tbuckley/cabot-search huggingface dataset:
A clinical score to predict the early death at 100 days after a comprehensive geriatric assessment (CGA) in elderly metastatic cancers , analysis from a prospective cohort study with 1048 patients.
Authors: Rabia Boulahssass, Sebastien Gonfrier, Jean Marc Ferrero, Sanchez Marine, Dominique Saja, Véronique Mari, Thierry Piche, Jean Marc Bereder, Jerome Delotte, Jean-Michel Turpin, Delphine Ouvrier, Jerome Barrière, Remy Largillier, Cyrielle Rambaud, Daniel Benchimol, Philippe Follana, Josiane Otto, Joel Guigay, Eric Francois, Olivier Guerin
Journal: Journal of Clinical Oncology (2016)

e21532 Background: Trying to predict the very early death after a CGA is difficult in elderly metastatic cancers. Last year, we presented a clinical score to predict this risk in 815 elderly cancer patients (Boulahssass et al 9511 ASCO 2015). The aim of this new study is the next step by developing a score to estimate the risk of early death at 100 days in metastatic cancers (MC) in order to have the collective wisdom not to overtreat this population.100 days is nearly 3 months, if patients are going to die within 3 months , it’s maybe necessary to provide them best supportive care alone. Methods: This is a multicentric and prospective cohort study approved by an ethics committee. At the baseline, a standardized CGA was performed (MMSE,MNA,Grip strength, ADL, IADL ,CIRSg, Charlson, lee,PS,Gait speed, QLQc30, G8, Balducci) , type and localization of metastases were collected. During the follow up of 100 days, events, treatments made and targeted geriatric interventions were collected. A multivariate logistic regression permits to select risk factors.The internal validation was performed by a bootstrap with randomized samples. Score points were assigned to each risk factors by using the β coefficient. The accuracy of the score was assessed with the mean c-statistic and the calibration with the Hosmer-Lemeshow goodness of fit test. Results: In the cohort 312 patients had a MC with a median age of 82y. The indepedent predictors of death at 100 days in MC were: Age > 85y (OR 2,1 p = 0,03), Metastatic localizations (ML): 2ML (OR 2,4 p = 0,004) , > 2 ML (OR 6,3 p = 0,001),MNA < 17 (OR 8,7 p < 0,0001) or ≤ 23,5 and ≥ 17 (OR 5,4 p = 0,002), Home confinement (OR 1,8 p = 0,047) ,ADL < 5,5 (OR 2,1 p = 0,017),Cancers with global risk of early death at 100 days > 30% (OR 2,05 p = 0,016) We assigned in the score : 3 points for : MNA ≤ 23,5 , ML > 2 and 1 point for home confinement, ADL < 5,5, ML = 2 , age > 85y and types of cancers at risk > 30% The risk of death at 100 days in MC was 4 % for 0 to 2 pts, 18% for 3 to 4 pts,33% for 5 pts and 44% for 6 pts and 83% for > 6 pts Conclusions: In daily practice, this score should help to avoid unnecessary treatment for patients with a high risk of death, especially for those with a score > 6.
Comparison of the genetic profiles of primary colorectal cancers and their subsequent pulmonary metastases: Implications for targeted treatment.
Authors: Sing Yu Moorcraft, Thomas Jones, Brian Walker, George Ladas, Eleftheria Kalaitzaki, Lina Yuan, Ruwaida Begum, Zakaria Eltahir, Andrew Wotherspoon, Angeles Montero Fernandez, Larissa Sena Teixeira Mendes, David Gonzalez de Castro, Sanna Hulkki Wilson, Ye Mong To, Anne Bowcock, Ian Chau
Journal: Journal of Clinical Oncology (2016)

e15027 Background: Tumour heterogeneity may limit the efficacy of targeted therapies. Pulmonary metastases (PM) occur in 10-20% of patients (pts) with colorectal cancer, but little is currently known about the genetic characteristics of colorectal PM and whether they differ from the primary tumour. Methods: Clinical data and archival formalin fixed paraffin embedded tissue samples were retrospectively collected from pts who underwent ≥ 1 pulmonary metastastectomies for colorectal cancer between 1997 – 2012. Primary tumour and metastatic samples were analysed using a targeted capture sequencing panel of 45 cancer-associated genes (median depth 806x, median coverage 96.6%). Results: Clinical data were collected from 81 pts. The median progression-free survival (PFS) and overall survival (OS) were 24 months (95% CI 19 – 38) and 91 months (95% CI 72 – 130) respectively, and the 5-year PFS and OS rates were 32% and 77%. No clinicopathological factors were prognostic for PFS or OS by multivariate analysis. Fifty-four pts had samples available from ≥ 1 PM, and sequencing data was successfully obtained from 33 PM samples from 24 pts. The most frequently altered genes were APC (76%), KRAS (67%) and TP53 (48%). Mutations were also detected in a number of other genes ( < 20% frequency), including FBXW7, PIK3CA and ATM. Results were available from matched primary and PM samples for 15 pts, and 11 of these pts (73%) had concordant genetic profiles. The allele frequencies of key cancer mutations were slightly lower in the first PM in contrast to the primary tumour. Six of the 7 pts with results from ≥ 2 PM (86%) had concordant results. The overall concordance for all matched samples was 95% and 100% for KRAS and NRAS. Conclusions: Pts treated at our institutions for resectable colorectal PM had a favourable prognosis. In keeping with previously published data, KRAS mutations occurred at a higher frequency in pts with colorectal PM. Mutation status, and RAS status in particular, was highly concordant between the primary cancer and PM from the same individual. When PM develop, it may not be necessary to undertake repeat biopsies to determine pts’ suitability for anti-EGFR therapy.
A population-based registry study on relative survival from melanoma in Germany stratified by tumor thickness for each histologic subtype
Authors: Alicia Brunssen, Lina Jansen, Nora Eisemann, Annika Waldmann, Janick Weberpals, Klaus Kraywinkel, Andrea Eberle, Bernd Holleczek, Sylke Ruth Zeissig, Hermann Brenner, Alexander Katalinic, Karla Geiss, Martin Meyer, Sabine Luttmann, Roland Stabenow, Stefan Hentschel, Alice Nennecke, Joachim Kieschke, Eunice Sirri, Katharina Emrich, Hiltraud Kajüter, Volkmar Mattauch
Journal: Journal of the American Academy of Dermatology (2018)
Smoking and human papillomavirus (HPV) as pronostic factors of oropharyngeal squamous cell carcinoma in the population of salamanca: Spain.
Authors: Roberto Escala, Julia Ayuso Martín-Romo, María García Muñoz, Soledad Medina Valdivieso, Leydy Mallerling M Paredes Duran, María Jesús Baldeón Conde, Beatriz Barrios Collado, Diego Casado Elia, Arantxa Amores, Raquel Seijas-Tamayo, Elvira Del Barco Morillo, Dolores Ludueña De la Cruz, Juan J. Cruz-Hernández
Journal: Journal of Clinical Oncology (2018)

e18056 Background: Oropharyngeal Squamous cell carcinoma (OSCC) is an entity whose incidence has increased in recent years due to its relationship with HPV and is related with a better survival. We will evaluate the epidemiological characteristics and the prognostic relationship between smoking and HPV in patients with OSCC in the population of Salamanca -Spain. Methods: We conducted a retrospective analysis of patients diagnosed with OSCC between 2008 - 2013, using the pre-existing clinical records at the University Hospital of Salamanca. A comparative analysis by HPV status and smoking habit was performed. Survival analysis was performed using Kaplan-Meier estimate and logistic regression analysis. Results: Between years 2008-2013, 91 cases of OSCC were diagnosed: 27 (29.6%) women and 64 (70.4%) men. The median age: 66 years (range: 31-98 years). P16 was determined as a surrogate marker of HPV in the tissue samples of 50 patients (55.5%). Of these 50 patients, 15 (30%) were positive (HPV +) and 35 (70%) were negative (HPV -). All of the 50 patients (100%) had a history of smoking. Patients were classified as HPV +/ Smokers and HPV -/ Smokers. 60% of HPV + / Smokers and 57% of HPV- / Smokers were diagnosed in advanced stages. The median overall survival (OS) was: 37 months for HPV + / Smokers and 67.4 months for HPV- / Smokers, with a statistically significant difference (p = 0.039). Conclusions: According to the data obtained, we can conclude that smoking in our population continues to be the most influential prognostic risk factor in the appearance and evolution of OSCC. In addition, the staging and survival data of our cohort corroborate the scientific evidence that the association of HPV with smoking, is a factor of worse prognosis when compared with the absence of one of these 2 factors.
<i>CHK</i>1 inhibition as a therapeutic approach in <i>KRAS</i> mutated and squamous cell carcinoma NSCLC patients.
Authors: Daniela Morales-Espinosa, Silvia García-Román, Miguel Angel Molina-Vila, Ana Gimenez Capitan, Jordi Bertran-Alamillo, Pedro Mendez, Santiago Viteri Ramirez, Niki Karachaliou, Rafael Rosell
Journal: Journal of Clinical Oncology (2016)

11581 Background: Targeted therapy has improved outcomes in EGFR mutated and ALK translocated NSCLC but options for squamous cell carcinoma and KRAS-mutated tumors remain scarce. Genome re-replication may cause gene amplification, chromosomal translocation and loss, contributing to tumor progression. Cell cycle checkpoints and DNA damage response are activated by induced re-replication. CHK1/2-mediatedcell cycle checkpoints prevent re-replication and maintain genomic integrity. Specific CHK1 inhibitors delay tumor growth in combination with pemetrexed in NSCLC xenograft models. Methods: In a panel of NSCLC adenocarcinoma and squamous cell carcinoma cell lines with TP53, KRAS and EGFR mutations and six PC9-derived, TKI resistant cell lines treated with CHK1 and CHK1/2 inhibitors; IC50 was determined by MTT assay. We analyzed expression of genes involved in the re-replication pathway (MDC1, ATR, ATM, CHEK2, Rap80, Cdc1, Cdc6, MYC, SLX4, CHEK1, BRCA1, BRCA2, p53, ORC4, ORC5, ORC6, GMNN) by RT-PCR. Results: In KRAS-mutated cell lines, CHK1 inhibition resulted in very low IC50 for H23 0.2 µM, for A549 2.4 μM and for Calu6 0.3 μM; single CHK2 inhibition was less successful. Interestingly, a p53 mutated squamous cell line (SK MES1) had high basal expression levels of CHK1 and CHK2 and the lowest IC50 (0.024 μM) with CHK1 selective inhibitor. IC50 was significantly higher in SK MES1 cell line (84.62 µM vs 0.024 µM) with dual CHK1-CHK2 vs single CHK1 inhibition. Two EGFR-resistant cell lines, one with T790M mutation, were highly sensitive to CHK1inhibition (IC50 0.19µM, PC-GR5; 0.40 µM, PC9-GR4). We observed different expression levels of key genes of the re-replication pathway. Conclusions: Different expression of genes involved in the re-replication pathway and sensitivity of some squamous NSCLC cell lines to selective CHK-1 and dual CHK1-CHK2 inhibitors indicates a potential new therapeutic approach for these subgroups. Our experiments also showed that CHK1 inhibition has strong activity in KRAS mutated cell lines (H23, Calu6, A549), particularly when a P53 mutation is also present. Further studies are warranted after these findings.
Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis
Authors: Erik Ellwardt, Gautam Pramanik, Dirk Luchtman, Tanja Novkovic, Eduardo Rosales Jubal, Johannes Vogt, Isabelle Arnoux, Christina Francisca Vogelaar, Shibajee Mandal, Melanie Schmalz, Zeke Barger, Inigo Ruiz de Azua, Tanja Kuhlmann, Beat Lutz, Thomas Mittmann, Stefan Bittner, Frauke Zipp, Albrecht Stroh
Journal: Nature Neuroscience (2018)
Abstract 16418: Reinitiation of Antithrombotic Therapy After Emergency Procedures or After an Uncontrolled or Life Threatening Bleeding Event. Initial Experience From the Re-verse Ad Trial
Authors: Charles V Pollack, Jr., Paul A Reilly, John Eikelboom, Stephan Glund, Peter Verhamme, Richard A Bernstein, Robert Dubiel, Menno V Huisman, Elaine Hylek, Pieter W Kamphuisen, Jörg Kreuzer, Jerrold H Levy, Frank Sellke, Joachim Stangier, Thorsten Steiner, Bushi Wang, Chak-Wah Kam, Jeffrey I Weitz
Journal: Circulation (2015)

Background: In AF patients, oral anticoagulation is effective for stroke risk reduction, but there is uncertainty on how to manage re-initiation of anticoagulation after a bleeding complication. Ideally, therapy would be stopped immediately and reinitiated as soon as possible after the bleeding has resolved. In clinical trials comparing dabigatran to warfarin, urgent interventions were linked to higher rates of both bleeding and thromboembolic events than elective interventions. Idarucizumab immediately reverses the anticoagulant effects of dabigatran without prothrombotic effect. Due to idarucizumab’s specificity to dabigatran, other drug-drug interaction is not expected, allowing the clinician flexibility in managing antithrombotic therapy during and after the event. Methods: In the ongoing phase III RE-VERSE AD study, dabigatran-treated patients with uncontrolled bleeding (Group A) or who require emergency surgery (Group B) are given 5 g of idarucizumab IV. The primary endpoint was median maximum reversal of the anticoagulant effect of dabigatran, based on dilute thrombin time (dTT) or ecarin clotting time (ECT) within 4 h of study drug infusion. Data collection on re-initiation of antithrombotic therapy was studied as a secondary endpoint. Results: In the interim analysis of 90 patients, median maximum reversal of the anticoagulant effect of dabigatran was 100%. For antithrombotic re-initiation data, see Table. Conclusions: Idarucizumab is an immediate-acting, specific reversal agent for dabigatran. Preliminary results from RE-VERSE AD suggest that idarucizumab facilitates the periprocedural management of dabigatran-treated patients. Of note is that after an acute event, alternative antithrombotic therapy can be initiated at any time after idarucizumab application. Reintroduction of dabigatran was possible as early as 24 h after idarucizumab treatment. This is desirable to protect patients from their underlying thromboembolic risk.
Phase I STORM study (KEYNOTE 200): Intravenous delivery of a novel oncolytic immunotherapy agent, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients.
Authors: Hardev S. Pandha, Kevin J. Harrington, Christy Ralph, Alan Melcher, David Mansfield, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren
Journal: Journal of Clinical Oncology (2016)

TPS3108 Background: Coxsackievirus A21 (CVA21, CAVATAK) is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. Tumor infection by CVA21 can increase levels immune-checkpoint molecules, immune-cell infiltration and enhancement of systemic antitumor immune response. Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody that has yielded significant solid tumor responses via reversal of tumor induced T-cell suppression. Preclinical studies in an immune-competent mouse model of melanoma confirmed that combinations of IV CVA21 + anti-PD-1 mAbs mediated significantly greater antitumor activity compared to use of either agent alone. We postulate that the combination of CVA21+pembrolizumab may translate to a similar benefit in the clinic. We describe a Phase I study assessing safety and efficacy of IV CVA21 ± pembrolizumab in advanced cancer pts. Methods: The Phase I STORM: Systemic Treatment Of Resistant Malignancies: NCT02043665 (KEYNOTE 200): Primary objectives are to assess dose-limiting toxicities (DLT) of CVA21 ± pembrolizumab. Secondary objectives are to assess ORR as by irRECIST 1.1 criteria, PFS, and OS. Treatment: Part A: Pts are infused with CVA21 in 100 mL saline in Cohort 1 (n = 3), at a dose of 1 x 108 TCID50 , in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = 12-18) at a dose of 1 x 109 TCID50 on study days 1,3,5,22 and Q3W for 6 additional infusions. Part A enrollment is almost complete. Part B: Pts are infused with CVA21 in 100 mL saline + pembrolizumab. In Cohort 1 (n = 3), CVA21 is administered at a dose of 1 x 108 TCID50 , in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = ~80) at a dose of 1 x 109 TCID50 on study days 1,3,5,8,29,and Q3W for 6 additional infusions. Pembrolizumab is given in all cohorts at 200 mg IV Q2W from Day 8 for up to 2 years. Treatment with CVA21 ± pembrolizumab will continue until confirmed CR or PD (whichever comes first) per irRECIST 1.1 or DLT. Key eligibility: Pts with advanced disease considered appropriate treatment with CVA21 ± pembrolizumab, lesion(s) accessible for core biopsy, ECOG PS 0-1, no active cerebral metastases, no autoimmunity/immunosuppression. Clinical trial information: NCT02043665.
The impact of pain in recurrent ovarian cancer patients: An individual participant data meta-analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO) of 1226 patients.
Authors: Hannah Woopen, Rolf Richter, Sara Alavi, Guelhan Inci, Radoslav Chekerov, Jalid Sehouli
Journal: Journal of Clinical Oncology (2018)

10112 Background: Pain has a major impact on quality of life in ovarian cancer (OC) patients. The influence of pain on survival is unclear in OC. Aim of this study was to analyze the impact of pain on quality of life and survival in recurrent OC patients. Methods: Raw data including the QLQ-C30 questionnaire from three phase II/III trials (“Topotecan phase III”, “Hector” and “TRIAS”) conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) were synthesized and analyzed using logistic and cox regression analyses. Results: Out of 1226 patients there were data on pain available for 952 patients. More than one third of patients (36.6%) experienced moderate to severe pain, defined as pain ≥ 50 in the QLQ-C30 symptom scale, which was independent from the administered chemotherapy. 31% were taking non-opioid pain medication and 16% opioids. Median age at randomization was 61 years (range 25-84). Most patients (84.7%) were diagnosed in advanced stages. Pain was independent from age, FIGO stage, grading, amount of recurrences and chemotherapy free interval. ECOG was significantly worse in patients with pain (p < 0.001). These patients experienced more frequently fatigue, nausea/vomiting, sleeping disorders, abdominal symptoms such as loss of appetite, diarrhea and constipation (all p < 0.001). Quality of life was significantly diminished (p < 0.001). Pain was also an independent marker for overall survival (OS). Median OS was 18.2 months in patients with pain compared to 22.0 months in patients without pain (p = 0.013, HR 1.25, 95% confidence interval 1.05-1.48). OS was shorter in patients with pain and without pain medication compared to those on sufficient pain medication, whereas OS was mostly decreased in patients having pain despite pain medication (18.5, 19.6 and 15.0 months respectively; p = 0.026). There was no difference regarding progression free survival and prior treatment discontinuation. Conclusions: Effective pain management is crucial for both quality of life and overall survival in patients with recurrent ovarian cancer. Patients shall therefore receive best supportive care as early as possible.
A retrospective, feasibility study of biweekly docetaxel in patients with high-risk, metastatic, hormone-sensitive, or castration-naive prostate cancer (mHSPC or mCNPC).
Authors: Sung Won Lim, Youjin Kim, Su Jin Lee, Jangho Cho, Sehhoon Park, Hee Kyung Kim, Hansang Lee, Song Ee Park, Se Hoon Park
Journal: Journal of Clinical Oncology (2018)

e17000 Background: The results from randomized phase III trials showed that 3-weekly docetaxel added to androgen-deprivation therapy (ADT) has a significant impact on survival of patients with mCNPC and established early chemotherapy as part of the standard of care for high-risk disease. Controversy remains, however, because some patients would experience critical toxicities related to docetaxel. The purpose of the current study was to evaluate the feasibility and adverse events of biweekly-administered docetaxel in patients with previously-untreated, high-risk, mCNPC. Methods: The study included 35 consecutive patients with high-risk mCNPC who received ADT plus docetaxel 40 mg/m2. Oral prednisone 5 mg twice daily also was given. Treatment was repeated every 2 weeks up to 12 cycles, or until disease progression or unacceptable toxicity. High-risk was defined as bone metastases beyond axial skeleton and/or visceral disease. Results: Patients’ median age was 68 years (range, 31-86) and 17 (49%) had visceral metastases. Biweekly docetaxel was generally well-tolerated: most commonly observed adverse events of all grades included alopecia (74%), nail changes (42%) and constipation (31%). Hematologic adverse events were infrequent and no patient received hematopoietic growth factors. One patient died after fourth cycle due to respiratory failure which occurred as a complication of pneumonia. Among 35 patients, 28 completed the planned 12 cycles of biweekly docetaxel. PSA response ( > 50% decrease from baseline) was recorded in 33 patients (94%), and the radiologic response rate was 49%. Median progression-free survival was 13.6 months (95% CI, 6.7-20.4). Conclusions: In patients with high-risk mCNPC, ADT plus biweekly-administered docetaxel appeared tolerated and effective in delaying CRPC. Because results suggest tolerability when compared to standard 3-weekly docetaxel, a prospective study evaluating this biweekly regimen (ClinicalTrials.gov, NCT03061643) is under way.
Perfusion Defect–Concordant Progression of Unilateral Refractory Pulmonary <i>Mycobacterium avium</i> Complex Disease
Authors: Takanori Asakura, Yoshitake Yamada, Makoto Ishii, Toshiki Ebisudani, Soichiro Ueda, Tomoko Betsuyaku, Naoki Hasegawa
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Germinal Centers in Diagnostic Biopsies of Patients With Primary Sjögren's Syndrome Are Not a Risk Factor for Non‐Hodgkin's Lymphoma but a Reflection of High Disease Activity: Comment on the Article by Sène et al
Authors: Erlin A. Haacke, Bert van der Vegt, Arjan Vissink, Fred K. L. Spijkervet, Hendrika Bootsma, Frans G. M. Kroese
Journal: Arthritis & Rheumatology (2018)

With great interest we have read the article of Sène et al. (1) in which ectopic germinal centres (GCs) in labial gland biopsies of primary Sjögren syndrome (pSS) patients were found predictive for Non-Hodgkin's lymphoma (NHL) development later in the disease.In the univariate analysis the presence of