tbuckley/cabot-search huggingface dataset:
Association of adverse events (AEs) with efficacy outcomes for cabozantinib (C) in patients (pts) with advanced hepatocellular carcinoma (aHCC) in the phase III CELESTIAL trial.
Authors: Ghassan K. Abou-Alfa, Tim Meyer, Ann-Lii Cheng, Irfan Cicin, Luigi Bolondi, Heinz Josef Klümpen, Stephen Lam Chan, Vincenzo Dadduzio, Steven Milwee, Sarita Dubey, Robin Kate Kelley, Anthony B. El-Khoueiry
Journal: Journal of Clinical Oncology (2019)

4088 Background: Class-specific AEs occurring with tyrosine kinase inhibitors have been associated with improved efficacy outcomes in several tumor types including aHCC. In the phase 3 CELESTIAL trial (NCT01908426), C, an inhibitor of VEGFR, MET, and AXL, improved overall survival (OS) and progression-free survival (PFS) vs placebo (P) in pts with previously treated aHCC. Here, we retrospectively evaluate the association of palmar-plantar erythrodysaesthesia (PPE) and hypertension (HTN) with OS and PFS for C in the CELESTIAL trial. Methods: 707 pts with aHCC were randomized 2:1 to receive 60 mg C or P once daily. Eligible pts had Child-Pugh score A, ECOG PS ≤1, must have received prior sorafenib, and could have received up to two prior regimens of systemic therapy for HCC. OS and PFS with C were evaluated for pts with any grade PPE or grade ≥3 HTN within the first 8 weeks of study treatment. Results: Overall, 374 (80%) pts in the C arm and 179 (76%) pts in the P arm completed ≥8 weeks of treatment. In the first 8 weeks, 188 (40%) of C-treated pts developed any grade PPE vs 11 (5%) of P-treated pts, and 61 (13%) of C-treated pts developed grade ≥3 HTN vs 3 (1%) of P-treated pts. Median OS with C was 14.4 mo for pts with any grade PPE vs 8.4 mo for pts without PPE (HR 0.59, 95% CI 0.47-0.74), and median PFS with C was 6.5 mo vs 3.7 mo, respectively (HR 0.63, 95% CI 0.51-0.78). Median OS with C was 16.1 mo for pts with grade ≥3 HTN vs 9.5 mo for pts without grade ≥3 HTN (HR 0.56, 95% CI 0.39-0.80), and median PFS with C was 7.4 mo vs 4.4 mo, respectively (HR 0.59, 95% CI 0.43-0.82). Some imbalances in baseline characteristics were present. Pts with PPE had better ECOG PS (60% vs 47% ECOG 0), better liver function (48% vs 34% ALBI grade 1), and less macrovascular invasion (24% vs 30%) than those without. Likewise, pts with grade ≥3 HTN had better ECOG PS (61% vs 51% ECOG 0), better liver function (56% vs 37% ALBI grade 1), and less macrovascular invasion (20% vs 29%) than those without. Conclusions: The development of PPE or grade ≥3 HTN with C was associated with prolonged OS and PFS in pts with previously treated aHCC although some imbalances in baseline characteristics between comparator groups were present. Clinical trial information: NCT01908426.
Effect of grade on survival in IDH-mutant grade II and grade III gliomas.
Authors: Giuseppe Lamberti, Enrico Franceschi, Alicia Tosoni, Antonella Mura, Alexandro Paccapelo, Maria Pia Foschini, Sofia Asioli, Dario De Biase, Annalisa Pession, Giovanni Tallini, Stefania Bartolini, Felice Giangaspero, Alba Ariela Brandes
Journal: Journal of Clinical Oncology (2019)

2036 Background: The 2016 WHO classification dramatically changed the diagnosis of gliomas. Diffuse gliomas are classified according to the presence of IDH-mutation (IDH-mut) and the deletion of both 1p and 19q chromosome arms (1p/19q codel). Now debate is whether grade still has an independent prognostic value. The aim of this study was to find out if grade is a prognostic factor independently of molecular status. Methods: We analyzed our institutional data warehouse for all consecutive patients (pts) with newly diagnosed, histologically proven Grade II or Grade III IDH-mut gliomas. IDH 1/2 assessment by polymerase chain reaction (PCR)or immunohistochemistry (IHC) was accepted. Next Generation Sequencing (NGS) for IDH1(exon 4) and IDH2(exon 4) was performed on all specimens wild-type for the IDH. Results: The analysis included all the 399 pts who had a grade II (n = 250, 62.7%) or grade III (n = 149, 37.3%). Median follow-up time was 105.3 months. After surgery, 72 pts (18.0%) received RT alone, 44 (11.0%) received CT alone, 135 (33.8%) received both RT and CT, and 142 (35.6%) follow-up without any treatment. Median survival was 148.1 months. In multivariate analysis Grade (HR = 0.342, 95%CI: 0.221 – 0.531; P &lt; 0.001) and 1p/19q codeletion (HR = 0.440, 95%CI: 0.290 – 0.668; P &lt; 0.001) were independently associated with a lower risk for death. The difference in survival remained when adjusted for histological subtype. Residual disease after surgery or biopsy negatively affected survival (HR 2.151, 95%CI 1.375 – 3.367, P = 0.001). Post-surgical treatment with RT + adjuvant CT improves survival in respect to follow-up and other treatments (HR: 0.316, 95%CI 0.156 – 0.641, P = 0.001). Conclusions: Grade still affects survival in IDH mutant Grade II and III gliomas. This effect was independent onmolecular features, surgical extension and post-surgical treatments. Clinical management of gliomas should continue to take into account grade as well as molecular characteristics.
HOME palliative care-Nepal: A cell-phone/website it system.
Authors: Bishnu D. Paudel
Journal: Journal of Clinical Oncology (2019)

e23134 Background: Worldwide, major clinical barriers to effective palliative care are the absence of: 1. Current data on symptom type and intensity; 2. Immediately accessible information on practical, affordable, and effective interventions; and 3. Self-sustaining systems to facilitate currently limited physician engagement in continuing palliative care. In Nepal, essentially all families have a cell phone, the majority of which are Android smart phones. 80% of the population lives in rural settings. Methods: Following a cross sectional study in 383 Nepalis with advanced cancers using a cell-phone “app” on the Android platform with a validated 15-item symptom questionnaire, in which all approached patients agreed and were able to complete the instrument in under 3 minutes, we assembled a Nepali/US development team of clinicians and computer scientists to create a tele-home palliative care system centered on use of this app. Results: We have developed an internet website (homepalliativecareNepal.net) with patient/family and physician information pages, a guest health professional site, and a password-protected physician site with organized patient demographic and medical summary data, and telephone-submitted app-symptom reports, local clinical practice guidelines, and an intervention menu of 30 written and mini-video items and links (the majority non-pharmacologic) including start-up drug prescriptions (5), which can be personalized and directly sent to the patient by phone. The system is managed by a local organization that also ensures regular physician/clinic visits by the patient, or by a family member with a patient phone check-in, at least every two weeks, with creation of documentation of provided services. Conclusions: Our adaptable, patient-centered, IT-tools-facilitated, and economical system offers significant potential for addressing the need to engage all types of health care practitioners in palliative care in different cultural settings.
Problem gambling and associated mental health concerns in elite athletes: a narrative review
Authors: Jeffrey Lee Derevensky, David McDuff, Claudia L Reardon, Brian Hainline, Mary E Hitchcock, Jeremie Richard
Journal: British Journal of Sports Medicine (2019)

Opportunities to participate in gambling have dramatically changed during the past 20 years. Casinos have proliferated as have electronic gambling machines, lotteries, sports betting, and most recently online gambling. Gambling among the general population has moved from being perceived negatively to a socially acceptable pastime. As over 80% of individuals have reported gambling for money during their lifetime, governments recognise that regulating gambling-a multibillion dollar industry-is a significant source of revenue. While the vast majority of individuals engaged in some form of gambling have no or few gambling-related problems, an identifiable proportion of both adolescents and adults experience significant gambling-related problems. Elite athletes have not been immune to the lure of gambling nor its concomitant problems. Prevalence studies suggest higher rates of gambling problems among athletes than the general population. In this narrative review, we examine several risk factors associated with gambling problems among elite athletes and new forms of gambling that may be problematic for this population. Given the potential serious mental health and performance consequences associated with a gambling disorder for athletes, we aim to increase coaches', athletic directors' and health professionals' knowledge concerning the importance of screening and treatment referrals.
Case 49-1984
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely
Journal: New England Journal of Medicine (1984)

Presentation of Case A 64-year-old man was admitted to the hospital because of chills and fever. He was in a static state of health until four days earlier, when fever, chills, and sweats developed, with general malaise. Two days before admission a dry cough appeared. He was admitted to the hospital. The patient was a disabled driver for a mailing firm. There was a history of rheumatoid arthritis and osteoarthritis of many years' duration that affected multiple joints and was accompanied by dryness of the eyes. Twenty-four years before admission a partial gastrectomy was performed at another hospital for a . . .
Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: A randomized phase III study.
Authors: Zefei Jiang, Min Yan, Xichun Hu, Qingyuan Zhang, Quchang Ouyang, Jifeng Feng, Yongmei Yin, Tao Sun, Zhongsheng Tong, Xiaojia Wang, Herui Yao, Jianjun Zou, Xiaoyu Zhu
Journal: Journal of Clinical Oncology (2019)

1001 Background: Pyrotinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising anti-tumour activity and acceptable tolerability in patients with HER2+ metastatic breast cancer (MBC) in phase 1/2 trials. Methods: This double-blinded, multicentre, randomised phase 3 trial was conducted in Chinese patients with HER2+ MBC previously treated with taxanes and trastuzumab. Patients were randomly assigned (2:1) to receive 400 mg pyrotinib or placebo orally once daily for 21-day cycles in combination with capecitabine (1000 mg/m 2 orally twice daily on days 1–14). The primary endpoint (IRC-assessed progression free survival [PFS]) was assessed in patients who received ≥1 dose of study treatment. Patients whose disease progressed on placebo plus capecitabine received subsequent single agent pyrotinib. Results: Between July, 2016 and November, 2017, 279 patients were randomised to pyrotinib plus capecitabine (n = 185) or placebo plus capecitabine (n = 94) arms. The median PFS was 11.1 months (95% CI 9.66, 16.53) in the pyrotinib plus capecitabine arm and 4.1 months (95% CI 2.79, 4.17) in the placebo plus capecitabine arm. seventy-one patients in placebo plus capecitabine arm received subsequent pyrotinib, showing single-agent response rate of 38.0% (95%CI 26.7%, 49.3%) and median PFS of 5.5 months (95% CI 4.07, 6.90). The most frequent (≥5%) treatment-related ≥ grade 3 adverse events were diarrhoea (30.8% vs 12.8% ) and hand-foot syndrome (15.7% vs 5.3%). Conclusions: In women with HER2+ MBC previously treated with taxanes and trastuzumab, pyrotinib plus capecitabine yield statistically significant better PFS. Pyrotinib monotherapy showed anti-tumour activity. Clinical trial information: NCT02973737. [Table: see text]
Role of OncoTherad immunotherapy in the regulation of toll-like receptors-mediated immune system and RANK/RANKL signaling: New therapeutic perspective for non-muscle invasive bladder cancer.
Authors: Wagner José Fávaro, Sonia Regina Iantas, Juliana Mattoso Gonçalves, Queila Cristina Dias, Ianny Brum Reis, Athanase Billis, Nelson Duran, João Carlos Cardoso Alonso
Journal: Journal of Clinical Oncology (2019)

e16004 Background: The new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom Bacillus Calmette-Guerin (BCG) has failed or is contraindicated are recently increasing due to the development of new drugs. In this scenario, a new perspective is represented by OncoTherad immunomodulator. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein, developed by University of Campinas/ Brazil, which exhibits antitumor properties. This study detailed and characterized the therapeutic effects of OncoTherad based on activation of Toll-Like Receptors (TLRs) signaling pathways and regulation of receptor activator of nuclear factor kβ (RANK)/RANK ligand (RANKL) cytokine system in an animal model of NMIBC, as well as, compared these effects with BCG treatment. Methods: Fisher 344 female rats were submitted to NMIBC induction with N-methyl-N-nitrosourea (MNU). MNU treated animals were further divided into 3 groups (10 animals per group): the NMIBC group received 0.30 mL of saline solution; the NMIBC-BCG group received of 2 mg/mL of BCG; the NMIBC-OncoTherad group received 20 mg/Kg dose of OncoTherad. All animals were treated intravesically every other week for 6 weeks. Results: Our results demonstrated that OncoTherad intravesical immunotherapy led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interferons signaling pathway, which was more effective (80.0%) in the NMIBC treatment, when compared to BCG treatment (20.0%). Interferon signaling pathway activation induced by OncoTherad led to increase of iNOS expression, resulting in apoptosis and histopathological recovery. Also, OncoTherad immunotherapy decreased RANK/RANKL expression, resulting in reduced regulatory T (Treg) cells. Conclusions: The decreased of RANK/RANKL expression by OncoTherad was fundamental to up-regulation interferon signaling pathway and in suppresion of abnormal cell proliferation. Thus, OncoTherad immunotherapy could be considered an important therapeutic strategy for NMIBC, as well as, opens a new perspective for treatment of BCG-refractory or relapsed patients.
Erdafitinib in high-risk patients (pts) with advanced urothelial carcinoma (UC).
Authors: Se Hoon Park, Yohann Loriot, Bob Zhong, Syed A. Hussain, Parthiv Jasvant Mahadevia, Peter De Porre, Arlene O. Siefker-Radtke
Journal: Journal of Clinical Oncology (2019)

4543 Background: The pan-FGFR inhibitor erdafitinib exhibited a robust objective response rate (ORR) and tolerability among pts with FGFR2/3-altered advanced UC in the BLC2001 (NCT02365597) phase 2 study (Siefker-Radtke ASCO 2018 #4503). Here we report a post hoc subgroup analysis to explore efficacy among high-risk pts. Methods: The analysis included 99 BLC2001 pts who received the optimized dose regimen of 8 mg/d continuous (pharmacodynamically guided uptitrated to 9 mg/d per serum phosphate). Results for ORR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were analyzed by select baseline variables, with high-risk defined as age &gt;75 y, ECOG PS 2, hemoglobin &lt;10 g/dL, visceral metastases, and 2 or 3 Bellmunt risk factors. Results: Efficacy results (Table) show investigator-assessed ORR &gt;36% and median PFS &gt;5 mo across all subgroups except ECOG PS 2. OS data are immature but generally follow the trend of PFS. With the exception of ECOG 2, there were no differences in G3/4 serious AE proportions by subgroup. Conclusions: The post hoc subgroup findings support that erdafitinib generally provides comparable efficacy in high-risk pts with FGFR-altered advanced UC as the overall population. Clinical trial information: NCT02365597. [Table: see text]
Significance of systemic and local immune responses to the pathological therapeutic effect of neoadjuvant chemotherapy in breast cancer.
Authors: Ryungsa Kim, Ami Kawai, Megumi Wakisaka, Yuri Funaoka, Sayaka Sawada, Mika Shimoyama, Naomi Yasuda, Masayuki Hidaka, Yukitaka Morita, Shoichiro Ohtani, Koji Arihiro
Journal: Journal of Clinical Oncology (2019)

e12084 Background: Activation of the immune response including T lymphocytes, natural killer (NK) cells, and tumor microenvironment factors (TMEFs) is important in inducing a therapeutic response after neoadjuvant chemotherapy (NAC) in breast cancer. We examined the significance of systemic and local immune responses to the pathological therapeutic effect of NAC in breast cancer. Methods: From 2012 to 2018, 38 patients with stage II–III breast cancer received NAC with anthracyclines and taxanes followed by surgery. Therapeutic effects were evaluated according to the histopathology criteria for the assessment of therapeutic effects in breast cancer indicated by the Japanese Breast Cancer Society. Peripheral NK (pNK) cell activity was measured by chromium release assay. Levels of TMEFs were assessed by next-generation sequencing for CD4, CD8, NK, FOXP3, CTLA-4, PD-1, PD-L1, IL-2, IL-6, IL-12, IFN-γ, IL-10, TGF-β, and VEGF in FFPE sections collected from preoperative VAB samples and surgical specimens. Results: The stages, tumor subtypes, and therapeutic outcomes were as follows: II (N = 21), III (N = 17); luminal (N = 22), HER-2 positive (N = 12), TN (N = 4); G1a (N = 8), G1b (N = 13), G2a (N = 7), G2b (N = 4), G3 (i.e. complete) (N = 6). A G2 or better therapeutic effect were significantly associated with high post-NAC levels of NK, and potentially associated with higher CD4, CD8, and lower CTLA-4 after NAC. Multivariate logistic regression analysis showed that a G2 or better therapeutic effect was significantly associated with higher NK after NAC (OR = 1.07; 95% CI, 1.00–1.14; P = .0255). Disappearance of axillary lymph node metastasis was significantly associated with increased NK and pNK cell activity, as well as decreased VEGF level, and potentially associated with lower CTLA-4 after NAC. Conclusions: Increased NK cells after NAC are critical in producing a better therapeutic effect in collaboration with increased CD4 and CD8, and decreased CTLA-4 and VEGF. Systemic activation of pNK cells may improve the elimination of metastatic tumor cells in axillary lymph nodes by coordinating with release of immunosuppression derived from VEGF and activation of immune cells in the tumor microenvironment in breast cancer patients after NAC. An immune checkpoint inhibitor targeting CTLA-4 may improve NAC efficacy for breast cancer.
AB0619 FAMILY MEMBERS WITH BS MAY NOT CLUSTER IN SIMILAR CLINICAL CHARACTERISTICS
Authors: Mutianur Özkorkmaz, Mehmet Engin Tezcan, Nesrin Şen, Sibel Yilmaz-Oner, Özcan Keskin
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Both genetic and environmental factors may have roles in the pathogenesis of Behcet's Syndrome (BS). Likewise, occurrence of different clinical cluster of BS may be also influenced by the combination of these two factors. But we do not know the weight of the factors during the emergence of the disease and clinical clusters. <h3>Objectives</h3> We conducted a study for evaluating the frequency of family history for BS in different clinical BS clusters. Furthermore, we assessed the hypothesis that "BS patients in the same family generally accumulate in the similar clinical cluster." <h3>Methods</h3> Eighty-five patients and their relatives in our BS cohort were participated to the study. We used international Study Group Criteria for Behçet Disease (ISBD) criteria (1) for classifying our index patients and their first and second degree relatives as BS. We sub-classified BS patient to mucocutenous, vascular, acne-arthritis-enthesis, eye, neurologic, intestinal and undetermined clusters (2). Firstly, we re-evaluated the family history of our BS patients. Then, the relatives of the patients with already known BS or with having symptoms related with BS were interviewed with phone. All participants have been informed about the study and we have taken consent from them. <h3>Results</h3> Twenty-two (25.9%) of the patients had first or second degree relatives with BS. Furthermore, 27 (31.8%) of our patient were classified to mucocutenaous cluster. In our study, the BS patient with enthesis-arthritis-acne cluster had highest frequency (44.4%) of family history. However, there was no apparent accumulation of similar findings in index BS cases and their close relatives (Table). <h3>Conclusion</h3> According to result of these studies, there was no finding that supports the hypothesis"<i>BS patients in the same family generally accumulate in the similar clinical cluster".</i> Still genetic may have major role in the emerging of the BS, such as it is accepted as a member of a group of diseases called MHC-I –opathy (3). However, like most of the diseases, genetic background is not enough for the expression of full-blown disease. Briefly, even in the similar genetic background, multiple and separate hits of environmental or non-genetic factors may take role in the pathogenesis. <h3>References</h3> [1] Criteria for diagnosis of Behcet's disease. International Study Group for Behcet's Disease. Lancet. 1990;335(8697):1078-80. [2] Tunc R, Keyman E, Melikoglu M, Fresko I, Yazici H. Target organ associations in Turkish patients with Behcet's disease: a cross sectional study by exploratory factor analysis. J Rheumatol. 2002;29(11):2393-6. [3] McGonagle D, aydin SZ, Gul a, Mahr a, Direskeneli H. 'MHC-I-opathy'-unified concept for spondyloarthritis and Behcet disease. Nature reviews Rheumatology. 2015;11(12):731-40. <h3>Acknowledgement</h3> None <h3>Disclosure of interests</h3> None declared