bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deconvolution of gene expression for microenvironmental cell types in thymomas.
Authors: Badve Sunil S. , Polar Alper , Solzak Jeffrey Peter , Radovich Milan , Loehrer Patrick J. , Gokmen-Polar Yesim 
Published: June 2022

e20623 Background: Thymomas are rare neoplasms in the anterior mediastinum that account for less than 1% of tumors. The presence of immune cells within the tumor is one of the cardinal features of thymomas. However, the nature of the immune infiltration is not well characterized. Methods: Deconvolution of the gene expression of thymomas in the TCGA-THYM cohort was performed using the CIBERSORT and xCELL programs. Pairwise correlative analyses were performed to study the relationships of cell types and thymoma histological subtypes. Results: The differences in presence of immune cells was better highlighted using xCELL, which identifies 67 categories of cells rather than in the 23 categories identified by CIBERSORT. As expected, there were dramatic differences in the presence of T-cells (almost all subtypes) and B-cells between A/AB and type B (-1, -2, -3) thymomas. A significant difference (P < 0.0001) in different type B thymomas was observed for the presence of monocytes, macrophages, and M1, but not in M2 macrophages. Significant differences in dendritic cells were observed within subtypes of B thymoma. Similarly, statistically significant differences were observed between most subtypes in Immunoscore (except AB/B3) and MicroenvironmentScore (except A/B3; AB/B2 and AB/B3). However, StromalScore differences were observed only in comparisons of type A/AB with B type thymomas (except AB/B3). Interestingly, there also differences in postulated pre-adipocytes, hepatocytes, mesangial cells and osteoblasts in types A vs B, and melanocytes between subtypes of B thymomas. Conclusions: The differences in lymphoid content of the tumor microenvironment is associated with dramatic changes in cell type distribution in subtypes of thymoma. These differences in composition underpin their clinicopathological behavior including incidence of myasthenia and likelihood of recurrence.
Longitudinal molecular analysis of tumor exome and transcriptome to evaluate clonal evolution and identify novel therapeutic targets in thymoma.
Authors: Nabel Christopher Sheild , Kurilovich Anna , Lopareva Aleksandra , Dias-Santagata Dora , Batashkov Nikita , Shin Nara , Louissant Abner 
Published: June 2022

e20624 Background: The rarity of thymic epithelial tumors has limited mechanistic understanding of tumor biology and the rational identification of potential therapeutic targets for patients with advanced disease. While the Cancer Genome Atlas Project enabled multi-omic profiling of thymic epithelial tumors, the majority of samples were early-stage and chemotherapy-naïve. Furthermore, next generation sequencing for patients with advanced disease often provides only a limited breadth of genome coverage. The genetic changes in thymic epithelial tumors that evolve through disease progression and treatment represent a current knowledge gap and opportunity for reassessment of new therapeutic targets. Methods: To address these points, we conducted whole exome and bulk RNA transcriptome sequencing for serially-collected FFPE archival tumor samples from a patient with Stage IVA, WHO B2/B3 thymoma using the BostonGene Tumor Portrait Test version 1.3. Samples analyzed include the initial primary tumor resected without induction treatment; two subsequent, metachronous pleural recurrences resected without any induction treatment; and a third pleural metastasis resected following two cycles of induction chemotherapy with Cisplatin/Adriamycin/Cyclophosphamide without interval radiographic evidence of treatment response. Results: Tumor characteristics were largely consistent with prior molecular studies, and without significant evidence of major clonal evolutionary changes based on single nucleotide polymorphisms, insertions/deletions or copy number alterations. Tumor mutational burden was recurrently low (< 1 mutation per megabase) with stable microsatellite status. EGFR copy number gain was observed (+1 copy) across recurrent pleural resection specimens. While the degree of copy number gain did not change with disease progression, increasing EGFR transcript counts were observed and evaluated by IHC. Other notable therapeutic biomarkers included absent TGFB1 and present VEGFA expression. Collective RNA-based gene expression changes were compared with the Thymic TCGA cohort for reference. Conclusions: Our analysis illustrates the narrow clonal evolution of a thymic epithelial tumor through treatment—both with and without the selective pressures of induction chemotherapy. This suggests that the genomic features of advanced thymoma may reflect the treatment-naïve state as described in the TCGA, one marked by a low mutational burden but with recurrent copy number alterations in select genes. Complementary transcriptome sequencing identified EGFR expression as a promising therapeutic target for further study. Taken together, these findings illustrate the hypothesis-generating potential for deep molecular analysis with whole exome and transcriptome sequencing to improve the understanding of rare tumors.
Thymoma and pure red cell aplasia: A single institution experience.
Authors: Seibert Tara , Loehrer Patrick J. , O'Brien Andrew 
Published: June 2022

e20625 Background: Thymoma is an uncommon malignancy often associated with paraneoplastic syndromes including pure red cell aplasia (PRCA), occurring in up to 5% of patients with thymoma. Considering the rarity of thymoma-associated PRCA, optimal treatment regimens and impact on thymoma disease course have yet to be established. Methods: A retrospective chart review was conducted for patients seen at the IUSCCC with thymoma and PRCA to extract and synthesize data on patient demographics, thymoma histology, hemoglobin levels, timeline of diagnoses, treatment regimens, and outcomes. Results: From 1993 to 2022, 10 patients (M:F = 4:6) with thymoma and PRCA were identified. Median follow-up duration was 75.0 months (range 32-202). Median age at thymoma diagnosis was 53.5 (range 40-80). Median age at PRCA diagnosis was 64.0 (range 40-80). Mean hemoglobin at PRCA diagnosis was 6.6. WHO classifications of thymoma included 10.0% A, 40.0% B1, 10.0% B2, 10.0% B2/B3, 30.0% not otherwise specified. Masoaka stages of thymoma included 20.0% stage I, 10.0% stage II, 10.0% stage III, 30.0% stage IVA, 30.0% stage IVB. Patients initially presented with thymoma (n = 7), PRCA (n = 1), or concurrent thymoma and PRCA (n = 2). For those initially presenting with thymoma, PRCA was subsequently diagnosed after a median 19.5 months (range 9-144). Of these 7 patients 3 experienced a relapse or progression of their thymoma at time of PRCA diagnosis, 3/7 had stable disease (1-insufficient data). Additional paraneoplastic syndromes were seen in 6 patients (hypogammaglobulinemia-2; pure white cell aplasia-1; myasthenia gravis-1; autoimmune neutropenia-1; colitis -1). Other diminished immunologic parameters observed were: immunoglobulin levels (n = 3); CD4 counts (n = 2); CD4:CD8 ratio (n = 4); and total B cell (n = 6). The primary outcome of the study was transfusion dependence, defined as requiring ≥1 PRBC transfusion per month for ≥3 months. Six achieved transfusion independence, while 3 remained transfusion dependent despite therapy (1 LTFU). Both patients with concurrent thymoma and PRCA underwent thymectomy, but only one achieved transfusion independence with additional adjuvant immunosuppressive therapies. Median duration of transfusion independence was 18.5 months (range 4-204). Median survival after bone marrow biopsy diagnosis of PRCA was 50.0 months (range 9-202). Conclusions: The impact of PRCA on thymoma disease course is variable. Most patients will recover with immunosuppressive therapy, but approximately 30.0% patients remained transfusion dependent. Our experience does not support thymectomy alone as primary treatment of PRCA. More research is needed to evaluate the mechanism of developing PRCA in thymoma and to define the optimal therapeutic approach.
The impact of BMI on the response to immunotherapy in lung cancer.
Authors: Ying Yuan , Gujju Veena , Hallum Gideon , Shikdar Sufana , Vesely Sara , Hall Spencer , Ayanambakkam Adanma , Aljumaily Raid 
Published: June 2022

e21003 Background: Over the past few years immunotherapy was incorporated in the first line treatment for advanced lung cancer. Obesity leads to a state of low grade chronic inflammation and plays a role in many pathophysiological processes including tumorigenesis. Recently evidence indicates that obesity and related inflammatory state may also impact the efficacy of immunotherapy. Methods: We conducted a retrospective study to look at the impact of body mass index (BMI) on the outcomes in patients with advanced lung cancer treated with immune check point inhibitors (ICI). According to their baseline BMI, patients were grouped into obese (BMI ≥ 30, n = 54) and non-obese (BMI < 30, n = 158). In another comparison using 25 as BMI cut off, patients were grouped into higher BMI (BMI ≥ 25, n = 105) and lower BMI (BMI < 25, n = 107). Results: From June 2012 to December 2020, 212 patients from our institute were included in this study. The median age was 64.5, average BMI was 26.4 kg/m2, and 52% male sex. Median follow-up time in this study was 21.7 months. Patients with higher BMI using 25 as cut off had longer progression free survival (PFS) (8.1 months vs 5.3 months, p = 0.0034). Overall survival (OS) was better in higher BMI group than lower BMI group (10.8 months vs 5.9 months, p = 0.0008). The differences of PFS and OS for obese and non-obese groups were not statistically different (11.1 months vs 5.9 months, p = 0.157 for PFS; 12.0 months vs 6.9 months, p = 0.1512 for OS.). Conclusions: Our results suggest that excess weight may be associated with favorable PFS and OS in advanced lung cancer patients treated with ICI. Future studies are needed to investigate the underlying mechanism of this association.
Gut microbiota and association with clinical response to anti-PD-1 based immunotherapy combined with chemotherapy in Chinese patients with lung cancer.
Authors: Zhao Honghui , He Liyuan , Feng Li , Fan Zhisong , Wang Long , Han Jing , Zhou Xinliang , Zhang Xue , Li Dan , Liu Jiayin , Liu Feiran , Zuo Jing , Wang Yudong 
Published: June 2022

e21005 Background: The gut microbiome has been demonstrated to be closely related to not only the occurrence of lung cancer but also its anti-PD-1 based immunotherapy and chemotherapy. There is little characteristic analysis of gut microbiota in Chinese lung cancer patients, and the impact of gut microbiota on combined anti-PD-1 treatment and chemotherapy remains unclear. Methods: Fecal samples from 22 healthy volunteers and advanced-NSCLC 21 patients who were treated in the Fourth Hospital of Hebei Medical University from 2019 to 2021 before and after anti-PD-1 treatment combined with chemotherapy were collected. DNA was extracted from all samples, and the V3-V4 region of the bacterial 16S rRNA gene was PCR-amplified using the Illumina sequencing platform. The study results were analyzed using bioinformatic data. Results: The composition of gut microbes in NSCLC patients and healthy people at the phylum level was roughly similar, with Firmicutes as the main phylum. However, there were significant differences in Beta diversity (P<0.05). The bray_curtis principal coordinate analysis revealed a significant difference in the microbiota between patients before and after combined treatment (P<0.05). According to the RECIST 1.1 criteria, the efficacy of the combination therapy was evaluated. The patients with complete remission, partial remission, or stable efficacy after 6 cycles were the clinical benefit response group (CBR, n=10), and the patients with disease progression in the efficacy evaluation were the non-clinical benefit group (NCB, n=8). The results suggested that the CBR group was enriched in Bifidobacterium_longum, Bifidobacterium_adolescentis, Bifidobacterium_bifidum, and Bifidobacterium_breve at the species level (P<0.05) compared with the NCB group. Compared with the median progression-free survival (mPFS) of patients without Bifidobacterium_breve at baseline, the mPFS of patients with the kind of gut bacteria was significantly prolonged (P<0.001).Specifically, mPFS without Bifidobacterium_breve group was 106 days (95% CI: 37-175), mPFS of the Bifidobacterium_breve group was Not Reached (95% CI: NC-NC). Conclusions: The clinical response of combined anti-PD-1 treatment and chemotherapy in advanced NSCLC patients was closely associated with the gut microbiome,and Bifidobacterium_breve may be effective biomarkers to predict the survival benefit of NSCLC combined therapy, which provided new therapeutic targets for modulating the response to cancer therapy.
The frequency of rare ALK fusions and their clinical significance in NSCLC.
Authors: Zhu Bowen , Zhen Xinlin , Gao Zeqing , Peisu Suo , Zhang Jing , Fan Wenzhe 
Published: June 2022

e21012 Background: ALK fusion is one of the key driver mechanisms in non-small cell lung cancer. In some case reports, some rare mutant forms have also been found to be active and drug-susceptible. There are few reports on the detection and verification methods of rare ALK fusions. Here, we counted the rare fusions of ALK detected by NGS and verified them by other methods. Methods: We analyzed 184 patients with NSCLC harboring ALK-rearrangement detected by NGS from January 2020 to January 2022. We counted the rare ALK fusion forms, and selected two of them for verification by RNA sequencing or immunohistochemistry. Results: Of the 184 patients with ALK fusion that we included, 105 were female and 79 were male (medium age 53). Most female were non-smokers except one while nearly 50% male were smokers. EML4-ALK fusion accounted for the highest proportion (170, 92.4%), 5 were ALK fusions with other 5’ partners ( C2orf44, KCNG3, KIF5B, KDM5A, DCTN1), 6 were intergenic region- ALK rearrangements, 2 were fusions without transcription initiation region, and 1 was LOC399815 -ALK and ALK-EML4 double fusion. Rare fusion forms accounted for less than 10%. We further verified two of these rare fusion mutations by RNA sequencing or immunohistochemistry. Interestingly, one of the patients with a KCNG3-exon1- ALK-exon20 fusion detected by DNA sequencing was confirmed to be an EML4-ALK fusion by RNA sequencing, and another patient with an intergenic region- ALK fusion was confirmed positive by immunohistochemistry. Conclusions: The vast majority of ALK fusions are EML4-ALK fusions, but there are a small number of other forms of fusions. DNA sequencing, RNA sequencing and ICH may give different conclusions for ALK fusions, which may be limited by the detection method. For some rare fusion forms, a variety of methods can be used to detect whether it is an active ALK fusion form.
Race-specific genomic determinants of therapeutic response in African American NSCLC patients.
Authors: Pilling Amanda , Li Pin , Kane Kaitlyn , Wolf Frank M. , Berry Anna B. , Gadgeel Shirish M. 
Published: June 2022

e21015 Background: African American (AA) individuals are disproportionately affected by lung cancer in terms of incidence and mortality, despite lower tobacco exposure compared to Caucasian Americans (CA). Since molecular profiling is critically important to guide therapy selection in non-small cell lung cancer (NSCLC), we compared treatment-relevant molecular data in a cohort of AA and CA patients with EGFR or KRAS-driven NSCLC. Methods: This is a retrospective study using a clinicogenomic electronic medical record database from health systems in the United States designed to evaluate outcomes in advanced stage NSCLC. Eligibility criteria for analysis included a diagnosis of NSCLC between 2010 and 2020, stage III or IV, available race/ethnicity data, and identification of common KRAS or EGFR activating variant within 60 days of diagnosis. The primary objective was to define the type of EGFR or KRAS activating variant and determine the frequency of co-occurring alterations in NSCLC-associated genes by cohort (AA and CA). Secondary objectives included examining the timing of genetic testing and use of targeted therapy in these cohorts. Results: A total of 642 NSCLC patients with KRAS (15.0% AA; 81.6% CA) and 348 patients with EGFR oncogenic mutations (13.8% AA; 70.1% CA) met inclusion criteria. Mean time from diagnosis to first molecular test result was 20.9 days for AA vs. 19.9 days for CA (p = 0.5). The EGFR G719S variant was more prevalent in the AA cohort (6.3% AA v 0.4%) with no significant differences observed in the most common KRAS or EGFR variants tested (Table). A total of 100 KRAS-mutant patients (16 AA, 86 CA) had a reported result in at least one co-mutation of interest. The most frequent co-mutations were TP53 (81.3% AA v 65% CA, p = 0.92); KEAP1 (18.8% AA v 8.3% CA, p = 0.52); ATM (18.8% AA v 9.5% CA, p = 0.54); and PTEN (0% AA v 8.3% CA, p = 0.5). A total of 35 EGFR-mutant patients (4 AA, 31 CA) had a co-mutation reported in TP53 (75% AA v 65% CA, p = 0.77). EGFR targeted therapy was reported in 47.9% of AA and 52.9% of CA (p = 0.639). In the KRAS-mutant cohort, delivery of immune checkpoint inhibitors (ICIs) was reported in 29.2% of AA and 39.3% of CA (p = 0.08); chemotherapy was reported in 36.5% AA and 45.2% of CA (p = 0.14). Delivery of both ICI and chemotherapy was reported in 13.5% of AA and 21.9% of CA (p = 0.08). Conclusions: In a real-world cohort of NSCLC patients, we found similar frequencies of common KRAS and EGFR variants in AA and CA, but higher rates of EGFR G719S variant in AA patients. A more comprehensive analysis is needed to further evaluate the trends in co-mutations observed in our analysis, to determine the race-specific impact of these alterations in EGFR and KRAS-driven NSCLC.[Table: see text]
Circulating tumor cells as a biomarker for precise management in lung cancer.
Authors: Chen Juan , Li Qian , Xu Chen-yu , Qian Ying-ying , Yang Zhen-hua , Chen Dong-sheng 
Published: June 2022

e21018 Background: Circulating tumor cells (CTCs) have potential utility in various clinical application for cancer management. In this study, we evaluated whether circulating tumor cells (CTCs) provide early diagnostic information and/or precisely indication of patient response to chemotherapy. Methods: 56 patients with newly diagnosed lung cancer, 42 patients with nonmalignant pulmonary disease and 27 healthy controls were enrolled in this study. CTCs were measured at baseline in all eligible subjects and after two cycles of chemotherapy in 25 advanced lung cancer patients, with a strategy of negative enrichment combined with immunostaining-fluorescence in situ hybridization (imFISH). The receiver operating characteristic (ROC) curve was plotted to determine the sensitivity and specificity of the CTC detection for diagnosis. Kaplan-Meier curve and two-sided log-rank test were used for univariate survival analyses. Results: The number of CTCs was significantly increased in lung cancer patients, compared with benign lung disease patients and healthy controls. And it reached 87.5% sensitivity and 95.7% specificity at a cutoff value of 2 cells/3.2ml (AUC = 0.975, 95%CI, 0.953-0.998, p＜0.001).Moreover, the sensitivity of CTCs was much higher than individual or the combination of serum tumor markers, especially in the early detection of lung cancer. Twenty-five advanced lung cancer patients were subsequently followed for an average of 18.2 months (range 6-36 months) ， during which all patients experienced disease progression, and 16 patients died. A change in CTC count after two cycles of chemotherapy was highly predictive for PFS (13.5 v 8.5 months; p = 0.025) and OS (27.6 v 16.8 months; p = 0.009) in favor of a reduction in CTC number compared with an increase. Interestingly, among the patients whose post-treatment computed tomography(CT) results indicated stable disease(SD), PFS (14.0 v 8.7months; p = 0.033) and OS(25.8 v 15.9 months; p = 0.018) in patients whose CTC number decreased after two cycles of treatment were still significantly longer than those whose post-treatment CTCs number increased or unchanged. Conclusions: CTCs may act as precise biomarker for early detection and therapy monitoring that could compensate for imaging.
Blood monocyte and lymphocyte counts patient outcomes in non-small cell lung cancer after immune checkpoint inhibitor therapy: Real-world data of 12,416 patients.
Authors: Goldschmidt Jerome H. , Chan Philip K , Chou Lin-Na , Chen Liwei , Robert Nicholas J. , Kinsey Joyce , Nestor Matt , Lazarus Hillard M. , Rock Edwin P. 
Published: June 2022

e21023 Background: Immune checkpoint inhibitors (ICPi) are now commonly used in non-small cell lung cancer (NSCLC) treatment. Beyond PD-L1 status, no clinically validated predictive biomarkers guide therapeutic decision making regarding their use. Blood monocyte, lymphocyte counts, or their ratio might inform clinical utility of these expensive, potentially toxic agents. Methods: Adults with advanced/metastatic NSCLC receiving any ICPi after diagnosis from January 2015 to November 2020 were included. Treatment outcomes were followed until 31 May 2021. Data were sourced from structured fields of electronic health records from The US Oncology Network and non-Network practices. The primary end point was overall survival (OS), and time to treatment discontinuation (TTD) was secondary. Baseline absolute monocyte count (AMC), absolute lymphocyte count (ALC), and monocyte-to-lymphocyte ratio (MLR) were subdivided into quintiles (Q) with Q1 lowest and Q5 highest. Patient (pt) and treatment characteristics were described. Time-to-event outcomes were assessed by Kaplan-Meier methods. Univariate and multivariate Cox regression analyses described associations among baseline biomarkers, OS, and TTD. Results: For 12,416 pts with NSCLC, median OS and TTD were 13.6 months (mos) and 4.5 mos, respectively. For AMC, patients in Q2 and Q3 had the longest median OS of 15.9 mos. Median TTD by AMC was longest for Q1 and Q2 (5.1 mos), declining sequentially to 3.3 mos for Q5. For ALC, Q5 had longest median OS of 19.2 mos, as well as longest median TTD of 5.8 mos. For MLR, Q1 had the longest median OS and TTD of 22.3 and 6.2 mos., respectively. In univariate Cox regression, AMC, ALC, and MLR each associated with OS and TTD (p < 0.0001). Pts in AMC Q5, compared with AMC Q1, had an OS hazard ratio (HR) of 1.48 (95% CI 1.38-1.60). For ALC, each successive increasing quintile, compared to ALC Q1, demonstrated a lower risk of death (p < 0.0001). Pts in MLR Q5, compared with MLR Q1, had an OS HR of 2.21 (95% CI 2.04-2.39). Conclusions: This data set is the largest to date to examine interactions among baseline immune cell counts, ICPi use, and pt outcome in NSCLC. These data inform efforts to describe immune-based prognostic risk groups among NSCLC pts receiving immunotherapy.[Table: see text]