tbuckley/cabot-search huggingface dataset:
NSABP FC-9: Phase II study of dual immune checkpoint blockade (ICB) with durvalumab (D) plus tremelimumab (T) following palliative hypofractionated radiotherapy (SBRT) in patients (pts) with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) progressing on chemotherapy.
Authors: James J. Lee, Greg Yothers, Thomas J. George, Marwan Fakih, Atrayee Basu Mallick, Bassam Nabih Maalouf, John C. Krauss, Dwight Earl Heron, Carmen Joseph Allegra, Samuel A. Jacobs
Journal: Journal of Clinical Oncology (2018)

e15681 Background: Monotherapy with ICB has not been effective in MSS mCRC. Preclinical data demonstrated that immunomodulators synergize with radiotherapy (RT) resulting in tumor regression at irradiated sites and rarely at non-irradiated sites. Anecdotal reports in pts have confirmed an abscopal effect of RT and ICB. This phase II, open-label, single-arm study tests dual ICBs following SBRT in pts with MSS mCRC who have progressed on chemotherapy. Preliminary efficacy and safety results of the NSABP FC-9 will be reported. Methods: Eligible pts have MSS mCRC and progressed on prior oxaliplatin and irinotecan-based regimens, measurable lesions with at least one amenable to SBRT and another for core biopsy, and performance status ECOG < 2. Following 3 doses of SBRT at 9 Gy (D −2, −1, and D 0 prior to Cycle 1), pts received the combination of T (75 mg IV infusion) and D (1500 mg IV infusion) on D 1 of Cycles 1-4. Beginning with Cycle 5 -Cycle 12, pts received D alone on D 1 q 28d. Tumor response at non-irradiated target lesions was measured at baseline and every 2 cycles using RECIST 1.1. Toxicity was graded according to the NCI CTCAE v 4.0. Sample size will be between 12 and 21 evaluable pts with a Simon two-stage design. Primary aim is to determine objective response rate (ORR). Secondary objectives are clinical benefit rate, duration of response, tolerability, and correlates of response. Results: The trial has opened at six academic centers. Between October 2017 and January 31, 2018, 14 pts were enrolled in the first stage; two pts were not evaluable and were replaced. Median age is 58 yrs (range, 37-71). Without regard to attribution, there were 5 grade 3 toxicities: anemia 1, fatigue 1, dehydration 1, peripheral neuropathy 1, and thromboembolism 1. There were no grade 4 or 5 toxicities. Response data will be presented. Conclusions: To date, no unexpected toxicities have been observed with SBRT followed by dual ICB. We will report the response observations in the first stage of this phase II trial. Support: Astra-Zeneca Clinical trial information: NCT03007407.
Effectiveness of EGFR-tyrosine kinase inhibitors (TKI) versus EGFR-TKIs plus talc pleurodesis in preventing recurrence of malignant pleural effusion (MPE) in advanced lung adenocarcinoma.
Authors: Akash Verma, Akhil Chopra, John Abisheganaden
Journal: Journal of Clinical Oncology (2016)

e21684 Background: Approximately 15% of patients have pleural effusion at the initial diagnosis of advanced lung cancer. The best treatment approach to prevent re-accumulation of symptomatic MPE after initial thoracentesis remains unclear; especially in EGFR Mutation positive advanced lung cancer patients. Methods: An observational cohort study of 70 patients hospitalized with lung adenocarcinoma and MPE in the year 2012 was conducted. Treatment approach to the MPE after initial thoracentesis (including use of talc pleurodesis) was assessed and time to recurrence of MPE, if any was recorded. Results: Among patients with EGFR mutation positive lung cancer receiving TKI as first line therapy (n = 34), those with pleurodesis (n = 14) and those without pleurodesis (n = 20) showed similar effusion-recurrence-free survival after initial drainage, 9.9 vs. 11.7 months, p = 0.80 respectively. In the entire cohort, effusion-recurrence-free survival was 3.2 vs. 3.9 months in no-pleurodesis and pleurodesis group respectively using talc as the sclerosing agent. Effusion-recurrence-free survival was significantly longer in EGFR positive group(10.8 months) treated with TKIs vs. 1.8 month in EGFR negative group (p = 0.006). More patients (n = 10, 25.6%) with activating EGFR mutation presented with complete opacification (white-out) of the hemithorax compared to none without activating EGFR mutation (p = 0.02) Conclusions: In lung adenocarcinomas presenting with symptomatic MPE, use of EGFR-TKI alone was associated with the longest effusion-recurrence-free survival. In TKI eligible patients, early talc pleurodesis confers no additional benefit and should be reserved for non-adenocarcinoma histology, wild type EGFR or EGFR negative adenocarcinoma.
Safety and efficacy of buparlisib (BKM120) and chemotherapy in advanced, squamous non-small cell lung cancer (sqNSCLC): Results from the phase Ib/II BASALT-2 and BASALT-3 studies.
Authors: Alex A. Adjei, Jaafar Bennouna, Natasha B. Leighl, Enriqueta Felip, Diego Luigi Cortinovis, Juergen Alt, Eric Scott Schaefer, Michael Thomas, Christos Chouaid, Alessandro Morabito, Javier De Castro, Francesco Grossi, Luis Paz-Ares, Tommaso Martino De Pas, Joan Maier, Arunava Chakravartty, Marie Chol, Paola Aimone, David Planchard
Journal: Journal of Clinical Oncology (2016)

e20522 Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation may contribute to primary and secondary resistance to platinum (Pt)-based chemotherapy (CT) in sqNSCLC. The pan-PI3K inhibitor buparlisib (BUP) was assessed for first-line (BASALT2; NCT01820325) or second-line (BASALT-3; NCT01911325) treatment of sqNSCLC. Methods: BASALT-2 and BASALT-3 were phase Ib/II trials designed to establish the maximum tolerated dose (MTD) of BUP and CT (in phase Ib). In BASALT-2, patients (pts) with untreated Stage IV sqNSCLC received BUP 80 mg/day (continuous or intermittent [5 days on/2 days off] schedules in 21-day cycles) with 3-weekly carboplatin (CBP) AUC = 6 and paclitaxel (PAC) 200 mg/m2. In BASALT-3, pts with Stage IIIb/IV sqNSCLC pretreated with one Pt-based CT received BUP 80 or 100 mg/day with 3-weekly docetaxel (DOC) 75 mg/m2. Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. MTD was based on dose-limiting toxicities (DLTs) reported in Cycle 1. Results: In BASALT-2, 6 pts received BUP 80 mg (continuous [n = 5] or intermittent [n = 1]). Median age was 69 years and 50% of pts were male. Of 3 evaluable pts, 2 had DLTs of Grade (Gr) 3 stomatitis and Gr4 neutropenia (n = 1 each). One pt had a partial response (PR) and 3 had stable disease (SD). The most common primary reason for treatment discontinuation was pt decision (n = 3). MTD for BUP + CBP + PAC was not determined due to early study closure. In BASALT-3, 27 pts received BUP 80 mg (n = 16) or 100 mg (n = 11). Median age was 65 years and 89% of pts were male. DLTs were Gr3 asthenia (n = 1) and Gr2 mood altered (n = 1) at 80 mg; and Gr4 neutropenia (n = 1) and Gr2 and Gr3 hyperglycemia (n = 1 each) at 100 mg. MTD was declared as BUP 80 mg + DOC. Median progression-free survival was 2.8 months at both dose levels. Overall response rate (complete response + PR) was 6% at 80 mg and 18% at 100 mg. All pts discontinued treatment, most frequently due to disease progression (38% of pts at 80 mg and 36% at 100 mg). Conclusions: Based on the challenging safety profile observed in both studies, as well as the evolving treatment landscape, buparlisib will not be further developed in lung cancer. Clinical trial information: NCT01820325; NCT01911325.
A phase II prospective study about the efficacy and toxicity of the locally advanced NPC patients treated with CCRT followed with metronomic chemotherapy.
Authors: Mei Feng, Yuan Gao, Jinyi Lang, Binyu Fu
Journal: Journal of Clinical Oncology (2018)

e18023 Background: The CCRT is the standard treatment modality for NPC, however the adjuvant chemotherapy is still controversial. Metronomic chemotherapy is a new dosing modality which is in low-dosages with high frequency and continuous administration. We aimed to preliminary evaluate the possible efficacy and toxicity in locally advanced NPC patients treated with CCRT followed with the capecitabine metronomic chemotherapy. Methods: 67 III-IV stage (UICC 8th) locally advanced NPC were included. All the patients received definitive CCRT followed with the capecitabine metronomic chemotherapy. For the control group, we selected 75 patients treated with definitive CCRT. 2-3 cycles of cisplatin-based chemotherapy and 3 cycles of capecitabine (750mg/m2, bid) was used. Results: The median follow-up time was 24 months. The 2-year OS and LC were similar. Compared with the control group, the 2-year DMFS and PFS were improved in the observation group (94.9%, 89.5%; 89%, 85.3%). However, there was no statistical difference about the survival rate. For the acute toxicities, the incidence of grade 1-2 and grade 3-4 neutropenia in observational and control group were 50.7%, 58.6% and 10.4%, 8%, that of thrombocytopenia were 22.4%, 25.3% and 6%,5.3%, and that of oral mucous reaction were 65.7%,61.3% and 17.9%,20% respectively. For the late toxicities, the incidence of grade 1-2 and grade 3-4 xerostomia were 56.7% 54.7% and 3%, 1.3% in the observational and control group respectively; and that of hearing impairment were 41.8%, 38.7% and 0%, 1.3%. In addition, for the specific toxicity, the toxicities were all grade 1-2. The incidence of limb numbness, rash, neuropathic headache and anaphylaxis were 32.8%, 28.3%, 17.9% and 3.0%. There was no significant difference about the toxicities between two groups (P > 0.05). Conclusions: The CCRT followed with the capecitabine metronomic chemotherapy was a promising modality for locally advanced NPC patients. The 2-year DMFS and PFS was improved compared, and the acute and late toxicity were all tolerable. The more and long follow-up studies should be carried out in the future.
Contemporary approaches for identifying individual risk for periodontitis
Authors: Kenneth S. Kornman
Journal: Periodontology 2000 (2018)

Key breakthroughs in our understanding of the etiology and principles of predictable treatment of patients with chronic periodontitis first emerged in the late 1960s and carried on into the mid-1980s. Unfortunately, some generalizations of the evidence led many to believe that periodontitis was a predictable result of exposure to bacterial plaque accumulations over time. For a brief period, the initial plaque concept was translated by some to implicate specific bacterial infections, with both concepts (plaque exposure and specific infection) being false assumptions that led to clinical outcomes which were frustrating to both the clinician and the patient. The primary misconceptions were that every individual was equally susceptible to periodontitis, that disease severity was a simple function of magnitude of bacterial exposure over time, and that all patients would respond predictably if treated based on the key principles of bacterial reduction and regular maintenance care. We now know that although bacteria are an essential initiating factor, the clinical severity of periodontitis is a complex multifactorial host response to the microbial challenge. The complexity comes from the permutations of different factors that may interact to alter a single individual's host response to challenge, inflammation resolution and repair, and overall outcome to therapy. Fortunately, although there are many permutations that may influence host response and repair, the pathophysiology of chronic periodontitis is generally limited to mild periodontitis with isolated moderate disease in most individuals. However, approximately 20%-25% of individuals will develop generalized severe periodontitis and probably require more intensive bacterial reduction and different approaches to host modulation of the inflammatory outcomes. This latter group may also have serious systemic implications of their periodontitis. The time appears to be appropriate to use what we know and currently understand to change our approach to clinical care. Our goal would be to increase our likelihood of identifying those patients who have a more biologically disruptive response combined with a more impactful microbial dysbiosis. Current evidence, albeit limited, indicates that for those individuals we should prevent and treat more intensively. This paper discusses what we know and how we might use that information to start individualizing risk and treat some of our patients in a more targeted manner. In my opinion, we are further along than many realize, but we have a great lack of prospective clinical evidence that must be accumulated while we continue to unravel the contributions of specific mechanisms.
Multimodal Meta-Analysis of 1,494 Hepatocellular Carcinoma Samples Reveals Significant Impact of Consensus Driver Genes on Phenotypes
Authors: Kumardeep Chaudhary, Olivier B. Poirion, Liangqun Lu, Sijia Huang, Travers Ching, Lana X. Garmire
Journal: Clinical Cancer Research (2018)

Abstract Although driver genes in hepatocellular carcinoma (HCC) have been investigated in various previous genetic studies, prevalence of key driver genes among heterogeneous populations is unknown. Moreover, the phenotypic associations of these driver genes are poorly understood. This report aims to reveal the phenotypic impacts of a group of consensus driver genes in HCC. We used MutSigCV and OncodriveFM modules implemented in the IntOGen pipeline to identify consensus driver genes across six HCC cohorts comprising 1,494 samples in total. To access their global impacts, we used The Cancer Genome Atlas (TCGA) mutations and copy-number variations to predict the transcriptomics data, under generalized linear models. We further investigated the associations of the consensus driver genes to patient survival, age, gender, race, and risk factors. We identify 10 consensus driver genes across six HCC cohorts in total. Integrative analysis of driver mutations, copy-number variations, and transcriptomic data reveals that these consensus driver mutations and their copy-number variations are associated with a majority (62.5%) of the mRNA transcriptome but only a small fraction (8.9%) of miRNAs. Genes associated with TP53, CTNNB1, and ARID1A mutations contribute to the tripod of most densely connected pathway clusters. These driver genes are significantly associated with patients' overall survival. Some driver genes are significantly linked to HCC gender (CTNNB1, ALB, TP53, and AXIN1), race (TP53 and CDKN2A), and age (RB1) disparities. This study prioritizes a group of consensus drivers in HCC, which collectively show vast impacts on the phenotypes. These driver genes may warrant as valuable therapeutic targets of HCC.
A new method for gene expression analysis of pure lymphocytes recovered from heterogeneous fixed mouse tissue.
Authors: Jennifer Chow, Ana Paula Galvão Da Silva, Gianni Medoro, Nicolò Manaresi, Paul David Lira, Farideh Z. Bischoff
Journal: Journal of Clinical Oncology (2017)

e23089 Background: Tumor infiltrating lymphocytes (TILs) are biomarkers that play a critical role in cancer diseases, including differential diagnosis, determination of prognosis, prediction of response to treatment, and evaluation of disease progression. Gene expression analysis in TILs derived from fresh tissue may not accurately depict the gene profile of the tissue microenvironment as it can change aggressively during lymphocyte isolation and RNA extraction. In addition, tissue sample size can limit the isolation of TILs with current technologies. In this study, we demonstrate the use of the DEPArray™platform to isolate pure populations of lymphocytes from a fixed mouse tissue for RNA analysi. Methods: Mouse splenocytes were activated in vitro with anti-CD3 and -CD28 for 72hs. Cells were harvested, fixed with 2% paraformaldehyde (PFA) for 20 min at RT, and stained for either CD4 or CD8 expression. Gene expression analysis of CD45, ADORA2A, GLS and GAPDH was performed in CD4+ and CD8+ DEPArray™sorted cells using the TaqMan PreAmp Cells-to-Ct kit. Results: The table below summarizes the Ct values for CD45, ADORA2A, GLS and GAPDH expression in 300 fixed unsorted control and DEPArray™sorted lymphocytes. Conclusions: We have demonstrated the feasibility of gene expression analysis on pure populations of CD4+ and CD8+ cells isolated from a fixed tissue using the DEPArray™ platform. The advantage of this approach is the DEPArray’s ability to identify and isolate subpopulations of cells from complex heterogeneous samples and/or specimens that are limited by size or content. This methodology will be applied for isolation of TILs in syngeneic and xenograft models of cancers for downstream RNA applications. [Table: see text]
P05.24 The diagnosis and comprehensive treatment of leptomeningeal metastases--results of a phase II trial
Authors: Y Ma, J Xiao, S Yang, R Zhao, H Zhang, Y Xu, Y Tian, N Bi, Q Liu, X Chen, J Yi, Y Li
Journal: Neuro-Oncology (2018)

A prospective phase II trial was conducted to investigate the diagnosis of leptomeningeal metastases (LMs) and clinical outcomes of comprehensive treatment. Patients who were clinically suspected to have LMs and received comprehensive treatment based on Tomotherapy were enrolled. Whole brain radiotherapy (WBRT) with or without simultaneously boost to LM or craniospinal irradiation (CSI) was given to them. The diagnosis and response were assessed by the results of enhanced MRI, clinical symptoms and signs, cerebrospinal fluid (CSF) cytology, liquid biopsy and liquid genomics detection. The primary endpoint was local control (LC), and the secondary endpoints were intracranial progression-free survival (IPFS) and overall survival (OS). From 2014 to 2017, 88 patients were enrolled (Male: Female=36:52), and the median age was 55 years old (range, 29–81). The major primary diagnosis was NSCLC (64.8%). Typical clinical signs included cerebral (70.5%), cranial nerve palsies (30.7%), and spinal complaints (33.0%). 20.5% of patients showed no obvious symptoms. MRI findings before treatment included 4 types: multiple brain metastases (BMs) with focal LMs, large BMs invaded meningeal, extensive LMs and LMs proved by clinical symptoms or CSF without changes in MRI. The lesions appeared as nodular (67.1%), linear enhancement (18.2%), both (10.2%), or narrowing brain fold without other appearance (4.5%). MRI changes after radiation mainly included decreased lesions and weakened enhancement (65.9%), increased and strengthened followed by decreased lesions and weakened enhancement (18.2%), and increased lesions and strengthened enhancement but with cystic change (5.7%). 9 patients were diagnosed with distinct spinal cord metastases. 31 patients received lumbar puncture, and CSF cytology mainly showed increased leukocyte counts (64.5%), evaluated protein (54.8%) and decreased glucose (51.6%). Tumor cells were found in 19 patients, who were administrated intrathecal chemotherapy (mostly methotrexate; the median cycles were 4), in which 9 turned to be negative. 4 patients received CSF genetic testing and 2 had mutation.Patients received WBRT with boost (40 Gy in 20 fractions (f) for WBRT and 60 Gy in 20 f for boost; 64.8%), focal radiation to LMs (26.2%), WBRT and CSI (50 Gy in 25 f for WBRT and 36 Gy in 20 f for CSI; 9.1%). Response rates of CR, PR and SD were 5.7%, 71.6% and 13.6%, respectively. The median follow-up and survival time was 13.5 and 17.6 months, respectively. The 1-year LC, IPFS and OS was 75.2%, 52.9%, and 71.3%, respectively. Neuroimaging, clinical signs and CSF findings may be prior inspection items for diagnosis of LMs. Early detection with reasonable comprehensive treatment including precise radiotherapy, intrathecal chemotherapy and targeted agents can improve local control and survival time of these patients.
Comprehensive genomic profiling of acral and mucosal melanomas to support clinical decision making.
Authors: Anthony Classon, Kasey Couts, Laurie M. Gay, Bahar Yilmazel, Caitlin Patriquin, Allison Applegate, Keith Ryan Wells, Jacqueline Turner, Siraj Mahamed Ali, Adam Benson, Vincent A. Miller, Jeffrey S. Ross, Tariq I. Mughal, William Robinson
Journal: Journal of Clinical Oncology (2018)

e21629 Background: Melanomas are heterogenous tumors that develop on many skin regions and harbor diverse genomic alterations (GA). Lesion subtypes are identifiable by location and/or genomic profile. Cutaneous melanomas (CT) form largely on sun-damaged skin, and often have BRAFV600 and TERT promoter mutations. Acral (AC) or mucosal (MC) melanomas frequently display mutations in RAS, predominantly NRAS, or KIT but their genomic landscape is currently incompletely understood and few therapeutic options are available. Methods: Oncogenic GA detected by hybrid-capture next-generation-sequencing (NGS) of exons from 315 and select introns from 28 cancer-related genes (for 28 specimens, RNA of 265 genes and DNA with a different set of exons from 406 and select introns of 31 genes). DNA from formalin-fixed, paraffin-embedded specimens was evaluated for microsatellite instability (MSI), tumor mutational burden (TMB), and GA (substitution, insertions/deletions, copy number alterations, and rearrangements). Genomic profiles were created for 80 adult patient (pt) melanomas, including 44 AC/MC melanomas. Associations between mutational profile, clinical phenotype, signaling pathways and targeted therapies were assessed; high TMB (≥20 mut/Mb) indicated potential for immune check-point inhibitors. Results: AC and MC melanoma subtypes most often harbored RAS hotspot driver mutations (e.g., G12, G13, and Q61). TMB varied significantly between AC/MC and CT subtypes (p < 10-3). Driver-negative AC/ MC exhibit significant copy number amplification (AMP) of cell-cycle regulatory genes and GAs in the PI3K or DNA damage repair pathway, including BRCA2. Mucosal specimens have a higher proportion of mutations than their acral counterparts (p < 0.029). Conclusions: Acral and mucosal melanomas have targetable genomic features that warrant further assessment. GAs in pathways affecting CDK kinases, PARPi sensitivity, PI3K, and pre-mRNA splicing machinery offer potential therapeutic modalities. Acral Mucosal Cutaneous Unknown Primary Samples, n 21 23 23 13 Median TMB 3.26 5.26 11.85 N/A GA: BRAF/NRAS 9 8 20 7 KIT 2 4 1 0 SF3B1 1 7 0 0 Cell-cycle AMPs 6 5 2 1 PI3K pathway 4 5 6 2 DNA Damage 8 16 10 7