tbuckley/cabot-search huggingface dataset:
Abstract IA05: Emerging therapeutic strategies for androgen indifferent prostate cancer
Authors: Himisha Beltran
Journal: Cancer Research (2018)

Abstract The development of castration resistance in prostate cancer most commonly involves reactivation of androgen receptor (AR) signaling; this knowledge has informed the clinical development of potent AR-targeted agents now commonly used in the clinic. However, a subset of prostate cancers may evolve under therapeutic pressure of the AR towards non-AR driven, or “androgen indifferent,” disease. This has been associated with aggressive clinical features with repeat biopsies enriched with TP53 and RB1 genomic loss, overexpression of MYCN, epigenetic changes, and activation of alternative lineage programs such as neuronal and neuroendocrine pathways. One extreme manifestation is complete transformation to a small cell/neuroendocrine carcinoma with loss of AR expression. Although castration-resistant neuroendocrine prostate cancer evolves clonally from prostate adenocarcinoma likely through a trans-differentiation process, it acquires molecular alterations seen in other poorly differentiated neuroendocrine cancers. This talk will focus on emerging biomarker-driven therapeutic strategies for androgen-indifferent disease, including updates on targeting the N-myc/Aurora kinase A complex, the potential role for epigenetic therapies, and new data to inform ADC and immunotherapy development for this subset. Citation Format: Himisha Beltran. Emerging therapeutic strategies for androgen indifferent prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA05.
Correlation of mesothelin expression and CD8 tumor infiltrating lymphocytes with prognosis in cholangiocarcinoma.
Authors: Paul Raymond Kunk, Joseph Mounir Obeid, Kevin Winters, Patcharin Pramoonjago, Dirk G. Brockstedt, Chan C. Whiting, Amanda Enstrom, Edward B Stelow, Todd W. Bauer, Craig L. Slingluff, Osama E. Rahma
Journal: Journal of Clinical Oncology (2017)

e15650 Background: Cholangiocarcinoma (CC) is a rapidly progressing malignancy with an unmet treatment need. Little is known about the CC tumor immune microenvironment or about relevant antigenic targets. We hypothesized that lack of T cell infiltration or PD-L1 expression may identify patients at high risk of death, and that mesothelin may be a relevant antigenic target. Methods: A retrospective analysis was conducted of CC tumors at the University of Virginia from 2000-2014. TMAs were constructed of 3-4 cores from each tumor and were stained by IHC for CD4 and CD8 tumor infiltrating lymphocytes (TILs), mesothelin and PD-L1. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. TILs and protein expression were analyzed for association with overall survival, grouped as high or low expression based either on the median or the 33 rd percentile. Correlation with overall survival was assessed using a log rank test and a classification and regression tree with p-values &lt; 0.05 being considered statistically significant. Results: Ninety-nine tumors were available for analysis: 26 intrahepatic, 37 hilar, and 36 distal. PD-L1 and mesothelin expression &gt; 1% of tumor cells were found in 16% and 92% of tumors, respectively. CD4 and CD8 TILs were found in nearly all tumors (98% and 96%), with the majority showing intraepithelial CD4 and CD8 infiltration (73% and 68%). There were no significant associations between survival and PD-L1, mesothelin, or CD4 and CD8 infiltration. However when considered together, the group with low mesothelin/low CD8 (each below 33 rd percentile) had worse survival (9.1 months) compared to high mesothelin/high CD8 (25 months), high mesothelin/low CD8 (30.1 months) and low mesothelin/high CD8 (26.1 months), p = 0.015. Conclusions: CC tumors that lack CD8 infiltration and mesothelin expression have a poor prognosis. Mesothelin represents an attractive target in cholangiocarcinoma, opening the door for future immunotherapy for CC.
Risk factors for pneumonitis in solid tumors treated with anti-programmed death-1 therapy: A case-control study.
Authors: Pengfei Cui, Zhefeng Liu, Guoqiang Wang, Junxun Ma, Yuanyu Qian, Fan Zhang, Chun Han, Yaping Long, Ye Li, Xuan Zheng, Danyang Sun, Jing Zhang, Shangli Cai, Shun Chang Jiao, Yi Hu
Journal: Journal of Clinical Oncology (2018)

e15132 Background: Despite its great efficacy in patients with solid tumors, immune checkpoint blockade (ICB) might also lead to a series of inflammatory effects known as immune-related adverse events (irAEs) as results of imbalance of immune system homeostasis. Of these, ICB-related pneumonitis may be infrequent but potentially life-threatening. Previous studies have clarified the clinical features, diagnosis and management of ICBs related-pneumonitis thoroughly, nevertheless, the risk factors of ICBs-related pneumonitis are poorly studied directly. Methods: This case-control study was proposed to describe the clinical features and identify the risk factors for ICB-related pneumonitis in patients undergoing anti-PD1 therapy. All patients who developed pneumonitis during the treatment in the Cancer Center of the Chinese People’s Liberation Army from September 2015 to September 2017 were included. Two controls per case were matched in accordance with a propensity-score matching algorithm that accounted for confounding effects of individual baseline variables. Demographic and clinical features were extracted from their medical records. Results: In total, 55 cases and 110 controls were included in this study. The onset time of pneumonitis ranged from 2 to 277 days (median: 85 days). Of these, 85.7% of patients were resolved/improved via steroid therapy (12 of 14). No association was observed between risk of pneumonitis and smoking status or primary lung cancer. Significant risk factors for the pneumonitis induced by anti-PD-1 therapy contained: prior thoracic radiotherapy, underlying lung condition and combination therapy with odds ratios of 3.34 (1.51-7.39), 2.86 (1.45-5.64) and 2.73 (1.40-5.31) respectively. In multivariate logistic regression analysis, prior thoracic radiotherapy, combination therapy and underlying lung condition were significantly related to the risk of pneumonitis. Conclusions: Risk of anti-PD-1-related pneumonitis is associated with prior thoracic radiotherapy, underlying lung condition and combination therapy. Clinicians should beware of these characteristics in patients receiving anti-PD-1 immunotherapy to optimize clinical safety and efficacy.
Quantitative urinary KRAS for treatment decisions in patients with metastatic colorectal cancer (mCRC).
Authors: Vladislava Melnikova, Cecile Rose T. Vibat, Yan Ning, Raluca Dana Agafitei, Diana L. Hanna, Saege Hancock, Mark G. Erlander, Heinz-Josef Lenz, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2016)

e15011 Background: Mutant KRAS is a predictive biomarker for mCRC patient treatment selection. Recent technological advances enable quantification of mutational load in circulating tumor (ct) DNA, with the potential to assess treatment response in lieu of or in addition to imaging. Methods: 9 patients with mutant KRAS G12/13 in the tumor tissue were evaluated in a blinded biomarker study of mCRC patients receiving chemotherapy (n = 6), chemotherapy and surgical treatment (n = 2), or immunotherapy in the 3rd line (n = 1). Urine and plasma specimens were collected at pre-treatment, 2 weeks after starting chemotherapy, then at monthly intervals. ctDNA was extracted and analyzed with assays employing wild-type blocker mutation enrichment followed by next generation sequencing-based detection (MiSeq). Results were reported as mutant copies per 10^5 genome equivalents. Results: Of 9 patients, 8 had evaluable urine or plasma specimens at baseline and 7 had serial collections for up to 17 months. Overall, tumor tissue concordance of G12/13 KRAS mutations was observed in 6 of 8 baseline patients by urine and 7 of 8 patients by plasma. 7 of 8 patients on 1st line FOLFOX or chemotherapy and surgery showed a significant decrease in urine ctDNA KRAS (ctKRAS) as early as 2 weeks into therapy, and this molecular response translated to subsequent documented radiographic response. In our patient with longest follow up and with documented progressive disease, an increase in urinary ctKRASG12/13 signal was observed 2 months prior to radiographic progression. In the patient on immunotherapy, positive ctDNA signal remained throughout the course of treatment. Conclusions: The dynamics of urine ctKRAS mutational load correlated with radiographic responses, depicting the utility of urine ctDNA for disease monitoring in mCRC patients. Results support the potential of ctDNA to enable early identification of progression well before imaging, guide patient transition to other therapies, and improve evaluation of maintenance or experimental therapies prior to compromise in patients’ performance status and organ function.
The future of precision medicine, strengths and weaknesses: An expert position paper.
Authors: Vicente Guillem Porta, Antonio Anton, Enrique Aranda, Alfredo Carrato, Manuel Constenla, Juan J. Cruz-Hernández, Eduardo Diaz Rubio, Jesus Garcia-Foncillas, Pedro Gascon, Rafael Lopez, Fernando Caballero, Diana Monge, Cristina Garcia de Leonardo, Francisco J Campos, Carlos Camps
Journal: Journal of Clinical Oncology (2018)

e18879 Background: Precision medicine (PM) is an emerging field. Guidelines are needed to develop this approach in an efficient and sustainable way. Methods: Twenty-one Spanish top oncologists met to reach consensus on PM, considering 5 aspects: efficacy, efficiency, organization, humanization and training. The meeting was promoted by the ECO Foundation (Excellence and Quality in Oncology) with the collaboration of Francisco de Vitoria University (Madrid). Results: In terms of efficacy, PM is a reality, but more independent studies are needed to determine its role within the current therapeutic arsenal. PM is inefficient if it focuses on the development of new drugs with similar efficacy than alternatives for the same targets. Genetic analysis allows identifying subgroups of patients with very low prevalence. This fact hinders the development of conventional phase III studies and suggests implementing other strategies for monitoring patients and analyzing the effectiveness of PM, i.e., through the use of multicentric clinical, genetic and molecular records. Regarding efficiency, centralizing analytical procedures in reference centers and carrying out technology purchasing processes at a European level is necessary. Although financing shall be mainly public, public-private collaboration shall be taken into account. Comprehensive measurement of health outcomes, including Health-Related Quality of Life (HRQOL), Patient Reported Outcome Measures (PROMs) and Patient Reported Experience Measures (PREMs) is critical, as well as procedure standardization. The organization of health services shall be networked and include new roles such as clinical bioinformatics or big data experts. Training oncologists in fields such as genetics or in the evaluation of HRQOL, PROMs and PREMs is necessary. In addition, it is of paramount importance to guarantee humane medical practice, preserving personalized attention against the uncritical intrusion of technology. Conclusions: Although PM is a reality, defining it conceptually and setting its limits is necessary to achieve a greater development of the field. The positioning of professionals such as the ones presenting this paper may serve as the basis for its sustainable development
Current trends and inpatient outcomes of venous thromboembolism-related admissions among patients with diffuse large B-cell lymphoma: A Nationwide Inpatient Sample Database analysis.
Authors: Xavier Alberto Andrade Gonzalez, Harry Eduardo Fuentes Bayne, Hashim Mann, Andres Mendez Hernandez, Alfonso Javier Tafur, Roberto Antonio Leon-Ferre
Journal: Journal of Clinical Oncology (2018)

e19546 Background: Up to 16% of patients with diffuse large B-cell lymphoma (DLBCL) will develop venous thromboembolism (VTE), which is associated with increased healthcare expenditure. However, annual rates of VTE-related hospitalizations, their cost burden and in-patient mortality remain largely unknown. We aim to describe recent trends in annual rates of VTE-related admissions, cost of hospitalization, length of stay and in-patient mortality in patients with DLBCL. Methods: We identified adult patients with DLBCL from the Nationwide Inpatient Sample database from 2010 to 2014. Patients were identified using ICD9-CM coding. Hospitalizations where VTE was among the top-three diagnoses were considered a VTE-related admission. We compared in-hospital outcomes between VTE-related and non VTE-related admissions using Chi-squared and Mann-Whitney U-test and linear regression for trend analysis. Results: From a total of 35,887 DLBCL admissions, 1,189 (3.3%) were VTE-related. Patients were predominantly white (72%), male (54%), with a median age of 68 years (range 18-98). There was a non-significant trend towards a decline in the annual rates of VTE-related admissions (2010: 3.77% vs 2014: 2.70%, p = 0.37). However, the median length of stay (5 vs 4 days p < 0.01) and cost of hospitalization (median: $41,904 vs $34,561, p < 0.01) were significantly higher in patients with a VTE-related admission. In-hospital mortality was similar in VTE vs non VTE-related admissions (5.7% vs 5.4%, p = 0.64). Conclusions: While the rate of VTE-related admissions in patients with DLBCL has decreased between 2010 and 2014, length of stay and healthcare expenditure was higher for VTE-related admissions. Possibly newer therapies for DLBCL have contributed to decrease VTE occurrence, nonetheless development of DLBCL-specific VTE risk-stratification models and earlier intervention may help prevent VTE and improve resource utilization. Non-VTE VTE p N 34,698 1,189 Age -yr median 68 70 Male (%) 18,568 (54) 545 (46) Length of stay -days median 4 5 0.001 Cost -median (USD) 34,561 41,904 0.001 Inpatient Mortality (%) 1,875 (5.4) 68 (5.7) 0.37
Phase I study of the pan-HER inhibitor neratinib given in combination with everolimus, palbociclib or trametinib in advanced cancer subjects with <i>EGFR</i> mutation/amplification, <i>HER2</i> mutation/amplification or <i>HER3/4</i> mutation.
Authors: Sarina Anne Piha-Paul, Siqing Fu, David S. Hong, Filip Janku, Daniel D. Karp, Aung Naing, Shubham Pant, Jordi Rodon Ahnert, Vivek Subbiah, Apostolia Maria Tsimberidou, Timothy Anthony Yap, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2018)

TPS2611 Background: Over expression and aberrant function of ErbB receptor tyrosine kinases (EGFR, HER2, HER3 and HER4) contributes to tumorigenesis. Multiple drugs targeting EGFR or HER2 are already approved for various cancers. In spite of clinical successes with EGFR or HER2 inhibitors, single-agents are prone to drug resistance due to aberrant or compensatory activation of additional downstream signaling pathways. We sought to determine whether neratinib, a potent irreversible pan-HER tyrosine kinase inhibitor, would be safe and efficacious in combination with approved inhibitors of mTOR, CDK4/6, or MEK. Methods: This is an investigator-initiated, single-center, non-randomized, multi-arm phase I trial of subjects ≥18 years old with measurable advanced solid tumors with no curative therapeutic options and whose tumors harbor somatic mutations or amplifications in ErbB genes. Prior HER2 or EGFR directed therapy are allowed. The study will have 3-arms: Arm 1: neratinib + everolimus, Arm 2: neratinib + palbociclib, Arm 3: neratinib + trametinib. Patients are selected for each arm at investigator's discretion based on tumor type and molecular aberrations present. A standard 3 + 3 dose-escalation design will be utilized and patients will be recruited into five dose levels for each arm of the study. Additional subjects will be treated in dose-expansion cohort(s) once the MTD has been established. A treatment cycle is 28 days. Primary endpoint is determination of the maximum tolerated dose and dose limiting toxicities for each treatment arm. Secondary endpoints include pharmacokinetic and pharmacodynamic analysis along with preliminary anti-tumor efficacy. Prophylactic use of antidiarrheal medication is mandatory during first cycle. Imaging will be performed at 8 week intervals and response will assessed by RECIST v1.1. Enrollment to the study has already commenced. Clinical trial information: NCT03065387.
Chimeric Antigen Receptor T-Cell Therapy
Authors: Ndiya Ogba, Nicole M. Arwood, Nancy L. Bartlett, Mara Bloom, Patrick Brown, Christine Brown, Elizabeth Lihua Budde, Robert Carlson, Stephanie Farnia, Terry J. Fry, Morgan Garber, Rebecca A. Gardner, Lauren Gurschick, Patricia Kropf, Jeff J. Reitan, Craig Sauter, Bijal Shah, Elizabeth J. Shpall, Steven T. Rosen
Journal: Journal of the National Comprehensive Cancer Network (2018)

Patients with relapsed or refractory (R/R) cancers have a poor prognosis and limited treatment options. The recent approval of 2 chimeric antigen receptor (CAR) autologous T-cell products for R/R B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma treatment is setting the stage for what is possible in other diseases. However, there are important factors that must be considered, including patient selection, toxicity management, and costs associated with CAR T-cell therapy. To begin to address these issues, NCCN organized a task force consisting of a multidisciplinary panel of experts in oncology, cancer center administration, and health policy, which met for the first time in March 2018. This report describes the current state of CAR T-cell therapy and future strategies that should be considered as the application of this novel immunotherapy expands and evolves.
<i>Vital Signs</i>: State-Level Variation in Nonfatal and Fatal Cardiovascular Events Targeted for Prevention by Million Hearts 2022
Authors: Matthew D. Ritchey, Hilary K. Wall, Pamela L. Owens, Janet S. Wright
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Despite its preventability, cardiovascular disease remains a leading cause of morbidity, mortality, and health care costs in the United States. This study describes the burden, in 2016, of nonfatal and fatal cardiovascular events targeted for prevention by Million Hearts 2022, a national initiative working to prevent one million cardiovascular events during 2017-2021.Emergency department (ED) visits and hospitalizations were identified using Healthcare Cost and Utilization Project databases, and deaths were identified using National Vital Statistics System data. Age-standardized Million Hearts-preventable event rates and hospitalization costs among adults aged ≥18 years in 2016 are described nationally and across states, as data permit. Expected 2017-2021 event totals and hospitalization costs were estimated assuming 2016 values remain unchanged.Nationally, in 2016, 2.2 million hospitalizations (850.9 per 100,000 population) resulting in $32.7 billion in costs, and 415,480 deaths (157.4 per 100,000) occurred. Hospitalization and mortality rates were highest among men (989.6 and 172.3 per 100,000, respectively) and non-Hispanic blacks (211.6 per 100,000, mortality only) and increased with age. However, 805,000 hospitalizations and 75,245 deaths occurred among adults aged 18-64 years. State-level variation occurred in rates of ED visits (from 56.4 [Connecticut] to 274.8 per 100,000 [Kentucky]), hospitalizations (484.0 [Wyoming] to 1670.3 per 100,000 [DC]), and mortality (111.2 [Vermont] to 267.3 per 100,000 [Mississippi]). Approximately 16.3 million events and $173.7 billion in hospitalization costs could occur during 2017-2021 without preventive intervention.Million Hearts-preventable events place a considerable health and economic burden on the United States. With coordinated efforts, many of these events could be prevented in every state to achieve the initiative's goal.
Phase II trial of sorafenib plus doxorubicin (SD) in patients (Pts) with advanced hepatocellular carcinoma (HCC) after progression of disease (PD) on sorafenib (S).
Authors: Imane H. El Dika, Marinela Capanu, Joanne F. Chou, James J. Harding, Anna D. Hrabovsky, Richard K. G. Do, Jinru Shia, Joseph Germino, Eileen Mary O'Reilly, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2018)

4080 Background: SD may synergistically improve outcome after PD on S by promoting ASK-1 mediated apoptosis through RAF-1 inhibition. In a prior retrospective analysis of 14 pts who in the lack of other choices of therapy received SD after PD on S, progression free survival (PFS) and overall survival (OS) were 3.4 and 10.1 months (m) respectively Methods: A non-randomized, open label, single institution, single arm phase II study of SD in pts with histologically confirmed advanced HCC. Eligibility: RECIST 1.1 radiologic PD on S, ECOG 0-1, Child-Pugh A, and adequate major organ function. Therapy: S 400mg twice a day (once a day if bilirubin (B) ≥1.3mg/dl ≤3mg/dl) and D 60mg/m2 (30mg/m2 if B ≥1.3 mg/dl ≤3mg/dl) on day 1 of 3-week cycle. Cross-sectional imaging was performed every 3 cycles. The primary endpoint was OS at 6m (OS6), based on Simon two-stage design, unacceptable OS6 50%, acceptable OS6 72%, type I and II errors 5 and 15% respectively. Secondary endpoints included PFS, OS, response rate by RECIST 1.1, and associations between duration of prior S and OS and PFS. Baseline and on-treatment biopsies evaluated ASK-1 and p-ERK expression levels (separate report) Results: N = 30 pts enrolled. The majority were male (86%), median age 64 years (range 24-82), 16 pts had hepatitis (53%). OS6 was 76.6% [95%CI: 57.2-88.1%]. Median doses of D and S were 94mg and 380mg respectively. OS was 8.6 [95%CI: 7.3-12] m, and PFS was 3.6 [95%CI: 2.4-4.4] m. There were 3 (10.7%) partial responses and 17 (60.7%) stable disease. Median duration of prior S treatment was 3.3 [range: 0.9-27] m. Neither OS nor PFS were associated with previous S duration (p value 0.11 and 0.15 respectively). Grade 3-4 adverse events occurring in ≥ 10% of pts: neutropenia (16%), febrile neutropenia (10%), lymphopenia (43%), anemia (10%), thrombocytopenia (10%), elevated AST (23%) and ALT (10%), hypophosphatemia (10%), and fatigue (10%). There was no treatment related death. Conclusions: Despite the study meeting its primary endpoint, SD resulted in significant toxicity and a median OS of 8.6 m. Based on front-line evaluation of SD and the results reported herein, further development of SD in HCC is not warranted Clinical trial information: NCT01840592.