tbuckley/cabot-search huggingface dataset:
Safety and efficacy of decitabine-primed anti-PD-1 (SHR-1210) treatment in patients with relapsed/refractory classical Hodgkin lymphoma.
Authors: Chunmeng Wang, Yang Liu, Jing Nie, Lianjun Shen, Qingming Yang, WeiDong Han
Journal: Journal of Clinical Oncology (2018)

7537 Background: More than 50% unprecedented objective clinical response rate led to a rapid approval of anti-PD-1 antibodies by FDA using in patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL). However, anti-PD-1 monotherapy can induce complete remission (CR) only in about 10% patients. Decitabine, a demethylating agent, was documented to directly boost T cell function and also possibly delay/reverse PD-1-blocked T cell exhaustion. This Phase I/II study was designed to assess the safety and efficacy of decitabine-primed anti-PD-1 (SHR-1210, a novel humanized IgG4/kappa monoclonal antibody) treatment in r/r cHL patients. Methods: Enrolled patients without anti-PD-1 history were 1:2 assigned into SHR-1210 monotherapy (4 mg/kg per 3 weeks) cohort 1 or decitabine (10mg/d on day 1-5) plus SHR-1210 (4mg/kg, day 8, per 3 weeks) cohort 2. Patients refractory to anti-PD-1 monotherapy were allocated into cohort 2. Safety was assessed by CTCAEv4.0, and clinical response by PET-CT referred to standard international criteria. Results: A total of 57 patients with heavily treated history (14-cycle median systemic treatment or with average 8-cycle anti-PD-1 monotherapy) were enrolled and 41 completed serial response evaluation by the end of Jan. 2018. The most common adverse events were clinically negligible cherry hemangioma (75% in cohort 1 and 93% in cohort 2), and unattended leukocytopenia (32% in cohort 2). Six from 13 patients in cohort 1 were evaluated as 1 CR (17%), 2 PR (34%), and 3 SD. Twenty cases from cohort 2, before enrollment were evaluated to be refractory to anti-PD-1 alone therapy, 17 were evaluated and showed 4 CR (23%), 5 PR (30%), 4 SD, and 4 PD. Eighteen of 26 patients without anti-PD-1 history before enrollment were evaluated as 12 CR (67%), 4 PR (22%), and 2 SD. So far, 88% evaluated patients had a > 24-week progression-free survival. Conclusions: Addition of decitabine not only largely increased the CR rate of anti-PD-1 therapy in r/r cHL, but significantly reversed the resistance of anti-PD-1 therapy. Combination therapy had an acceptable safety profile. Clinical trial information: NCT02961101 and NCT03250962.
State mandated insurance benefits and off-label use of cancer drugs.
Authors: Fabrice Smieliauskas, Hari Sharma, Jonas A. De Souza, Ya-Chen T. Shih
Journal: Journal of Clinical Oncology (2016)

6536 Background: Access to cancer drugs used off-label is considered vital to the treatment of many cancer patients. Yet policymakers are concerned that use of drugs in this way may drive up health care costs with little rigorous evidence of benefit to patients. There is little empirical work on trends in off-label use nor in how public policies influence off-label use. We hypothesized that state health insurance mandates for private insurers to provide coverage for off-label use of cancer drugs cause higher rates of off-label use. Methods: We paired a tabulation of state laws mandating coverage for off-label usage of cancer drugs with Truven Marketscan data on utilization of cancer drugs in private health plans nationwide from 1999-2007, covering the period when changes took place in the laws of 8 states. We studied all 35 infused chemotherapies approved between 1987 and 2007, and designated on-label, appropriate and inappropriate off-label use for each drug according to the two main drug compendia cited by state laws on off-label coverage. We studied trends in the three types of case-mix adjusted drug use, and estimated difference-in-difference regressions of the effect of state laws on off-label use. Results: Our sample includes 71,493 patient-years of data. We estimate 41% of utilization was off-label, including 17% of use conservatively defined as inappropriate. Trends show gradual declines in appropriate and inappropriate off-label use over time. There was no observable change in off-label use trends after state laws changed to require off-label coverage. The regression analyses demonstrate no effects of state policies on either appropriate or inappropriate off-label use. These results were robust to several changes in model specification and sample restrictions. Conclusions: Off-label use has been declining in importance in recent years, perhaps due to the boom in therapies approved in new indications. Several factors may underlie the the lack of effectiveness of state mandates for off-label coverage to increase off-label chemotherapy use. The ineffectiveness of state policy may actually improve patient outcomes, given that compendia updates and state policymaking are not always evidence-based processes.
Significance of aromatase-estrogen receptor axis in EGFR status of lung adenocarcinoma.
Authors: Kazumi Tanaka, Susumu Rokudai, Kimihiro Shimizu, Seshiru Nakazawa, Kai Obayashi, Kyoichi Kaira, Tetsunari Oyama, Ken Shirabe, Akira Mogi, Masahiko Nishiyama, Hiroyuki Kuwano
Journal: Journal of Clinical Oncology (2018)

8553 Background: Aromatase alongside with estrogen receptor beta (ERβ) is a potential target for novel therapeutic strategy in lung adenocarcinoma (AC). The purpose of this study is to examine the correlations of expressions of aromatase and ERβ with other prognostic factors including epidermal growth factor receptor (EGFR) in lung AC. Methods: We analyzed 186 consecutive patients with lung AC who underwent surgical resection at Gunma University Hospital between Dec. 2003 and Feb. 2010. The clinicopathological characteristics and survivals of patients were subclassified based on the expressions of aromatase, ERα, ERβ, and progesterone receptor (PR) as determined by immunohistochemical staining. Gene alterations of EGFR and KRAS were evaluated with SmartAmp2. Multivariate analysis using Cox regression model was carried out to evaluate the effect of aromatase expression. In vitro experiment was performed with shRNA transduced aromatase-depleted lung AC cells. Results: Expressions of aromatase, ERα, ERβ, and PR were detected in 86.6%, 1.6%, 78.5%, 2.7% of all patients, respectively. In all patients, the expression of aromatase is an independent prognostic factor in OS (Hazard Ratio [HR] = 2.1; 95% confidential interval [CI], 1.2-3.6; P= .008) and RFS (HR = 1.8; 95%CI, 1.1-2.8; P= .022), while that of ERβ is not statistically significant. In patients with wild-type EGFR, high aromatase expression is also an independent prognostic factor in OS (HR = 2.4; 95%CI, 1.2-4.6; P= .009) and RFS (HR = 2.5; 95%CI, 1.3-4.7; P= .006). Interestingly, high aromatase expression is significantly correlated with poor survival only in women (OS, P= .019; RFS, P= 0.033) in patients with wild-type EGFR, while no prognostic significance is observed in patients with EGFR mutations. In line with this, depletion by shRNA of aromatase suppressed oncogenic activity in soft agar assays. Conclusions: Aromatase expression is independent negative prognostic factor in especially EGFR wild-type adenocarcinoma. We further showed that in patients with wild-type EGFR, high aromatase expression is a significant correlated with poor survival only in women. Aromatase-depleted lung AC cells transduced shRNA, demonstrate decreased tumorigenicity.
Induction chemotheraphy (IC) for locoregionally advanced head and neck cancer (LA-HNC): Experience at Instituto Oncológico Nacional SOLCA Guayaquil.
Authors: Katherine Garcia, Mayra Santacruz, Ruth Engracia, Miguel Puga-Tejada, Guillermo Paulson, Elizabeth Gamarra, Jose Maria Cabezas, Kerly Jurado, Joan Prias
Journal: Journal of Clinical Oncology (2016)

e17540 Background: IC followed by Concurrent Chemoradiotherapy (CCRT) or Cetuximab plus Radiotherapy (CeRT) are ways we use to treat LA-HNC. Our main problem is Radiotherapy (RT) delay starting. Survival benefit of IC has not been reported yet, but in stage II-IV we could see some complete remissions. We described our experience with IC in LA-HNC not treated with surgery, in terms of overall survival (OS). Methods: Diagnosed with LA-HNC stage II-IVb were analyzed retrospectively reviewed clinical records of pre-existing data from 2008 to 2012. We focused on squamous cell carcinoma (SCC). Results: After meeting exclusion criteria, leaving 109 cases. Median age was 61 (23 – 92) years. 69.7% were male. Histology was: SCC 100 (91.7%), adenocarcinoma 4 (3.7%), cystic adenoid 2 (1.8%), mucoepidemoid 2 (1.8%) and pleomorphic adenocarcinoma 1 (0.9%). SSC localizations were: larynx 31%, oropharynx 27%, oral cavity 25%, sinuses 7%, nasopharynx 5%, hypopharynx 4%, and salivary glands 1%. SSC patients with stage II (24%), III (29%) and IVa-b (47%) received IC protocols: TPF: 62% (Docetaxel 75 mg/m2 day 1, Cisplatin 75 mg/m2 day 1, 5-FU 750 mg/m2 day 1-4, every three weeks); PF: 31% (Cisplatin 100 mg/m2 day 1, 5-FU 1000 mg/m2 day 1-5, every three weeks); remaining 7% another protocols. 79/100 patients who underwent IC started RT. 21/100 didn’t continue with RT. 14/79 received RT without concurrent chemotherapy. 12/79 patients didn’t finish RT. 23/65 patients received CeRT. 42/65 received CCRT. Median number of IC cycles was 5 before start RT. In 67/79 patients who complete RT successfully, complete remission was showed in 25, partial remission in 4, stable disease in 16 and progression in 22. Recurrence was local in 6/25 and regional in 19/25. 2/100 patients showed severe febrile neutropenia using IC protocol (TPF) in CCRT. Three years OS rate and median survival of IC followed by CCRT was (60.8%; 39.90 months), CeRT (54.2%; 32.28 months; HR 0.759, 0.274 – 1.018, p = 0.313) and IC followed by RT alone (60.0%; 24.61 months; HR 0.531, 0.237 – 0.632, p = 0.008). Conclusions: In this single center most patient are diagnosed in advanced stage (III-IV). IC followed by CCRT or CeRT are valid options for LA-HNC.
Inhibition of TLR9-NF-κB-mediated sterile inflammation improves pressure overload-induced right ventricular dysfunction in rats
Authors: Keimei Yoshida, Kohtaro Abe, Mariko Ishikawa, Keita Saku, Masako Shinoda-Sakamoto, Tomohito Ishikawa, Takanori Watanabe, Masahiko Oka, Kenji Sunagawa, Hiroyuki Tsutsui
Journal: Cardiovascular Research (2018)

Recent accumulating evidence suggests that sterile inflammation plays a crucial role in the progression of various cardiovascular diseases. However, its contribution to right ventricular (RV) dysfunction remains unknown. The aim of this study was to elucidate whether toll-like receptor 9 (TLR9)-NF-κB-mediated sterile inflammation plays a critical role in the pathogenesis of RV dysfunction.We performed main pulmonary artery banding (PAB) in rats to induce RV pressure overload and dysfunction. On Day 14 after PAB, the pressure overload impaired RV function as indicated by increased RV end-diastolic pressure concomitant with macrophage infiltration and fibrosis, as well as maximal activation of NF-κB and TLR9. Short-term administration (days 14-16 after PAB) of a specific TLR9 inhibitor, E6446, or an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) significantly attenuated NF-κB activation. Furthermore, long-term administration of E6446 (treatment: days 14-28) or PDTC (prevention: days -1 to 28; treatment: days 14 to 28) improved RV dysfunction associated with mitigated macrophage infiltration and fibrosis in right ventricle and decreased serum brain natriuretic peptide levels.Inhibition of TLR9-NF-κB pathway-mediated sterile inflammation improved PAB-induced RV dysfunction in rats. This pathway plays a major role in the progression of pressure overload-induced RV dysfunction and is potentially a novel therapeutic target for the disorder.
Experience of nivolumab and pembrolizumab in metastatic non-small cell lung cancer in routine clinical practice (mNSCLC.).
Authors: Doran Ksienski, Edward Geoffrey Brooks, Dave Fenton, Leathia Fiorino, Georgia Samantha Geller, Zia Poonja, Daniel Glick
Journal: Journal of Clinical Oncology (2018)

e21227 Background: Pembrolizumab (P) in first line if PD-L1 expression > 50% (KEYNOTE-024) or nivolumab (N) in second line (CheckMate 017 and 057) improves overall survival compared to chemotherapy in mNSCLC. Efficacy and toxicity of immunotherapy (IO) in clinical practice outside clinical trials may be significantly different. Methods: All mNSCLC patients (pts) treated with N or P between 11/2015 to 10/2017 at BC Cancer were identified. Demographic, tumor characteristic, treatment details, frequency and grade (Gr, CTCAE v4.0) of immune related adverse events (irAE), and physician determined best response were collected. Results: 271 pts were treated with N (230) or P (41). Characteristics of the study cohort at diagnosis of mNSCLC: median age 64y (range 41-82), gender: females 50%, primary histology: non-squamous (76%)/ squamous(24%), brain metastases rate 11%; at start of IO, ECOG PS > 1: 35% and mean Charlson Comorbidity Index score 8.8. IO delivery occurred in the 1st (7%)/2nd (67%)/3rd+ (26%) line. Median number of cycles administered was 6 (range 1-59). 103 pts (38%) experienced at least 1 irAE and 28 pts (10%) had more than one. Percentage of pts experiencing an irAE: Gr 1 (25%), Gr 2 (18%), Gr 3 (4%), Gr 4 (3%), and Gr 5 (2%). Common irAE were thyroid changes (37pts), dermatitis (32pts), and colitis (20pts). Treatment related deaths were caused by pneumonitis (2pts), hepatitis (1pt), and colitis (1pt). 21% of pts required steroids for a median 8.4 weeks (range 1-41). 26% of pts experiencing an irAE received no further IO. With median follow-up of 10 months, 109 pts (41%) had died. Best response for N treated pts: CR (0.5%)/PR (13%)/SD (33%)/PD (54%) and for P treated pts 0/17%/44%/39%. Conclusions: Despite 35% of pts having PS > 1 and multiple comorbidities, incidence of severe irAE (9%) and clinical benefit rate (CR+PR+SD, 46.5% for N and 61% for P) were consistent with those reported in CheckMate 017 and 057 and KEYNOTE-024. However, treatment discontinuation due to irAE was considerably higher than in clinical trials. This highlights the importance of continued education regarding irAE management to avoid early discontinuation of potentially life saving therapies.
Comparison of myocardial strain in cancer patients undergoing chemotherapy with and without anthracycline.
Authors: Haoyi Zheng, Nathaniel Reichek, Ann Way, Rena Toole, Sajal Verma, Bhoomi Mehrotra
Journal: Journal of Clinical Oncology (2017)

e21600 Background: Cardiotoxicity has been reported in cancer patients treated with anthracycline- and non-anthracycline-based chemotherapy. Myocardial strain assessed by speckle-tracking echocardiography enables early detection of subclinical chemotherapy-induced cardiotoxicity. However, comparisons of strain indices in patients undergoing chemotherapy with and without anthracyclines have not been reported. The prupose of this study was to compare myocardial strain in patients treated with these two chemotherapy regimens. Methods: This study was approved by the institutional review board at Saint Francis Hospital. 43 adult cancer patients (30 with solid tumors, 6 with lymphomas, 6 with leukemias and 1 with multiple myeloma) treated with anthracyline-based or non-anthracycline-based chemotherapy, were studied with conventional 2D and 3D echocardiography, 2D speckle-tracking imaging, and cardiac biomarkers. Results: Of the 43 patients, 22 received anthracycline-based chemotherapy, with an average cumulative anthracycline dose of 235 mg/m 2 . The other 21 patients received non-anthracycline-based chemotherapy including VEGF inhibitors and HER-2 receptor antagonists. There was no difference in 2D or 3D left ventricular ejection fraction (LVEF) (60.9 ± 4.5% vs 62.0 ± 4.9% by 2D; 60.5 ± 5.4 % vs 62.1± 5.2% by 3D, p = 0.35 for both 2D and 3D), troponin or NT-proBNP between anthracyline-treated patients and non-anthracycline treated patients. However, global longitudinal strain (GLS) and global circumferential strain (GCS) were decreased in patients treated with anthracycline-based chemotherapy compared with patients treated with non-anthracycline-based chemotherapy (-17.8 ± 2.8 vs 19.9 ± 2.9, p = 0.018 for GLS; -21.6 ± 4.8 vs 24.8 ± 4.8, p = 0.041 for GCS). Conclusions: In contrast with patients treated with non-anthracyline-based chemotherapy, patients treated with anthracyclines had reduced myocardial systolic strain even at low cumulative doses. This occurred in the absence of detectable reductions in LVEF. Thus early assessement of myocardial strain abnormality and early intervention with cardioprotective agents may be considered for these patients.
A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis
Authors: Lucia Masarova, Srdan Verstovsek, Juliana E. Hidalgo-Lopez, Naveen Pemmaraju, Prithviraj Bose, Zeev Estrov, Elias J. Jabbour, Farhad Ravandi-Kashani, Koichi Takahashi, Jorge E. Cortes, Jing Ning, Maro Ohanian, Yesid Alvarado, Lingsha Zhou, Sherry Pierce, Romany Gergis, Keyur P. Patel, Rajyalakshmi Luthra, Tapan M. Kadia, Courtney D. DiNardo, Gautam Borthakur, Kapil Bhalla, Guillermo Garcia-Manero, Carlos E. Bueso-Ramos, Hagop M. Kantarjian, Naval Daver
Journal: Blood (2018)
TCT-687 Paravalvular leak in the RESPOND post-market study: predictors and impact on 2-year clinical outcomes following TAVR with a fully repositionable and retrievable aortic valve in routine clinical practice
Authors: Jochen Wöhrle, Daniel Blackman, Mohamed Abdel-Wahab, David Hildick-Smith, Sabine Bleiziffer, Dominic Allocco, Ian Meredith, Volkmar Falk, Nicolas Van Mieghem
Journal: Journal of the American College of Cardiology (2018)
Neurotoxicity associated with anti-PD1 therapy: A multi-center case series.
Authors: Jess Louise Smith, Alexander M. Menzies, Justine Vanessa Cohen, Margarida Mut Lioret, Alpaslan Ozgun, Lavinia Spain, John J. Park, Douglas Buckner Johnson, Jennifer Leigh McQuade, Sophie Feng, Shahneen Kaur Sandhu, Victoria Atkinson, Katy K. Tsai, Georgina V. Long, James M. G. Larkin, Zeynep Eroglu, Ryan J. Sullivan, Andrew Henderson, Matteo S. Carlino
Journal: Journal of Clinical Oncology (2017)

e21641 Background: The anti-PD1 antibodies (PD1) pembrolizumab and nivolumab are now FDA-approved in multiple malignancies. With increased use, rarer immune-related adverse events (irAEs) not well characterized in clinical trials are being identified, including neurotoxicities. Methods: Patients (Pts) who developed neurotoxicites while being treated with PD1 (alone or in combination) were retrospectively identified from 10 cancer centers. Data regarding treatment, toxicity and outcome were examined. Results: 40 pts (38 melanoma and 2 non-small cell lung cancer pts) developed neurotoxicity; 14 on anti-PD1 monotherapy, 23 in combination or sequence with ipilimumab, and 3 on blinded trials or in combination with interferon. The overall response rate was 90% and median progression free survival was not reached. The median time from treatment initiation to development of neurotoxicity was 7 weeks (range 1-86.5 weeks). 8 pts had died, 5 from disease progression and, 2 from neurotoxicity. 26 pts (65%) developed other irAEs. 27 (67.5%) pts developed toxicities affecting the peripheral nervous system including motor sensory neuropathies (6), sensory neuropathies (4), and Myasthenia Gravis (3). 13 (32.5%) pts developed central nervous system toxicities including aseptic meningitis (6) and encephalitis (4). 24 (60%) pts were treated with steroids alone. 9 pts required further immunomodulation including IVIG (7), plasmapheresis (3), MMF (1) and rituximab (1). 17 (43%) had complete resolution of symptoms, 5 (13%) had stable or worsening neurological disease, and 22 ( 55%) were improving at the time of datacut . 10 pts were retreated with PD1, of which 2 developed exacerbation of prior neurological symptoms. Conclusions: While rare, a variety of neurotoxicities can occur with PD1 treatment. Management may require immunomodulation beyond corticosteroids. Given the high response rate observed in this cohort, such toxicities and their management do not appear to negatively impact treatment response.
Evaluation of an interactive patient-reported outcome (I-PRO) system in outpatients receiving oral chemotherapy..
Authors: Marika Anna Rasschaert, Jan Van den Brande, Konstantinos Papadimitriou, Pol Specenier, Sven De Keersmaecker, Sevilay Altintas, Manon Huizing, Jo Ravelingien, Christian Diego Rolfo, Marc Peeters
Journal: Journal of Clinical Oncology (2017)

e18208 Background: Health Information Technology (HIT) is increasingly integrated in clinical cancer care. Simultaneous routine assessment of patient reported outcomes (PROs) reliably improve symptom management, patient-provider communication and ultimately survival. Methods: his pilot study is a single center experience with the development and validation of an I-PRO tool (AMOCT). After obtaining informed consent, outpatients, using oral anticancer treatment, recorded their medication intake and 17 PRO measures (PROM) using this I-PRO tool. The device allowed real time data collection via a central platform. The registered data were processed by an algorithm, which stratifies the data into different grades according to international standards of care (CTCAE v4.0). In response to registration of data, patients received either automated symptom management suggestions or were referred to their caregivers. Patient clinical and demographic information is collected from medical records and analyzed using descriptive statistics. Results: 63 Patients were included, 51% male, mean age 61.5 (range 28-83). 41% Of patients used capecitabine, 24% regorafenib, 16% TAS 102, 5% pazopanib and 5% sunitinib. Of the 1873 PROM-scores, 308 scores needed nurses’ attention, ultimately leading to dose reductions in 7 patients (12%). Most often due to weight loss, skin toxicity and asthenia. 41 Patients stopped registration: 51% because treatment ended, 27 % died, 10% dropped out, 5% progressed, 5% were lost to follow up and 2% never started. This tool was well adopted and demonstrated treatment compliance in &gt; 85% patients. Conclusions: This study confirms the feasibility of the program, in an outpatient setting. This I-PRO tool provides a means to register compliance and toxicity of treatment. The compliance to the I-PRO tool will be confirmed, with further development of this program in a multicenter, randomized design. Evaluation of quality of life, PROM’s and further exploration of the relationship between optimal pharmacovigilance and improvement of patient’s outcome will ensue.
Don't forget about neuromuscular disorders!
Authors: Wolfram Windisch
Journal: European Respiratory Journal (2018)

<b>In patients with NMD, ineffective coughing, recurrent aspiration and airway infections, respiratory failure and home mechanical ventilation require the expertise of respiratory physicians. Therefore, we should not forget about neuromuscular disorders!</b>http://ow.ly/UeEA30lFMxn
Review of Lori A. Roscoe and David Schenck, <i>Communication and Bioethics at the End of Life: Real Cases, Real Dilemmas</i>
Authors: Lisa Anderson-Shaw
Journal: The American Journal of Bioethics (2018)

"Review of Lori A. Roscoe and David Schenck, Communication and Bioethics at the End of Life: Real Cases, Real Dilemmas." The American Journal of Bioethics, 18(9), pp. W1–W2