tbuckley/cabot-search huggingface dataset:
Metastatic Merkel cell carcinoma and myasthenia gravis: contraindication for therapy with immune checkpoint inhibitors?
Authors: Anne Zaremba, Eleftheria Chorti, Finja Jockenhöfer, Saskia Bolz, Selma Sirin, Martin Glas, Jürgen C. Becker, Selma Ugurel, Alexander Roesch, Dirk Schadendorf, Elisabeth Livingstone, Tim Hagenacker, Lisa Zimmer
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> PD-1/PD-L1 inhibitors are promising approaches for advanced Merkel cell carcinoma (MCC). Nevertheless, these inhibitors bear a high risk for induction of immune-related adverse events (irAEs), particularly flares of preexisting autoimmune diseases. Neurological irAEs of PD-1/PD-L1 inhibitors are possibly underestimated and potentially fatal toxicities. Additionally, exacerbations of preexisting myasthenia gravis (MG) with a high MG-specific-related mortality have been reported. <h3>Case presentation</h3> A 61-year-old woman with a history of MG since 2005 was treated with azathioprine and pyridostigmine after thymectomy. In March 2016, she was diagnosed with MCC. Six months later the tumor had progressed to stage IV and metastases were detected in lymph nodes and the pancreas. The immunosuppressive therapy was therefore changed to mycophenolatmofetil (MMF) and an immune checkpoint blockade with the PD-1 inhibitor pembrolizumab was initiated in November 2016. Due to MMF-induced liver toxicity, MMF was switched to cyclosporine A (CsA) with normalized liver transaminases six weeks later. After six cycles of pembrolizumab the patient achieved a partial response. Follow up analysis sixty-five weeks later revealed a long-lasting tumor response with a partial remission of pancreatic and inguinal metastases and no flare of MG. <h3>Conclusions</h3> Patients with a preexisting MG can be considered for treatment with immune checkpoint inhibitors if they have a life-threatening cancer and if other effective, long-lasting treatment options are not available. The risks and benefits of therapy should be weighed in a multidisciplinary setting and should be discussed thoroughly with the patient. Exacerbation of underlying MG can be potentially life-threatening and requires close monitoring in collaboration with neuromuscular specialists.
Real-world application of next generation sequencing to guide therapeutic options in lymphoma.
Authors: Molly Tokaz, Anthony Scott, Maryann Shango, Sumana Devata, Shannon Carty, Arul Chinnaiyan, Mark Kaminski, Tycel Jovelle Phillips, Ryan A. Wilcox
Journal: Journal of Clinical Oncology (2019)

e14645 Background: Despite the increasing availability of targeted and novel therapies, successful treatment of many relapsed/refractory lymphomas remains a challenge. Tumor sequencing is becoming an increasingly available technique to identify potential therapeutic targets; however, there remains considerable uncertainty about the successful application of this data in a “real world” clinical setting. Methods: Herein, we describe 91 lymphoma patients who underwent DNA &amp; RNA sequencing of tumor biopsies via the MIONCOSEQ protocol to identify actionable therapeutic targets. Their charts were reviewed for the clinical use of MIONCOSEQ recommendations. Results: Among the 91 patients were 13 Lymphoma subtypes. Most patients had Stage III/IV disease (68%) at diagnosis, underwent an average of 4 treatments before sequencing (range 0-16) and had approximately 47 distinct molecular alterations (range 2-447). Of the cohort, 60 patients (65%) had actionable targets identified of which 11 ultimately received treatment based on MIONCOSEQ recommendations. The remaining patients did not receive treatment due to multiple reasons: prior CR or on surveillance not requiring treatment (10); death (12); trial ineligibility (4); trial unavailability at the institution (8); patient preference for local treatment (6); and already on alternative treatments (9). Taken as a whole, sequencing late in the disease course and a lack of available clinical trials were identified as barriers for the incorporation of MIONCOSEQ data into clinical practice. Therefore, earlier sequencing and strategies to bolster the availability of targeted therapies may significantly increase the application of genomic data and precision medicine in clinical practice. Conclusions: While next generation sequencing (NGS) is a powerful tool for advancing precision medicine, meaningful clinical application of these results remains a challenge. Our study indicates that early sequencing and improved trial availability could be beneficial in increasing real-world therapeutic options for relapsed/refractory lymphoma. Further research is needed to determine the extent to which a personalized approach, informed by NGS data, improves outcomes.
Abstract 16676: Ambient UFP Exposure Impairs the Integrity of the Gut Vascular Barrier
Authors: Kyung In Baek, Chih-Chiang Chang, Andrew Pieterson, Arian Saffari, Constantinos Sioutas, Tzung K Hsiai
Journal: Circulation (2017)

Introduction: Epidemiological studies have consistently supported the link between particulate matter (PM2.5) in air pollution and gastrointestinal diseases. Ultrafine particles (UFP, d < 0.1 μm), ...
A phase I study of neoadjuvant combination immunotherapy in locally/regionally advanced melanoma.
Authors: Yana Najjar, Dustin McCurry, Huang Lin, Yan Lin, Diwakar Davar, Joseph J. Drabick, Rogerio Izar Neves, Marc S. Ernstoff, Igor Puzanov, Joseph J. Skitzki, James F. Pingpank, Matthew Peter Holtzman, Cindy Sander, Amy Rose, John M. Kirkwood, Ahmad A. Tarhini
Journal: Journal of Clinical Oncology (2019)

9586 Background: A trial of neoadjuvant pembrolizumab (P) in combination with high dose interferon-α (HDI) in high-risk patients (pts) with locoregionally advanced melanoma (mel) has completed enrollment. Methods: Primary endpoint: safety of combination P-HDI. Pts were treated with P x 2 doses followed by definitive surgery, then x1 year. HDI was given concurrently, and both agents were per standard regimen. Tumor and blood samples were obtained at baseline and at surgery (wk 6-8), blood at 6 wks, 3,6,12 months (mos). Results: 30 pts were treated (22 male, 8 female, age 26-83). 16 had cutaneous primary, 3 mucosal, 11 unknown. At enrollment, 16 had recurrent disease, 6 received prior adjuvant therapy with ipilimumab (4) or HDI (2). 16 had AJCC 7 stage IIIB, 9 IIIC, 5 IV. 332 P cycles have been delivered (median 13), 496 doses of HDI induction (median 17), 1329 doses of HDI maintenance (median 44). HDI was dose reduced in 20 pts, discontinued in 27, P discontinued in 8. Radiologic preoperative RR was 77% (95% CI, 59-88) (6 CR, 17 PR). 20% (6) had SD and 1 had PD. All pts underwent definitive surgery. The pathologic complete response (pCR) of 26 pts was 32% (95% CI, 18-51). 6 pts recurred and 3 died. No pt with pCR has recurred. Median f/u time is 17.4 mos, median PFS/OS not reached. Most common grade (Gr) 3 toxicities: hypophosphatemia (10; 33%), fatigue (10; 33%), ↑CPK (6; 20%), ↑lipase (4; 13%). 3 Gr 4 events (↑CPK, hyperglycemia, lymphocyte count decreased). 1 suspected grade 5 event occurred 6 months after completion of therapy. PD-L1 expression at baseline did not correlate with clinical outcomes. In 8 pts with pre and post treatment tumor samples, IHC expression of PD-1, PD-L1, CD11b, CD8, Foxp3 and CD25 increased post-treatment (p &lt; 0.05). Conclusions: Neoadjuvant P-HDI has promising clinical activity, although treatment is limited by HDI toxicity. Treatment increases the immune cell infiltrate, and outcomes do not correlate with baseline expression of PD-L1. Longer follow up and further mechanistic studies are underway. Clinical trial information: NCT02339324.
FRI0064 INCREASE OF RHEUMATOID ARTHRITIS AS A CONTRIBUTORY CAUSE OF DEATH IN THE ELDERLY. A NATIONWIDE STUDY IN ITALY, 2003–2015
Authors: Francesca Ometto, Ugo Fedeli, Costantino Botsios, Leonardo Punzi, Enrico Grande
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Metanalyses failed to show a decrease of the mortality risk in cohorts of patients with rheumatoid arthritis (RA) between 1950 and 1995. Mortality rates obtained with the analysis of multiple causes of death (MCD) can provide a more complete estimate of the burden of mortality related to RA compared to analysis considering only the underlying cause of death (UCD). Such analyses are available from a limited number of countries, and trends for RA mortality based on MCD were divergent. <h3>Objectives</h3> The objective of the study was to evaluate trends of rheumatoid arthritis (RA) mortality reported as the underlying cause of death (UCD) and as multiple cause of death (MCD) in Italy between 2003 and 2015. <h3>Methods</h3> Analyses were carried out on the Italian National Cause of Death Register, managed by the Italian National Institute of Statistics (ISTAT). Diseases mentioned in the death certificate are coded according to the International Classification of Diseases, 10th Edition (ICD-10, 2009 version). Deaths from January 1, 2003 to December 31, 2015 with mention of RA were included. Time trends of age-standardized rates were analyzed for RA both as UCD and MCD; and the annual percent change (APC) was estimated. <h3>Results</h3> Overall 26,564 deaths with mention of RA were retrieved out of 7,595,214 deaths (0.35% of all certificates). The yearly number of RA-related deaths increased through the study period, meanwhile the probability of selection as the UCD decreased: MCD/UCD ratio was 3.7 in 2003-2006 and 4.8 in 2012-2015 in males; 3.0 and 4.1 in females (Tab.). Mortality rates based on the UCD decreased (males APC -3.1%, CI -3.9, -2.3; females APC -3.3%, CI -4.1, -2.4); while MCD rates for RA-related mortality were stable. Specifically, rates were stable or declined among younger subjects, whereas an increase was registered for the elderly: RA-related deaths in subjects aged ≥80 years raised from 48% in 2003-2006 to 59% in 2012-2015 (Fig.). <h3>Conclusion</h3> RA is increasingly mentioned among diseases contributing to death in Italy. Rheumatoid arthritis declined as underlying cause of death in the last decades. We observed a shift of RA-related mortality towards the elderly, possibly because of the progress in therapeutic strategies allowing increased survival of RA patients. <h3>Disclosure of Interests</h3> None declared
Phase III randomized sequential open-label study to evaluate the efficacy of FOLFOX + panitumumab followed by FOLFIRI + bevacizumab (Sequence 1) versus FOLFOX+ bevacizumab followed by FOLFIRI + panitumumab (Sequence 2) in untreated patients with wild-type RAS metastatic, primary left (L)-sided, unresectable colorectal cancer (CRC): The CR-SEQUENCE.
Authors: Ramon Salazar, Alfredo Carrato, Teresa Garcia Garcia, Javier Gallego Plazas, Auxiliadora Gómez-España, Cristina Gravalos Castro, M. Pilar Escudero, Maria Jose Safont, Antonieta Salud Salvia, Carles Pericay, Begoña Graña Suárez, David Marrupe, Rosario Vidal, Ferran Losa, Teresa Fernandez Rodriguez, Jose Luis Manzano Mozo, Josep Tabernero, Helder Mansinho, Clara Montagut, Enrique Aranda
Journal: Journal of Clinical Oncology (2019)

TPS3618 Background: Both anti-EGFR and anti-VEGF therapies have shown clinical benefit when they are added in first and second-line in L-sided CRC. The conflicting results in anti-VEGF vs. anti-EGFR studies (FIRE-3, PEAK and CALGB/SWOG 80405 studies) suggest that the sequence of targeted therapies added to FOLFOX or FOLFIRI regimens in first- and second-line treatment could be an important factor in the overall survival (OS) of mCRC patients. Currently, there are no randomized data on the sequential use of an anti-EGFR followed by an anti-VEGF or vice versa. Therefore, the aim of this randomized clinical trial is to compare the efficacy of two treatment sequences, panitumumab followed by bevacizumab versus bevacizumab followed by panitumumab in combination with FOLFOX chemotherapy in first-line and with FOLFIRI in second-line in patients with wild-type RAS, primary L-sided, metastatic colorectal cancer (mCRC). Methods: A phase III, multicentre, open-label and randomized two-arm clinical trial. Untreated patients with wild-type RAS mCRC (determined locally), primary L-sided and unresectable will be screened for this trial. Eligible patients will be randomized 1:1 to receive first-line (1L) panitumumab plus FOLFOX and then bevacizumab plus FOLFIRI as second-line (2L) treatment (Seq. 1) or bevacizumab plus FOLFOX as 1L and then panitumumab plus FOLFIRI as 2L treatment (Seq. 2). Randomization will be stratified by number of metastatic organs involved (1 vs &gt; 1). Primary objective is the comparison of the progression free survival (PFS) rate at 35 months (m) of Seq 1 vs Seq. 2. Secondary objectives: PFS from randomization to 2 nd progression or death, OS rate at 35 months and OS of Seq. 1 vs Seq. 2; PFS, objective response rate, disease control rate, early tumour shrinkage, Depth of Response, duration and time to response and safety in 1L treatment and in 2L treatment in each Sequence arm. Exploratory objectives: impact of baseline biomarkers predictive of the efficacy in each Sequence arm and the clinical impact of clonal dynamics by longitudinal analysis of circulating tumour deoxyribonucleic acid (ctDNA) in plasma. The trial is in progress; 28 of up to 370 planned patients have been recruited at the end of January 2019 (first patient in 31 October 2018). Clinical trial information: NCT03635021.
Polysomy is associated with poor outcome in 1p/19q codeleted oligodendroglial tumors
Authors: Hui Chen, Cheddhi Thomas, Felipe Andres Munoz, Sanda Alexandrescu, Craig M Horbinski, Adriana Olar, Declan McGuone, Sandra Camelo-Piragua, Lu Wang, Elena Pentsova, Joanna Phillips, Kenneth Aldape, Wen Chen, A John Iafrate, Andrew S Chi, David Zagzag, John G Golfinos, Dimitris G Placantonakis, Marc Rosenblum, Pamela Ohman-Strickland, Meera Hameed, Matija Snuderl
Journal: Neuro-Oncology (2019)

Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of polysomy in gliomas tested for 1p/19q status.We analyzed 412 histologic oligodendroglial tumors with use of 1p/19q testing at 8 institutions from 1996 to 2013; fluorescence in situ hybridization (FISH) for 1p/19q was performed. Polysomy was defined as more than two 1q and 19p signals in cells. Tumors were divided into groups on the basis of their 1p/19q status and polysomy and were compared for progression-free survival (PFS) and overall survival (OS).In our cohort, 333 tumors (81%) had 1p/19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy, 79 (19%) had 1p/19q maintenance; of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the group with 1p/19q loss had significantly better PFS and OS than did the group with 1p/19q maintenance (P < 0.0001 each). Patients with 1p/19q loss and polysomy showed significantly shorter PFS survival than patients with 1p/19q codeletion only (P < 0.0001), but longer PFS and OS than patients with 1p/19q maintenance (P < 0.01 and P < 0.0001). There was no difference in survival between tumors with >30% polysomic cells and those with <30% polysomic cells. Polysomy had no prognostic significance on PFS or OS in patients with 1p/19q maintenance.The presence of polysomy in oligodendroglial tumors with codeletion of 1p/19q predicts early recurrence and short survival in patients with 1p/19q codeleted tumors.
Tumor immune microenvironment (TiME) changes by multiplex IF staining in a pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation.
Authors: Evthokia Hobbs, Fei Yang, Tapsi Kumar, Alejandro Contreras, Edwin Roger Parra Cuentas, Haven Garber, Marion Scoggins, Beatriz E Adrada, Gary J Whitman, Banu Arun, Elizabeth A. Mittendorf, Jennifer Keating Litton
Journal: Journal of Clinical Oncology (2019)

585 Background: We previously reported a median tumor volume loss of 88% (range 30-98%) in 13 patients with early stage BRCA1/2 mutant breast cancer treated on a neoadjuvant trial of the PARP inhibitor talazoparib. The effects of PARP inhibition on immune aspects of the TiME in early-stage breast cancer has not been well described. The goal of this study was to evaluate the TiME in pre and post-treatment core biopsies from enrolled patients. Methods: Eleven paired core biopsies were available for examination. Tumor infiltrating lymphocytes (TILs) were quantified by H&amp;E stained slides by a central pathologist. Specimens were assessed by multiplex immunofluorescence (mIF) using a panel of 6 biomarkers (PD-1, PD-L1, CD3, CD8, CD68 and CK) with the Opal 7-color Kit in LEICA BOND auto stainer, Vectra automated quantitative pathology imaging system and inForm software (PerkinElmer). Results: In the analyzed core biopsies, there was an increase in TILs evaluated by H&amp;E in post-treatment compared to baseline (mean 36 vs 11%). By mIF there was an increase in CD3+ T cell and CD3+CD8+ cytotoxic T cell density in post-treatment samples compared to baseline, summarized in table. PD-L1 expression in tumor cells was rare in the cohort. There was no difference in CD3+PD-1+ or CD3+CD8+ PD-1+ lymphocytes in pre and post-treatment specimens. There was also no differences in macrophages (CD68+). Evaluation of immune phenotype and imaging response will be presented in the final analysis. Conclusions: This is the first study phenotyping the immune response to neoadjuvant talazoparib in BRCA-mutant breast cancer patients. In this small cohort, intratumoral and stromal CD3+ T cells and CD3+CD8+ cytotoxic T cells increased after two months of talazoparib. Clinical trial information: NCT02282345. [Table: see text]
E-consult: To better inform patient.
Authors: Jean-Francois LE Brun, Julie Babin-Commeny, Sandrine Martin Francoise, Guillaume Babin
Journal: Journal of Clinical Oncology (2019)

e17049 Background: All surgeons have a personalized way of consulting, some deliver information exclusively orally, others through free-form diagrams or anatomical charts. Most patients go home with these patterns that are more or less readable with all the uncertainty of what they really understood or assimilated. Methods: To meet the expectations of patients, we made a computer application to help the surgeon during the consultation.During the consultation, gynecologist surgeons from Center F BACLESSE explained, with the help of the e-consult application, the pathology, surgical intervention, postoperative consequences and potential drug treatments to a cohort of 61 patients admitted for consultation. At the end of the consultation, all the patients received a PDF sheet or an email containing the diagrams constructed in collaboration with the surgeon. Using a questionnaire, we evaluated the satisfaction of the patients. Results: The computer tool was popular with the majority of patients. Regarding the information on the surgical procedure, 86% of the patients judged them as very good, 80% judged the information on adjuvant treatment (radiotherapy, chemotherapy, hormone therapy) as very good and 89% were very satisfied with the information given by the doctor. For the computer tool, 81% of patients found the illustrations very clear, 79% found that the application is a very good help to understanding and 89% found that the interaction with the doctor is sufficient. During the consultation, 100% of the patients were able to ask the desired questions, and 97% think that this computer tool completes the information. For the submitted document, 100% of the patients found it very clear and 100% found that it meets the expectations of the patients. Discussion: E-consult is a unique app created to improve the quality of information delivered to patients during the consultation. The doctor can prove that the information was delivered to the patient, through the development of a PDF during the consultation. A video demonstration is available with the following link: Play the video . Conclusions: e-health is becoming more and more important in medicine. Patients are becoming more connected. E-consult improves the quality of the information received in a simple and personalized way, it is the first application, available at will, designed to improve the understanding of patients. This application integrates with each step in the patient care path.
Peripheral neuropathy among patients with NSCLC undergoing chemotherapy.
Authors: Jerzy Edward Tyczynski, Dongmu Zhang, Bruce Allen Bach
Journal: Journal of Clinical Oncology (2019)

e20552 Background: Peripheral neuropathy (PN) occurs in NSCLC patients and may be due to various factors. One of the major factors is chemotherapy treatment. This study assessed the frequency and risk of PN among chemotherapy exposed NSCLC patients. Methods: This retrospective cohort study used the Optum claims in 2015-2017. The main inclusion criteria included: at least 2 diagnosis (Dx) claims for lung cancer; no other systemic cancer Dx within 6 months prior to the NSCLC Dx; at least one line of systemic anti-cancer treatment after the NSCLC Dx; presence of secondary metastatic disease. NSCLC was identified using a published algorithm. PN was identified by at least one claim with ICD-9/ICD-10 PN diagnosis code. Patients were followed from the earliest chemotherapy treatment date until a censoring event (PN Dx, end of enrollment, death, or end of study interval). Descriptive statistics were used to describe demographics; the Cox model and logistic regression were used to analyze risk associated with PN. Results: A total of 5082 patients were identified with an average age of 70.9 years (SD = 8.7) and 52% of male. Most common first line of treatment (LoT) was carboplatin + paclitaxel (31.9%); 32.7% of patients received a 2 nd line, 7.6% received a 3 rd line, and 1.7% received a 4 th or higher line. 857 patients had PN during the follow-up period (16.9%). Median Charlson comorbidity index (CCI) was 1, and mean 1.7 (SD = 1.8). Patients with CCI of 4+ (716 patients) had nearly 60% elevated risk of PN as compared with CCI = 0. Patients with diabetes presented the OR (odds ratio) of 1.58; patients with a history of PN had a higher risk of PN after the initiation of chemotherapy (OR = 3.90). Compared with the PN risk during 1 st LoT (reference), the OR of developing PN during 2 nd and 3 rd + LoTs was elevated to 1.78 (95%CI 1.49-2.11; p &lt; 0.0001) and 2.61 (95%CI 2.03-3.34; p &lt; 0.0001), respectively. The most common type of PN was sensory neuropathy (33%), then polyneuritis (21%) and diabetic polyneuropathy (18%). Conclusions: PN is common in NSCLC patients. This analysis shows that the risk of PN in NSCLC patients increases significantly along increasing number of LoT. A history of PN and presence of diabetes play an important role as risk factors of PN during anti-cancer systemic treatment.