He was a co-founder of Seragon, purchased by Genentech/Roche in 2014. J.M. is a science advisor and owns company stock in Scholar Rock. H.C. is an inventor on several patents related to organoid technology. S.W.L. is a co-founder and scientific advisory board member for ORIC Pharm, Blueprint, and Mirimus. He also serves on the scientific advisory board for Constellation, Petra, and PMV and has recently served as a consultant for Forma, Boehringer Ingelheim, and Aileron. J.G.-A. has received support from Medtronic (honorarium for consultancy with Medtronic), Johnson & Johnson (honorarium for delivering a talk), and Intuitive Surgical (honorarium for participating in a webinar by Intuitive Surgical). P.B.R. has received honorarium from Corning to discuss 3D cell culture techniques, has served as a consultant for AstraZeneca, and is a consultant for EMD Serono for work on radiation sensitizers.
In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV); these guidelines were updated in 1997 and 1999. This fourth edition of the guidelines, made available on the Internet in 2001, is intended for clinicians and other health-care providers who care for HIV-infected persons. The goal of these guidelines is to provide evidence-based guidelines for preventing OIs among HIV-infected adults and adolescents, including pregnant women, and HIV-exposed or infected children. Nineteen OIs, or groups of OIs, are addressed, and recommendations are included for preventing exposure to opportunistic pathogens, preventing first episodes of disease by chemoprophylaxis or vaccination (primary prophylaxis), and preventing disease recurrence (secondary prophylaxis). Major changes since the last edition of the guidelines include 1) updated recommendations for discontinuing primary and secondary OI prophylaxis among persons whose CD4+ T lymphocyte counts have increased in response to antiretroviral therapy; 2) emphasis on screening all HIV-infected persons for infection with hepatitis C virus; 3) new information regarding transmission of human herpesvirus 8 infection; 4) new information regarding drug interactions, chiefly related to rifamycins and antiretroviral drugs; and 5) revised recommendations for immunizing HIV-infected adults and adolescents and HIV-exposed or infected children.
Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.
Purpose: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patientderived xenografts from SMAD4-deficient and SMAD4retained tumors were used to examine chemoresistance.Results: The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P ¼ 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P ¼ 0.002 and P ¼ 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival.Conclusions: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.
Purpose-To describe cytomegalovirus (CMV) end-organ disease (EOD) rate in AIDS patients with low CD4+ cell count despite HAART who were enrolled in a randomized, placebo-controlled trial of preemptive valganciclovir (VGCV) to prevent CMV EOD in those with CMV viremia. (N = 338) were HIV-infected with CD4+ count <100 cells/mm 3 , plasma HIV RNA >400 copies/mL, and on stable or no HAART. All underwent plasma CMV DNA PCR testing every 8 weeks (Step 1); those with detectable CMV DNA were randomized to VGCV or placebo (Step 2). Methods-SubjectsResults-Plasma CMV DNA was detected in 68 (20%), of whom 4 developed CMV EOD. DuringStep 1, 53 died. Of the 47 who entered Step 2 (24 VGCV, 23 placebo), CMV EOD was diagnosed in 10 (4 VGCV, 6 placebo) and 15 died (7 VGCV, 8 placebo). Of those randomized to placebo, 14% were diagnosed with CMV EOD at 12 months. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptConclusions-We observed a lower CMV EOD rate among subjects receiving HAART than predicted based on published literature. However, mortality was high in this study. Our findings suggest that preemptive anti-CMV therapy in patients with persistently low CD4+ cell counts in the current treatment era may not be warranted given the low incidence of CMV EOD and high all-cause mortality observed in this study population. KeywordsAIDS; CMV; opportunistic disease prevention; valganciclovir Cytomegalovirus (CMV) infection is present in 50% to 95% of HIV-infected individuals in the United States. During advanced AIDS, CMV can produce debilitating end-organ disease (EOD) including retinitis, colitis, and pneumonitis. [1][2][3][4] Prior to the advent of highly active antiretroviral therapy (HAART), detection of CMV in the blood was strongly associated with development of CMV EOD and mortality. 5,6 Subsequent to the development of HAART, several studies of patients receiving these potent regimens demonstrated that detection of CMV viremia continued to be predictive of CMV EOD, with CMV viremia producing a 40% to 60% increased risk of CMV EOD. [7][8][9][10][11] Further, CMV viremia has also been associated with heightened risk of mortality -including death not directly related to CMV EOD -in patients prescribed HAART. 10,11 The enhanced risk of CMV EOD among individuals with HIV infection and CMV viremia led us to conduct a randomized clinical trial of a strategy of preemptive therapy for CMV EOD in patients with suboptimally controlled HIV disease and CMV viremia and therefore at heightened risk for disease due to this opportunistic infection. This strategy entailed regular screening for CMV viremia followed by treatment with oral valganciclovir (VGCV) versus placebo among those with detectable CMV viremia.Although participants were HIV-infected patients with profound CD4+ cell depletion and uncontrolled HIV viremia despite widespread use of HAART, the rate of CMV EOD during the study was substantially lower than that seen in earlier studies of HAART-receiving patients, which led to the halting of the t...
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