tbuckley/cabot-search huggingface dataset:
Combination of gefitinib and olaparib versus gefitinib alone in EGFR mutant non-small-cell lung cancer (NSCLC): A randomized phase 2 study (GOAL, Spanish Lung Cancer Group).
Authors: Rosario Garcia Campelo, Oscar Gerardo Arrieta Rodriguez, Bartomeu Massuti, Delvys Rodriguez-Abreu, Ana Laura Ortega Granados, Margarita Majem, David Vicente, Pilar Lianes, Joaquim Bosch-Barrera, Amelia Insa, Manuel Domine, Noemi Reguart, Maria Guirado, María Ángeles Sala, Sergio Vazquez-Estevez, Reyes Bernabe Caro, Ana Drozdowskyj, Ana Verdu, Niki Karachaliou, Rafael Rosell
Journal: Journal of Clinical Oncology (2018)

9012 Background: Low BRCA1 mRNA levels correlate with longer progression free survival (PFS) in erlotinib treated EGFR mutant NSCLC patients (p), while risk of shortened PFS was associated with intermediate/high BRCA1 levels (HR, 8.46; P<0.0001). We explored the combination of the poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib with gefitinib in EGFR mutant NSCLC p. In a previous phase 1 trial, the safety of the combination was confirmed. Recommended phase 2 dose (RP2D) is gefitinib, 250 mg daily, and olaparib, 200 mg thrice daily. Methods: Stage IV treatment naïve NSCLC p with centrally confirmed EGFR mutations and measurable disease were recruited in the study (NCT01513174). We randomly allocated p (1:1) to receive gefitinib 250 mg daily or the combination at the RP2D. The primary endpoint was PFS. PFS related to BRCA1 mRNA was a secondary endpoint, and 53BP1 and enhancer of zeste homolog 2 (EZH2) were analyzed as modulators of BRCA1, overall survival (OS), response rate (RR), safety and tolerability. Target accrual was 186 p. This sample provided 80% power to detect HR of 0.63 after 116 PFS events. The first PFS analysis, side effect profile and RR had a February 28th, 2018 cut-off, minimum follow-up of 18 months (mo). Results: Of the 182 p who underwent randomization, 91 received gefitinib and 91 received gefitinib+olaparib, with no differences in gender, age, never smoker, performance status, bone or brain metastases or EGFR mutation. Median PFS for exon 19 deletions and exon 21 L858R EGFR mutations was 10.4 mo for gefitinib group and 12.8 mo for gefitinib + olaparib group (HR for disease progression or death, 0.83; P=0.329). RR was 68% in gefitinib group and 78% in gefitinib + olaparib group. Conclusions: The gefitinib+olaparib combination did not provide significant benefit over gefitinib alone. Median PFS was 2.4 mo longer for the combination and risk of disease progression or death was 17% lower with gefitinib+olaparib than gefitinib alone. The pre-specified assessment of BRCA1, 53BP1 and EZH2 could determine if a subgroup of p might obtain major benefit from the combination. Clinical trial information: NCT01513174.
Role of neutrophil to lymphocyte ratio in addition to revised international prognostic index (R-IPI) in patients with extranodal diffuse large B-cell lymphoma of head and neck.
Authors: Kamila Izabela Cisak, Amitoj Gill, Erin Faber, Rebecca A. Redman, Neal E Dunlap, Shesh Rai, Xiaoyong Wu, Cesar Augusto Perez
Journal: Journal of Clinical Oncology (2017)

e19032 Background: Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL). One third of DLBCLs cases have a primary extranodal origin and head and neck localization is second most common localization after gastrointestinal tract. The Revised-International Prognostic Index (r-IPI) is commonly used as prognostic tool, but there is growing evidence that neutrophil to lymphocyte ratio (NLR) also has prognostic significance in DLBCL. Methods: We retrospectively reviewed all cases of extranodal DLBCLs diagnosed between 2006 and 2016 at a single academic institution. Collected data included race, gender, primary site, baseline laboratory data, IPI score, pathology, treatment and survival. Results: A total of 33 patient were included, with 18 (54.5%) being females. Median age at diagnosis was 68 (range 28-92). 15% of patients had a r-IPI of 0, 30% a r-IPI of 1-2, 12% a rIPI of 3-5 and 36% a not evaluable (NE) r-IPI. Twelve (36%) patients had germinal center B cell subtype (GCB) and 17 (51%) patients had activated B cell subtype (ABC) by immunohistochemistry. Among all patients, 13 (39%) had pretreatment NLR equal or more than 3.5 and 11 (33%) patients had NLR less than 3.5 and 9 patients had a NE NLR. . Among deceased patients, 5 (56%) of them had NLR of more that 3.5 (p =0.011). Nine (27%) patients had pretreatment monocyte count less than 700/mm3 and 14 (42%) patients had monocyte count at least 700/mm3 (p=0.611). The 2-year overall survival was 77% (95% CI 0.61 - 0.93). Conclusions: (R-IPI) is the most common tool to predict outcome in DLBCL and our study showed that pretreatment NLR can be used as additional poor prognosis marker for patients with extranodal DLBCL of the head and neck. [Table: see text]
Oncologic effectiveness of transarterial chemoembolization in local control of large hepatocellular carcinoma.
Authors: Jason M. Low, Mohamed E. Abdelsalam, Bruno C. Odisio, Tomas Appleton Figueira, Reham Abdel-Wahab, Manal Hassan, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2018)

e16148 Background: To evaluate the oncologic effectiveness of Transarterial chemoembolization (TACE) in Local control of hepatocellular carcinoma (HCC) up to 7cm. Methods: We reviewed our institutional database for HCC patients who underwent TACE. Data were collected for patients with solitary HCC (up to 7cm) who received TACE in our institution. For each patient, we recorded demographics, lesion size, and number of TACE sessions, TACE regimen, Response using mRECIST, and duration of follow up radiological imaging. Results: Sixty Nine patients (47 male and 22 female) met our inclusion criteria with median age of 67 years (range: 43-86 years). Median lesion size is 3.7 cm (1.5 – 7cm). Of the 72 lesions, 16 were between 5-7 cm. Mean number of TACE sessions for each patient is 2 (range 1-6 sessions).Forty patients received mixture of chemotherapy with gel foam or ethiodol and 29 patients received drug eluting beads. Mean follow up imaging was 2 years (range 0.1 – 7.93 years). Eight patients didn’t have follow up imaging after the last TACE. Of the remaining 61 patients, 37( 60.6 %), 15 (24.6%), 6 (9.8 %) and 3 (5 %) patients had CR , PR, SD and PD respectively. Of the 16 patients with tumor size between 5-7 cm, 15 patients had radiological follow up. Nine (60 %), 3 (20 %), 2 (13 %) and 1 (7%) patients had CR, PR, SD and PD respectively. Conclusions: Transarterial chemoembolization is highly efficacious and provides favorable local oncologic control for HCC lesions up to 7cm
Association of Cannabinoid Administration With Experimental Pain in Healthy Adults
Authors: Martin J. De Vita, Dezarie Moskal, Stephen A. Maisto, Emily B. Ansell
Journal: JAMA Psychiatry (2018)

<h3>Importance</h3> Cannabinoid drugs are widely used as analgesics, but experimental pain studies have produced mixed findings. The analgesic properties of cannabinoids remain unclear. <h3>Objective</h3> To conduct a systematic review and meta-analysis of the association between cannabinoid drug administration and experimental pain outcomes in studies of healthy adults. <h3>Design, Setting, and Participants</h3> A systematic search of PubMed, EMBASE, MEDLINE, PsycINFO, and CINAHL was conducted from the inception of each database to September 30, 2017. Studies were eligible for inclusion if they met criteria, including healthy participants and an experimentally controlled administration of any cannabinoid preparation in a quantified dose. Studies that used participants with chronic pain were excluded. Data extracted included study characteristics, cannabinoid types and doses, sex composition, and outcomes. Study quality was assessed using a validity measure previously established in published reviews. Random-effects meta-analyses were used to pool data and generate summary estimates. <h3>Main Outcomes and Measures</h3> Experimental pain threshold, pain tolerance, pain intensity, pain unpleasantness, and mechanical hyperalgesia. <h3>Results</h3> Eighteen placebo-controlled studies (with 442 participants) were identified. Of the 442 participants, 233 (52.7%) were male and 209 (47.3%) were female. For sample ages, 13 (72%) of the 18 studies reported a mean sample age (26.65 years), 4 (22%) reported a range, and 1 (6%) reported a median value. The search yielded sufficient data to analyze 18 pain threshold comparisons, 22 pain intensity comparisons, 9 pain unpleasantness comparisons, 13 pain tolerance comparisons, and 9 mechanical hyperalgesia comparisons. Cannabinoid administration was associated with small increases in pain threshold (Hedges<i>g</i> = 0.186; 95% CI, 0.054-0.318;<i>P</i> = .006), small to medium increases in pain tolerance (Hedges<i>g</i> = 0.225; 95% CI, 0.015-0.436;<i>P</i> = .04), and a small to medium reduction in the unpleasantness of ongoing experimental pain (Hedges<i>g</i> = 0.288; 95% CI, 0.104-0.472;<i>P</i> = .002). Cannabinoid administration was not reliably associated with a decrease in experimental pain intensity (Hedges<i>g</i> = 0.017; 95% CI, −0.120 to 0.154;<i>P</i> = .81) or mechanical hyperalgesia (Hedges<i>g</i> = 0.093; 95% CI, −0.059 to 0.244;<i>P</i> = .23). The mean quality rating across studies was good. <h3>Conclusions and Relevance</h3> Cannabinoid drugs may prevent the onset of pain by producing small increases in pain thresholds but may not reduce the intensity of experimental pain already being experienced; instead, cannabinoids may make experimental pain feel less unpleasant and more tolerable, suggesting an influence on affective processes. Cannabis-induced improvements in pain-related negative affect may underlie the widely held belief that cannabis relieves pain.
Implementation of precision medicine clinical care pathways and a systemwide molecular tumor board at Henry Ford Health System (HFHS).
Authors: Nadia Z Haque, Igor I. Rybkin, Ding Wang, Dhananjay Chitale, Louisa Laidlaw, Spencer C. Hoover, Steven N. Kalkanis
Journal: Journal of Clinical Oncology (2018)

e18541 Background: Advances in precision medicine (PM) offer new promises for cancer care delivery. Genomic analysis provides guidance on selecting molecularly targeted therapies for favorable outcomes and clinical trial opportunities. At HFHS, we implemented a clinically oriented precision medicine program (PMP) to scale the delivery of precision cancer care. Methods: At the data cutoff of 12/31/2017, the PMP at HFHS implemented systemwide cancer care standardized pathways under the PM structure across each of 15 disease-specific tumor boards (DTBs), along with building bioinformatics interfacing with the electronic medical record. Systemwide execution of the PMP allows for molecular mutation analysis using an internal next generation sequencing (NGS) platform from patients who were members of HFHS’ owned insurance plan, and patients of other payors. Appropriateness of genetic test criteria were developed, internal NGS expanded, and software integrated data and supported treatment decisions. A multidisciplinary molecular tumor board (MTB) was designed to discuss and interpret available molecular profile data; thus, providing guidance through each clinical care pathway. The PMP engaged oncology fellows for case curation and presentation at the MTB. Results: To date, we have loaded 157,678 cancer patients into the PM software. The MTB began meeting in the 3rd quarter of 2017. DTBs reviewed 3356 patient cases in the 3rd and 4th quarter, with 20 referred to the MTB. Clinical trial and off-label treatment was recommended. PMP execution within HFCI has been highly regarded as a valuable process with broad impact on standardizing cancer care, systemwide education; and as a clinical research endeavor to restructure disparate clinical and molecular data into an electronic data warehouse and report metrics and outcomes for operations and quality improvement. Conclusions: By creating a consistent methodology for ordering molecular tests, and referring appropriate patients to the MTB, clinicians can easily incorporate effective precision medicine into workflows and decision-making processes to improve care quality and clinical trial enrollment.
Milestone analyses with immune checkpoint inhibitors (ICI), targeted therapy (TT), and standard therapy in metastatic non-small cell lung cancer (mNSCLC) trials submitted to the U.S. FDA: An updated pooled analysis.
Authors: Gideon Michael Blumenthal, Lijun Zhang, Hui Zhang, Dickran Kazandjian, Sean Khozin, Shenghui Tang, Rajeshwari Sridhara, Patricia Keegan, Richard Pazdur
Journal: Journal of Clinical Oncology (2016)

9010 Background: Recent trials of ICIs in mNSCLC suggest that Objective Response Rate (ORR) and Progression Free Survival (PFS) may not fully capture clinical benefit. Novel endpoints such as milestone analyses to capture the tail of the survival curve and identify long term responders should be explored as potential intermediate endpoints. We updated our pooled analysis of mNSCLC trials to include 2 randomized controlled trials (RCTs) with ICIs to explore trial-level associations between milestone analyses with ORR, PFS, and Overall Survival (OS). Methods: For details of our pooled analysis, see Blumenthal et al JCO 2015. We identified an additional 5 trials from our original analysis, 2 RCTs with ICIs, 1 with TT, and 2 with standard therapy (updated n=19 trials of 15,490 patients). In addition to ORR odds ratio (OR), PFS hazard ratio (HR), and OS HR, we calculated the following trial-level milestone ratios: ORR within 6 month (m); PFS-9m; OS-9m and OS-12m. We performed weighted linear regression analyses (weight equal to the number of patients in each trial) for HR versus milestone ratios on the log scale and calculated coefficients of determination (R-sq). Results: (See Table.) Conclusions: On a trial level, this exploratory analysis of milestone ratios suggests moderate associations between OS milestone at 12 months and OS HR, and between ORR within 6 months and PFS HR. In our current database, some patients were censored before the milestone, potentially impacting the robustness of milestone rate estimates. A limitation of milestone analyses is that the totality of the survival curves is not considered. Nevertheless, further exploration of optimal timepoints to conduct milestone analyses and long-term follow up of patients is warranted to explore whether milestone rate may serve as an intermediate endpoint in mNSCLC trials. Comparison R-sq PFS HR vs PFS-9m RR 0.06 OS HR vs OS-9m RR 0.45 OS HR vs OS-12m RR 0.65 PFS HR vs ORR-6m OR 0.75 OS HR vs ORR-6m OR 0.01 RR=Risk Ratio; OR=Odds Ratio
Comparison of comorbidity to socioeconomic status in patients with non-small cell lung cancer in a safety net population.
Authors: Kristen Marie Strasser, Daulath Singh, Jonah Graves, Jill A. Moormeier
Journal: Journal of Clinical Oncology (2016)

e18070 Background: We have previously studied survival rates of patients in our inner city hospital with non-small cell lung cancer and have found poorer outcomes in our population when compared to national averages. We studied comorbidities and socioeconomic data for our patients to determine which is more prognostic, hypothesizing that the burden of comorbidity and socioeconomic challenges in our patient population substantially contributed to their adverse outcomes. Methods: We used retrospective medical record chart review of patients with NSCLC diagnosed at Truman Medical Center between 1995-2009. We collected comorbidity data using the ACE-27 index. To estimate our patients’ socioeconomic status, we used the 2010 census tract data to estimate median household income. Descriptive statistics were used to characterize the morbidity burden of our patient population. The primary outcome measured was the association between comorbidity index, estimated socioeconomic status, and lung cancer survival. Secondary outcomes were the association between these two predictive factors and cancer stage at presentation as well as treatment received. Associations were analyzed using Cox Regression Model Results: The comorbidity statistics, utilizing the ACE-27 index, showed that 12.2% of patients had a score of 0, 36.2% had a score of 1, 16.3% scored 2, and 35.4% of patients scored 3. Geocoding analysis showed an annual median household income of $27,524.50. Cox regression analysis showed that neither median household income nor ACE-27 score significantly impacted overall survival. Variables that did affect overall survival with statistical significance were stage at diagnosis (p = 0.000), gender (p = 0.005), and age at diagnosis (p = 0.014). Conclusions: Our results did not support our hypothesis that socioeconomic status and comorbidities significantly influence survival in our patients. Instead, statistical significant variables in survival were higher stage, gender (male) and higher age at diagnosis.
P01.084 Re-irradiation in recurrent glioblastoma: proton therapy with or without chemotherapy
Authors: D Amelio, D Scartoni, P Farace, L Widesott, S Vennarini, F Fellin, S Brugnara, R Pagone, M Schwarz, M Amichetti
Journal: Neuro-Oncology (2018)

To report preliminary results of re-irradiation with proton therapy (PT) with or without chemotherapy (CHT) in difficult-to-treat recurrent glioblastoma (rGBM): patients (pts) were selected for PT because of the large tumor size or proximity to dose-limiting organs at risk that previously had received near-maximum dose tolerance during the first radiation course Between January 2015 and January 2018, 34 pts with rGBM were re-irradiated with PT. All pts had been previously treated with Stupp regimen. Twenty-nine (85%) were re-irradiated at first relapse/progression, 5 at the second/third one. Nine pts (26%) were re-irradiated after partial tumor resection. Median (med) age and KPS at re-irradiation were 56 years and 90%, respectively. Med time between prior radiotherapy and PT was 13 months. Target definition was based on CT, MR, and 18F-DOPA PET imaging. Gross Tumor Volume (GTV) included any area of contrast enhancement after contrast medium administration plus any pathological PET uptake regions. Clinical Target Volume (CTV) was generated by adding to GTV a 3-mm margin. Med CTV volume was 47 cc (range, 13–153 cc). All pts received 36 GyRBE in 18 fractions. PT was delivered with or without chemotherapy as follows: eight (23.5%) pts (Group 1) also received concomitant TMZ (75 mg/m2/die, 7 days/week); 4 (12%) pts (Group 2) also received concomitant (as above) and adjuvant TMZ (150–200 mg/m2/die, 5 days/month); 9 (26.5%) pts (Group 3) received PT only; 13 (38%) pts (Group 4) received PT followed by CHT (different regimens/drugs). All pts were treated with active pencil beam scanning PT. Registered side effects were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment response was assessed according to Response Assessment in Neuro-Oncology criteria. Survival and progression-free survival after re-irradiation were calculated from initiation of PT until tumor progression or death (by any cause), using the Kaplan Meier method All pts completed the treatment without breaks. There were no grade 3 or higher acute toxicities. One pts developed TMZ-related grade 1 neutropenia. There were no grade 3 or higher late toxicities. During follow-up five pts (15%) developed radionecrosis (diagnosed at imaging) with mild symptoms controlled with steroids. The med progression-free survival (PFS) was 6.3 months, while 6-month PFS rate was 60%. The med PFS was 6.8, 4.3, 5.4, and 5.5 for Group 1-2-3-4, respectively. Med overall survival (OS) after PT was 10.7 months PT re-irradiation of difficult-to-treat rGBM showed to be feasible and safe even with concomitant and adjuvant chemotherapy administration. Despite the small number of patients of this series and the retrospective nature of the study PFS and OS rates are promising and deserve further evaluation in a larger pts sample to assess the most effective strategy
Actionable targets involving FGF receptors in gliomas: Molecular specificities, spatial distribution, clinical outcome and radiological phenotype.
Authors: Anna Luisa Di Stefano, Alberto Picca, Edouard Saragoussi, Giulia Berzero, Agusti Alentorn, Mehdi Touat, Francois Ducray, Chiara Villa, Elena Trisolini, Yohann Schmitt, Ahmed Idbaih, Khe Hoang-Xuan, Jean-Yves Delattre, Anna Lasorella, Antonio Iavarone, Karima Mokhtari, Julien Savatovsky, Franck Bielle, Marc Sanson
Journal: Journal of Clinical Oncology (2018)

2005 Background: to characterize clinical, molecular and radiological features of diffuse gliomas with FGFR3-TACC3 fusions or FGFR1 mutations, which are both actionable with new oral anti-FGFR inhibitors. Methods: We screened for FGFR3-TACC3 fusions 1112 gliomas (861 grade IV, 140 grade III and 111 grade II) by RT-PCR. We performed sequencing for hotspot FGFR1 mutations (N546 and K656) in 73 midline gliomas (8 grade II, 10 grade III, 54 grade IV, affecting cerebellum, spinal cord, brainstem, thalamus and diencephalon) and 479 hemispheric gliomas (170 grade IV, 151 grade III, 157 grade II). Results: We identified 50 gliomas (all IDH wild-type) with FGFR3-TACC3 fusion (45 grade IV, 2 grade III and 3 grade II). FGFR3-TACC3 fusion was mutually exclusive with EGFR amplification (p = 0.000) and co-occured with CDK4 and MDM2 amplifications (p = 0.011 and p = 0.005). FGFR3-TACC3 positive glioblastoma patients had a longer median overall survival (OS) (40.1 months versus 19.0; p = 0.006). Multivariate analysis showed that FGFR3-TACC3 fusion is an independent predictor of better outcome for glioblastoma patients. Paired case-control analysis on pre-operative Magnetic Resonance Imaging MRI (24 FGFR3-TACC3 positive cases and 48 controls) by the VASARI vocabulary and sparse canonical correlation showed that FGFR3-TACC3 gene fusions have specific radiological features, are constantly unifocal and involve specifically cortico-subcortical regions. We identified recurrent FGFR1 mutations in 13 out of 73 midline gliomas with diverse locations and in only one hemispheric glioma with corpus callosum involvement. FGFR1 mutations occurred in both K27M mutated and K27wild-type and were constantly IDH wild-type. FGFR1 mutations tended to be associated with younger age (p = 0.06) and ATRX loss (p = 0.05) and was an independent predictor of better outcome (median OS 45.0 months versus 13.8 months, p = 0.01). Conclusions: gliomas with FGFR3-TACC3 gene fusions and FGFR1 mutations represent two specific entities with distinct anatomical, clinical and molecular features . They should be recognized because both alterations are eligible for currently ongoing anti-FGFR clinical trials.