tbuckley/cabot-search huggingface dataset:
Volumetric modulated arc therapy versus conformal radiation therapy for conditioning of allogenic bone marrow transplantation (ABMT) in acute lymphoblastic leukemia.
Authors: María Fátima Chilaca Rosas, Jesus Gerardo Gutierrez Marquez, Alberto López Valencia, Héctor Urueta Cuellar, Juan Carlos Hernández García, Juan Carlos Heredia Gutierrez, Alejandro Olmos Guzmán, Christian Salvador Adame Gonzalez, Saul Campos Gomez, Daniel Motola, Alicia Guillermina González Noguez, Jeanette Rodrìguez Cortes, Carla Montaño García, Marco Aurelio Rosales Gamboa, Jose Luis Aguilar
Journal: Journal of Clinical Oncology (2017)

e18532 Background: Total body irradiation is performed as part of the conditioning regimen for patients eligible for ABMT. New techniques have been investigated to target more selectively of total medular irradiation. Purpose:In this study a preclinical investigation was undertaken to explore a treatment technique for total marrow irradiation using a volumetric modulated arc technique (VMAT) versus conformal radiation therapy. Methods: Ten patients conditioning for ABMT between the periods of April to October 2016 were evaluated. A comparative dosimetric analysis between conformal and VMAT radiation therapy techniques was performed. Treatment plan was performed by using ten arcs with three isocenters with a collimator angle between 10°-100°, optimized for energy of 6MV. The prescribed dose was 12 Gy. In order to cover the bone marrow the PTV was defined as the bones from the cranium vertex to the middle third of the femur. The organs at risk constraints had a median restriction of ≤ 10Gy. Radiation therapy integral dose, conformity, homogeneity and coverage index were evaluated. Results: The average volume of body irradiated was 52,433cc (37,221-73,968cc), the average volume of the PTV was 10,379cc (8,449-13,325cc). The average dose for the planning target volume (PTV) using conformal radiation technique and with VMAT was 15.3Gy and 13.1 Gy (p &lt; 0.0001), respectively. The median dose for the organs at risk with the conformal technique was 17.5Gy and 10.4Gy for the VMAT (p = 0.0013). The median of index of conformity using the conformal technique was 5.21 and 1.99 with VMAT (p = 0.0003). The homogeneity index was 1.87 and 1.37(p &lt; 0.0001) respectively. The quality of coverage was 0.82 and 0.81 (p = 0.951), respectively. The integral dose was 7,699.73 and 6,615.8 kg/Gy (p &lt; 0.0001) respectively. Conclusions: For patients conditioning for ABMT requiring bone marrow irradiation the intensity modulated VMAT radiation therapy technique offers a better conformity and homogeneity index and also offers a reduction in the integral dose, suggesting the possibility of incorporating this technique in the treatment options for patients.
Long term efficacy and safety of nimotuzumab in unresectable locally advanced squamous cell carcinoma of head and neck: A real world Indian experience.
Authors: Sundaram Subramanian, Sridharan Nithya, Sameer Chaudhari
Journal: Journal of Clinical Oncology (2018)

e18077 Background: Nimotuzumab is an anti-EGFR monoclonal antibody approved for the treatment of head and neck cancer (HNC) in India and 20 other countries. However, available evidence on long term survival benefits of addition of nimotuzumab to concurrent chemoradiotherapy (CCRT) is limited. This study was conducted to evaluate long term efficacy and safety of nimotuzumab with CCRT in patients with unresectable locally advanced HNC. Methods: Between October 2010 to November 2016, 61 patients of unresectable locally advanced (stage III – IVb) HNC with histologically confirmed squamous cell carcinoma were included in this study. All patients were administered nimotuzumab (200mg IV) weekly for six weeks along with standard chemoradiotherapy. Overall survival(OS) and possible association of various dependent factors with survival was analysed. All patients were assessed for toxicity and adverse events (AEs) were reported as per the common terminology criteria for AEs v 4.0. Statistical analysis was done using STATA (V. 12) software. Results: A total of 61 patients (44 male/17 female, median age 57.0 ± 12.42 years) were considered for the analysis. Survival rate at 1 year, 3 year and 5 year was 92.92 %, 72.87% and 62.78% respectively. Median overall survival was 77 months (95% CI, 38.67 - NR). Median OS was higher in women, patients aged less than 65 years, ECOG score 1, tumour stage T3, nodal stage N0, laryngeal cancer patients. However, the difference was not statistically significant. Patients aged ≥ 65 years (N = 20) showed median OS of 56.97 months (95% CI; 19.63 - NR). All adverse events were either grade I or grade II. No grade III or grade IV adverse events were observed due to nimotuzumab. Unlike other anti-EGFR drugs, nimotuzumab related skin rash was seen in only 2 (5.9%) patients. Conclusions: Adding nimotuzumab to CCRT for treatment of unresectable locally advanced head and neck cancer was found to be efficacious and safe. Similar efficacy and safety was also seen in subset of patients aged ≥ 65 years in whom treatment options are limited.
A dose escalation phase 1 study of radiotherapy (RT) in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab in patients (pts) with metastatic melanoma.
Authors: Celine Boutros, Christine Mateus, Emilie Lanoy, Emilie Routier, Salem Chouaib, Dominique Schwob, Stephan Vagner, Isabelle Girault, Caroline Caramella, Salima Hibat, yun Gan Tao, Kim Cao, Nathalie Chaput, Julien Adam, Jean-Charles Soria, Alexander M. Eggermont, Eric Deutsch, Caroline Robert
Journal: Journal of Clinical Oncology (2017)

9549 Background: Preclinical findings have shown a synergy between RT and anti-CTLA-4 monoclonal antibody in several tumor animal models for both local tumor control and distant effects. Preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of RT combined with ipilimumab in pts with metastatic melanoma. Methods: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of RT (in 3 fractions) at week 4 combined with 10 mg/kg ipilimumab (every 3 weeks for 4 doses). Pts with evidence of clinical benefit at week 12 were eligible for maintenance ipilimumab at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). Results: 19 pts with advanced melanoma received ipilimumab between August 2011 and July 2015. Nine pts received the 4 doses of ipilimumab and 2 pts received maintenance ipilimumab (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, desease-related pain and fever. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). Nine pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy dose. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis). The median progression-free survival [95% CI] was 7.2 months [2.4 – 16.8]. The median overall survival [95% CI] was 14.4 months [7.2 – 20.4]. Conclusions: When combined with ipilimumab at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity. Clinical trial information: 2010-020317-93.
Analysis of lymphocyte-neutrophil relationship in patients with advanced kidney cancer and the response to one-line treatment with target therapies.
Authors: Luciana Paola Acosta, Martin Eduardo Richardet, Matias Molina, Eduardo Richardet
Journal: Journal of Clinical Oncology (2017)

e23034 Background: In kidney cancer, some important prognostic factors of survival are known and inflammation plays a key role. It has been proven that cancer progress is not only determined by the characteristics of the tumor but also by the response of the host. It is known that a high RNL has been identified as an independent prognostic factor associated to poor survival in several/different types of cancer, including breast cancer, colon cancer, gastric cancer, mesothelioma and pancreas. The primary aim was to evaluate if RNL can be used as a prognostic indicator of SLP in patients with advanced CCR with 1st line treatment with tirosin-kinasa inhibitors. The secondary aim was to evaluate whether there was a relationship between prognostic factors, smoking habits, BMI, anemia, calcemia, KPS and nephrectomized patients as opposed to those who were not operated with RNL and SLP. Methods: Retrospective and analytical study. The medical histories from patients with metastatic kidney cancer diagnosis were analyzed as well as those who were undergoing treatment with Sunitinib and Pazopanib. The cut value of &gt; ó &lt; 3 was taken as a reference point for RNL. Overall survival analysis will be evaluated through the Kaplan-Meier curve and the meaning will be verified by the log-rank test. The multivariate analysis will be done through the Chi-square test. Results: A total of 65 patients were included in this study. 50 patients (75.38%) received treatment with Sunitinib and 15 patients (24.62%) with Pazopanib. It was observed that RNL &lt; 3 was correlated with a higher SLP 21,6 months vs 8.9 months, p = 0,00002 and it was statistically significant. In subgroup analysis, those patients with normal values of corrected calcium the survival was 20 months vs 12, 2 months (p: 0.01), non-smokers 21 months vs 12 months (p: 0.05), KPS &gt; 1 17,72 months Vs 8,8 months (p: 0.03) and a RNL &lt; 3 showed a higher survival in a statistically significant way. There were no differences in survival when we performed the anemia analysis, BMI, smoking habits and KPS 0 to 1. Conclusions: We can conclude that those patients with RNL &lt; 3 and who had already undergone treatment with ITK revealed a better SLP in a statistically significant way.
Upfront short course radiotherapy (SCRT) in metastatic rectal cancer (mRC): A way forward.
Authors: Shanu Jain, Reena Engineer, Vikas S. Ostwal, Anant Ramaswamy, Supriya Chopra, Ashwin Desouza, Shirley Christabel Lewis, Suprita Arya, Prachi Patil, Avanish Saklani
Journal: Journal of Clinical Oncology (2017)

3570 Background: To evaluate the feasibility and efficacy of SCRT followed by chemotherapy (CT) in locally advanced metastatic rectal cancer (LAmRC). Methods: Between May 2012 and August 2015, 70 patients having LAmRC with or without circumferential resection margin (CRM) positive disease treated with SCRT (25Gy/5#) followed by 3-6 cycles of capecitabine/5-FU, oxaliplatin or irinotecan based CT were assessed. Results: Fifty one had single site metastases (23 liver, 16 lung, 10 retroperitoneal lymph nodes and 2 peritoneum), 9 had combined lung and liver metastases and 10 had combined nodal and organ metastases. Sixty five (93%) patients could complete planned SCRT and 3-6 cycles of chemotherapy (starting 7-10 days after RT completion) with dose reduction in 21 (32%) patients owing to CT induced toxicities. Local tumor down-staging was achieved in 43 (61.4%) patients and the rest had a stable primary disease. Radiologically, CRM was free in 25 (46.3%) patients out of 54 initially involved. Surgery of the primary was planned in 38 (58%). R0 resection in 26 (40%), R1 in 7 (pCRM positive). Five refused surgery in spite of being resectable. Rest of the 27 (41%) received palliative CT due to progression of distant disease. Metastatectomy along with primary surgery was done in 16 (25%) patients. Median follow up was 29 months. Overall survival (OS) of entire cohort at 2 years was 40%. Median progression free survival (PFS) and OS of patients with resected primary was 17 (10-24) and 37 (28-45) months, respectively, which is significantly better than those who were not resected (p = &lt; 0.001). Of these 33 resected patients, 13 (39.4%) are disease free and 20 have progressed (16 distant, 2 loco-regional and 2 local and systemic). Conclusions: Upfront SCRT followed by systemic CT in an unresectable group of metastatic rectal cancer patients is safe and feasible and is having encouraging results in terms of downstaging and resectability of the primary. [Table: see text]
AB1372 Towards reforming the taxonomy of human disease: the precisesads cross sectional study
Authors: L. LAIGLE, L. BERETTA, J. WOJICK, J. MAROVAC, J.-O. PERS, B. LAUWERYS, J. FROSTEGARD, F. MAC DONALD, M. JUAREZ, R. BENSCHOP, E. DOW, S. RAO, C. CHAMBERLAIN, J. MARTIN, M.E. ALARCON-RIQUELME
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> The PRECISESADS project aims at using OMICs, and bioinformatics to identify new classifications for systemic autoimmune diseases (SADs) known to share common pathophysiological mechanisms in view of personalised treatments. Multi OMICs parameters collected in addition to routine clinical data in a cross-sectional study involving patients suffering from systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren’s syndrome (Sjs), rheumatoid arthritis (RA), primary antiphospholipid syndrome (PAPs), mixed connective tissue disease (MCTD), undifferentiated connective tissue disease (UCTD) and healthy controls (HC) will be analysed to identify clinically relevant clusters. <h3>Methods</h3> A European multi centre, non-randomised, cross-sectional clinical study was conducted in 18 sites and 9 countries. Collection of OMIC data including genetic, epigenomic, transcriptomic (from peripheral blood and from isolated cells), flow cytometry, metabolomics and proteomic in plasma and urine, exosome analysis and classical serology (antibodies and autoantibodies) was organised. Novel and innovative methodologies including fine flow cytometry were conducted. Quality procedures were established to ensure standardisation of samples collection, processing, transportation and storage. Techniques were validated to ensure reproducibility of analyses. Unsupervised bioinformatics and biostatistics approaches will be applied. <h3>Results</h3> Recruitment started in <sup>December 2014</sup> and ended in October 2017. A total of 2656 participants were recruited: 377 RA, 470 SLE, 402 SSc, 385 SjS, 99 MTCD, 106 PAPs, 166 UCTD patients and 651 HCs. Median age was between 46 and 59 years and was consistent with each disease onset peak. 97% of the population was Caucasian. Most of the patients were treated with standard of care therapies and less than 10% were on biologics. OMICs and bioinformatics analyses are on-going. <h3>Conclusions</h3> We have established one of the largest collaborative multi-OMICs studies from patients with SADs. The most important challenge is now the integration of all these novel data to support hypothesis-free, machine learning-led analytical protocols. It is expected that the integration of data from affected patients, in comparison with well-matched controls, will provide new biomarker-led descriptions of clusters of potentially etiologically distinct disease entities. <h3>Acknowledgements</h3> This work has received support from the EU/EFPIA/Innovative Medicines Initiative Joint Undertaking PRECISESADS grant n° 1 15 565 <h3>Disclosure of Interest</h3> None declared
Immune profile and outcomes of patients (pts) with gynecological malignancies (GYN) enrolled in early phases immunotherapy (IO) trials.
Authors: Victor Rodriguez Freixinos, Angel Garcia, Roberta Fasani, Josep Castellvi, Fiorella Ruiz-Pace, Cristina Viaplana, Lorena Fariñas-Madrid, Cristina Casal, Ignacio Matos, Juan Martin-Liberal, Irene Braña, Cinta Hierro, Jose Jimenez, Elena Garralda, Paolo Nuciforo, Rodrigo Dienstmann, Ana Oaknin
Journal: Journal of Clinical Oncology (2018)

5595 Background: Immune checkpoint inhibitors have shown promising activity in multiple tumor types. However, there are no approved IO for GYN. Methods: We identified GYN pts treated with IO from 2014-2017 in phase I/II trials at Vall d´Hebron. Tumor infiltrating lymphocites (TILs); PD-L1 expression by immunohistochemistry (IHC) (SP263 antibody); microsatellite instability (MSI) by IHC and Gynecological Immune Prognostic Index (GIPI) (baseline derived NLR (dNLR) (neutrophils/(leucocytes-neutrophils)) > 3 and LDH > upper limit of normal) were correlated with outcomes. Results: Sixty GYN cases (32 ovarian (OC); 8 endometrial(EC);15 cervical(CC) and 5 vulvar (VC)) were selected. Median number of metastatic sites and prior lines were 2 (1-4) and 2 (0-8) respectively. Median TILs was 10% (1%-90%); 10% of pts had high TILs (≥ 50%) and CC showed higher TILs (p = 0.007). PD-L1 > 1% was shown in 60% of pts (46% OC, 43% CC, and 11% EC). Single agent IO involved 47% of cases. Median follow-up was 69m. Overall response rate was 15%. Median progression-free survival (PFS) and clinical benefit rate (CBR) (complete/partial response or stable disease ≥ 6 months (m)) were 2.63m [95% CI 2.07-5.13] and 32% respectively, without differences in any subgroup (4 EC pts with CBR are ongoing). Two EC pts (14%) from the population with CBR had MSI. dNLR and > 3 metastatic sites correlated with worse PFS (p = 0.035 and p < 0.0007 respectively). PD-L1 expression as continuous variable (p = 0.017) but not TILs (p = 0.37) correlated with improved outcomes. PD-L1≥20% associated with longer mPFS (NR (95% CI 5.13-NA) vs. 2.47m (95% CI 1.9-3.77); HR = 0.08, p = 0.017).“Hyperprogression” (HPD) (≥40% tumor burden increase or ≥20% plus multiple new lesions) was shown in 23% of pts without differences in any subgroup. Poor GIPI group (2 factors (+)) had a trend for worse overall survival (4.43 vs. 18.23m; HR = 2.63 (95% CI 0.9-7.5), p = 0.07). Conclusions: Although IO drug development is slowly evolving in GYN, we found encouraging activity in a significant proportion of GYN pts. HPD is not a rare event in GYN. Further work is needed to better characterize pts at risk of HPD and optimize immune-related biomarkers, particularly PD-L1 assessment.
Lume-meso: A double-blind, randomized, phase II/III study of nintedanib (N) + pemetrexed (P)/cisplatin (C) followed by maintenance N versus placebo + P/C followed by maintenance placebo for patients with unresectable malignant pleural mesothelioma (MPM).
Authors: Giorgio V. Scagliotti, Rabab M. Gaafar, Anna K. Nowak, Jan P. Van Meerbeeck, Nicholas J. Vogelzang, Ute von Wangenheim, Arsene-Bienvenu Loembe, Nassim Morsli, Derek Velema, Sanjay Popat
Journal: Journal of Clinical Oncology (2016)

TPS8574 Background: Median overall survival (OS) is ~1 year with P/C, the standard front-line treatment for patients (pts) with unresectable MPM; additional improvement is needed. Nintedanib (N) is an oral, twice-daily, triple angiokinase inhibitor of VEGF, PDGF and FGF as well as Src and Abl kinase signalling, all of which are involved in regulating tumor angiogenesis, growth, and metastasis of MPM. Inhibition of the VEGF pathway has been validated as a treatment approach for MPM (J Clin Oncol 2015;33:A7500). Nintedanib (VARGATEF) in combination with docetaxel is approved in the European Union and other countries for locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after first-line chemotherapy and has shown clinical benefit in trials in several tumor types. The current study was extended from a Phase II to a confirmatory Phase II/III trial after all Phase II pts had enrolled. Methods: Chemo-naive pts from 25 countries ( ≥ 18 years of age, ECOG PS 0–1, and histologically confirmed epithelioid/biphasic MPM; 87 pts in Phase II/310‒450 pts in Phase III) will be randomized (1:1) to receive up to 6 cycles of P (500 mg/m2)/C (75 mg/m2) on Day 1 plus N (200 mg bid) or placebo from Days 2–21. Pts without disease progression (PD) will continue to receive maintenance treatment with N or placebo until PD. The primary endpoint is progression-free survival (PFS); OS is the key secondary endpoint. The study will use an adaptive design strategy, with sample size reassessment by an external DMC based on interim analysis to ensure sufficient power for PFS/OS. Additional secondary endpoints include objective tumor response and disease control according to modified RECIST. Other assessments include frequency/severity of adverse events, laboratory parameters, change in forced vital capacity, health-related quality-of-life and exploratory predictive biomarker analyses in tumor/blood specimens. The study is currently enrolling pts into Phase III. Clinical trial information: NCT01907100.
Modulating tumor-specific tissue penetration via peptides enhances the efficacy of radiotherapy.
Authors: Fanyan Meng, Jun Liu, Huizi Sha, Shu Su, Jie Shao, Qiuping Xu, Zhengyun Zou, Xiaoping Qian, Jia Wei, Baorui Liu
Journal: Journal of Clinical Oncology (2018)

e24324 Background: Radiotherapy resistance of tumor cells remains a major therapeutic problem in tumor therapy, and hypoxia is one of the most major resistance mechanisms in various tumor types. A number of drugs and strategies have been designed to enhance the radiosensitivity of solid tumors, however, the nontumor-specific mechanism of the radiation modulators limits its utility in clinical care. Here, we revealed that treatment with tumor-specific tissue penetrating peptides (TPPs) iRGD and LyP-1 enhanced the radiosensitivity of breast cancer 4T1 multicellular tumor spheres (MCTSs) in vitro and 4T1 tumors in vivo. Methods: The growth and migration potentials of MCTSs were evaluated. The 4T1 Tumor growth were measured by calipers and lung metastasis were detected by HE staining. Hypoxia was detected by Hypoxyprobe-1 (hpi). The expression of hypoxia-related genes was measured by Q-PCR. Apoptosis were detected by annexin V and TUNEL. Results: The growth and migration potentials of MCTSs treated with radiation and TPPs decreased significantly, comparing to those of groups of control and single treatment with radiation or TPPs. In contrast, the growth of one-layer cultured 4T1 cells did not change significantly between radiation groups treated with or without TPPs. The growth and metastasis of 4T1 tumors were also delayed dramatically after treatments with radiation and TPPs. The percentages of hypoxic cells in MCTSs were reduced significantly after treatment with TPPs, other than control peptides. The mRNA levels of four hypoxia-related genes Hif-1a, Angptl-4, Mmp-9 and Gapdh were also decreased significantly after MCTSs were treated with TPPs. The hypoxia areas of 4T1 tumor tissues were declined after mice treated with TPPs. Apoptosis assay demonstrated that the percentages of apoptotic cells were increased after radiation with TPPs. Together, these results suggested that TPPs enhanced the efficiency of radiation by reducing hypoxia. Conclusions: This is the first report that remodeling tumor-specific tissue penetration with TPPs enhances the efficiency of radiation, implying the potential application in clinic in future.