tbuckley/cabot-search huggingface dataset:
Belvarafenib, a novel pan-RAF inhibitor, in solid tumor patients harboring BRAF, KRAS, or NRAS mutations: Phase I study.
Authors: Tae Won Kim, Jeeyun Lee, Sang Joon Shin, Jin-Soo Kim, Yu Jung Kim, Hye Sook Han, Soo Jung Lee, Hyeong-Seok Lim, Yoon-hee Hong, Young Su Noh, Yujung Kyoung, Oakpil Han, Jiyeon Yoon, Jeong Ah Lim, Suk Ran Kim
Journal: Journal of Clinical Oncology (2019)

3000 Background: Belvarafenib (HM95573/GDC-5573) is an oral type II pan-RAF kinase inhibitor which demonstrates selective anti-tumor activity in several non-clinical cancer models and in cancer patients with RAS- or RAF- mutation. Here we present overall safety and efficacy findings of two phase 1 studies, consisting of dose escalation and dose expansion stages. Methods: Patients with advanced solid cancers harboring documented RAS- or RAF- mutation were enrolled. In the dose escalation study, patients were treated with Belvarafenib at a starting dose of 50 mg once daily (QD) to 800 mg BID to assess safety and tolerability and identify the recommended dose (RD). Dose escalation was guided based on pharmacokinetic data and used a traditional 3+3 design. The dose expansion study was comprised of 6 cohorts (according to the type of tumor and RAS- or RAF gene mutation) and patients received the RD of Belvarafenib. The primary objective was to explore anti-tumor activity (per RECIST 1.1) and pharmacodynamic effects. Results: The dose escalation study included 72 patients in 9 dose cohorts (cut-off date of 18 Jan 2017). Dose dependent increase in exposures observed up to 650 mg BID. The most common treatment-emergent adverse events that occurred in more than 20% of patients were rash, dermatitis acneiform and pyrexia. A total of 4 DLTs (different kinds of rashes) were reported and included 2 DLTs at the 800 mg BID level. Therefore, 650 mg BID was considered the MTD and 450 mg BID was identified as the RD for Belvarafenib. There were 7 partial responses (3 confirmed PRs) from 200 mg QD to 800 mg BID in NRAS-mutant melanoma, BRAF-mutant melanoma, KRAS-mutant sarcoma, and BRAF-mutant GIST. Four of nine patients with NRAS-mutant melanoma had a PR (ORR 44%). The dose expansion study included 63 patients in 5 indication-specific and basket cohorts administered with 450 mg BID Belvarafenib (cut-off date of 6 Oct 2018). No new safety signal was detected. There were two PRs each in patients with NRAS-mutant melanoma (2/9), BRAF-mutant melanoma (2/6) and BRAF-mutant CRC (2/7), respectively. Conclusions: Belvarafenib was well tolerated and exhibited anti-tumor activity in patients with advanced solid tumors harboring RAS or RAF mutations. Belvarafenib is being further investigated in combination with the MEK inhibitor cobimetinib. Clinical trial information: NCT02405065, NCT03118817.
Evaluating the prognostic significance of significant weight loss in patients with stage III non-small cell lung cancer (NSCLC) undergoing definitive chemoradiation (CRT) after FDG-PET staging.
Authors: Clare Senko, Julie Moore, Karen Hay, Zarnie Lwin, Gary Pratt, Kwun Fong, Brett Gordon Maxwell Hughes
Journal: Journal of Clinical Oncology (2019)

e20045 Background: In the pre-PET era, weight loss is a harbinger of occult metastatic disease in patients with stage III NSCLC. Identifying the relationship between weight loss and pattern of relapse (POR), may enable stratification of patients into prognostic groups associated with increased risk of relapse. We sought to identify if weight loss remains a negative independent prognostic factor after FDG-PET staging. Methods: A retrospective audit (using web-based and electronic databases) was conducted in all patients with stage III NSCLC treated with definitive CRT between 01/07/2013 and 30/06/2018 at the Royal Brisbane and Women’s Hospital and The Prince Charles Hospital, Queensland, Australia. A descriptive analysis was applied to describe the primary end-point of PFS and secondary end-points of OS and POR, in relation to the percentage of pre-treatment weight loss (0-10% vs &gt; 10-20% vs &gt; 20%). A subset analysis looked at other prognostic factors identified in NSCLC to account for potential confounders. Results: Of the 127 patients (mean age 65 years, mean weight 76kg, 57% male, 42% current smokers) who commenced treatment during the study period, 24% lost &gt; 10% and 3% lost &gt; 20% weight. Median TTP for the entire cohort was 9 months. Based on multivariable modelling, risk of PD or death was 45% higher with &gt; 10% loss of body weight (p = 0.004), and risk of death was 36% higher with &gt; 10% of body weight (p = 0.05). Of the 54% that died during follow-up, 31 had distant PD, 18 had locoregional PD, 6 had local PD, and 10 had no PD. Males were at increased risk of PD. Conclusions: A prognostic link continues to be identified between significant (&gt; 10%) weight loss and risk of progressive disease or death in stage III NSCLC treated with definitive CRT despite pre-treatment FDG-PET. These findings identify a sub-group of patients where weight loss could still be a surrogate for micro-metastases not detected on PET, or other adverse prognostic markers. Other treatment strategies or improved diagnostic strategies are warranted.
CDKN2A/B gene loss and MDM2 alteration as a potential molecular signature for hyperprogressive disease in advanced NSCLC: A next-generation-sequencing approach.
Authors: Raffaele Giusti, Marco Mazzotta, Marco Filetti, Daniele Marinelli, Arianna Di Napoli, Stefania Scarpino, Giorgia Scafetta, Monica Mei, Andrea Vecchione, Luigi Ruco, Paolo Marchetti
Journal: Journal of Clinical Oncology (2019)

e20628 Background: Hyperprogressive disease (HPD) incidence ranges from 8% to 21% in patients treated with anti-PD-1/PD-L1 mAbs in NSCLC and is associated with poor survival. Previously published data underlined a link between HPD across different cancers types and specific genetic alterations, such as MDM2 amplification and EGFR aberrations. We present a single-center cohort of patients with NSCLC and PD-L1 &gt; 50% treated with 1st-line pembrolizumab. We performed NGS, IHC and FISH analysis to evaluate genetic correlations with the clinical phenotype. Methods: Clinical data from 20 patients with diagnosis of advanced NSCLC treated with 1stline immunotherapy pembrolizumab were retrospectively collected. HPD was defined by Time to Treatment Failure ≤2 months and raising in Tumor Burden ≥50% compared with basal CT-scan. MDM2 amplification was investigated by FISH on FFPE tissue sections using the MDM2/CON12 break apart FISH Probe. Positive cases were defined as those with &gt; 10% positive tumor cells. We performed IHC for MDM2 protein on FFPE tissue sections. The staining was semiquantitatively graded for the intensity as: 0, negative; 1+, weak positive; 2+, moderately positive; 3+, strongly positive, and for the extent as 0– &lt; 1% (negative), 1–50% (focal), and &gt; 50% (diffuse). We also performed NGS analysis (FoundationOne CDX, Foundation Medicine Inc.) on 324 preidentified genes. Results: We identified 5 cases of HPD; all five cases showed MDM2amplification by FISH analysis and a focal protein expression by IHC with the strongest nuclear staining observed in the cases showing a higher degree of MDM2 amplification (8/9 dots) and a weaker expression in those with a lower MDM2amplification (4/5 dots). NGS analysis showed MDM2amplification in 1/5 HPD patient and a loss of CDKN2A/B in 4/5 patients. None of the non-HPD patients had IHC expression of MDM2 or amplification of the gene. Among the non-HPD patients no genetic alterations regarding MDM2 and/or CDKN2A/B were found on NGS analysis. Conclusions: Our data suggest a potential role of CDKN2A/B gene loss and alteration of MDM2 on the establishment of HPD in NSCLC patients treated with immunotherapy. Because the HPD logic is not yet clear, more data is needed to better understand the link between this genomic signature and the development of HPD.
Lupus-associated atypical memory B cells are mTORC1-hyperactivated and functionally dysregulated
Authors: Chunmei Wu, Qiong Fu, Qiang Guo, Sheng Chen, Shyamal Goswami, Shuhui Sun, Teng Li, Xingjian Cao, Fuying Chu, Zechuan Chen, Mei Liu, Yuanhua Liu, Ting Fu, Pei Hao, Yi Hao, Nan Shen, Chunde Bao, Xiaoming Zhang
Journal: Annals of the Rheumatic Diseases (2019)

Objectives A population of atypical memory B cells (AtMs) are greatly expanded in patients with active lupus, but their generation and pathophysiological roles are poorly defined. The aim of this study was to comprehensively characterise lupus AtMs with a purpose to identify therapeutic clues to target this B cell population in lupus. Methods Peripheral B cell subsets were measured by flow cytometry. Sorting-purified B cell subsets were subject to RNA sequencing and functional studies. Plasma cytokines and secreted immunoglobulins were detected by Luminex or ELISA. In situ renal B cells were detected by multiplexed immunohistochemistry. Results CD24 − CD20 hi AtMs were strongly increased in two Chinese cohorts of patients with treatment-naïve lupus. Gene expression profile indicated that B cell signalling and activation, lipid/saccharide metabolism and endocytosis pathways were abnormally upregulated in lupus AtMs. In addition, the mammalian target of rapamycin complex 1 (mTORC1) pathway was remarkably activated in lupus AtMs, and blocking mTORC1 signalling by rapamycin abolished the generation of T-bet + B cells and terminal differentiation of lupus AtMs. Furthermore, lupus AtMs displayed a dysfunctional phenotype, underwent accelerated apoptosis, poorly co-stimulated T cells and produced proinflammatory cytokines. Interestingly, lupus AtMs were in a paradoxically differentiated status with markers pro and against terminal differentiation and enriched with antinucleosome reactivity. Finally, AtMs were accumulated in the kidneys of patients with lupus nephritis and associated with disease severity. Conclusions These findings demonstrated that mTORC1-overactivated lupus AtMs are abnormally differentiated with metabolic and functional dysregulations. Inhibiting mTORC1 signalling might be an attractive option to target AtMs and to improve therapeutic effectiveness in patients with lupus.
Creating the real-world medical record: Using digital patient-generated data to create an updated picture of patients outcomes.
Authors: Maytal Bivas-Benita, Irad Deutsch, Eliran Malki, Lior Hasid
Journal: Journal of Clinical Oncology (2019)

e18092 Background: Value-based healthcare requires integration of real-world data (RWD) generated by patients in parallel to clinical documentation. This gives a holistic perspective of the patients’ health and care and could lead to reduced costs and better patient care and safety. Belong digital patient-powered network (PPN) is a social network for cancer patients and caregivers providing them access to other patients, healthcare professionals and disease management tools. In this study we compared the clinical data generated by Belong users with classical clinical documentation. Furthermore we explored the additional information generated in the PPN and its value. Methods: RWD collected from users of the Belong PPN was retrospectively analyzed. We evaluated patient-reported outcomes in parallel to medical records provided voluntarily and anonymously. Data of patient journeys was extracted and mapped from medical records and social engagement in our platform using artificial intelligence (AI) engines. Data was further validated manually by the research team to assure accuracy. Results: We compared 40 treatment journeys reported by patients in Belong to their doctor summary. The data showed that patients can accurately describe their cancer diagnosis and treatment, mentioning 85% and 90% of their diagnosis and treatment, respectively. In 38% of the cases, patients’ engagement data provided additional insights in the categories of OTC drugs, supplements, diet, alternative treatments, lifestyle changes and emotional health. Complementary information from patients with possible clinical consequences (changes in sugar levels, blood pressure, body minerals levels etc.) was also reported and could affect patients’ treatment and well-being. Conclusions: RWD collected in the Belong PPN recreated a comparable clinical description of standard medical documents and provided additional insights that created a more comprehensive picture of patients’ health. Superimposing the social data layer onto the clinical one could provide significant advancement of how we treat patients and result in better cost-efficiency, improved healthcare services and patients’ outcomes.
Evaluating Unconscious Bias: Speaker Introductions at an International Oncology Conference
Authors: Narjust Duma, Urshila Durani, Cynthia B. Woods, Lionel A. Kankeu Fonkoua, Joselle M. Cook, Christopher Wee, Harry E. Fuentes, Miguel Gonzalez-Velez, Martina C. Murphy, Shikha Jain, Ariela L. Marshall, Stephanie L. Graff, Miriam A. Knoll
Journal: Journal of Clinical Oncology (2019)

PURPOSE In a professional setting, the introduction of female speakers without their professional title may have an impact on the public’s perception of the female speaker. We examined how professional titles were used during speakers’ introductions at the ASCO Annual Meeting. METHODS We conducted a retrospective, observational study of video-archived speaker introductions at the 2017 and 2018 ASCO Annual Meetings. A “professional address” was defined as the professional title followed by the speaker’s full name or last name. Multivariable logistic regressions were used to identify factors associated with the form of address. RESULTS Of 2,511 videos reviewed, 781 met inclusion criteria. Female speakers were addressed less often by their professional title compared with male speakers (62% v 81%; P &lt; .001). Males were less likely to use a professional address when introducing female speakers compared with females when introducing male speakers (53% v 80%; P &lt; .01). When women performed speaker introductions, no gender differences in professional address were observed (75% v 82%; P = .13). Female speakers were more likely to be introduced by first name only (17% v 3%; P &lt; .001). Male introducers were more likely to address female speakers by first name only compared with female introducers (24% v 7%; P &lt; .01). In a multivariable regression including gender, degree, academic rank, and geographic location of the speaker’s institution, male speakers were more likely to receive a professional address compared with female speakers (odds ratio, 2.43; 95% CI, 1.71 to 3.47; P &lt; .01). CONCLUSION When introduced by men, female speakers were less likely to receive a professional address and more likely to be introduced by first name only compared with their male peers.
Deep learning algorithm improves identification of men with low-risk prostate cancer using PSMA-targeted <sup>99m</sup>Tc-MIP-1404 SPECT/CT.
Authors: Alexa Meyer, Nancy Stambler, Karl Sjöstrand, Jens Richter, Mohamad Allaf, Steven P. Rowe, Vivien Wong, Aseem Anand, Michael A. Gorin
Journal: Journal of Clinical Oncology (2019)

e16572 Background: Previous work has shown that the degree of expression of prostate-specific membrane antigen (PSMA) correlates with prostate cancer (PCa) grade and stage. We evaluated the additive value of a deep learning algorithm (PSMA-AI) of a PSMA-targeted small molecule SPECT/CT imaging agent ( 99m Tc-MIP-1404) to identify men with low risk PCa who are potential active surveillance candidates. Methods: A secondary analysis of a phase III trial (NCT02615067) of men with PCa who underwent 99m Tc-MIP-1404 SPECT/CT was conducted. Patients with a biopsy Gleason score (GS) of ≤6, clinical stage ≤T2, and prostate specific antigen (PSA) &lt; 10 ng/mL who underwent radical prostatectomy (RP) following SPECT/CT were included in the present analysis. SPECT/CT images were retrospectively analyzed by PSMA-AI, which was developed and locked prior to analysis. PSMA-AI calculated the uptake of 99m Tc-MIP-1404 against the background reference (TBR). The automated TBR of 14 was used as a threshold for PSMA-AI calls of positive disease. Multivariable logistic regression analysis was used to develop a base model for identifying men with occult GS ≥7 PCa in the RP specimen. This model included PSA density, % positive biopsy cores, and clinical stage. The diagnostic performance of this model was then compared to a second model that incorporated PSMA-AI calls. Results: In total, 87 patients enrolled in the original trial contributed to the analysis. The base model indicated that PSA density and % positive cores were significantly associated with occult GS ≥7 PCa (p &lt; 0.05), but clinical stage was not (p = 0.23). The predictive ability of the model resulted in an area under the curve (AUC) of 0.73. Upon adding PSMA-AI calls, the AUC increased to 0.77. PSMA-AI calls (p = 0.045), pre-surgery PSA density (0.019) and % positive core (p &lt; 0.004) remained statistically significant. PSMA-AI calls increased the positive predictive value from 70% to 77% and the negative predictive value from 57% to 74%. Conclusions: The addition of PSMA-AI calls demonstrated a significant improvement over known predictors for identifying men with occult GS ≥7 PCa, who are inappropriate candidates for active surveillance. Clinical trial information: NCT02615067.
RNA-sequencing and bioinformatic analysis to pre-assess sensitivity to targeted therapeutics in recurrent glioblastoma.
Authors: Ella L Kim, Anton Buzdin, Maxim Sorokin, Elena Poddubskaya, Artem Poddubskiy, Sven R Kantelhardt, Darius Kalasauskas, Bettina Sprang, Sven Ernoe Bikar, Alf Giese
Journal: Journal of Clinical Oncology (2019)

e13533 Background: This study developed molecular guided tools for individualized selection of chemotherapeutics for recurrent glioblastoma (rGB). A consortium involving clinical neurooncologists, molecular biologists and bioinformaticians identified gene expression patterns in rGB and quantitatively analyzed pathways involved in response to FDA approved oncodrugs. Methods: From2016 to 2018 biopsies from GB were collected using a multisampling approach. Biopsy material was used to isolate glioma stem-like cells and examined by RNA-sequencing. RNA-seq results were subjected to differential expression (DE) analysis and Oncobox analysis – a bioinformatic tool for quantitative pathway activation analysis. Results for newly diagnosed (nGB) and rGB (tissue samples and cell cultures) were compared. Oncobox analysis was further used to examine differential activation of pathways involved in response to existing chemotherapeutics. Results: 128 tissue samples and 28 cell cultures from a total of 44 GBs including 23 nGB, 19 rGB and 2 second-recurrent GBs were analyzed. 14 patient-matched pairs of nGB and rGB were obtained. DE analysis of nGB and rGB, showed a distinct “signature” associated with rGB. Oncobox analysis found down regulation of pathways related to cell cycle and DNA repair and upregulation of immune response pathways in rGB vs corresponding nGB. Specifically, pathways targeted by temozolomide, which is the first line chemotherapy for GB, were found down regulated in rGB. Among the top pathways upregulated in rGB were the pathways targeted by durvalumab and pomalidomide currently under investigation in phase II or III trials for GB. Conclusions: Specific pathway analysis revealed regional and clinical stage-associated differences in the transcriptional landscapes of nGB and rGB. Our results support a concept of treatment-induced resistance to cytotoxic therapeutics and indicate that temozolomide and radiation treatment have important impacts on gene expression changes associated with GB recurrence. Systematic molecular profiling of rGB is a promising avenue towards predicting sensitivity to targeted therapeutics in rGBs on an individual basis.
Interdisciplinary surgery for advanced gynecologic malignancies: Outcome and complication rate.
Authors: Jelena Boeckhoff, Luisa terGlane, Uwe A. G. Wagner, Rainer Hofmann, Axel Hegele
Journal: Journal of Clinical Oncology (2019)

e17002 Background: Advanced gynecologic malignancies are known to have a poor prognosis. Due to local invasion in adjacent organs, finding the most suitable therapeutic option is often difficult. This study aims to assess the outcome of interdisciplinary surgery for locally advanced gynecologic malignancies focusing on women treated by pelvic exenteration (PE). Methods: All women that were treated with PE at the University Hospital Marburg between 04/2011 and 06/2016, were enrolled in this retrospective study. A data sheet was prepared assessing e.g. demographic informations, tumor type and previous therapies. Furthermore, complication rate (Clavien Dindo, follow-up and outcome were evaluated. Results: From the 57 women identified, the indications for PE were malignancies of the cervix (47.2%), vagina (15.1%), vulva (13.2%), endometrium (11.3%), ovaries (5.7%) and undifferentiated (uterus) (1.9%). 51.9% were treated for recurrent cancer. 26% received no treatment prior to PE, 16%, 38%, 20% received 1, 2 or 3 previous treatments respectively (chemotherapy, radiation, surgery). 54.7% of the patients underwent anterior, 37.8% total and 7.5% posterior PE. Urinary diversion was predominantly ileum conduit (76%). Major complications (Clavien Dindo &gt; 2) were observed for 40.4%, 19.2% had no complications. No correlation with clinical parameters (e.g. BMI, age, time of surgery), previous therapy or urinary diversion could be shown. Renal function improved significantly postoperatively (p &lt; 0.05). Mean hospital stay was 25 d. Median overall survival (OS) was 15.2 months. It was not influenced by the entity of the tumor. Two years survival rate (SR) was 38.2%; 3 years SR 27.3%. After 47 months median follow-up time, 23.7% of the treated women were still alive. Conclusions: PE remains to be a meaningful treatment option for women with invasive gynecologic malignancies also after multiple previous therapies, showing acceptable complication rates and satisfactory OS in regard to the extensive nature of the malignancies and the procedure.