HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives.

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27-29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

Valproic acid hepatic fatalities. II. US experience since 1984.

We have analyzed the usage pattern of valproate and the associated hepatic fatalities that have been reported in the 2 years since our first study evaluating US experience during the period 1978-1984. In this follow-up study (1985-1986), we have observed a nearly fivefold decrease in the incidence of hepatic fatality during a time when the overall use of valproate has increased significantly. The dramatically decreased incidence, from 0.93 per 10,000 (1/10,000) in 1978-1984 to 0.20 per 10,000 (1/49,000) in 1985-1986 appears to be due to changes in the prescribing patterns of physicians, prompted by greater awareness of low-risk versus high-risk patients. More patients are receiving valproate as monotherapy, considerably more low-risk patients are being treated with valproate, and fewer high-risk patients (0 to 2 years old) are being treated with valproate. During 1985-1986, no hepatic fatalities were reported in any patients above the age of 10 years, regardless of whether valproate was administered as monotherapy or polytherapy. The altered exposure pattern, with an increased use of monotherapy, appears to have had a positive impact on the number of hepatic fatalities (four among 198,000 patients treated during 1985-1986) and contributed to a decreased rate of valproate-associated hepatic fatality.

Small-Cell Carcinoma of the Cervix Presenting with Severe Hypokalemia as a Manifestation of Cushing's Syndrome.

OBJECTIVES: A case of small-cell carcinoma of the cervix and severe hypokalemia is presented. The need for surveillance of paraneoplastic syndromes in these patients is emphasized. METHODS: The patient's clinical course is presented. The available literature regarding small-cell carcinoma of the cervix and Cushing's syndrome is reviewed. RESULTS: A 32-year-old woman had diagnosed small-cell carcinoma after simple hysterectomy. After radical parametrectomy, she developed liver metastases that did not respond to chemotherapy. Subsequently, she developed severe and unremitting hypokalemia, which was determined to be the initial manifestation of Cushing's syndrome secondary to ectopic adenocorticotropic hormone production. Typical clinical features of Cushing's syndrome were noted to arise during subsequent examinations. CONCLUSIONS: Though paraneoplastic syndromes associated with small-cell carcinoma of the cervix are rare, this case report describes one of these syndromes as an etiology for metabolic derangements.

Biochemical evidence for the involvement of tyrosine in epoxide activation during the catalytic cycle of epoxide hydrolase.

Epoxide hydrolases (EH) catalyze the hydrolysis of epoxides and arene oxides to their corresponding diols. The crystal structure of murine soluble EH suggests that Tyr(465) and Tyr(381) act as acid catalysts, activating the epoxide ring and facilitating the formation of a covalent intermediate between the epoxide and the enzyme. To explore the role of these two residues, mutant enzymes were produced and the mechanism of action was analyzed. Enzyme assays on a series of substrates confirm that both Tyr(465) and Tyr(381) are required for full catalytic activity. The kinetics of chalcone oxide hydrolysis show that mutation of Tyr(465) and Tyr(381) decreases the rate of binding and the formation of an intermediate, suggesting that both tyrosines polarize the epoxide moiety to facilitate ring opening. These two tyrosines are, however, not implicated in the hydrolysis of the covalent intermediate. Sequence comparisons showed that Tyr(465) is conserved in microsomal EHs. The substitution of analogous Tyr(374) with phenylalanine in the human microsomal EH dramatically decreases the rate of hydrolysis of cis-stilbene oxide. These results suggest that these tyrosines perform a significant mechanistic role in the substrate activation by EHs.