Myocarditis during lenalidomide therapy.

OBJECTIVE: To report the first case of pathologically confirmed myocarditis in a patient receiving treatment with lenalidomide for non-Hodgkin's lymphoma. CASE SUMMARY: An 85-year-old woman with recurrent follicular lymphoma was treated with lenalidomide 10 mg daily and low-dose dexamethasone 8 mg once weekly in a clinical trial. She had a past medical history of hypertension and breast cancer. Within 17 days of starting lenalidomide and dexamethasone, she developed symptoms and signs of congestive heart failure. Despite aggressive supportive care, she had progressive and refractory multiorgan failure and died. Postmortem examination of the heart confirmed the absence of coronary artery disease, and histopathological examination of the myocardium revealed a diffuse lymphocytic/eosinophilic inflammatory infiltrate with associated acute and chronic myocardial injury affecting all 4 chambers of the heart, consistent with myocarditis. DISCUSSION: Lenalidomide is an immunomodulatory agent derived from thalidomide and is approved for the treatment of multiple myeloma and myelodysplastic syndromes. The efficacy of lenalidomide has been reported in B-cell malignancies. Common toxicities are myelosuppression, fatigue, diarrhea, skin rash, venous thromboembolism, peripheral neuropathy, and tumor flare reaction. Cardiovascular toxicity has been limited to atrial fibrillation and an increased risk for venous thromboembolism. Autoimmune hemolytic anemia, pneumonitis, and dermatitis have been described with lenalidomide. We propose an immunological mechanism for myocarditis based on the predominantly T-cell infiltration of the myocardium. CONCLUSIONS: Our findings suggest that lenalidomide may be a cause of drug-induced myocarditis. When patients treated with lenalidomide present with signs and symptoms of heart failure in the absence of other obvious causes, lenalidomide hypersensitivity should be considered in the differential diagnosis and a myocardial biopsy should be considered when other common causes of heart failure have been excluded. A reasonable management approach is drug discontinuation and early institution of corticosteroid therapy. An objective causality assessment, using the Naranjo probability scale, revealed that the adverse drug event was probable.

Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results.

OBJECTIVE: To determine the endometrial safety of 2 years of treatment with lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). DESIGN: Randomized, double-blind, placebo-controlled, multicenter metabolic and osteoporosis substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) study. SETTING: Nineteen study centers across the United States. PATIENT(S): Healthy, postmenopausal women (n = 822) with an intact uterus were recruited. INTERVENTION(S): Patients received CEE 0.625, CEE 0.625/MPA 2.5, CEE 0.45, CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3, CEE 0.3/MPA 1.5 (all doses mg/day), or placebo for 2 years. Endometrial biopsies were evaluated at baseline and years 0.5, 1, 1.5, and 2 using a centralized protocol. MAIN OUTCOME MEASURE(S): Efficacy of lower doses of CEE/MPA in reducing the incidence of endometrial hyperplasia rates associated with unopposed estrogen (E). RESULT(S): No cases of endometrial hyperplasia were seen in the four CEE/MPA groups. For the CEE-alone groups, a dose-related increase in incidence rates from 3.17% (CEE 0.3 mg) to 27.27% (CEE 0.625 mg) was seen at 2 years. The number of cases increased from year 1 to year 2. For the CEE-alone groups, the incidence rates and types of hyperplasia diagnosed varied among the pathologists. CONCLUSION(S): Two years of treatment with lower doses of CEE/MPA provided endometrial protection comparable to that seen with commonly prescribed doses. These regimens should be considered for postmenopausal women who are candidates for hormone therapy.

Reproductive factors and ovarian cancer risk in Jewish BRCA1 and BRCA2 mutation carriers (United States).

OBJECTIVE: To determine whether oral contraceptive (OC) use, childbearing, breastfeeding and tubal ligation differ between ovarian cancer cases with and without a BRCA1/2 mutation. METHODS: A case-only study of 242 Jewish women with invasive epithelial ovarian cancer. Women were genotyped for three Ashkenazi founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). We obtained data on OC use, childbearing, breastfeeding, gynecologic surgeries and other reproductive factors from each woman. We compared the frequencies of these risk factors in carriers and non-carriers using unconditional logistic-regression, controlling for other covariates. RESULTS: Among the 242 cases, 64 (26.4%) carried one of the BRCA1 founder mutations, and 31 (12.8%) carried the BRCA2 mutation. Although there were no differences in the percent of nulliparous women between carriers and non-carriers, parous BRCA1 carriers reported fewer live births than non-carriers (average of 2.1 versus 2.5 live births, OR = 0.61, 95% CI = 0.39-0.95, adjusted for age at diagnosis, tubal ligation and duration of OC use). Carriers and non-carriers did not differ in their history of breastfeeding, or in their lifetime use of OCs. BRCA1 carriers were more likely than non-carriers to have had a tubal ligation (25.0 versus 10.2%, OR = 3.67, 95% CI = 1.55-8.70, adjusted for age at diagnosis, number of live births and OC duration). CONCLUSIONS: In general, OC use, childbearing and breastfeeding do not differ between BRCA1/2 carriers and non-carriers with ovarian cancer. However, the effects of tubal ligation may differ between BRCA1 carriers and non-carriers.

Usefulness of pipelle endometrial biopsy in the diagnosis of women at risk for ectopic pregnancy.

OBJECTIVE: The purpose of this study was to determine the accuracy of endometrial Pipelle (Unimar) biopsy to detect chorionic villi in suspected ectopic pregnancy. STUDY DESIGN: This was a blinded prospective trial that involved 32 women who were in stable condition with suspected ectopic pregnancy. Endometrial pipelle sampling was performed before uterine dilation and curettage. Pipelle and frozen section results were compared with final disease. RESULTS: Ten of 32 patients (31%) had chorionic villi that was consistent with a miscarriage; 22 of 32 patients (69%) had none detected. Pipelle biopsy had a sensitivity of 30% (95% CI, 6.7-65.2), a specificity of 100% (95% CI, 84.5-100), a positive predictive value of 100% (95% CI, 29.2-100), and a negative predictive value of 76% (95% CI, 56.5-87). Frozen section had a sensitivity of 87.5% (95% CI, 47.3-99.7), a specificity of 100% (95% CI, 83.1-100), a positive predictive value of 100% (95% CI, 59-100), and a negative predictive value of 95.3% (95% CI, 76.1-99.8). CONCLUSION: In patients with suspected ectopic pregnancy, Pipelle sampling is not a substitute for curettage because the sensitivity and predictive values are unacceptable.

C-kit immunoreactivity in endometrial adenocarcinomas and its clinicopathologic significance.

The proto-oncogene c-kit is a transmembrane-tyrosine-kinase receptor that is structurally related to the platelet-derived growth-factor receptor (PDGFR) and is involved in cell differentiation. C-kit has been found to be expressed in certain solid tumors and may play a role in their tumorigenesis. Recently, a tyrosine-kinase inhibitor specific for the PDGFR family, bcr-abl, and c-kit (STI571) has been reported to have therapeutic effects in tumors expressing the aberrant forms or high quantities of target proteins. Expression of c-kit has not been well evaluated in endometrial adenocarcinomas. In this study, c-kit immunoreactivity was evaluated on paraffin sections of 72 endometrial adenocarcinomas (57 endometrioid, 10 serous, and 5 clear cell) with a polyclonal antibody. Immunoreactivity of c-kit was analyzed semiquantitatively and correlated with various clinicopathologic factors. Cytoplasmic c-kit immunoreactivity was detected in 42 (58%) tumors. Thirty-four (60%) endometrioid, 8 (80%) serous, and 0 of the 5 clear-cell adenocarcinomas were c-kit positive. There was a significant correlation between c-kit positivity and the depth of myometrial invasion. Patients with c-kit-positive endometrial adenocarcinomas more frequently had metastases and shorter disease-free survival. Expression of c-kit may be a potentially adverse prognostic feature in endometrial adenocarcinoma. Patients with c-kit-positive advanced endometrial adenocarcinoma might benefit from tyrosine-kinase-inhibitor therapy.