bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiation fractionation effect on IDO1 through NF-kB/COX2 axis in non-small cell lung cancer.
Authors: Lan Yanli , Pi Wenhu , Zhou Zhangjie , Mei Dan , Xu Yixiu , Xia Xinhang , Wang Wei , Yang Haihua , Kong Feng-Ming (Spring) 
Published: June 2023

e20613 Background: Lung cancer is the leading cancer mortality worldwide. Radiotherapy(RT) plays an important role in lung cancer treatment. Different does fractionation of RT has different effects on the prognosis of lung cancer. For example, stereotactic body radiotherapy can significantly improve the prognosis compared with conventionally Fractionated Radiotherapy. In non-small cell lung cancer, we have previously shown that Indoleamine 2,3-dioxygenase 1 (IDO1) metabolites and radiation induced changes had significant effects on long-term survival in patients treated with either Stereotactic body Radiation Therapy of 10Gy fraction size or conventional fractionated radiotherapy of 2Gy fraction size. However, the underlining molecular mechanism is unknown. In this study, we aimed to elaborate the molecular mechanism of such clinical differential effects in the laboratory. Methods: This study applied two dose/fractionation regimens with a similar BED10: 10Gyx1 and 2Gyx8. 10Gyx1 and 2Gyx8 were tested in cell lines of A549, H1299, Calu-1, TC-1 of human and murine NSCLC as well as normal rat cardiomyocyte cell line H9c2, and in vivo (TC-1 implanted C57Bl/6 mice). The mRNA and protein levels of IDO1, p-NF-kB, COX2 from cells and tumor tissues were determined by using qPCR, western blot and immunohistochemistry. Survival outcome was tested by colony formation assay in vitro and tumor growth curve in vivo. Results: In vitro, 10Gyx1 and 2Gyx8 induced IDO1 expression in all tested cell lines and the level of IDO1 expression induced by 10Gyx1 was lower than 2Gyx8. Both 10Gyx1 and 2Gyx8 increased p-NF-kB and COX2 expression and the level induced by 10Gyx1 was lower than 2Gyx8. In tumor bearing mice, two dose/fractionation regimens also induced intratumor IDO1 expression and increased the levels of p-NF-kB and COX2. Interestingly, the increased levels of IDO1, p-NF-kB, COX2 after 10Gyx1 were also significantly lower than 2Gyx8 in vivo. IDO inhibitor synergized with RT and enhanced cell killing efficacy of RT. Conclusions: The findings of this study suggest different does fractionation of RT induced up-regulation of IDO1 through NF-kB/COX2 axis in NSCLC and non-cancerous cell lines, what’s more, hypofractionated radiotherapy 10Gyx1 had less upregulation that of conventionally fractionated radiotherapy 2Gy x8 on IDO1 immune inhibitory pathway. The finding of hypofractionated radiotherapy less immune suppression differ from the traditional belief of more immune stimulation. Our current study provides a rationale in using IDO1 as a biomarker to design RT dose fractionation and/or immunotherapy in combination and possibilities for clinical trials to design IDO1 inhibitors in combination with radiotherapy.
Early detection of lung cancer using a panel of circulating cell-free DNA methylation biomarkers.
Authors: Hu Shuo , Tao Jinsheng , Peng Minhua , Wang Bo , Ye Zhujia , Chen Zhiwei , Chen Haisheng , Yu Haifeng , Fan Jianbing , Ni Bin 
Published: June 2023

e20614 Background: Lung cancer remains the leading cause of cancer mortality worldwide. Early detection of lung cancer helps improve treatment and survival. Numerous aberrant DNA methylations have been reported in early-stage lung cancer. Here, we sought to identify novel DNA methylation biomarkers that could potentially be used for noninvasive early diagnosis of lung cancers. Methods: This prospective-specimen collection and retrospective-blinded-evaluation trial enrolled a total of 317 participants (198 tissues and 119 plasmas) comprising healthy controls, patients with lung cancer and benign disease from The First Affiliated Hospital of Soochow University between January 2020 and December 2021. Tissue and plasma samples were subjected to targeted bisulfite sequencing with a lung cancer specific panel targeting 9,307 differential methylation regions (DMRs). DMRs associated with lung cancer were identified by comparing the methylation profiles of tissue samples from patients with lung cancer and benign disease. Markers were selected with minimum redundancy and maximum relevance (mRMR) algorithm. A prediction model for lung cancer diagnosis was built through logistic regression algorithm and validated independently in tissue samples. Furthermore, the performance of this developed model was evaluated in a set of plasma cell-free DNA (cfDNA) samples. Results: We identified 7 DMRs corresponding to 7 differentially methylated genes (DMRs, including HOXB4, HOXA7, HOXD8, ITGA4, ZNF808, PTGER4, and B3GNTL1), highly associated with lung cancer by comparing the methylation profiles of lung cancer and benign nodule tissues. Based on the 7-DMR biomarker panel, we developed a new diagnostic model in tissue samples, termed “7-DMR model”, to distinguish lung cancers from benign diseases, achieving AUCs of 0.966 (95%CI: 0.933-1.000)/0.961 (0.924-1.000), sensitivities of 0.887 (0.824-0.951)/0.922 (0.863-0.980), specificities of 0.938 (0.889-0.986)/1.000 (1.000-1.000), and accuracies of 0.896 (0.835-0.957)/0.938 (0.886-0.991) in the discovery cohort (n = 96) and the independent validation cohort (n = 81), respectively. Furthermore, the 7-DMR model was applied to noninvasive discrimination of lung cancers and non-lung cancers including benign lung diseases and healthy controls in an independent validation cohort of plasma samples (n = 106), yielding an AUC of 0.935 (0.862-1.000), sensitivity of 0.808 (0.733-0.883), specificity of 0.975 (0.945-1.000), and accuracy of 0.934 (0.887-0.981). Conclusions: The 7 novel DMRs could be promising methylation biomarkers that merits further development as a noninvasive test for early detection of lung cancer.
Role of adjuvant chemotherapy (CT) in node negative 4-5 cm non-small cell lung cancer in elderly population.
Authors: Gaire Suman , Budhathoki Pravash , Shah Anish Kumar , Jasaraj Ranjit , Uprety Dipesh 
Published: June 2023

e20615 Background: The role of adjuvant CT for 4-5 cm primary lung tumors without any regional lymph node involvement following surgical resection is somewhat controversial. While it is favored in most cases, it should be individualized depending on other pathological risk factors and the patient's performance status. In this study, we investigated the benefit of adjuvant CT in elderly patients with 4-5 cm tumor size following complete surgical resection. Methods: We utilized Surveillance, Epidemiology, and End Results Program (SEER) database to identify elderly patients (≥65 years) with 4 to 5 cm sized non-small cell lung cancer after complete surgical resection diagnosed from 2010-2015. The baseline characteristics among the patients who received and didn’t receive adjuvant CT were compared using relevant parametric/non-parametric tests. Kaplan Meir curve was generated for the univariate survival analysis, and the log-rank test was used for comparison. Multivariate survival analysis was done using the cox proportional hazards regression model. Results: The database included 2582 patients. Among them, 492 (19.1%) cases had received adjuvant chemotherapy while 2090 (80.9%) cases had not. The population that received chemotherapy was younger than those that did not (Median:75 years vs 71 years, p < 0.001). The 5-year overall survival for patients who received chemotherapy was significantly higher than those who did not (53.9% vs 46.5%, P = 0.002). On the multivariate analysis adjusted for age, gender, race, income status, and type of surgery, cases with adjuvant chemotherapy had lower hazards as compared to those who had not received adjuvant chemo (Hazard Ratio (HR):0.86, confidence interval (CI): [0.75,0.99], P value = 0.04). Conclusions: Our study demonstrated a survival benefit with adjuvant CT for node-negative NSCLC of 4-5 cm size in the elderly population.
The combination therapy of anlotinib and penpulimab for the treatment of small cell lung cancer after platinum-based chemotherapy: Results of a phase II exploratory study.
Authors: Yang Nong , Zhang Yongchang , Zeng Liang , Yang Haiyan , Zhou Chunhua , Liu Li , Xiong Yi , Jiang Wenjuan , Wang Zhan , Zeng Fanxu , Chen Qun , Feng Yuanqing , Zhou Chengzhi , Wu Zhijun , Zhang Bing , Li Xiantao , Xiao Maoliang , Wang Cunji 
Published: June 2023

e20628 Background: Anlotinib is a multi-target receptor tyrosine kinase inhibitor that has been developed in China. It works by inhibiting various kinases involved in angiogenesis and tumor cell proliferation, including VEGFR, FGFR, PDGFR, and c-Kit. The results of the Phase II ALTER1202 trial showed that patients who received anlotinib as a third-line or later treatment after failing at least two chemotherapy regimens had a better progression-free survival (PFS) and overall survival (OS) compared to those who received placebo. In light of these results, the combination of anlotinib and penpulimab (a novel PD-1 inhibitor) is being studied as a second-line treatment for small cell lung cancer patients who failed first-line chemotherapy with platinum-containing drugs. Methods: This open-label, single-arm, multi-center, Phase II exploratory study (NCT050019710) enrolled patients with small cell lung cancer who had previously received platinum-based chemotherapy. Participants were given 200mg of penpulimab every three weeks and 10mg of anlotinib daily, with a two-week on and one-week off schedule, until disease progression, unacceptable toxicity, or study discontinuation. The primary objective of the study was to evaluate the antitumor activity of the combination therapy using the objective response rate (ORR) as measured by RECIST v1.1. Secondary objectives included evaluating the disease control rate (DCR), PFS, OS, and the safety and tolerability of the combination therapy. Results: As of January 31, 2023, 21 patients (median age 58 years, with 66% having ECOG performance status of 0 or 1, 95% being male) had been enrolled and received treatment. Of these, 18 patients were evaluable for RECIST and had an ORR of 33.33% (6/18) and a DCR of 77.78% (14/18). The median PFS was 5.934 months with a 6-month PFS rate of 33.33%. The median duration of response was 8 months. Nineteen of the 21 patients (90%) experienced treatment-related adverse events, with 4 patients (21%) experiencing grade 3 or higher adverse events. The most common adverse events related to anlotinib were hepatic injury, hematotoxicity, and hypertension. Conclusions: The combination of penpulimab and anlotinib showed promising clinical benefits and a favorable safety profile in small cell lung cancer patients who failed first-line platinum-based chemotherapy. Clinical trial information: NCT05001971 .
Treatment of extensive stage small cell lung cancer (ES-SCLC) in geriatric patients before the advent of immunotherapy: Real-life experience from one centre.
Authors: Medina Soledad , Gudiel Arriaza Paola , Rodriguez Angel , Lopez Mariana , López González Ana , Nieto Mangudo Beatriz , Pedraza Manuela , Castañon Carmen , De Sande González Luis , López Fernández Juan Ignacio , Sáez Álvarez Samuel , Segovia Alonso Pablo , Fernandez Fernandez Elvira , Fernandez Fernandez Manuel , García Palomo Andrés , Diz Pilar 
Published: June 2023

e20635 Background: SCLC is an aggressive and difficult-to-treat type of lung cancer that in recent years is increasing in incidence in those over 70 years of age. Moreover, in geriatric patients, treatment of ES-SCLC may be even more difficult due to the lack of prospective data in this more vulnerable population. In this study we will evaluate first-line chemotherapy-based treatment in the elderly. Methods: Retrospective observational trial. Patients over 70 years of age diagnosed with ES-SCLC who were treated at the Hospital Universitario de León between January 2017 and January 2022 were analysed. Data were collected from each patient's electronic medical record. To limit bias, those who had previously received treatment for limited stage or who had undergone combination chemotherapy with immunotherapy were excluded. SPSS Statics was used to analyse treatment response, 1- and 2-year survival rate, overall survival (OS) and progression-free survival (PFS). Results: 22 patients (pat.) met the elegibility criteria. Mean age 75.6 (±3.99 SD), 86.4% male (19 pat.). Eastern Cooperative Oncology Group (ECOG) score: ECOG-0 18% (4 pat.), ECOG-1 59% (13 pat.), ECOG-2 5% (1 pat.), ECOG-3 18% (4 pat.). At diagnosis, 36.4% (8 pat.) were current smokers and 63.6% (14 pat.) were former smokers; 68.2% (15 pat.) were taking more than 5 drugs. The mean Charlson scale score was 11 (±1.7 SD), while the mean Frail scale score was 2.23 (±0.97 SD). All patients received platinum-etoposide chemotherapy, 77.3% (17 pat.) with carboplatin-etoposide, 22.7% (5 pat.) with cisplatin-etoposide and of the total. There were only 6 patients with reduced starting doses and of the total patients, 54.5% (12 pat.) completed 6 cycles; 18.2% (4 pat.) 5 cycles and 27.3% (6 pat.) 2 cycles or less. Response was evaluable in 18 patients: 15 had partial response, 1 had stable disease and 2 had progression disease. At the time of analysis, there had been 21 deaths. Median OS was 10 months (95% CI 5,4-14,6) and median PFS was 6 months (95% CI 4,2-7,8). The 1-year survival rate was 45% and the 2-year survival rate was 9%. Conclusions: Despite the small number of patients, our data are similar to those obtained in the control arms of immunotherapy trials. A larger sample would be needed to consolidate our results and we plan to extend the study to other hospitals. Nevertheless, these results suggest elderly patients may benefit from treatment procedures applied in younger populations.
Prophylactic cranial irradiation in small cell lung cancer patients in the era of magnetic resonance imaging: A systematic review and meta-analysis.
Authors: Gaebe Karolina , Erickson Anders W. , Li Alyssa Y. , Ahluwalia Manmeet Singh , Mehta Minesh P. , Lok Benjamin H. , Leighl Natasha B. , Chan Kelvin K. , Das Sunit 
Published: June 2023

e20636 Background: Patients with small cell lung cancer (SCLC) are at a particularly high risk for the development of brain metastases. Current guidelines recommend prophylactic cranial irradiation (PCI) for these patients to prevent brain metastases and prolong overall survival (OS), although the clinical evidence for recommendations stems from an era without routine use of brain imaging. We performed a systematic review and meta-analysis of all available studies reporting on PCI for SCLC patients with minimal inclusion restrictions to assesses the efficacy of PCI in patients with limited disease (LD) and extensive disease (ED) SCLC and focus on the impact of routine brain imaging. Methods: A literature search for studies reporting on PCI in SCLC patients performed in EMBASE, MEDLINE, CENTRAL, and grey literature sources identified 4,783 studies. Random-effects meta-analyses pooled hazard ratios (HR) for overall survival (OS) between PCI and no intervention groups. Results: 208 individual studies reported on outcomes related to PCI with 175 studies assessing survival differences associated with PCI, and 87 of these being amenable to meta-analysis. The majority (n = 79) were retrospective cohort studies. PCI was associated with improved OS in all SCLC patients (HR 0.60; 95% CI 0.55-0.65; n = 87 studies; n = 50,339 patients; I2= 77%), as well as in cohorts exclusively consisting of LD patients (HR 0.60; 95% CI 0.54-0.66; n = 58 studies; n = 22,417 patients; I2= 76%) or ED patients (HR 0.63; 95% CI 0.53-0.75; n = 23 studies; n = 24,997; I2= 75%). Only eight studies confirmed absence of IMD at restaging using magnetic resonance imaging in all patients and found OS no longer to be in favour of PCI (HR 0.75; 95% CI 0.50-1.12; n = 1,318 patients; I2= 77%). Pooled OS from randomized controlled trials was not associated with PCI (HR 0.88; 95% CI 0.65-1.12; n = 5 studies; n = 925 patients; I2= 62.5%). Among studies not amenable to meta-analysis for OS, 4 radiographically confirmed absence of IMD, but none found OS to be in favour of PCI. Conclusions: Administration of PCI is associated with a significant OS benefit, but not when considering studies that radiographically confirmed absence of IMD at restaging or randomized controlled trials, suggesting that patient selection may be contributing to this observation.
Temporal trends in small cell lung cancer: Analysis of the U.S. Surveillance, Epidemiology and End Results (SEER) database.
Authors: Cohen Sean , Brennan Ben , Banerjee Mousumi , Kalemkerian Gregory Peter 
Published: June 2023

e20641 Background: Prior studies reported that the incidence of small cell lung cancer (SCLC) had decreased, while overall survival (OS) had improved, from 1973-2002. In 2019, immunotherapy was integrated into the standard therapy for patients with extensive-stage (ES) SCLC based on studies demonstrating an improvement in OS. This study aims to provide an update on SCLC incidence and survival at the dawn of this new therapeutic age. Methods: We analyzed data on all patients with primary lung cancer in the SEER17 database from 2000-2019. Patients with ICD-O codes 8002 and 8041-8044 were classified as SCLC. Incidence rates were calculated based on the standard U.S. population. OS was calculated based on censored time to death or last follow-up, whichever occurred earlier. Temporal trends in incidence and OS were evaluated using the Mantel-Haenszel chi-square statistic. Results: Of 847,747 patients with primary lung cancer, 111,263 (13.1%) had SCLC. The incidence rate of SCLC steadily declined from 8.8/100,000 in 2000 to 4.8/100,000 in 2019. Over this time, the incidence rate decreased among both males (10.7 to 5.1/100,000) and females (7.5 to 4.6/100,000), and among all examined races (NHW: 10.1 to 6.0/100,000, NHB: 8.3 to 4.7/100,000, NHA/PI: 3.5 to 1.6/100,000, Hispanic: 4.0 to 1.9/100,000). The proportional incidence of SCLC relative to NSCLC also continued to decline, from 14.5% in 2000 to 11.8% in 2019. The male:female ratio of SCLC patients decreased from 1.14:1 in 2000 to 0.93:1 in 2019. The percentage of patients with limited-stage (LS) SCLC decreased from 31.1% in 2000 to 26.4% in 2019. The majority of patients with LS-SCLC were female throughout the study period (53.9%), while most of those with ES-SCLC were male (51.8%). Among patients with LS-SCLC, 2-year OS increased from 26.7% in 2000 to 36.7% in 2017, while 5-year OS increased from 11.3% in 2000 to 15.6% in 2014. Among patients with ES-SCLC, 2-year OS increased from 6.4% in 2000 to 8.4% in 2017, while 5-year OS increased from 2.2% in 2000 to 2.9% in 2014. Both 2-year and 5-year OS increased in LS-SCLC over the study period in both males and females (M: 2-year: 23.4% to 36.2%, 5-year: 9.9% to 15.2%; F: 2-year: 29.9% to 37%, 5-year: 12.8% to 16.0%). In ES-SCLC, 2-year OS increased in both males and females (M: 5.8% to 7.3%, F: 7.0% to 9.5%), while 5-year OS increased in females (2.2% in 2000 to 3.9% in 2014), but remained stable in males (2.3% in 2000 to 2.0% in 2014). Conclusions: Both the incidence and proportional incidence of SCLC have continued to decline in the U.S. over the past 20 years. The male:female ratio also declined, with women now accounting for the majority of patients with SCLC. The percentage of patients with LS-SCLC decreased, likely due to improvements in staging procedures. Overall survival has continued to improve, with greater gains seen in LS-SCLC than in ES-SCLC prior to the integration of immunotherapy.
Investigation of the prognostic significance of CD5, CD117, EZH2, POU2F3, MTAP and BAP1 in thymic carcinoma.
Authors: Naso Julia R. , Jenkins Sarah M. , Vrana Julie A. , Koepplin Justin W. , Olivier Kenneth R. , Cassivi Stephen D. , Molina Julian R. , Roden Anja C. 
Published: June 2023

e20646 Background: Thymic carcinomas tend to be aggressive malignancies with variable patterns of immunostaining. We aimed to assess whether the outcome of patients with thymic carcinomas was associated with immunoreactivity for conventional and emerging immunohistochemical markers of thymic carcinoma versus thymoma. Methods: Scoring of CD5, CD117, EZH2, POU2F3, BAP1, and MTAP immunohistochemistry on whole slide sections was compared to overall survival (OS) and progression free survival (PFS) for 36 thymic carcinoma patients, 28 of whom had complete tumor resection and 8 of whom had incomplete tumor resection. Results: Positive CD5 staining (defined as staining in ≥50% of tumor cells) was present in 13/36 cases (36%) and was significantly associated with longer OS (P = 0.005, hazard ratio = 0.18, CI 0.03-0.63) but not PFS (P = 0.14, hazard ratio = 0.48, CI 0.16-1.26), whereas the other markers were not significantly associated with OS or PFS. Positive CD5 staining remained significantly associated with OS in squamous cell carcinoma subgroup analysis (n = 23, HR = 0.17, CI 0.03-0.65, P = 0.009), patients who did not receive neo-adjuvant treatment (n = 24, HR = 0.21, CI 0.03-0.85, P = 0.03) and after adjusting for incomplete resection (HR = 0.20, CI0.03-0.73, P = 0.01), M1 stage (HR = 0.19, CI 0.03-0.71, P = 0.01) or neoadjuvant treatment (HR = 0.19, CI 0.03-0.71, P = 0.01) in bivariate models. Positive CD5 staining was also significantly associated with age ≥60 years, absence of neoadjuvant treatment, and positive POU2F3 staining. Conclusions: CD5 staining in ≥50% of tumor cells was significantly associated with longer OS for thymic carcinoma patients. Our study supports the notion that CD5 immunohistochemistry may have utility as a prognostic marker for thymic carcinomas.