tbuckley/cabot-search huggingface dataset:
Design and conduct of early clinical studies of immunotherapy agent combinations: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies
Authors: M. Smoragiewicz, J. Bogaerts, E. Calvo, A. Marabelle, A. Perrone, L. Seymour, A. Shalabi, L.L. Siu, J. Tabernero, G. Giaccone, M. Atkins, U. Banerji, S. Bates, J. Bogaerts, E. Calvo, F. De Braud, J.Y. Douillard, G. Giaccone, P. Keegan, R. Kumar, P. LoRusso, A. Marabelle, A. Perrone, F. Pignatti, R. Plummer, L. Seymour, G. Schwartz, A. Shalabi, G. Shapiro, L.L. Siu, M. Smoragiewicz, J. Tabernero, P. Therasse, A. Yang
Journal: Annals of Oncology (2018)

The Methodology for the Development of Innovative Cancer Therapies task force considered aspects of the design and conduct of early studies of combinations of immunotherapy agents during their 2018 meeting. The task force defined the relevant data to justify combination clinical trials, which includes a robust hypothesis for the combination, pre-clinical data with evidence of efficacy and an understanding of the pharmacodynamics effects of each agent, and ideally evidence of single agent activity. Evaluation of pharmacodynamic biomarkers is critical in early phase combination trials, and should be incorporated into trial objectives and go/no-go decisions. The task force also identified the need to develop assessment tools and end points that capture the unique patterns of tumour responses to immunotherapy, including pseudoprogression and hyperprogression. At least one additional tumour measurement before baseline and an early CT scan (at 4 weeks for example) would help define the incidence of hyperprogression, although a common definition is needed. Finally, the task force highlighted substantial redundancy and inefficiency in the combination immunotherapy space, and recommended the adoption of innovative trial designs.
TCT-446 Feasibility study of a single synchronized diastolic injection with low contrast volume for aortography in a progressive aortic regurgitation porcine model.
Authors: Rodrigo Modolo, Chun Chin Chang, Yosuke Miyazaki, Maaike Hekkert, Todd Suchecki, Jean-Paul Aben, Osama Soliman, Yoshinobu Onuma, Dirk Duncker, Patrick Serruys, Nicolas Van Mieghem
Journal: Journal of the American College of Cardiology (2018)
Feasibility of desensitizing children highly allergic to peanut by high‐dose oral immunotherapy
Authors: Tonje Reier‐Nilsen, Merethe Melbye Michelsen, Karin C. Lødrup Carlsen, Kai‐Håkon Carlsen, Petter Mowinckel, Unni C. Nygaard, Ellen Namork, Magnus P. Borres, Geir Håland
Journal: Allergy (2018)

Abstract Background There are limited data on the feasibility, efficacy and safety of high‐dose oral immunotherapy ( OIT ) in children highly allergic to peanuts. Objective In children highly allergic to peanut, we primarily aimed to determine the feasibility of reaching the maximum maintenance dose ( MMD ) of 5000 mg peanut protein or, alternatively, a lower individual maintenance dose ( IMD ), by OIT up‐dosing. Secondarily, we aimed to identify adverse events ( AE s) and determine factors associated with reaching a maintenance dose. Methods The TAKE ‐ AWAY peanut OIT trial enrolled 77 children 5‐15 years old, with a positive oral peanut challenge. Fifty‐seven were randomized to OIT with biweekly dose step‐up until reaching MMD or IMD and 20 to observation only. Demographic and biological characteristics, AE s, medication and protocol deviations were explored for associations with reaching maintenance dose. Results All children had anaphylaxis defined by objective symptoms in minimum two organ systems during baseline challenge. The MMD was reached by 21.1%, while 54.4% reached an IMD of median (minimum, maximum) 2700 (250, 4000) mg peanut protein, whereas 24.5% discontinued OIT . During up‐dosing, 19.4% experienced anaphylaxis. Not reaching the MMD was caused by distaste for peanuts (66.7%), unacceptable AE s (26.7%) and social reasons (6.7%). Increased peanut s‐IgG 4 /s‐IgE ratio ( OR [95% CI ]: 1.02 [1.00, 1.04]) was associated with reaching MMD. Conclusion Although 75.5% of children with peanut anaphylaxis reached a maintenance dose of 0.25‐5 g, only 21.1% reached the MMD . Distaste for peanuts and AE s, including high risk of anaphylaxis, limited the feasibility of reaching MMD .
Association of immune-related adverse events (irAEs) with improved response, progression-free survival, and overall survival for patients with metastatic head and neck cancer 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)

6014 Background: Anti-programmed death receptor-1 (PD-1) therapies are approved for recurrent/metastatic head and neck (H&N) cancer progressing on or after platinum-based chemotherapy, and immune competence may modulate anti-tumor response. We hypothesized that developing immune-related adverse events (irAEs) while receiving anti-PD-1 therapy for metastatic H&N cancer would be associated with improved outcomes. Methods: 114 patients with metastatic H&N cancer unselected for PD-ligand 1 (PD-L1) status received anti-PD-1 therapy. Adverse events (AEs) were prospectively graded using CTCAE v4.0. irAEs were any possibly immune-mediated AE regardless of attribution. Univariate and multivariate logistic regression analyzed the relationship between irAEs and overall response rate (ORR) measured 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, and follow-up did not significantly differ between irAE+/- groups (p = 0.72). Baseline characteristics including known PD-L1+ (53.1% irAE+ vs. 49.2% irAE-, p = 0.76) were comparable. 59 irAEs occurred in 49 patients. irAEs were classified as dermatologic (n = 20), pulmonary (n = 1), GI (n = 1), endocrine (n = 14), musculoskeletal (n = 15), ophthalmologic (n = 2), or hepatic (n = 6). 5 patients (10.2%) experienced grade ≥3 irAE. ORR was higher for the irAE+ (30.6%) compared to the irAE- (12.3%) group (p = 0.02). Median PFS was 6.9 months for irAE+ and 2.1 months for irAE- patients (p = 0.0004), while median OS was 12.5 months and 6.8 months (p = 0.007), respectively. On multivariate analyses, irAE+ was independently associated with improved ORR (p = 0.03), PFS (p = 0.009), and OS (p = 0.003). Conclusions: Developing irAEs while receiving anti-PD-1 therapy is associated with superior ORR, PFS, and, in particular, OS in this cohort of H&N cancer patients unselected for PD-L1 status. The ability to develop irAEs may be an indicator of immune competence and further investigation of biomarkers of immune competence is warranted.
TCT-6 The CENTER-Collaboration: Outcomes in patients undergoing transfemoral transcatheter aortic valve implantation with balloon-expandable valves versus self-expandable valves.
Authors: Wieneke Vlastra, Jaya Chandrasekhar, Antonio Munoz-Garcia, Didier Tchetche, Fabio Brito, Marco Barbanti, Ran Kornowski, Azeem Latib, Augusto D'Onofrio, Flavio Ribichini, Jan Baan, Jan Tijssen, Ramiro Trillo, Nicolas Dumonteil, Alexandre Abizaid, Samantha Sartori, Paola D'Errigo, Chiara Fraccaro, Mattia Lunardi, Katia Orvin, Matteo Pagnesi, Raquel Del Valle, Thomas Modine, Roxana Mehran, Jan Piek, Ronak Delewi
Journal: Journal of the American College of Cardiology (2018)
Longitudinal monitoring of circulating tumor DNA and peripheral T cell repertoire in patients with small cell lung cancer.
Authors: Wade Thomas Iams, Karinna Almodovar, Catherine Meador, Sally Jane York, Leora Horn, Chris Raymond, Jennifer Hernandez, Tristan Shaffer, Dan DiPasquo, Lee Lim, Christine Marie Lovly
Journal: Journal of Clinical Oncology (2017)

8571 Background: Advances in the treatment of small cell lung cancer (SCLC), an aggressive disease with poor prognosis, will require the development of diagnostic methods during treatment that are more sensitive and descriptive than are currently available. The emergence of “liquid biopsy” technologies coupled with comprehensive genomic information about common mutations in SCLC prompted us to implement a blood-based assay for simultaneous sequencing of circulating, cell-free tumor DNA (cfDNA) and determination of the peripheral a and b T cell receptor repertoire in patients with SCLC. Methods: Our SCLC assay uses targeted hybrid capture and next generation sequencing of cfDNA extracted from patient plasma to detect somatic mutations in 14 frequently mutated genes in SCLC. We also sequenced rearranged T cell receptor α and β genes, each with 5000 unique α and β CDR3 open reading frames per microgram of gDNA. Over 26 months we followed 27 patients with SCLC (16 with extensive stage and 11 with limited stage disease) and examined cfDNA from 141 plasma samples and T cell repertoire from 41 samples. Results: We detected somatic, disease-associated mutations in 85% of patient samples (23/27) with allele frequencies of cfDNA ranging from ≤0.5% to ≥85%. The most commonly mutated genes were TP53 (17/27 patients) and RB1 (10/27 patients) . We detected 87 unique genomic alterations in 12 different genes (in addition to TP53 and RB1 these included PTEN, NOTCH1-4, MYC, MYCL1, PIK3CA, KIT, and BRAF). The observed mutant allele frequencies in longitudinal samples tracked with treatment response, including cases in which cfDNA allele frequencies increased before clinical evidence of relapse. Longitudinal monitoring of T cell repertoire demonstrated both variability between patients and sequential changes during therapy, including one case of decreased T cell numbers accompanying disease relapse. Conclusions: As the field of immuno-oncology matures, we anticipate that coupled determination of T cell repertoire together with cfDNA monitoring will merge into a clinically useful “molecular image” of each patient’s disease status and real-time host immune response.
Air pollution and bronchitic symptoms in Southern California children with asthma.
Authors: R A Etzel
Journal: Environmental Health Perspectives (1999)

People who live in cities with dirty air have blacker lungs than people who live in rural areas with less air pollution. This is because, although particulates larger than 10 microm are filtered out when inhaled air passes through the nose, smaller particulates reach the lower airways. The particulates that reach the alveoli (the terminal air pockets of the lungs) stay there permanently. This accounts for the fact that a person who has lived in a polluted city for many years has blacker lungs than one who has lived in a polluted city for a shorter time.
Study of patient risk factors for febrile neutropenia in non-Hodgkin lymphoma receiving R-CHOP regimen: STOP FN single institution analysis in Japan.
Authors: Masahiro Yokoyama, Yoshiharu Kusano, Anna Takahashi, Norihito Inoue, Tadahiro Gunji, Hideaki Nitta, Kyoko Ueda, Noriko Nishimura, Yuko Mishima, Yasuhito Terui, Kiyohiko Hatake
Journal: Journal of Clinical Oncology (2016)

e21605 Background: Cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP) is standard therapy for patients (pts) with CD20 positive non-Hodgkin lymphomas (CD20+NHLs). American Society of Clinical Oncology (ASCO) guideline 2006 for the use of white blood cell growth factors reported that the rate of febrile neutropenia (FN) receiving R-CHOP regimen is 18%, but analyzed No. of pts were only 33. To reconfirm the rate of FN in pts treated with R-CHOP, we conducted a retrospective study. Methods: From Jan 2006 to Dec 2013, pts with CD20+NHLs receiving R-CHOP in Cancer Institute Hospital, Japan were studied retrospectively. Results: Four hundred sixty-six pts were enrolled. Total of 2506 cycles of R-CHOP was administered. Pts characteristics were: 263 (56%) male, 203 (44%) female; median age, 65 yrs. (range 17-88); 249 (53%) 65 yrs. or older; 439 (94%) performance status (PS) 0-1; 378 (81%) pts with diffuse large B-cell lymphoma (DLBCL), 36 (8%) pts with follicular lymphoma, 15 (3%) pts with transformed DLBCL, and 37 (8%) pts with other B-cell lymphomas. The rate of FN in first cycle of R-CHOP was 9.1% (95% confidence interval (CI): 6.6-12.1%), and the rate of FN during all cycles of R-CHOP was 11.8% (95% CI: 9.0-15.1%), respectively. No pts with grade 5 FN and infections were observed. Univariable logistic regression analysis performed that age 65 yrs. or older (odds ratio (OR) 2.7 (95% CI 1.3-5.4; p = 0.007)), female (OR 2.0 (95% CI: 1.1-3.9; p = 0.033)), PS 2-4 (OR 2.6 (95% CI: 0.9-7.2; p = 0.073)), advanced stage (OR 1.8 (95% CI: 1.0-3.5; p = 0.065)), albumin < 3.5g/dL (OR 2.6 (95% CI: 1.3-5.0; p = 0.006)), and hemoglobin < 12g/dL (OR 2.2 (95% CI: 1.2-4.2; p = 0.016)) may be associated with the incidence of FN in first cycle of R-CHOP. Conclusions: We reconfirmed that the rate of FN in pts with CD20+NHLs treated with R-CHOP was lower 20% in Japan. To reduce the incidence of FN and infections, primary prophylactic hematopoietic colony-stimulating factors for pts with high risk factors of FN receiving curative chemotherapy such as R-CHOP is recommended. (Clinical trial number: UMIN000015121)
A pilot trial assessing apatinib in advanced head and neck squamous cell carcinoma that failed in previous standard chemotherapy or chemoradiotherapy.
Authors: Hui Wu, Xiaoxu Lu, Jing Xu, Xueming Sun, Shujuan Wang, Wei Du, ShanTing Liu, DingJie Li
Journal: Journal of Clinical Oncology (2018)

e18009 Background: Effective therapy is not available for patients (pts) with recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN) that was previously treated with standard chemotherapy or chemoradiotherapy. This study aimed to investigate apatinib (a novel anti-angiogenic agent) in combination with or without radiotherapy (RT) in treatment of this cohort of patients. Methods: Unresectable SCCHN pts after failure of at least one line of therapy were initially treated with 500 mg qd apatinib. Dose reduction to 250 mg qd was allowed. Palliative local RT (GTV: 50-60 Gy/25-30 f; CTV: 40-50 Gy, 5 f/w) was given to Stage IVB pts who could tolerate concurrent RT. Results: Between Jun 2017 and Nov 2017, 16 pts were enrolled. The median age was 60 yrs; 75.0% were male; 68.8% had 2 lines of chemotherapy, 25.0% failed after postoperative chemotherapy following second surgery, and 6.2% experienced RT and multiline chemotherapy. In this study, 8 (50.0%) pts received apatinib plus RT. At the cut-off date of 01/10/2018, the best objective response rate (ORR) and disease control rate (DCR) were 25.0% and 50.0% for apatinib alone and up to 87.5% and 100.0% for apatinib plus RT, respectively. Treatment related adverse events (TRAEs) were reported by 3 (37.5%) apatinib-treated pts and all pts receiving apatinib plus RT. The incidence of grade 3/4 TRAEs was 25.0% for apatinib alone, mainly hypertension. While 75.0% pts receiving apatinib plus RT had grade 3/4 TRAEs, including fistula (n = 3), hand-foot skin reaction (n = 1), heart failure (HF; n = 1) and leukocyte decrease (n = 1). Fistula and HF were improved by treatment interruption for one week and symptomatic therapy, and the dose were reduced to 250 mg qd thereafter. There was no treatment-related death. Conclusions: Over 50% of pretreated SCCHN pts responded to apatinib. Apatinib plus RT seems to be more effective; however, occurrence of fistula should be paid close attention. These results support further investigation of this regimen in a larger confirmatory clinical trial. Clinical trial information: NCT03424291.
Anti-PD1 antibodies in late elderly advanced melanoma patients: A retrospective multicentre study.
Authors: Francesco De Rosa, Laura Ridolfi, Enrica Teresa Tanda, Elena Marra, Jacopo Pigozzo, Riccardo Marconcini, Michele Guida, Giulia Gallizzi, Marcella Occelli, Laura Pala, Elisabetta Gambale, Melissa Bersanelli, Raffaele Conca, Alessio Cortellini, Francesca Morgese, Federica Zoratto, Luigia Stefania Stucci, Sabino Strippoli, Elisabetta Petracci, Massimo Guidoboni
Journal: Journal of Clinical Oncology (2018)

10038 Background: advanced age is associated with comorbidities and impairment of the immune system: these aspects may influence efficacy and tolerability of immune checkpoint inhibitors. Limited data suggest that anti-PD1 antibodies in advanced melanoma are equally effective in patients (pts) aged over 65 years; however, the information on late elderly pts ( > 75 years) is still lacking, as comorbidities and logistic reasons often exclude them from clinical trials. Methods: we retrospectively reviewed clinical records of late elderly advanced melanoma pts treated in any line with an anti-PD1 agent (nivolumab or pembrolizumab) at our institutions to investigate efficacy and toxicity in a real practice setting. Clinical response was assessed according to RECIST criteria; toxicity was assessed according to CTCAE 4.0. Survival was estimated according to Kaplan-Meier method. Results: we identified 161 pts fulfilling inclusion criteria (68 M, 93 F). Median age was 79 (range 75-93); 110 pts (68%) had multiple comorbidities including history of other cancers (25 pts) and autoimmune/inflammatory disorders (13 pts). Eighty-eight pts received nivolumab, 73 pembrolizumab; basal LDH was elevated in 76 pts (47.2%). Fourteen pts (8.7%) obtained a complete response and 44 (27.3%) a partial response; additional 30 patients (18.6%) obtained a stable disease. Median overall survival was 8.71 months; normal LDH was significantly associated with better prognosis (14.45 vs 6.08 months; P = 0.016). Fifty-five pts have died; 48 of them because of progressive disease and the others for comorbidities. In our series treatment was well tolerated: only 5 pts had severe (G3-4) toxicity and no treatment-related death was reported. Adverse events were managed with corticosteroids and no pt needed additional immunosuppressive agents. Conclusions: anti-PD1 antibodies seem equally effective and well tolerated even in late elderly advanced melanoma pts, whose access to treatment should not be restricted solely because of advanced age.
Is Cystic Fibrosis–related Diabetes Reversible? New Data on CFTR Potentiation and Insulin Secretion
Authors: Andrew W. Norris
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

presence of a profound lung heterogeneity and a severe impairment of lung function beyond the oxygenation values.Some questions concerning the VR remain unanswered.It is not known whether this index will maintain its predictive value in the evolution of ARDS over time, as has been demonstrated for VD/VT (6).As was previously suggested for Pa O 2 /FI O 2 (15), it is possible that a standardized evaluation of the VR under predefined ventilator settings could improve its predictive/prognostic abilities.The possibility of an early characterization of the severity of ARDS by a simple, easy to measure bedside index that contains important pathophysiological information is certainly good news.It will help clinicians and researchers become more efficient!n
Prevalence [P] of molecular biomarkers [MB] expression [exp] in patients [pts] with metastatic adenocarcinoma lung [MAC]: Illinois CancerCare [ILCC] analysis.
Authors: Nikhil Kumar, Patrick Leigh Gomez, Jamie Harper
Journal: Journal of Clinical Oncology (2021)

e21004 Background: Treatment of MAC is guided by MB. These include Programmed Death Ligand 1 (PDL1), Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK) &amp; ROS1. There is little information available on P of MB in US Midwestern population, a largely homogenous Caucasian group. We examined the expression (exp) of the MB in pts with MAC who presented at ILCC in 2018, one of the largest practices in US Midwest. Methods: We conducted a retrospective analysis of all MAC pts who presented at ILCC in 2018. We analyzed the exp of PDL1, EGFR, ALK, and ROS1 in these pts. PDL1 status was defined as high if PDL1 was ≥50%, low if 1- &lt; 50% and -ve if 0- &lt; 1%. High and low groups [all pts with &gt; 1%] were designated +ve. Results: In 2018 there were 125 pts seen at ILCC with MAC. As of 6/2019, 57/125 [46%] pts were alive. Pts: median age 69 yrs [45-89], median PS 1 [0-3], males 62%, current/former smokers 90%, Caucasians 95%. PDL1 results were available in 104/125 pts [83%], EGFR in 95 (76%), ALK in 97 (78%), and ROS1 in 95 (76%). Previously reported papers have described PDL1+ to be as high as 58% in MAC. However, in our study only 53/104 (51%) pts were PDL1+. Though, 26/104 (25%) did have high PDL1 exp [consistent with other reports]. 27/104 (26%) had low PDL1 exp and 51/104 (49%) pts were PDL1-ve. EGFR mutation [M] was found in 11/95 (12%), ALK M was found in 5/97 (5%) pts &amp; ROS1 M was found in 2/95 (2%), the results of these three mutations are consistent with other groups. Conclusions: Our results indicate that exp of PDL1+ pts at ILCC is lower than reported by others, yet the proportion of those with ≥50% PDL1 in our group is similar to others. Exp of EGFR, ALK, and ROS1 in our pts is similar to other studies.[Table: see text]
Two novel registry-based prediction models for overall survival in patients with metastatic esophageal or gastric cancer.
Authors: Héctor van den Boorn, Ameen Abu-Hanna, Emil ter Veer, Jessy Joy van Kleef, Florian Lordick, Michael Stahl, Jaffer A. Ajani, Rosine Guimbaud, Se Hoon Park, Susan J. Dutton, Yung-Jue Bang, Nadia Haj Mohammad, Mirjam A.G. Sprangers, Rob H.A. Verhoeven, Aeilko H. Zwinderman, Martijn G.H. van Oijen, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2018)

4021 Background: Prediction models for decision-making in oncology are increasingly being used, but few are available for esophagogastric cancer, particularly in the metastatic setting. The aim of this study is to construct prediction models for overall survival in patients with metastatic esophageal or gastric cancer. Methods: Data from patients with metastatic esophageal (N = 8670) and gastric (N = 4804) cancer diagnosed in the period 2005-2015 were retrieved from the nationwide Dutch cancer registry. Multivariate Cox regression models, extended with treatment interactions, were created to predict overall survival. Multiple imputations were used to handle missing data. Predictor selection was performed via the Akaike Information Criterion (AIC) and was extended by a Delphi consensus among experts in the field of palliative esophagogastric cancer. Validation was performed with an 11-fold temporal validation. Both the concordance-index (c-index) and calibration were used to assess model quality. Results: The Delphi consensus yielded seven important predictors of survival and are shown with the AIC-selected predictors in Table 1. The c-indices show consistent discriminative ability during validation, i.e. 0.71 and 0.68 for respectively the esophageal and gastric cancer models. There is close agreement between predicted and observed survival, with an error of 1.7% and 2.2% for respectively the esophageal and gastric cancer models. Conclusions: The models yield fair discrimination and high calibration levels, and provide a good foundation for further investigation in clinical practice to determine their added value in decision-making. Overview of selected predictors in the esophageal and gastric cancer models (#: selected during Delphi consensus). Predictor Esophageal cancer model Gastric cancer model Gender X X Age# X X cT-stage X X cN-stage X X Primary tumor location# X X Tumor morphology# X X Number of distant metastatic sites# X X First line treatment type# X X Metastasis only in distant lymph nodes X X Liver metastasis# X Peritoneal metastasis# X Age * First line treatment X X Liver metastasis * first line treatment X Number of distant metastatic sites * First line treatment X