bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II study on gemcitabine with or without ramucirumab as second-line treatment for advanced malignant pleural mesothelioma (MPM): Results of Italian Rames Study.
Authors: Pagano Maria , Ceresoli Giovanni Luca , Zucali Paolo Andrea , Pasello Giulia , Garassino Marina Chiara , Grosso Federica , Tiseo Marcello , Soto Parra Hector J. , Zanelli Francesca , Cappuzzo Federico , Grossi Francesco , de Marinis Filippo , Pedrazzoli Paolo , Gnoni Roberta , Bonelli Candida , Berselli Annalisa , Boni Luca , Normanno Nicola , Pinto Carmine 
Published: May 2020

9004 Background. The RAMES Study (EudraCT Number 2016-001132-36) is a multicenter, double-blind, randomized phase II trial exploring the efficacy and the safety of the addition of ramucirumab to gemcitabine as the second-line treatment in MPM patients (pts) after platinum/pemetrexed regimens. Methods. The pts were assigned (1:1) to receive Gemcitabine 1000 mg/m2 i v on days 1 and 8 every 21 days with Placebo (Arm A) or Ramucirumab 10 mg/kg i v on day 1, of a 21-day cycle (Arm B), until tolerability or progressive disease. Pts was stratified by ECOG/PS (0-1 vs 2), age (≤ 70 vs > 70 yrs), histology (epithelioid vs non-epithelioid) and time to progression (TTP) after first-line therapy. The primary endpoint was overall survival (OS). Assuming a proportion of OS equal to 40% at 1 year in arm A, a 12% absolute improvement in OS at 1 yrs was expected in Arm B (hazard ratio = 0.70).114 events (156 subjects) are required for a one-sided log-rank test with α = 0.15 to have 80% power. Results. From December 2016 to July 2018, 164 pts were randomized, 81 pts in Arm A and 80 Arm B; 3 pts were randomized but not treated. Characteristics of pts were: median age 69 yrs (44-81), males 119 (73.9%), females 42 (26.1%); ECOG/PS0 96 (59.6%) ECOG/PS1-2 65 (40.4%); histotype epithelioid 132 (81.9%), non-epithelioid 29 (18.1%); stage III 98 (60.7%), stage IV 60 (37.3%), 3 (2.0%) missing; asbestos exposure assessed 80 (49.7%). Median of courses was 3.50 in Arm A and 7.50 in Arm B. OS was significantly longer in Arm B with median 13.8 mths (70% CI 12.7-14.4) vs Arm A with 7.5 mths (70% CI 6.9-8.9), HR 0.71 (70% CI 0.59-0.85, p = 0.057). OS at 6 and 12 mths was in Arm A 63.9% and 33.9%, and in Arm B 74.7% and 56.5%, respectively. In Arm B OS was not correlated to TTP at first-line therapy (13.6 mths in TTP ≤6 mths and 13.9 mths in TTP > 6 mths) and histotypes (13.8 months in the epithelioid and 13.0 months in non-epithelioid). No significant differences in thromboembolism G3-4 events were observed in Arm A vs Arm B (p= 0.64). None hypertension G3-4 was reported in Arm A vs 5 pts (6.3%) in Arm B (p= 0.022). No significant differences in G3-4 haematological toxicities between the two arms were reported. Conclusion: In the RAMES Study the addition of Ramucirumab to Gemcitabine significantly improved OS regardless of age of pts, tumor histotype and TTP at the first-line treatment. Gemcitabine plus Ramucirumab can be considered a manageable regimen in second-line treatment of advanced MPM pts. Clinical trial information: NTC03560973.
A phase II trial of atezolizumab and bevacizumab in patients with relapsed/refractory and unresectable malignant peritoneal mesothelioma.
Authors: Raghav Kanwal Pratap Singh , Overman Michael J. , Liu Suyu , Willett Anneleis , Royal Richard Eldon , Malpica Anais , Scally Christopher , Wistuba Ignacio Ivan , Futreal Andrew , Mahvash Armeen , Yun Cindy , Dervin Shannon , Mckenna Edward Francis , Schulze Katja , Hwu Patrick , Yao James C. , Kopetz Scott , Varadhachary Gauri Rajani , Halperin Daniel M. 
Published: May 2020

9013 Background: Malignant peritoneal mesothelioma (MPeM) is an orphan malignancy. No recommended/FDA approved therapies exist for salvage treatment beyond first-line platinum and pemetrexed based chemotherapy. While immune checkpoint inhibition has shown preliminary efficacy in mesotheliomas, data and efficacy is limited in MPeM patients (pts) [objective response rate (ORR) ~ 11%; median progression-free survival (mPFS) ~ 4 months (m); median overall survival (mOS) ~ 11 m]. We aimed to prospectively assess the safety and efficacy of combined anti-PD1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) in pts with MPeM. Methods: In this phase 2 study, eligible pts with histologically confirmed MPeM, ECOG PS 0-1, and prior platinum and pemetrexed treatment were treated with 1200 mg of atezolizumab and 15 mg/kg of bevacizumab IV every 21 days until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint was confirmed ORR by RECIST 1.1 by independent radiology review. Duration of response (DOR), PFS and OS were pre-specified secondary endpoints. Results: Among 20 enrolled pts (3/2017 - 2/2019), median age was 63 (range, 33-87) years, 12 (60%) were female, 12 (60%) had PS 0, and 2 (10%) had biphasic MPeM. Among 20 evaluable pts (median cycles 14), confirmed ORR was 35% (7 pts; 95% CI: 15.4-59.2) (median DOR 8.8 m). Responses were ongoing in 5/7 (71.4%) pts at data cutoff. The median follow-up was 20.5 months. Six deaths were observed during follow-up, and the 1-year OS was 79% (95% CI: 52 – 91) (median OS ~ NR). Median PFS was estimated as 17.6 m (95% CI: 9.1 – NR). The 1-year PFS was 54% (95% CI: 28 – 74). Grade 3 (no grade 4/5) treatment-emergent adverse events occurred in 10 (50%) pts; most common being hypertension (40%) and anemia (10%). Two (10%) pts had grade 3 immune-related adverse events. Translational studies are ongoing. Conclusions: AtezoBev showed promising and durable efficacy in relapsed/refractory MPeM with acceptable safety profile. Ongoing multiomic analyses of pre and on-treatment tissue/liquid biopsies obtained on all these pts will provide additional insight into mechanisms and biomarkers of response and resistance. Clinical trial information: NCT03074513.
PIT-1: Randomized phase II trail of pemetrexed-cisplatin plus bevacizumab or concurrent thoracic radiation therapy followed by surgery in stage IIIA (N2) nonsquamous non-small cell lung cancer.
Authors: Takamochi Kazuya , Suzuki Kenji , Tsuboi Masahiro , Niho Seiji , Ishikura Satoshi , Oyamada Shunsuke , Yamaguchi Takuhiro , Yoshino Ichiro , Ito Hiroyuki , Okumura Norihito , Tanaka Fumihiro , Saji Hisashi , Tsuchida Masanori , Horio Hirotoshi , Shiono Satoshi , Matsuura Motoki , Ikeda Norihiko , Tanaka Toshiki , Okada Morihito 
Published: May 2020

9014 Background: PIT-1 (Personized Induction Therapy-1) is a multicenter, open-label, randomized phase II study using selection design of platinum doublet chemotherapy plus angiogenesis inhibitor or concurrent thoracic radiation therapy (TRT) as induction therapy followed by surgery in patients with stage IIIA (N2) nonsquamous non-small cell lung cancer (NSCLC) to investigate the efficacy and safety of these treatment strategies. Methods: Patients with stage IIIA (pathologically proven N2) nonsquamous NSCLC randomly received (1:1) induction therapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) plus bevacizumab (15 mg/kg) intravenously every 3 weeks for three cycles (arm A) or concurrent TRT (45 Gy in 25 fractions) (arm B) followed by surgery. The primary endpoint was 2-year progression-free survival (PFS) rate and key secondary endpoints included overall survival (OS), the objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the pathological complete remission (pCR) rate, feasibility and toxicity. Results: Eighty-eight patients were randomly assigned (each arm, n = 44) between October 2013 and June 2017 and 82 (arm A, n = 42; arm B, n = 40) were treated. Patient demographics were balanced between the two arms. The percentage of patients who received induction therapy followed by surgery was 88.1% (37/42) in arm A and 92.5% (37/40) in arm B. The complete resection rate was 81.1% (30/37) in arm A, and 91.9% (34/37) in arm B. The 2-year PFS rate was 36.8% (95% CI: 22.4-51.2) in arm A, and 50.0% (95% CI: 33.8-64.2) in arm B. The 2-year OS rate was 80.5% (95% CI: 64.7-89.7) in arm A, and 80.0% (95% CI: 64.0-89.5) in arm B. The ORR was 50.0% (21/42) in arm A and 60.0% (24/40) in arm B. The pCR rate was 8.1% (3/37) in arm A and 10.8% (4/37) in arm B. Grade 3 or 4 toxicities occurred during induction therapy in 35.7% of the patients in arm A and 22.5% of the patients in arm B. Grade 3 or 4 surgical complications occurred in 21.4% of the patients in arm A and 20.0% of the patients in arm B. Although no fatal toxicity was observed during induction therapy in either arm, two patients in arm A died after surgery due to bronchopleural fistula. Conclusions: The 2-year PFS rate in arm B was higher than that in arm A. Fatal surgical complications were only observed in arm A. Therefore, we chose pemetrexed-cisplatin plus concurrent thoracic radiation therapy as the investigational induction treatment strategy for a future phase III study. Clinical trial information: 000011941.
Reliable detection of the presence of pulmonary carcinoma on whole-slide images by a deep learning model.
Authors: Toyokawa Gouji , Kanavati Fahdi , Momosaki Seiya , Rambeau Michael , Kozuma Yuka , Shoji Fumihiro , Yamazaki Koji , Takeo Sadanori , Iizuka Osamu , Tsuneki Masayuki 
Published: May 2020

9025 Background: Lung cancer is one of the leading causes of cancer-related death worldwide, and its histopathological diagnosis is crucial for deciding on optimum treatment strategies. Recently, artificial intelligence (AI) models have been widely shown to be useful in various medical fields, particularly image and pathological diagnoses; however, AI models for the pathological diagnosis of pulmonary lesions that have been validated in large-scale test sets are yet to be seen. Methods: We trained a convolution neural network based on the Efficient Net B3 architecture to classify carcinoma from whole slide images (WSIs) using a training dataset of 3640 images. WSI diagnoses were available. We used a transfer learning approach, in which the starting weights were obtained from a pre-trained model on ImageNet. The model was then trained on our dataset using multiple instance learning, a semi-supervised learning approach. To classify a WSI, the model was applied in a sliding window fashion with an input tile size of 512x512 and a stride of 256. The maximum probability was then used as a WSI diagnosis. Results: We evaluated our model on a total of 2680 WSIs originating from five independent sources (two hospitals in Japan and three public datasets from around the world). The model achieved a Receiver Operator Curve Area Under the Curves (ROC AUCs) of 0.974, 0.974, 0.996, 0.988, and 0.981, respectively. Conclusions: We successfully established a reliable AI model for differentiating between lung carcinoma and non-neoplasm with a high ROC AUC on five independent test sets. If used in clinical practice, our model could help reduce the burden on pathologists and be useful for diagnosing pulmonary lesions in areas in which there are shortages of pathologists. Further prospective multicenter studies are warranted in order to validate the results obtained in the current study.
Role of T0 status in overall survival for unresectable stage III non-small cell lung cancer.
Authors: Komiya Takefumi , Powell Emily , Vu Charles , Guddati Achuta Kumar 
Published: May 2020

9026 Background: Occult (T0) primary non-small cell lung cancer (NSCLC) with mediastinal involvement is a known but rare clinical condition. Its prognosis has not been evaluated well in the literature. Methods: Using National Cancer Database (NCDB), cases diagnosed between 2004 and 2016 with unresectable clinical stage III NSCLC with N2 or N3 involvement were selected and assigned to T0 or T1-4 group according to AJCC staging version 6th or 7th. Clinical demographics including use of chemotherapy/immunotherapy in first course of treatment were collected. As validation, independent data using Surveillance, Epidemiology, and End Results Program (SEER) was analyzed accordingly. Survival analyses were conducted using Kaplan-Meier and log-rank tests. Results: A total of 458 and 84,263 cases met criteria for unresectable, N2/N3 stage III NSCLC with T0 and T1-4 status, respectively. T0 status was associated with younger age, recent diagnosis, adenocarcinoma histology, N3, and use of chemotherapy. Overall survival (OS) was improved in T0 over T1-4 group (p < 0.0001) with a five-year survival rate of 30.5% and 12.7%, respectively, with a validation with multivariate proportional hazard models. Propensity score matching analyses using all 458 patients in each group demonstrated a significant difference in OS (p < 0.0001). The difference was also significant in a subset of those who have undergone chemoradiation (p < 0.0001). Independent analysis using SEER data confirmed its superior survival of T0 over T1-4 with a five-year survival rate of 35.3% and 13.5%, respectively. Conclusions: Both NCDB and SEER analyses demonstrated better survival of T0 than T1-4 counterpart in the setting of unresectable stage III NSCLC, irrespective of chemotherapy status. This group may require a distinct assignment to new staging group after further investigation.
Prognostic role of mid-treatment PET/CT and plasma cytokines in patients undergoing chemoradiation for locally advanced non-small cell lung cancer (LA-NSCLC).
Authors: Zeng Jing , Rengan Ramesh , Baik Christina S , Eaton Keith D. , Goulart Bernardo H. L. , Lee Sylvia , Martins Renato G. , Santana-Davila Rafael , Hippe Daniel S , Lampe Paul D. , Houghton A. McGarry , Vesselle Hubert , Kinahan Paul , Bowen Stephen R. 
Published: May 2020

9040 Background: Patients with unresectable LA-NSCLC are treated with concurrent chemoradiation (CRT) and consolidation immunotherapy with survival that range from months to years or even decades. Early predictive biomarkers have potential to identify patients who are unlikely to benefit from continuing standard of care therapy and require a change in management. We investigated biomarkers that are widely available (PET/CT scan and plasma cytokine levels) to develop early predictors (mid-CRT) of survival in a phase II clinical trial of chemoradiation for LA-NSCLC. Methods: 37 Patients with AJCC v7 stage IIB-IIIB NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238) from 2016-9. All patients underwent chemoradiation; 18 also received adjuvant durvalumab. PET/CT exams were performed at week 3 of CRT and response status was pre-defined by published metrics. 21 patients consented to peripheral blood collection at baseline and week 3, and plasma levels of 43 common inflammatory cytokines were measured. Bootstrapping over 100 iterations of the least absolute shrinkage and selection operator (LASSO) was performed to reduce feature dimensionality and guard against false discoveries. Cox regression of selected cytokine levels and PET response status, as well as time-dependent receiver-operating characteristic (ROC) analysis, were evaluated for associations to overall survival (OS). Results: Median follow-up was 18 months with 1-year OS 81% and PFS 52%. Mid-CRT PET response (as determined by pre-defined metrics) was strongly associated with OS (HR 5.6 [1.4-22.0], p = 0.015) after adjusting for radiation target volume, with 1-yr OS 94% for responders vs. 68% for non-responders (p = 0.017). Plasma TNFα level was also prognostic for OS (HR 1.9 [1.1-3.5], p = 0.030). TNFα retained significance for OS (HR 2.3 [1.2-4.6], p = 0.016) after adjusting for PET response. Bivariate mid-CRT PET response and TNFα generated a parsimonious model to predict OS (AUC = 0.85, 18-month horizon). Conclusions: Risk stratification for long-term survival after chemoradiation in patients with LA-NSCLC may be achievable based on mid-chemoradiation assessment of widely available biomarkers (PET imaging and plasma TNFα level). Combined functional imaging and peripheral blood biomarkers will be validated in a larger sample of our trial cohort, along with other independent patient populations. Clinical trial information: NCT02773238.
Peripheral blood T-cell receptor immune repertoire characterization of resectable stage IIIA non-small cell lung cancer patients receiving neo-adjuvant chemo-immunotherapy treatment from NADIM study.
Authors: Cruz Bermudez Alberto , Casarrubios Marta , Laza Briviesca Raquel , Sierra-Rodero Belen , Barquin Miguel , Romero Atocha , Franco Fernando , Calvo Virginia , Nadal Ernest , Insa Amelia , Garcia-Campelo Rosario , Casal Joaquin , Domine Manuel , Massuti Bartomeu , Majem Margarita , Rodriguez-Abreu Delvys , Martinez-Marti Alex , De Castro Javier , Provencio-Pulla Mariano 
Published: May 2020

9041 Background: Characterization of the peripheral blood T-cell receptor (TCR) repertoire has become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, there is lack of knowledge about the clinical relevance of TCR repertoire in terms of pathological response and clinical outcomes (PFS and OS) in chemo-immunotherapy. To answer this question we have analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab. Methods: Using ION Torrent-based next-generation sequencing we have analysed TCR repertoire of peripheral blood from 30 patients receiving chemo-immunotherapy. Using 25ng of total RNA from PBMCs, clonal convergence, evenness and diversity were calculated at diagnosis (pre-treatment) and after 3 cycles of Nivolumab plus carboplatin (post-treatment). Regarding pathological responses, patients were classified in 3 groups: complete response (pCR) (0% viable tumour at the resection specimen), mayor response (pMR) ( < 10% viable tumour) and incomplete response (pIR) ( > 10% of viable tumour). At data analysis, PFS and OS median follow-up times were longer than 20 months. Results: No statistically significant differences in TCR repertoire in terms of evenness (p = 0,373), diversity (p = 0,691) or convergence (p = 0,054) between pre- and post-neoadjuvant treatment were observed. Similarly, no significant differences were observed in these metrics between pathological response groups. However, a detailed analysis of the clones showed that the percentage of frequent clones (greater than 0.1%) that increase after neoadjuvant therapy does show differences between the different pathological response groups (pIR vs pMR), being elevated in patients who presented responses greater than 90% (p = 0.0385). Regarding the clinical benefit, having this parameter higher than the median (43,90% in this cohort) is associated with a higher PFS (p = 0.0490) and OS (p = 0.078) using KM Log-rank test. Conclusions: Evenness, Diversity and Convergence derived from immune repertoire analysis do not appear to be clinically useful in the context of neoadjuvant chemo-immunotherapy in lung cancer. However, the detailed analysis of the clones seems promising. The increase of the most frequent clones after treatment seems to be associated to different clinical variables such as pathological response and PFS in these patients. Clinical trial information: NCT03081689.
Efficacy and safety of nivolumab for malignant mesothelioma in the real world.
Authors: Mikami Koji , Yokoi Takashi , Takahashi Ryo , Shibata Eisuke , Niki Maiko , Nakajima Yasuhiro , Negi Yoshiki , Ishigaki Hirotoshi , Tada Akio , Higashiyama Tomoki , Kamei Takao , Minami Toshiyuki , Kuribayashi Kozo , Kijima Takashi 
Published: May 2020

9052 Background: Until recently, the standard treatment for advanced malignant pleural mesothelioma (MPM) was only cisplatin plus pemetrexed. Nivolumab, an anti-programmed death-1 monoclonal antibody, shows efficacy against pretreated MPM and has been approved in Japan, but the data regarding the efficacy and safety of nivolumab in MPM are limited to those from a small number of patients of the MERIT study. Therefore, it is important to accumulate real-world data on the efficacy and safety of nivolumab for MPM. Methods: We retrospectively analyzed all patients with MPM who received nivolumab at Hyogo College of Medicine Hospital from August 2018 to December 2018. Results: A total of 77 patients (61 males and 16 females) were included. There were 62, 10, and 5 patients with performance statuses of 0–1, 2, and 3, respectively. There were 63, 8, and 6 patients with epithelioid, sarcomatoid, and bi-phasic histologies, respectively. Nivolumab was administered as second-, third-, and ≥fourth-line treatment to 48, 15, and 11 patients, respectively. In 66 patients who were examined for efficacy, the response rate (RR) was 24.2% and the disease control rate (DCR) was 63.6%. By the histology type, the RR and DCR were 15.1% and 62.3% for the epithelioid type, 62.5% and 87.5% for the sarcomatoid type, and 20.0% and 40.0% for the bi-phasic type, respectively. The median progression-free survival (mPFS) was 4.1 months and the median overall survival (mOS) was 13.3 months. Analyzing the efficacy based on the neutrophil-to-lymphocyte ratio (NLR) in the peripheral blood, the RRswere 14.7% in the NLR≥3.5 group and 25.8% in the NLR < 3.5 group. The mPFS and mOS in the NLR≥3.5 group were 3.1 months and 11.4 months, respectively,whereas those in the NLR < 3.5 group were 5.6 months and not reached, respectively. There were no significant differences in the RR, PFS, and OS between the groups, but a trend of better RRs and longer survivals wasobserved in the NLR < 3.5 group than in the NLR≥3.5 group. Regarding adverse events, fatigue (grades 1−2) was observed in 8, hypothyroidism (grade 1–2) in 11, renal dysfunction (grade 1–3) in 6, loss of appetite (grade 1–2) in 2, pneumonitis (grade 3) in 1, rash (grade 1) in 2, and hypopituitarism (grade 3) in 1 patient(s). Conclusions: This retrospective study revealed the effectiveness and safety of nivolumab for MPM in the real-world setting.Nivolumab can be used as a standard second-line treatment for MPM. Furthermore, it has been suggested that the NLR may be a predictive marker of the effect of nivolumab for MPM, as pointed out in other carcinomas.