Mice prematurely expressing human CR2 (hCR2) in the B cell lineage have a defective B cell ontogeny and humoral immune response. We have previously determined altered tyrosine phosphorylation patterns within hCR2 transgenic mice, suggesting that irreversible changes in B cell signaling pathways had occurred, which could explain the B cell unresponsiveness associated with hCR2 transgene expression. In support of that assertion, we found that increasing antigen dose or addition of adjuvant had a minimal impact on the ability of B cells to respond to antigen. However, analysis of aged hCR2high mice (1 year plus) revealed that both B cell numbers, B cell sub-population distribution including expansion of a newly described B regulatory cell subset, and immune responses were comparable with age-matched hCR2 negative mice. Finally, we established that B cell unresponsiveness to antigen in aging wild type mice (1 year plus) was equivalent to that noted in 3-month-old hCR2high mice. This data provides evidence that 3-month-old hCR2high mice have a humoral immune system resembling aged mice and suggests that further examination of the precise molecular and cellular parallells between aged wild type mice and 3-month-old hCR2high mice could provide an important insight into the mechanisms which lead to B cell unresponsiveness in the aging immune system.

Background Eribulin mesylate is approved for the treatment of metastatic breast cancer (mBC) after two prior chemotherapy regimens including an anthracycline or a taxane in either the metastatic or adjuvant setting. Eribulin in combination with trastuzumab (E+T) has demonstrated tolerability and anti-tumor activity in phase I and II trials but is not FDA-approved for the treatment of HER2-positive mBC. Case series and retrospective research have noted the use of E+T in clinical practice. We sought to describe patient characteristics and long-term outcomes of treatment with E+T for HER2-positive mBC patients treated outside of clinical trials in the US. Methods US-based community oncologists from an open network of over 7,000 oncologists, hematologists, and urologists were invited to participate in identifying HER2-positive mBC patients treated with E+T between 01/01/11 and 12/31/13 outside of clinical trials. Data were collected from 03/18/2016 until 09/01/2016. Providers completed an electronic case report form (CRF) by abstracting data on disease characteristics, treatment patterns, disease response (per provider assessment), adverse events (Aes), and date of death. Duration of treatment and overall survival (OS) were calculated from the initiation of the E+T regimen. The target sample size was 60 patients and patients were selected according to resource available for chart data abstraction. Results Twenty-three providers submitted CRFs for 62 total patients. After data collection, 59 of 62 submitted records were validated for analysis. At mBC diagnosis, 69.4% of patients were ER/PR negative and 42.4% of patient had de novo stage IV disease. At initiation of E+T, the median age was 57 years and 81.4% were ECOG-OS 0/1. Mean length of follow-up from the initiation of any therapy was 33.6 months. Twenty-two (37.3%) patients initiated E+T as their first- or second-line of treatment; those remaining were in third-line or greater. At initiation of E+T, 72.8% of patients had prior treatment with trastuzumab in combination with chemotherapy, 25.4% had prior trastuzumab in combination with pertuzumab and chemotherapy, and 16.9% had received TDM-1. Mean duration of E+T treatment was 5.2 months (SD=2.4). A response (complete [CR] or partial [PR]) was recorded by the providers for 64.4% of patients (not independently verified). The most common Aes reported were fatigue (67.8%), weakness (50.8%), decreased appetite (28.8%), decreased hemoglobin (27.1%), peripheral neuropathy (25.4%), and neutropenia (18.6%). At the end of the study period, 34 patients (57.6%) were deceased; the median OS from the initiation of E+T was 23.9 months (95% CI: 17.8-30.4). Conclusions In a small cohort of patients treated with E+T in the community setting, the observed response rate of 64.4% (CR+PR) was comparable to that of a prior phase II trial of E+T which reported an ORR with first-line E+T of 71.2% overall, 77.4% among T-naïve and 61.9% in T-pretreated patients. Further research is warranted to examine the tolerability and efficacy of E+T for metastatic HER2-positive breast cancer patients in different treatment settings. Citation Format: Mougalian SS, Copher R, McAllister L, Radtchenko J, Wang EC, Broscious M, Yu H-T, Kish J. Outcomes of real-world use of eribulin plus trastuzumab for HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-28.

Objectives: This study aims to evaluate the impact of cancer and its treatment on HbA1c-values among individuals with colorectal cancer (CRC) using glucose lowering drugs (GLDs). MethOds: Patients with primary CRC (1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011) were selected from the Eindhoven Cancer Registry and linked to the PHARMO Database Network including out-patient pharmacy and clinical laboratory data. Patients with more than two years of GLDs use prior to cancer diagnosis were included. Linear mixed effects models were conducted to evaluate changes in HbA1c for colon cancer (CC) and rectal cancer (RC) patients in the four years around CRC diagnosis. Results: Of all CRC patients (n= 4,714), 294 (6%) GLDs users with CC and 144 (3%) with RC were selected. In the crude model, mean HbA1c at cancer diagnosis was 6.9% (51.6 mmol/ mol) among CC patients and 7.1% (53.5 mmol/mol) among RC patients. Among CC patients, HbA1c decreased with 0.12% per year (p= 0.0002) before cancer diagnosis in the adjusted model and after diagnosis it increased with 0.12% per year (p= 0.02). In subgroup analyses, effects on HbA1c were more pronounced in users of anti-anaemic preparations, these preparations are suggested to interfere with HbA1c. Among RC patients, HbA1c decreased before diagnosis with 0.18% per year (p= 0.0006), whereas after diagnosis it changed not-significantly. cOnclusiOns: Among users of GLDs, HbA1c decreased with 0.12%-0.18% (1-2 mmol/mol) per year before CRC diagnosis. Only among CC patients, HbA1c increased after diagnosis (0.12% per year; 1.3 mmol/mol). In (un)diagnosed cancer patients the HbA1c measure to visualise glycaemic control might be influenced by anti-anaemic preparations.Objectives: Castration resistant prostate cancer (CRPC), which occurs in 10-20% of patients with prostate cancer (PC), has had a historically poor prognosis. However, there are a number of emerging treatment options. The aim of this study was to describe the real-world treatment patterns of CRPC in Japan. MethOds: A retrospective chart review of patients with mCRPC (N= 445) was conducted from December 2014 to February 2015 with urologists (N= 176) from online physician panels. Charts from the most recent patient visits meeting the inclusion criteria were used. Patient demographics, health history, healthcare resource use, treatment information, and clinical outcomes were entered into an online data collection form. Results: Patients (N= 445) were an average of 73.57 years old (SD= 8.34), had been diagnosed with PC for 5.12 years (SD= 6.22), and had been castration resistant for 2.31 years (SD= 1.98). Androgen deprivation therapy was used among 43.64% of patients in 1st line and 40.68% in 4th line. Enzalutamide and abiraterone were also common, though more so in later lines because of their recent availability (used among 14.46% and 8.73%, respectively, of patients in 1st line and 40.68% and 20.34%, respectively, in 4thline). NSAIDs and opioids were used frequently for pain management. The prese...

Objectives: Leading medical professional societies (eg, ASCO, ESMO, NCCN) have recently released frameworks to facilitate discussions on the value of cancer therapies. This literature review summarizes recent trends on the concept of evaluating value in cancer care, using mCRC as an example. MethOds: Relevant publications were identified using predetermined search criteria in Medline (01/01/2005-12/31/2015) and abstracts presented at key conferences (01/01/2015-12/31/2015). Publications were reviewed if they addressed the following topics: providers/prescriber oncology value frameworks, factors influential for payer/reimbursement decision making in oncology, and components of "value assessment" in oncology. Results: From 13,914 unique results, 322 described mCRC-related pharmacotherapies; 90 met the inclusion criteria (46 in Europe and 39 in US; some covered > 1 country). Value evaluations published as journal articles increased more steadily across the review timeframe in Europe:

Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate and adaptive immunity. We have employed two novel, orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins downregulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterised, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.