bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and validation of a deep learning model to assess tumor progression to immunotherapy.
Authors: Yang Yi , Yang Jiancheng , Ye Yuxiang , Xia Tian , Lu Shun 
Published: May 2019

e20601 Background: Manual application of length-based tumor response criteria is the standard-of-care for assessing metastatic tumor response. It is technically challenging, time-consuming and associated with low reproducibility. In this study, we presented a novel automatic Deep Neural Networks (DNNs) based segmentation method for assessing tumor progression to immunotherapy. Next stage, AI will assist Physicians assessing pseudo-progression. Methods: A data set of 39 lung cancer patients with 156 computed tomography (CT) scans was used for model training and validation. A 3D segmentation DNN DenseSharp, was trained with an input size of on CT scans of tumor with manual delineated volume of interest (VOI) as ground truth. The trained model was subsequently used to estimate the volumes of target lesions via 16 sliding windows. We referred the progression-free survival (PFS) only considering tumor size as PFS-T. PFS-Ts assessed by longest tumor diameter (PFS-Tdiam), by tumor volume (PFS-Tvol), and by predicted tumor volume (PFS-Tpred-vol) were compared with standard PFS (as assessed by one junior and one senior clinician). Tumor progression was defined as > 20% increase in the longest tumor diameter or > 50% increase in tumor volume. Effective treatment was defined as a PFS of > 60 days after immunotherapy. Results: In a 4-fold cross-validation test, the DenseSharp segmentation neural network achieved a mean per-class intersection over union (mIoU) of 80.1%. The effectiveness rates of immunotherapy assessed using PFS-Tdiam (32 / 39, 82.1%), PFS-Tvol (33/39, 84.6%) and PFS-T pred-vol (32/39, 82.1%) were the same as standard PFS. The agreement between PFS-Tvol, and PFS-Tpred-vol was 97.4% (38/39). Evaluation time with deep learning model implemented with PyTorch 0.4.1 on GTX 1080 GPU was hundred-fold faster than manual evaluation (1.42s vs. 5-10 min per patient). Conclusions: In this study, DNN based model demonstrated fast and stable performance for tumor progression evaluation. Automatic volumetric measurement of tumor lesion enabled by deep learning provides the potential for a more efficient, objective and sensitive measurement than linear measurement by clinicians.
Clinical implications of monitoring circulating tumor DNA in early- and late-stage non-small cell lung cancer patients.
Authors: Peng Muyun , Chin Lihan , Huang Qi , Yin Wei , Tan Sichuang , Chen Chen , Liu Wenliang , Tang Jingqun , Wang Xiang , Wang Lientu , Yu Fenglei 
Published: May 2019

e20607 Background: Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the most common types of NSCLC are squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The development of noninvasive methods to monitor circulating tumor DNA (ctDNA) continues to be a major challenge in NSCLC. Methods: We investigated if detection of ctDNA after resection of NSCLC identifies the patients with risk of relapse, and furthermore, informs about response to management.In this cohort study, high-throughput 168 target-gene capture technology and high-sensitivity circulating single molecule amplification and re-sequencing technology (cSMART) were used to detect the somatic mutations in tissues and plasma of patients with NSCLC, respectively. Moreover, ctDNA somatic mutations were used to monitor changes in minimal residual disease during a follow-up period. Results: A total of 169 patients with lung squamous cell carcinoma and adenocarcinoma were included. Detectable levels of ctDNA were present in 60.7% of patients with stage I and 68.8% of patients with late-stage. In patients not treated with adjuvant chemotherapy, ctDNA was detected preoperatively in 46 of 81 (56.8%) patients, 14 (30.4%) of whom had recurred at follow-up of 44 months; recurrence occurred in only 2 (5.7 %) of 35 patients with negative ctDNA. Serial ctDNA status changed from positive to negative during the initial phase of post operation in four patients. Then, ctDNA became positive again after 2 weeks to 3 months, all the four patients with relapse during the follow-up of 44 months. Conclusions: Detection of ctDNA supplies evidence of residual disease and identifies patients at risk of relapse. These observations have implications for the intervention of lung squamous cell carcinoma and adenocarcinoma patients.
Activity of osimetrinib/AZD9291 in pretreated patients (pts) with epidermal growth factor receptor mutant (EGFRmt) non-small cell lung cancer (NSCLC), according to EGFR mutations detected in circulating plasma DNA (ctDNA).
Authors: Kontopodis Emmanouil , Nuria Jordana , Ntzifa Aliki , Katsaounis Panayiotis , Charalambous Charalambos Haris , Boukovinas Ioannis , Tsaroucha Emily , Psyrri Amanda , Koumarianou Anna , Nikolaou Michail , Kentepozidis Nikolaos K. , Rosell Rafael , Georgoulias Vassilis , Karachaliou Niki , Kotsakis Athanasios 
Published: May 2019

e20608 Background: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI), selective for EGFR TKI-sensitizing mutations and the T790M resistance mutation. We sought to determine the activity of osimertinib after progression on EGFR TKIs in pts with T790-negative ctDNA. Methods: A multicenter phase II study ( clinicaltrials.gov NCT02771314) of osimertinib (80 mg daily) was conducted in pts with metastatic EGFRmt NSCLC, who had progressed after previous treatment with EGFR TKIs. Serial serum and/or plasma samples were drawn for ctDNA analysis at enrollment, 1 month and every 3 months of treatment, until disease progression. Efficacy outcomes in pts without the T790M mutation in ctDNA at baseline are reported. Results: Thirty-seven NSCLC patients with undetectable baseline T790M in the plasma have been enrolled. Median age was 67 years, 21.6% were male, and histology was adenocarcinoma in 100%. More frequent adverse events (grade 1/2) included diarrhea (12.5%), fatigue (12.5%), anorexia (12.5%) and acneiform rash (10.4%). The overall response rate (ORR) was 40.5% (95% CI, 24.7-56.4%) and the disease stabilization rate 37.8%; the median progression-free survival (PFS) was 8.9 months (range, 1.6-30), and the estimated median overall survival (OS) 26 months (range, 2.2-30). At enrollment, EGFR mutations del19 and L858R were detected in ctDNA in 9 and 3 pts, respectively. After one month of treatment with osimertinib, EGFR mutations in ctDNA were not detectable in 4/9 and 2/3 of pts with del19 and L858R at baseline, respectively. Pts without detectable EGFRm ctDNA at baseline remained negative throughout the study. Efficacy according to baseline ctDNA status was as follows: Clinical trial information: NCT02771314. Conclusions: Osimertinib was effective in EGFR TKI pretreated pts without EGFR T790M mutation in plasma. Pts with detectable del19 or L858R mutations in ctDNA before treatment had worse clinical outcomes, despite the elimination of EGFRmt ctDNA.[Table: see text]
Early clinical experience with the pan-FGFR inhibitor rogaratinib in patients with non-small cell lung cancer selected based on FGFR mRNA expression levels.
Authors: Joerger Markus , Cho Byoung Chul , Mach Nicolas , Caballero Cristina , Soo Ross A. , Wirth Manfred , Sayehli Cyrus , Navarro Alejandro , Keam Bhumsuk , Piciu Ana-Maria , Bender Sebastian , Nogai Hendrik , Ellinghaus Peter , Schuler Martin H. 
Published: May 2019

e20661 Background: FGFR1 gene amplifications are observed in squamous (sq) non-small cell lung cancer (NSCLC) and may suggest tractable oncogenic dependency. However, their value in predicting clinical activity of FGFR inhibitors is unclear. We explored tumor FGFR1-3 mRNA expression levels to select patients (pts) for treatment with rogaratinib, an oral, potent, small-molecule inhibitor of FGFR1-4. The first-in-human study of rogaratinib included pts with all NSCLC histologies. Methods: Pts with refractory advanced NSCLC were screened for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples, and FGFR1-3 overexpression was defined by pre-specified cut-offs. Pts received rogaratinib 800 mg BID on a continuous 21-day cycle. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1 after cycles 2, 5, and 8. Results: 260 NSCLC biopsies were screened for FGFR1-3 tumor mRNA expression; 244 (93.8%) were evaluable. FGFR1-3 mRNA overexpression was found in 47% of sq NSCLC, and only 14% of non-sq NSCLC, with FGFR3 being the most commonly overexpressed subtype. 40 FGFR mRNA-positive pts were enrolled and treated. Rogaratinib was well tolerated; hyperphosphatemia (75%), diarrhea (53%), and decreased appetite (35%) were the most frequent treatment-emergent adverse events. Events were mostly mild or moderate. 36 treated pts were evaluable for response. The overall response rate was 5.6% (2 partial responses, 1 lasting for > 16 months). Disease control rate was 64%. Disease stabilization was seen in pts with mRNA overexpression across all FGFR subtypes and also in pts who failed prior lines of therapy, including anti-PD-L1. Molecular studies are ongoing to identify additional predictors of response to improve pt selection. Conclusions: Rogaratinib has a favorable safety and tolerability profile and clinical activity in pts with refractory FGFR1-3 tumor mRNA-positive NSCLC. It has potential for further exploration in combination with other agents. A clinical trial is currently enrolling FGFR mRNA-overexpressing pts with advanced and pre-treated sq NSCLC. Clinical trial information: NCT03762122.
Bone metastases as predictors of treatment response and rapidly progressive disease in NSCLC patients on PD-1/PD-L1 immune checkpoint inhibitors (ICI).
Authors: Lau Sally CM , Le Lisa W , Smith Elliot Charles , Chan Sze Wah Samuel , Ryan Malcolm , Brown M. Catherine , Hueniken Katrina , Eng Lawson , Patel Devalben , Chen RuiQi , Sung Mike Ru , Zer Alona , Bradbury Penelope Ann , Ohashi Pamela S , Shepherd Frances A. , Tsao Ming Sound , Liu Geoffrey , Leighl Natasha B. , Sacher Adrian G. 
Published: May 2019

e20667 Background: The tissue microenvironment associated with specific organ metastases potentially influences the efficacy of checkpoint inhibitors. The presence of liver metastases is a predictor of poor response and survival in melanoma and is correlated with reduced CD8+ T cell infiltration. Our study examined clinicopathologic characteristics, focusing on sites of metastatic disease, that are associated with poor outcomes. Methods: Advanced NSCLC patients treated with ≥1 cycle of ICI were reviewed. Baseline age, sex, histology, stage, smoking status, ethnicity, PD-L1 expression and sites of metastases were recorded. Best overall response (BOR) was determined by clinical imaging response and categorized ordinally as shrinkage, stable, or progression, adapted from RECIST for CR/PR, SD, PD. A rapidly progressive phenotype (RPP) was defined as BOR of progression and ICI use of ≤2 months. The association between sites of metastases and clinical outcomes were investigated using logistic and cox regression models. Results: Among 219 eligible patients, bone was the most common metastatic site (34.7%), followed by brain (21.5%), adrenals (14.2%), and liver (13.7%). Bone metastases (OR 0.45, p = 0.004) were associated with a worse BOR, while only a trend was observed for liver metastases (OR 0.47, p = 0.06). Adrenal metastases were associated with a better BOR (OR 2.08, p = 0.04). But thorax limited disease did not associate with BOR (OR 1.08, p = 0.76). In a multivariate model, bone was the only metastatic site associated with a worse BOR (OR 0.50, p = 0.01). Further, bone metastases were associated with RPP (adjusted OR 1.91, p = 0.04). Both bone (adjusted hazard ratio/aHR 1.61, p = 0.01) and liver metastases (aHR 1.80, p = 0.02) were associated with a shorter time-to-treatment-failure. The presence of liver (aHR 2.63, p < 0.001) but not bone (aHR 1.04, p = 0.86) metastases was a significant predictor of poor OS. Conclusions: We report a novel finding that the presence of bone metastases was associated with a worse clinical overall response on ICI and a rapidly progressive phenotype. Further investigations into the mechanisms of RPP in the presence of bone metastases are needed.
Real-world clinical and economic outcomes among newly-diagnosed merkel cell carcinoma (MCC) patients initiating first-line (1L) checkpoint inhibitors (CPIs) or chemotherapy (CT) in the veterans health administration (VHA).
Authors: Phatak Hemant , Pandya Shivani , Yu Ting , Kearney Mairead , Wang Li , Kim Ruth , Zheng Ying 
Published: May 2019

e21002 Background: The use of CPIs among patients (pts) with metastatic MCC, a rare and aggressive skin cancer, has increased since the US FDA approval of avelumab and the National Cancer Comprehensive Network (NCCN) recommendation of CPIs in 2017. Given the growing interest in understanding real-world clinical and economic outcomes associated with CPI use, this study assessed time to treatment failure (TTF), overall survival (OS), healthcare resource utilization (HRU), and costs among MCC pts receiving NCCN-recommended 1L regimens including CPIs and CT in the VHA. Methods: This is a retrospective analysis of pts with newly-diagnosed MCC who initiated 1L treatment between October 2013 and January 2018 (index date = 1L therapy start date) and had continuous enrollment from ≥6 months pre-initial MCC diagnosis date until ≥2 months post-index date (follow-up). The index date to earliest of death or subsequent line of therapy start was used as a proxy for TTF. TTF and OS were estimated using Kaplan Meier method. All-cause HRU and costs (2018 USD) per patient per month (PPPM) were evaluated during TTF or until end of follow-up, whichever occurred first. Results: Of 120 MCC pts (72% pre-2017) initiating 1L therapy, 62% received NCCN-recommended regimens, including 17% and 45% treated with CPIs and CTs. Pts receiving CPIs were on average older with higher baseline comorbidity burden. The clinical and economic outcomes of these two pt groups are summarized in the table below. Conclusions: The current descriptive non-comparative analyses provide new information on the trends in clinical and economic outcomes of MCC pts treated in the VHA. Despite higher costs, the utilization of newly-approved CPIs in 1L setting showed delayed treatment failure and reduced all-cause HRU vs. CTs. These findings require further validation in studies with larger patient cohorts and longer follow-up. [Table: see text]
Mucosal melanoma staging and classification: Firstly established.
Authors: LIAN BIN , Cui Chuanliang , Song Xin , Zhang Xiaoshi , Wu Di , Si Lu , Chi Zhihong , Sheng Xinan , Zhou Li , Mao Lili , Tang Bixia , Wang Xuan , Li Si Ming , Yan Xieqiao , Balch Charles M. , Guo Jun 
Published: May 2019

e21008 Background: Mucosal melanomas (MM) have a significantly worse survival outcome than cutaneous melanoma. The current staging rules for cutaneous melanoma do not apply to mucosal melanoma. Our previous studies have demonstrated mucosal melanomas arising from different anatomic sites can be staged and treated as a single disease entity. We are recommending a new evidence-based staging system for mucosal melanoma. Methods: The mucosal melanoma staging recommendations were made on the basis of a multivariate analysis of 543 patients with stages I, II, and III melanoma and 547 patients with stage IV melanoma to clarify TNM classifications and stage grouping criteria. Results: New staging definitions include the following: (1) in patients with localized melanoma, the depth of tumor invasion of the primary melanomas is the most dominant prognostic factor: T1 for tumor invading mucosa or submucosa; T2 for tumor invading the muscularis propria; T3 for tumor invading adventitia; T4 for tumor invading adjacent structures; (2) The dominant prognostic factor for regional nodal metastases is the number of metastatic nodes: N1 for 1 regional metastatic node; N2 for 2 or more regional metastatic nodes; (3) On the basis of a multivariate analysis of patients with distant metastases, the dominant component in defining the M category is the site of distant metastases (M1:lung only vs. M2:liver only vs. M3:brain only vs. M4:all other visceral metastatic sites). An elevated serum lactate dehydrogenase level would be designated in parenthesis. The staging grouping of mucosal melanoma can be defined as follow: (1) stage I: T1N0M0; (2) Stage II:T2-4N0M0; (3) Stage IIIA: T1-4N1M0, Stage IIIB: T1-4N2M0; (4) Stage IV: anyTanyNM1-4. Conclusions: Using an evidence-based approach, the proposed staging system of mucosal melanoma is the first to be established that reflects our improved understanding of this disease.
Local experience with ipilimumab and nivolumab in treatment of metastatic melanoma: From world standards to individualized approaches in real clinical practice.
Authors: Manikhas Georgy M. , Orlova Rashida , Zhukova Natalia V. , Antimonik Nina , Kutukova Svetlana I. , Beliak Natalia P. , Popova Natalia V. 
Published: May 2019

e21023 Background: Ipilimumab (Ipi) is the first agent in metastatic melanoma treatment that achieved long-term efficacy in selected patients. Nivolumab (Nivo) is one of agents, PD-1 inhibitors, that change treatment paradigm of advanced melanoma due to improving OS for lots of patients. There is still needed to evaluate efficacy of this drugs in regular medical settings. Methods: 43 patients with advanced melanoma were treated in SPb Clinical Oncology Dispensary from 2014 till now: 16 male and 27 female, median age is 58y.o. (from 39 to 84). 31 patients received Ipi, 12 patients received Nivo. Almost of patients are progressed after 1-4 lines of previous systemic therapy before starting treatment with Ipi or Nivo. Initial performance status (PS) assessed by ECOG scale was following; 1 patient had PS = 0 by ECOG, 37 patients – PS = 1 by ECOG and 5 patients had PS = 2 status by ECOG. Adverse events (AEs) are collected according to CTC AE v4.03. Results: At the time of analysis median FU is 25.75 month (95% CI: 6,6-35.9). The most frequently reported AEs are: pruritis 20%, fatigue 10%, diarrhea 7%, hepatitis 4%. 6% of AEs are grade 3/4. There are no any infusion reactions to Ipi and Nivo. Ipilimumab: median PFS is 6.0 month (95% CI: 4.9;7.1), 19% of patients (n = 6) have no PD at the moment. Median OS is 12.0 months (95% CI: 9.7;14.3), 29% of patients are still alive (n = 9). 6-months OS is 81%, 1-year OS is 35%. Nivolumab: Only 3 from 12 patients have PD after Nivo on the time of analysis. Median PFS and OS is not reached: 10 patients are still alive. 1-year OS is 83,33%. 52% of patients have reported AEs. Conclusions: Efficacy and tolerability of Ipi and Nivo in our clinical practice is similar to data from international clinical studies. The treatment with Ipi and Nivo is not associated with drug related infusion reactions and immediate AEs and doesn’t require supervision of patients at in-patient departments.Ipi and Nivo treatment is safe, could be used on out patients’ basis in regular medical settings.
Outcomes of melanoma patients with brain metastases receiving immune checkpoint inhibitor (ICI) therapy.
Authors: Ardeshir-Larijani Fatemeh , Nelson Ariel Ann , Martin Petra , Mendiratta Prateek , Sloan Andrew E. , Choi Serah , Mansur David B. , Hoimes Christopher J. 
Published: May 2019

e21028 Background: The effect of ICI therapy on brain metastasis (mets) in melanoma patients has been described, however the impact of genomic alterations and local treatment (trt) including radiation therapy (RT) on CNS outcomes and overall survival (OS) has not yet been explored. Methods: Under institutional IRB approval, we reviewed our electronic medical record to identify patients (pts) with metastatic melanoma and brain mets who received trt with ICI. Trt history, CNS responses as indicated by the treating physician and available genomic data were recorded. OS was estimated using a multivariable Cox regression model adjusting for genomic alteration, age, ICI regimen and brain mets. Results: A total of 49 pts were identified (65% male). Thirty seven pts had testing for tumor genomic alterations (alt, hotspot and comprehensive genomic testing); BRAFV600E( 30%), cKIT(5%), NRAS(16%), no alt (38%). Prior to initiation of ICI, 78% had known CNS mets, of these, 61% received RT. There was no difference in median OS for pts who started RT prior to ICI compared to those without RT (mOS = 75.71 vs 49.4 weeks, p = 0.75). Median OS was improved for those pts who received RT > 90 days prior to initiation of ICI trt however this was not statistically significant (45.7 vs 136 weeks, p = 0.12) and HR = 0.45 (95% CI 0.08, 2.36). OS was not significantly different in pts with genomic alterations compared with those without alterations (p = 0.264). Of the pts with known brain mets at the time of ICI start, 34% had progressive disease at 3 months and 11% were felt to have pseudoprogression. 18% survived to undergo 6-month disease assessment, of these 12% had further progression. All pts with cKIT mutations survived to 6-month disease assessment. 75% of pts with known brain mets developed new lesions, 15% had increased mass size. Pts who developed new brain mets while on trt with ICI had worse survival than those with preexisting brain mets and developed new brain lesions (28 vs 58 weeks, p = 0.05). 6% of all pts developed CNS immune related adverse effects. Conclusions: Most patients with melanoma and known brain metastasis prior to ICI developed new brain lesions as a site of metastatic spread. The development of new brain mets was associated with worse outcomes. Neither genomic alterations nor RT prior to ICI start were associated with improved survival.
Patterns of major surgeries among patients diagnosed with cutaneous squamous cell carcinoma (CSCC).
Authors: Chen Chieh-I , Jalbert Jessica J , Andria Michael , Zhang Haixin Raymond , Ruiz Emily S 
Published: May 2019

e21034 Background: CSCC is the second most common skin cancer. Most CSCC cases can be cured with surgical excision alone (5-year cure rate > 95%). We sought to evaluate patterns of major surgeries among patients with CSCC, overall and among those requiring systemic therapy. Methods: From Truven MarketScan claims data, we identified patient’s first CSCC diagnosis between 2013 and 2018 and required that they be continuously enrolled in their healthcare plan and have no CSCC diagnosis in the previous 12 months. Major surgeries included facial excisions over 3.1 cm, parotidectomy, removal of ear/eye/nose, amputations, craniectomy, excision of extracranial nerves, sentinel lymph node biopsy, lymphadenectomy, complex repairs of over 7.5 cm, integra, free flaps, and large grafts over 20 sq cm. Risk of a major surgery was assessed using Kaplan-Meier estimators for patients with CSCC overall and for those who received prior or concurrent systemic therapy, stratified by immune status. Results: A total of 240,122 patients with CSCC (mean age [SD]: 67.7 [12.9] years; male: 56.5%; immunocompromised: 12.4%) were identified with a mean (SD) follow-up of 1.34 (1.15) years. Risk of major surgery (95% confidence interval [CI]) at 1 and 2 years was 15.1% (14.9–15.2) and 18.6% (18.4–18.8), respectively. 782 patients received prior or concurrent systemic therapy, of which 22.4% (n = 175) were immunocompromised. Among those who received systemic therapy, 1- and 2-year risks (95% CI) were 8.4% (5.8–11.0) and 14.2% (10.0–18.2) for immunocompetent and 14.1% (7.7–20.0) and 19.3% (10.7–27.0) for immunocompromised patients, respectively. Conclusions: Over 2 years, approximately one in five patients with CSCC will undergo at least one major surgery. Prior or concurrent treatment with systemic therapy did not appreciably diminish the risk of requiring major surgery. For patients who received systemic therapy, the 1-year and 2-year risk of major surgery was higher for immunocompromised patients compared to immunocompetent patients.