Steven T. Brower

Frequency and Carrier Risk Associated with Common BRCA1 and BRCA2 Mutations in Ashkenazi Jewish Breast Cancer Patients

Based on breast cancer families with multiple and/or early-onset cases, estimates of the lifetime risk of breast cancer in carriers of BRCA1 or BRCA2 mutations may be as high as 85%. The risk for individuals not selected for family history or other risk factors is uncertain. We determined the frequency of the common BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in a series of 268 anonymous Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset. DNA was analyzed for the three mutations by allele-specific oligonucleotide hybridization. Eight patients (3.0%, 95% confidence interval [CI] 1.5%-5.8%) were heterozygous for the 185delAG mutation, two (0.75%, 95% CI 0.20-2.7) for the 5382insC mutation, and eight (3.0%, 95% CI 1.5-5.8) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be 36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5-5.8). For the 5382insC mutation, because of the low number of carriers found, further studies are necessary. The results differ markedly from previous estimates based on high-risk breast cancer families and are consistent with lower estimates derived from a recent population-based study in the Baltimore area. Thus, presymptomatic screening and counseling for these common mutations in Ashkenazi Jewish women not selected for family history of breast cancer should be reconsidered until the risk associated with these mutations is firmly established, especially since early diagnostic and preventive-treatment modalities are limited.

Malignant small bowel neoplasms: histopathologic determinants of recurrence and survival.

INTRODUCTION Small bowel neoplasms account for only a small percentage of gastrointestinal tumors, but their prognosis is one of the worst. PURPOSE This study examines the histopathology, treatment, recurrence, and overall survival of a group of patients with primary small bowel tumors. METHODS From 1970 to 1991, a retrospective review identified 73 patients with primary small bowel tumors. Four histologic groups were identified: 1) group 1, adenocarcinoma, 29 patients; group 2, lymphoma, 18 patients; group 3, sarcoma, 8 patients; and group 4, carcinoid, 18 patients. There were 44 men and 29 women. The median age was 57 years (range, 26 to 90). Median follow-up was 15 months. Survival analysis was by the Mantel-Cox and Breslow methods. RESULTS The most common, by type, was group 1, duodenum; group 2, jejunum; group 3, jejunum; and group 4, ileum. The preoperative diagnosis was made in only 14 patients. The median survival for adenocarcinomas and lymphomas was 13 months, 18 months for sarcomas, and 36 months for carcinoids. Curative resection could be achieved in 48 (65%) of 73 patients, and the median survival was significantly longer for this group (26 months vs. 11 months, p < 0.05). Of the 48 curative resections, 20 patients (42%) recurred: group 1, 8/19 (42%); group 2, 4/12 (33%); group 3, 4/13 (31%); group 4, 4/4 (100%). The median time to recurrence was 17 months, and the median survival after recurrence was 20 months. Adjuvant chemotherapy-radiation therapy did not alter survival in any group. CONCLUSIONS The preoperative diagnosis of small bowel tumors rarely is made because symptoms are vague and nonspecific. Surgical resection for cure results in improved survival. Recurrence is common and survival after recurrence is poor. Other treatment methods have no role in the management of these patients.

Predictors of nonsentinel lymph node metastasis in breast cancer patients

BACKGROUND In order to define a future subset of breast cancer patients in whom the axilla may be staged by sentinel lymph node biopsy alone, the conditions under which nonsentinel axillary lymph node metastases occur must be delineated. METHODS A prospective database including 212 breast cancer patients who underwent sentinel lymph node biopsy followed by completion axillary dissection at our institution was reviewed. A multivariate, logistic, stepwise regression was performed to evaluate the relationship between nonsentinel lymph node metastasis and patient age, primary tumor size, presence of lymphatic invasion, use of radioisotope to identify the sentinel node and degree of metastasis in the sentinel node. RESULTS Tumor size greater than 2 cm, lymphatic invasion of the primary tumor, macrometastasis in the sentinel node, and use of radioisotope all positively correlated independently with metastasis in the nonsentinel lymph node (P = 0.0001, P = 0.0483, P = 0.0008, P = 0.0271, respectively). CONCLUSIONS Predictors of nonsentinel axillary node metastasis exist and are important in defining those patients in whom a sentinel lymph node biopsy alone may not be adequate.

Standardization of Surgical and Pathologic Variables is Needed in Multicenter Trials of Adjuvant Therapy for Pancreatic Cancer: Results from the ACOSOG Z5031 Trial

BackgroundStandardization of surgical and pathologic techniques is crucial to the interpretation of studies evaluating adjuvant therapies for pancreatic cancer (PC).MethodsTo assess the degree to which treatment administered prior to enrollment of patients in trials of adjuvant therapy is quality controlled, the operative and pathology reports of patients in American College of Surgeons Oncology Group (ACOSOG) Z5031—a national trial of chemoradiation following pancreaticoduodenectomy (PD)—were rigorously evaluated. We analyzed variables with the potential to influence staging or outcome.Results80 patients reported to have undergone R0 (75%) or R1 (25%) pylorus-preserving (38%) or standard (62%) PD were evaluated. A search for metastases was documented in 96% of cases. The proximity of the tumor to the superior mesenteric vein was reported in 69%; vein resection was required in 9% and lateral venorrhaphy in 14%. The method of dissection along the superior mesenteric artery (SMA) was described in 68%, being ultrasonic dissection (17%), stapler (24%), and clamp and cut (59%). SMA skeletonization was described in 25%, and absence of disease following resection was documented in 24%. The surgeon reported marking the critical SMA margin in 25%; inking was documented in 65% of cases and evaluation of the SMA margin was reported in 47%. A range of 1–49 lymph nodes was evaluated. Only 34% of pathology reports met College of American Pathologists criteria.ConclusionsTrials of adjuvant therapy following PD suffer from a lack of standardization and quality control prior to patient enrollment. These data suggest areas for improvement in the design of multidisciplinary treatment protocols.

Awareness and attitudes concerning BRCA gene testing

AbstractBackground: The availability of a commercial test for the breast cancer susceptibility genes, BRCA1 and BRCA2, has generated interest in both the medical community and the general public. Methods: Patients and family members were approached in the waiting room and asked to fill out an anonymous questionnaire about their awareness of breast cancer genes and breast cancer gene testing, and their desire to be tested. χ2 analysis was used to analyze frequencies between groups. Results: A total of 354 women completed a questionnaire concerning the breast cancer genes BRCA1 and BRCA2. The very young, the very old, and African-Americans were the least informed in terms of awareness of the genes and the availability of testing for the breast cancer susceptibility genes. Jewish people, people with a college education or beyond, people earning more than

Breast carcinoma associated with pregnancy and lactation.

30,000 a year, and Caucasians were more aware of the genes and of testing for these genes. Interest in being tested was similar in all groups, except for participants over 60 and those who had only an elementary-school education. Conclusions: Information concerning the breast cancer susceptibility genes has not reached the general public uniformly. A concerted effort is needed if this information is to be passed on to those people at risk.

The Efficacy of Neoadjuvant Chemotherapy Compared to Postoperative Therapy in the Treatment of Locally Advanced Breast Cancer

The most common malignancy concurrent with pregnancy is breast cancer. Since an increasing number of women are electing to postpone pregnancy to their late thirties and forties, the incidence of breast cancer concurrent with pregnancy is increasing. This article critically reviews the incidence, unique diagnostic and therapeutic considerations, the natural history and ultimate prognosis of breast carcinoma associated with pregnancy and lactation.

Anti-tumor immunity induced by interleukin-12 gene therapy in a metastatic model of breast cancer is mediated by natural killer cells.

The current approach to the treatment of locally advanced breast cancer is sequential chemotherapy, surgery and/or radiation, and consolidation chemotherapy. Although significant tumor response is seen with this regimen, there are few studies that compare this approach to postoperative chemotherapy. The purpose of this study was to compare the disease-free and overall survival of patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and surgery to patients treated with surgery followed by adjuvant chemotherapy. Ninety-four patients with stage IIB, IIIA, and IIIB breast cancer were treated with a standardized chemotherapy regimen. The first group, 60 patients who were followed prospectively, was treated with neoadjuvant chemotherapy (NCT) consisting of vincristine, prednisone, cytoxan, methotrexate, and 5-FU (CVFMP) followed by surgery and consolidation chemotherapy with adriamycin. The second group, 34 patients evaluated retrospectively, had surgery followed by postoperative chemotherapy (PCT) with CVFMP followed by adriamycin. Overall median follow-up was 38 months. In the NCT group, 45/60 (75%) patients had a clinical response to induction therapy and the median reduction in tumor size was 50%. The rates of local recurrence, distant recurrence, and death from disease were similar in the two groups. The time to local recurrence was similar for the two groups. However, the median time to distant recurrence was shorter in the NCT group (19 month vs. 31 months, p = NS). Overall median survival among the NCT patients was shorter than for the PCT group (30 vs. 47 months, p = NS). The current study suggests that postoperative therapy is comparable to a neoadjuvant regimen in patients with locally advanced breast cancer with regard to local recurrence, distant recurrence, and overall survival.

Complications requiring reoperation following pancreatectomy

An intrahepatic tumor model for metastatic breast cancer was generated in syngeneic mice by direct inoculation of JC cells, a murine mammary adenocarcinoma cell line. Intratumoral administration of a recombinant adenoviral vector expressing the murine Interleukin-12 (ADV-mIL-12) resulted in significant reduction in the tumor volume compared to control vector. Tumor regression was also evident on histopathologic analysis of the liver, where inflammatory changes as opposed to nuclear atypia predominated after IL-12 vector treatment. There was a significant prolongation in the long term survival of IL-12 treated animals, with complete tumor rejection in 40% of the animals. In vivo depletion studies using specific monoclonal antibodies against the various lymphocyte subsets showed a significant reduction in long term survival after natural killer (NK) cell depletion. This suggests that the NK cell is a critical effector in the antitumor effect mediated by IL-12. These results strongly support the potential role of gene mediated cytokine therapy for the treatment of metastatic breastcancer.

Prognostic variables in invasive breast cancer: Contribution of comedo versus noncomedo in situ component

SummaryConclusionsIn this series, the overall reoperative rate following pancreatic surgery is 9%. Complications following pancreatectomy that require reoperation fall into four categories: hemorrhage, infectous, delayed gastric emptying, and anastomotic leak. A delay in the management of these types of complications can be fatal.BackgroundDespite the improvement in the morbidity and mortality rates associated with pancreatic resection, complications still arise that require surgical intervention. This study reviews the pancreatic surgical experience at a major medical center to determine the overall reoperative complication rate.Study DesignFrom 1985 to 1995, 107 patients underwent pancreatic resection. There were 50 pancreaticoduodenectomies, 20 total pancreatectomies, and 37 distal pancreatectomies for 102 periampullary or pancreatic cancers and five for chronic pancreatitis. The operative mortality rate was 6.5% and the morbidity rate was 43%. Ten patients (9%) developed complications that required reoperation.ResultsRe-exploration was performed in five patients for hemorrhage. Four patients had bleeding intra-abdominally and one had a suture line bleed. One patient developed a wound infection and fascial necrosis which necessitated reoperation. Three patients were explored for sepsis and one was found to have a pancreatic leak. One patient had persistent gastric outlet obstruction and he required conversion of the gastrojejunostomy to a Roux-en-y anastomosis. The mortality rate for re-exploration was 3/10 (30%).