tbuckley/cabot-search huggingface dataset:
Frequent allelic imbalance in <i>NRAS</i> mutant melanomas.
Authors: Zofia Hélias-Rodzewicz, Elisa Funck-Brentano, Ute Zimmermann, Nathalie Terrones, Philippe Saiag, Jean-François Emile
Journal: Journal of Clinical Oncology (2016)

9578 Background: We recently showed that 19% of BRAF mutant melanomas have an increased mutant allele percentage ( > 60%) (BMC Cancer 2015). This allelic imbalance was mainly related to a polysomy of chromosome 7. We investigated the percentage of NRAS mutant allele in BRAFwild type (WT) melanomas. Methods: We searched for NRAS Q61 mutation by pyrosequencing method in 216 FFPE samples of cutaneous melanomas WT for BRAFV600. FISH was performed with probes specific for NRAS (RP11-245I3) and 1p34.1 (RP11-269F19) on 105 cases NRAS WT (n = 42), or NRAS mutant with equilibrate (E%, n = 43) and high (H%, n = 20) mutant allele percentage. Loss of Heterozygoty (LOH) was evaluated with 8 microsatellite (MS) markers (3 localized near NRAS, 3 at 1p and 2 at 1q) on 17 samples (E% n = 8 or H% n = 9). Pathological data of 73 NRASmutant melanomas, clinical characteristics and survival data of matching patients were analyzed. Results: NRAS mutation was detected in 109 (50.5%) of BRAF WT samples, of which 31 (34%) were H%. Allelic NRAS imbalance was observed in all mutation types: Q61R (n = 22), Q61K (n = 6), Q61L (n = 2) and Q61H (n = 1). Chromosome 1 disomy, disomy with rare polysomic cells and polysomy were observed in 24% (24% WT vs 24% mutant NRAS), in 24% (33% WT vs 18% mutant NRAS) and in 12% (3% WT vs 18% mutant NRAS) of samples, respectively. NRAS amplification and monosomy of chromosome 1 were rare aberrations in both groups (3.4% and 4.6%, respectively). Intra-tumor heterogeneity concerning chromosome 1 was defined as monosomic or polysomic cells (or both) accompanying disomic tumor cells. Heterogeneity was observed in 24% WT and 35% mutant NRAS samples (P < 0.01), and was more frequent in H% than E% mutant NRAS (47% vs 29.7%). MS analysis revealed no LOH in 8 E%, while LOH was present in 9 H% NRAS samples. No differences were observed between E% and H% NRAS mutant melanomas for clinic, histology and survival data. Conclusions: Allelic imbalance is more frequent in NRAS than in BRAF mutant melanomas (34% versus 19% of H%, P < 0.01). Amplification was rare in NRAS, as shown in BRAF mutant melanomas. NRAS mutant melanomas had high intra-tumor heterogeneity. Allelic imbalance of H% NRAS was closely related to LOH.
Differentiation of low grade from high grade clear cell renal cell carcinoma neoplasms using a CAD algorithm on four-phase CT.
Authors: Heidi Coy, Michael Douek, Jonathan Young, Matthew S. Brown, Jonathan Goldin, James Sayre, Steven Raman
Journal: Journal of Clinical Oncology (2016)

4564 Background: Up to 70% of renal masses are found incidentally on imaging. Pretreatment percutaneous biopsy is commonly used to diagnose tumor grade. A non-invasive method to assess grade on imaging would be of clinical value, especially in characterization of clear cell renal cell carcinoma (ccRCC), the most common subtype with the highest metastatic potential. In addition, patients with different Fuhrman tumor grades have a different prognosis and therapeutic pathway. The purpose of our study was to differentiate low grade from high grade ccRCC tumors using a CAD algorithm on four-phase CT. Methods: With IRB approval for this HIPAA-compliant retrospective study, our pathology and imaging databases were queried to obtain a cohort of histologically proven ccRCC with preoperative CT imaged with a four-phase renal mass protocol. A whole lesion 3D contour was obtained in all phases with proprietary software. The CAD algorithm determined a circular ROI with a 0.5cm diameter region of peak lesion enhancement ≤ 300HU within the 3D lesion contour. All contours were confirmed by a genitourinary radiologist. A model was derived using logistical regression with CAD derived peak lesion enhancement from all four phases, %wash-in and %wash-out of tumor enhancement, and tumor size as input. Discrimination was evaluated using receiver operator characteristic (ROC) curves. Results: 112 patients (64% men, 36% women) with 118 unique ccRCCs were analyzed. In the low grade cohort, there were 83 (70%) lesions (Fuhrman grade 1 = 17, Fuhrman grade II = 66), and 35 (30%) lesions in the high grade cohort (Fuhrman grade III = 27, Fuhrman grade IV = 8). Mean low grade lesion size was 2.85 cm (range = 0.8-11.1) and mean high grade lesion size was 6.35 cm (range 1.0-14.7). The model demonstrated discriminatory power in predicting low grade from high grade ccRCC lesions with an area under the curve of 0.765 (0.667-0.893 95% CI). Conclusions: Differentiation of Fuhrman grades on imaging can aid the clinician in stratifying patients to the appropriate therapeutic pathway, and assist in determining which patients can undergo watchful waiting, surgical intervention, or which may be candidates for clinical trials.
Resident memory T cells, critical components in tumor immunology
Authors: Fathia Mami-Chouaib, Charlotte Blanc, Stéphanie Corgnac, Sophie Hans, Ines Malenica, Clémence Granier, Isabelle Tihy, Eric Tartour
Journal: Journal for ImmunoTherapy of Cancer (2018)

CD8<sup>+</sup> T lymphocytes are the major anti-tumor effector cells. Most cancer immunotherapeutic approaches seek to amplify cytotoxic T lymphocytes (CTL) specific to malignant cells. A recently identified subpopulation of memory CD8<sup>+</sup> T cells, named tissue-resident memory T (T<sub>RM</sub>)&nbsp;cells, persists in peripheral tissues and does not recirculate. This T-cell subset is considered an independent memory T-cell lineage with a specific profile of transcription factors, including Runx3<sup>+</sup>, Notch<sup>+</sup>, Hobit<sup>+</sup>, Blimp1<sup>+</sup>, BATF<sup>+</sup>, AHR<sup>+</sup>, EOMES<sup>neg</sup> and Tbet<sup>low</sup>. It is defined by expression of CD103 (α<sub>E</sub>(CD103)β<sub>7</sub>) and CD49a (VLA-1 or α<sub>1</sub>β<sub>1</sub>) integrins and C-type lectin CD69, which are most likely involved in retention of T<sub>RM</sub> cells in non-lymphoid tissues, including solid tumors. CD103 binds to the epithelial cell marker E-cadherin, thereby favoring the location and retention of T<sub>RM</sub> in epithelial tumor regions in close contact with malignant cells. The CD103-E-cadherin interaction is required for polarized exocytosis of lytic granules, in particular, when ICAM-1 expression on cancer cells is missing, leading to target cell death. T<sub>RM</sub> cells also express high levels of granzyme B, IFNγ and TNFα, supporting their cytotoxic features. Moreover, the local route of immunization targeting tissue dendritic cells (DC), and the presence of environmental factors (i.e. TGF-β, IL-33 and IL-15), promote differentiation of this T-cell subtype. In both spontaneous tumor models and engrafted tumors, natural T<sub>RM</sub> cells or cancer-vaccine-induced T<sub>RM</sub> directly control tumor growth. In line with these results, T<sub>RM</sub> infiltration into various human cancers, including lung cancer, are correlated with better clinical outcome in both univariate and multivariate analyses independently of CD8<sup>+</sup> T cells. T<sub>RM</sub> cells also predominantly express checkpoint receptors such as PD-1, CTLA-4 and Tim-3. Blockade of PD-1 with neutralizing antibodies on T<sub>RM</sub> cells isolated from human lung cancer promotes cytolytic activity toward autologous tumor cells<i>.</i> Thus, T<sub>RM</sub> cells appear to represent important components in tumor immune surveillance. Their induction by cancer vaccines or other immunotherapeutic approaches may be critical for the success of these treatments. Several arguments, such as their close contact with tumor cells, dominant expression of checkpoint receptors and their recognition of cancer cells, strongly suggest that they may be involved in the success of immune checkpoint inhibitors in various cancers.
Phase I/II study of spartalizumab (PDR001), an anti-PD1 mAb, in patients with anaplastic thyroid cancer.
Authors: Lori J. Wirth, Ekkehard Eigendorff, Jaume Capdevila, Luis G. Paz-Ares, Chia-Chi Lin, Matthew H. Taylor, Rodryg Ramlau, Marcus Butler, Jean-Pierre Delord, Zsolt Horvath, Hans Gelderblom, Paolo A. Ascierto, Angelica Fasolo, Dagmar Führer, Hongqian Wu, Geraldine Bostel, Scott Cameron, Jason Edward Faris, Andrea I. Varga
Journal: Journal of Clinical Oncology (2018)

6024 Background: Spartalizumab, a humanized IgG4 mAb, binds programmed death-1 (PD-1) with subnanomolar affinity and blocks interaction with PD-L1/PD-L2. Anaplastic thyroid cancer (ATC) is an aggressive tumor, with nearly 100% disease-specific mortality (NCCN Guidelines 2018) and few treatment options. Methods: This Phase I/II, open-label, dose escalation/expansion study (NCT02404441) characterized the safety and efficacy of spartalizumab in patients (pts) with advanced solid tumors. The recommended Phase II dose was 400 mg once every 4 weeks (Q4W). Results: During the dose escalation phase of the study, a patient with ATC treated at 3 mg/kg Q2W experienced a mixed response with overall stable disease (SD) for 7 months before developing progressive disease. Based on this encouraging patient, an expansion cohort was opened in ATC. At the safety cut-off of Nov 13, 2017, 26 pts with ATC had been treated in the spartalizumab 400 mg Q4W expansion group. The median age was 62 (46–79), 54% were men, and ECOG performance status was 0 (42%) or 1 (58%). 77% of pts had received prior treatment for ATC, with 19% of pts receiving ≥2 prior therapies. AEs suspected to be related to treatment ( > 5% of pts) were diarrhea, pruritus, and asthenia (8% each). G3/G4 AEs suspected to be related to treatment were anemia, hypophosphatemia, lymphopenia, and oncologic complication (inflammation around the tumor; 1 pt each). At the efficacy cut-off of Jan 23, 2018, 37 pts had been treated and 30 pts were evaluable for efficacy. The overall response rate (ORR) by RECIST 1.1 (confirmed + unconfirmed PRs) was 5/30 (17%), with four confirmed responses and one patient awaiting a confirmatory scan. At the efficacy cut-off, all responses were ongoing, and PFS and OS data were immature. The ORR by irRC was 6/30 (20%). Three additional pts had RECIST and/or irRC SD ongoing after 5, 5, and 12 months of treatment. The overall disease control rate was 8/30 (27%) by RECIST and 10/30 (33%) by irRC. Conclusions: Spartalizumab showed encouraging response rates, clinical benefit, and durability in pts with ATC, with no unexpected safety concerns. Clinical trial information: NCT02404441.
Agile research to complement agile development: a proposal for an mHealth research lifecycle
Authors: Kumanan Wilson, Cameron Bell, Lindsay Wilson, Holly Witteman
Journal: npj Digital Medicine (2018)

Mobile health (mHealth) technology is increasingly being used, but academic evaluations supporting its use are not keeping pace. This is partly due to the disconnect between the traditional pharmaceutical approach to product evaluation, with its incremental approach, and the flexible way in which mHealth products are developed. An important step to addressing these problems lies in establishing agile research methods that complement the agile development methodologies used to create modern digital health applications. We describe an mHealth research model that mirrors traditional clinical research methods in its attention to safety and efficacy, while also accommodating the rapid and iterative development and evaluation required to produce effective, evidence-based, and sustainable digital products. This approach consists of a project identification stage followed by four phases of clinical evaluation: Phase 1: User Experience Design, Development, & Alpha Testing; Phase 2: Beta testing; Phase 3: Clinical Trial Evaluation; and Phase 4: Post-Market Surveillance. These phases include sample gating questions and are adapted to accommodate the unique nature of digital product development.
Abstract A011: Hypoxia-inducible PIM kinase expression promotes resistance to antiangiogenic agents in prostate cancer
Authors: Andrea Casillas, Rachel Toth, Alva Sainz, Andrew S. Kraft, Noel A. Warfel
Journal: Cancer Research (2018)

Abstract Angiogenesis is known to play an important role in prostate cancer pathogenesis. Although the addition of VEGF-targeting agents (i.e., bevacizumab) to docetaxel improved response rates in mCRPC patients, it failed to improve overall survival. Patients can develop resistance to antiangiogenic drugs due to changes in the tumor microenvironment, including hypoxia. PIM kinases are prosurvival kinases whose expression is increased in hypoxia and advanced prostate cancer. The goal of this study was to determine whether targeting hypoxia-induced PIM kinase expression is effective in combination with VEGF-targeting agents. The rationale for this therapeutic approach is based on the fact that antiangiogenic drugs can make tumors hypoxic, and thus more sensitive to PIM inhibitors. We establish PIM kinase expression as a novel mechanism of resistance to antiangiogenic agents. Xenograft and orthotopic models of prostate cancer were used to assess the effect of PIM activation on the efficacy of VEGF-targeting agents. We show that PIM is upregulated following treatment with anti-VEGF therapies, and PIM expression reduces the ability of these drugs to effectively disrupt tumor vasculature. Combinatorial inhibition of PIM and VEGF produces a synergistic antitumor response that is characterized by enhanced cell death, growth arrest, decreased angiogenesis, and reduced metastasis. Mechanistically, small-molecule PIM inhibitors reduce HIF-1 activity, opposing a shift to the proangiogenic gene signature associated with hypoxia. Our data provide justification for combining PIM and VEGF inhibitors to treat advanced prostate cancer. Citation Format: Andrea Casillas, Rachel Toth, Alva Sainz, Andrew S. Kraft, Noel A. Warfel. Hypoxia-inducible PIM kinase expression promotes resistance to antiangiogenic agents in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A011.
Survival in the population-based Mid-South Quality of Surgical Resection (MSQSR) Cohort.
Authors: Matthew Smeltzer, Meredith Ray, Nicholas Ryan Faris, Meghan Brooke Meadows, Carrie Fehnel, Cheryl Houston-Harris, Philip Ojeabulu, Olawale Akinbobola, Yu-Sheng Lee, Lynn Wiggins, David Talton, Ed Owen, Lawrence Deese, Richard Eubanks, Bradley Aaron Wolf, Edward T Robbins, Raymond U. Osarogiagbon
Journal: Journal of Clinical Oncology (2018)

e20550 Background: Surgical resection is the main curative modality for non-small cell lung cancer (NSCLC), but surgical outcomes are often poor. We evaluated overall survival (OS) in patients before and after an organized quality improvement initiative in a population-based cohort from a high US lung cancer mortality region. Methods: The MSQSR cohort includes all NSCLC resections in 11 hospitals in 4 contiguous Dartmouth Hospital Referral Regions in AR, MS, and TN. We evaluated all NSCLC resections from 2004-2013, separated into eras before and after onset of a benchmarked performance feedback campaign to surgery and pathology teams in 2009. We compared patients from 2004-2009 (pre-era) with those from 2010-2013 (post-era). We evaluated OS with the Kaplan Meier method, log-rank test, and Cox models with unadjusted (HR) and fully adjusted hazard ratios (aHR) with 95% confidence intervals.aHR controlled for mediastinal lymph node (LN) sampling (Yes/No), margin status, eligibility for chemo and radiation therapy, total number LN sampled, age, pathologic stage, surgeon type, institution type, extent of resection, and tumor grade. OS updated in November 2017, for a median follow-up of 7.4 years in censored patients. Results: There were 2,261 patients: 56% pre-era and 44% post-era. Age, sex, race, and insurance were similar between eras. Preoperative PET/CT (82% v 47%, p < 0.0001), brain scans (21% v 6%, p < 0.0001), and bronchoscopy (26% v 8%, p < 0.0001), were more frequently used in the post-era. Patients in the pre-era had a 5-year OS of 48% (45%, 50%) compared to 53% (50%, 56%) in the post-era (p = 0.008). The pre-era had a HR of 1.17 (1.04, 1.31; p = 0.006) and an aHR of 1.14 (1.01, 1.30; p = 0.0363) compared to the post-era. aHR for era differed significantly based on the extent of resection (0.0072). Compared to post-era, the pre-era aHR was 2.1 (1.4, 3.0) in pneumonectomy, 1.1 (0.81, 1.4) in lobectomy/bilobectomy, and 1.1 (0.81, 1.43) in segmentectomy/wedge resections. Conclusions: OS after surgical resection has improved significantly in a high lung cancer mortality region of the US. Contributing factors may include quality improvement initiatives, more thorough pre-operative staging, and better selection of patients for pneumonectomy.
5-year survival outcomes in patients (pts) with advanced melanoma treated with pembrolizumab (pembro) in KEYNOTE-001.
Authors: Omid Hamid, Caroline Robert, Adil Daud, F. Stephen Hodi, Wen-Jen Hwu, Richard Kefford, Jedd D. Wolchok, Peter Hersey, Richard Wayne Joseph, Jeffrey S. Weber, Roxana Stefania Dronca, Tara C. Mitchell, Amita Patnaik, Hassane M. Zarour, Anthony M. Joshua, Erin Jensen, Nageatte Ibrahim, Sama Ahsan, Antoni Ribas
Journal: Journal of Clinical Oncology (2018)

9516 Background: Pembro has demonstrated robust antitumor activity and safety in several studies of advanced melanoma, including KEYNOTE-001, -002, and -006. Here, we describe the 5-year outcomes for all pts and for those who were treatment naive in the phase 1b KEYNOTE-001 study (NCT01295827). Methods: Pts aged ≥18 y with previously treated or treatment-naive, advanced or metastatic melanoma received pembro 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W until disease progression, intolerable toxicity, or pt/investigator decision to withdraw. The Kaplan-Meier method was used to estimate OS and PFS. ORR and PFS were based on immune-related response criteria by investigator assessment. Data cutoff was Sep 1, 2017. Results: KEYNOTE-001 enrolled 655 pts (151 treatment naive; 504 previously treated). After a median follow-up of 55 mo (range, 48-69), 35 pts are on pembro treatment. 63% (n = 412) of all pts died. The estimated 5-year OS rate was 34% in all pts and 41% in treatment-naive pts, similar to the 4-year rates of 38% and 48%, respectively. Median OS was 23.8 mo (95% CI, 20.2-30.4) in all pts and 38.6 mo (95% CI, 27.2-NR) in treatment-naive pts. 5-year PFS rates were 21% in all pts and 29% in treatment-naive pts; median PFS was 8.3 mo (95% CI, 5.8-11.1) and 16.9 mo (95% CI, 9.3-35.5) in all pts and treatment-naive pts, respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cutoff; the longest response observed in all pts was ongoing at 66 mo. Treatment-related AEs (TRAEs) occurred in 86% (n = 562) of pts, including 17% (n = 114) with grade 3/4 TRAEs and 7.8% (n = 51) who discontinued because of a TRAE. Conclusions: Pembro provides a 5-year OS rate of 34% in pts with previously treated and treatment-naive advanced melanoma, with a 5-year OS rate of 41% in treatment-naive pts. These data, representing the longest follow-up for pembro to date in any cancer, confirm the durable antitumor activity and tolerability of pembro in advanced melanoma. Clinical trial information: NCT01295827.
Role model: Hugh Herzig
Authors: Abi Rimmer
Journal: BMJ (2018)

Throughout his career, Hugh Herzig has valued the access that his work gives him to his patients' thoughts and feelings."I sit down with people and within a couple of sentences we're talking about something painful and personal and important in their lives which is really troubling them," he says."I think that's unusual.It's a privilege that I find enriching and rewarding, and something of an honour.
The role of FDG-PET during osimertinib treatment to predict the responsiveness of tumor early in patients with stage IV non-small cell lung cancer: A pilot study.
Authors: Shinkyo Yoon, Dae Ho Lee, Jungsin Lee, Kang-Seo Park, Jae Ho Jeong, Kyoungmin Lee, Heejung Chae, Sang-We Kim
Journal: Journal of Clinical Oncology (2018)

e21150 Background: Despite osimertinib revealed marked antitumor activity in EGFR T790M mutant lung adenocarcinoma, second tumor biopsy is inevitably required for detection of T790M mutation. We investigated the predictive value of the metabolic response by 18F [18F]fluorodeoxyglucose (FDG)-PET during osimertinib treatment. Methods: In this prospective, open-label, single center pilot study, patients who had shown disease progression in previous 1st generation EGFR TKI were recruited. Second tumor biopsy and liquid biopsy were performed. FDG-PET image was obtained before starting therapy and after 7 days of osimertinib. The primary objective was to elucidate whether the metabolic response by FDG-PET during the first week osimertinib treatment could predict the response to osimertnib. The secondary objectives were to analyze the response according to the EGFR T790M mutation status in second tumor biopsy and liquid biopsy, and overall survival. Results: Between Nov 2016, and Dec 2017, 25 patients were enrolled. Median age was 63 years (39-85) and 9 patients (36%) were male. With median follow-up duration of 8.4 months (1.4-14.5), overall response rate (ORR) was 76%. EGFR T790M mutation in tumor tissue was seen in 68% of patients. Given the definition of metabolic response as 20% or more than 20% decrease of ΔSUVmax, metabolic responder was 80%. ORR and median PFS of metabolic responder vs. non-responder; tumor tissue T790M positive vs. negative; baseline plasma ctDNA T790M positive vs. negative are demonstrated at Table 1. Conclusions: Osimertinib showed anti-tumor activity even in patients harboring no T790M mutation. Therefore, initial metabolic response evaluated by FDG-PET would be a promising indicator to predict tumor response to osimertinib after disease progression in previous 1st generation EGFR TKIs. Clinical trial information: 30953. mSUV -20% vs. > -20% Tumor tissue T790M Positive vs. Negative ctDNA T790M Positive vs. Negative ORR 90% vs. 20% (p = 0.005) 82.4% vs. 62.5% (p = 0.344) 95.7% vs. 70.0% (p = 0.615) median PFS Not reached (NR) vs. 4.1 months HR 30.17; p = 0.002 NR vs. NR HR, 1.373; p = 0..679 NR vs. 11.0 months HR 0.822; p = 0.798