Jonathan L. Hecht

Molecular and Pathologic Aspects of Endometrial Carcinogenesis

Endometrial cancer is the most common gynecological malignancy, with 41,000 new cases projected in the United States for 2006. Two different clinicopathologic subtypes are recognized: the estrogen-related (type I, endometrioid) and the non-estrogen-related types (type II, nonendometrioid such as papillary serous and clear cell). The morphologic differences in these cancers are mirrored in their molecular genetic profile with type I showing defects in DNA-mismatch repair and mutations in PTEN, K-ras, and beta-catenin, and type II showing aneuploidy and p53 mutations. This article reviews the genetic aspects of endometrial carcinogenesis and progression. We will define the precursor lesion of type I endometrioid cancer and the role of genetics and estrogen in its progression.

Human Epididymis Protein 4 (HE4) Is a Secreted Glycoprotein that Is Overexpressed by Serous and Endometrioid Ovarian Carcinomas

Among the genes most commonly identified in gene expression profiles of epithelial ovarian carcinomas (EOC) is the gene for human epididymis protein 4 (HE4). To ascertain its clinical utility, we did a comprehensive assessment of HE4 protein expression in benign and malignant ovarian and nonovarian tissues by immunohistochemistry. In comparison with normal surface epithelium, which does not express HE4, we found that cortical inclusion cysts lined by metaplastic Mullerian epithelium abundantly express the protein. Its expression in tumors was restricted to certain histologic subtype: 93% of serous and 100% of endometrioid EOCs expressed HE4, whereas only 50% and 0% of clear cell carcinomas and mucinous tumors, respectively, were positive. Tissue microarrays revealed that the majority of nonovarian carcinomas do not express HE4, consistent with our observation that HE4 protein expression is highly restricted in normal tissue to the reproductive tracts and respiratory epithelium. HE4 is predicted to encode a secreted protein. Using reverse transcription-PCR, we identified ovarian cancer cell lines that endogenously overexpress HE4. Cultured medium from these cells revealed a secreted form of HE4 that is N-glycosylated. This observation is consistent with the recent report that HE4 circulates in the bloodstream of patients with EOC. Therefore, HE4 is a secreted glycoprotein that is overexpressed by serous and endometrioid EOCs. Its expression in cortical inclusion cysts suggests that formation of Mullerian epithelium is a prerequisite step in the development of some types of EOCs.

Molecular Biology of Burkitt’s Lymphoma

The diagnostic category of Burkitts lymphoma encompasses a closely related group of aggressive B-cell tumors that includes sporadic, endemic, and human immunodeficiency virus-associated subtypes. All subtypes are characterized by chromosomal rearrangements involving the c-myc proto-oncogene that lead to its inappropriate expression. This review focuses on the roles of c-myc dysregulation and Epstein-Barr virus infection in Burkitts lymphoma. Although the normal function of c-Myc remains enigmatic, recent data indicate that it has a central role in several fundamental aspects of cellular biology, including proliferation, differentiation, metabolism, apoptosis, and telomere maintenance. We discuss new insights into the molecular mechanisms of these c-Myc activities and their potential relevance to the pathogenesis of Burkitts lymphoma and speculate on the role of Epstein-Barr virus.

Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis

BACKGROUND & AIMS A previously published study by our group suggested that adenoma-like dysplasia-associated lesions or masses (DALMs) in ulcerative colitis (UC) may be treated adequately by polypectomy and continued endoscopic surveillance. The length of follow-up evaluation in these patients averaged only 42 months. The purpose of this study was to evaluate the long-term outcome of our previously defined group of UC patients, all with adenoma-like DALMs, who were treated by polypectomy. METHODS The clinical, endoscopic, and pathologic outcome of 34 UC patients, 24 with an adenoma-like DALM, and 10 with a coincidental sporadic adenoma, 28 of whom were treated by polypectomy and continued endoscopic surveillance, and 6 by colonic resection, were compared with the outcome of 49 non-UC patients who were treated similarly for a sporadic adenoma. The mean length of follow-up evaluation averaged 82.1 months and 71.8 months for the 2 UC subgroups, respectively, and 60.4 months for the non-UC controls. RESULTS Overall, 20 of 34 UC patients (58.8%) developed at least one further adenoma-like DALM on follow-up evaluation. One patient had flat low-grade dysplasia present in the colon, which was resected within 6 months of the initial polypectomy, and another patient, with primary sclerosing cholangitis, developed adenocarcinoma 7.5 years after her initial polypectomy. There was no significant difference in the prevalence of polyp formation on follow-up evaluation between UC patients with an adenoma-like DALM (62.5%) and UC patients with a sporadic adenoma (50%), or between either of these 2 UC patient subgroups and the non-UC sporadic adenoma patient group (49%; P > 0.05). CONCLUSIONS UC patients who develop an adenoma-like DALM may be treated adequately by polypectomy with complete excision and continued endoscopic surveillance.

Management of asymptomatic ovarian and other adnexal cysts imaged at US: Society of Radiologists in Ultrasound Consensus Conference Statement.

The Society of Radiologists in Ultrasound convened a panel of specialists from gynecology, radiology, and pathology to arrive at a consensus regarding the management of ovarian and other adnexal cysts imaged sonographically in asymptomatic women. The panel met in Chicago, Ill, on October 27-28, 2009, and drafted this consensus statement. The recommendations in this statement are based on analysis of current literature and common practice strategies, and are thought to represent a reasonable approach to asymptomatic ovarian and other adnexal cysts imaged at ultrasonography.

Lymphomas of the breast: Primary and secondary involvement

The involvement of the breast by lymphoma is a rare form of extralymph node lymphoma and represents either primary disease or systemic involvement. The authors hypothesized that screening mammography may influence the detection of lymphomatous involvement of the breast.

Keap1 Mutations and Nrf2 Pathway Activation in Epithelial Ovarian Cancer

Resistance to platinum-based chemotherapy develops in the majority of patients with epithelial ovarian cancer (EOC). Platinum compounds form electrophilic intermediates that mediate DNA cross-linking and induce double-strand DNA breaks. Because the cellular response to electrophilic xenobiotics is partly mediated by Keap1-Nrf2 pathway, we evaluated the presence of Kelch-like ECH-associated protein 1 (Keap1) mutations and NF-E2-related factor 2 (Nrf2) pathway activation in EOC and correlated these with platinum resistance and clinical outcome. Nrf2 immunohistochemistry revealed nuclear localization (a surrogate of pathway activation) in over half of EOC patient specimens examined, with more common occurrence in the clear cell EOC subtype. Quantitative real-time PCR revealed that Nrf2 target genes were upregulated in tumors with nuclear positivity for Nrf2. Microarray analysis also showed upregulation of Nrf2 target genes in clear cell EOCs compared with other EOC subtypes. In addition, Keap1 sequence analysis revealed genetic mutations in 29% of clear cell samples and 8% of nonclear cell tumors. RNAi-mediated knockdown of Keap1 was associated with Nrf2 pathway activation and resistance to carboplatin in vitro. Importantly, patients with evidence of Nrf2 pathway activation had fewer complete clinical responses to platinum-based therapy, were enriched for platinum resistance, and had shorter median overall survival compared with those who did not show evidence of Nrf2 pathway activation. Our findings identify Keap1 mutations in EOC and they suggest a previously unrecognized role for the Keap1-Nrf2 pathway in mediating chemotherapeutic responses in this disease.

Microbiologic and histologic characteristics of the extremely preterm infant's placenta predict white matter damage and later cerebral palsy. the ELGAN study.

Inflammatory phenomena seem to contribute to the occurrence of perinatal cerebral white matter damage and CP. The stimulus that initiates the inflammation remains obscure. One thousand two hundred forty-six infants born before the 28th postmenstrual week had a protocol ultrasound scan of the brain read concordantly by two independent sonologists. Eight hundred ninety-nine of the children had a neurologic examination at approximately 24-mo postterm equivalent. The placenta of each child had been biopsied under sterile conditions and later cultured. Histologic slides of the placenta were examined specifically for this study. Recovery of a single microorganism predicted an echolucent lesion, whereas polymicrobial cultures and recovery of skin flora predicted both ventriculomegaly and an echolucent lesion. Diparetic CP was predicted by recovery of a single microorganism, multiple organisms, and skin flora. Histologic inflammation predicted ventriculomegaly and diparetic CP. The risk of ventriculomegaly associated with organism recovery was heightened when accompanied by histologic inflammation, but the risk of diparetic CP was not. Low-virulence microorganisms isolated from the placenta, including common skin microflora, predict ultrasound lesions of the brain and diparetic CP in the very preterm infant. Organism recovery does not seem to be needed for placenta inflammation to predict diparetic CP.

Breastfeeding and risk of ovarian cancer in two prospective cohorts.

ObjectiveTo describe the association between breastfeeding and ovarian cancer risk in two prospective cohorts.Materials & methodsWe pooled data from the Nurses’ Health Study and Nurses’ Health Study II. There were 391 cases of epithelial ovarian cancer diagnosed among 149,693 parous women with up to 16 years of follow-up. Data were analyzed using multivariate Cox proportional hazards models, controlling for age, parity, duration of oral contraceptive use, tubal ligation, and age at menarche.ResultsEver breastfeeding was associated with a non-significant reduction in ovarian cancer risk compared with never breastfeeding (RR = 0.86, 95% CI 0.70–1.06); the median duration of breastfeeding among women who breastfed was nine months. Breastfeeding of 18 or more months was associated with a significant decrease in ovarian cancer risk compared to never breastfeeding (RR = 0.66, 95% CI 0.46–0.96). For each month of breastfeeding the relative risk decreased by 2% (RR = 0.98 per month, 95% CI 0.97–1.00).ConclusionsThese data support a linear inverse association between breastfeeding and risk of epithelial ovarian cancer.

Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex

The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans but virtually absent in rodents, called outer radial glia (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined progenitor subtype–specific sorting with transcriptome-wide RNA sequencing to identify genes enriched in human ORG, which included targets of the transcription factor neurogenin and previously uncharacterized, evolutionarily dynamic long noncoding RNAs. Activating the neurogenin pathway in ferret progenitors promoted delamination and outward migration. Finally, single-cell transcriptional profiling in human, ferret and mouse revealed more cells coexpressing proneural neurogenin targets in human than in other species, suggesting greater neuronal lineage commitment and differentiation of self-renewing progenitors. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors.