Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer.

PURPOSE: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. RESULTS: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy (P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy (P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P \u3c .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. CONCLUSION: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN

α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes.

Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant β cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and β cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-β cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia. Cell Rep 2018 Mar 6; 22(10):2667-2676

Perturbations of the T-cell immune repertoire in kidney transplant rejection

In this cross-sectional and longitudinal analysis of mapping the T-cell repertoire in kidney transplant recipients, we have investigated and validated T-cell clonality, immune repertoire chronology at rejection, and contemporaneous allograft biopsy quantitative tissue injury, to better understand the pathobiology of acute T-cell fraction, T-cell repertoire and antibody-mediated kidney transplant rejection. To follow the dynamic evolution of T-cell repertoire changes before and after engraftment and during biopsy-confirmed acute rejection, we sequenced 323 peripheral blood samples from 200 unique kidney transplant recipients, with (n=100) and without (n=100) biopsy-confirmed acute rejection. We report that patients who develop acute allograft rejection, have lower (p=0.01) T-cell fraction even before transplantation, followed by its rise after transplantation and at the time of acute rejection accompanied by high TCR repertoire turnover (p=0.004). Acute rejection episodes occurring after the first 6 months post-transplantation, and those with a component of antibody-mediated rejection, had the highest turnover; p=0.0016) of their T-cell repertoire. In conclusion, we validated that detecting repertoire changes in kidney transplantation correlates with post-transplant rejection episodes suggesting that T-cell receptor sequencing may provide recipient pre-transplant and post-transplant predictors of rejection risk

Phase III randomized trial of chemotherapy with or without bevacizumab (B) in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Survival analysis of E1305, an ECOG-ACRIN Cancer Research Group trial

6000 Background: The addition of B, an anti-VEGF monoclonal antibody, to chemotherapy has improved outcomes in several solid tumors. Pemetrexed plus B showed promising efficacy in R/M SCCHN (Argiris et al. JCO 2011). E1305 was designed to evaluate the addition of B to a platinum doublet in R/M SCCHN. Methods: B-eligible pts with performance status 0-1, not having received chemotherapy for R/M SCCHN (prior chemotherapy for locally advanced disease allowed ≥ 4 months) and without factors predisposing to bleeding (history of bleeding due to SCCHN, anticoagulation, central cavitary lung metastasis, carotid invasion) were randomized to: A) one of 4 regimens (investigator's choice) given every 3 weeks: A1, cisplatin (C) 100 mg/m 2 , 5-FU 1000 mg/m 2 /day x 4 days; A2, carboplatin (Cb) AUC 6, 5-FU 1000 mg/m 2 /day x 4 days; A3, C 75 mg/m 2 , docetaxel (D) 75 mg/m 2 ; A4, Cb AUC 6, D 75 mg/m 2 , or B) the same regimen (B1, B2, B3, B4) plus B 15 mg/Kg IV, every 3 weeks, until progression. Chemotherapy could be stopped after 6 cycles after maximum response. All pts received prophylactic antibiotics. The primary endpoint was overall survival (OS). Control median OS of 8.5 months (mo) was projected; the addition of B was hypothesized to increase median OS to 11.5 mo with a hazard ratio (HR) of 0.74. Results: 403 pts were randomized (200 in arm A; 203 in arm B). Baseline characteristics were well balanced. 38% in arm A/42% in arm B had an oropharyngeal primary; 87% received C or Cb plus D. With a median follow-up of 23.1 mo, median OS was 11 mo in arm A and 12.6 mo in arm B; HR 0.84 (95% CI 0.67-1.05), p = 0.13. The 1-, 2-, 3-, and 4-year OS were 46% vs 51%, 18% vs 26%, 8% vs 16%, 6% vs 13%, in arm A vs B, respectively. Median PFS was 4.4 mo in arm A and 6.1 mo in arm B (HR 0.71, 95% CI 0.58-0.87; p = 0.0012). Objective response rate was 25% in arm A vs 36% in arm B (p = 0.013). Grade 3-5 bleeding occurred in 3.5% in arm A vs 7.7% in arm B (p = 0.08). Conclusions: B added to a standard platinum doublet improved response rate and PFS but not OS in first-line treatment of R/M SCCHN. The control arm in this study performed better than expected. Clinical trial information: NCT00588770

DataSheet_1_Perturbations of the T-cell immune repertoire in kidney transplant rejection.docx

In this cross-sectional and longitudinal analysis of mapping the T-cell repertoire in kidney transplant recipients, we have investigated and validated T-cell clonality, immune repertoire chronology at rejection, and contemporaneous allograft biopsy quantitative tissue injury, to better understand the pathobiology of acute T-cell fraction, T-cell repertoire and antibody-mediated kidney transplant rejection. To follow the dynamic evolution of T-cell repertoire changes before and after engraftment and during biopsy-confirmed acute rejection, we sequenced 323 peripheral blood samples from 200 unique kidney transplant recipients, with (n=100) and without (n=100) biopsy-confirmed acute rejection. We report that patients who develop acute allograft rejection, have lower (p=0.01) T-cell fraction even before transplantation, followed by its rise after transplantation and at the time of acute rejection accompanied by high TCR repertoire turnover (p=0.004). Acute rejection episodes occurring after the first 6 months post-transplantation, and those with a component of antibody-mediated rejection, had the highest turnover; p=0.0016) of their T-cell repertoire. In conclusion, we validated that detecting repertoire changes in kidney transplantation correlates with post-transplant rejection episodes suggesting that T-cell receptor sequencing may provide recipient pre-transplant and post-transplant predictors of rejection risk.</p

A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans

The tumor suppressor protein, p53, is activated upon cellular stresses such as DNA damage and oncogene activation and initiates a transcriptional program which leads to DNA repair, cell cycle arrest, and in some cases