10547 Background: Large-scale screening for germ-line mutations that lead to the onset of disease in adulthood is possible owing to recent technical advances. The care of those with inherited predisposition to breast and ovarian cancer is now becoming a mainstream component of medical care. It is more difficult to identify those with Lynch Syndrome (LS) as various criteria (Amsterdam and Bethesda) have not proved definitive. An important development is the examination of tumor tissue to detect mismatch repair (MMR) protein loss using immunohistochemical (IHC) techniques. When coupled with family history those at risk of harbouring a mutation for LS can be identified. Once a mutation is identified predictive testing can be offered to family members, risk-reduction measures applied and mortality from colorectal cancer reduced. Methods: Screening for MMR protein expression (MLH1, MSH2, MSH6, PMS2) was planned on all colorectal cancer (CRC) cases using IHC on formalin-fixed tumor tissue from January 1st 2002. Local ethics committee approval was obtained and then written informed-consent from patients. Family history data was gathered from the index case or an appropriate relative. An aliquot of blood was stored from index cases for subsequent genetic screening if indicated by IHC analysis and genetic counseling. Results: 108 cases with CRC (62 male, 46 female, median age 59 years) from a potential total of 612 have been screened for MMR protein expression by a gastrointestinal pathologist and independently validated. Turn-around time for IHC analysis was 9 weeks. 5 patients (4.6%) had loss of MMR proteins, MSH2/MSH6- 2 cases, MSH6 alone- 1 case and MLH1/PMS2- 2 cases. All 5 have opted for genetic counselling and sequencing of relevant genes. Conclusion: These early results in an Irish cohort with CRC showing MMR loss in 4–5% of cases is consistent with other population findings. Microsatellite instability analysis is difficult, expensive and relatively unavailable. IHC, however, is an established technique in pathology departments and can be the cheapest and most reproducible approach to identify LS cases. IHC results along with robust family data can guide the genetic counseling process towards preventing deaths from CRC and other LS-associated cancers. No significant financial relationships to disclose.
BRCA1-mutant breast tumors are typically estrogen receptor alpha (ERα) negative, whereas most sporadic tumors express wild-type BRCA1 and are ERα positive. We examined a possible mechanism for the observed ERα-negative phenotype of BRCA1-mutant tumors. We used a breast cancer disease–specific microarray to identify transcripts that were differentially expressed between paraffin-embedded samples of 17 BRCA1-mutant and 14 sporadic breast tumors. We measured the mRNA levels of estrogen receptor 1 (ESR1) (the gene encoding ERα), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ERα protein expression was assessed in human breast cancer HCC1937 cells that were stably reconstituted with wild-type BRCA1 expression construct and in human breast cancer T47D and MCF-7 cells transiently transfected with BRCA1-specific short-interfering RNA (siRNA). Chromatin immunoprecipitation assays were performed to determine if BRCA1 binds the ESR1 promoter and to identify other interacting proteins. Sensitivity to the antiestrogen drug fulvestrant was examined in T47D and MCF-7 cells transfected with BRCA1-specific siRNA. All statistical tests were two-sided. Mean ESR1 gene expression was 5.4-fold lower in BRCA1-mutant tumors than in sporadic tumors (95% confidence interval [CI] = 2.6-fold to 40.1-fold, P = .0019). The transcription factor Oct-1 recruited BRCA1 to the ESR1 promoter, and both BRCA1 and Oct-1 were required for ERα expression. BRCA1-depleted breast cancer cells expressing exogenous ERα were more sensitive to fulvestrant than BRCA1-depleted cells transfected with empty vector (T47D cells, the mean concentration of fulvestrant that inhibited the growth of 40% of the cells [IC 40 ] for empty vector versus ERα: >10 −5 versus 8.0 × 10 −9 M [95% CI = 3.1 × 10 −10 to 3.2 × 10 −6 M]; MCF-7 cells, mean IC 40 for empty vector versus ERα: >10 −5 versus 4.9 × 10 −8 M [95% CI = 2.0 × 10 −9 to 3.9 × 10 −6 M]). BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ERα expression.
Summary Two patients presented with co-existing large cell immunoblastic and well-differentiated lymphocytic lymphomas. Prolonged remissions from the large cell lymphomas were achieved following intensive combination chemotherapy but both patients suffered relapses after many years. Previous reports have grouped such patients with those developing classical Richter's syndrome implying a uniformly poor prognosis. This report suggests that this is not the case. It was not possible with immunohistochemical stains to prove or disprove that these tumours had the same stem cell origins.
Seventy-nine platelet transfusions to 73 thrombocytopenic patients with cancer were analyzed to determine whether a platelet count obtained one hour after transfusion could help differentiate between alloimmunization and other clinical factors that result in rapid platelet destruction. These transfusions were selected because 18- to 24-hour increments were inadequate in response to fresh, random donor platelets. A corrected count increment (CI) (CI=[posttransfusion count—pretransfusion count]×body surface area [sq m]/platelets transfused×1011) at one hour of 10×103/μL or greater was associated with absence of lymphocytotoxic antibody, whereas increments of less than 10×103/μL were generally associated with high levels of strongly cytotoxic antibody. HLA-matched transfusions produced no improvement in increments when the previous one-hour CI had been 10×103/μL or greater, whereas in the other group significantly better increments were obtained. A one-hour posttransfusion count is a simple test that correlates well with the presence of antibody against HLA antigens, is valuable in predicting the need for HLA-matched platelets, and helps avoid wasteful, empirical use of such transfusions. (JAMA243:435-438, 1980)
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