Purpose:The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. Patients and Methods:STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib...
21h
Purpose:Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. Patients and Methods:In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut...
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Purpose:To evaluate the safety and feasibility of preoperative locoregional cytokine therapy (IRX-2 regimen) in early-stage breast cancer, and to evaluate for intratumoral and peripheral immunomodulatory activity. Patients and Methods:Sixteen patients with stage I–III early-stage breast cancer (any histology type) indicated for surgical lumpectomy or mastectomy were enrolled to receive preoperative locoregional immunotherapy with the IRX-2 cytokine biological (2 mL subcutaneous x 10 days to periareolar...
21h
Purpose:Patients with metastatic prostate cancer are increasingly presenting with treatment-resistant, androgen receptor–negative/low (AR–/Low) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here, we explore the role of the developmental transcription factor Sox9 in the process of prostate cancer therapy response...
21h
Purpose:Immunogenicity derived from the murine scFv, a major molecular compomemt of chimeric antigen receptors (CARs), may limit the persistence of CAR T cells, resulting in tumor relapse of patients in complete remission (CR). In this study, we developed a humanized anti-CD19 scFv CAR-T (hCAR-T) to treat patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL). Patients and Methods:In this one-arm, open-labeled study, we infused the T cells modified with hCAR to patients with r/r...
21h
Purpose:PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of...
21h
Purpose:To determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of cervical intraepithelial neoplasia (CIN) 3. Patients and Methods:We conducted a prospective, randomized, multicenter, open-label, phase II clinical trial of GX-188E in CIN3 patients positive for human papillomavirus (HPV) type 16/18. The primary endpoint was to determine the histopathologic regression to ≤CIN1 at visit seven (V7; 20 weeks after the first GX-188E injection), and an extension study...
21h
Purpose:Immune components of the tumor microenvironment (TME) have been associated with disease outcome. We prospectively evaluated the association of an immune-related gene signature (GS) with clinical outcome in melanoma and non–small cell lung cancer (NSCLC) tumor samples from two phase III studies. Experimental Design:The GS was prospectively validated using an adaptive signature design to optimize it for the sample type and technology used in phase III studies. One-third of the samples were...
21h
Purpose:TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion–positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion–positive cancers. Experimental Design:Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were...
21h
Purpose:Glioblastoma (GBM) is one of the most aggressive and lethal cancer types in humans. The standard treatment approach is surgery followed by chemoradiation. However, the molecular mechanisms of innate tumor radioresistance remain poorly understood. Experimental Design:We tested the expression of Smoothened (Smo) in primary and recurrent GBM tissues and cells. Then, we determined radiation effectiveness against primary and recurrent GBM cells. Lastly, the functional role of Smo in GBM radioresistance...
21h
Purpose:Although KRAS represents the most commonly mutated oncogene, it has long been considered an "undruggable" target. Novel covalent inhibitors selective for the KRASG12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS–MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance. Experimental Design:A panel of KRASG12C cell lines were treated with the KRASG12C inhibitors ARS-1620 and AMG...
21h
Purpose:Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma. Experimental Design:Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8+ T cells and their functional restoration by ex vivo treatment with anti–PD-1 and TGFβ inhibitors. Results:We...
21h
Purpose:Tumor cells from patients with lung cancer are expelled from the primary tumor into the blood, but difficult to detect in the peripheral circulation. We studied the release of circulating tumor cells (CTCs) during surgery to test the hypothesis that CTC counts are influenced by hemodynamic changes (caused by surgical approach) and manipulation. Experimental Design:Patients undergoing video-assisted thoracic surgery (VATS) or open surgery for (suspected) primary lung cancer were included....
21h
21h
Background:There is tremendous potential to leverage the value gained from integrating electronic health records (EHR) and population-based cancer registry data for research. Registries provide diagnosis details, tumor characteristics, and treatment summaries, while EHRs contain rich clinical detail. A carefully conducted cancer registry linkage may also be used to improve the internal and external validity of inferences made from EHR-based studies. Methods:We linked the EHRs of a large, multispecialty,...
21h
Background:We examined the nicotine metabolite ratio's (NMR) relationship with smoking intensity, nicotine dependence, and a broad array of biomarkers of exposure and biological effect in commercial cigarette smokers. Methods:Secondary analysis was conducted on two cross-sectional samples of adult, daily smokers from Wave 1 (2013–2014) of the Population Assessment of Tobacco Use and Health (PATH) Study and baseline data from a 2014–2017 randomized clinical trial. Data were restricted to participants...
21h
Background:Long-term antiviral therapy (AVT) for chronic hepatitis B (CHB) reduces the risk of hepatocellular carcinoma (HCC). We assessed the temporal trends in the incidence of HCC over time during long-term AVT among Asian patients with CHB. Methods:Patients with CHB receiving entecavir/tenofovir (ETV/TDF) as a first-line antiviral were recruited from four academic hospitals in the Republic of Korea. We compared the incidence of HCC during and after the first 5 years of ETV/TDF treatment. Results:Among...
21h
We conducted a systematic review and meta-analysis of observational studies evaluating survival in patients with anal cancer, according to human papillomavirus (HPV) DNA, p16INK4a, and combined HPV DNA/p16INK4a status. We systematically searched PubMed, EMBASE, and Cochrane Library databases to identify studies published in English until July 25, 2018, directly providing or allowing estimation of survival of patients with anal cancer according to the presence of HPV DNA and/or overexpression of p16INK4a....
21h
Background:Large-scale cancer epidemiology cohorts (CEC) have successfully collected, analyzed, and shared patient-reported data for years. CECs increasingly need to make their data more findable, accessible, interoperable, and reusable, or FAIR. How CECs should approach this transformation is unclear. Methods:The California Teachers Study (CTS) is an observational CEC of 133,477 participants followed since 1995–1996. In 2014, we began updating our data storage, management, analysis, and sharing...
21h
Background:Efficient capture of routine clinical care and patient outcomes is needed at a population-level, as is evidence on important treatment-related side effects and their effect on well-being and clinical outcomes. The increasing availability of electronic health records (EHR) offers new opportunities to generate population-level patient-centered evidence on oncologic care that can better guide treatment decisions and patient-valued care. Methods:This study includes patients seeking care...
21h
Background:Like other cancer epidemiologic cohorts, the California Teachers Study (CTS) has experienced declining participation to follow-up questionnaires; neither the reasons for these declines nor the steps that could be taken to mitigate these trends are fully understood. Methods:The CTS offered their 6th study questionnaire (Q6) in the fall of 2017 using an integrated, online system. The team delivered a Web and mobile-adaptive questionnaire to 45,239 participants via e-mail using marketing...
21h
Background:Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms. Methods:Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs,...
21h
Background:Large-scale prospective cohorts traditionally use English, paper-based, mailed surveys, but Web-based surveys can lower costs and increase data quality, and multi-language surveys may aid in capturing diverse populations. Little evidence exists examining item response for multiple survey modalities or languages in epidemiologic cohorts. Methods:A total of 254,475 men and women completed a comprehensive lifestyle and medical survey at enrollment (2006–2013) for the Cancer Prevention Study-3,...
21h
Background:There is often a lack of transparency in research using online panels related to recruitment methods and sample derivation. The purpose of this study was to describe the recruitment and participation of respondents from two disparate surveys derived from the same online research panel using quota sampling. Methods:A commercial survey sampling and administration company, Qualtrics, was contracted to recruit participants and implement two Internet-based surveys. The first survey targeted...
21h
Background:Cleveland, Ohio, is home to three major hospital systems serving approximately 80% of the Northeast Ohio population. The Cleveland Clinic, University Hospitals Health System, and MetroHealth are direct competitors for primary and specialty care, and patient overlap between these systems is high. Fragmentation of health data that exist in silos at these health systems produces an overestimation of disease burden due to double and sometimes triple counting of patients. As a result, longitudinal...
21h
Background:Physical activity and sleep are behavioral risk factors for cancer that may be influenced by environmental exposures, including built and natural environments. However, many studies in this area are limited by residence-based exposure assessment and/or self-reported, time-aggregated measures of behavior. Methods:The Nurses' Health Study 3 (NHS3) Mobile Health Substudy is a pilot study of 500 participants in the prospective NHS3 cohort who use a smartphone application and a Fitbit for...
21h
Background:Previously, family-based designs and high-risk pedigrees have illustrated value for the discovery of high- and intermediate-risk germline breast cancer susceptibility genes. However, genetic heterogeneity is a major obstacle hindering progress. New strategies and analytic approaches will be necessary to make further advances. One opportunity with the potential to address heterogeneity via improved characterization of disease is the growing availability of multisource databases. Specific...
21h
Background:We field tested new-to-market portable, digital applications to assess hearing, pulmonary, and cognitive function to determine the feasibility of implementing these applications across a range of age groups in the pilot phase of the 10,000 Families Study (10KFS), a new Minnesota family–based prospective cohort study. Methods:We followed manufacturer recommended protocols for audiometry (SHOEBOX Inc), spirometry (NuvoAir), and the digital clock drawing test (dCDT; Digital Cognition Technologies...
21h
Background:Low socioeconomic status (SES) is associated with higher risk of certain gastrointestinal (e.g., colorectal, pancreatic, and liver) cancers in Western populations. Evidence is very limited in China, where correlates and determinants of SES differ from those in the West. Methods:The prospective China Kadoorie Biobank recruited 512,715 adults (59% women, mean age 51 years) from 10 (5 urban, 5 rural) regions. During 10 years of follow-up, 27,940 incident cancers (including 3,061 colorectal,...
21h
Background:Diet is associated with colorectal cancer survival. Yet, adherence to nutrition guidelines is low among colorectal cancer survivors. Methods:We conducted a pilot trial among colorectal cancer survivors to evaluate a 12-week remote dietary intervention. Participants received print materials and were randomized (1:1) to intervention (website, text messages) or wait-list control. Primary outcomes included feasibility and acceptability. We also explored change in diet from 0 to 12 and 24...
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Background:A large number of studies have been conducted to investigate associations between genetic variants and esophageal cancer risk in the past several decades. However, findings from these studies have been generally inconsistent. We aimed to provide a summary of the current understanding of the genetic architecture of esophageal cancer susceptibility. Methods:We performed a comprehensive field synopsis and meta-analysis to evaluate associations between 95 variants in 70 genes or loci and...
21h
Background:Regular physical activity (PA) is associated with a lower risk of several types of cancers. However, two-thirds of overweight/obese adults are not sufficiently active; this, in combination with the unfavorable effect of excess body weight, puts them at a greater risk for cancer. One reason that these individuals do not engage in enough PA may be their lack of motivation to change their current behavior due to the perception of putting in effort for possible future gain without obvious...
21h
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