tbuckley/cabot-search huggingface dataset:
Association analysis of the combination of tumor burden and PD-L1 expression and response to PD-1/L1 inhibitors in Chinese cancer patients.
Authors: Kunsong Li, Geng Tian, Senming Wang, William Lewis, Xiaodong Pan, XiaoWei Dong, Donglin Chen, Ming Yao, Kai Wang
Journal: Journal of Clinical Oncology (2018)

e13520 Background: PD-1/L1 inhibitors have demonstrated their remarkable clinical efficacy in multiple tumors. PD-L1 expression and tumor mutation burden (TMB) are the most studied biomarkers for immune check point inhibitors in western cohort. However, sufficient evidences are still lacking in Chinese cancer patients (pts). Methods: Totally 32 advanced cancer pts including 19 NSCLC, 11 intrahepatic cholangiocarcinoma, 1 hepatocellular carcinoma and 1 gastric cancer who received anti-PD-1/PD-L1 treatment as multi-line therapies were recruited. Genomic alterations were assayed by deep sequencing panel assay targeting the whole exons of 450 cancer genes and selected introns in 39 genes. TMB was acquired by NGS algorithm. Tumor tissues from selected patients were analyzed for PD-L1 expression by IHC. Results: The median age of the 32 pts was 53.5 years (range: 35-69) including 23 males and 9 females. These patients were administrated for FDA approved PD-1/L1 inhibitors with or without chemo or antiangiogenesis therapies. The overall response rate was 43.8%, including one CR and 13 PR in multi tumor types. Moreover, durable clinical benefits (DCB) which was defined as CR/PR or SD for at least 6 months was observed in 21 pts, and the DCB rate was 65.6%. The median TMB of the DCB group was 15.5 muts/Mb (range: 3.2-369), but the no clinical benefits (NCB) group had the median TMB value at 9.3 muts/Mb (range: 0.8-19). All of the pts with TMB value greater than 20 muts/Mb achieved DCB from the treatment. The DCB rate dropped to 72.7% in pts with TMB greater than 10 muts/MB. As for the PD-L1 expression, the DCB rate in 14 pts with positive tumorous PD-L1 expression was 71.4%. In addition, the DCB rate in 8 pts with TMB greater than 10 muts/Mb and positive in PD-L1 expression was 100%. Conclusions: Our preliminary results based on a small number of real world pts showed a significant association (p = 0.0048) between high TMB and response of anti-PD-1/L1 therapies in Chinese cancer pts. Moreover, the combination of TMB-H and PD-L1 positive predicted the response of immune checkpoint inhibitors better than TMB or PD-L1 along. Further larger cohort study is warranted in Chinese cancer pts.
Drug repurposing as a source of innovative therapies in osteosarcoma.
Authors: Gauthier Bouche, Pan Pantziarka
Journal: Journal of Clinical Oncology (2018)

11524 Background: Chemotherapy and surgery achieve a 5-year event-free survival of 60-70% in localized osteosarcoma (OS), but little additional progress has been made in recent decades. Clinical research in OS is hampered by a limited pipeline of new agents. Drug repurposing, an alternative development pathway that seeks to reuse existing drugs as the source of new treatment options, represents an interesting opportunity to solve this issue. Repurposing benefits from existing data on safety, dosing and clinical experience. Our goal was to list existing non-cancer drugs active against OS to prioritize future research and trials. Methods: We used the Repurposing Drugs in Oncology (ReDO) list of 240 approved non-cancer drugs. We queried PubMed for each drug and screened all abstracts to assess relevance, type of evidence (in vitro, in vivo, human data) and mechanism(s) of action (MoA). Results: From the 240 drugs, 65 (27%) have evidence of activity against OS. Of these, 10 (15%) are supported by human data. We found certain MoA patterns and grouped drugs in 7 categories. Drugs affecting coagulation, adhesion and chemotaxis: aspirin, heparin, warfarin, plerixafor, disulfiram. Epigenetic drugs: histone deacetylase inhibitors, DNA methyltransferase inhibitors. Immunomodulators: all-trans retinoid acid (ATRA), thalidomide, sirolimus. Differentiating agents: calcitriol, ATRA. Drugs targeting osteosarcoma stem cells: plerixafor, metformin, disulfiram. Chemo-potentiating drugs: caffeine, proton pump inhibitors, verapamil, piroxicam. Direct cytotoxicity drugs: simvastatin, glucocorticoids. Conclusions: 65 FDA-approved drugs have shown activity against OS. In terms of clinical setting, cytototoxic, epigenetic, differentiating and chemo-potentiating drugs could be tested in the neoadjuvant period to enhance the effect of chemotherapy. Immunomodulators and drugs affecting coagulation and chemotaxis could be tested during the perioperative period to prevent early recurrences. Based on our results, we are exploring the possibility of conducting international collaborative multi-arm trials to accelerate progress in OS.
Abstract 18310: Long Term Atrial Fibrillation Success is Predicted by the Degree of Pre-Ablation Left Atrial Fibrosis
Authors: Mihail G Chelu, Pim Gal, Gagandeep Kaur, Kara A Johnson, Promporn Suksaranjit, Christina Pacchia, Nassir F Marrouche
Journal: Circulation (2016)

Introduction: Late gadolinium enhancement magnetic resonance imaging (LGE-MRI) is an effective tool for quantification of atrial fibrosis. The degree of left atrial fibrosis is a good predictor of atrial fibrillation (AF) ablation success at 1 year but has not been studied for long term. Methods: LGE-MRIs of sufficient quality to quantify atrial fibrosis were obtained prior the first AF ablation in 208 consecutive patients. Left atrial fibrosis was classified in 4 Utah stages (I: 0-10%; II: 10-20%; III: 20-30%; IV: >30%). Patients were followed for a median of 4.8 years. Results: The mean age was 63.0 ±12.2 years. Fifty four percent of patients had paroxysmal AF and the mean LA fibrosis score was 16.3 ±11.2%. Patients with more advanced atrial fibrosis were more likely to have multiple AF ablations (I: 1.29, II: 1.32, III: 1.47, IV: 1.8, P=0.003). There was a significant difference in arrhythmia recurrences among Utah stages (I: 28% II: 37%: III: 58% IV: 91%, P<0.001) (Figure 1). Conclusions: The degree o...
The effect and safety of an immune checkpoint inhibitor rechallenge in non-small cell lung cancer.
Authors: Hiromi Watanabe, Toshio Kubo, Kiichiro Ninomiya, Kenichiro Kudo, Daisuke Minami, Etsuko Murakami, Nobuaki Ochi, Takashi Ninomiya, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Kadoaki Ohashi, Keiichi Fujiwara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2018)

e21147 Background: Several kinds of immune checkpoint inhibitors (ICIs) have demonstrated longer survival compared with chemotherapy in advanced non-small cell lung cancer (NSCLC). However, the effect and safety of ICI rechallenge is not fully evaluated. In this study, we performed a multicenter collaborative and retrospective analysis of ICI rechallenge in NSCLC patients. Methods: We defined "rechallenge" as re-administration of ICIs in those who were previously treated with ICIs and discontinued for any reason and received subsequent chemotherapy. To investigate the efficacy and safety, we retrospectively analyzed 434 patients with advanced NSCLC who received ICIs from December 2015 to December 2017 in seven centers. Results: Of the 434 patients who received ICIs, 317 patients discontinued the ICI treatment. Fourteen patients (4.4%) received rechallenged ICIs. All 14 patients discontinued the first ICIs due to disease progression. The types of ICIs were as follows: nivolumab (11), pembrolizumab (1), and atezolizumab (2) as the first ICIs, and nivolumab (9) and pembrolizumab (5) as the rechallenged ICIs. 8 patients received the same ICIs, and 6 patients changed ICIs. The objective response rate (ORR) was 21.4% (CR: 0, PR: 3, SD: 5, PD: 6, and NE: 0) in the first ICI treatments and 7.1 % (CR: 0, PR: 1, SD: 1, PD: 11, and NE: 1) in the rechallenged ICI treatments. The ORR of the same ICIs was 12.5% and that of the changed ICIs was 0%. Median progression-free survival (PFS) and median overall survival of rechallenged ICIs were 46 days [95% confidence interval (CI): 14–62] and 150 days [95% CI: 24–not reached], respectively. In the patients who received anti-PD-1 antibody as both "the first" and "rechallenged" ICIs (n = 12), the correlation coefficient between PFS of the first and rechallenged ICIs was -0.49 (p = 0.105). It suggests the PFS of rechallenged ICIs tended to be longer in those with short PFS by the first ICIs. Adverse events were not significantly different compared with the first ICIs. Conclusions: In this analysis, rechallenge of ICIs showed a lower, but some effects. ICI rechallenge may be worthwhile in those whose first ICIs were discontinued early. This is a study of a few cases, and it is necessary to study additional cases.
Hidden Curricula, Ethics, and Professionalism
Authors: Mano Soshi, Yasuharu Tokuda
Journal: Annals of Internal Medicine (2018)

Letters18 September 2018Hidden Curricula, Ethics, and ProfessionalismMano Soshi, MD and Yasuharu Tokuda, MD, MPHMano Soshi, MDMinamiseikyo Hospital, Aichi, Japan (M.S.)Search for more papers by this author and Yasuharu Tokuda, MD, MPHMuribushi Okinawa, Urasoe, Japan (Y.T.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0349 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We read Lehmann and colleagues' (1) position paper with interest. The need for education on professionalism for undergraduate medical students is increasing in Japan, and many universities are establishing ways to evaluate professionalism among Japanese medical students. One of Japan's solutions is to identify and penalize medical students who act in a seemingly unprofessional or disruptive way. We believe that this solution poses a serious issue, because it tries to assess not only the behavior of medical students (their “doing”) but also their character or personality (their “being”). What we truly need to assess is whether a ...References1. Lehmann LS, Sulmasy LS, Desai S; ACP Ethics, Professionalism and Human Rights Committee.. Hidden curricula, ethics, and professionalism: optimizing clinical learning environments in becoming and being a physician: a position paper of the American College of Physicians. Ann Intern Med. 2018;168:506-8. [PMID: 29482210]. doi:10.7326/M17-2058 LinkGoogle Scholar2. Arnold L, Stern DT. What is medical professionalism?. In: Stern DT, eds. Measuring Medical Professionalism. New York: Oxford Univ Pr; 2006:15-37. Google Scholar3. Mak-van der Vossen M, van Mook W, van der Burgt S, Kors J, Ket JCF, Croiset G, et al. Descriptors for unprofessional behaviours of medical students: a systematic review and categorisation. BMC Med Educ. 2017;17:164. [PMID: 28915870] doi:10.1186/s12909-017-0997-x CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Minamiseikyo Hospital, Aichi, Japan (M.S.)Muribushi Okinawa, Urasoe, Japan (Y.T.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0349. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoHidden Curricula, Ethics, and Professionalism: Optimizing Clinical Learning Environments in Becoming and Being a Physician: A Position Paper of the American College of Physicians Lisa Soleymani Lehmann , Lois Snyder Sulmasy , Sanjay Desai , and Hidden Curricula, Ethics, and Professionalism Dinesh John and Tanya George Hidden Curricula, Ethics, and Professionalism Lisa Soleymani Lehmann , Lois Snyder Sulmasy , and Sanjay Desai Metrics 18 September 2018Volume 169, Issue 6Page: 425KeywordsBehaviorDisclosureMedical educationUndergraduates ePublished: 18 September 2018 Issue Published: 18 September 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Adherence to geriatric assessment (GA)-based recommendations in older patients (pts) with cancer.
Authors: Lore Decoster, Cindy Kenis, Johan Flamaing, Philip DeBruyne, Inge DeGroof, C. N. J. Focan, Frank Cornelis, Vincent Verschaeve, Karen Vanoverbeke, Yves Libert, Sylvie Luce, Nathalie Nols, Heidi Van Den Bulck, Jean Charles. Goeminne, Abdelbari Baitar, Katrien Geboers, Jean Pierre Lobelle, Koen Milisen, Hans Wildiers
Journal: Journal of Clinical Oncology (2017)

10010 Background: In the general older population, GA-guided treatment plans improve overall survival, quality of life and functional status. In geriatric oncology, studies mainly focused on screening and assessment but not on geriatric interventions and follow-up. The aim of this study was to investigate the adherence to recommendations and subsequent interventions based on GA results in older pts with cancer. Methods: A prospective Belgian multicenter (n = 22) cohort study included pts ≥70 years with a malignant tumor when an oncological treatment decision had to be made. Pts with an abnormal G8 (≤14/17) underwent GA and were included in this study. Recommendations for interventions were formulated based on GA results. At follow-up adherence to GA-based recommendations was documented. Results: From 11-2012 till 2-2015, G8 screening was performed in 8451 pts. 5838 pts with an abnormal G8 were included in the study. Geriatric recommendations were given in 79.2% of pts with a median of 2/pt (range 0-10), most frequently consultation of a dietician (73%) for malnutrition, a social worker (54.8%) for social and functional status problems and a geriatrician (42.1%) for general geriatric problems. Follow-up data were available for 4167 pts. In the group of pts where recommendations were given, at least one intervention was performed in 69% with a median of 1/pt (range 0-6), most frequently dietician (43.4%), social worker (26.1%) and geriatrician (22.6%). A total of 7569 actions were undertaken for a total of 5725 geriatric recommendations. Recommendations were most frequently adhered to for malnutrition, social status and functional status problems. The most frequent actions undertaken were nutritional support and supplements, extended home care and psychological support. Conclusions: This large scale Belgian study focusses on the adherence to GA based interventions in older pts with cancer and contributes to the optimization of care for these pts. We identified the domains for which geriatric interventions are most frequently recommended and adhered to and which health care professionals and referrals are essential in the multidisciplinary approach of older pts with cancer.
Do We Truly Care About the Functional Outcomes for Renal Cancer Patients? Multidisciplinarity Is Still Far Away
Authors: Umberto Capitanio, Alessandro Larcher, Maximilian C. Kriegmair, Riccardo Bertolo, Maciej Salagierski, Riccardo Campi, Tobias Klatte, Francesco Trevisani, Francesco Montorsi, Maria Carmen Mir, Idir Ouzaid
Journal: European Urology (2018)
Results from a second-line (2L) NSCLC cohort treated with M7824 (MSB0011359C), a bifunctional fusion protein targeting TGF-β and PD-L1.
Authors: Luis G. Paz-Ares, Tae Min Kim, David Vicente Baz, Enriqueta Felip, Dae Ho Lee, Ki Hyeong Lee, Chia-Chi Lin, Massimo A. Di Nicola, Rosa Maria Alvarez Alvarez, Isabelle Dussault, Christoph Helwig, Laureen Ojalvo, James L. Gulley, Byoung Chul Cho
Journal: Journal of Clinical Oncology (2018)

9017 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which promotes tumor immunosuppression, may enhance the response to PD-(L)1 monoclonal antibodies (mAbs). 2L+ overall response rates (ORRs) with PD-(L)1 inhibitors in patients (pts) with advanced NSCLC range from 12% to 19% (PD-L1 unselected), highlighting the need for better treatments. M7824 is an innovative first-in-class bifunctional fusion protein composed of a human anti–PD-L1 IgG1 mAb fused with 2 extracellular domains of TGF-β receptor II (a TGF-β “trap”). Methods: In this expansion cohort of the ongoing, phase 1 trial NCT02517398, pts with advanced NSCLC unselected for PD-L1 who progressed following 1L standard treatment (no prior immunotherapy) were randomized to receive M7824 500 mg (n = 40) or 1200 mg (n = 40) q2w until disease progression, unacceptable toxicity, or trial withdrawal. The primary objective is to assess BOR per RECIST v1.1; other objectives include dose exploration and safety/tolerability assessment. Tumor cell PD-L1 expression was evaluable in 75 pts (Ab clone 73-10 [ > 80% = > 50% with 22C3]). Results: As of October 25, 2017, 80 pts received M7824 for a median of 11.9 (range, 2-48) wk, with a median follow-up of 35.2 wk; 17 pts remain on treatment. Investigator-assessed unconfirmed ORR was 25.0% (500 mg ORR, 22.5%; 1200 mg ORR, 27.5%). Clinical activity was observed across PD-L1 expression levels (Table); ORR was 40.7% in PD-L1+ and 71.4% in PD-L1–high pts at 1200 mg. The most common treatment-related adverse events (TRAEs) were pruritus (18.8%), maculopapular rash (17.5%), and decreased appetite (12.5%). Grade ≥3 TRAEs occurred in 20 pts (25.0%). 6 pts (500 mg, n = 2; 1200 mg, n = 4) discontinued treatment due to TRAEs. No treatment-related deaths occurred. Clinical trial information: NCT02517398. Conclusions: M7824 monotherapy had promising efficacy across PD-L1 subgroups, with an ORR at the RP2D of 1200 mg of 40.7% and 71.4% in PD-L1+ and –high pts, respectively. Treatment was well tolerated. ORR 500 mg 1200 mg Total All 9/40, 22.5 11/40, 27.5 20/80, 25.0 PD-L1+ (≥1%) pts, n, % 7/31, 22.6 11/27, 40.7 18/58, 31.0 PD-L1 high (≥80%) pts, n, % 2/6,33.3 5/7,71.4 7/13,53.8
Analysis of liquid biopsies from metastatic colorectal carcinoma (mCRC) patients (pts) enrolled in the ERMES clinical trial.
Authors: Nicola Normanno, Carlo Barone, Evaristo Maiello, Francesco Di Costanzo, Antonio Cassata, Emiliano Tamburini, Giuseppe Tonini, Roberto Bordonaro, Gerardo Rosati, Alberto Zaniboni, Sara Lonardi, Daris Ferrari, Giovanni Luca Frassineti, Stefano Tamberi, Salvatore Pisconti, Francesca Di Fabio, Laura Forgione, Anna Maria Rachiglio, Raffaella Pasquale, Carmine Pinto
Journal: Journal of Clinical Oncology (2018)

e15507 Background: Liquid biopsy is an alternative to tissue biopsy for biomarker testing. In addition, it can be used to monitor the response to therapy and the molecular evolution of the disease. Methods: The ERbitux MEtastatic colorectal cancer Strategy (ERMES) Study is a phase III randomized trial with FOLFIRI+Cetuximab (arm A) compared to 8 cycles of FOLFIRI+Cetuximab followed by Cetuximab alone until disease progression (PD) (arm B) in first-line treatment of KRAS/NRAS/BRAF wild type (wt) mCRC pts. Plasma samples at baseline (n = 37), at 8 weeks (w) of treatment (n = 31), at PD (n = 37) and at 3 months (mo) after PD (n = 21) were collected from 37 pts (10 arm A/27 arm B) and analyzed for mutations in exons 2, 3 and 4 of KRAS and NRAS and in BRAF V600 using the Idylla system (Biocartis). Results: Analysis of basal plasma samples revealed KRAS/NRAS/BRAF mutations not found in the tumor tissue in 6/37 cases (concordance with tissue mutational status 83.8%). In the 31 plasma samples at 8 w, the test discovered KRAS/NRAS/BRAF mutations in 6 pts (19.3%). The frequency of mutant cases increased at PD, with 14/37 cases positive (37.8%), 2 of which with multiple mutations. Among the 21 samples obtained 3 mo after PD, only 2 were KRAS/NRAS mutant (9.5%). The median progression free survival (mPFS) of pts with KRAS/NRAS/BRAF mutations at PD was 7.3 mo (CI 95% 5.9-8.7) versus 7.1 mo (CI 95% 6.2-8.0) in pts with wt plasma samples (p = 0.407). In 4/5 cases with baseline mutations and paired 8 w samples, we observed a partial response and plasma samples become negative. Four cases that were positive at w 8, became negative for KRAS/NRAS/BRAF mutations at PD. Conclusions: These data suggest that the Idyllasystem can detect KRAS/NRAS/BRAF mutations in plasma samples from pts receiving anti-EGFR agents at the same frequency as described with other techniques. Occurrence of plasma mutations seems a transient phenomenon in some pts and does not correlate with a shorter mPFS. Clinical trial information: 2014-004299-41.
Optimizing brief, focused symptom assessment in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN): The FHNSI-10.
Authors: Sara Shaunfield, Susan Yount, Lara Boyken, Boyka Stoykova, Mark Agulnik, Sandeep Samant, David Cella
Journal: Journal of Clinical Oncology (2018)

e18743 Background: The FHNSI-10 assesses 10 priority patient-reported symptoms and concerns of head and neck cancer patients. We assessed whether this measure was indeed asking the right “short list” of questions (content validity) for patients with recurrent and/or metastatic SCCHN. Methods: Before seeing the FHNSI-10, 18 patients with a confirmed SCCHN diagnosis who were currently receiving, or had received treatment within 60 days, were interviewed to identify the most important symptoms and concerns related to their disease. This was followed by cognitive debriefing of each FHNSI-10 item to assess comprehension, response process, and relevance. Symptoms and concerns from the interviews were analyzed via Dedoose, and results were mapped to the FHNSI-10. Expert input from the original measure development and published literature were reviewed to further inform content validity assessment. Results: Average patient age was 64.9 (range 49-86). Most were male (94%), white (81%), did not have a college degree (69%), and were undergoing active treatment (83%). Data saturation (complete information) was achieved after 17 interviews. The most common symptoms mentioned in the interviews were lumps/swelling (n = 12), pain (n = 6), sore throat (n = 6), difficulty swallowing (n = 5), and voice changes (n = 3). Other reported symptoms were difficulty breathing, cough, hearing impairment, fatigue, nausea, and tooth loss. Mapping of the FHNSI-10 to the qualitative data showed that it covers all high-priority symptoms except for cough and hearing impairment, which were not reported frequently, but were considered important when they occurred. For all items, at least 88% of respondents considered the items relevant. Conclusions: Results provide support for the content validity of the FHNSI-10, inasmuch as all 10 items were reported by patients in interviews. Full content validity might be enhanced by adding cough and hearing impairment to the list of 10 items; however, the existing FHNSI-10 appears to cover most of the symptom content uncovered in these interviews of patients diagnosed with recurrent and/or metastatic SCCHN.