tbuckley/cabot-search huggingface dataset:
Chemotherapy with or without definitive radiation therapy in locally advanced pancreatic cancer.
Authors: Jim Zhong, Jeffrey M. Switchenko, Madhusmita Behera, David A. Kooby, Mark William McDonald, Bassel F. El-Rayes, Jerome Carl Landry, Pretesh R Patel
Journal: Journal of Clinical Oncology (2017)

4103 Background: The recently reported LAP07 randomized trial calls into question the role of radiation therapy (RT) in the modern treatment of locally advanced pancreatic cancer (LAPC). However, advances in chemotherapy and RT limit application of the LAP07 results to current clinical practice. Here we utilize the National Cancer Database (NCDB) to evaluate the effects of RT in patients receiving chemotherapy for LAPC. Methods: Using the NCDB, patients with AJCC clinical stage T2-T4, N0-1, M0 adenocarcinoma of the pancreas from 2004-2014 were analyzed. Only those that received chemotherapy and did not undergo surgery were included. Patients were stratified into chemotherapy only (CT) and chemoradiation (CRT) cohorts. Patients undergoing definitive RT, defined as at least 20 fractions (fxs) or ≥ 5 Gy per fraction (i.e. SBRT) were included in the CRT cohort. Propensity-score matching (PSM) and landmark analysis were used to address selection bias and lead-time bias, respectively. The primary endpoint was overall survival (OS). Results: 13,004 patients met inclusion criteria, of which 7,034 (54%) received CT and 5,970 (46%) received CRT. After PSM, 5,215 patients remained in each cohort. Median follow-up was 22.6 months. The CRT group had younger median age (65 vs. 67) and less treatment at academic centers (44 vs. 51%); performance status was similar between groups. The median fractionated RT dose was 50.4 Gy in 28 fxs and SBRT dose was 24 Gy in 3 fxs. The CRT cohort demonstrated better OS compared with CT alone, with median and 1-yr OS of 12 vs. 10 months, and 50% and 41%, respectively (p &lt; 0.001). On multivariable analysis, CRT was associated with superior OS with a hazard ratio (HR) of 0.79 (95% confidence interval (CI): 0.76-0.83, p &lt; 0.001) compared with CT alone. The SBRT subgroup demonstrated the best survival (HR 0.71 [95% CI: 0.64-0.80], p &lt; 0.001). OS was superior for CRT after PSM and for all patient subsets. Conclusions: In unresected LAPC, the addition of definitive radiotherapy to chemotherapy is associated with superior OS when compared with chemotherapy alone. Survival was greatest when SBRT was used. Definitive radiotherapy should remain a standard option for LAPC but optimal selection criteria remain unclear.
Antibody-independent isolation and characterization of circulating tumor cells using dielectrophoresis: Fluid flow fractionation in metastatic colorectal cancer.
Authors: Callisia Clarke, Krittiya Korphaisarn, Zhiqin Jiang, Shadarra Crosby, Darren W. Davis, Weiguo Wu, Kanwal Pratap Singh Raghav, Michael J. Overman, Van Karlyle Morris, Bryan K. Kee, Cathy Eng, David R. Fogelman, Nicholas Navin, Scott Kopetz
Journal: Journal of Clinical Oncology (2016)

e23023 Background: Molecular study of CRC provides insight into mechanisms that drive tumor recurrence, metastasis and resistance. Tumor biopsies are invasive and may not accurately represent tumor heterogeneity. Liquid biopsies are less invasive and may provide timely information regarding dynamic tumor response to treatment. Most methods for capture of rare CTCs employ antibodies to epithelial cell adhesion molecule (EpCAM) and cytokeratin (CK). However, CTCs that undergo epithelial-mesenchymal transition (EMT) have been implicated in the establishment of metastasis and elude capture using these traditional markers. We report the use of a novel method to isolate CTCs from mCRC patients that is not antibody dependent. Methods: Blood was collected from mCRC patients, processed with dielectrophoretic fractionation (DEP-FFF) to exploit differences in properties between cancer cells and normal cells (ApoStream, ApoCell, Houston, TX). Isolated cells were enumerated using multiplex immunofluorescent (MIF) assay and laser scanning cytometry to identify CD45, CK, DAPI, β-catenin, EpCAM, MUC1, CEA staining. Results: Blood from 14 pts with mCRC was subjected to DEP-FFF resulting in a median CD45+ cell count of 564 cells/mL, ≈ 3,000-fold depletion from peripheral blood. Cells staining CK, EpCAM, or β-catenin + where defined as epithelial type (Epi), cells with MUC1 or CEA staining were considered mesenchymal (EMT). EpiCTCs were defined as [CK/EpCAM/β-catenin]+/DAPI+/CD45- and EMTCTCs as [MUC1/CEA]+/DAPI+/CD45-. EpiCTCs were isolated in 12 of 14 pts with a mean of 31.8 cells/8ml of blood [Median 11, IQR 4-32] and represented 88% of CTCs isolated. EMTCTCs accounted for 12% (mean 7 cells/8ml [Median 3, IQR 1-8]). MIF allowed identification of an unexpected CD45+ population with Epi or EMT markers, present at a 3-fold higher count than traditional EpiCTC/EMTCTC populations (mean 105 cells/8ml, median 69, IQR 9-107]. Conclusions: DEP-FFF enriches for CTCs with both Epi and EMT features and may prove a suitable alternative to tissue biopsy. Atypical CD45+cells with Epi or EMT features were identified and represents an additional population of interest.
A whole-blood RNA transcript-based gene signature is associated with the development of CTLA-4 blockade-related diarrhea in patients with advanced melanoma treated with the checkpoint inhibitor tremelimumab
Authors: Philip Friedlander, Kevin Wood, Karl Wassmann, Alan M. Christenfeld, Nina Bhardwaj, William K. Oh
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Anti-CTLA-4 immune checkpoint blockade is associated with immune-related adverse events (irAEs). Grade 3–4 diarrhea/colitis is the most frequent irAE requiring treatment discontinuation. Predicting high-risk diarrhea/colitis patients may facilitate early intervention, limit irAE severity, and extend treatment duration. No biomarkers currently predict for anti-CTLA-4 immunotherapy related severe diarrhea. <h3>Methods</h3> Whole-blood was collected pre-treatment and 30&nbsp;days post-treatment initiation from patients with stage III or IV unresectable melanoma who received 15&nbsp;mg/kg tremelimumab at 90&nbsp;day intervals in two clinical trials. The discovery dataset was a phase II study that enrolled 150 patients between December 2005 and November 2006. The validation dataset was a phase III study that enrolled 210 patients between March 2006 and July 2007. RT-PCR was performed for 169 genes associated with inflammation, immunity, CTLA-4 pathway and melanoma. Gene expression was correlated with grade 0–1 versus grade 2–4 diarrhea/colitis development. <h3>Results</h3> Pre-treatment blood obtained from the discovery dataset (<i>N</i> = 150) revealed no gene predictive of diarrhea/colitis development (<i>p</i> &lt; 0.05). A 16-gene signature (CARD12, CCL3, CCR3, CXCL1, F5, FAM210B, GADD45A, IL18bp, IL2RA, IL5, IL8, MMP9, PTGS2, SOCS3, TLR9 and UBE2C) was identified from 30&nbsp;days post-tremelimumab initiation blood that discriminated patients developing grade 0–1 from grade 2–4 diarrhea/colitis. The 16-gene signature demonstrated an AUC of 0.814 (95% CI 0.743 to 0.873, <i>p</i> &lt; 0.0001), sensitivity 42.9%, specificity 99.2%, positive predictive value (PPV) 90.0%, and negative predictive value (NPV) 91.4%. In the validation dataset (<i>N</i> = 210), the 16-gene signature discriminated patients developing grade 0–1 from grade 2–4 diarrhea/colitis with an AUC 0.785 (95% CI 0.723 to 0.838, <i>p</i> &lt; 0.0001), sensitivity 57.1%, specificity 84.4%, PPV 57.1% and NPV 84.4%. <h3>Conclusion</h3> This study identifies a whole-blood mRNA signature predictive of a clinically relevant irAE in patients treated with immune checkpoint blockade. We hypothesize that immune system modulation induced by immune checkpoint blockade results in peripheral blood gene expression changes that are detectable prior to clinical onset of severe diarrhea. Assessment of peripheral blood gene expression changes in patients receiving anti-PD-1/PD-L1 immunotherapy, or combination anti-CTLA4 and anti-PD-1/PD-L1 immunotherapy, is warranted to provide early on-treatment mechanistic insights and identify clinically relevant predictive biomarkers. <h3>Trial registration</h3> Clinicaltrials.gov, NCT00257205, registered 22 November 2005
Age, player position and 2 min suspensions were associated with match injuries during the 2017 Men’s Handball World Championship (France)
Authors: Montassar Tabben, Philippe Landreau, Karim Chamari, Gerard Juin, Hosny Ahmed, Abdulaziz Farooq, Roald Bahr, Nebojsa Popovic
Journal: British Journal of Sports Medicine (2018)

To study the association between player characteristics, technical components of the game and the risk of match injuries during the 2017 Men's Handball World Championship.Team physicians of the participating teams (n=24) were requested to provide injury report forms throughout the Men's Handball World Championship (France, January 2017). The individual time played, age, number of international matches played and all technical and penalty variables for each player were extracted from the official International Handball Federation (IHF) online database and used as risk factors in a general logistic linear model analysis.Of 387 players, 49 sustained one or more injuries (93 injuries in total). The total incidence of match injuries was 82.1 injuries per 1000 hours (95% CI 66.2 to 100.5), non-time-loss injury incidence was 40.6 injuries per 1000 hours (95% CI 29.3 to 54.9), while time-loss injury incidence was 30.9 injuries per 1000 hours (95% CI 21.5 to 42.9). Multivariate analysis showed that age (OR 1.1, 95% CI 1.02 to 1.18, p=0.011), player position (backs: OR 6.79, 95% CI 2.25 to 20.54, p=0.001; goalkeepers: OR 5.03, 95% CI 1.15 to 21.94, p=0.031) and 2 min suspensions (1-2 times: OR 2.77, 95% CI 1.27 to 6.04, p=0.011; 3 or more times: OR 2.66, 95% CI 1.18 to 6.38, p=0.029) were significant risk factors for getting injured during competition matches.Age, player position (backs, goalkeepers) and 2 min suspensions were associated with match injury. Stricter rule enforcement should be considered to prevent match injuries in elite handball.
Use of Topical Glycolic Acid Plus a Lovastatin-Cholesterol Combination Cream for the Treatment of Autosomal Recessive Congenital Ichthyoses
Authors: Samar Khalil, Tara Bardawil, Serena Saade, Adele Chedraoui, Nehmat Ramadan, Divina Justina Hasbani, Ossama Abbas, Georges Nemer, Nelly Rubeiz, Mazen Kurban
Journal: JAMA Dermatology (2018)

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders caused by defects in signaling pathways involved in epidermal proliferation and differentiation, leading to a wide range of skin manifestations. Therapeutic options are limited and often unsatisfactory. Topical cholesterol and statin as a combined formulation has proven successful in the treatment of patients with CHILD syndrome (congenital hemidysplasia ichthyosis and limb defects).To assess change in disease severity score after a 3-month therapeutic regimen consisting of a glycolic acid, 10% to 20%, cream and a combination cream of lovastatin, 2%, with cholesterol, 2%, in the treatment of ARCI.This case series of 15 patients with ARCI was conducted at the American University of Beirut, a referral center in the Middle East region for genodermatoses, between May 2017 and January 2018. No age groups were excluded; all patients were from the Middle East area; and all were initially not responsive to treatment with hydrating creams in combination with urea creams, 30% to 40%, or glycolic acid, 10% to 20%. Excluded were patients who had been taking systemic retinoids within 3 months before the start of the study.A 3-month therapeutic regimen of glycolic acid, 10% to 20%, cream and a combination of lovastatin, 2%, with cholesterol, 2%, cream.Percentage change in disease severity scores following 2 and 3 months of study treatment.Of the 15 patients included in the study, 10 were male (mean age, 11.2 years; age range, 2-38 years). The average percentage reduction in the disease severity score was 33.7% at 2 months (from 60.8 to 40.2) and 57.5% at 3 months (from 60.8 to 21.9). Adverse effects were mild and consisted mainly of irritation and burning.These findings suggest a benefit from a treatment regimen consisting of glycolic acid, 10% to 20%, and a combination of lovastatin, 2%, with cholesterol, 2%, in the treatment of ARCI. This combination of creams might also prove to be beneficial in other types of ichthyoses and other dermatological diseases with a defective skin barrier.
Association between lymph node examination and nodal staging for pancreatic adenocarcinoma: A population-based analysis.
Authors: Rui-hua Xu, Zi-Xian Wang, Miaozhen Qiu, Ying Jin, Ming-ming He, Feng Wang, Fenghua Wang
Journal: Journal of Clinical Oncology (2017)

e15772 Background: The minimum number of examined lymph nodes (ELNs) for accurate nodal staging remains controversial and has not been recommended by the NCCN guidelines for pancreatic adenocarcinoma (PADC). We aimed to evaluate the time trends in the ELN count and the proportion of node-positive PADC (N+%), as well as determine the minimal threshold for the ELN count. Methods: We analyzed 9258 patients with resectable PADC between 2000 and 2012 in the SEER database (18 registries). Changes in the ELN count and N+% over time were evaluated using the Spearman correlation analysis and the Cochran-Armitage test, respectively. Multivariable logistic and Cox models were used to evaluate the association between the ELN count and N+% and overall survival after adjusted for clinicopathologic features (i.e., race/ethnicity, sex, age, marital status, SEER region, year of diagnosis, tumor grade, tumor site, 8th AJCC T stage, and surgical type). Restricted cubic spline modeling was used to handle possible nonlinear effects of the ELN count as a continuous covariate in the multivariable models. Structural breakpoints, which were considered the threshold of clinical impact, were determined by the Chow test. Results: The median ELN count increased from 9 (interquartile range: 5−15) in 2000 to 16 (11−23) in 2012 ( P trend &lt; 0.001), and the N+% increased from 61.1% to 67.2% ( P trend &lt; 0.001). An increased ELN count was associated with a nonlinear increase in N+% ( P &lt; 0.001), and the Chow test revealed a threshold ELN count of 8 (OR adjusted for ≥ 8 vs. &lt; 8 ELNs, 2.42 [95% CI, 2.19−2.68]). The 8-ELN threshold was confirmed in patients with declared N0 disease: A larger number of ELNs was correlated with a nonlinear increase in overall survival among these patients ( P &lt; 0.001), with the threshold ELN count also being 8 (HR adjusted for ≥ 8 vs. &lt; 8 ELNs, 0.79 [95% CI, 0.75−0.87]). Moreover, the 8-ELN threshold remained valid regardless of T stage and year of diagnosis. Conclusions: Lymph node examination has increased markedly over time and was associated with an overall shift toward higher-staged PADC. We recommend 8 ELNs as the cut point for improvement of prognostic accuracy and quality measurement of lymph node examination.
Impact of prior radiation on survival in metastatic lung cancer ECOG-ACRIN trials.
Authors: Saad A. Khan, Maneka Puligandla, Suzanne Eleanor Dahlberg, Gregory A. Masters, Corey J. Langer, Julie R. Brahmer, Nasser H. Hanna, Philip Bonomi, David E. Gerber, David H. Johnson, Joan H. Schiller, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2017)

9051 Background: Up to 50% of advanced NSCLC patients receive radiation therapy at some point in their course. We sought to determine whether patients with prior radiation demonstrate altered outcomes on subsequent metastatic clinical trials. Methods: We reviewed 8 ECOG-ACRIN advanced non-small cell lung cancer studies conducted between 1993 and 2011 in which information was collected about receipt of prior radiation. Whether radiotherapy was given with curative or palliative intent, or to specific sites was not recorded. Median follow-up among all trials was 66 months. We used the log-rank, Wilcoxon and Fisher’s exact tests to compare patients, and Cox Model and Kaplan-Meier method to calculate survival. Results: 574/3041 (18.9%) patients had received prior radiation. These patients were more likely to be male (64% vs 58%), have squamous histology (20% vs 14%) and have had prior surgery (48% vs 33%) compared to those with no prior radiation. At registration, prior radiation patients were more likely to have an ECOG PS of 1 (66% vs 58%), while they were less likely to have a PS of 0 (24% vs 36%) or have a pleural effusion (23% vs 37%). Patients who received radiation were more likely to have been registered on to studies between 1993-1999 than 2000-2011 (69% vs 31%) (all p &lt; 0.001). Median Overall Survival (OS) for patients with prior radiation was 7.6 months (range 7-8.3) vs 9.5 (9.1-9.8) for those without (p &lt; 0.001). Median Progression Free Survival (PFS) for those with prior radiation was 3.5 months (3-3.9) vs 4.2 (4.1-4.4) for those without (p &lt; 0.001). In multivariable analysis controlling for stage IIIB/IV, sex, PS, histology, and prior surgery, the impact of prior radiation on overall survival remained significant (p = 0.042, HR (95% CI) = 1.11 (1.00, 1.22)). Conclusions: Almost one-fifth of lung cancer patients on systemic therapy trials for advanced disease previously received radiation. They are more likely to be male, have squamous histology, have an ECOG PS of 1 and have had prior surgery. Prior radiation is significantly associated with inferior OS and PFS. For advanced NSCLC clinical trials, documentation of whether curative intent/palliative intent radiation was given and stratification by prior radiation exposure should be considered.
Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer
Authors: Leisha A. Emens, Cristina Cruz, Joseph Paul Eder, Fadi Braiteh, Cathie Chung, Sara M. Tolaney, Irene Kuter, Rita Nanda, Philippe A. Cassier, Jean-Pierre Delord, Michael S. Gordon, Ehab ElGabry, Ching-Wei Chang, Indrani Sarkar, William Grossman, Carol O’Hear, Marcella Fassò, Luciana Molinero, Peter Schmid
Journal: JAMA Oncology (2018)

Atezolizumab (anti-programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported.To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC.Women with mTNBC (defined by investigator assessment) were enrolled between January 2013 and February 2016 in a multicohort open-label, phase 1 study at US and European academic medical centers. Median follow-up was 25.3 months (range, 0.4-45.6 months). Eligible patients regardless of line of therapy had measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1; Eastern Cooperative Oncology Group performance status of 0 to 1; and a representative tumor sample for assessment of immune cell (IC) PD-L1 expression.Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects or loss of clinical benefit.Primary outcome was safety and tolerability. Activity and exploratory outcomes included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Outcomes were assessed in all patients and in key patient subgroups.Among 116 evaluable patients (median age, 53 years [range, 29-82 years]), treatment-related adverse events occurred in 73 (63%); 58 (79%) were grade 1 to 2. Most adverse events occurred within the first treatment year. The ORRs were numerically higher in first-line (5 of 21 [24%]) than in second-line or greater patients (6 of 94 [6%]). Median duration of response was 21 months (range, 3 to ≥38 months). Median PFS was 1.4 (95% CI, 1.3-1.6) months by RECIST and 1.9 (95% CI, 1.4-2.5) months by irRC. In first-line patients, median OS was 17.6 months (95% CI, 10.2 months to not estimable). Patients with PD-L1 expression of at least 1% tumor-infiltrating ICs had higher ORRs and longer OS (12% [11 of 91]; 10.1 [95% CI, 7.0-13.8] months, respectively) than those with less than 1% ICs (0 of 21; 6.0 [95% CI, 2.6-12.6] months, respectively). High levels of ICs (>10%) were independently associated with higher ORRs and longer OS.Single-agent atezolizumab was well tolerated and provided durable clinical benefit in patients with mTNBC with stable or responding disease and in earlier lines of treatment.ClinicalTrials.gov identifier: NCT01375842.
Use of revised International Prognostic Scoring System (IPSS-R) in hypocellular myelodysplastic syndromes (MDS): Mayo Clinic experience.
Authors: Sonia Cerquozzi, Darci Zblewski, Kebede Begna, Hassan Alkhateeb, Kirsten Schultz, Dong Chen, Mark Robert Litzow, Aref Al-Kali
Journal: Journal of Clinical Oncology (2016)

7063 Background: Hypocellular myelodysplastic syndrome (h-MDS) is a rare subtype of MDS that shares immune-mediated pathogenic mechanisms similar to aplastic anemia. The Revised International Prognostic Scoring System (IPSS-R) is a global risk score for MDS. We retrospectively reviewed h-MDS outcomes to understand the validity of the IPSS-R. Methods: A total of 827 MDS patients from June 1997 to May 2010 at Mayo Clinic were reviewed following IRB approval. Hypocellularity was defined as ≤ 30% in patients < 70 years old, and ≤ 20% in > 70 years old (Tuzuner et al, BJH 1995). Prognostic factors analyzed by univariate and multivariate analysis included: poor risk cytogenetics ≥ 3 abnormalities, del7 or monosomy 7), normal karyotype, Hgb < 10g/dL, platelets < 100 x 109/L, bone marrow blasts ( ≥ 5%) and IPSS-R (at diagnosis). Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analysis was based on log-rank testing. Results: We identified 65 (8%) h-MDS patients with a median age of 68 years (range, 20-90). Thirteen (20%) of patients had ≥ 3 chromosomal abnormalities, monosomy 7 or del7. Based on the IPSS-R, 20% and 8% of patients had either poor or very poor risk cytogenetics, respectively. The total IPSS-R scores were very low, low, intermediate, high, and very high in 4%, 26%, 39%, 20% and 15%, respectively. The 4 year OS and PFS was 35% and 34%, respectively. Median OS was 30 months. Based on IPSS-R, OS was more favorable for h-MDS: 115, 49, 39, 21 and 21 months for very low, low, intermediate, high, and very high risk disease (p = 0.02). We demonstrate a lesser ability of IPSS-R to predict OS among higher risk h-MDS. Thrombocytopenia (platelets < 100 x 109/L) negatively impacted OS (20 vs. 49 months, p = 0.0087). Conclusions: Currently, the IPSS-R remains most widely used in all subtypes of MDS. IPSS-R was less powerful in detecting differences between high and very high risk h-MDS groups. Our cohort of h-MDS patients shows the importance of thrombocytopenia (plts < 100 x 109/L) as a single factor in predicting OS. This suggests that thrombocytopenia may be considered an alternative and simpler method of risk stratifying h-MDS compared to the IPSS-R.