tbuckley/cabot-search huggingface dataset:
Using administrative laboratory result data to describe adverse events.
Authors: Tamara P. Miller, Kelly D. Getz, Emily Jen, Yuan-Shung Huang, Donna Przepiorka, Yimei Li, Rochelle Bagatell, Alix Eden Seif, Brian Fisher, Richard Aplenc
Journal: Journal of Clinical Oncology (2018)

e18698 Background: Adverse events (AE) on cooperative group trials are manually reported by research assistants using the Common Terminology Criteria (CTC). Our prior work demonstrated that pediatric trials markedly underreport laboratory AEs and that automated AE ascertainment using electronic health record (EHR) data at 1 hospital are as accurate as gold standard chart abstraction. This study sought to prove that laboratory data in the Pediatric Health Information System Plus (PHIS+) administrative database are consistent with EHR data and use PHIS+ data to describe AE rates in Induction for pediatric acute myeloid and lymphoblastic leukemias (AML, ALL). Methods: PHIS+ includes laboratory results submitted by 6 hospitals from 2007 to 2012. EHR and PHIS+ laboratory dates, times, and results for 3 tests at 1 site were compared to assess PHIS+ accuracy. PHIS+ results were cleaned, graded and processed according to CTC v4 definitions for 12 AEs. AE rates were summarized by highest grade during Induction. Results: Laboratory data on 171 AML and 1099 ALL patients were extracted from chemotherapy start date to D+35. Numbers of results varied by laboratory test as some patients only had those tests prior to chemotherapy initiation. PHIS+ and EHR data at 1 hospital showed good concordance (K: AML 97%, ALL 95.5%; ALT: AML 96.5%, ALL 82.2%; ANC: AML 96.9%, ALL 91.2%). Missing PHIS+ data were from outpatient tests or admissions ending in 2012, PHIS+’s last year. Table 1 describes the percentage of grades 3-4 AEs. Conclusions: PHIS+ data can be used to determine accurate laboratory AE rates regardless of trial enrollment status. These AE estimates can be used to counsel patients and as a baseline comparison for experimental therapies. GRADE Glu K Na ALT AST Bili Hgb ANC Plt Hyper Hypo Hyper Hypo Hyper Hypo Increased Increased Hyper Decreased Decreased Decreased AML ALL AML ALL AML ALL AML ALL AML ALL AML ALL AML ALL AML ALL AML ALL AML ALL AML ALL AML ALL N 150 1003 150 1005 170 1098 170 1098 170 1098 170 1098 130 671 106 605 98 555 171 1098 171 1099 171 1099 3 28.7 17.4 0.0 0.3 1.8 3.4 22.4 17.7 0.6 0.5 0.6 19.5 8.5 14.9 0.0 2.8 2.0 3.8 93.0 73.3 0.0 3.2 1.2 17.5 4 8.0 8.0 -- 0.3 1.8 4.4 14.1 6.6 2.4 0.4 0.0 1.3 0.8 3.1 0.0 0.5 1.0 0.2 N/A N/A 99.4 62.0 97.7 56.9
IDH mutations to predict shorter survival in chondrosarcoma.
Authors: Iwona Lugowska, Michal Mikula, Pawel Teterycz, Maria Kulecka, Anna Kluska, Magdalena Piatkowska, Aneta Balabas, Michal Wagrodzki, Andrzej Pienkowski, Piotr Rutkowski, Jerzy Ostrowski
Journal: Journal of Clinical Oncology (2016)

11024 Background: Recent studies have shown that isocitrate dehydrogenase 1/2 (IDH1/2) activating mutations occur in a variety of cancers, including acute myeloid leukemia, gliomas, and chondrosarcomas. In chondrosarcoma no effect of IDH mutation on overall survival (OS) has been reported. The aim of our study was to assess the prevalence of known cancer-related genes mutations in chondrosarcomas, as well as their prognostic role on patients’ survival. Methods: We included 80 patients (F:M- 1:1.3; mean age: 58 years; range 27-86) with histologically confirmed chondrosarcoma (G1:29; G2:34; G3:17) treated at our center between 1996 and 2013. DNA from FFPE samples was subjected to library preparation with the Ion AmpliSeq Cancer Hotspot Panel v2, that allows probing 2 800 COSMIC mutations from 50 oncogenes and tumor suppressor genes, and sequenced on PGM Ion Torrent. Reads were mapped to human genome assembly hg19 and variant calls were made by Torrent Variant Caller. Variants annotation and its consequence on a mature protein was conducted by Variant Effect Predictor while the deleteriousness was assessed with SIFT, PolyPhen and Condel. The following clinical factors were analyzed: tumor location, histological subtype and grade, type of surgery, presence of metastases, age and sex. Statistical analysis of impact of IDH1/2 mutation on OS was performed with log-rank test with significance level of 5%. Results: Among clinical features only histological grade influenced OS. Through deep sequencing 1784 single nucleotide variants (SNVs) with quality 20 or higher were identified in 50 genes. Of them, 426 were considered as pathogenic or likely pathogenic. Activating IDH mutations were found in 27 patients (33.75%) including 17 R132 IDH1 (21.25%), 10 R172 IDH2 (12.5%) and 3 R140 IDH2 variants (3.75%). Three patients had concurrent mutation in IDH1 and 2. The R140 IDH2 mutant has not been reported to date in chondrosarcoma patient. OS for chondrosarcoma patients with IDH mutations was significantly lower than those without mutation (p = 0.00624). No other genetic feature had impact on OS. Conclusions: In chondrosarcomas tumor grade and IDH-mutation status are important predictors for OS. The R140 IDH2 may also be the novel target for treatment of chondrosarcoma patients.
Health-related quality of life (HRQoL) in the KEYNOTE-189 study of pembrolizumab (pembro) or placebo (pbo) + pemetrexed (pem) + platinum (plt) for metastatic NSCLC.
Authors: Marina Chiara Garassino, Delvys Rodriguez-Abreu, Shirish M. Gadgeel, Emilio Esteban González, Enriqueta Felip, Flavia De Angelis, Manuel Domine, Maximilian J. Hochmair, Steven Francis Powell, Susanna Y. Cheng, Helge Bischoff, Nir Peled, Martin Reck, Rina Hui, Edward B. Garon, Michael J. Boyer, Jing Yang, Thomas A. Burke, Maria Catherine Pietanza, Leena Gandhi
Journal: Journal of Clinical Oncology (2018)

9021 Background: In the double-blind, phase 3 KEYNOTE-189 study (NCT02578680), pembro + pem + plt significantly improved OS and PFS over pbo + pem + plt as first-line therapy for nonsquamous NSCLC. Grade 3-5 drug-related AE rates were higher with pembro. We report the prespecified patient-reported outcome (PRO) analyses from KEYNOTE-189. Methods: 616 patients (pts) were randomized to pembro 200 mg Q3W or pbo for 2 y; all pts received pem + 4 cycles of carboplatin or cisplatin. The EORTC QLQ-C30 and QLQ-LC13 were administered at cycles 1-5, then every 3 cycles during yr 1 and every 4 cycles during yrs 2 and 3. Key PRO outcomes were change from baseline to wks 12 and 21 in the QLQ-C30 global health status/QoL score and time to deterioration in the composite of cough, chest pain, or dyspnea. PROs were analyzed in all treated pts who completed ≥1 PRO instrument (n = 602). P values are nominal and 2-sided. Results: QLQ-C30 and QLQ-LC13 compliance was ~90% at baseline and wk 12 in both arms and was ~75% with pembro and ~63% with pbo at wk 21. Mean baseline scores were 61.98 and 60.56 in the pembro and pbo arms. At wks 12 and 21, global health status/QoL scores were stable with pembro and decreased with pbo, with significantly greater decrement with pbo at wk 21 (Table). The proportion of improved global health status/QoL was similar at wk 12 (28.9% with pembro vs 26.5% with pbo; P = .5450) but was greater with pembro at wk 21 (30.1% vs 22.5%; P = .0496). Median time to deterioration in the composite of cough, chest pain, or dyspnea was NR with pembro (95% CI 10.2 mo-NR) vs 7.0 mo (95% CI, 4.8-NR) with pbo (HR 0.81; 95% CI 0.60-1.09; nominal 2-sided P = .081). Conclusions: In this double-blind trial, pembro + pem + plt maintained or improved HRQoL over pem + plt alone despite a higher grade 3-5 treatment-related AE rate. Along with superior efficacy, these data support the use of pembro + pem + plt as first-line therapy for metastatic nonsquamous NSCLC. Clinical trial information: NCT02578680.
An integrated workflow to identify targetable mutations in FFPE samples of HNSCC.
Authors: Nabil F. Saba, Kelly R. Magliocca, Mihir Patel, Conor Ernst Steuer, Scott Newman, Hongzheng Zhang, Mark El-Deiry, J. Trad Wadsworth, Jeanne Kowalski, Dong Moon Shin, Zhuo Georgia Chen, Michael R. Rossi
Journal: Journal of Clinical Oncology (2016)

e17517 Background: Although comprehensive sequencing technologies such as RNA-Seq are promising they have been difficult to implement in standard clinical diagnostic workflows. With this in mind, we sought a methodology that could detect coding mutations, fusions and differential gene expression in formalin-fixed paraffin embedded (FFPE) HNSCC tumor specimens received by our pathology department and reported within a 7-10 day timeframe Methods: RNA Sequencing (RNA-Seq) using the Illumina RNA-Access protocol was performed on 16 base of tongue, 12 tonsil, 7 oral tongue, 1 alveolar ridge, 1 laryngeal, 1 floor of mouth and 2 indeterminate head and neck location tumors from 40 consented patients. A pathologist reviewed original Hematoxylin and Eosin (H&E) stained tumor slide(s) and selected the FFPE block with the largest viable, un-decalcified tumor sample. Nucleic acid extraction and quality control was Matched fresh frozen specimens were available for 6 of the 40 FFPE specimens. . Sequencing libraries were prepared from RNA specimens using the Illumina TruSeq RNA Access kit ; Data analysis was performed using a custom bioinformatics workflow using Galaxy (usegalaxy.org). Results: We generated very high quality data for all 40 FFPE and the 6 matched fresh-frozen specimens with overall alignment rates exceeding 95 Compared to 40 random TCGA samples. Importantly, our data produced high quality coding mutations that were later confirmed by DNA sequencing; differential gene expression and coding fusions, specifically FGFR3-TACC3 gene fusions were detected in 2 specimens. Both of the FGFR3-TACC3 fused specimens originated from p16 positive tumors of the tonsil suggesting this to be potentially drug gable and possibly recurrent. Conclusions: High quality RNA-Seq data is achievable with standard workflows using FFPE HNSCC samples. RNA-Seq analysis may facilitate the detection of actionable alterations in HNSCC and has several advantages over DNA-based sequencing assays alone. Standardization and clinical use of RNA-Seq may better inform the current standard of care and future clinical trials. This project was supported by an R21 CA182662 grant to NFS and GZC
Mutation frequencies in a gene panel among primary tumors and metastases in patients with melanoma.
Authors: Antonella Manca, Maria Colombino, Milena Casula, Amelia Lissia, Tiziana Scotto, Antonio Pazzola, Rosanna Satta, MariaCristina Sini, Grazia Palomba, Valentina Doneddu, Gerardo Botti, Corrado Caraco, Paolo Antonio Ascierto, Antonio Cossu, Giuseppe Palmieri
Journal: Journal of Clinical Oncology (2018)

e21554 Background: The prevalence of mutations in main genes involved in tumorigenesis during melanoma progression remains a controversial issue. Different melanoma tissues from the same patients were investigated for prevalence and distribution of mutations in these genes. Methods: Ninety-eight tumor tissues from 36 patients with metastatic melanoma patients were screened for sequence variants in a panel of 25 genes associated with cell cycle progression, cell differentiation, angiogenesis, and tumor growth by next generation sequencing (NGS) assays. Paired samples of primary melanomas (n = 36) and synchronous or asynchronous metastases from the same patients (n = 62) were included. Secondary lesions included lymph nodal (n = 28), subcutaneous (n = 19), and visceral (n = 15) tumor samples. Results: BRAF, CDKN2A, RAS, and TP53 genes were the most frequently mutated genes. Deleterious mutations were also found in also in ARID2, CDK4, NF1, CCND1, and PTEN genes. Of 28 patients with lymph node metastases, 23 (82%) presented consistent mutation patterns in paired primary and secondary tumor samples. For visceral metastases, 11/15 (73%) patients showed a similar mutation spectrum between primary and secondary tumors. A significantly less consistency was observed in skin metastases (11/19; 58%). Conclusions: Our findings are consistent with previous studies from our group (Colombino, JCO 2012; Casula JID 2016) indicating a low heterogeneity in matched primary and lymph node metastatic samples. Assessment of the prevalence of mutations in genes involved in melanomagenesis among paired tumor lesions from patients with metastatic melanoma may further improve the management of such a disease.
Neurotemplates: Pioneering Effects and Enhanced Neurite Complexity of Primary Hippocampal Neurons on Hierarchical Neurotemplated Scaffolds (Adv. Healthcare Mater. 18/2018)
Authors: Beom Jin Kim, Matthew Park, Ji Hun Park, Sunghoon Joo, Mi‐Hee Kim, Kyungtae Kang, Insung S. Choi
Journal: Advanced Healthcare Materials (2018)

A neuron culture on a neurotemplated silica scaffold is reported by Insung S. Choi and co-workers in article 1800289. The scaffold, mimicking a real neuronal network, enhances neurite complexity of the cultured hippocampal neurons, as well as providing a physical guidepost for neurite development like pioneer neurons in the brain.
Research Reveals Mechanism That May Drive Alcohol Use Disorder
Authors: Tracy Hampton
Journal: JAMA (2018)

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A phase II randomized study of docetaxel +/- low-dose, short course sunitinib in advanced solid tumours.
Authors: Yvonne Li'en Ang, Ross A. Soo, Gwo Fuang Ho, Raghav Sundar, Sing Huang Tan, Joline Si Jing Lim, Wei-Peng Yong, Wan Qin Chong, Jingshan Ho, Nesaretnam Barr Kumarakulasinghe, May Ingyin Aung, Esther Koh, Mira Ramlee, Pyar Soe Phyu, Lily Kyin, Boon Cher Goh, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2016)

e14124 Background: Low dose, short course anti-angiogenic agents may normalize tumor vasculature to improve drug delivery. We previously showed 12.5mg sunitinib (Su) for 7 days before neoadjuvant doxorubicin/cyclophosphamide (AC) to normalize tumor vasculature and improve response. However, Su prolonged myelosuppression and delayed AC cycles, reducing overall efficacy. In this study, we combined Su with docetaxel with an earlier neutrophil nadir to improve chemotherapy dose intensity. Methods: Patients with metastatic cancers were stratified by primary site (breast, lung and others) and randomized 1:1 to docetaxel 75mg/m23 weekly (Arm A) or with Su 12.5mg daily for 7 days before docetaxel (Arm B), up to 6 cycles. Primary endpoints were objective response (ORR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD); secondary endpoints were tolerability, toxicity and progression free survival (PFS). Results: 46 patients participated, 23 in each arm. Median age was 62 (36-76 years). Arm B patients were more heavily pretreated ( ≥ 2 prior lines of palliative chemotherapy 33% vs 71% for A vs B, p = 0.127). Mean total docetaxel dose was similar (347 vs 327mg/m2for A vs B, p = 0.690) with minimal delays in each arm. Use of GCSF was more frequent in Arm B (52.9% vs 92.9%, p = 0.015), and grade 3-4 toxicities less common (52.2% vs 19%, p = 0.023), mainly neutropenia (43.5% vs 9.5%, p = 0.012). ORR was 39.1% and 30.4% (p = 0.194), while CBR was 91.3% and 65.2% in A and B respectively (p = 0.097). Median PFS was 7.4 (95% CI 5.7-9.0) vs 4.2 months (95% CI 2.3-6.2) (p = .001), and median overall survival (OS) was 12.5 months (95% CI 6.1-18.9) vs not reached (p = 0.494). After excluding non-breast/lung primaries, median PFS was 7.1 (95% CI 5.2-8.9) vs 4.4 months (95% CI 2.0-6.7) (p = 0.017); median OS was 16.7 months (95% CI 8.9-24.5) vs not reached (p = 0.474). Conclusions: Su with docetaxel is better tolerated than with AC but did not improve outcomes and appeared adverse particularly in non-breast/lung primary tumors. Clinical trial information: NCT01803503. ORR CBR PFS (months) Lung (n = 16) 50% vs 25% (p = 0.283) 87.5% vs 75% (p = 0.215) 4.9 vs 3.2 (p = 0.130) Breast (n = 20) 50% vs 40% (p = 0.774) 90% vs 80% (p = 0.589) 11.4 vs 5.3 (p = 0.101) Others (n = 10) 0% vs 20% (p = 0.019) 100% vs 20% (p = 0.036) 19.7 vs 2.1 (p = 0.013)
Effect of renal impairment (RI) on intravenous bisphosphonates (IVBP) and multiple myeloma (MM) treatment.
Authors: Debajyoti Bhowmik, Ningqi Hou, Laura Kauffman, Sam Colman, Sarah Vidito, Michele Intorcia
Journal: Journal of Clinical Oncology (2018)

e20007 Background: RI is prevalent in MM patients and associated with poor survival and increased costs. IVBPs are recommended to prevent skeletal-related event (SREs), a common and devastating complication in MM. This study assessed the impact of RI on time to initiation of IVBP, time to discontinuation of IVBP; and time to start of Next line of anti-MM Therapy (NT), a proxy for disease progression. Methods: In this retrospective cohort study, adults with MM diagnosis between 07/01/2012 and 06/30/2016 were identified from the Oncology Services Comprehensive Oncology Records (OSCER) electronic health records database, that include over 750,000 patients from > 200 hematology/oncology practices across the United States. All patients had ≥6-months of follow-up records after initial serum creatinine results on or after MM diagnosis. RI was defined as estimated Glomerular Filtration Rate < 60 mL/min/1.73m2. RI status was assessed before IVBP initiation, during treatment with IVBP, and MM treatment. The impact of RI on IVBP and MM treatment was assessed, using Cox proportional hazard regression analyses, with occurrence of RI as time-varying covariate. Results: A total of 11,136 patients met the study criteria, 6,998 (62.8%) of them experienced RI during the entire observation period [mean age: 70.8 (±9.5) years, male: 52.9%, White: 71.4%]. Occurrence of RI was associated with IVBP discontinuation and progress to NT, but did not significantly impact IVBP initiation (Table 1). Conclusions: Prevention of SREs in MM patients is important. In this study, occurrence of RI was associated with 15% higher likelihood of IVBP discontinuation. Renal complication is a core feature of MM disease; 28% higher likelihood of MM NT observed in this study suggest that RI may indicate disease progression in MM. Table 1: Cox Proportional Hazard Regression Results Time-to-Event Endpoints Hazard Ratios (95% Confidence Interval) P-values Time to IVBP initiation 0.95 (0.87-1.04) 0.3043 Time to IVBP discontinuation 1.15 (1.06-1.24) 0.0007 Time to progress to next line of MM therapy 1.28 (1.15-1.42) < 0.0001 *The models were adjusted for age, gender, race, payer, and comorbidities - diabetes, hypertension, cardiovascular disease, and anemia
Nomogram to assess survival benefit of new over historical agents as salvage therapy for metastatic urothelial carcinoma (mUC) in non-randomized trials.
Authors: Guru Sonpavde, Gregory Russell Pond, Jonathan E. Rosenberg, Toni K. Choueiri, Joaquim Bellmunt, Ashley Marie Regazzi, Stephanie Anne Mullane, Andrea Necchi, Daniele Raggi, Jae-Lyun Lee, Soon Il Lee, Joseph Simpson, Christina Louise Derleth, Lin Shih-Wen, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2017)

e16012 Background: Surrogate endpoints of benefit in mUC phase 2 salvage therapy trials are necessary to identify promising drugs, particularly for checkpoint inhibitors where response and progression-free survival are inadequate. We developed a nomogram using prognostic variables from phase 2 trials of historical agents to estimate 12 month survival to which observed survival in phase 2 trials could be compared. Methods: Data were obtained from phase 2 trials of salvage therapy for mUC for survival and 5 prognostic factors: hemoglobin, performance status, liver metastasis, treatment-free interval and albumin. Patients (pts) were randomly allotted to discovery:validation (DIS:VAL) datasets in a 2:1 ratio. A nomogram was developed for estimating 12-month survival. Calibration plots were constructed in the VAL dataset by plotting estimated vs. observed 12-mo survival and data bootstrapped to assess performance. The nomogram was applied to external nonrandomized salvage therapy data: 1) retrospective pemetrexed data or 2) trials of atezolizumab: PCD4989g and IMvigor210. Results: Data were available from 340 pts receiving sunitinib (n = 77), everolimus (n = 45), docetaxel + vandetanib or placebo (n = 109), pazopanib (n = 42), paclitaxel (n = 36) and docetaxel (n = 31). Calibration and prognostic ability of the model was acceptable (c-index = 0.634, 95% CI = 0.596-0.652). Observed 12-month survival for pts on pemetrexed (n = 127, 23.5% [95% CI: 16.2%-31.7%]) were similar to nomogram-predicted survival (19% [95% CI: 16.5-21.5], P&gt; 0.05), while observed result with atezolizumab (n = 403, 39.0% [95% CI: 34.1-43.9]) exceeded predicted result (24.6% [95% CI: 23.4-25.8], P&lt; 0.001). Conclusions: Atezolizumab was associated with a significantly longer 12-mo survival compared to nomogram-predicted survival while pemetrexed was not. This nomogram incorporates baseline prognostic factors to provide expected 12-mo survival of phase 2 patient cohorts with which to compare observed survival, providing a useful tool to quantify benefit in phase II studies while controlling the impact of clinical variables.