bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating liquid biopsy with advanced imaging analysis to improve the prediction of response to immunotherapy in patients with NSCLC.
Authors: Del Re Marzia , Fontanelli Lorenzo , Romano Alessandra , Pasquini Giulia , Gri Nicole , Rofi Eleonora , Vivaldi Caterina , Crucitta Stefania , Belluomini Lorenzo , Frassoldati Antonio , Petrini Iacopo , Falcone Alfredo , Porta Camillo , Vasile Enrico , Neri Emanuele , Danesi Romano 
Published: May 2019

e14054 Background: Immunotherapy has revolutionized the treatment of NSCLC. However, response rate is variable, with a substantial failure rate. Thus, the identification of predictive biomarkers of response to immunotherapy is an area of great interest. Methods: Patients with locally advanced or metastatic NSCLC treated with nivolumab or pembrolizumab were enrolled. Disease response was defined following RECIST criteria (v. 1.1). Four ml of plasma were collected for the analysis of exosomal mRNA levels of PD-L1 (e-PD-L1) and IFN-γ (e-IFN-γ) at baseline and at the time of first radiological assessment. Exosome isolation and mRNA extraction was obtained by the exoRNeasy kit (Qiagen, Valencia, CA). e-PD-L1 and e-IFN-γ were evaluated by the QX100 ddPCR (Bio-Rad, Hercules, CA) and expressed as allele frequency (%). Chest computed tomography (CT) scan at baseline was used for the radiomic analysis. Tumor segmentation was performed on DICOM-formed images taken from the picture archiving, and the regions of interest were delineated manually and analyzed using the QUIBIM SL software. Survival was calculated stratifying patients based on e-PD-L1 and e-IFN-γ median values. Results: Nivolumab was given to 17 patients as 2nd line and to 8 subjects as further line of treatment, while 13 patients received 1st line pembrolizumab. Median PFS was 11 vs 16.2 months (mos) in patients with baseline e-PD-L1 of < 0.3% vs ≥0.3%, respectively (p = 0.16). e-PD-L1 significantly increased in disease progression (PD) vs partial response (PR) and disease stabilization (SD) (p = 0.01) after 2 mos of treatment. In patients with e-IFN-γ ≥4.1% vs < 4.1% at baseline, median PFS was 5.6 mos vs not reached, respectively (p = 0.003). The multiparametric radiomic analysis identified the Cluster Prominence Value (CPV, p = 0.012) and the Cluster Shade Value (CSV, p = 0.034) as significantly correlated with treatment outcome. Moreover, the D2d parameter and e-IFN-γ were inversely correlated (p < 0,0001). CPV and D2d reflect the intra-tumor architecture, including necrosis, cell proliferation, and angiogenesis. Conclusions: Liquid biopsy data correlate with radiomic parameters and predict response to immunotherapy.
Immunotherapy with checkpoint inhibitors in mismatch repair deficient (dMMR) cancers: Looking for a needle in a haystack— But, joy on finding one.
Authors: Rauthan Amit , Patil Poonam , Sood Tanvi , Kulkarni Shriniwas Subhash , Yashas Nitin , Nigade Gaurav , Somashekhar S.P. , Zaveri Shabber 
Published: May 2019

e14073 Background: Pembrolizumab is approved for deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) metastatic solid tumors with objective response rate (ORR) of 39.6% and response lasting for more than 6 months in 78% patients. Nivolumab is also approved in dMMR metastatic colorectal cancers (mCRC) with ORR of 28% and response lasting greater than 6 months in 67% patients. But finding these patients is difficult as only about 5% of metastatic cancers have dMMR. There is limited data from India in this population. We report our experience with testing and treatment in these patients. Methods: This is a single centre, retrospective study of metastatic solid tumors which had progressed on standard treatment. 137 patients were tested between May 2017 and Dec 2018. MMR testing was done by immunohistochemistry (IHC). The aim was to identify patients with dMMR; and to see their ORR, progression free survival (PFS) at 1 year, and adverse events on treatment with Nivolumab. Results: 137 metastatic cancer patients were tested. 75 had colorectal cancer (mCRC), 30 gastric, 10 hepatobiliary, 10 pancreatic, 8 endometrial, 2 small bowel cancer and 2 had breast cancer. 15 (11%) patients had dMMR. 3 (37%) of endometrium, 5 (16.6%) of stomach, 6 (8%) of mCRC and 1(10%) of hepatobiliary tree cancer had dMMR. 5 of the 15 dMMR patients received immunotherapy with Nivolumab - 2 in mCRC, 2 in stomach and 1 in endometrium. ORR was 60% with 3 partial responses, stable disease was seen in 1 (20%) and progression in 1 (20%). PFS at 1 year was 80%. Treatment was well tolerated.1 patient had hypothyroidism and 1 patient had grade 1 skin toxicity. Conclusions: Testing for dMMR is important in metastatic solid tumors as these patients are ideal for treatment with immunotherapy. But finding dMMR is difficult due to its infrequent presentation, and has been seen in 11% of our unselected patients. We recommend testing for dMMR by IHC in our Indian patients, as this is fast and cost effective. Finding dMMR cancers, and then treating with immunotherapy is rewarding irrespective of the site of origin. High ORR of 60% and 1 year PFS of 80% is very heartening to see in this relapsed metastatic patient group. Treating more dMMR patients and longer followup, will further elucidate the benefit of immunotherapy in our patients.
Is inmunotherapy a safe treatment in bladder cancer? A retrospective study in daily practice.
Authors: Vidal Casinello Natalia , Aguado De La Rosa Carlos , Puente Javier , Gonzalez-Larriba Jose-Luis 
Published: May 2019

e14083 Background: Several checkpoint inhibitors antibodies have been approved to treat bladder cancer, and many trials are still ongoing. However, few data about their efficacy and safety outside of a clinical trial have been published. Here we report our experience in managing immune-related toxicity in our daily practice. Methods: We performed a retrospective analysis of 23 patients (pts) with metastatic bladder cancer treated with checkpoint inhibitors in Clínico San Carlos University Hospital from April 2016 to September 2018. The aim of this study is to evaluate the safety of checkpoint inhibitors in daily practice. Results: Median age was 75 years (range 53-92) and 75% were men. The performance status at the beginning of immunotherapy treatment was 0 in 4 pts (17.4%), 1 in 16 pts (69.6%) and 2 in 3 pts (13%). Thirteen pts (56.5%) received the treatment as first line, 6 (26.1%) as second line and 4 (17.4%) as third line and beyond. 18 pts (78.3%) received immunotherapy as monotherapy (15 pts Atezolizumab and 2 pts Pembrolizumab), 3 pts (13%) received an immunotherapy combination with Durvalumab plus Tremelimumab, and 2 pts (8.7%) received chemotherapy plus immunotherapy (Carboplatin plus Avelumab or Atezolizumab). Of the analyzed patients, 36% did not develop any immune related adverse event (irAE). However, 64% did present some side effect. The most common side effect was asthenia (12.5%), cutaneous (8.3%), endocrine (5.6%), gastrointestinal (4.2%) and hepatic (2.8%). Only16.6% of the events required some kind of treatment (9.7% required steroids). Three patients had grade 3 or 4 toxicity, 1 patient on Atezolizumab presented with grade 3 diarrhea and grade 3 hepatic toxicity, another patient on Atezolizumab presented two heart attacks after the two infusions and eventually died, lastly a patient on Durvalumab + Tremelimuab suffered grade 3 hypophysitis. Conclusions: Incidence and therapeutic management of irAEs occurring in our clinical setting closely resembles that reported in retrospective series even though they were mostly elderly patients and many of them were heavily pretreated. Increasing our experience and knowledge in the clinical setting will improve and optimize the use of these drugs.
Comparison of panendoscopy directed biopsies with percutaneous and image-guided biopsies during immune checkpoint inhibitor therapy.
Authors: Hashmi Ahmad F , Smith Daniel Arnold , Rahnemai-Azar Amir Ata , Ravishankar Pavitra , Pfau David , Nelson Ariel Ann , Hoimes Christopher J. , Ramaiya Nikhil H. 
Published: May 2019

e14084 Background: Immune checkpoint inhibitors (ICI) have been shown to be helpful in the treatment of a several cancers. Response to ICI therapy is varied. The goal of this study was to examine the role of pan-endoscopy guided biopsies as well as image-guided and percutaneous biopsies as a means to tailor treatment regimens for patients receiving ICI therapy. Methods: A retrospective chart review was performed on oncology patients at a single institution from 2010 from 2018 undergoing treatment with ICI (n = 1044). Patients undergoing biopsies within the treatment period and up to one month following conclusion of treatment were analyzed and separated into a pan-endoscopy guided biopsy cohort or image-guided/percutaneous biopsy cohort. Data regarding biopsy results and subsequent treatment plans was then gathered and compared. Results: 5.3% of patients underwent pan-endoscopy guided biopsy (n = 55). 6.0% of patients underwent image-guided/percutaneous biopsy (n = 63). The most common endoscopic procedures included EGD 42.6%, bronchoscopy 38.9%, and flexible sigmoidoscopy/colonoscopy 20.4%. The most common image/percutaneously sampled tissues included skin/soft tissue 24.6%, lymph nodes 19.7%, and liver 16.4%. Breakdown of treatment complications in the pan-endoscopy group included pneumonitis 3.2%, inflammatory or infectious esophagitis 6.4%, or colitis 4.3%. Treatment complications in the image guided/percutaneous group included skin reactions 2.2% and inflammatory mediastinal changes 1.1%. Conclusions: In our cohort, Pan endoscopy and image guided/percutaneous biopsies were successfully performed along multiple cancer cell lines and helped in the decision making process.[Table: see text]
Prevalence of immunotherapy-related adverse events due to checkpoint inhibitors: First report in Mexico.
Authors: Rodriguez Melendez Elina Alexandra , Martinez Herrera J. Fabian , Olivares Guillermo , Villalobos Alberto , Serrano Juan Alberto , Perez-Zincer Fernando , Aguayo Alvaro , Rivera Rivera Samuel , Lazaro Leon Jesus Miguel , Salcedo Ivonne , Regalado Porras Gabriela Olivia , Alatorre Alexander Jorge , Camacho Limas Christian Patricio , Imaz Victoria , Gerson Raquel 
Published: May 2019

e14090 Background: Since 2010, immune checkpoint inhibitors (ICI) have been approved for the treatment of several neoplasms. Their immune-mediated toxicity profile, used as monotherapy (nivolumab [N], Ipilimumab [Ip], pembrolizumab [P]) or in combination (Nivolumab/Ipilimumab [N/Ip]) and their management is still being described, recently. Methods: A retrospective review of medical records, included all cancer patients treated, in our institution, with ICI from January 2014 to February 2018. Frequency, type and grade of immune related adverse events (irAE) by neoplasm, individual agent or combination were recorded. Time to first ir-AE (TTF-irAE) was estimated by Kaplan Meir Method and compared by Cox regression model. Results: 140 patients were evaluated, all in pretreated metastatic setting. Median age 65.8+/-11.8, men in 59.3%. The most frequent neoplasms treated with ICI were: lung (34%), melanoma (33%), genitourinary (17%), H&NC (6%), and GI (6%). Ip alone was indicated in 11.4% cases; N, 30%; P, 54.29%; N/Ip 4.29%. Median number of cycles per drug: Ip: 3 cycles, N/Ip: 4; N: 6; and P: 4 cycles. Toxicity (G1-4) was seen in Ip: 62.5%, N/Ip: 50%, N: 40.5%, P: 31.6%, p > 0.05. The most frequent irAE's were: dermatological 40%, gastrointestinal 18.3%, and endocrine 13.4%; other irAE´s were reported in: pulmonary 7.3%, ophthalmologic 6%, muscle-skeletal 6%, neurologic 2.4%, renal 1.2%, hematologic 1.2%. Severe toxicities (G3-4) were observed with N/Ip: 33.3%, P: 17.4%, Ip: 10%, N: 5.6%. TTF-ir-AE per drug: I: 1st cycle (dermatitis, pruritus, colitis), N/Ip: 2nd cycle (dermatitis, conjunctivitis), N: 3rd cycle (dermatitis, thyroiditis, colitis, hepatitis), P: 1st cycle (pruritus, neuritis, adrenalitis). Ipilimumab was an independent prognostic factor for developing severe ir-AE´s [OR = 12.8, p = 0.038], and any grade toxicity [OR = 1.9 (IC95% 0.92 - 4.1, p = 0.079)]. Conclusions: In this study, the dermatological, gastrointestinal and endocrine toxicities were the most frequent ir-AE´s, and they were observed in a low grade toxicity. The irAE´s profile is different among ICI or their combination and number of cycles administered. Ipilimumab alone or combined was associated to higher risk of severe irAEs.
Impact of IDO1 expression and inhibition on the sensitivity of anti-PD-1.
Authors: Zhu Jian , Zhu Rebecca L 
Published: May 2019

e14094 Background: Concurrent inhibition of IDO1 and PD-1 may have enhanced anti-tumor effects. However, inhibition of IDO1 failed to enhance efficacy of anti-PD-1 in late phase clinical trials. In this study, computational models were established to identify factors involved in interactions between these two types of agents. Methods: Abstracts published on IDO1, PD-1, PD-L1, anti-PD1/PD-L1 were downloaded from PubMed, and analyzed by text mining. The information on interactions among gene, compound/therapy, cell/animal model, pathway/disease, and clinical study was extracted. Networks were constructed to simulate effects of IDO1 inhibition on anti-PD-1. Results: The IDO1/anti-PD-1 network consists of 79 nodes, 227 interactions with 1277 possible regulatory paths from IDO1 to anti-PD-1. 675 paths are associated with agonism and 602 with antagonism between IDO1 inhibition and anti-PD-1. Up-regulation of [TNF-alpha, IFN-gamma, type I immunity & CD8+ T cells], and down-regulation of [Tregs, MDSC, JAK/STAT pathway, IL-6 and PD-L1] are associated with enhancement of anti-PD-1 by IDO1 inhibition. Besides, treatments with PARP inhibitor, EGFR inhibitor or radiation may enhance the combination efficacy of IDO1 and PD-1 inhibitors. Up-regulation of TIM-3 and NK cells are associated with reduced activities of anti-PD-1 upon IDO1 inhibition. PD-L1 is a predictive biomarker for anti-PD-1 response and its expression can be regulated by IDO1. The IDO1/PD-L1 network consists of 83 nodes, 204 interactions and 318 paths. Up-regulation of IL-6, AhR, MDSC, JAK/STAT, HIF1A, IL10, NF-kappaB & MYC was associated with induction of PD-L1 by IDO1. Conclusions: As the network analyses revealed, inhibition of IDO1 could either up- or down-regulate PD-L1, and enhance or reduce efficacy of anti-PD-1. Multiple factors, other than PD-L1, play roles in determining the efficacy of combining IDO1 and PD-1 inhibitors.
Evaluation of radiotherapeutic and immune-modulatory response to whole brain radiotherapy or stereotactic radiosurgery in patients with brain metastases from malignant melanoma treated with or without ipilimumab (ELEKTRA).
Authors: Hassel Jessica Cecile , Smetak Heiko , Salzmann Martin , Haefner Matthias , Bernhardt Denise , Hülsmeyer Ingrid , Enk Alexander , Debus Juergen , Beckhove Philipp 
Published: May 2019

e14104 Background: Immune checkpoint blockers have dramatically improved the survival of patients (pts) suffering from advanced metastasized melanoma. In pts with melanoma brain metastases (MBM) a combination with radiotherapy (RT) is routinely used. Methods: We prospectively included 106 pts with MBM in a non-randomized observational trial with 7 treatment cohorts. Patients in cohort 1-4 were treated with ipilimumab (+/- nivolumab) and either stereotactic (up to 3 MBM) or whole brain RT (≥ 4 MBM) before or after the start of immunotherapy. Cohort 5 and 6 included pts who received RT with an ipilimumab-free systemic treatment and cohort 7 pts were treated with ipilimumab (+/- nivolumab) and no RT. Primary endpoints were immunological response in the peripheral blood (FACS of T cell subsets, ELISpots against melanoma antigens) and radiological response, secondary endpoints were progression free and overall survival. Results: Included pts were in median 61 years old, 72% were male. At trial inclusion, 31% of pts had an elevated LDH. 39% of ipilimumab treated pts received combination therapy with nivolumab. Clinically, ipilimumab treated pts in the early RT groups had better responses of both intra- and extracranial disease (p = 0.04 for both). Multivariate analyses showed a better PFS for pts with early RT (p = 0.02) and normal LDH (p = 0.049). Type of radiation (p = 0.6) and immune therapy (p = 0.8) had no significant influence in this small cohort of pts. Immune monitoring revealed that ipilimumab leads to an increase in activated CD4+ and CD8+ T cells in the peripheral blood which was maintained in responding pts and higher in pts receiving early RT. Treg were not depleted in general but activated by ipilimumab. However, responders displayed a temporary decrease of Treg and activated Treg under treatment. An increase in the detection of melanoma antigens could be observed after 2 cycles of ipilimumab which was higher in pts with combined radioimmunotherapy compared to ipilimumab only. Conclusions: Preliminary data from this small observational trial might lead to a preference of a treatment sequence with radiotherapy first, followed by checkpoint inhibition in pts with MBM.
Gastrointestinal, pancreatic, and hepatic toxicity profile of CTLA-4 immune checkpoint inhibitors alone and in combination with PD-1/PD-L1 inhibitors: A meta-analysis of clinical trials.
Authors: Ali Faisal , Hussain Maryam R , Deep Aman , Abu-Sbeih Hamzah , Alrifai Taha , Myint Phyo Thazin , Gong Zimu , Kozma Kelley Elizabeth 
Published: May 2019

e14117 Background: Cytotoxic T-lymphocyte activator-4 immune checkpoint inhibitors (CTLA-4-ICPI) is believed to cause more toxicity than programmed cell death/Ligand-1 (PD-1/PD-L1) ICPIs. We conducted a meta-analysis to outline the gastrointestinal (GI), pancreatic, and hepatic toxicity of CTLA-4 ICPIs when used alone and in combination with PD-1/PD-L1 ICPIs (C-ICPI). Methods: Ovid MEDLINE, EMBASE, Cochrane Library, SCOPUS, Web of Science, ClinicalTrials.gov, and WHO ICTRP were queried from January 2007-October 2018. Clinical trials reporting ICPI associated adverse events (AEs) were included. Colitis was defined as the development of diarrhea or documented colitis of any grade. Pancreatitis was defined as an elevation of amylase or lipase. Hepatitis was defined as elevation of ALT, AST, or transaminitis of any grade. A meta-analysis of proportions was conducted to report pooled AEs rate with 95% confidence intervals (CI) using a random effects model. Results: Overall, 30 study arms (20 CTLA-4, 10 C-ICPI) enrolling 3721 patients were included. There were a total of 3944 and 3317 AEs with CTLA-4 and C-ICPI use, respectively, with a pooled incidence of high grade AEs (grade 3-5; HAEs) of 23% (95% CI 16-33%) with CTLA-4 use and 52% (95% CI 37-67%) with C-ICPI use ( Table). The incidence of high-grade colitis was higher among patients treated with CTLA-4 ICPI. The proportion of high-grade pancreatitis was higher among patient who received C-ICPI. Two GI perforations were reported with CTLA-4 use. Pooled incidence of treatment related mortality was 1% in both groups. Conclusions: Though the overall GI, hepatic and pancreatic safety profile of CTLA-4 is comparable to C-ICPI, a higher incidence of high-grade colitis was found with CTLA-4. Two GI perforations were reported with CTLA-4 and warrant further investigation. No difference in treatment related mortality was found among the two groups. [Table: see text]
Clinical and immunological analyses of immune checkpoint inhibitor-associated neuromuscular (NM) toxicities.
Authors: Siddiqui Bilal A. , Durand Jean-Bernard , Gao Jianjun , Wang Jianbo , Aparicio Ana , Campbell Matthew T , Siefker-Radtke Arlene O. , Tannir Nizar M. , Corn Paul Gettys , Msaouel Pavlos , Shah Amishi Yogesh , Zurita Amado J. , Tu Shi-Ming , Suarez-Almazor Maria E. , Sudhakar Tummala , Logothetis Christopher , Sharma Padmanee , Subudhi Sumit Kumar 
Published: May 2019

e14118 Background: A rare and often fatal spectrum of NM immune-related adverse events (irAEs) includes myositis, myocarditis, and myasthenia gravis (MG). A deeper understanding of their clinical and immunologic features may improve outcomes. Methods: Sixteen patients (pts) with genitourinary cancers who were treated with ICI and developed myositis, myocarditis, MG, or overlap syndrome (≥2) were identified. Diagnostic criteria included serum CK (n=16), aldolase (n=14), troponin (n=12), BNP (n=15), autoantibodies (n=16), and cytokines (n=9). Biopsies of skeletal muscle (n=13) and endomyocardium (n=4) were also obtained. Immune profiling is being performed on blood and tissue for pts consented to an institutional-approved laboratory protocol. Results: ICI-associated NM irAEs consisted of isolated myositis (n=8, 50%), myocarditis (n=1, 6%), MG (n=1, 6%), or overlap syndrome (n=6, 38%), with the most common presenting symptom being weakness (n=9, 56%). CK levels were elevated in 15 (94%) pts, and autoantibodies were detected in 9 (56%). Muscle biopsies showed predominantly T cell infiltration. All 16 pts received corticosteroids, 12 (75%) were treated with other immunosuppressive agents, and 14 (88%) underwent plasmapheresis. Five pts (50%) with isolated irAEs achieved symptom resolution, and none in the overlap group. (Table) Conclusions: NM irAEs occurred more frequently with combination ICI, and were associated with weakness, and elevated CK level and serum autoantibodies. Both T and B cells appear to drive disease pathogenesis. The presence of one toxicity on the spectrum warrants evaluation for associated irAEs. Compared to isolated NM irAEs, the overlap syndrome appears to be more treatment refractory. Current guidelines require refinement to identify effective treatments to improve outcomes. [Table: see text]