bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-reported efficacy and toxicity in CAR T-cell therapy for multiple myeloma via Internet-based platforms.
Authors: Sweeney Nathan W. , Franco Hernandez Eduardo , Cole Nolan , Goldsmith Scott Ryan , Crees Zachary , Ahlstrom Jenny 
Published: June 2021

e20024 Background: Chimeric antigen receptor (CAR) T-cell therapies are in clinical development for multiple myeloma (MM). Patient-reported outcomes (PRO) can provide valuable insights into how patients perceive the relative risks and benefits of these new therapies. This study aimed to evaluate CAR T-cell therapy in relapsed/refractory MM (RRMM) patients. Methods: We utilized HealthTree Cure Hub for Multiple Myeloma to analyze patient-reported data from 17 patients who participated in CAR T-cell clinical trials. In this study, we examined total prior lines of therapy, time to next treatment (TNT), overall survival (OS), patient-reported toxicity and severity, and patient-reported outcomes (myeloma reduction or no myeloma reduction). The Kaplan-Meier model was used to calculate overall survival. The severity of toxicity was assessed using a 1 to 10 scale (1 = minimal and 10 = severe). Results: Our analysis of the 17 patients found a median of 10 lines of therapy prior to CAR T-cell treatment. Ten patients had no new treatments to report at the time of this study, 5 patients reported new treatment with a median TNT of 15.9 months, and for 2 patients we did not have data. The median OS was 24 months (95% CI 21-30 months). The probability that a patient remained alive at 2 years was 0.48 (95% CI: 0.195, 1). Four of the 17 patients died with a median of 22.5 months post-CAR T-cell therapy. Two of these patients died without reporting a change in treatment. There was a total of 36 different side effects reported by patients as a result of the therapy. Table lists the side effects experienced by 2 or more patients and the corresponding average severity. Finally, 76% of patients treated with CAR T-cell therapy reported a reduction in their myeloma, four of these patients had m-protein levels reported and saw an average decrease of 93%. Of the remaining patients, three (18%) reported little to no reduction in their myeloma, and one patient (6%) did not know their response at the time of this analysis. Conclusions: Our investigation of patient-reported results suggests an emerging and viable immunotherapy treatment option for RRMM, with encouraging outcomes and manageable side effects. Future directions include analysis of genetics and treatment options post CAR T-cell therapy. These data highlight the expedited benefit of using PROs via an online platform, like HealthTree Cure Hub, to assess new therapeutics in the research community.[Table: see text]
Diagnostic signatures for lung cancer by gut microbiome and urine metabolomics profiling.
Authors: Qiu Bo , Xi Yu , Li Ying , Xie XinQiang , Liu FangJie , Wu Lei , Liang TingTing , Li Longyan , Feng Ying , Guo JinYu , Wang DaQuan , Zeng Yu , Yang Lingshuang , Zhang Jumei , Wang Juan , Chen Moutong , Xue Liang , Ding Yu , Wu QingPing , Liu Hui 
Published: June 2021

e20514 Background: To develop the diagnostic signatures for lung cancer (LC) by gut microbiome and urine metabolomics profiling with multi-omics approach. Methods: We surveyed 145 Fecal Samples and 120 Urine Samples in a cohort containing 109 LC patients and 50 healthy individuals. The total cohort had been separated into testing set and validation set. The testing set comprised 47 patients and 20 healthy individuals (8 first-degree relatives and 12 non-relatives), while the validation set had 48 patients and 30 healthy individuals (14 first-degree relatives and 16 non-relatives). The urine research set comprised 100 patients and 18 first-degree relatives as healthy individuals. Gut microbiota was analyzed through the 16S ribosomal RNA (rRNA) gene sequencing and shotgun metagenomics. Urine untargeted metabolomics was analyzed by liquid chromatography–mass spectrometry (LC–MS) metabolomic analysis. Results: LC patients had a significant shift of intestinal microbiota composition and functional genes distribution compared with healthy individuals. Diagnostic model had been achieved by combining gut microbiome and urine metabolomics profiling, the area under curve (AUC) of the testing set was 0.9997. The model performed reasonably well in the validation set with the AUC of 0.9769. We also found a significant decrease of Prevotella in LA-NSCLC patients and it was negatively correlated with multiple functions in KEGG level 2 in healthy individuals. Conclusions: The current study employs a multi-omics approach, analyses the fecal microbiome and urine metabolites from LC patients and healthy individuals/relatives using a standardized pipeline, and identified disease-associated microbiome shifts across datasets using statistical analysis. We inferred a microbiome-metabolite catalog and its molecular pathway and functional link to host targets, which could be further utilized to aid lung cancer diagnosis and treatment decision.
Comprehensive characterization of genomic and radiologic features reveals distinct driver patterns of RTK/RAS pathway in pulmonary nodules presenting as ground-glass opacity.
Authors: Peng Muyun , Yu Fenglei , Chen Xiaofeng , Bai Jing , Xia Xuefeng , Xing Guanlan 
Published: June 2021

e20516 Background: GGO-associated pulmonary nodule has been known as radiological appearances of early stage and exhibit more indolent biological behavior. The correlation of different driver gene and radiological features remain poorly understood. Methods: We performed high-depth sequencing of 334 resected pulmonary nodules presenting as GGO from 262 Chinese patients with a custom 1021-gene panel. 130 were multiple pulmonary nodules from 58 patients (2-4 samples per patient). Clinical-pathologic and radiologic parameters of these pulmonary nodules were collected. Immunohistochemistry and multiplex immunofluorescent staining were applied to analyze proliferation and immune cell markers of GGO-associated pulmonary nodules. Results: Mixed GGO enriched in the pathology of invasive LUAD comparing to pure GGO (182/216 vs 73/118, p < 0.001). 88.0% (294/334) of GGO-associated nodules carried at least one gene mutation in EGFR/ERBB2/BRAF/KRAS/MAP2K1 of the RTK/RAS signaling pathway and these driver genes were mutual exclusive to each other. T790M mutation was detected in one patient who had a nodule with CTR > 0.5 and was pathologically defined as MIA. 96.4% (54/56) multiple pulmonary nodules from the same patients showed distinct oncogenic alterations, but 72.4% (42/58) patients carried at least one mutant gene in RTK/RAS pathway across each pulmonary nodule. Nodules with ERBB2/ BRAF/ MAP2K1 mutations tended to be more indolent than those with EGFR and KRAS mutations, showing fewer mutations in radiology status of mGGO or pathology of invasive LUAD. KRAS-mutant subgroup possessed the highest expression of Ki-67 and PD-L1, more infiltration of CD4+ T cell and CD8+T cell. The second highest Ki67-expression was in EGFR-mutant subgroup, together with more CD8+T cell. For EGFR-mutant nodules, co-mutations with TP53 or RBM10 enriched in nodules with CTR > 0.5 and showing higher values of mean CT attenuation and TMB, which may relate to GGO evolution or invasiveness progression. Conclusions: This study elucidated a comprehensive genomic landscape of Chinese radiologically detected GGO-associated pulmonary nodules and highlighted different driver patterns of RTK/RAS pathway corresponding to radiologic features. Our findings provided valuable insight for further research on driver event of RTK/RAS pathway and cancer interception of GGO-associated pulmonary nodules.
Association between CNVs of BMI-related gene and survival status of LUAD and LUSC patients.
Authors: Luo Haifeng ,   UCSF
Published: June 2021

e20524 Background: In recent decades, many GWAS studies help to discover the gene related to BMI or obesity. FTO, BDNF, LEPR, MC4R, SH2B1, GNPDA2, INSIG2, KCTD15, LEP, MTCH2, NEGR1, NPC1, PCSK1, POMC, TMEM18 and UCP2 are 16 genes showing most significant association with BMI. Those genes impact BMI by either alternating sex hormone metabolism, influencing insulin and insulin-like growth factor, or mediating inflammatory and adipokines. Those pathways impact cancer cells also. Here we report the association between copy number variables (CNV) of those genes and outcome of lung adenocarcinoma (LUAD) and lung squamous cell cancer (LUSC). Methods: 522 individuals in LUAD dataset of TCGA and 504 individuals in LUSC dataset of TCGA are included in this study. CNVs of each gene are main predictors, the survival time is the main outcome in the study, and gender, tumor stage, smoking status are chosen to adjust model. Multivariable Cox models are generated for LUAD patients and LUSC patients respectively. To control false discovery rate (FDR), Benjamini-Hochberg procedure is employed. Results: For LUAD patients, tumor stages impact survival status significantly, but age, gender and smoking status don’t impact survival time significantly. At the same time, CNV of TMEM18 has hazard ratio of 0.0353 (95% CI: 0.0032, 0.3910), which means the gain of genetic materials on the position of TMEM18 gene will protect patients to die after diagnosis of LUAD, and the effect is extremely large. The p-value of 0.006 is less than 0.00625, which is derived with Benjamini-Hochberg procedure with false discovery rate of 0.1. For LUSC patients, only serious tumor stages, tumor stage III and tumor stage IV, impact survival status significantly, and old age will cause patients die earlier significantly. Neither gender nor smoking status don’t impact survival status significantly. When adjusting age, gender, smoking status, and tumor stage, gain of genetic materials on the position of NEGR1 gene does increase the risk of death significantly, and the hazard ratio of CNV of NEGR1 is 9.920 (95% CI: 1.237, 79.552). The p-value of 0.031 is large than 0.00625, which is derived with Benjamini-Hochberg procedure with fase discovery rate of 0.1. Conclusion: Copy number variable of TMEM18 gene impact outcome of LUAD patients significantly. The gain of TMEM18 genetic materials protects patients to die, meanwhile the loss of TMEM18 genetic materials cause patients to have shorter overall survival time. TMEM18 affect the central nervous system to imbalance energy metabolism in previous murine models, and here we found TMEM18 has significant impact on survival status of LUAD patients, so the transmembrane protein gene TMEM18 may be a key factor to outcome of LUAD.
The effect and safety of anlotinib combined with irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: A single-arm phase I study.
Authors: Zhang Minna , Chen Xueqin , Jiang Hong , Wang Jiaoli , Ye Jian , Ma Shenglin , Xia Bing 
Published: June 2021

e20583 Background: Current standard of care for SCLC relapsed within six months after first-line treatment was mainly chemotherapy alone, such as irinotecan or docetaxel, of which the clinical benefit is unsatisfactory. Anlotinib, a novel oral multi-target tyrosine kinase inhibitor primarily targeting VEGFR2/3, FGFR1-4, PDGFRα/β and c-Kit, significantly improved progression-free survival (PFS) and overall survival (OS) for SCLC in third-line setting and beyond treatment (ALTER1202 trial). Here, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anlotinib combined with irinotecan or docetaxel in SCLC relapsed within six months after first-line treatment. Methods: Eligible patients with cytologically or histologically confirmed SCLC, aged 18-75 years, ECOG PS 0-1, relapsed within six months after first-line platinum-based treatment, received anlotinib (12mg, QD, from day 1 to 14 of a 21-day cycle) combined with irinotecan (65mg/m2, day1,8, q3w, up to 4 cycles) or docetaxel (60mg/m2, q3w, up to 4 cycles) until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included PFS, the disease control rate (DCR), OS and safety. Results: Between March 2020 and February 2021, 21 patients with a median age of 61.7 years, male (76.2%), ECOG PS 1 (81.0%), brain metastasis (42.9%), liver metastasis (38.1%), were enrolled in this trial. At data cut-off (February 8, 2021), 15 patients were evaluable, among which 5 patients reached partial response (PR) and 8 had stable disease (SD). The ORR was 33.3% (5/15) and the DCR was 86.7% (13/15), respectively. The median PFS was 4.0 months (95%Cl: 3.18-4.83). The most common grade 1-2 treatment-related adverse events (TRAEs) were weakness (64.7%), anorexia (41.2%), anemia (29.4%), hypertension (23.5%), leukopenia (17.6%), oral mucositis (17.6%). Grade 3 TRAEs mainly included leukopenia (11.8%), thrombocytopenia (11.8%) and anemia (5.9%). There were no grade 4 or higher toxicities. Conclusions: Anlotinib combined with irinotecan or docetaxel showed promising ORR, DCR and PFS in SCLC relapsed within six months after first-line platinum-based treatment and was well-tolerated. No unexpected toxicities were observed. Further exploration and longer follow-up are ongoing. Clinical trial information: NCT04757779.
Possible immunologic predictors of the PD-1/PD-L1 checkpoint inhibitors' efficiency in lung cancer patients.
Authors: Zlatnik Elena Yu. , Kit Oleg I. , Bondarenko Elena S. , Sagakyants Aleksandr B. , Teplyakova Maria A. , Vladimirova Liubov Yu , Storozhakova Anna E. , Novikova Inna A. , Abramova Natalia A. , Popova Irina L. , Ryadinskaya Ludmila A. , Agieva Aza A. , Alieva Faina V. , Novoselova Kristina A. , Tikhanovskaya Natalia M. , Kalabanova Elena A. , Kabanov Sergey N. , Tishina Anna V. , Lazutin Yuriy N. 
Published: June 2021

e21035 Background: Immunotherapy with PD-1/PD-L1 check-point inhibitors (CPI) is a new trend in oncology. Their effect significantly depends on the patients` immune status. The aim of the study was to search the immunologic parameters of lung cancer (LC) patients receiving immunotherapy as factors that could predict their effect. Methods: 20 patients (12 male and 8 female) with LC had adenocarcinoma – 15 (75%), squamous cell carcinoma – 5 (25%). PD-1/PD-L1 CPI were used: 9 patients received atezolizumab (43%), 9 (43%) – pembrolizumab and 3 (14%) – nivolumab. The effect of therapy was evaluated according to imRECIST v.1.1. Factors of cell-mediated immunity were assessed by flow cytometry before treatment including immunotherapy. CD8+CD279+, CD4+CD279+, TLR2, TLR4, TLR3, TLR8 were studied. Results: Complete response was observed in 2 (9%) patients, partial response in 5 (24%), stabilization in 4 (19%) and progression in 8 (38%). In one patient the treatment was cancelled due to the development of immune-mediated complication (Guillain-Barre syndrome). The factors studied varied depending on different effect. In cases of LC stabilization/progression the initial amount of CD8+CD279+ cells were twice lower than in cases with complete/partial response. In the first group CD8+CD279+ cells` level before the treatment was 0,1-3,4%, while in the other group 4,1-9% (7,0±1,16%). In patients with stabilization/progression CD4+CD279+ cells` level before the immunotherapy was 0,1-3,3 and in patients with response to treatment 1,4-7,8% (3,4±0,8%) of total CD4+ lymphocytes. Besides, the LC patients with different effect of treatment had different initial amount of CD4+ Tem cells: stable response to CPI developed in patients with their higher levels (40,8±3,9%) vs 15,3±3,9% in cases of tumor progression (p < 0.05). Initial high expression of TLR2 and TLR4 as well as low expression of TLR3 and TLR8 on monocytes in patients with response to immunotherapy suggests the contribution of innate immunity to its effect. Conclusions: Complete or partial response should be expected in cases of initially high per cent of T lymphocytes (CD4+, CD8+) CD4+ Tem cells and TLR2+, TLR4+ as well as low amount of TLR3+ and TLR8+ monocytes. These factors should be studied in future as predictive factors for effectiveness of CPI.
An integrative scoring system for survival prediction following gefitinib therapy in non-small cell lung cancer: From a long-term real-world study.
Authors: Guan Shaoxing , Chen Xi , Chen Youhao , Huang Min , Zhang Li , Wang Xueding 
Published: June 2021

e21041 Background: Gefitinib is first-line therapy for patients with EGFR-activating mutation in non-small cell lung cancer (NSCLC). Meanwhile, ̃30% patients were progression within 12 months even harboring EGFR-activating mutation. Furthermore, integrative scoring models for prediction of gefitinib outcomes are still lacking. Variations in genes of DNA repair and cell cycle pathway may have potential impacts on proliferation, migration and invasion of tumor cells. Therefore, we investigated a series of single nucleotide polymorphisms (SNP) in DNA repair and cell cycle genes based on an efficient algorithm machine learning algorithm for establishing an integrative scoring system for survival prediction following gefitinib therapy in NSCLC patients. Methods: A total of 282 patients with activating EGFR mutations were enrolled and divided into train cohort and test cohort, randomly. 125 SNPs in 47 candidate genes were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. Predictive features were selected by randomForestSRC, an efficient algorithm machine learning algorithm to analyze survival data, for PFS following gefitinib therapy. The top candidate variables were presented into COX regression models with hazard ratio as weight for each predictor (HR = 1-1.49 = 1; HR = 1.5-2.49 = 2; HR = 2.5-3.49 = 3), providing p < 0.1. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: The progression risk predictive model was established by random forest survival and validated by COX regression analysis, included XRCC1 rs3213263(CT vs CC, RR = 1.997, 95%CI = 1.314-3.036, p = 0.001), FOXO3 rs75544369(GA vs GG, RR = 1.942, 95%CI = 1.139-3.309, p = 0.012), FOXM1 rs2302257(CC vs GG, RR = 2.889, 95%CI = 1.477-5.691, p = 0.002) and ERCC1 rs10408989(TT vs GT, RR = 1.735, 95%CI = 1.152-2.613, p = 0.008; GG vs GT, RR = 3.788, 95%CI = 1.625-8.832, p = 0.002). The progression risk score ranged from 0-10. 49 patients (25.52%) and 20 patients (22.22%) were scored 0, 18(9.38%) and 10(11.11%) patients were scored more than 5 in train cohort and test cohort, respectively. According to the risk score of patients, we divided the patients into four groups, the median PFS were 26.23(95%CI:14.23-35.37), 16.80(95%CI:12.87-23.60), 11.13(95%CI:8.87-16.70) and 6.25 (95% CI:4.43-11.67) months for 0, 2, 3&4 and ≥5 group (p < 0.0001) in the train cohort. Meanwhile, the median PFS were 18.80(95%CI:11.80-64.53),13.60(95%CI:9.17-27.33), 13.47(95%CI:9.83-18.40), 13.47(95%CI:9.83-18.40) and 7.40(95%CI:3.33- NA) months for 0, 2, 3&4 and ≥5 group in validation cohort (p = 0.0017). Conclusions: The risk score system is a simple tool for risk stratification in patients undergoing gefitinib. Widespread application of the score system will require further independent validation.
A clinical study of camrelizumab combined with chemotherapy and sequential apatinib in the second-line treatment of patients with advanced non-small cell lung cancer.
Authors: Pan Yueyin , Jiang Fengshou , Du Yingying , Wang Yong , Liu Hu , Wang Zishu , Liang Hui , Bi Minghong , Yao Yiwei 
Published: June 2021

e21051 Background: Camrelizumab combined with chemotherapy has shown a higher efficiency and survival benefit in clinical studies of the first-line treatment of lung cancer. This study aims to observe the clinical efficacy and safety of camrelizumab combined with chemotherapy and sequential apatinib in the second-line treatment of patients with advanced non-small cell lung cancer in a real environment. Methods: This is a prospective, open, multi-center observational study that includes advanced lung cancer that is older than 18 years old, regardless of gender, with an ECOG score of 0-1, and recurrence or failure after first-line platinum-based dual-drug chemotherapy patient. Results: As of January 25, 2021, a total of 18 patients were enrolled, of which 12 were female (66.67%), 11 patients had an ECOG PS score of 1 point (61.11%), and 15 patients were stage IV (83.33%), patients, 5 patients with tissue poorly differentiation (27.78%), 55.56% of the patients had undergone immunohistochemical testing, and 66.67% of the patients had become positive for the gene. A history of radiotherapy accounted for 11.11%, and a history of surgery on the primary lesion accounted for 27.78%. Previous first-line chemotherapy options were pemetrexed combined with cisplatin (22.22%), pemetrexed combined with lobaplatin (22.22%), pemetrexed combined with carboplatin (11.11%), bevacizumab combined with Platinum dual-drug regimen (38.89%); Among the 10 patients with evaluable efficacy, 0 had CR, 2 had PR, 6 had SD, and 2 had PD. The ORR reached 20.00% and the DCR reached 80.00%. The overall incidence of adverse reactions is low, and the medication process is safe and controllable. Conclusions: In this second-line clinical study of lung cancer, most of the patients enrolled were patients with poor PS scores and later stages, but the effectiveness and safety of carrelizumab in patients with advanced lung cancer were still confirmed. The dominant population and the combined treatment plan are still being studied. Clinical trial information: ChiCTR2000034597.
Association of LRP1B mutants with immune biomarkers in Chinese non-small cell lung cancer patients.
Authors: Zhang Yi , Guo Taiyan , You Xia , Zhang Qin , Duan Qianqian , Qi Chuang 
Published: June 2021

e21060 Background: LRP1B (low-density lipoprotein receptor-related protein 1B) is frequently mutated in non-small cell lung cancer (NSCLC). Previous studies showed LRP1B mutations were associated with prolonged survival in melanoma and NSCLC immunotherapy cohort. Higher tumor mutation burden was found in LRP1B mutated patients, suggesting potential benefit of immunotherapy. Herein, we investigate the relationship of LRP1B and immunotherapy biomarker in lager cohort of Chinese and Western NSCLC patients. Methods: Next-generation sequencing data and clinical data were collected from 1053 TCGA NSCLC patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 1056 Chinese pan-cancer patients (Chinese cohort). Both LRP1B mutation ratio and TMB were calculated on the two cohorts following the same criteria. TMB-H was defined as the top quartile of all TMB values. Results: In total, 208 (20%) of the 1056 Chinese patients and 385 (37%) of the 1053 Western patients had at least one mutation of LRP1B genes (LRP1B mutant group). The frequency of LRP1B mutation between Western cohort and Chinese cohort had significant difference (20% vs. 37%, p＜0.001). In both cohorts, TMB was higher in the LRP1B mutant group compared to non-LRP1B mutant group. In Chinese cohort, PD-L1 positive was not associated with LRP1B mutation. Patients with LRP1B mutation were associated with prolonged survival in Western immunotherapy cohort. Conclusions: Our study provided a landscape of LRP1B mutations in a much larger Chinese NSCLC group, which could be a valuable complement to TCGA dataset and previous study. Results of our study was consistent with previous studies. Both in Chinese and Western cohorts, the higher TMB in LRP1B mutant patients suggested potential efficacy from immunotherapy of LRP1B mutant group. This result and the potential predictive value of LRP1B in immunotherapy should be validation in a larger Chinese LRP1B mutant cohort in the further.