bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of time period of diagnosis, race, and military exposures on the survival of US military veterans with multiple myeloma and/or plasmacytoma.
Authors: Mahmood Sharmeen , Gupta Pankaj , Ma Helen 
Published: June 2023

e20061 Background: The aging veteran population represents a unique demographic with potential exposures to carcinogens. Multiple myeloma has been linked to exposure to Agent Orange, burn pits, radiation, and water contamination. There have been remarkable advances in the management of multiple myeloma. We investigate whether the survival of veterans diagnosed with multiple myeloma and/or plasmacytoma has changed over time. Methods: Using ICD-O criteria we identified 14,026 veterans diagnosed with multiple myeloma and/or plasmacytoma between 1/1/2000 and 12/31/2020 in the national electronic Veterans Administration (VA) medical records. Variables including age and date of diagnosis, race, gender, branch of military service, tobacco use, military exposures, cause of death and survival were analyzed. Patients were subdivided into 4 time periods for analysis based on date of diagnosis: Group 1 (1/1/2000-12/31/2005), Group 2 (1/1/2006-12/31/2010), Group 3 (1/1/2011-12/31/2015), Group 4 (1/1/2016-12/31/2020). Results: Of the 14,026 cases, 98% of patients were male, 58% were white and 28% black; 57% were current or previous tobacco users, 26% were never users. The table summarizes military exposures and causes of death. Median overall survival (OS) for Group 1 was 0.9 years [95% CI, 0.8-1], Group 2 was 2 years [95% CI, 1.8-2.9], Group 3 was 2.8 years [95% CI, 2.6-2.9], and Group 4 was 3.5 years [95% CI, 3.3-3.6]. These differences in OS were statistically significant (p<0.0001). Deaths attributed to myeloma accounted for 67%, 65%, 63%, and 56% of patients in Group 1, 2, 3, and 4, respectively. On multivariable analysis of 6023 cases where selected variables were consistently available, tobacco use, exposure to Agent Orange or burn pits, older age and earlier time period of diagnosis were significantly associated with shorter survival. However, race did not significantly impact survival. Conclusions: In US military veterans diagnosed with multiple myeloma and/or plasmacytoma, survival has significantly improved over the past two decades. Survival was adversely impacted by tobacco use and military exposures, but not impacted by race. Advances in diagnosis, therapies and supportive care may have contributed to the observed improvement in survival over time. Future research should investigate if differences exist in the pathophysiology of malignancies developing in veterans with military exposures, and whether novel treatments can improve their outcomes. [Table: see text]
Peripheral pre-existing cancer-antigen specific T-cell immunity as predictive biomarker for immunotherapy in NSCLC patients.
Authors: Xagara Anastasia , Fortis Sotirios P. , Goulielmaki Maria , Koinis Filippos , Chantzara Evangelia , Kokkalis Alexandros , Samaras Ioannis , Papadopoulos Vasileios , Georgoulias Vasileios , Baxevanis Constantin N , Kotsakis Athanasios 
Published: June 2023

e20504 Background: Pre-existing Tumor Antigen specific T-cells describe the endogenous adaptive immunity before any treatment that may represent a valuable novel predictive biomarker for ICI treatment. We investigate the potential value of pre-existing cancer-antigen specific CD8+ T-cells as a circulating predictive biomarker. Additionally, we analyze the major differences of known immune-cell phenotypes between Pre-existing positive (PreI+) and Pre-existing negative immunity (PreI-) NSCLC patients. Here, we present the preliminary results of this study. Methods: Blood was collected from 24 patients with NSCLC, stage III PD-L1+, after completion of radical chemoradiation, before initiation of maintenance durvalumab. PBMCs were isolated with Ficoll density gradient centrifugation from patients and 10 healthy donors (HD). PreI was calculated by detecting endogenous IFNg expressing cells with FACS after in-vivo co-cultures of PBMCs with mixes of hTERT, MAGEA1, NY-ESO-1 και Survivin cancer-associated antigens. Immunophenotyping was performed by multi-color flow cytometry using antibodies against CD3, CD4, CD8, CD45RA, CD45RO, CCR7, PD-1, PD-L1 for T-cells. Results: From 24 patients receiving Durvalumab, 10/24 (41.6%) had peptide specific T-cells (PreI + patients), 60% (6/10) had detectable peptide specific T cells for all (4/4) antigens tested. Survival analysis revealed better PFS in PreI+ than PreI – patients (Log-rank = 0.06, median 333.5 and 185 days ) and better OS (p = 0.032, median not reached and 254 days). The levels of CD3CD4PD-1 were higher in patients compared to HD (p = 0.019) but there was not a difference between PreI+ and PreI- patients (p = 0.25). PreI+ patients had significantly higher numbers of CD3CD8PD-1 cells compared to PreI- (p = 0.024) but not CD3CD8PD-L1. Prei+ patients had high numbers of Teff (CD3+CD8+CD45RA+CD45RO-CCR7) compared to both HD (p = 0.0039) and PreI- (p = 0.032). Conclusions: Pre-existing tumor antigen specific immunity before initiation of ICI in NSCLC patients could serve as a good predictive factor of response. The study is ongoing.
Clinical and molecular Characterization of NSCLCs with MET exon 14 skipping mutation coexist MET amplification.
Authors: Tian Huimin , Tan Yuan , Zhang Qin , Duan Qianqian , Sun Tingting , Qi Chuang 
Published: June 2023

e20506 Background: MET exon 14 skipping mutation (METex14) and MET amplification are the most prevalent molecular alterations associated with MET carcinogenesis in non-small cell lung cancer, with respective frequencies of 3-4% and 1-5%. Recent research indicates that patients with METex14 may also carry MET amplification, and that MET-TKI therapy has a higher response rate in this patient population. We evaluated the clinical and molecular characteristics of patients with altered or co-altered MET using NGS data of non-small cell lung cancer cases from Jiangsu Simcere diagnostic Co., ltd. Methods: During 2019-2021, samples from 33074 NSCLC patients underwent comprehensive genomic profiling (CGP) using hybrid-capture technology at the Simcere diagnostic laboratory (Nanjing, China). To detect gene mutations in tumor tissue or blood samples of patients, next-generation sequencing (NGS) was performed. MET amplification was defined as MET copy number greater than 2.25. Results: MET exon 14 skipping was found in 325 pts (0.98%), MET amplification was found in 136 pts (0.41%), and the co-alter population consisted of only 36 pts (0.11%). Receptor, Donor, D1010, Y1003, and other METex14 subtypes represented 12.0%, 36.6%, 24.6%, 0.2%, and 26.2%, respectively, of the population. Then, we divided MET-altered NSCLC patients into three groups: MET14 (carrying only METex14), AMP (carrying only MET amplification), and MET14&AMP (MET14 concomitant MET amplification). The differences in age, gender, TMB copy number, and MET copy number were then compared between these groups. Patients with AMP were considerably younger than those with METex14&AMP or AMP. (MET14&AMP: 69.0±9.27 vs AMP: 63.5±10.6, P = 0.032; MET14: 70.0±10.9, P < 0.001). The AMP group contained significantly more male patients than the MET14 group (68.0% vs. 54.5%, P = 0.019), but there were no significant differences between the remaining groups. In contrast to tissue-based TMB, the AMP group was significantly higher than the other two (AMP:17.059.5 vs MET 14: 2.945.79; P0.001; MET14&AMP: 3.650.63, P = 0.005). In spite of this, there was no statistically significant difference between the AMP and MET14 & AMP groups in terms of MET copy number or percentage of MET CN > = 10. Conclusions: In general, AMP pts are younger and have a higher TMB than co-alteration pts; however, there is no significant difference in MET CN between AMP and co-alteration pts; whether the coexisting group is sensitive to MET-TKI is unknown, and future research should focus on the treatment of co-alteration and AMP pts.
Comparing the prognostic implications of spread through airspaces versus lymphovascular invasion in non-small cell lung cancer.
Authors: Epstein Rebecca Elizabeth , Seetharamu Nagashree , Esposito Michael J. 
Published: June 2023

e20509 Background: Risk stratification for patients with non-small cell lung cancer (NSCLC) has historically been evaluated using TNM staging, but there are several other pathological features that have been identified as poor prognostic factors such as lymphovascular invasion, visceral pleural invasion, micropapillary pattern, and more recently, spread through airspaces. There is considerable data linking lymphovascular invasion to poor prognosis and emerging data suggesting spread through airspaces as a poor prognostic factor, but there is limited data comparing the prognostic power of lymphovascular invasion to spread through airspaces. This study aims to distinguish lymphovascular invasion from spread through airspaces as a prognostic factor and to further investigate the correlation of these to other pathologic markers. Methods: Retrospective review of the histopathologic diagnosis, recurrence, and survival status of 720 patients who underwent surgical excision of NSCLC between 2015 and 2019 was conducted. The relationships between pathological factors and prognosis were evaluated with chi square tests and a binary logistic regression was performed. Patients with stage V disease and those treated with neoadjuvant chemotherapy were excluded. Prognosis was assessed using documentation of recurrence of the primary tumor and survival status at the time of chart review. Results: Of the 720 patients, 61 patients had lymphovascular invasion (7.2%) and 56 patients had spread through airspaces (7.1%). Lymphovascular invasion was associated with a statistically significant increase in recurrence and patient mortality across stages I-III collectively, and stage I disease independently. Spread through airspaces was not associated with a statistically significant increase in recurrence or patient mortality in stage I-III or in stage I disease independently. Lymphovascular invasion was also significantly correlated to a greater number of nodal metastases, higher frequency of a micropapillary component, higher frequency of visceral pleural invasion, and increased tumor size. Spread through airspaces was significantly correlated to each of the same pathological risk factors except increased frequency of visceral pleural invasion and increased tumor size. Conclusions: The presence of lymphovascular invasion increases risk of recurrence and mortality and is associated with all of the additional pathological risk factors measured making it more relevant pathologically and prognostically than spread through airspaces.
Tumor immune microenvironment (TIME) analysis of stage I lung adenocarcinoma with micropapillary pattern.
Authors: Han Yun , Yu Yue , Xu Chongyuan , He Qianru , Zhang Qin , Sun Tingting , Qi Chuang 
Published: June 2023

e20510 Background: Micropapillary is one of the most aggressive histologic subtypes of lung adenocarcinoma, which is considered a poor prognostic marker. Comprehensive analysis of tumor immune microenvironment (TIME) features of micropapillary of early invasive lung adenocarcinoma may provide better insight and facilitate the development of novel strategies for early detection and intervention. Methods: A total of 15 patients who underwent anatomical resection and were pathologically diagnosed with stage I micropapillary adenocarcinomas were included in this study. Gene expression profiles (GEPs) of tumor immune-related 289 genes were analyzed using NanoString nCounter. Differentially expressed genes(DEGs), estimation of TIME cell infiltration, and TIME signatures between micropapillary and non-micropapillary were assessed. Results: The number of micropapillary and non-micropapillary patients was 5 and 10. The comparison revealed CD69, IL6, CXCL8, CXCL2, POLR2A and so on were significantly upregulated in the micropapillary group compared with the non-micropapillary group, while HLA-DPA1, IFIT2, and other seven genes were down-regulated in the micropapillary group. These DEGs were mostly enriched in “positive regulation of cytokine production”， “T cell activation”， “receptor ligand activity，” and “signaling receptor activator activity” pathways according to GO enrichment analysis. The results of the KEGG analysis revealed that genes were significantly enriched in “IL-17 signaling pathway”, “TNF signaling pathway”, “cytokine-cytokine receptor interaction”, and so on. Meanwhile, different immune infiltration of the two groups was analyzed. Totally, there was a better TIME cell infiltration in the micropapillary group compared with the non-micropapillary group. Especially, the score of DCs and mast cells was significantly higher in micropapillary group. However, TIME signature scores were similar in both groups. Conclusions: Our study demonstrated that the TIME between micropapillary and non-micropapillary of stage I lung adenocarcinoma was different. Increased mast cells explained poor prognosis in lung adenocarcinoma with micropapillary pattern. A high level of DCs infiltration indicated that micropapillary adenocarcinoma might benefit from immunotherapy.
Association of CAR-T cell secreting CD47 blocking protein with an enhanced antitumor activity in small cell lung cancer.
Authors: Guo Fuchun , Ma Qizhi , Wang Yongsheng 
Published: June 2023

e20512 Background: Notch ligand family DLL3 has been considered a therapeutic target for small cell lung cancer. CD47/SIRPa is an important immunosuppressive factor in the tumor microenvironment and is considered to be a "checkpoint" of innate immune cells. Here, we described an DLL3 targeting CAR-T cells secreting CD47/SIRPa signal blocking protein. We hypothesized that the armored CAR-T cells, by blocking the CD47/SIRPa signal with specific antibodies may promote macrophages to engulf tumor cells and induce anti-tumor immune response, thus addressing a clinical need of cell therapy in SCLC. Methods: Bioinformatics analysis of immune cell composition in the microenvironment of small cell lung cancer, focusing on macrophage content and phenotypic characteristics. The CAR genes were cloned into the lentiviral vector pWPXLd, the expression, phenotype, activation, proliferation, killing and cytokine release of CAR-T cells were detected by flow cytometry, Western blot, RTCA and ELISA; NSG mice were injected subcutaneously with H446-DLL3 cells or H446-DLL3(+/-) combined with CAR-T cells or armored CAR-T cells. Tumor size was measured every 3rd day. The number and phenotype of macrophages in tumors were detected by FCM. Results: Bioinformatics analysis showed that tumors with high expression of DLL3 were often accompanied by downregulation of antigen presentation-related genes; there is a large amount of macrophage infiltration in SCLC, and the later the stage, the more the infiltration. CAR-T cells co-cultured with target cells could effectively activate T cells, promote CAR-T cell proliferation, secrete IL-2, IFN-γ and TNF-α cytokines, and specifically kill DLL3 positive tumor cells. We have established a solid tumor model with heterogeneous antigen expression. CAR-T cells can effectively inhibit the growth of tumors with positive DLL3 expression in vivo, but the inhibition on tumors with heterogeneous antigens is not obvious. Blocking CD47 can promote phagocytosis of tumor cells by macrophages. Western blot analysis revealed the presence of CD47 blocking protein CV1-Fc in the supernatant of secreted CAR-T cells, which can effectively promote the phagocytic effect of macrophages; Armored CAR-T cells have a better anti-tumor effect in antigen heterogeneous tumor model in vivo, delays tumor progression, and promotes the aggregation of M1 type macrophages. Conclusions: CAR-T cells that specifically target DLL3 can effectively kill antigen-positive tumor cells in vivo and in vitro. Blocking CD47 can promote the non-specific anti-tumor effect of macrophages. CAR-T cells secreting CD47 blocking protein have dual anti-tumor effects, not only killing antigen-positive tumor cells, but also recruit and activate macrophages to exert phagocytosis, and have better anti-tumor effects in antigenic heterogeneous solid tumors.
Using next-generation sequencing for RET fusion detection in Chinese cancer patients.
Authors: Dang Huashao , Nguyen Thi Phuong Anh , Kai Zhentian , He Hongsheng , Luo Peng 
Published: June 2023

e20516 Background: Approval Selpercatinib of FDA for lung and thyroid cancer patients harboured RET mutations or fusions attracts the investigation RET fusion partners and their ability for RET‐based targeted therapy. Here, we presented a genomic characteristics of RET fusion in six cancer type among 24,087 Chinese cancer patients. Methods: Tumor samples (including tissues, formalin-fixed paraffin-embedded or plasma) obtained from patients between March 2021 and February 2023 were used for RET fusion detection. Customed probes were designed to covered all exonic and intronic regions of 6, 10 and 11 for RET. GeneFuse and Delly softwares were used for analyzing RET fusion. To ensure both sensitivity and accuracy of fusion calling, RET fusions were only reported to fuse with a set of 600 cancer-related genes and require at least two individual supporting reads. Results: A total of 233 cases with RET fusion was identified among 24,087 patients with the given six cancer types including lung cancer, thyroid cancer, coloretal cancer, pancreatic cancer, oesophageal cancer and cancer of unknown primary site. A total of 6 fusion patterns were identified in the study cohort with KIF5B, CCDC6, NCOA4 and ERC1 being the most common RET fusion partners. Notably, two novel fusion partners (i.e. GOPC and VCL) were first reported in this study. RET variants frequencies were the highest in thyroid carcinoma (13/210, 6.19%), lung cancer (212/20,402; 1.04%), esophageal cancer (1/156, 0.64%), cancer of unknown primary site (2/374, 0.53%) , pancreatic cancer (1/337, 0.29%) and colorectal cancer (5/2,608, 0.19%). The results of the analysis revealed that different tumor types tend to have preferred fusion partners. For instance, KIF5B is highly specific in lung cancer, account for 72% of cases. Meanwhile, CCDC6 and NCOA4 are both enriched in thyroid cancer (both 46%). NCOA4 also present frequently in colorectal cancer, with 80% of cases displaying this partner. Conclusions: Detection of co‐occurrence of partner and RET fusions provide a guide to clinicians in deciding tumors as candidates for RET targeted therapies.
Comparative analysis of the mutation detection using malignant pleural effusion and blood cell-free DNA samples in lung cancer.
Authors: Lin Yaobin , Ji Sunwen , Jiang Yiling , Wang Tao 
Published: June 2023

e20518 Background: Malignant pleural effusion (MPE) is an abnormal amount of fluid to collect between the chest wall and the lung, and it denotes an advanced malignant disease process. MPE presents a severe medical condition which can result in breathlessness, pain, cachexia and reduced physical activity. MPE is considered to bear cancer signatures because it contains tumor cells released from malignancies, thus can be applied in high-throughput sequencing for cancer screening. Cell-free DNA (cfDNA) in blood consists of small fragments released from apoptotic cells or cancer cells, and pathological conditions can influence this process. Therefore, detection of cfDNA in peripheral blood can identify abnormalities of individuals in a noninvasive manner. Here, we wonder the difference of MPE and cfDNA in lung cancer-related mutation detection. Methods: In this study, MPE and blood samples from 216 patients with late-stage lung cancer were collected and applied to library construction and next-generation sequencing. All samples were collected during August 2018 to December 2022. We focused on the key mutations in cancer-causing genes and drug treatment-related genes (e.g., EGFR, KRAS, BRAF, ERBB2, etc.). Statistical analysis was conducted to compare the detection results between MPE and cfDNA samples by Fisher’s exact test. Results: Among the 216 patients, 60 patients (60/216 = 27.8%) were identified as negative detection with no mutation detected in cancer-causing genes in MPE and blood samples. Of the remaining 156 pairs of samples, there were 118 (118/216 = 54.6%) pairs showing the positive detection in both MPE and blood samples. 12 patients (12/216 = 5.6%) demonstrated the positive detection in blood samples while negative detection in MPE samples. The other 26 patients (26/216 = 12%) demonstrated the positive detection in MPE but negative detection in blood samples. There is no significant difference in detection rates between two types of samples (p = 0.194). Similarity, we next focused on the mutations in drug treatment-related genes and identified 91 patients (91/216 = 42.1%) as negative detection. There were 85 patients (85/216 = 39.4%) showing the same positive detection both in MPE and blood samples. 13 patients (13/216 = 6%) demonstrated the positive detection in blood samples but negative detection in MPE samples. The other 27 patients (27/216 = 12.5%) demonstrated the positive detection in MPE but negative detection in blood samples. No significant difference in detection rates was observed between two types of samples (p = 0.211). Conclusions: The mutation detection results in MPE and blood samples turned out to be consistent in most conditions, suggesting an alternative application of MPE or blood samples in cancer screening. Nonetheless, it is still valuable to integrate the information in both MPE and blood samples for a higher detection sensitivity.