bluuebunny/crossref_metadata_2025_split huggingface dataset:
The efficacy and safety profile of anlotinib plus docetaxel as second-line treatment in advanced non-small cell lung cancer.
Authors: Xu Zhiqiao , Zhang Yan 
Published: June 2021

e21068 Background: Docetaxel is a standard second line treatment in advanced NSCLC, but the treatment effect is limited. Previous studies, such as REVEL, demonstrated that anti angiogenic therapy combined with docetaxel had significantly therapeutic efficacy. Anlotinib is an oral multi target angiogenesis TKI targeting the VEGFR, FGFR, PDGFR and c Kit. The ALTER 0303 trial showed that anlotinib improved both PFS and OS in later-line treatment for advanced NSCLC, and this study aims to investigate the efficacy and safety of Anlotinib combined with docetaxel in second-line treatment in advanced non-small cell lung cancer (NSCLC). Methods: This is a single-center, single-arm clinical trial. A group of 30 patients of histologically or cytologically confirmed, locally advanced stage IIIB-IV NSCLC and with ECOG PS 0-1 were admitted to the Kaifeng Central Hospital Cancer Center. Patients who progressed after first-line treatment were treated with anlotinib (12 mg p.o., QD d1 to 14, q3w) combined with docetaxel (75mg/m2, iv, QD, d1 to 14, q3w) as the second-line therapy. The primary endpoint was PFS. Secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 30 patients were enrolled from October 2018 to April 2020. At data cutoff (Sept. 30, 2020), 30 patients were available for efficacy analysis. The median progression-free survival (mPFS) was 7.5 months (2.0-18.5). Among these patients, there was 1 CR, 9 PR, 15 SD, 5 PD, resulting in the ORR = 33.33% and the DCR = 83.33%. The Cox multivariate analysis showed that stage is an independent risk factor affecting prognosis ( p= 0.003). The most common grade 3 AEs were leukopenia (23,3%), neutropenia (13.3%), hypertension (13.3%), which can be controlled, and no grade 4 or grade 5 AEs occurred. Conclusions: Second line anlotinib plus docetaxel showed clinical benefit in advanced NSCLC patients in terms of PFS, ORR and DCR, and the incidence of adverse reactions are tolerable. This combination might be a promising option for patients advanced NSCLC.
Efficacy of first-line treatments for patients (pts) with advanced EGFR mutated NSCLC: Network meta-analysis of TKI monotherapy and combinations trials.
Authors: Bogdanov Alexey , Moiseenko Fedor Vladimirovich , Zhabina Albina , Volkov Nikita , Artem'eva Elizaveta , Fedyanin Mikhail 
Published: June 2021

e21120 Background: Various EGFR TKIs and several combinations are the standard of initial treatment for NSCLC with EGFR mutations. For this moment one size fits all approach is used. Due to the limited nature of this subgroup direct prospective survival comparison of various options is time and resource consuming. The main objective of this study was to compare available prospective trials in a network meta-analysis in order to determine the overall survival (OS) advantage. Methods: Using frequentist approach (netmeta R package) we performed a network meta-analysis of prospective randomized trials comparing having platinum doublet or 1G TKI as a control arm and 1G TKI, 2G TKI, 3G TKI, combination of chemotherapy (CT)+1G TKI, combination anti-VEGF/R+1G TKI as investigation arm in pts with EGFRmut NSCLC. Between trials we compared OS and progression free survival (PFS ) for overall population and subgroups by mutation, sex, age, smoking status. Results: 17 trials involved 4671 pts were considered eligible for meta-analysis. Trials investigated various combinations of TKIs in untreated EGFR mutated NSCLC: 8 had chemotherapy (CT) as control arm (ENSURE, EURTAC, IPASS, NEJ002, OPTIMAL CTONG-0802, WJTOG3405, LUX-Lung-3/6) and 9 with 1G TKIs as control arm (JO25567, NEJ026, 14034 H3E-CR-JIMIT, NEJ009, Noronha et. al, LUX-LUNG7, ARCHER1050, SWOGS1403, FLAURA). Compared to 1G TKIs improved OS was observed for combination of 1G TKI and CT (HR 0.64 (0.53– 0.78)), 3G TKIs (HR 0.80 (0.64-1.00)), 2G TKIs (HR 0.83 (0.72-0.96)) (The OS benefit was ranked No.1 for TKI+chemo (P-score – 0.96), No.2 – 3G TKI (P-score – 0.68), No.3 – 2G TKI (P-score – 0.64)) Addition of anti-VEGF/R therapy did not improve OS (HR 0.91 (0.68-1.21) over 1G TKIs alone. Importantly OS advantage remained significant in a subgroup of ex19del only for 2G TKIs (HR 0.71 (0.53-0.96)). No advantage for particular regimen was seen for L858R subgroup. 3G TKIs (HR 0.46 (0.27-0.78)), combinations with CT (HR 0.55 (0.40-0.75)) and anti-angiogenic agents (HR 0.57 (0.37-0.89), improved PFS over 1GTKIs, while 2G TKIs had a tendency for improving (HR 0.78 (0.58-1.06)). Conclusions: Our network meta-analysis showed that compared to initial treatment with 1G TKI monotherapy - 1G combination with CT, monotherapy with 3G and 2G may provide OS advantage. Still for ex19del subgroup OS benefit was significant only for 2G TKI. The availability of multiple first line options force the importance of stratification of patients for particular treatment type.
Associations between longitudinal pretreatment BMI and neutrophil/lymphocyte ratio(NLR) and progression-free(PFS) and overall survival(OS) in advanced NSCLC patients treated with single agent anti-PD-1/anti-PDL1 monoclonal antibodies(mAbs).
Authors: Randall Megan , Basu Sanjib , Kollipara Revathi , Batus Marta , Bonomi Philip D. , Moudgalya Hita , Borgia Jeffrey Allen , Fidler Mary J. 
Published: June 2021

e21189 Background: Several parameters that have been associated with outcomes in patients with metastatic NSCLC treated with anti-PD1/PDL1 mAbs include tumor PD-L1 expression, tumor mutational burden, and baseline NLR. Further investigation into clinical correlates of benefit with immune checkpoint inhibitors remains an unmet need. Methods: The objective of this retrospective study was to examine the potential influence of pretreatment cachexia and chronic inflammation in patients with NSCLC that received second- or third- line single agent anti-PD1/PDL1 mAbs. Weight, BMI, and NLR, as well as longitudinal changes in these variables from at least six-weeks prior to initiation of treatment were correlated with progression-free and overall survival (PFS/OS). These associations were assessed using statistical methods for time-to-event analysis. Results: 192 patients were included: 59% female, 72% Caucasian, 18% African American, 79% current or former smokers. 185 patients had pretreatment NLR values and 63% and 42% had NLR ratios > 3.5 and > 5, respectively. 187 patients had pretreatment weight and BMI available. Of these, 63% had a loss in BMI prior to initiation of anti-PD1/PDL1 mAbs, 29% with > 5% loss. Any BMI loss as well as BMI loss > 5% over the time period prior to treatment initiation were associated with shorter PFS (p < 0.01, 2.1 vs 4.37 mos for loss > 5% vs ≤ 5%) and change in BMI assessed in continuous scale was also associated with PFS (HR = 0.94, p < 0.05). Similarly, any BMI loss and BMI loss > 5% were associated with shorter OS (p < 0.01. 7.33 vs 12.23 mos for loss > 5% vs ≤ 5%) and change in BMI and baseline BMI assessed in continuous scale were additionally associated with OS (HR = 0.97 and 0.94, p < 0.05). Baseline NLR > 5 was associated with shorter PFS (p < 0.01) and baseline NLR assessed in continuous scale was negatively associated (HR = 1.01, p < 0.05). Moreover, pre-treatment NLR > 5 and baseline NLR > 3.5 were associated with shorter OS (p < 0.05). Pre-treatment NLR, baseline NLR, and %change in NLR, assessed in continuous scale, were negatively associated with OS (HR = 1.04, 1.02, 1.12, p < 0.01). Conclusions: This retrospective study identified clinical features of NLR and BMI at treatment initiation and in the immediate pre-treatment period that were associated with PFS and OS on anti-PD1/PDL1 mAbs therapy. These parameters can easily be investigated in the front-line population. They may also have utility in identifying patients that would benefit from therapeutic strategies to reverse weight loss and inhibit immunosuppressive effects associated with elevated NLR in order to increase the effectiveness of immunotherapy.
Mir-34a as predictor of immunotherapy efficacy in NSCLC patients.
Authors: Monastirioti Alexia , Papadaki Chara , Rounis Konstantinos , Kalapanida Despoina , Makrakis Dimitrios , Vardakis Nikolaos , Mavroudis Dimitrios , Agelaki Sofia 
Published: June 2021

e21191 Background: MicroRNAs are critical modulators of the immune response and regulate the expression of various immune checkpoints during immunotherapy. In the present study we evaluated the predictive significance of immune related miRNAs in the plasma of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. Methods: Plasma was obtained from 62 NSCLC patients before the initiation of immunotherapy, administered as second- or third-line treatment. The expression profile of immune-related miR-34a, miR-146a, miR-155, miR-200b, miR-202 and miR-223 was assessed by RT-qPCR. Patients were classified in high and low expression groups according to the median value of each miRNA. Patients that had achieved partial response (PR) or stable disease (SD) were classified as responders, whereas patients with progressive disease (PD) were classified as non-responders. Results: No statistical correlations were observed among miRNA expression and clinical outcomes in the whole group of patients (N = 62). However, in the non-squamous subgroup (N = 36) lower miR-34a expression levels were observed in non-responders compared to responders (80% vs 20%; p = 0.029). Univariate binary logistic regression analysis revealed that only low miR-34a expression (HR: 8.000, 95% CI: 1.215-52.693; p = 0.031) was correlated with the probability of developing progressive disease as best response to immunotherapy. Patients with low miR-34a expression levels were associated with shorter progression free survival (PFS) and overall survival (OS) compared to patients with high 34a expression (1.97 vs 6.33 months; p = 0.042 and 2.93 vs 9,60 months; p = 0.012, respectively). Furthermore, low miR-34a expression emerged as an independent predictor of shorter PFS and OS (HR: 2.449; p = 0.049 and HR: 3.203; p = 0.016, respectively). No other correlations were observed among the rest of the miRNAs and clinical outcomes. Conclusions: Our findings suggest that circulating miR-34a may serve as a potential predictive biomarker in NSCLC patients treated with immunotherapy. These observations need to be further validated in a larger cohort of patients.
Genetic landscape of melanoma in China reveals enrichment of fusions in driver-negative melanoma.
Authors: Lin Xiaohua , Zhang Fan , Liu Jie , Niu Yanling , Wang Chunyang , Li Wei , Ma Tonghui 
Published: June 2021

e21577 Background: Melanoma in China has unique characteristics, especially compared with those in euramerican white race. In european and american countries, nearly 90% of melanoma patients are cutaneous melanoma; while 60% of melanoma in China are acral melanoma, accompanied with a considerable proportion of mucosal melanoma. Mapping the mutation landscape of melanoma in China can provide an important basis for targeted therapy of melanoma patients. Methods: Tissue samples from 223 patients with melanoma were sequenced using multi-gene NGS panel Onco PanScan to detect somatic mutations in melanoma. Results: As a result, BRAF (24.2%) and NRAS (15.7%) were the top two most mutated driver genes. In BRAF, V600E was the most common mutation, which accounted for 80% of all BRAF mutations. And Q61R/K was the most common mutation in NRAS, which accounted for 68.6% of all NRAS mutations. As to CNVs, the most frequently amplified genes were CCND1 (23, 10.3%), CDK4 (18, 8.1%), MDM2 (17, 7.6%), FGF19 (16, 7.2%), FGF4 (13, 5.8%), FGF3 (12, 5.4%), KIT (12, 5.4%), RICTOR (12, 5.4%). At the same time, a small number of EGFR, HER2, MET, MYC amplifications were detected. Interestingly, a considerable proportion of CNVs were related with hyperprogressive disease, including amplification of MDM2, CCND1, FGF3, FGF4, FGF19. Except for SNVs and CNVs, 16 gene fusions were detected in 13 samples (5.8%), among which the frequency of fusions involving BRAF, ALK, RAF1 was 2.2% (5/223), 1.3% (3/223) and 1% (2/223) respectively. Among these 16 fusions, only 4 fusions (AGAP3-BRAF, GTF2I-BRAF, TPM3-ALK, DCTN1-ALK) were reported previously, leaving the remaining 12 fusions new detected. As was reported, AGAP3-BRAF fusion was the mechanism by which melanoma patients with BRAF V600E mutations developed resistance to vemurafenib; GTF2I-BRAF fusion mediated the activation of MAPK pathway in fibrous astrocytoma. At last, we also compared the frequency of fusion detected in driver-positive and driver-negative melanoma (no somatic mutations detected in BRAF, HRAS, KRAS, NRAS, NF1, KIT, GNAQ, GNA11), and the result showed the frequency of fusion detected in driver-negative melanoma was significantly higher (9/78, 11.5% vs. 4/145, 2.8%). Conclusions: Through DNA-based NGS, the mutation landscape of Chinese melanoma patients was depicted. BRAF was the most frequently mutated driver gene with the main mutation type of V600E (19.7%) which was significantly lower than that of white race in TCGA-SKCM database (44.2%). On the other hand, DNA-based NGS can detect potentially druggable fusions, and compared with driver positive melanoma patients, fusions were enriched in patients with no driver mutations detected. Perhaps for driver negative melanoma patients, RNA-based NGS should be used to detect more potential druggable fusions which would bring clinical benefit.
The predictive value of MAP2K1/2 mutations for efficiency of immunotherapy in melanoma.
Authors: Ye Ting , Zhang Jieying , Liu Xinyi , Yang Mengmei , Zhou Yuhan , Yuan Siyue , Chen Yaoxu , Gao Chan , Huang Mengli , Ye Chengzhi , Chen Jing 
Published: June 2021

e21587 Background: Immunotherapies targeting immune checkpoint receptors have become the cornerstone of systemic treatment options for malignant melanoma. The response to these immunotherapies may correlate with driver mutations. MAP2K1/2 genes are mutated in approximately 10% of melanomas, however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. Methods: Six metastatic melanoma clinical cohorts treated with ICIs were included to investigate the association between clinical efficacy of immunotherapy and MAP2K1/2 mutations. Survival analyses were conducted in cohorts receiving two kinds of ICB agents, namely anti-CTLA-4 or anti-PD-1. RNA expression profiling from these cohorts and from the TCGA melanoma cohort were used to explore the potential mechanism related to immune activation. Results: In an independent anti-CTLA-4-treated cohort (n = 110), we found that MAP2K1/2 mutations are predictive of high objective response rate (17.6% vs 1.3%, p = 0.0185) and long progression-free survival [median OS, 49.2 months vs 8.3 months; hazard ratio (HR) = 0.37; 95% CI, 0.15–0.91; p = 0.0307] and overall survival (median PFS, 19.4 months vs 2.8 months; HR = 0.2; 95% CI, 0.05–0.83; p = 0.0262). This predictive value was further validated in a pooled anti-CTLA-4-treated cohort (n = 235) in terms of overall survival (median OS, 49.3 months vs 22.0 months; HR = 0.44; 95% CI, 0.22–0.91; p = 0.0255). However, no correlation between MAP2K1/2 mutations and overall survival was observed in the anti-PD-1-treated cohort (n = 285). Subgroup Cox regression analysis indicated that MAP2K-mutated patients receive less benefit from the anti-PD-1 monotherapy than from the anti-CTLA-4 treatment (median OS, 27.0 months vs 49.3 months; HR = 3.26; 95% CI, 1.18–9.02; p = 0.0225), which was contrary to the result obtained for the total population. Furthermore, transcriptome profiling analysis revealed that MAP2K-mutated tumors are enriched in CD8+ T cells, B cells, and neutrophil cells and also express high levels of CD33 and IL10, which might be the underlying mechanism for melanoma patients with MAP2K1/2-mutated benefit more from anti-CTLA-4 treatment. Conclusions: We identified mutations in MAP2K1/2 genes as the independent predictive factors for anti-CTLA-4 therapy in melanoma patients and found that anti-CTLA-4 treatment in patient harbouring MAP2K1/2 mutations might be more effective than the anti-PD-1 therapy.
Urinary biomarkers for monitoring treatment response in neuroblastoma patients.
Authors: Amano Hizuru , Hinoki Akinari , Uchida Hiroo , Yokota Kazuki , Ishigaki Takashi , Sakairi Minoru , Abe Mayumi , Takahashi Yoshiyuki , Narita Atsushi , Tainaka Takahisa , Shirota Chiyoe , Sumida Wataru , Makita Satoshi , Takimoto Aitaro , Kano Yoko , Yasui Akihiro , Okamoto Masamune , Nakagawa Yoichi 
Published: June 2021

e22008 Background: Neuroblastoma is the most common extracranial solid tumor in children. Its heterogeneity may account for the non-uniform response to therapy; thus, accurate predictive biomarkers are required. We focused on urinary biomarkers since urine contains numerous low molecular weight metabolites that can be used as reliable and non-invasive biomarkers. We detected more than 2,000 metabolites by liquid chromatography-mass spectrometry (LC-MS) through a comprehensive analysis of metabolites in urine samples of patients with neuroblastoma and identified potential urinary biomarker candidates using the Wilcoxon rank-sum test and random forest. In this study, the levels of urinary biomarker candidates were compared between the responder and resistant groups to identify urinary biomarkers for monitoring treatment response. Furthermore, their effectiveness was compared with minimal residual disease (MRD) markers, which are currently considered to predict tumor relapse. Methods: Thirty-two patients with neuroblastoma were divided into two groups according to their responsiveness to therapy: the responder group, in which patients had no recurrence (60 urine samples from 24 patients) and the resistant group in which patients had a recurrence or died (18 urine samples from 8 patients). Levels of urinary metabolites (homovanillic acid [HVA], vanillylmandelic acid [VMA], 3-methoxytyramine sulfate [3-MTS], vanillactic acid [VLA], 3-methoxytyrosine [3-MTR]), and MRD markers (TH, PHOX2B, MK) were compared between the two groups during treatment. Results: The levels of five urinary metabolites (HVA, VMA, VLA, 3-MTR, 3-MTS) were significantly increased in the resistant group compared to that in the responder group. Conclusions: This study shows that three novel urinary metabolites (VLA, 3-MTR, 3-MTS) are significantly associated with the recurrence or death from neuroblastoma.
Noninvasive detection of chromosomal instability in plasma circulating cell-free DNA for early pan-cancer diagnosis using low-pass whole-genome sequencing.
Authors: Lv Ran , Lv Fang , Zhihua Pei , Yu Jianing , Zhao Xiuyu , Liu Yiqian , Zhang Yaxi , Chen Geng , Chen Weizhi , He Ji 
Published: June 2021

e22509 Background: Genomic instability is a typical characteristic of the majority of cancers. Early non-invasive detection of cancer is the most effective way of improving the success of treatment and prognosis at present. Traditional tumor screening methods have limitations in terms of selection methods, sensitivity, specificity, cost, and comfortability. Furthermore, although traditional tumor screening is useful for common cancers, there is no available screening test for rare cancers. Here we developed a novel method for cancer detection with Low-Pass Whole Genome Sequencing (WGS) of cell-free DNA (cfDNA). Methods: The cfDNA samples from 52 healthy donors were first used to establish a blacklist of bins. Then the baseline was established to calculate the chromosomal instability score (CINscore). We optimized the parameters of our model using the following discovery datasets: healthy controls (n = 50), breast invasive carcinoma (BRCA) (n = 44), ovarian serous cystadenocarcinoma (OV) (n = 25), colon adenocarcinoma/rectum adenocarcinoma esophageal carcinoma (COREAD) (n = 52), hepatocellular carcinoma (HCC) (n = 43), Gastric adenocarcinoma (GAC) (n = 31); pancreatic adenocarcinoma (PAC) (n = 38), non-small cell lung cancer (NSCLC) (n = 45). Results: We further evaluated the performance of our method using the confirmation datasets of healthy controls (n = 30), BRCA (n = 20), prostate adenocarcinoma (PRAD) (n = 6), OV (n = 7), head and Neck squamous cell carcinoma (HNSC) (n = 10), Uterine Corpus Endometrial Carcinoma (UCEC) (n = 6), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) (n = 5), COREAD (n = 75), HCC (n = 50), GAC (n = 31), cholangiocarcinoma (CHOL) (n = 8), PAC (n = 10), NSCLC (n = 98), esophageal carcinoma (ESCA) (n = 10), and nasopharyngeal carcinoma (NAC) (n = 4). Overall, the area under the curve (AUC) for pan-cancer is 88.7%, and for BRCA, COREAD, HCC, NSCLC, and GAC are 91.7%, 90.0%, 94.5%, 83.4%, and 88.6%, respectively. Moreover, our approach achieved good performance on the the early stage samples of pan-cancer (AUC = 84.3%) as well as COREAD (AUC = 89.3%) and NSCLC (AUC = 79.0%). Conclusions: Collectively, we show that the CINscore inferred from low-pass WGS could be applied in early non-invasive detection of different cancers with high accuracy. Our approach may aid the improvement of the cancer diagnosis.
Impact of medical mistrust (MM) on perceptions of tumor genomic profiling (TGP) among African American (AA) cancer patients: Application of perceptual mapping (PM).
Authors: Hall Michael J. , D'Avanzo Paul , Chertock Yana , Brajuha Jesse A , Bass Sarah Bauerle 
Published: June 2021

e22527 Background: TGP is widely used to identify targetable mutations for precision cancer treatment and clinical trials. Many patients have poor understanding of TGP and are unaware of possible secondary hereditary risks. Lack of clarity regarding the relevance of informed consent and genetic counseling further magnify risks for patients. AA patients have lower genetic knowledge and health literacy and higher MM than Caucasian patients, making them especially vulnerable in the clinical setting. Perceptions of TGP in AA cancer patients have not been well-characterized. Methods: 120 AA pts from 1 suburban and 1 urban site (Fox Chase Cancer Center[FCCC] and Temple University Hospital[TUH]) were surveyed. A k-means cluster analysis using a modified MM scale was conducted; chi-square analysis assessed demographic differences. Perceptual mapping (PM)/multidimensional scaling and vector modeling was used to create 3-dimensional maps to study how TGP barriers/facilitators differed by MM group and how message strategies for communicating about TGP may also differ. Results: Data from 112 analyzable patients from FCCC (55%) and TUH (45%) were parsed into less MM (MM-L, n = 42, 37.5%) and more MM (MM-H, n = 70, 72.5%) clusters. MM-L and MM-H clusters were demographically indistinct with no significant associations by sex (p = 0.49), education (p = 0.3), income (p = 0.65), or location (p = 0.43); only age was significant (older = higher MM, p = 0.006). Patients in the MM-H cluster reported higher concerns about TGP, including cost (p < 0.001), insurance discrimination (p < 0.001), privacy breaches (p = 0.001), test performance/accuracy (p = 0.001), secondary gain by providers (p < 0.001) and provider ability to explain results (p = 0.04). Perceptual mapping identified both shared and contrasting barriers between MM clusters (Table). Conclusions: More than 2/3 of AA patients comprised a MM-H cluster. Communication strategies should focus on concerns about family and how to discuss TGP with an oncologist. PM can identify distinct and shared information needs of vulnerable populations undergoing TGP. [Table: see text]