tbuckley/cabot-search huggingface dataset:
The changing paradigm of management in melanoma brain metastases.
Authors: Rahul Ladwa, Victoria Atkinson
Journal: Journal of Clinical Oncology (2017)

e21027 Background: Brain metastases (BM) are a frequent complication in patients with metastatic melanoma (MM). We aimed to explore the outcome of these patient with modern therapeutic options. Methods: We retrospectively analysed 142 patients diagnosed with BM at a single site in Brisbane, QLD, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected. Results: Patient characteristics included a median age of 57(17-82) years, presence of seizures (N = 18), dexamethasone use (N = 106) and BRAF mutant mm (N = 117). BM were categorised as solitary (N = 45), 2-6 (N = 65), more than 6 (N = 28) and leptomeningeal only (N = 4). BM were found on systemic treatment in 62 patients. Tyrosine kinase inhibitor (TKI) was used after the diagnosis of BM (N = 50). Management of BM included surgical resection (N = 39), Stereotactic radiosurgery (SRS) (N = 33) and Whole Brain Radiotherapy (N = 45). Immunotherapy with Ipilimumab (N = 35), Pembrolizumab (N = 36) and Nivolumab (N = 21) was used. With a median follow up of 8 months, 115 patients had died, 112 from MM. Death occurred due to progressive disease in the brain (N = 66), systemically (N = 13) or both (N = 33). The number of patients dying of mm were statistically higher on dexamethasone, increasing number of BM, BRAF mutants, absence of surgical resection or SRS and absence of immunotherapy use. Statistically Improved OS were found with solitary BM, treatment naive patients and surgical management of BM. In BRAF mutant patients who were TKI naïve at diagnosis of BM the mean OS was 14.7 versus 6.5 months in patients on TKI treatment (P &lt; 0.05). In BRAF wild type patients mean OS was 11.7 months with PD1 use versus 8.3 months without PD1 use (Not Significant). Conclusions: Despite improvements in systemic treatment for mm the outcomes of those with BM remains poor. Solitary BM amenable to resection or ablation provides optimal treatment. The use of TKIs in BRAF mutant mm post BM diagnosis and the use of immunotherapy are effective treatment options.
Real-world first-line advanced gastric cancer in western and Asian countries: Treatment patterns and impact on quality of life (QOL).
Authors: Sun Young Rha, Kei Muro, Alex Rider, Gregory Maglinte, Marta Contente, Beth Clarke, Emiliano Calvo
Journal: Journal of Clinical Oncology (2018)

e16018 Background: Given the 5-year survival rate for advanced/metastatic gastric cancer (AGC) is only ~5%, it is important to understand real-world first-line (1L) treatment patterns and QOL in these patients. Methods: Real-world data were collected through a cross-sectional survey administered to physicians in Western (Canada, France, Germany, Italy, Spain, UK) and Asian (Korea, Japan) countries, Nov 2016 to Mar 2017. Each physician provided data on the next ~8 consecutive presenting patients (AGC diagnosis, ≥18 years old, not in a clinical trial); ~4 patients were currently on any line of advanced treatment. European and Japanese patient-reported health utility and overall health were assessed with the EQ-5D utility index (scores ranging 0 [dead] to 1.0 [full health]; scores < 0 implying a health state worse than dead) and Visual Analog Scale (VAS; scores ranging 0 to100, higher scores indicating better overall health), respectively. Results: A total of 360 physicians provided information for 1,132 patients currently on 1L active drug treatment for AGC. Most patients were male (66%), with ECOG PS of 0 or 1 (73%), had gastric vs. GEJ (71% vs. 28%) for primary site of disease, no prior gastrectomy (84%), and about half (48%) with ≥2 organs with metastases. Among those tested, 73% were HER-2 negative. Treatment patterns were similar across Western and Asian countries for platinum-based (81% vs 78%), fluoropyrimidine analogue-based (88% vs 85%), and HER2-directed-based (19% vs 13%) therapies. Though, differences persisted in anthracycline-based (24% vs 1%) therapies, use of triplet/doublet regimens, and duration of treatments. Relative to general population norms for ages 65-74 among Europeans and Japanese (EQ-5D index, 0.80-0.94 and 0.88; VAS, 72.0-81.7 and 76.6), 1L AGC patients had worse health utility [mean (SD) EQ-5D index score = 0.71 (0.29) and 0.76 (0.21)] and overall health [mean (SD) VAS score = 58.3 (18.9) and 54.9 (20.8)]. Conclusions: While similar 1L treatment regimens were used in Western and Asian countries, real-world data identified meaningful reductions in patient-reported outcomes, and highlight the need for new treatment options to improve QOL in these patients.
Accurately identifying neoantigens for therapeutic and diagnostic use in immuno-oncology.
Authors: Sean Michael Boyle, Jie Wang, Ravi Alla, Eric Levy, Gabor Bartha, Jason Harris, Rena McClory, John West, Richard Chen
Journal: Journal of Clinical Oncology (2018)

e24148 Background: Neoantigens are increasingly critical in immuno-oncology as a therapeutic target for neoantigen-based personalized cancer vaccines and as a potential biomarker for immunotherapy response. However, the methods for identifying which neoepitopes are more likely to provoke an immune response remains an important challenge for improving both the effectiveness of neoantigen-based vaccines and enabling the potential use of neoantigens as a biomarker in immunotherapy. Methods: We sought to improve overall neoantigen identification performance by systematically improving critical components of our ACE ImmunoID assays and neoantigen pipeline. To improve MHC-epitope binding prediction, we trained neural networks on mass spectrometry derived MHC-epitope binding data, which produces a more accurate training set of peptides that have been processed, loaded, and shuttled natively into the HLA binding domain. HLA typing was improved through exome augmentation and optimized HLA typing algorithm. Other enhancements include RNA based somatic variant calling, somatic HLA mutation calling, peptide phasing, identification of indel and fusion derived neoepitopes, and comprehensive immuno-genomics biomarker reporting. Results: Our ACE augmented exome demonstrates high sensitivity and specificity for SNVs and indels. When compared with available MHC binding algorithms for specific HLA alleles, our MHC binding prediction algorithm consistently achieves a higher overall sensitivity and specificity. For example, our MHC class I-epitope binding prediction algorithm demonstrated an aggregative precision value of 0.88 across HLA alleles, as opposed to 0.50 for other widely used tools. To assess overall HLA-typing performance, we performed a blinded clinical HLA typing validation demonstrating 98% and 94% concordance with Class I and II results (respectively). Conclusions: Effective neoantigen identification requires an accurate variant detection and characterization pipeline built upon a comprehensive exome and transcriptome platform. We have developed an accurate solution for detection of neoantigens with emphasis on correct HLA typing and peptide presentation from a broad genomic footprint.
John Cunningham virus infection and the risk of colorectal cancer: A meta-analysis of case-control studies.
Authors: Lenka J Kimla
Journal: Journal of Clinical Oncology (2018)

e15650 Background: John Cunningham virus (JCV) is a human polyomavirus encoding T-antigen protein, which is implicated in carcinogenesis. JCV is prevalent in the upper and lower gastrointestinal track. Several studies have reported JCV association with the risk of developing colorectal cancer (CRC), however, these findings remain controversial. The aim of this study is to conduct the first meta-analysis of case-control studies to investigate if there is a significant association between JCV infection and risk of CRC. Methods: A systematic review was performed using PubMed to identify studies reporting JCV DNA prevalence in CRC. The strength of the association was estimated by odds ratio (OR) and 95% confidence intervals (95% CI). Results: Meta-analysis of CRC vs. controls showed that JCV infection increases the risk of CRC by 2-fold vs. matched normal tissues and 4.5-fold vs. non-CRC healthy controls (p = 0.0008 and p < 0.0001, respectively). Meta-analysis of adenoma vs. controls showed that JCV infection increases the risk of adenoma development by 5.7-fold vs. non-CRC healthy controls and 6.7-fold vs. matched normal tissues (p = 0.0004 and p = 0.0019, respectively). Results from a meta-analysis for T-antigen protein expression in JCV DNA positive samples showed a 10-fold increased risk of CRC development vs. matched normal tissues (p = 0.00447). Statistical significance was not found in meta-analysis of T-antigen protein expression for adenoma development vs. controls, however the number of studies included in the analysis was limited. Conclusions: The results of this meta-analysis of JCV infection and risk of CRC support the argument that JCV infection significantly increases the risk of colorectal cancer.
Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy
Authors: Paul Nghiem, Shailender Bhatia, Evan J. Lipson, William H. Sharfman, Ragini R. Kudchadkar, Andrew S. Brohl, Phillip A. Friedlander, Adil Daud, Harriet M. Kluger, Sunil A. Reddy, Brian C. Boulmay, Adam I. Riker, Melissa A. Burgess, Brent A. Hanks, Thomas Olencki, Kim Margolin, Lisa M. Lundgren, Abha Soni, Nirasha Ramchurren, Candice Church, Song Y. Park, Michi M. Shinohara, Bob Salim, Janis M. Taube, Steven R. Bird, Nageatte Ibrahim, Steven P. Fling, Blanca Homet Moreno, Elad Sharon, Martin A. Cheever, Suzanne L. Topalian
Journal: Journal of Clinical Oncology (2019)

PURPOSE Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus–positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1–positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION Here, we present the longest observation to date of patients with aMCC receiving first-line anti–programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.
TCT-840 The Impact of Transcatheter Aortic Valve Replacement on Short and Long-Term Outcomes in High Gradient Versus Low Flow – Low Gradient Versus Paradoxical Low Flow – Low Gradient Severe Aortic Stenosis: A network meta-analysis of randomized controlled trials
Authors: Abdulah Alrifai, Fahed Darmoch, Mohamad Soud, None Amjad Kabach, Amr Idris, M Chadi Alraies, Zaher Fanari
Journal: Journal of the American College of Cardiology (2018)
Association of clinical progression at initiation of a life-extending therapy (LET) in metastatic castration-resistant prostate cancer (mCRPC) with poor prognosis: Results of the CATS database.
Authors: Stephane Oudard, Anne-Claire Hardy-Bessard, Sylvestre Le Moulec, Umberto Basso, Alison Jane Birtle, Alastair H Thomson, Aline Guillot, Ugo De Giorgi, Ali Hasbini, Kirsten Gedske Daugaard, Simon Chowdhury, Orazio Caffo, Philippe Beuzeboc, Dominique Spaeth, Aude Flechon, Jerome Alexandre, Rafael Morales Barrera, Antoine Thiery-Vuillemin, Karim Fizazi, Eleni Efstathiou
Journal: Journal of Clinical Oncology (2018)

e17007 Background: We previously reported that cancer pain was associated with a poor prognosis in mCRPC patients (pts) treated with docetaxel (D) (Oudard, BJU Int 2009). Recently, we also reported that mCRPC pts treated with 3 LETs [D, cabazitaxel (C) and one novel androgen receptor axis targeted agent (A)] appeared to have a longer overall survival (OS), regardless of the order, than 2 LETs (Oudard, ESMO 2016 & ASCO 2017). Here, we investigated the impact on OS of the type of progression at initiation of LETs in a large cohort of mCRPC patients treated with D, C and A. Methods: 669 consecutive mCRPC pts treated with 3 LETs (DCA, n = 158; DAC, n = 456, ADC, n = 55) were retrospectively reviewed. The type of progression (PSA alone, radiological, clinical) at initiation of LETs was evaluable in 661 pts. Clinical progression was defined by worsening of cancer-related pain or symptoms as per physician judgment. Results: At initiation of first LET, 151 pts (23%) had PSA progression only, 225 pts (34%) had radiological progression (±PSA progression) and 285 pts (43%) had clinical progression (pain 93%, other symptoms 7%). Pts initiating first LET based on PSA progression and rPFS only, had a 14.2-and 7.2 month greater OS duration versus those having clinical progression, respectively (table). A consistently greater OS duration of at least 7 months was also observed in pts initiating the second and third LET based on PSA or radiological progression only (p < 0.001). Conclusions: This large retrospective cohort of mCRPC pts treated with 3 LETs (D, C, A) suggests that clinical progression at LET initiation is consistently associated with a worse OS as compared to PSA or radiological progression only. Whether earlier therapeutic intervention, as suggested by several randomized controlled trials (RCTs), can improve outcomes in mCRPC pts is debated. Therefore, confirmation of these results by RCTs is needed. Type of progression PSA alone Radiological Clinical Median OS , months (range) 44.9 37.9 30.7 Hazard ratio for death ref 1.31 1.92 [95% CI] - [1.02; 1.68] [1.52; 2.43] p 0.033 < 0.0001
Use of hypofractionated radiotherapy for early stage breast cancer after implementation of evidence-based clinical guidelines.
Authors: Santosh Gautam, Robert Paul Zimmerman, David Joseph Debono, John Barron, Gosia Sylwestrzak
Journal: Journal of Clinical Oncology (2018)

6593 Background: Evidence-based guidelines have endorsed use of hypofractionated whole breast irradiation (WBI), a shorter course regimen delivered over 3-4 weeks instead of conventional WBI over 5-6 weeks, for certain early stage breast cancer patients. In 2016, health insurer Anthem updated its clinical guidelines making hypofractionated WBI the standard for eligible members in its fully-insured plans. This change did not apply to self-insured groups allowing these members to serve as an internal control. The objective of the study was to evaluate the impact of this guideline change on adoption of hypofractionated WBI. Methods: We used Anthem claims data to identify women with incident breast cancer diagnosis followed by lumpectomy and subsequent WBI during 2015-2016. We further retained patients guideline-endorsed for hypofractionated WBI, i.e. those aged 50 or older, without prior chemotherapy or lymph node involvement. We defined hypofractionated WBI as 11-24 fractions (3-5 weeks of WBI) and conventional WBI as 25-40 (5-8 weeks of WBI). We compared pre-and post-intervention (year 2015 vs 2016) hypofractionated WBI rates between members in fully insured plans (intervention group) and members in other plans (comparison group) using a regression-adjusted difference-in-difference (DID) analysis controlling for age and comorbid conditions. Results: Compared to patients in comparison group (N = 2,333), those in intervention group (N = 728) were older (mean age 63.1 vs 61.4; p < .001) and had more comorbid conditions (mean Deyo-Charlson index 0.74 vs 0.60; p = 0.002). The rate of hypofractionated WBI increased from 53% in pre- to 68% post-intervention period for intervention group, an increase of 28%. In contrast, the rate changed from 58% to 63%, an increase of just 9%, in comparison group. The adjusted DID results suggested that change in guidelines increased the hypofractionated WBI adoption rate by 9% (p = 0.035). Conclusions: The changes in health plan guidelines resulted in higher rates of hypofractionated WBI adoption. Health plans could play an important role in accelerated adoption of evidence-based guidelines.
Oncology patients with emergency based admissions: Targets for improvement.
Authors: Jennifer Nadine Slim, Michelle Marie Loch
Journal: Journal of Clinical Oncology (2017)

e18180 Background: Oncology patients frequently utilize emergency room services with increased admission rates and, often, significant consequences on health care costs. National Hospital Ambulatory Medical Care Survey data from 2011 reports non-ischemic heart disease, chest pain and pneumonia as the most common emergency room discharge diagnoses for adults. Previous studies on cancer survivors found that the most common emergency room admission complaints were fever without neutropenia, pain and febrile neutropenia suggesting alternate active problems are more relevant in oncology patients. Other studies have indicated acute conditions and refractory symptoms are leading admission concerns. We would suggest that looking within populations of oncology patients and comparing those admitted emergently to those not admitted would provide further insight for prospective research targets. Methods: We utilized anonymous data obtained from an EPIC query involving oncology patients seen in LSU oncology clinic from July 2014 to August 2015. We were able to determine how many emergency room based admissions were attributed to these patients. Specifically, we reviewed the active problem lists, malignancy diagnosis, patient age and gender. Any identified disparities could identify oncology patients at increased risk for future admissions. Results: 1,627 patients were seen in our oncology clinic with 163 emergency room based admissions. Males accounted for 87 of these admissions. Only two patients had 3 or fewer co-morbid diagnoses. The most common diagnoses among patients with emergency room based admission were abdominal pain, anemia, and chest pain. According to the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project (HCUP) a cancer diagnosis was not listed in the top 10 diagnoses that account for 30% of all hospital stays. Conclusions: We would suggest the risk factors and management strategies are unique to survivors. An indepth review of the specific admission diagnoses and outcomes from admission could provide additional targets for future interventions. Further study focused on interventions unique to oncoloyg patients are warranted.
Differences in cerebral blood flow in early stage breast cancer survivors in comparison to healthy women.
Authors: Hibba tul Rehman, Kim Dittus, Chris E. Holmes, Richard Watts, Jenna Makarewicz, Julie Dumas
Journal: Journal of Clinical Oncology (2016)

10104 Background: Cognitive dysfunction has been identified among breast cancer survivors (BCS) particularly those who receive chemotherapy. While decreases in multitasking-related brain activation have been observed on fMRIs in breast cancer patients, the mechanisms that underpin cognitive dysfunction are not clear. We hypothesized that changes in cerebral blood flow may be a potential mechanism contributing to cognitive dysfunction in BCS. Methods: We compared the cerebral blood flow measured by pseudo continuous arterial spin labeling (pCASL) magnetic resonance imaging (MRI) between early stage breast cancer patients and age matched healthy women. A total of 66 subjects were enrolled. Thirty-two patients with early stage breast cancer (mean age 55.9 years) who had completed chemo-radiotherapy were compared to 36 women (mean age 56.2 years) with no history of breast cancer. Patients with active neurologic disease, traumatic brain injury, severe psychiatric disease or contra indications to MRI were excluded. Each group of subjects performed a battery of cognitive tests and common across both groups was the N-back test of working memory. Results: The demographic characteristics such as higher education level and tobacco use were similar between the groups. Cerebral blood flow was found to be significantly decreased in the medial temporal lobes (MTLs) of BCS. Decreased blood flow was noted regardless of the modality of treatment (chemo- and/or radiation therapy). Subjective complaints of cognitive decline were reported by BCS, however, the test of working memory (N-Back) did not reveal statistically significant differences between the groups. Conclusions: A significant reduction in cerebral blood flow in the medial temporal lobe (MTL) occurs in early stage breast cancer survivors treated with surgery and chemotherapy/radiotherapy when compared to healthy women. Reductions in cerebral blood flow in MTL have not been previously reported in BCS. Given that the MTL is involved in preservation of episodic and declarative memory, further study is needed to determine the mechanisms responsible for decreased flow and the cognitive impact.