A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals.

Recent studies have identified mutations in the breast and (ovarian cancer susceptibility gene 2 (BRCA2), one which has been found in the germline of several males and one female affected with breast cancer. To establish the carrier frequency of this mutation in a large population of individuals affected with cancer, we evaluated constitutional DNA isolated from 83 individuals diagnosed with breast cancer and 93 diagnosed with ovarian cancer at any age, 42 of whom reported a family history of cancer. Using a simple allele-specific PCR-based nonradioactive method, we detected a total of eight individuals (4.5%) carrying a 1-bp deletion at nucleotide 6174 of the BRCA2 gene (6174delT). The age of disease onset in the mutant allele carriers was highly variable and typically late onset (41-72 years for breast cancer and 48-73 years for ovarian cancer). Evaluation of family histories for the eight mutant allele carriers revealed that several individuals had significant cancer histories that included, in addition to breast and/or ovarian cancer, an increased incidence of colon, esophageal, pancreatic, stomach, and hematopoietic cancers. Interestingly, seven of the eight individuals were of Ashkenazi Jewish descent. Haplotype data for the mutant allele carriers using markers spanning the region of the BRCA2 gene on chromosome 13ql2-ql3 suggest that only two of the confirmed Jewish Ashkenazi individuals share a single common ancestry, indicating several independent origins for this mutation. These data provide evidence for the presence of a specific BRCA2 mutation which has its origins in both Jewish Ashkenazi and non-Jewish populations. The observed overrepresentation of specific mutations within a subgroup of the general population may eventually help contribute to the development of inexpensive and routine tests such as the one described in our study.

The I1307K APC mutation does not predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds.

An increased incidence of colorectal cancer has been observed in breast and breast-ovarian cancer syndrome families, including those of Ashkenazi origin. Recently, a germ-line missense mutation in the APC gene, I1307K, was identified that may indirectly cause colorectal cancer in Ashkenazi Jews. To determine whether the excess of colon cancer in some breast-ovarian cancer families is related to the I1307K mutation, we evaluated 264 Ashkenazi Jews from 158 families. Most of these individuals had either a personal or a family history of breast and/or ovarian cancer, and 19.3% (51 of 264) carried one of the recurrent BRCA1 (185delAG or 5382 insC) or BRCA2 (6174delT) mutations. We detected the APC I1307K mutation in 7% (11 of 158) of the Ashkenazi Jewish families and in 4.5% (12 of 264) of the individuals participating in these studies. Of the families studied, 26.6% (42 of 158) had at least one case of colorectal cancer in a first-, second-, or third-degree relative of the proband. Significantly, of the 12 individuals who possessed the I1307K mutation, none was diagnosed with colorectal cancer and none had a known first-, second-, or third-degree relative diagnosed with colon cancer. The results suggest that factors other than the I1307K mutation contribute to the increased incidence of colon cancer in Ashkenazi breast-ovarian cancer families. Our results emphasize that only a subset of Ashkenazi Jewish individuals with a family history of colorectal cancer should be viewed as candidates for genetic susceptibility testing for the I1307K APC mutation.

Distension test in passive external rotation: Validation of a new clinical test for the early diagnosis of shoulder adhesive capsulitis.

OBJECTIVE: The aim of this study is to evaluate the internal validity of a clinical test for the early diagnosis of shoulder adhesive capsulitis, called the Distension Test in Passive External Rotation (DTPER). MATERIAL AND METHOD: The DTPER is performed with the patient standing up, the arm adducted, and the elbow bent at 90°. From this position, a smooth passive external rotation is started, the affected arm being supporting at the wrist with one hand of the examiner and the other maintaining the adducted elbow until the maximum painless point of the rotation is reached. From this point of maximum external rotation with the arm in adduction and with no pain, an abrupt distension movement is made, increasing the external rotation, causing pain in the shoulder if the test is positive. This term was performed on a group of patients with shoulder pain of many origins, in order to analyse the predictive values, sensitivity, specificity, and the likelihood ratio. RESULTS: The DTPER showed a sensitivity of 100% (95% CI; 91.8 to 100%) and a specificity of 90% (95% CI; 82.4 to 94.8%). The positive predictive value was 0.62 and a likelihood ratio of 10.22 (95% CI; 5.5 to 19.01). False positives were only found in patients with subscapular tendinopathies or glenohumeral arthrosis. DISCUSSION: The DTPER has a high sensitivity for the diagnosis of adhesive capsulitis, and is excluded when it is practically negative. False positives can easily be identified if there is external rotation with no limits (subscapular tendinopathy) or with a simple shoulder X-ray (glenohumeral arthrosis).

The treatment of relapsed or refractory intermediate grade non-Hodgkin's lymphoma with autologous bone marrow transplantation followed by cyclosporine and interferon.

In an effort to decrease the relapse rate following autologous bone marrow transplantation for non-Hodgkin's lymphoma, patients were given cyclosporine and interferon following autologous marrow transplantation. Forty patients with intermediate grade non-Hodgkin's lymphoma that was relapsed or refractory to standard chemotherapy underwent autologous marrow transplantation. The preparative regimen consisted of cyclophosphamide 6.8 g/m2, etoposide 1600 mg/m2, and carmustine 400 mg/m2 over 4 days followed by reinfusion of bone marrow. Intravenous cyclosporine was started on day -1 as a 16 mg/kg loading dose followed by 3.6 mg/kg/day for 28 days after transplant. Patients were begun on alpha-interferon (starting dose, 0.5 million units s.c. every other day) following platelet engraftment (median day 24 post-transplant) and continued on 1.5 million units s.c. daily for 2 years. Regimen-related toxicities resulted in four (10%) deaths. Twenty-one (53%) patients developed marked erythema of the palms, soles, and arms. Biopsies of the erythema were consistent with grade I GVHD. Patients who did not develop rashes were not biopsied. The erythema persisted for a median of 10 days and resolved in all cases without treatment. Visceral GVHD was not apparent. All patients have been followed for a median of 24 months (range 12-54 months). To date, only five patients (13%) have relapsed after bone marrow transplant. Multivariant analysis could not identify risk factors for relapse post-transplant. Disease-free survival of all patients is 77% (95% confidence interval, 67-93%). The results of this pilot study suggest that the administration of cyclosporine and interferon may decrease the relapse rate of relapsed/refractory non-Hodgkin's lymphoma following autologous bone marrow transplantation.

Chemoprevention of cancer.

Chemoprevention is a strategy used to block the development of cancers in human beings. This emerging field has broad potential for influencing cancer incidence rates in defined high-risk groups and the general population. In this review, we define some of the mechanisms of carcinogenesis, describe some of the genetic markers of carcinogenesis, and list possible biomarkers that may serve as surrogate end points in chemoprevention studies. A major component of this review is a description of the agents that are currently under investigation in animal systems or in human trials. They are grouped according to the agents that block or suppress mutation, such as oltipraz, selenium, vitamin C and the flavones, or according to agents that block promotion and proliferation, such as difluoromethylornithine, tamoxifen, nonsteroidal antiinflammatory drugs, and the vitamin A derivatives. We describe the issues that are considered in the design of chemoprevention trials and in the phase I, II, and III components of these trials. The following national trials are discussed: the Breast Cancer Prevention Trial, which uses tamoxifen; the Prostate Cancer Prevention Trial, which uses finasteride; and a Lung Cancer Prevention Trial, which uses 13-cis-retinoic acid. The review ends with some insights about future studies in chemoprevention.

The incidence and follow-up of the trophoblastic disease in ten-years period 1971-80.

The Authors examined 57 cases of trophoblastic disease out of 36,656 obstetric in-patients, from 1971 to 1980, and report the therapy and the follow-up.

Our experience in the second look laparotomy for ovarian cancer.

Our experience in second-look laparotomy for ovarian carcinoma is reported: in seven patients the second-look was negative; in two patients a neoplastic dissemination was found; in three patients we performed a debulking surgery.

Polychemotherapeutic treatment for ovarian carcinoma (our experience).

Since September 1980 to June 1983 we have treated 32 patients with ovarian cancer. Most patients were submitted to time polychemotherapy cyclophosphamide, adriamycin and cis-platinum. The maximum of survival time was 24 months; six patients died; the period of survival of the remaining 24 patients is between 2 and months.

Adjuvant aromatase inhibitor therapy for early breast cancer: A review of the most recent data.

Tamoxifen is the established adjuvant treatment for postmenopausal women with hormone-sensitive early breast cancer. However, the side-effects associated with tamoxifen therapy have prompted a search for safer and potentially more effective endocrine agents. Results from randomized trials of the third-generation aromatase inhibitors, anastrozole, letrozole and exemestane, demonstrating improved efficacy compared with tamoxifen and favorable tolerability profiles, are discussed in this review.

Assessment of blocking activity in patients with at least two consecutive spontaneous abortions.

The activity of the blocking factor (BF) was studied in 88 patients affected by recurrent abortion syndrome (RAS) by means of the determination of lymphocyte proliferation rate (LPR) in one-way mixed maternal-paternal lymphocyte cultures (MLC). Forty patients (45.5%) showed inadequate blocking activity (LPR greater than 80%). Pearson's correlation did not reveal any link between patient age and LPR (m2 = 0.031), or between LPR and number of aborted pregnancy (m20.058). Fifteen of the 88 patients had had only two consecutive abortions, but Pearson's correlation did not result in any particular differences in the link between LPR and number of abortions in this group; we therefore felt perfectly justified in extending the study to these subjects.

Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase.

Clopidogrel, like the homologous thienopyridine derivative ticlopidine, selectively inhibits platelet aggregation induced by ADP. We have previously described two nucleotide-binding sites on platelets related to ADP-mediated platelet responses. The first is a high-affinity binding site for 2-methylthio-ADP (2-MeSADP) that is linked to the inhibition of stimulated adenylate cyclase. The second is the 100-kd exofacial membrane protein aggregin, which is labeled by the reactive ADP analogue 5'-p-fluorosulfonylbenzoyl adenosine (FSBA) that is related to shape change and aggregation. We set out to determine if either of these sites is blocked in vivo by clopidogrel or its active metabolite. Six subjects were given clopidogrel (75 mg/day for 10 days) in a double-blind crossover experiment. All of the subjects developed prolonged bleeding times while taking the drug. The rate of onset of the effect on bleeding time varied among subjects. Platelet aggregation induced by ADP or thrombin was significantly impaired by the drug treatment, but no effect was detected on shape change. The incorporation of [3H]FSBA into aggregin was also unaffected. Inhibition of adenylate cyclase by ADP or by 2-MeSADP was greatly reduced in all subjects, and in the case of 2-MeSADP, there was evidence for a noncompetitive effect. Inhibition of adenylate cyclase by epinephrine was unaffected. In the three subjects for whom binding measurements were made, the number of binding sites for [32P]2-MeSADP was reduced from 534 +/- 44 molecules per platelet during control and placebo periods (11 determinations) to 199 +/- 78 molecules per platelet during drug treatment (three determinations). There was no consistent change in the binding affinity.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic testing for susceptibility to adult-onset cancer. The process and content of informed consent.

OBJECTIVE: To provide guidance on informed consent to clinicians offering cancer susceptibility testing. PARTICIPANTS: The Task Force on Informed Consent is part of the Cancer Genetics Studies Consortium (CGSC), whose members were recipients of National Institutes of Health grants to assess the implications of cancer susceptibility testing. The 10 task force members represent a range of relevant backgrounds, including various medical specialties, social science, genetic counseling, and consumer advocacy. EVIDENCE: The CGSC held 3 public meetings from 1994 to 1996. At its first meeting, the task force jointly established a list of topics. The cochairs (G.G. and J.R.B) then developed an outline and assigned each topic to an appropriate writer and reviewer. Writers summarized the literature on their topics and drafted recommendations, which were then revised by the reviewers. The cochairs compiled and edited the entire manuscript. All members were involved in writing this report. CONSENSUS PROCESS: The first draft was distributed to task force members, after which a meeting was held to discuss its content and organization. Consensus was reached by voting. A subsequent draft was presented to the entire CGSC at its third meeting, and comments were incorporated. CONCLUSIONS: The task force recommends that informed consent for cancer susceptibility testing be an ongoing process of education and counseling in which (1) providers elicit participant, family, and community values and disclose their own, (2) decision making is shared, (3) the style of information disclosure is individualized, and (4) specific content areas are discussed.