Medullary carcinomas of the pancreas are a recently described, histologically distinct subset of poorly differentiated adenocarcinomas that may have a unique pathogenesis and clinical course. To further evaluate these neoplasms, we studied genetic, pathological, and clinical features of 13 newly identified medullary carcinomas of the pancreas. Nine (69%) of these had wild-type K-ras genes, and one had microsatellite instability (MSI). This MSI medullary carcinoma, along with three previously reported MSI medullary carcinomas, were examined immunohistochemically for Mlh1 and Msh2 expression, and all four expressed Msh2 but did not express Mlh1. In contrast, all of the medullary carcinomas without MSI expressed both Msh2 and Mlh1. Remarkably, the MSI medullary carcinoma of the pancreas in the present series arose in a patient with a synchronous but histologically distinct cecal carcinoma that also had MSI and did not express Mlh1. The synchronous occurrence of two MSI carcinomas suggests an inherited basis for the development of these carcinomas. Indeed, the medullary phenotype, irrespective of MSI, was highly associated with a family history of cancer in first-degree relatives (P < 0.001). Finally, one medullary carcinoma with lymphoepithelioma-like features contained Epstein-Barr virus-encoded RNA-1 by in situ hybridization. Therefore, because of medullary carcinoma's special genetic, immunohistochemical, and clinical features, recognition of the medullary variant of pancreatic adenocarcinoma is important. Only by classifying medullary carcinoma as special subset of adenocarcinoma can we hope to further elucidate its unique pathogenesis.

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Objective To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Design Prospective observational study Setting 483-bed hospital affiliated with a large academic institution Participants Eighty patients started on warfarin and managed by a newly implemented pharmacogenetics service. Intervention Routine warfarin genotyping and clinical pharmacogenetics consultation Measurements and Main Results The primary outcomes were percent of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders during the first 6 months of the service, 190 were deemed appropriate. For 80 patients on the service who consented to data collection, 77% of genotypes were available prior to the second warfarin dose. The median (range) time from the genotype order to the genotype result was 26 (7 to 80) hours, and the time to genotype-guided dosing recommendation was 30 (7 to 80) hours. Seventy-three percent of warfarin doses ordered by the medical staff were within 0.5 mg of the dose recommended by the pharmacogenetics consult service. Conclusions Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with the majority of genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff.

The transcription factor (TF) RUNX1 cooperates with lineage-specifying TFs (eg, PU.1/SPI1) to activate myeloid differentiation genes, such as macrophage and granulocyte macrophage colony-stimulating factor receptors (MCSFR and GMCSFR). Disruption of cooperative gene activation could contribute to aberrant repression of differentiation genes and leukemogenesis initiated by mutations and translocations of RUNX1. To investigate the mechanisms underlying cooperative gene activation, the effects of Runx1 deficiency were examined in an in vitro model of Pu.1-driven macrophage differentiation and in primary cells. Runx1 deficiency decreased Pu.1-mediated activation of Mcsfr and Gmcsfr, accompanied by decreased histone acetylation at the Mcsfr and Gmcsfr promoters, and increased endogenous corepressor (Eto2, Sin3A, and Hdac2) coimmunoprecipitation with Pu.1. In cotransfection experiments, corepressors were excluded from a multiprotein complex containing full-length RUNX1 and PU.1. However, corepressors interacted with PU.1 if wild-type RUNX1 was replaced with truncated variants associated with leukemia. Histone deacetylase (HDAC) enzyme activity is a major component of corepressor function. HDAC inhibition using suberoylanilide hydroxamic acid or MS-275 significantly increased MCSFR and GMCSFR expression in leukemia cell lines that express PU.1 and mutated or translocated RUNX1. RUNX1 deficiency is associated with persistent corepressor interaction with PU.1. Thus, inhibiting HDAC can partly compensate for the functional consequences of RUNX1 deficiency.