tbuckley/cabot-search huggingface dataset:
Association of FASL and FAS polymorphisms, enrolled in extrinsic apoptosis pathway, with head and neck squamous cell carcinoma risk and outcomes.
Authors: Vitor Teixeira Liutti, Tathiane Regine Penna Lima, Ericka Francislaine Dias Costa, Leisa Lopes-Aguiar, Guilherme Augusto Silva Nogueira, Frederico Leal, Vivian Antunes Santos, Camila Borges Martins Oliveira, Jose Augusto Rinck, Gustavo Jacob Lourenco, Carmen Silvia Passos Lima
Journal: Journal of Clinical Oncology (2016)

6053 Background: Apoptosis plays an important role in origin of head and neck squamous cell carcinoma (HNSCC). Inherited genetic alterations, such as single nucleotide polymorphisms (SNPs), may influence the individual apoptotic capacity, having development of tumors as consequence. To the best of our knowledge, the roles of FASL c.-844C > T and FAS c.-671A > G SNPs in HNSCC risk, clinic pathological aspects, overall survival and progression free survival are unclear, and therefore these were the aims of our study. Methods: DNA of 463 patients and 470 controls were analyzed by PCR-RFLP. Patients were treated according to the Institutional protocol. The statistical analyses were realized using chi-square, logistic regression model, multifactor dimensionality reduction (MDR), Kaplan-Meier, and univariate and multivariate Cox analyses. Results: FASL TT genotype was more frequent in overall HNSCC patients (27.9% vs 16.2%, P = 0.001) and in those with SCC of oral cavity (30.0% vs 16.2%, P= 0.006), pharynx (29.9% vs 16.2%, P= 0.007), and larynx (25.4% vs 16.2%, P= 0.03) than in controls. Carriers of the genotypes were under a 3.24, 5.86, 2.93 and 2.54-fold increased risks of overall HNSCC and SCC of the mentioned subsites than others, respectively. An excess of FASL CT or TT plus FAS AA or AG combined genotype was seen in overall HNSCC patients compared to controls (91.1% vs 84.1%, P= 0.04); carriers of the genotype were under a 2.31-fold increased risk overall HNSCC than others. Among smokers, FASL TT and FAS AA genotypes were associated with 165.89 and 81.05-fold increased risks of HNSCC (P< 0.001), respectively. FASL c.-844C > T, FAS c.-671A > G SNPs and tobacco was the best interaction MDR model for risk of overall HNSCC and SCC of oral cavity, pharynx and larynx (P< 0.001). The median follow-up time of HNSCC patients was 46.0 months (1.6-166.0); no association of SNPs and patients´ survival was seen in study. Conclusions: Our data present preliminary evidence that inherited abnormalities in FASL c.-844C > T and FAS c.-671A > G SNPs are determinants of overall HNSCC and SCC of oral cavity, pharynx and larynx, particularly among smokers, possibly due to their action in tumor carcinogenesis.
Survival after recurrence following curative intent resection of pancreatic adenocarcinoma.
Authors: Susannah G. Ellsworth, Melissa Stanley, Michael Garrett House, Attila Nakeeb, Safi Shahda, Christian Schmidt, Nicholas J Zyromski, Bert H. O'Neil, Amikar Sehdev
Journal: Journal of Clinical Oncology (2017)

e15760 Background: Limited data exist on outcomes after recurrence after curative intent resection for pancreatic adenocarcinoma (PC). We analyzed the prognostic significance of time to recurrence and associated factors in patients with post-pancreatectomy recurrence. Methods: Patients with a documented recurrence were identified from a prospectively maintained database of all patients undergoing pancreatectomy for PC between 2009-2015 at Indiana University Simon Cancer Center. Patients were divided into early (≤12 mos after surgery) and late recurrence ( &gt; 12 mos after surgery) groups. Demographic (age, race, sex) and clinical (CA19-9, bilirubin, tumor location, diabetes at presentation, ECOG performance status, margin status, adjuvant radiation, and adjuvant and metastatic chemotherapy) data were obtained by manual chart abstraction and the IUSCC cancer registry. The primary outcome was survival after recurrence (SAR- time from recurrence to death). Chi-square was used for univariate analysis (except t-test for age). SAR was estimated with the Kaplan-Meier method and 95% CI. Cox proportional-hazard model was used for multivariate analysis (MVA). Results: Of 437 patients undergoing surgical resection for PC, 235 had documented recurrence. More patients had an early recurrence (ER) as compared to late recurrence (LR; 58.3% vs 41.7%). Median SAR was significantly shorter in ER vs LR patients (6.2 vs 8.6 months; HR, 0.71; 95% CI, 0.53-0.95; P = 0.02). Median age was higher in ER vs LR groups (64.7 and 64.2 years, P = 0.002). Diabetes at presentation was more common in ER vs LR group (42.3% vs 30.6%, P = 0.09). ER patients were significantly less likely to have received adjuvant chemotherapy (70.7% vs 84.7%, P = 0.02) or adjuvant radiation (17.8% vs 40%, P &lt; .001). MVA showed a trend towards longer SAR in LR vs ER group (adjusted HR = 0.75, 95% CI, 0.55-0.1.03, p = 0.08) however age, adjuvant chemotherapy, adjuvant radiation and diabetes at presentation were not significant predictors of SAR. Conclusions: Early recurrence after resection of PC is associated with poor SAR. Patients with early recurrence tend to be older, diabetic at presentation and were less likely to have received adjuvant chemotherapy or adjuvant radiation.
Study on compliance with breakthrough cancer pain guidelines by medical oncologists in Spain.
Authors: Rafael Lopez, Carlos Camps, Parham Khosravi-Shahi, Vicente Guillem, Alfredo Carrato, Jesus Garcia-Foncillas, Juan J. Cruz, Pedro Gascon, Antonio Anton, Eduardo Diaz-Rubio, Margarita Feyjoo, Enrique Aranda
Journal: Journal of Clinical Oncology (2017)

e18260 Background: Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for cancer patients, which remains undertreated and underdiagnosed. The Spanish Society for Medical Oncology (SEOM) developed a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP. Methods: With the objective of evaluate compliance with SEOM’ guideline, Fundación ECO designed a survey to identify awareness, perceptions, implementation and gaps, among Spanish medical oncologists. Results: A total of 83 oncologists with a median experience of 13 years responded. Although 87% of oncologists considered their clinical practice complied with SEOM recommendations, there were discrepancies between what oncologists agreed to do versus how they do in clinical practice, as shown in the table. Main barriers identified in our study were time pressure together with vague statements in some recommendations, and the need to regularly update to reflect the most recent knowledge on therapeutic management. Conclusions: Nonetheless, this nationwide survey reflects that oncologist’s clinical practice is increasingly guided by GPC, and thus, the evaluation process is necessary, both to gauge the true application of the GPC by the professionals and to evaluate their impact on health care. [Table: see text]
Association of a baseline neutrophil-to-lymphocyte ratio (NLR) with progression-free and overall survival in head and neck cancer patients receiving anti-PD-1 therapy.
Authors: Corey Christian Foster, Sara Kochanny, Arun Khattri, Rajesh Acharya, Allison Dekker, Yi-Hung Carol Tan, Elaine Klema, Ryan J. Brisson, Vassiliki Saloura, Alexander T. Pearson, Everett E. Vokes, Rom S. Leidner, Hisham Mohamed Mehanna, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2018)

6038 Background: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with tumor-induced inflammation and poor prognosis in a variety of treatment settings. Moreover, tumor-derived myeloid growth factors (Seiwert et al. ASCO 2017) could elevate the NLR and suppress cytotoxic T-cell activity and anti-PD-1 efficacy. We hypothesized that high baseline NLR will associate with poor outcomes in patients with metastatic head and neck (H&N) cancer receiving anti-PD-1 therapy. Methods: 114 patients with metastatic H&N cancer unselected for PD-ligand 1 (PD-L1) status received anti-PD-1 therapy. Baseline NLRs were divided into quartiles with high NLRs being the highest quartile ( > 8.77). Univariate logistic regression analyzed the relationship between NLR and overall response rate (ORR) by RECIST v1.1. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and Cox proportional hazard regression. Results: Median follow-up was 8.6 months. Baseline characteristics including known PD-L1 positivity (n = 15/29 high NLR vs. n = 38/78 low NLR, p = 0.15) were comparable between groups. ORR was 22.3% with a trend towards lower ORR for the high NLR group (odds ratio: 0.42, 95% confidence interval [CI]: 0.11-1.57, p = 0.20). Median PFS was 1.7 months (95% CI: 1.0-3.6) for high NLR patients and 3.6 months (95% CI: 2.6-5.6) for low NLR patients (p = 0.02). Notably, median OS was 4.1 months (95% CI: 2.1-5.5) in the high NLR group and 12.5 months (95% CI: 9.0-17.2) in the low NLR group (p = 0.007). NLR more strongly associated with outcome than PD-L1+, which was not associated with PFS (p = 0.67) or OS (p = 0.53). On multivariate analyses, a high baseline NLR remained independently associated with reduced PFS (p = 0.04) and OS (p = 0.01). Conclusions: A high baseline NLR showed a strong inverse relationship with OS and PFS in patients receiving anti-PD-1 therapy for metastatic H&N cancer regardless of PD-L1 expression. Future investigation of NLR as a clinically-useful biomarker, NLR kinetics over time, and a mechanistic understanding of tumor-driven factors influencing NLR and anti-PD-1 efficacy are warranted.
Adverse impact of polypharmacy and potentially inappropriate medication use in newly diagnosed, elderly lymphoma patients.
Authors: Richard Jirui Lin, Robin Guo, Daniel Jacob Becker, Michael L. Grossbard, Catherine S. Magid Diefenbach
Journal: Journal of Clinical Oncology (2016)

6562 Background: Survival outcomes for elderly non-Hodgkin’s lymphoma (NHL) patients are disproportionally inferior to those of younger patients. While their tumor biology may differ, elderly patients are often frail with comorbidities and polypharmacy, and use potentially inappropriate medications (PIM) as defined by the Beers Criteria. Methods: Using Cox proportional hazard and logistic regression models, we retrospectively analyzed all NHL patients age 60 and above diagnosed at our institution from 2009-2014 to examine the impact of polypharmacy and PIM use on primary end-points of progression-free survival (PFS) and overall survival (OS), and the secondary end-point of treatment-related toxicities. Results: We included 246 patients with evaluable data after excluding patients with incomplete record or treated elsewhere. The median age was 71 years. Aggressive lymphoma accounted for 57% of patients. At the time of diagnosis, 49% of patients had more than 4 medications and 48% used at least one PIM. During first-line treatment 45% of patients experienced grade 3 or greater toxicities (CTCAE v4). Charlson Comorbidity Index (CCI), polypharmacy, and PIM use correlated with each other. Number of medications (p = 0.004) and PIM use (p < 0.001) were associated with shortened PFS by log-rank test, and PIM use remained an independent predictor of PFS in multivariable analysis (HR 1.62, p = 0.001). Number of medications (p = 0.004) and PIM use (p = 0.002) were also associated with shortened OS by log-rank test. However, only CCI and lymphoma grade predicted OS in multivariable analysis. Finally, PIM use was strongly associated with grade 3 or greater toxicities in multivariable analysis (OR 3.1, p = 0.002). Conclusions: We report here for the first time adverse impact of geriatric polypharmacy and PIM use in elderly lymphoma patients. It seems plausible that the reduced survival is due to drug-drug interactions during intensive chemotherapy that lead to increased toxicities or impair delivery of full dose chemotherapeutics. Our findings support the use of geriatric principles to guide meticulous medication management to improve outcomes for elderly lymphoma patients during active treatment.
Next generation sequencing for diagnosis of severe pneumonia: China, 2010–2018
Authors: Yun Xie, Jiang Du, Wei Jin, Xiaolei Teng, Ruijie Cheng, Peijie Huang, Hui Xie, Zhigang Zhou, Rui Tian, Ruilan Wang, Tienan Feng
Journal: Journal of Infection (2018)
ODENZA: A study of patient preference between ODM-201 (darolutamide) and enzalutamide in men with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Geraldine Martineau, Stéphanie Foulon, Jean-Christophe Eymard, Yohann Loriot, Giulia Baciarello, Jean Francois Berdah, Carole Helissey, Pernelle Lavaud, Florence Joly, Nadia Zaghdoud, Anne Sophie Hue, Karim Fizazi
Journal: Journal of Clinical Oncology (2018)

TPS5093 Background: In recent years, the treatment of mCRPC has evolved and next-generation androgen receptor (AR)-axis targeting drugs (enzalutamide (ENZ), and abiraterone) have been approved and are routinely used. Darolutamide (DARO) is a new next-generation AR inhibitor which has shown strong activity and minimal toxicity in two phase I-II trials ARADES (Fizazi, Lancet Oncol 2014) and ARAFOR (Massard, Eur Urol 2016) and is currently evaluated in a study in men with non-metastatic CRPC (ARAMIS trial). In contrast to ENZ, DARO does not significantly penetrate the blood-brain barrier in vivo, and this may reduce the risk of fatigue, cognitive impairment, and seizure. Assessing patient preference between DARO and ENZ may contribute further differentiating between these two agents. Methods: ODENZA is a prospective, randomized, open-label, multicenter, cross-over phase II trial assessing patient preference between DARO and ENZ (NCT03314324). It was initiated in November 2017. Eligibility criteria include: men with asymptomatic or mildly symptomatic mCRPC, performance status 0-1, no prior next generation AR axis-targeted agent. The randomization is stratified on performance status and prior treatment with a taxane for CSPC. 250 patients will be randomized 1:1 to: 12-week ENZ followed by 12-week DARO or 12-week DARO followed by 12-week ENZ. The primary endpoint is patient preference between DARO and ENZ, assessed after the second treatment period. A two-sided binomial test with a power of 80% and a bilateral α of 0.05 will be used. Secondary endpoints include: reasons for patient preference, dose modifications and time to dose modification, safety, fatigue (BFI), cognitive function as assessed by Cogstate computerized cognitive tests, depression screening (CES-D) test, frequency of falls, PSA declines using Waterfall plots after each treatment period, Progression-Free Survival (PFS), association between 4-weeks PSA value and PFS, incidence of cancer progression or death, and tumor response. The study is recruiting. By February 13, 2018, 10 patients have been enrolled. Clinical trial information: NCT03314324.
TCT-233 Machine-Learned Algorithms Utilizing Novel Tomography for Evaluating Coronary Artery Disease
Authors: Tom Stuckey, Frederick Meine, Narendra Singh, Prashant Kaul, Jeremiah Depta, Roger Gammon, John Steuter, Horace Gillins, Tim Burton, Ali Khosousi, Ian Shadforth, Shyam Ramchandani, William Sanders
Journal: Journal of the American College of Cardiology (2018)
Specific Targeting of Oncogenes Using CRISPR Technology
Authors: Felix Oppel, Matthias Schürmann, Peter Goon, Andreas E. Albers, Holger Sudhoff
Journal: Cancer Research (2018)

In recent decades, tools of molecular biology have enabled researchers to genetically modify model organisms, including human cells. RNAi, zinc-finger nucleases, transcription activator-like effector nucleases, CRISPR-Cas9 (clustered regularly-interspaced short palindromic repeats and CRISPR-associated protein 9), retro- or lentiviral gene transfer, and many other methods can be utilized to remove genes, add genes, or change their expression. Within the same timeframe, survival rates for many highly malignant tumor diseases have not improved substantially. If modern medicine could apply even a subset of research methods in clinical management, which are already well established and controllable in basic research laboratories, this could strongly impact patients' prognosis. CRISPR-Cas9 is a method to precisely target and manipulate genomic loci and recent studies have attempted to use this method as a genetic treatment for Duchenne muscular dystrophy, blood disorders, autosomal-dominant hearing loss, and cancer. Some of these approaches target mutant genomic sequences specifically and try to avoid affecting the respective normal loci. Considering obvious genetic risks opposing the objected benefits, data are needed to show whether CRISPR technology is suitable as a future cancer therapy approach or not. Here, we develop strategies for the specific targeting of viral cancer drivers and oncogenes activated by mutation, using the latest CRISPR technology. Cancer Res; 78(19); 5506-12. ©2018 AACR.
Exploration of the ASCO and ESMO value frameworks for cancer drugs.
Authors: Daniel Lin, Steve Young Lee, Danil V. Makarov, Benjamin Philip Levy, Michael L. Grossbard, Daniel Jacob Becker
Journal: Journal of Clinical Oncology (2016)

6512 Background: In 2015 both ASCO and ESMO proposed frameworks to quantify the value of cancer drugs. We sought to examine these frameworks for drugs approved by the U.S. Food and Drug Administration (FDA) over the past 12 years, and evaluate the relationship between cost and value. Methods: We searched the FDA.gov database for drugs initially approved for solid tumors in 2004-2015. We queried Pubmed for data to calculate ASCO Net Health Benefit(NHB) and ESMO Magnitude of Clinical Benefit (MCBS) scores. We used the Average Wholesale Price from the Lexicomp database to calculate monthly drug costs. We calculated descriptive statistics, and explored correlations(Pearson/Spearman) and associations (linear regression) between value frameworks and independent variables. Results: We identified 55 drugs supported by trials with primary outcomes OS (37.04%), PFS (44.44%), or RR (18.52%). Both ESMO and ASCO scores were normally distributed; mean, SD, median and IQR for ASCO-NHB were 29.0, 15.8, 32, and 13. There was no association between ASCO-NHB and year of approval (ANOVA p=0.84), organ system (p=0.50), or trial outcome measure (p=0.054). Among 53 drugs with positive ASCO-NHB, the mean cost to NHB value ratio (CVR) was $445.30/value point/month (SD $289.49). Prior to 2010, 1/13 (7.69%) approved drugs exceeded $500.00/value point/month, compared to 14/41 (34.15%) drugs subsequently approved. There was no correlation between value score and cost (ASCO Pearson r=0.09; ESMO Spearman r=-0.01). There was a moderate correlation between ASCO and ESMO value scores (Spearman r=0.46, p<0.001). The ASCO toxicity score component of the NHB, which quantifies number of adverse event (AE) types observed, changed NHB in 29.17%, by a mean of -3.96 points(SD 8.44). We propose an alternative toxicity score incorporating percent of patients experiencing each AE, which changed NHB in 64.29% by mean of -10.61 (SD 11.44). Conclusions: The ASCO and ESMO value frameworks illuminate the heterogeneous value of new drugs, but correlate only moderately with each other. Neither score correlates with drug cost, and they highlight an increasing number of high cost/value outliers. We propose an alternative toxicity scale to incorporate incidence of toxicity among treated patients.
Safety and efficacy of dendritic cell immunotherapy with ad-GMCAIX in an immunocompetent preclinical tumor model of renal cell carcinoma.
Authors: Frédéric D. Birkhäuser, Richard C. Koya, Caleb Neufeld, Xuyang Lu, Ewa D. Micewicz, Thinle Chodon, Mohammad Atefi, Nils Kroeger, Edward N. Rampersaud, Gadisetti V.R. Chandramouli, Gang Li, Jonathan W. Said, Antoni Ribas, William H. McBride, Fairooz F. Kabbinavar, Allan J. Pantuck, Arie S. Belldegrun, Joseph Riss
Journal: Journal of Clinical Oncology (2012)

e13045 Background: We have previously reported the successful ex vivo generation of hCAIX-specific cytotoxic T lymphocytes (CTLs) by adenoviral (Ad) transduction of the GMCAIX fusion protein in dendritic cells (DC). We then produced GMP-grade material (NIH-RAID program, NSC 740833). Now we test, for the first time, the in vivo anti-tumor activity of DC-Ad-GMCAIX against renal cell carcinoma (RCC) in a unique immunocompetent mouse tumor model. Methods: Tumor growth inhibition and specificity were studied in BALB/c mice s.c. transplanted with either syngeneic RENCA cells transduced with hCAIX (URCAIX) or with non-hCAIX-expressing RENCA cells (RENCA). In a tumor prevention model, cohorts of mice were first immunized s.c. twice with DC-Ad-GMCAIX, DC-Ad-null, or no DCs, followed by tumor challenge with s.c. transplantation of URCAIX or RENCA cells. In an intervention model, tumors were first established and then immunotherapy was employed. Tumor volume and body weight were regularly assessed. Partial necropsy, immunohistochemistry of harvested tumors, and complete blood count were performed at termination of each study. Results: In the prevention model, URCAIX tumor growth was specifically and significantly inhibited for 15 days (p&lt;0.0001). At termination, median growth inhibition reached 79% (113 vs. 531 mm 3 ) and half of the mice remained tumor-free. In the intervention model, DC-Ad-GMCAIX-treated mice showed specific and significant growth inhibition of URCAIX tumors for 8 days (p&lt;0.0018) with a median growth inhibition reaching 60% (487 vs. 1,205 mm 3 ). The threshold of 15% weight loss was delayed in the therapeutic groups of both models (p&lt;0.0167). No treatment-related weight loss or organ toxicity was observed. hCAIX staining was absent or minimally present in URCAIX-tumors that evaded DC-Ad-GMCAIX therapy. Conclusions: DC-Ad-GMCAIX therapy in a novel immunocompetent mouse model demonstrated, for the first time, both tumor prevention and growth inhibition of established RCC tumors without evidence of systemic toxicity. These studies form the basis for first-in-human clinical trial in patients with advanced RCC.