age 61.2) and 57 doctors of both genders specialized in oncology or affiliated domains. Both groups were administered questionnaires referring to goals of adjuvant treatment, the chances of attaining these goals, side effects, and difficulty of the treatment. Doctors were specifically asked about the views they thought proper to communicate to patients in regard to the mentioned issues. Patients were also asked about whether they had doubts about the treatment and sources of information. RESULTS: The findings showed disparities between the views of patients and doctors in regard to goals, chances of attainment, side effects, and difficulty of treatment. Patients endorsed more goals than doctors and tended to assign to them lower chances of attainment. Doctors were divided in their views about whether to communicate the side effects and difficulties. SIGNIFICANCE OF RESULTS: The results reveal the importance of outlining goals for patients undergoing adjuvant treatment and the disagreements between doctors about what should be communicated to patients, and highlight the complexity of providing to patients information that is both scientifically correct and emotionally helpful.

Simultaneous Breast Cancer and Kaposi's Sarcoma Complicating Rheumatoid Arthritis.

For a number of years we have been following the medical literature to find a relationship between chronic treatment with methotrexate and breast cancer occurrence, because we had had in our clinic a female patient who had had two consecutive cancers following methotrexate treatment for rheumatoid arthritis (RA). We were much surprised to find in some papers that breast cancer incidence is low in women with RA. Since then, we have found several papers explaining the low incidence of breast cancer among women being under NSAIDs, but those papers are not univocal. Methotrexate is a known antifolate agent and it has been demonstrated that dietary shortage of folate is a risk factor for breast cancer development.

BRCA germline mutations in women with uterine serous carcinoma--still a debate.

OBJECTIVE: To determine the incidence of BRCA1 and BRCA2 mutations in an enlarged series of uterine serous carcinoma (USC) patients and to determine whether patients with USC are associated with a personal or familial history of breast or ovarian carcinoma. METHODS: A cohort of all consecutive patients with diagnosed USC was identified for 9 years. Family pedigrees were drawn as far back and laterally as possible. In all patients, genomic DNA was extracted from peripheral blood samples and analyzed for the 3 mutations common in Ashkenazi Jewish patients. All patients went through total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Tubal, ovarian, and peritoneal carcinoma were ruled out clinically and pathologically in all patients. RESULTS: Of 51 consecutive patients with USC in Ashkenazi Jews studied, we identified 13 patients (25.5%) who were previously found to have breast carcinoma, 17 patients (33.3%) who had a first-degree relative with breast or ovarian carcinoma, and 8 patients (15.7%) who were found to be carriers of 1 of the 3 BRCA germline mutations. CONCLUSIONS: This series of USC patients, the largest consecutive series to date, suggests a higher incidence of BRCA carriers among Ashkenazi Jews as compared with the general population. This high rate of BRCA germline mutations in USC patients coupled with a high rate of personal and familial cancer histories may suggest that USC is associated with the hereditary breast-ovarian syndrome. This potential association of USC to the BRCA-associated cancer spectrum may have implications for the clinical management and intervention of unaffected BRCA1-2 germline mutation carriers. However, at the current time, there are insufficient data to provide evidence-based guidelines regarding the optimal timing or specific intervention to prevent cancers in these high-risk women.

The rate of the predominant Jewish mutations in the BRCA1, BRCA2, MSH2 and MSH6 genes in unselected Jewish endometrial cancer patients.

OBJECTIVES: The genes associated with familial Endometrial Cancer (EC) are largely unknown. While EC is an integral part of Hereditary Non-Polyposis Colon Cancer, there is an ongoing debate if EC is indeed overrepresented in hereditary breast/ovarian cancer families. METHODS: Unselected Jewish women with EC who were diagnosed from January 1982 to January 2008 were genotyped for the predominant mutations in Jewish individuals in BRCA1 (185delAG, 5382InsC, Tyr978X) BRCA2 (6174delT), MSH2 (A636P, 324delCA) and MSH6 (c.3984_3987dup). RESULTS: Overall, 289 Jewish women with EC were included, the majority (217-75%) were Ashkenazim. Mean age at diagnosis was 62.6 ± 12 years, the most common histopathology was type I (endometrioid carcinoma) (80.4% of participants) with 29 having type II (Uterine papillary serous and clear cell cancer) Most patients (85.4%) had stage 1 disease by the FIGO staging. Five women (1.7%-2.3% of the Ashkenazim) carried either the BRCA1*185delAG (n = 4) or BRCA2*6174delT (n = 1) mutations, a rate similar with that of the general Ashkenazi population. Notably, none of 34 women with type II EC carried any BRCA1/BRCA2 mutations. Four (1.8%) and three (1.4%) of the 217 Ashkenazim patients harbored the c.3984_3987dup, A636P, MSH6 and MSH2 mutations, respectively, and 1/72 (1.4%) of the non-Ashkenazi patients harbored the 324delCA MSH2 mutation. Three of 42 (7.1%) women with EC diagnosed < 50 years carried either BRCA1 MSH6 or MSH2 mutations. CONCLUSIONS: Our data do not support screening for BRCA1/2 mutations in consecutive EC patients.

The leucine rich repeat kinase 2 (LRRK2) G2019S substitution mutation. Association with Parkinson disease, malignant melanoma and prevalence in ethnic groups in Israel.

BACKGROUND: A single missense mutation (G2019S) in the leucine rich repeat kinase 2 (LRRK2) gene has been reported to be prevalent among Ashkenazi Jewish patients with Parkinson disease (PD). An association between malignant melanoma (MM) and PD was also recently reported. The nature of this association is still elusive. OBJECTIVE: To evaluate the rate of the G2019S(*) LRKK2 mutation among ethnically diverse, Jewish PD patients, MM patients, and Ashkenazi, Iraqi and Moroccan healthy controls. PATIENTS AND METHODS: Overall, 242 Jewish PD patients (155 Ashkenazim and 7 of mixed origin) and 169 Jewish MM patients (142 Ashkenazim) were genotyped for the G2019S mutation. In addition, 900 healthy ethnic Jewish controls (300 Ashkenazim, 300 Moroccans and 300 Iraqis) were similarly analyzed. Genotyping was performed using PCR amplification followed by restriction digest and gel electrophoresis. Statistical analysis was done using the Chi square test. RESULTS: Overall 19/242 (7.9 %) of the PD patients (16/155 of Ashkenazim, 10.3 %; 3/87 of non-Ashkenazim, 3.4 %) harbored the G2019S LRKK2 mutation. The age at diagnosis of PD in mutation carriers was 60.6 +/- 10.9 years compared with an age at diagnosis of 61.1 +/- 13.4 years in non-carriers (p = 0.87). Nine of 38 familial Ashkenazi PD patients (23.68 %) carried the mutation, as did 2/169 MM patients (1.2 %; 2/142, 1.4 % of the Ashkenazim). A single mutation carrier of Ashkenazi origin was detected among 900 controls (0.3 % of the Ashkenazi controls). CONCLUSION: The G2019S*LRKK2 mutation is significantly more prevalent in Ashkenazi PD patients than in controls (p = 1 x 10(-6)), it is less commonly detected in non-Ashkenazi affected individuals, and its contribution to MM predisposition in Jewish individuals needs to be explored further.

MC1R variant alleles and malignant melanoma risk in Israel.

To evaluate the contribution of MC1R variants to malignant melanoma risk in Israeli Jews, sequencing of the MC1R gene was performed in 132 melanoma patients and 184 ethnically matched controls. Overall, 22 MC1R variants were detected, two were novel (M73I and 496_497insG). Using age and sex-adjusted logistic regression, one specific variant, R151C, conferred significantly increased melanoma risk among Ashkenazim (OR=2.6, 95% CI: 1.3-5.3; p=0.05 after Bonferroni correction). A gene dosage effect was noted, with significantly increased melanoma risk being observed in subjects with at least two variants whether when all variants are pooled (OR=4.8, 95% CI: 2.0-11.2; p=0.002 after Bonferroni correction) or when red hair colour (RHC) variants and non-RHC variants are distinguished (OR=7.6, 95% CI: 2.8-20.3; p=0.0004 after Bonferroni correction). If further studies support these findings, the assessment of MC1R status may be useful in identifying Jewish Israeli individuals at high risk for melanoma.

Analysis of BRCA1/BRCA2 genes' contribution to breast cancer susceptibility in high risk Jewish Ashkenazi women.

BACKGROUND: Three mutations in BRCA1 (185delAG 5382InsC) and BRCA2 (6174delT) can be detected in a substantial proportion of Jewish Ashkenazi breast/ovarian cancer families. Family-specific pathogenic mutations in both genes can be detected in up to 5% of high risk Ashkenazim. The contribution of major gene rearrangements and seemingly pathogenic missense mutations to inherited breast cancer predisposition has never been systematically evaluated in Ashkenazim. MATERIAL AND METHODS: High risk, Jewish Ashkenazi women, non-carriers of the predominant Jewish BRCA1/BRCA2 mutations, were genotyped for major gene rearrangements in BRCA1/BRCA2 using Multiplex ligation-dependent probe amplification (MLPA), and for the occurrence rate of 6 seemingly pathogenic missense mutations in BRCA1 (R866C, R331S, R841W, Y179C, C61G, M1008I) using a modified restriction enzyme assay. RESULTS: Overall, 105 Jewish Ashkenazi high risk women, participated in the study: 104 with breast cancer [age at diagnosis (mean +/- SD) 51.05 +/- 11.13 years], one was affected with ovarian cancer (61 years). Two were found to carry the M1008I mutation in BRCA1 and none harbored any of the other missense mutations. MLPA reveled four changes (amplifications of exons 5, 17, 19 and 21) in BRCA1 in five patients, and six patients exhibited 4 MLPA-detectable abnormalities in BRCA2 (amplifications in exons 1b, 2, and deletions in exons 11a and 25). None of these abnormalities could be confirmed using quantitative PCR (qPCR) analysis. CONCLUSIONS: Major gene rearrangements involving BRCA1 BRCA2 contribute little to the burden of inherited predisposition of breast cancer in Ashkenazi Jews.

Complementary medicine regulations.

There is a need for regulations in applying complementary and alternative medicine methods, especially in the case of oncology patients.

Significance of lower uterine segment involvement in women with stage I endometrial adenocarcinoma.

OBJECTIVE: To determine whether lower uterine segment involvement (LUSI) correlates with recurrence and survival in women with stage I endometrial adenocarcinoma who do not receive postoperative radiotherapy on the basis of this histologic criterion. STUDY DESIGN: Eighty patients with endometrial adenocarcinoma stage I who underwent surgery between 1989 and 2002 were divided into 2 groups according to the presence of LUSI. Group 1 consisted of 25 patients with LUSI; group 2 consisted of 55 patients without LUSI. The 2 groups were compared with regard to prognostic factors and outcome measures. RESULTS: There were no statistically significant differences between the 2 groups with regard to the following parameters: age and proportion of patients who underwent complete surgical staging and postoperative adjuvant radiotherapy. Pathologic parameters of the 2 groups, such as histologic type, grade and deep myometrial invasion, were comparable. A greater proportion of patients with LUSI had capillary space-like involvement. The patients were followed for a median of 48 months (range, 11-168) from the date of surgery. The overall 5-year recurrence-free survival, disease-specific survival and overall survival rates were 91% (SE .04), 94% (SE .03) and 77% (SE .06), respectively. There was no significant difference between the two groups with regards to these measures (P < .05). CONCLUSION: In patients with state I endometrial cancer, the presence of lower uterine segment involvement does not correlate with their outcome.

Pain control in ambulatory cancer patients--can we do better?

To evaluate the degree of pain control among ambulatory cancer patients visiting the outpatient clinics of three oncology centers in south Israel, these patients were interviewed using the Brief Pain Inventory translated into Hebrew (BPI-Heb). Patients suffering from pain at least three times a week or reporting taking daily analgesics during the last two weeks were enrolled. Non-Hebrew speakers and patients too frail or ill were excluded. The study population included 218 subjects. Substantial pain was experienced by 77%, the majority was not adequately treated (81%), and 75% were undermedicated. The daily living activities of the majority of patients (64%) were moderately to severely impacted. Pain control was not associated with any of the sociodemographic or previous treatment profile variables, or by physicians' pain assessment. The physicians' and the patients' ratings of the extent to which pain interfered with the patients' activities fully agreed (+/-2) in fewer than half of the patients. Physicians estimated more severe pain levels, but underestimated its impact on everyday life. These data indicate that better pain control for ambulatory cancer patients is needed and that more information about patients' pain and its impact should be solicited. Further training of care providers is needed to improve the relief from cancer pain and the quality of life of patients.