tbuckley/cabot-search huggingface dataset:
Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis
Authors: Martin Kolb, Ganesh Raghu, Athol U. Wells, Jürgen Behr, Luca Richeldi, Birgit Schinzel, Manuel Quaresma, Susanne Stowasser, Fernando J. Martinez
Journal: New England Journal of Medicine (2018)

Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). A subgroup analysis of a previously published trial suggested that sildenafil may provide benefits regarding oxygenation, gas exchange as measured by the diffusion capacity of the lungs for carbon monoxide (DlCO), symptoms, and quality of life in patients with IPF and severely decreased DlCO. That idea was tested in this trial.We randomly assigned, in a 1:1 ratio, patients with IPF and a DlCO of 35% or less of the predicted value to receive nintedanib at a dose of 150 mg twice daily plus sildenafil at a dose of 20 mg three times daily (nintedanib-plus-sildenafil group) or nintedanib at a dose of 150 mg twice daily plus placebo three times daily (nintedanib group) for 24 weeks. The primary end point was the change from baseline in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 12 (the total score ranges from 0 to 100, with higher scores indicating worse health-related quality of life). Secondary end points included measures of dyspnea and safety.A total of 274 patients underwent randomization. There was no significant difference in the adjusted mean change from baseline in the SGRQ total score at week 12 between the nintedanib-plus-sildenafil group and the nintedanib group (-1.28 points and -0.77 points, respectively; P=0.72). A benefit from sildenafil treatment was not observed with regard to dyspnea as measured with the use of the University of California, San Diego, Shortness of Breath Questionnaire. No new safety signals were observed, as compared with previous trials.In patients with IPF and a DlCO of 35% or less of the predicted value, nintedanib plus sildenafil did not provide a significant benefit as compared with nintedanib alone. No new safety signals were identified with either treatment regimen in this population of patients. (Funded by Boehringer Ingelheim; INSTAGE ClinicalTrials.gov number, NCT02802345 .).
Two-year efficacy and safety update from JAVELIN Merkel 200 part A: A registrational study of avelumab in metastatic Merkel cell carcinoma progressed on chemotherapy.
Authors: Paul Nghiem, Shailender Bhatia, Andrew Scott Brohl, Omid Hamid, Janice M. Mehnert, Patrick Terheyden, Kent C. Shih, Isaac Brownell, Celeste Lebbé, Karl D. Lewis, Gerald P. Linette, Michele Milella, Meliessa Hennessy, Marcis Bajars, Christine Hicking, Sandra P. D'Angelo
Journal: Journal of Clinical Oncology (2018)

9507 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with poor prognosis. Studies of second-line chemotherapy for metastatic MCC (mMCC) have reported median progression-free survival (PFS) of up to 3 months and no benefit to overall survival (OS). Avelumab, a human anti–PD-L1 monoclonal antibody, is approved in several countries for the treatment of mMCC. Here, we report updated efficacy and safety data from part A of the pivotal, single-arm, phase 2, JAVELIN Merkel 200 trial of avelumab in patients (pts) with mMCC and ≥2 y of follow-up. Methods: Pts with mMCC and progression on prior chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until disease progression or intolerable adverse event (AE). Objective response rate (ORR), duration of response (DOR), and PFS were evaluated by independent review per RECIST v1.1; OS and AEs (per NCI CTCAE v4.0) were also evaluated. Results: As of Sep 26, 2017, 88 pts were followed for a median of 29.2 mo (range 24.8-38.1). The median duration of treatment was 3.9 mo (range 0.5-36.3); treatment was ongoing in 9 pts (10.2%). The confirmed ORR of 33.0% (95% CI 23.3-43.8; complete response in 11.4%) remained unchanged from previous analyses at 1 y and 18 mo; responses were ongoing in 19 of 29 pts, including 12 pts with > 2 y response duration. Median DOR had not been reached (range 2.8-31.8 mo; 95% CI 18.0-not estimable). Durable responses led to stable rates of PFS (29% at 1 y, 29% at 18 mo, and 26% at 2 y). Median OS was 12.6 mo (95% CI 7.5-17.1) and the 2-y OS rate was 36% (50% at 1 y and 39% at 18 mo). Clinical activity was observed across all pt subgroups, irrespective of tumor PD-L1 and MCPyV status. The AE profile remained consistent with previous analyses: 67 pts (76.1%) had a treatment-related AE (TRAE), 10 pts (11.4%) had a grade ≥3 TRAE, 20 pts (22.7%) had an immune-related AE, and no treatment-related deaths occurred. Conclusions: At ≥2 y of follow-up, avelumab shows continued durable responses and meaningful survival outcomes in pts with mMCC, exceeding the outcomes associated with cytotoxic chemotherapy. Efficacy and safety results confirm the lasting clinical benefit of avelumab in pts with mMCC. Clinical trial information: NCT02155647.
Periodontal complications of prescription and recreational drugs
Authors: Francis J. Hughes, P. Mark Bartold
Journal: Periodontology 2000 (2018)

Abstract Drug use for both therapeutic and recreational purposes is very widespread in most societies. The range of drugs used, the variations in response to these drugs and other health and behavioral confounders mean that drug use may be an important contributor to individualized periodontal diagnoses. In this narrative review, we review the main reported effects of drugs on the periodontal tissues and periodontal disease processes. Although some of the more common adverse drug reactions on periodontal tissues are well described, in many other cases the evidence for these drug effects is quite limited and based on small case series or isolated reports. Prescription drugs are responsible for a range of effects, including drug‐induced gingival overgrowth and increased gingival bleeding, and influence periodontal inflammation and periodontal breakdown. The effects of recreational drugs on the periodontal tissues is less well researched, perhaps for the obvious reason that assembling large cohorts of recreational drug users presents particular challenges. Use of nearly all of these substances is associated with poorer periodontal and dental health, although there is almost certainly a large degree of behavioral confounding in these findings. Overall, further studies of adverse drug reactions on the periodontal tissues are required as this continues to be an important and increasing factor in periodontal health determination.
Matching-adjusted indirect comparison (MAIC) of relative efficacy for brigatinib vs. ceritinib and alectinib in crizotinib-resistant anaplastic lymphoma kinase (ALK+) non-small cell lung cancer (NSCLC).
Authors: Karen L. Reckamp, Joseph Lee, Joice Huang, Irina Proskorovsky, William Reichmann, Mira Krotneva, David Kerstein, Hui Huang
Journal: Journal of Clinical Oncology (2017)

e20675 Background: Brigatinib (BRG), ceritinib (CER), and alectinib (ALEC) are second-generation ALK inhibitors developed for crizotinib (CRZ)-resistant ALK+ NSCLC. No randomized trial has directly compared the efficacy of these treatments. The goal of this analysis was to use an MAIC to indirectly compare progression-free survival (PFS) and overall survival (OS) for BRG vs CER and BRG vs ALEC in CRZ-resistant ALK+ NSCLC patients (pts). Methods: This analysis used pt-level data from arm B (180 mg qd with a 7-day lead-in at 90 mg, n=110) of the ALTA trial for BRG and published summary data from ASCEND-1/ASCEND-2 and NP28673 trials for CER and ALEC, respectively. PFS and OS curves from published data were digitized to generate virtual pt-level data for estimation of event rates. Pts in ALTA were assigned weights so that their weighted mean baseline characteristics matched baseline characteristics in each of ASCEND-1, ASCEND-2, and NP28673. Relative treatment effects pre- and post-matching were estimated using Cox proportional hazards models. Results: Prior to matching, baseline imbalances were noted in ECOG PS 2, prior chemotherapy, Asian race, smoking status, and best prior response to CRZ among trials. Weighting reduced effective sample sizes (ESSs) for ALTA pts in the matched comparisons. Relative efficacy results were robust and did not appreciably change after adjusting for the prognostic factors (Table 1). Conclusions: Both before and after matching, BRG had significantly longer PFS compared to CER and ALEC, significantly longer OS than CER, and a trend toward longer OS than ALEC. [Table: see text]
Characterization of 4q12 amplification in 8819 advanced solid tumor cases.
Authors: Jun Wu, Chen Chen, Tianxiang Huang, Shuanying Yang, Pingping Dai, Qichao Xie, Jiang Liu, Yu Zeng, Weiguo Cao, Jiaojiao Huan, Jie Gao, Chunwei Xu, Wen xian Wang, Bin Yi, Yan-Fang Guan, Ling Yang, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2018)

e24275 Background: The amplification of chromosomal segment 4q12, which includes three genes (PDGFRA, KIT and KDR), has been reported in 8-16% glioblastoma (GMB) and 4.2% non-small-cell lung cancer (NSCLC). However, little is known about the presence of 4q12 amplification (4q12amp) across different kinds of cancers and characterization of these tumors. Methods: We implemented next generation sequencing for the detection of 4q12amp across 8819 solid tumors. Besides copy number variations (CNVs), single nucleotide variants (SNVs), short insertions/deletions (indels) were analyzed at the same time. Results: Among 8819 cases, 0.32% (28/8819) harbored 4q12amp, including 11.11% (5/45) of GMB, 3.45% (1/29) of gastrointestinal stromal tumor (GIST), 3.28% (2/61) of soft tissue sarcoma, 0.38% (19/5,013) of lung cancer and 0.14% (1/716) of breast cancer, with an average copy number of 6.3. In lung cancer, 0.24% (10/4,210) of NSCLC and 4.4% (6/137) of small-cell lung cancer (SCLC) detected with 4q12amp. The majority (80%) of 4q12amp GBM cases didn’t contain known driver oncogene (IDH1/2) alternations indicating 4q12amp might play a driver oncogenic role in GBM. It was reported that two kinds of amplification correlate with different phenotypes. In our study, 60% (3/5) GMB cases carried amplification encompassing PDGFRA, KIT and KDR and 40% (2/5) carried amplification encompassing only PDGFRA and KIT. One case has co-amplifications of EGFR (36.3-fold) and CDK4 (7.4-fold), as well as homozygous deletions of CDKN2A and CDKN2B. 4q12amp overlapping with these multi-genes was reported to be related with long-term survival. Conclusions: We identify high frequencies of 4q12amp in GIST and SCLC cases. Due to lack of effective treatment in these cancers, this finding provide a potential drug target for cancer treatment. Future researches on multi-kinase inhibitors targeting 4q12amp are needed. In GBM, 4q12amp may be clinical significance biomarker in therapy, diagnosis and prognosis.
A randomized phase 2 study investigating 3 dosing regimens of radium-223 dichloride (Ra-223) in bone metastatic castration-resistant prostate cancer (mCRPC).
Authors: Cora N. Sternberg, Fred Saad, Julie Nicole Graff, Avivit Peer, Ulka N. Vaishampayan, Eugene Leung, Eli Rosenbaum, Howard Gurney, Richard Epstein, Ian D. Davis, Bingyan Wu, Lucia Trandafir, Volker Jean Wagner, Maha Hussain
Journal: Journal of Clinical Oncology (2018)

5008 Background: Ra-223, standard dose (SD) 55 kBq/kg q4w for 6 cycles improved overall survival (OS) and delayed time to symptomatic skeletal events (SSEs) in patients (pts) with mCRPC and bone metastases in the ALSYMPCA study (Parker C, N Engl J Med. 2013;369(3):213-23). The current study investigated different Ra-223 treatment regimens in a similar patient population. Methods: Pts with bone mCRPC were randomized 1:1:1 to Ra-223 SD or Ra-223 high dose (HD) 88 kBq/kg q4w for up to 6 cycles, or to Ra-223 SD extended (EXT) q4w for up to 12 cycles. The primary objective was to compare SSE-free survival (SSE-FS) between HD and SD, and EXT and SD. Hypothesis testing was performed at a 2-sided alpha level of 0.20 with no adjustment for multiplicity. Results: 391 pts were randomized; baseline characteristics were well balanced. No statistically significant differences in SSE-FS were observed between Ra-223 SD and HD [median 12.3 vs 12.9 months, hazard ratio (HR) 1.06, 80% CI 0.88–1.27, p = 0.70] or Ra-223 SD and EXT [median 13.2 vs 10.8 months, HR 1.26, 80% CI 0.94–1.69, p = 0.31]. Median OS was 15.8, 16.0 and 14.4 months in the SD, HD and EXT arms, respectively. A total of 370 pts received Ra-223 with a median number of doses of 6 in each arm. The most frequent treatment emergent adverse events (TEAEs) were fatigue, anemia and nausea. Grade ≥3 TEAEs were noted in 34%, 48% and 53% of pts in the SD, HD and EXT arms, respectively. The most frequent grade ≥3 TEAEs overall were anemia (13%), bone pain (5%), thrombocytopenia (4%) and hypertension (4%). TEAEs leading to permanent discontinuation occurred in 9%, 16% and 17% of pts in the SD, HD and EXT arms, respectively. Conclusions: No statistically significant differences in SSE-FS were noted between Ra-223 SD and HD or Ra-223 SD and EXT. However, HD and EXT arms had a higher incidence of grade ≥3 TEAEs than the SD arm. The study supports the currently approved dose and schedule of Ra-223. Clinical trial information: NCT02023697.
Clinical predictors of bevacizumab-associated intestinal perforation in non-small cell lung cancer.
Authors: Motohiro Tamiya, Hidekazu Suzuki, Takayuki Shiroyama, Ayako Tanaka, Naoko Morishita, Norio Okamoto, Kenichi Sakai, Hironori Shigeoka, Kunimitsu Kawahara, Tomonori Hirashima
Journal: Journal of Clinical Oncology (2018)

e21155 Background: Bevacizumab (Bev) is generally well-tolerated, and Bev-associated intestinal perforation (BAP) is a rare albeit serious side effect in cases of non-small cell lung cancer (NSCLC). However Bev has become increasingly used in various settings, based on its effects among patients with NSCLC, and this increased use is associated with an increasing incidence of BAP in the clinical setting. Therefore, the present study aimed to identify clinical predictors of BAP to help predict and manage the development of life-threatening intestinal complications among patients receiving Bev. Methods: This retrospective study evaluated demographic, clinical, and treatment factors for patients with NSCLC who were treated with Bev between February 2010 and August 2015 at Osaka Habikino Medical Center. Results: We identified 314 regimens (208 patients; median age: 65 years; 115 women) for analysis, which included 119 first-line regimens, 74 second-line regimens, and 121 third-line or later regimens. BAP occurred in 7 cases (2.23% among all regimens and 3.37% among all patients), which generally occurred during first- or second-line treatment and was caused by ulcerative colitis (1 case), colon diverticulitis (1 case), and idiopathic perforations (5 cases). Univariate analyses revealed that none of the patients’ pre-treatment clinicopathological characteristics were associated with BAP, however BAP was significantly associated with deteriorating PS during the first cycle of chemotherapy (odd ratio [OR]: 11.07, 95% confidence interval [CI]: 2.37–51.63, p = 0.0022), grade ≥3 diarrhea (OR: 11.37, 95% CI: 2.37–54.50, p = 0.0024), febrile neutropenia (OR: 9.16, 95% CI: 1.98–42.49, p = 0.0047), and stomatitis (OR: 4.60, 95% CI: 1.01–21.04, p = 0.0492). Conclusions: Among patients with NSCLC, BAP was associated with deteriorating PS during the first cycle of chemotherapy, grade ≥3 diarrhea, febrile neutropenia, and stomatitis. Therefore, careful observation is needed for patients with NSCLC who receive Bev in any line of treatment, especially if they develop serious side effects that affect their PS or mucous membrane.
Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan
Authors: Yiqiao Gao, Wei Li, Jiaqing Chen, Xu Wang, Yingtong Lv, Yin Huang, Zunjian Zhang, Fengguo Xu
Journal: Acta Pharmaceutica Sinica B (2018)

Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by Irinotecan (CPT-11), and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually, two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine.
Identification of histone deacetylase 2 (HDAC2) as a novel target for MDM2 directed therapies in dedifferentiated liposarcoma.
Authors: Colin W Stets, Bryce Demoret, Nicholas Grosenbacher, John L. Hays, James Lin Chen
Journal: Journal of Clinical Oncology (2018)

11583 Background: Dedifferentiated liposarcoma (DDLPS) is a common, but morbid mesenchymal tumor driven by amplifications in the mouse double minute 2 homolog (MDM2) gene. Prior studies have indicated that pan-HDAC inhibition may be able to lower MDM2 levels in vitro. However, there are multiple HDAC isoforms and pan-HDAC inhibitors used in the clinic have significant toxicities. We hypothesize that isoform specific HDAC inhibition may achieve modulation of MDM2 and limit the toxicities associated with pan-HDAC inhibition. We report here that HDAC2 is sufficient to lower the expression of MDM2 and improve tumor response to doxorubicin in DDLPS in vitro and in vivo. Methods: Bioinformatics analysis of RNA-Seq data from DDLPS cell lines was used to identify HDAC proteins associated with MDM2 expression. Potential targets were validated using shRNA mediated knockdown and pharmacologic agents. We examined and quantified MDM2 protein expression via immunoblotting. Cytotoxicity was determined using XTT reagents in vitro. Synergy calculations were performed using the Chou-Talalay algorithm on in vitro cytotoxicity assays. In vivo response was measured using mouse xenograft models. Results: Small molecule pan-HDAC inhibitor AR42 and HDAC2 specific inhibitor Mi-192 decreased MDM2 expression (2.5-fold and 7.1 fold decrease, respectively) and induced a 6500-fold increase in the expression of the tumor suppressor P21. HDAC2 shRNA knockdown further corroborated the HDAC2 specific effect on MDM2 expression (5-fold reduction). In vitro synergism with doxorubicin in DDLPS (cooperativity index < 0.7) was observed across a range of HDAC2i concentrations. In mouse xenograft model, MI-192 significantly reduced tumor volume (p = 0.02) without the induction of MDM2 mRNA expression. Conclusions: HDAC2 specific inhibition lowers MDM2 expression and synergizes with doxorubicin in DDLPS cell lines and slows tumor growth in vivo. Prospective clinical studies are necessary to confirm these findings.
Protecting Infants From Pertussis Disease
Authors: Kathryn M. Edwards
Journal: JAMA Pediatrics (2018)

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Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with non-small cell lung cancer (NSCLC) previously treated with anti-PD-(L)1 therapy.
Authors: Leena Gandhi, Pasi A. Janne, Mateusz Opyrchal, Suresh S. Ramalingam, Igor I. Rybkin, Navid Hafez, Luis E. Raez, Dmitry Gabrilovich, Fang Wang, Peter Ordentlich, Susan Brouwer, Serap Sankoh, Emmett V. Schmidt, Michael L. Meyers, Matthew David Hellmann
Journal: Journal of Clinical Oncology (2018)

9036 Background: Treatment options are limited in pts who progress on anti-PD-(L)1 therapy. HDAC inhibitors have the potential to modulate myeloid-derived suppressor cell (MDSC) function and may synergize with PD-(L)1 inhibition. We report the preliminary results of a Phase 2 trial of entinostat (ENT), a class I selective histone deacetylase (HDAC) inhibitor, plus pembrolizumab (PEMBRO) in patients with NSCLC previously treated with anti-PD-(L)1 therapy. Methods: ENCORE-601 is an open-label study evaluating the combination of ENT + PEMBRO in pts with recurrent or metastatic NSCLC and prior progression on anti-PD-1/PD-L1 therapy. Pts were eligible irrespective of histology or baseline PD-L1 expression. Pts were treated with ENT 5 mg PO weekly and PEMBRO 200 mg IV Q3W. The primary endpoint was ORR as assessed by irRECIST. The study was designed as a Simon 2-stage study such that if 3 of 31 pts responded in Stage 1, the study would enroll up to 56 pts. The study was further revised to accrue up to 70 patients to increase statistical power and decrease Type I error. Tumor biopsies and blood samples for immune correlates were taken pre- and on-treatment in a subset of patients. Results: Of the first 57 patients enrolled, 17 had refractory disease to prior to PD-(L)1 therapy, and only 2 had a documented prior response. Median duration of prior PD-(L)1 therapy was < 6 months and the median time from last dose of prior PD-(L)1 therapy was 65 days. To ENT + PEMBRO, 5 of 57 patients achieved a confirmed PR (ORR = 9%, 95% CI: 2.9-19.3). Of the responders, 4 had PD-L1 expression < 1% in tissue collected at baseline. The median duration of response is 4.2 months, with 3 responders ongoing. 20 pts (35.1%) experienced Grade 3/4 related AEs; 6 pts (10.5%) experienced Grade 3/4 related irAEs (3 events of pneumonitis). The most frequent ( > 15%) related AEs (irrespective of grade) include fatigue, anemia, decreased appetite, and diarrhea. Evaluation of gene expression and circulating immune cells to identify biomarkers of response is in progress. Conclusions: ENT + PEMBRO demonstrated anti-tumor activity and acceptable safety in patients with NSCLC who have progressed on prior PD-(L)1 blockade. Clinical trial information: NCT02437136.