bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal sequencing of TCR and circulating tumor DNA revealing radiotherapeutic efficacy and prognosis for non-small cell lung cancer patients with brain metastasis.
Authors: Dong Xiaorong , Chen Lingjuan , Tong Fan , Wei Chunhua , Wang Han , Xia Xuefeng , Xu Yaping , Liu Pian , Liao Zhongxing X. , Zhang Jianjun , Carbone David Paul 
Published: June 2021

e21181 Background: This study aimed to explore cerebrospinal fluid (CSF) and peripheral blood-based liquid biopsy before and after radiotherapy of non-small cell lung cancer (NSCLC) brain metastases. Methods: Thirty NSCLC patients with brain metastases receiving brain radiotherapy were enrolled in this study. CSF and peripheral blood were collected at baseline, 24 hours (T0) and 28 days (T28) after treatment. Somatic mutations and T-cell receptor (TCR) sequences were identified by high-throughput sequencing in both compartments. Results: At baseline, identical mutations shared by paired blood and CSF emerged in nine patients (30%). Dimension reduction analysis identified distinct signatures of V and J gene recombination in blood and CSF TCR sequences. Throughout treatment, both compartments experienced a TCR diversity decrease, however, the degradation of low-abundance clones and the expansion of emerging clones might be two separate processes underwent in blood and CSF, respectively. Diversity changes and ctDNA in blood were possibly related to pulmonary responses, while the increase of maximal clone abundance in CSF might indicate a favorable intracranial response. Blood-ctDNA clearance at T28 was significantly associated with better overall survival (OS, HR = 4.027, p = 0.028) and progression-free survival (PFS, HR = 4.176, p = 0.024), and superior blood TCR diversity at T28 against baseline was associated with longer OS (HR = 5.700, p = 0.039). Combined blood factors achieved a better predictive power (OS, HR = 10.53, p < 0.001; PFS, HR = 4.843, p < 0.001). Patients with increase of maximal clone abundance ≥ 50 in CSF also had a better intracranial PFS (HR = 8.320, p = 0.011). The predictive effects of these markers were independent of other clinical factors in multivariate Cox analysis. Conclusions: CSF and peripheral blood were independent compartments showing disparate genomic and immune signatures. Longitudinal surveillance of both compartments could be a promising method to predict clinical outcomes for NSCLC patients with brain metastases.
Long-term real-world outcomes of first-line (1L) pembrolizumab (pembro) monotherapy in PD-L1 ≥50% metastatic NSCLC.
Authors: Velcheti Vamsidhar , Hu Xiaohan , Piperdi Bilal , Yang Lingfeng , Burke Thomas A. 
Published: June 2021

e21184 Background: Pembro monotherapy was approved in the US in October 2016 as 1L therapy for patients with metastatic NSCLC and PD-L1 tumor proportion score (TPS) ≥50% based on findings from KEYNOTE-024. With 5-year follow-up in KEYNOTE-024, median overall survival (OS) was 26.3 months (95% CI, 18.3–40.4) in the pembro arm. With 4-year follow-up in KEYNOTE-042, median OS was 20.0 months (15.9–24.2) in the pembro PD-L1 ≥50% subgroup. Our aim was to describe long-term, real-world outcomes with 1L pembro monotherapy for patients treated at US oncology practices with disease characteristics similar to those in the KEYNOTE trials. Methods: Patients initiating 1L pembro monotherapy from December 1, 2016, through November 30, 2017, were selected from the US nationwide Flatiron Health de-identified, electronic health record-derived database if they had stage IV or recurrent metastatic NSCLC with PD-L1 TPS ≥50%, ECOG performance status 0–1, and no known EGFR/ALK/ROS1 aberration (confirmed negative EGFR/ALK for nonsquamous tumors). Enhanced manual chart review was used to determine real-world progression (rwP), tumor response (rwTR), and reasons for pembro discontinuation. OS and real-world progression-free survival (rwPFS) were estimated using the Kaplan-Meier method. Data cutoff was August 31, 2020. Results: Median study follow-up was 38.4 months (range, 33.1–44.9). Of 228 eligible patients, median age was 71 years (range, 46–82); 123 (54%) were women; 156 (68%), 12 (5%), and 60 (26%) had nonsquamous, not otherwise specified, and squamous NSCLC, respectively; and 209 (92%) were current/former smokers. History of brain metastasis was recorded for 17 (7%). Pembro was discontinued by 151 patients (66%), most commonly because of disease progression (70; 46%) and secondarily for toxic effect of therapy (35; 23%); 87 patients (38%) received ≥1 additional lines of therapy. OS, rwPFS, and rwTR results are shown below. Conclusions: In this real-world study with 3-year follow-up, patients with PD-L1 TPS ≥50% metastatic NSCLC without known EGFR/ALK aberrations and good performance status treated with 1L pembro monotherapy experienced median OS of 23 months, similar to the OS observed in phase III pivotal clinical trials, supporting the long-term OS benefits of 1L pembro monotherapy in this patient population.[Table: see text]
Clinical parameters combined with radiomics features to predict the efficacy of immunotherapy for advanced non-small cell lung cancer.
Authors: Zhao Qian , Wang Linlin 
Published: June 2021

e21187 Background: Many tools have been developed to predict the efficacy of immunotherapy, such as LIPI, EPSILoN and mLIPI scores. The aim of this study was to determine the ability of to predict outcomes in Chinese aNSCLC patients treated with ICIs.With the development of imaging technology, radiomics has increasingly received a great deal of attention. We use 3D-slicer to delineat the ROI in the patient's CT image, extract a large number of features, and further screen out the radiomics features that have predictive value for the outcome. Methods: We retrospectively enrolled 317 patients with histologically proven aNSCLC (IIIB–IV) treated with ICIs. The discriminative ability of the predictive models was evaluated by AUC in the ROC analysis. Patients were randomly divided into training and validation cohorts using a 2：1 ratio. We used the semi-automatic segmentation method of the 3D-slicer platform to delineate the ROI of the tumor’s lesion area and extract 854 image features for each patient. In the training set of patients, the LASSO algorithm was used to screen the radiomic features.Hosmer-Lemeshow tests (H-L tests) were conducted to determine the fit of the prediction models. PFS and OS curves were generated using the Kaplan-Meier method and differences were assessed using log-rank tests. Univariate and multivariate analyses were performed using Cox proportional-hazards regression models. The glmnet R package was used for the LASSO regression method. The rms, Hmisc R packages used for C-index. Results: Among the 317 patients included in the study, the median OS and PFS were 14.2 months and 5.6 months, respectively and the ORR was 23.1%. The AUC values of LIPI, mLIPI, and EPSILoN scores for predicting PFS were 0.649 (95% CI: 0.588–0.709), 0.765 (95% CI: 0.713–0.818]), and 0.637 (95% CI: 0.567–0.698), respectively (P < 0.001 for all models). The AUC value of mLIPI scores was significantly higher than that of LIPI and EPSILoN scores (P < 0.05). The C-index of mLIPI was 0.645 (95% CI: 0.617-0.673). In this study, 5 radiomics features with predictive value were selected from radiomics features. The C-indexs of the radscore were 0.643 (95% CI: 0.602–0.684) and 0.632 (95% CI: 0.571–0.693). Then we combined mLIPI and radscore to obtain a mixed model. The C-index of the combination mLIPI scores with radscore for predicting PFS was 0.810 (95% CI: 0.770–0.849) and 0.706（CI: 0.633–0.778) in the training and validation cohorts, respectively. Conclusions: By externally validating LIPI, mLIPI, and EPSILoN scores, we found that all three of these predictive models could identify different prognostic subsets of patients treated with ICIs to statistically significant degrees. We also found that mLIPI had the highest accuracy among the three models. With the addition of radiomics features, the prediction performance of the mixed model has been further improved.
Real-world outcomes of toripalimab (JS001) in advanced non-small cell lung cancer: A multicenter retrospective study.
Authors: Ruan Zhihua , Zhu Bo , Wang Yi Na , Liu Baogang , Li Mengxia , Xia Guohao , Dong Xiaorong , Liu Jie 
Published: June 2021

e21193 Background: In the past 3 years, immunotherapy has revolutionized the treatment paradigm of advanced non–small cell lung cancer (NSCLC). Checkpoint inhibitors showed promising results in the treatment of patients with advanced NSCLC with improved outcomes in clinical trials, but results from clinical trials can be difficult to generalize to real-world patient populations. Herein, we disclose the data of efficacy profile of toripalimab, a novel humanized IgG-4 mAb against programmed cell death protein 1 (PD-1), for NSCLC in a real-world setting in China. Methods: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in 8 cancer centers in China. The cohort included patients with mNSCLC who had received toripalimab for metastatic disease (n = 166) with > 1 EHR-documented visit from January, 2019, to June, 2020. Patients (age ≥ 18yrs) with pathologically or histologically diagnosed advanced NSCLC receiving toripalimab treatment were enrolled in this retrospective, multicenter, real-world study. The endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and duration of response (DOR). Results: Between January 2019 and June 2020, 166 patients from 8 centers were eligible. The median age was 60.6 years, 134(81.7%) male, 123(76.4%) diagnosed as stage IV lung cancer, 69(42.9%) squamous histology, 25 (21.9%) underwent prior surgery and 94 (57%) received prior chemotherapy. Toripalimab was administered as first, second, and further lines of therapy in 45(28.1%), 60(37.5%) and 55(34.4%) patients, respectively. Among them, 28(17.5%) patients received toripalimab as monotherapy. 22(13.8%) received in combination with antiangiogenic agent and 132(82.5%) in combination with chemotherapy. The 164 patients were eligible for efficacy evaluation. The ORR and DCR were 21.3% and 81.7% for all the evaluable patients. The median PFS was 15.0 months (95% CI 10.2 – NA). The median PFS of adenocarcinoma and squamous cell carcinoma were 15.4 months(95% CI 10.2-NA) and 13.4 months(95% CI 10.6-NA), respectively. The PFS in first line and further-line treatment were 15.4 months(95% CI 12.6-15.4) and 13.4 months(95% CI 7.0-NA). Stratified analysis revealed that the PFS of toripalimab monotherapy and combination treatment were 15.0 months(95% CI 12.6-15.0) and 15.4 months(95% CI 8-NA). The PFS were comparable between the patients received with or without anti-angiogenesis agents (11.5m vs 15.4m). Conclusions: Toripalimab monotherapy or in combination with chemotherapy and/or antiangiogenic agent in real world were effective in advanced NSCLC patients.
Thrombotic events in patients treated with immune checkpoint inhibitors for non-small cell lung cancer: A retrospective multicentric cohort study.
Authors: Deschenes-Simard Xavier , Galland Loik , Blais Florence , Desilets Antoine , Malo Julie , Cvetkovic Lena , Belkaid Wiam , Elkrief Arielle , Gagné Andréanne , Hamel Marc-Andre , Orain Michèle , Joubert Philippe , Ghiringhelli François , Routy Bertrand , Blais Normand 
Published: June 2021

e21198 Background: Venous thromboembolism is a frequent complication of non-small cell lung cancer (NSCLC) and is associated with a worse prognosis, a reduced quality of life, and increased healthcare costs. Immune checkpoint inhibitors (ICI) are revolutionizing the management of NSCLC, but little is known about their impact on thrombosis. This study aims to define the incidence and clinical relevance of thrombosis in NSCLC patients receiving these treatments. Methods: A retrospective multicentric cohort study including 593 patients from three centers in Canada and France was performed. The cumulative incidence of venous thrombotic events after ICIs was calculated, and the impact of these events on survival and response to treatment was determined. Finally, univariate log-rank tests were performed to identify thrombosis risk factors. Results: The incidence of venous thrombosis in the cohort was 9.9% for an incidence rate of 76.5 thrombosis per 1000 person-years, with most thromboses occurring rapidly after treatment initiation. Thrombosis was not correlated with overall survival, progression-free survival, or objective response to ICIs (summarized in the table below). Age ˂ 65 years old (HR = 1.66; 95 % CI = 1.00 – 2.82) and a delay of less than 12 months from diagnosis to the first ICI treatment (HR = 1.74; 95 % CI = 1.03 – 2.87) were associated with an increased risk of thrombosis. Tumors with PD-L1 > 1% were associated with more thrombosis in the first year since the beginning of therapy (HR = 3.06; 95 % CI = 1.19 – 4.76, p=0.015). Conclusions: This study suggests that the time distribution and incidence of thrombotic events in NSCLC patients treated with ICI are comparable to what is reported in other cohorts of patients treated with chemotherapy. In our cohort, thrombosis was not a prognostic factor for survival or response to therapy. Patient age < 65 and tumors with PD-L1 > 1% were associated to a higher risk of thrombotic events.[Table: see text]
Treatment of advanced mucosal melanoma in the immunotherapy era: A joint institutional case series.
Authors: Gee Abigail , Taylor Hannah , Herbert Christopher , Tillett Tania , Winter Helen 
Published: June 2021

e21503 Background: Treatment pathways for malignant melanoma have changed dramatically in recent years, with the advent of immunotherapy. Mucosal melanoma is a rare subtype, representing 1-2% of melanomas in Caucasians, with higher incidence reported in other populations. They commonly present at an advanced stage due to their occult, UV naïve location. Rarity limits adequate trial exposure and the literature offers contradictory data on the benefits of immune checkpoint inhibitor (ICI) therapy in this group. Methods: Patient databases at two specialised treatment centres were searched to identify all patients with mucosal melanoma treated with ICI therapy between 01.10.15 and 30.09.19. All patients were reviewed at the regional multi-disciplinary team meeting. Patient demographics, pathology reports, mutation status, stage at start of treatment and prior treatment modalities were noted. Results: Ten patients were identified with a median age 73 years (range 32-80) and M:F ratio of 4:6. The site of the primary cancer was head and neck in 5 cases, gastrointestinal in 3 cases and genitourinary in 2 cases. All patients were BRAF wild type. C-Kit was wild type in 3 patients tested. The median number of cycles of first line ICI was 5.5 (range 1 – 45). At first radiological assessment 7 patients had progressive disease (PD), 2 patients had stable disease and one patient had a complete response (CR). Two patients progressed to second line therapy with a second ICI. One of these demonstrated a partial response after a further 9 months of treatment and had a progression-free survival (PFS) of 30.1 months on second line treatment. One patient received 3 cycles of dual ICI therapy (ipilimumab/nivolumab) but demonstrated PD after 1.5 months. The longest surviving patient currently has a PFS of 43 months. He achieved a CR after just 3 months of pembrolizumab and completed a total of 18 cycles before switching to surveillance. Conclusions: The joint institutional case series demonstrates a poor response to ICI therapy in the majority of patients, yet as commonly reported, response when it occurs can be remarkable. Recent studies have shown increased overall response rate when anti-vascular endothelial growth factor therapies are added to cytotoxics or ICI. Further investigation of this rare subtype is required to identify predictive biomarkers of response to ICI therapy and other targeted and combination treatments.
Is adjuvant treatment for melanoma in clinical practice comparable to trials? The first population-based results.
Authors: de Meza Melissa Melanie , Ismail Rawa , Blokx Willeke , Blank Christian U. , van den Eertwegh Alfonsus Johannes Maria , Aarts Maureen J.B. , Van Akkooi Alexander Christopher Jonathan , van den Berkmortel Franchette , Boers-Sonderen Marye , Kapiteijn Ellen , de Groot Jan Willem , Haanen John B. A. G. , Hospers Geke , Piersma Djura , Van Rijn Rozemarijn , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Westgeest Hans , Suijkerbuijk Karijn , Wouters Michel W.J.M. 
Published: June 2021

e21523 Background: Little is known about the outcome of adjuvant therapy in melanoma patients beyond the clinical trial setting. The Dutch Melanoma treatment Registry (DMTR) is a population-based registry, set up in July 2013 to monitor the safety and quality of melanoma care. Since 2019, adjuvant treated melanoma patients have also been registered in the DMTR, following approval and reimbursement of adjuvant treatment in the Netherlands in December 2018. Methods: Analyses were performed on melanoma patients treated with adjuvant anti-PD1 therapy included in the DMTR between 01-07-2018 and 31-12-2019. Descriptive statistics were used to analyze patient-, and treatment characteristics, and death as well as relapse rates. Results: Six hundred and fifty-seven patients treated with adjuvant systemic therapy were included in the DMTR. The majority (94%) of these patients was treated with anti-PD1. Twenty percent of the anti-PD1-treated patients developed grade ≥3 toxicity. Of the 279 patients with a minimum follow-up of one year after start of anti-PD1, 170 (61%) prematurely discontinued therapy. Relapse and death occurred in respectively, 38% and 12% of patients within one year of follow-up. Relapse was significantly more frequent in older patients, with high Breslow thickness and ulcerated melanomas. Conclusions: These data show more frequent premature discontinuation of adjuvant anti-PD1 in daily clinical practice than reported in the registration trials. Moreover, incidence of severe toxicity, relapse and death during adjuvant treatment appears higher in the real-world setting.
Prognostic pathological and clinical factors associated with overall survival in metastatic melanoma undergoing anti PD-1 treatment.
Authors: Koczka Kim , Rigo Rodrigo , Suo Aleksi , Asad Mohammad , Wang Edwin , Batuyong Eugene , Cheng Tina 
Published: June 2021

e21531 Background: Anti-PD-1 immunotherapy has revolutionized metastatic melanoma treatment, as first-line monotherapy or in combination with Ipilimumab. Up to 40% of patients will progress within 3 months, with limited evidence on who derives benefit from immunotherapy. We report clinical and pathological predictive and prognostic factors from a multi-institutional cohort. Methods: Patients between 2014-2017 treated with Nivolumab and Pembrolizumab were identified from a provincial pharmacy database in Alberta, Canada. All patients had unresectable stage III or IV melanoma. Patient characteristics, investigations, treatment and clinical outcomes were obtained from electronic medical records. We utilized Cox regression and Kaplan-Meier methods to analyze progression free survival (PFS) and overall survival (OS). Results: 143 patients with either cutaneous (115) or primary unknown (28) melanoma were identified. Immunotherapy was median second line treatment and patients received a median of 7 doses. The median age was 64, and 144 (80%) were either ECOG 0 or 1 at treatment initiation. The overall response rate was 33%, with median follow up of 25 months. Ulcerated primary tumors had a lower mOS of 30 months vs. 49 months (p=0.042). Other pathologic factors (including Breslow Depth, tumor infiltrating lymphocytes, mitosis) were not associated with PFS or OS. Clinical factors associated with worsened mPFS and mOS were liver metastases, >3 sites of disease, and any visceral disease. Elevated LDH, platelets, neutrophils, and lower hemoglobin, lymphocytes, and a neutrophil/lymphocyte ratio were associated with worse mPFS and mOS. We identified 4 prognostic subgroups using LDH and number of visceral sites (Table) which was statistically significant for mPFS and mOS. Conclusions: Ulcerated primary tumors, liver metastasis, and more sites of disease had worse mPFS and mOS. We also identified 4 novel prognostic subgroups strongly associated with survival outcomes.[Table: see text]
Correlation analysis of gene and immune microenvironment for 87 melanoma cases.
Authors: Qin Lanqun , Ren Yu , Zhao Lianjun , Wu Yirong , Zhao Mengke , Huang Rong , Zou Zhengyun 
Published: June 2021

e21555 Background: To map the genome of Chinese melanoma patients and explore its correlation with the expression of tumor immune microenvironmental indicators. Methods: Next generation sequencing was performed on 87 cases of primary melanoma that had been surgically removed from Nanjing Drum Tower Hospital from July 2010 to May 2017. Immunohistochemistry was carried out to detect the expressions of PD1, PDL1, CD3+TIL, MSH2, MSH6, PMS2 and MLH1. Results: BRAF mutations were the most common (26.4%), followed by KIT mutations (12.6%) in melanoma patients. RB1 gene copy number deletion (55%) and CDK4 (25%)/CCND1 (22.5%) gene copy number amplification were also common. The prognosis of patients could be distinguished by grouping the expression of PDL1 and TIL, and the difference may be related to the expression of PD1. There were more copy number amplication of genes with poor prognosis in PDL1-TIL- patients. Conclusions: The classification of tumors into four microenvironmental subtypes based on PDL1 and TIL expression is an appropriate method to stratify patients with different clinical outcomes. At the genetic level, there are more copy number amplification of the genes with poor prognosis in patients with TIL-PDL1- type, so the prognosis is always worse than that of patients with TIL+PDL1+ type. Gene may affect the prognosis of patients by affecting the tumor immune microenvironment.