bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between TP53, PAR1 and CCR5 gene polymorphisms and non-small cell lung cancer susceptibility in the Amazon.
Authors: Pereira Esdras Edgar Batista , Barra Williams Fernandes , Fernades Marianne Rodrigues , Rodrigues Juliana Carla Gomes , Modesto Antônio André Conde , Fernandes Bruno Melo , Pastana Lucas Favacho , Burbano Rommel Mario Rodriguez , Assumpção Paulo Pimentel , Guerreiro João Farias , Santos Sidney Emanuel Batista dos , Santos Ney Pereira Carneiro dos
Published: June 2022

e20538

Background: Lung cancer is one of the most frequent neoplasms in the world, representing 11.4% of all registered cancers, and is responsible for 18% of cancer deaths. It is divided into two categories, small cell lung cancer, responsible for 15% of cases; and non-small cell lung cancer (NSCLC), which represents 85% of cases. The most well-known risk factor for the development of lung cancer is smoking, due to substances contained in tobacco associated with inflammation and carcinogenesis. Pulmonary carcinogenesis is a complex and gradual process, with synergistic and complex interactions between environmental risk factors and individual genetic susceptibility. The aim of this study was to investigate possible associations between TP53, PAR1, and CCR5 gene polymorphism for susceptibility to NSCLC in the Amazon. Methods: This is a pilot, case-control study, which included 263 subjects, 67 patients with NSCLC and 196 healthy subjects. The samples were analyzed for TP53 (rs17880560), PAR1 (rs11267092), and CCR5 (rs333) gene polymorphism, genotyped in PCR, followed by fragment analysis. To avoid misinterpretation due to population substructure, we applied a previously developed set of 61 informative ancestral markers that were genotyped by multiplex PCR. We used logistic regression to identify differences in genotypic frequencies between individuals with and without lung cancer. Results: We observed that some genotypes were associated with protection for NSCLC: TP53 gene LED/DEL genotype (p = 0.041, OR: 0.510, 95%CI: 0.267-0.974); DEL/DEL genotype of the PAR1 gene (p = 0.023, OR: 0.471, 95%CI: 0.247-0.971); and also the INS/INS genotype of the CCR5 gene (p = 0.033, OR: 0.331, 95%CI: 0.120-0.917). Conclusions: TP53 (rs17880560), PAR1 (rs11267092) and CCR5 (rs333) gene variants were significantly associated with NSCLC in patients from the Amazon. The validation of these findings may favor, in the future, the screening of individuals, facilitating the institution of preventive measures personalized, early diagnosis, consequently reducing the cost for health services and mortality from this malignant neoplasm. Keywords: Genetic Polymorphism; TP53; PAR1; CCR5; Biomarker; Non-Small Cell Lung Cancer.
Heterogeneity of tumor immune microenvironment and real-world analysis of immunotherapy efficacy in lung adenosquamous carcinoma.
Authors: Zheng Xiaobin , Lin Gen , Zheng Xinlong , Long Feng , Jiang Kan , Mok Tony S. K.
Published: June 2022

e20546

Background: Lung adenosquamous carcinoma (ASC) is an uncommon histological subtype. We aimed to characterize the tumor immune microenvironment (TIME) in lung ASC and estimate patient response to immune checkpoint inhibitors (ICIs), which have never been systematically investigated. Methods: In cohort I, we collected 30 ASCs from a single center for analysis of TIME characteristics, including immuno-phenotyping, tumor mutation burden (TMB), T cell receptor (TCR) repertoires, tumor-infiltrating lymphocytes (TILs), and immune checkpoint expression. In cohort II, the efficacy of ICI-based therapy were estimated using a real-world data of 46 ASCs from 11 centers. Results: In cohort I, 22 (73.3%) patients were EGFR-positive. The TIME were defined by immune-excluded (60%) and immune-desert phenotype (40%). Strikingly, PD-L1 and PD-1 were predominantly expressed in SCCC versus ACC, where enhanced CD4+ FOXP3+ regulatory T cell and attenuated CD57+ natural killer cell infiltration was present, consistent with a landscape of fewer innate immune cells, more immunosuppressive cells. SCCC had higher TMB, higher TCR clonality, and lower TCR diversity than ACC. In cohort II, majority of 46 patients were driver genes negative and unknown mutation status, 18 (39%) and 18 (39%), respectively. Overall objective response rate of 28%, median progression-free survival of 6.0 months (95% CI 4.3-7.7), and median overall survival of 24.7 months (95% CI 7.2-42.2) were observed in the ICI-based treatment. Conclusions: This work ascertains suppressive TIME in lung ASC and genetic and immuno-heterogeneity between ACC and SCCC. Lung ASC patients have a moderate response to ICI-based immunotherapy.
The utility of liquid biopsies for management of stage IV non-small cell lung cancer (NSCLC) in an academic community medical center.
Authors: Maity Alisha Paro , Gangireddy Mounika , Dessain Scott K. , Evans Tracey L.
Published: June 2022

e20577

Background: The management of stage 4 non-squamous non-small cell lung cancer (NSCLC) relies heavily on the use of tumor genotyping that allows for the preferential use of targeted therapies as first-line treatment to eligible patients. Recently, the “liquid biopsy”, a non-invasive genomic analysis of circulating tumor DNA, has been deemed a suitable complementary method to identify actionable mutations and guide therapy in NSCLC patients. At our community-based academic medical system in suburban Philadelphia, liquid biopsies began to be used more regularly for these patients in 2018. All patients in the study received tissue biopsies with molecular testing. Our study compared patients who also underwent liquid biopsy with patients who did not, in order to determine whether performance of this biopsy affected their treatment. Methods: This retrospective cohort study used a bank of Main Line Health patients diagnosed with Stage 4 non-squamous NSCLC from 2014-2020. Chart review was used to extract variables from these patients regarding dates of tissue biopsies and treatments, information on liquid biopsies, and demographic information. The primary objective was to compare the rate of detection of actionable mutations in the liquid biopsy vs. non-liquid biopsy cohorts. A secondary objective was to assess the time interval between the identification of a potential lung cancer by imaging and the initiation of first line therapy. Results: 152 patients met inclusion criteria and of these 68 patients underwent liquid biopsy testing and 84 patients did not. Of the 68 patients who underwent liquid biopsy testing, 34 patients (50% patients) did not have sufficient tissue on their tissue biopsy for a molecular diagnosis. Of these 34 patients, 15 patients (44%) had an actionable mutation detected with liquid biopsy. Thus, 28 patients (41%) of the liquid biopsy group had actionable mutations detected. In comparison, only 18 patients (21%) in the cohort without liquid biopsy testing had actionable mutations detected. The initiation of first line treatment occurred sooner for the group undergoing liquid biopsies, an average of 48.3 days (median 40.5 days, range 13-317) compared to 72.7 days (median 50.5 days, range 14-534), p = 0.012 by two-tailed T-test. Conclusions: In our community academic medical center, patients with stage IV non-squamous, NSCLC who underwent a liquid biopsy as part of their initial diagnostic workup had a higher rate of detection of actionable mutations and initiated first line therapy sooner than patients who received only tissue-based molecular diagnostic testing.
Meta-analysis of rates and causes of local recurrence in surgically-resected NSCLC and differences in recurrence and survival between Asian and non-Asian populations.
Authors: Varlotto John M. , Bosetti Cristina , Bronson Dwight , Santucci Claudia , Chiaruttini Maria Vittoria , Scardapane Marco , Hodgkinson Gerald
Published: June 2022

e20579

Background: Recently, the PORT-C (China) and Lung ART (Europe) trials have been reported for non-small cell lung cancer patients (NSCLC) with surgically resected N2 nodal disease subsequently randomized to post-operative radiation (PORT). The two studies noted widely different locoregional relapse (LR) rates in the control arms, 18.3% in PORT-C and 28.1%(46% of recurrences) in Lung ART. We performed a meta-analysis of patients with N0-N2 disease to better understand risk factors for LR, and the possible differences in risk and rates between Asian (AP) vs. non-Asian populations (NAP). Methods: The present systematic review and meta-analysis identified all original studies of curative NSCLC surgical resections which reported risk and rates of LR between January 1st, 2000 and January 10th, 2021. Studies were excluded if patient number was less than 10, if metastatic disease was present, or if any neo-adjuvant chemotherapy and/or radiation was given. Eighty-seven studies were included; of these, 56 were of high quality (HQ) based on the Newcastle-Ottawa Scale (ratings 7-9). For each risk factor, we derived pooled relative risk (RR) and rate estimates using random-effects models. Results: Overall, the three highest pooled RRs for LR were N2 vs. N0 (RR 3.01), lymphovascular invasion (LVI; 1.92), and advanced T stage (T3-T4) vs. T1 (1.86). For HQ studies, the highest RRs for LR were LVI (1.94), sublobar vs. lobar resection (1.86), and N1 vs. N0 (1.84), but N2 vs N0 was no longer significant (RR 3.0 (95% confidence interval 0.57 -15.61) based on only 2 studies. The RRs for LR were consistent for most factors across geographic areas, although the RRs for male vs. female sex were higher in AP (1.44) than in NAP (1.09). The pooled rate of LR at 5-years was lower in the AP 12.00% (6.92-17.09) vs. NAP 22.66% (17.06 - 28.26), despite similar overall recurrence rates (both LR and distal) at 5 years in both populations: 38.03% (25.15-50.90) in AP and 37.30% (32.44-42.17) in NAP. However, a lower 5-year mortality rate was noted in AP (24.30%, 15.56 -33.03) than in NAP (45.87%, 41.23-50.50). Conclusions: Our meta-analysis found that N2 nodal disease is not a risk factor for LR when considering HQ studies based upon scant data, and confirmed that LR is lower in AP. We propose that prospective evaluation of LR risk factors and rates should be undertaken prior to any other prospective evaluation of PORT because LR may not be dependent upon N2 node status and because LR rates may differ in AP.
Nodule vascularity as novel radiomics imaging endpoint for lung cancer diagnosis and prognosis.
Authors: Blistein François , Goffart Sebastien , Belmans Flore , van Peufflik Ingrid , Walsh Sean , Occhipinti Mariaelena , Vos Wim , Vaidyanathan Akshayaa
Published: June 2022

e20580

Background: The vascularization of lung nodules has been proven as severe risk factor for malignancy, and in lung cancer, indication of worse prognosis (1,2). For this reason, we developed a novel imagining endpoint based on the vasculature surrounding a lung mass and we tested this endpoint for the prediction of malignancy for lung nodules. Methods: The vasculature of the nodules (both arteries and veins) has been computed using the surface intersection between the nodule and the vascular structure 3D meshes. Both 3D structures were obtained by converting the segmentations of the nodule and of the vessels to meshes with a marching cubes algorithm. Nodule and vessels segmentation has been obtained with an in-house deep learning segmentation model. The features considered are the numbers of intersections, the total area of intersection and the mean area of intersection. These features have been used to predict nodule malignancy on thoracic CT scans from the Lung Image Database Consortium image collection (3). Quality controls on clinical data completeness and imaging parameters resulted in a cohort of 894 scans (715 for training and 179 for testing), from the original 1018 cases. The malignancy status is defined as high risk and low risk, based on the consensus classification of a panel of four radiologists. Firstly, an univariate analysis is performed to assess the variability of the features grouped by the malignancy score by using Mann-Whitney and ANOVA tests. After, seven combinations of features have been used to train generalized linear models (GLM) to predict nodule malignancy. To compare the models, the Area Under the Curve (AUC) is used as the main performance metric. Results: Univariate analysis of each feature grouped by the malignancy outcome showed that all the three features have good univariate discriminative power between high risk and low risk categories ( p value ≤ 0.05), with nb_connections as the most predictive singular feature ( p value of 1.343277 × 10-36). All the GLM models developed showed a good performance (AUC equal or higher than 0.7), with the best model in testing based on the combination of mean_area and sum_area (AUC of 0.84). Conclusions: The radiomics vascularity endpoint has been proven capable of predicting nodule malignancy with very good performance. The singular feature that is most related to malignancy is the number of vessels intersecting the nodule while the total area of intersection followed by the number of intersections are the most useful to model risk of malignancy. Wang et al., Lung Cancer 114: 38–43, 2017. Hamanaka et al., Diagn Pathol 10,17, 2015. G. Armato et al., Med. Phys., 38: 915-931, 2011.
Laterality and survival in mesothelioma: A SEER database analysis.
Authors: Parekh Jay , Yerlikaya Aslihan , Xie Yiyu , Eralp Yesim , Adjepong Yaw
Published: June 2022

e20594

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive and rare cancer type that carries dismal prognosis with a median survival of only 12 months. Often patients are diagnosed at advanced age and tend to have many co-morbid conditions. More precise prognostication should help physicians to decide on the best treatment approach for patients. Previous three studies suggest right sided involvement is associated with poorer prognosis. However, these were very small studies and estimates were not precise. We therefore decided to assess prognostic indicators, including laterality, using the large SEER database. Methods: Using SEER database, a total of 5064 cases diagnosed between 1975-2003 were included in this study. R software (4.0.5) was used. Prognostic indicators assessed included age, stage at diagnosis (distant versus regional/early), gender, and tumor laterality. We evaluated all-cause mortality using multivariate regression and introduced a competing risk regression to explore the association of clinical features and mesothelioma-related death. In analyses, we treated non-cancer related death as a competing factor. The prognostic significance of laterality was assessed at each stage of diagnosis. Results: The patients were predominantly male (81%), aged 60 years or older (79.1%) with right side predominance (58.9%). The overall median survival time was 8 months. The cumulative incidence of mesothelioma-specific death was 42% at 6 months and 62% at 12 months. In the multivariate analysis, male gender (HR = 1.23, p < 0.01), age 60 year or older (HR = 1.52, p < 0.01) and distant stage at diagnosis (HR = 1.2, p < 0.01) were independent predictors of shorter overall survival. In subgroup analyses of different stages, right sided mesothelioma was an independent predictor of mesothelioma-related death(HR = 1.14, CI 1.00-1.28, p = 0.042) in patients with regional/early-stage disease (Table) after adjustment for age and gender. When included all cohort with both early and late stages, there was no statistically significant association between laterality and all-cause mortality(HR = 1.02, CI 0.958-1.08, p = 0.61). Conclusions: Our study confirms that right-sided involvement is independently associated with increased risk of death in early stage/localized mesothelioma patients. The lack of association between laterality and survival in those with distant spread may be explained by the overall shorter survival in that group.[Table: see text]
High-definition PCR (HDPCR) detection of DNA and RNA variants in non-small cell lung cancer (NSCLC) samples.
Authors: Tsongalis Gregory J. , Leatham Bryan , McNall Katie , Subramanian Hari , Alvarado John G , Jacky Lucien , Yurk Dominic , Green Donald , Rajagopal Aditya , Schwartz Jerrod
Published: June 2022

e20603

Background: Digital PCR (dPCR) is an emerging technology platform for detecting genomic variants in cancer genomes due to its high sensitivity and fast time to results compared to sequencing. However, translational oncology applications often require the measurement of more biomarkers than there are color channels available on dPCR platforms. One approach to address this limitation with dPCR is to split a sample across many wells and profile a subset of variants in each well. For input-limited samples, however, this results in fewer molecules being profiled in each dPCR well, resulting in a reduction in sensitivity and fewer patient samples processed per instrument run. ChromaCode has developed a research use only (RUO) digital High Definition PCR (HDPCR) NSCLC assay, for multiplexed detection of 14 DNA variants and 15 RNA fusion variants relevant in non-small cell lung cancer samples. The assay is constructed using both amplitude modulation and multi-channel resilient signal encoding methods. Amplitude modulation enables different variants to generate a distinguishable signal at different intensity levels in a single color channel, allowing for multiple targets to be detected within that single-color channel. In addition, resilient encoding generates a signal in more than one color channel to create a form of error detection in the assay design. Methods: Assay benchmarking was performed using over 500 contrived human biological FFPE samples, consisting of synthetic DNA or RNA variants spiked into a background matrix of FFPE-extracted DNA or RNA; over 500 contrived human biological plasma samples, consisting of synthetic DNA or RNA variants spiked into a background matrix of plasma-extracted cell free DNA or RNA; and residual human biological FFPE and plasma NSCLC samples that were previously characterized using a targeted sequencing workflow. The samples were tested using the HDPCR NSCLC assay on the QuantStudio Absolute Q Digital PCR system, and data analysis was performed with custom analysis algorithms. Results: For the more than 500 contrived FFPE and plasma samples, the HDPCR NSCLC assay had high overall agreement with expectation across a range of mutant allele fractions for both DNA and RNA analytes (≥99% PPA and ≥99% NPA). For a set of N = 25 residual human biological FFPE samples, the assay was also highly concordant (100% PPA and 99% NPA) with a targeted panel sequencing comparator. The hands-on workflow time from isolation start to analysis complete was < 24 hours. Conclusions: The HDPCR NSCLC assay is a robust RUO tool for the sensitive and rapid detection of commonly targeted variants relevant to NSCLC samples. This technology could complement sequencing assays when there is a need for a rapid turnaround time or there are limited amounts of isolated nucleic acid.
Long-term survival in small-cell lung cancer patients: Extension of the SMALLBRAIN study.
Authors: Diaz-Santos Javier , Cantero-Gonzalez Alexandra , Muñoz-Ayllon Marta , Garrido-Almazan Lucia , Gutierrez Calderon Vanesa , Rueda Dominguez Antonio
Published: June 2022

e20605

Background: Long-term survivors of metastatic Small Cell Lung Carcinoma (SCLC) with overall survival (OS) greater than 12 months are not frequent and have not been deeply studied. Therefore, we conducted the descriptive study SMALLBRAIN to characterize these patients with central nervous system metastases (mCNS), since at least a 20% of SCLC patients has mCNS at the diagnosis. The survival results were reported at the NCCN 2022 Annual Conference, showing no statistically significant survival difference between presenting mCNS at diagnosis or later and no correlation between the mCNS volume and OS. After these results, we have extended our study to metastatic SCLC patients without mCNS to analyze possible differences. Methods: We carried out a systematic search for metastatic SCLC patients with OS > 12 diagnosed and first treatment between January 2016 and April 2020 in our academic medical center in Spain, we excluded those with missing data. The included patients were classified in 3 cohorts: COHORT NA: Stage III at diagnosis with metastatic progression and no mCNS. COHORT NB: Stage IV patients without mCNS. COHORT Y: mCNS during the course of the disease, regardless of onset time. The number of treatment lines received and the survival were analyzed using Kaplan-Meier and multi-variable Cox proportional hazard analysis. Results: A total of 45 patients met study criteria (NA = 5, NB = 11 and Y = 29). The female - male ratio was of 1:3.14 for cohort Y and 1:2.2 for all the patients without mCNS (NA+NB), not statistically significant. The median OS was 24.9 months for cohort NA (range 16 – 64.83), 21.4 months for NB (range 12.30 – 31.83) and 18.6 months for Y (range 12.67 – 60.83), not statistically significant. Only three patients are currently alive, two from cohort NA and one from Y. The median of treatment lines was 3 for all the cohorts with a maximum of 8 for one patient in cohort Y. Best responses were two complete response with later progression in one patient from cohort NA and one from NB. Best response of cohort Y was a partial response. Conclusions: No statistically significant differences were found regarding survival or treatment lines between the population of long-term survivors of metastatic SCLC with and without mCNS. Their infrequency with few living individuals makes their characterization a challenge. These patients are also highly complex, more than 50% received at least 3 lines of treatment. Future research should explore the possibility of extracting long-term SCLC survivors from existing cancer registries of different countries. [Table: see text]
Anlotinib combined with etoposide as maintenance treatment in extensive-stage small cell lung cancer (ES-SCLC): Updated results from a phase II trial.
Authors: Shen Bo , Wu Yuan , Shi Lin , Pan Banzhou , Yang Kaihua , Wang Qiong , Zhao Weiqing , Han Zhengxiang , Wang Lifeng , Feng Jifeng
Published: June 2022

e20610

Background: Existing maintenance treatment strategies for patients with ES-SCLC experiencing no progression after the standard first-line chemotherapy are limited. Anlotinib combined with etoposide as maintenance treatment in ES-SCLC after the standard first-line EP chemotherapy showed encouraging efficacy and good tolerability. This is an update of the phase II study (ChiCTR1800019421). Methods: Patients with histologically confirmed ES-SCLC who have not progressed after the standard first-line EP chemotherapy received anlotinib (12 mg, day 1 to 14 of a 21-day cycle) combined with etoposide (50 mg, QD, day 1 to 14 of a 21-day cycle, up to 6 cycles) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and safety. Results: Between April 2019 and October 2021, we screened 31 patients and enrolled 27 patients in this trial. At data cut-off (January 7, 2022), 20 (74%) patients had discontinued the trial, and 7 (26%) patients remained on treatment. The median follow-up time reached 12.9 months. Among 27 evaluable patients, there was 9 partial response, 17 stable disease and 1 disease progression, resulting in the objective response rate 33.3% and disease control rate 96.3%. The median PFS was 8.9 months (95%CI: 5.4-12.3). The median OS was 13.6 months (95%CI: 9.6-17.6). The most common grade 1-2 adverse events (AEs) were anorexia (9 of 27, 33.3 %), hypertension (8 of 27, 29.6 %) and fatigue (7 of 27, 25.9 %). The most common grade 3-4 AEs were anorexia (4 of 27, 14.8%), hypertension (2 of 27, 7.4%) and hand and foot skin reaction (2 of 27, 7.4 %). Nine patients had to adjust treatment dosage. Conclusions: This updated results have confirmed the combination of anlotinib and etoposide showed significant efficacy and favorable safety profile. The combination may represent a new treatment option as maintenance treatment in patients with ES-SCLC having not progressed after the standard first-line EP chemotherapy. The further exploration is ongoing. Clinical trial information: ChiCTR1800019421.
Patient characteristics and outcomes associated with small cell lung cancer by treatment status in a U.S. Medicare population.
Authors: Ramirez Robert A. , Surinach Andy , Cockrum Paul
Published: June 2022

e20614

Background: Globally, small cell lung cancer (SCLC) accounts for approximately 10% of lung cancers and is typically diagnosed at an advanced/extensive stage in elderly current or former smokers. The objective of this study was to describe patient characteristics (demographic and clinical) and outcomes (survival) associated with SCLC in the Medicare population by systemic anticancer treatment status (treated vs untreated). Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database. Patients were included if they had a record with a diagnosis of SCLC in the database from 1/1/2007 – 12/31/2017, were ≥65 years of age at diagnosis, and had continuous enrollment for ≥180 days pre-SCLC diagnosis. Patient characteristics and overall survival (OS) were stratified by treatment status. Median OS was estimated using the Kaplan Meier method. Results: 13,516 patients met the study criteria. Overall, 57.7% were female, mean age was 74 years, and 89.5% were white. Nearly three-fourths (73.1%) were diagnosed with stage 4 disease. Just over half (55.4%, N = 6,022) initiated 1L treatment. Older patients were less likely to be treated: 36.3%, 51.1%, and 78.5% of patients 65-74 yrs, 75-84 yrs, and 85+ yrs, respectively, were untreated. Patients diagnosed at stage I-III were more likely to be treated than those diagnosed with stage IV disease (68.2% vs 51.4% treated). Patients with metastasis in the brain and/or liver were also less likely to be treated than patients without metastasis in those sites. On average untreated patients had more comorbid conditions than treated patients (average Charlson Comorbidity Index [CCI] 9.2 vs 9.5). In particular, congestive heart failure (49.3% vs 32.6%), myocardial infarction (25.7% vs 18.9%), renal disease (31.5% vs 18.9%), dementia (13.3% vs 3.5%), hemiplegia/paraplegia (8.0% vs 3.2%), and diabetes with complications (21.1% vs 16.4%) were more common among untreated patients. Median survival among untreated patients was 1.1 months (95% CI: not estimable) versus 9.2 months (95% CI:9.0-9.5 months) among treated patients. Approximately 5% of untreated patients were alive 12 months after diagnosis whereas 40% of treated patients were alive 12 months after initiating 1L treatment. Conclusions: Nearly half of SCLC patients did not initiate systemic anticancer treatment. Those who were untreated were on average older, had more comorbid conditions, were more likely to be diagnosed with stage IV disease, and had shorter survival, affirming the continued need for safe and effective therapies for SCLC.
Neoadjuvant attelizumab combined chemotherapy in limited-stage and resectable small cell lung cancer: A multicentric, single-arm and open study.
Authors: Yan Xiaolong , Duan Hongtao , Shi Liang , Li Hongxia , Tong Liping , Liu Zhe
Published: June 2022

e20615

Background: Combine chemotherapy and immunotherapy have become the first-line treatment program for extensive small cell lung cancer. The aim of this study is to explore the safety and efficacy of neoadjuvant chemotherapy and immunotherapy in limited-stage small cell lung cancer. Methods: Treatment-naïve patients were enrolled and the patients received the 2-3 cycles of neoadjuvent chemotherapy and atezolizumab (1200mg, D1). surgery was performed within 4-6 weeks after the last treatment. The primary endpoint was surgery patients pathological complete response (PCR). Safety was assessed by adverse events (AEs) and postoperative complications. This trial was registered at the Chinese Clinical Trial Registry (Registration Number: (ChiCTR2100042367). Results: Recruitment started in May 2020. We reported 9 patients with neoadjuvent immunochemotherapy who have completed surgical treatment. Baseline characteristics: 7 males, with an average age of 52.1 years old, all ECOG PS 0-1; 6 current smokers; clinical stages IIB / IIIA / IIIB n = 6 / 1 / 2. There were 1 atezolizumab treatment-related Gr1 AEs (rush) and 4 treatment-related Gr 3-4 AEs. According to Recist 1.1, all patients achieved partial response. 9 patients completed surgery, 3 patients received bilobectomy, and 3 patients underwent pneumonectomy. Surgical methods included robot-assisted thoracoscopic surgery (RATS) /video-assisted thoracoscopic surgery (VATS) (3, 33.3%) and thoracotomy (6, 66.7%). Complete resection (R0) was achieved in 100% of patients (9/9). The mean operation time was 136 min; the mean bleeding volume was 194.4ml, and the mean hospital stay was 8.9 days. The postoperative pathology results showed a PCR (66.7%) in 6 patients and a MPR (88.9%) in 8 patients. Conclusions: Neoadjuvant chemotherapy and atezolizumab therapy significantly improves PCR in small cell lung cancer without unknown AE events and no surgical delay, so this protocol is safe and feasible. Whether the survival benefit is still unknown. Keywords: neoadjuvant therapy, Small cell lung cancer, immunotherapy, surgery, PCR. Clinical trial information: ChiCTR2100042367. [Table: see text]
Clinical characteristics and outcomes of extrapulmonary small cell cancer: A retrospective analysis of the SEER database.
Authors: Abdullah Hafez Mohammad , Ellithi Moataz , Ahmed Mamoon , Ali Lina , Ali Mohammad , Anwer Faiz
Published: June 2022

e20616

Background: Extrapulmonary small cell cancer (EPSCC) accounts for only 5-10% of small cell carcinoma, with the rest consisting of small cell lung cancer (SCLC). The incidence of this entity has been rising due to better diagnosis, however it is not well described and data is limited. We performed a Surveillance, Epidemiology and End Results (SEER) database analysis to further characterize the biology and clinical aspects of this entity, in comparison to SCLC. Methods: The Surveillance, Epidemiology and End Results (SEER) 18 database was used to obtain data on age, gender, ethnicity, survival, and tumor characteristics of n = 9,712 US patients diagnosed with EPSCC between 2000-2018 and these were compared to n = 118,514 patients with SCLC diagnosed during the same period. Results: Among the EPSCC cohort 58.1 % were males while in the SCLC cohort 50.3% were males. Median age of diagnosis was 65.50 years for EPSCC and 66.81years for SCLC. Among the EPSCC patients, 75.9 % were Caucasians, 9.2 % were African-Americans, and 8.8% were Hispanics. Amongst SCLC patients, Caucasians made up 83.1% of the patients, while African-Americans made up 8.6% and Hispanics made up 4.5 % of the patients. Most common sites for EPSCC were urinary bladder (20.2%), prostate (7%), cervix uteri (6.2%), pancreas (4.5%), rectum (3%), and ovaries (2.6%). Median OS for EPSCC was 8 months (95% CI: 8 - 8), while median overall survival for SCLC was 7 month (95% CI: 7 - 7). Hazard ratio for death for EPSCC: 0.77 (95% CI: 0.75 - 0.79), p < 0.001. The survival at 12 months, 24 months and 60 months was 36%, 22%, and 13 % for EPSCC and 29%, 13%, and 5% for SCLC. There were no significant gender or racial differences in overall survival (OS). Conclusions: EPSCC has better overall and 5-year survival as compared to SCLC. There are no significant differences in survival outcomes in EPSCC patients based on location of primary, gender or race.
Efficacy of lurbinectedin in a clinical trial versus other standard of care in a real-world comparator arm in relapsed/refractory small cell lung cancer patients.
Authors: Ganti Apar Kishor , Prince Patricia , Wang Xue , Estrin Adina , Boccuti Anne , Rengarajan Badri , Naveh Navit , D'Agostino Ralph , Alvord Trevor , Ben-Joseph Rami
Published: June 2022

e20619

Background: Lurbinectedin monotherapy is currently approved for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy based on the results of a single-arm phase 2 basket trial. The current study established real-world comparator arms (RWCAs) to enable retrospective comparison of the efficacy of lurbinectedin from the trial, notably overall survival (OS) and overall response rate (ORR), to other standard of care treatments. Methods: This exploratory study consisted of two arms, where the 1st arm was the lurbinectedin trial arm (LTA) comprised of data from the SCLC cohort of the trial (NCT02454972) and the 2nd arm was an RWCA sourced from ConcertAI electronic medical records in the US (2010 to 2019). Relevant inclusion and exclusion criteria from the trial were applied to the RWCA to ensure comparability at baseline. Given the absence of Eastern Cooperative Oncology Group performance status (ECOG) for a sizable portion of patients in the RWCA, two RWCA groups were studied, one that excluded patients with reported ECOG > 2 (RWCA1) and the other that excluded patients with reported ECOG > 2 and missing ECOG (RWCA2). Propensity score (PS) weighting was used to further balance measured baseline characteristics between LTA and each RWCA. OS was defined as the time from treatment initiation to death. Weighted cox regression was used to compare OS. ORR was defined as the percentage of patients with a complete or partial response. A weighted two-sample test of proportions was used to compare ORR. Results: This study included 105 patients in LTA and 121 in RWCA1 (74 in RWCA2). After PS weighting, baseline characteristics were mostly similar between LTA and each RWCA. ECOG was balanced between RWCA2 and LTA but was different between RWCA1 and LTA. A numerical median OS benefit of 3.8 and 4.7 months was observed in LTA, compared to RWCA1 and RWCA2, respectively (see table). Probability of survival was greater in LTA compared to RWCAs at 3 and 6 months. ORR was two-fold higher in LTA compared to RWCA1. Consistent findings were seen for LTA compared to RWCA2. Conclusions: Lurbinectedin monotherapy demonstrated improved median OS, lower risk of death at 3 and 6 months, and higher response rate compared to other standard of care treatments in relapsed/refractory SCLC. Future studies with larger sample size powered to detect statistical differences in OS are warranted.[Table: see text]
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.