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Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome (LS) with enrichment of germline MSH2 and MSH6 mutations when compared to 193 LS-associated colon cancer patients (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P less then .003). CONCLUSIONS Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for LS in dMMR rectal cancer patients. Copyright ©2020, American Association for Cancer Research.PURPOSE In this phase I study (NCT01307267) we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular (FL) and other CD20+ non-Hodgkin lymphomas (NHLs). EXPERIMENTAL DESIGN Primary objectives were to assess treatment safety and tolerability for estimating the maximum tolerated dose (MTD), using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D). RESULTS Sixty-seven patients received utomilumab (0.03-10.0 mg/kg every 4 weeks [Q4W]) and rituximab (375 mg/m2 weekly) in the dose escalation groups or utomilumab (1.2 mg/kg Q4W) plus rituximab in the dose expansion cohort. No patient experienced DLTThe MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg Q4W. The majority of the utomilumab treatment-related adverse events (AEs) were grade 1-2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03-10 mg/kg dose range. A low incidence (1.5%) of treatment-induced anti-drug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI 12.1, 33.0%) in all patients with NHL, including 4 complete and 10 partial responses. Analysis of paired biopsies from a relapsed/refractory FL patient with complete response showed increased T-cell infiltration and cytotoxic activity in tumors. Biomarker correlations with outcomes suggested that clinical benefit may be contingent on patient immune function. CONCLUSIONS Utomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20+ NHLs. Copyright ©2020, American Association for Cancer Research.PURPOSE The incidence of lung cancer has dramatically increased in women. Preclinical data have suggested that combining EGFR-TKI with an anti-estrogen may overcome resistance to EGFR-TKI. EXPERIMENTAL DESIGN The IFCT-1003 LADIE trial was a 2x2 arms parallel open-label randomized phase II trial. EGFR-TKI-naïve post-menopausal women with advanced lung cancer were treated with gefitinib (G) vs. G + fulvestrant (G+F) in the EGFR mutated group (EGFR+) or with erlotinib (E) vs. E + fulvestrant (E+F) in the EGFR wild-type group (EGFR-WT). The primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR-WT and EGFR+ patients. RESULTS Overall, 204 patients and 175 patients were enrolled in the EGFR+ and EGFR-WT cohorts. In the EGFR+ cohort, the primary endpoint was reached, with 58% of the G+F group patients being non-progressive at 9 months. Adding F to G was not associated with improved PFS (9.9 vs 9.4 months) or OS (22.1 vs 28.6 months). In the EGFR-WT cohort, the primary endpoint was also achieved (33.7% of the patients were non-progressive at 3 months). Adding F to E was not associated with improved outcome (PFS 1.8 vs 2.0 and OS 10.3 vs 7.3 months). No PFS difference was observed regarding Estrogen Receptor alpha expression. The tolerance was as expected with no treatment-related death. MRTX1719 CONCLUSIONS Adding fulvestrant to EGFR-TKI is feasible, but not associated with prolonged PFS regardless EGFR status. The lack of benefits while combining fulvestrant to EGFR-TKI does not support its future development in unselected population. Copyright ©2020, American Association for Cancer Research.Replication initiation in eukaryotic cells occurs asynchronously throughout S phase, yielding early and late replicating regions of the genome, a process known as replication timing (RT). RT changes during development to ensure accurate genome duplication and maintain genome stability. To understand the relative contributions that cell lineage, cell cycle, and replication initiation regulators have on RT, we utilized the powerful developmental systems available in Drosophila melanogaster. We generated and compared RT profiles from mitotic cells of different tissues and from mitotic and endocycling cells of the same tissue. Our results demonstrate that cell lineage has the largest effect on RT, whereas switching from a mitotic to an endoreplicative cell cycle has little to no effect on RT. Additionally, we demonstrate that the RT differences we observed in all cases are largely independent of transcriptional differences. We also employed a genetic approach in these same cell types to understand the relative contribution the eukaryotic RT control factor, Rif1, has on RT control. Our results demonstrate that Rif1 can function in a tissue-specific manner to control RT. Importantly, the Protein Phosphatase 1 (PP1) binding motif of Rif1 is essential for Rif1 to regulate RT. Together, our data support a model in which the RT program is primarily driven by cell lineage and is further refined by Rif1/PP1 to ultimately generate tissue-specific RT programs. Copyright © 2020, Genetics.OBJECTIVE We sought to compare the association of categorized ankle-brachial index (ABI) with mortality and complications of diabetes in persons with no symptoms of peripheral arterial disease (PAD) and in primary cardiovascular disease prevention. RESEARCH DESIGN AND METHODS This is a retrospective cohort study of persons with type 2 diabetes aged 35-85 years, from 2006 to 2011. Data were obtained from the Sistema d'Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAPQ). Participants had an ABI measurement that was classified into six categories. For each category of ABI, we assessed the incidence of mortality; macrovascular complications of diabetes acute myocardial infarction (AMI), ischemic stroke, and a composite of these two; and microvascular complications of this metabolic condition nephropathy, retinopathy, and neuropathy. We also estimated the HRs for these outcomes by ABI category using Cox proportional hazards models. RESULTS Data from 34 689 persons with type 2 diabetes were included.