bluuebunny/crossref_metadata_2025 huggingface dataset:
Update to role of the neutrophil lymphocyte ratio in patients with advanced NSCLC undergoing immunotherapy.
Authors: Richardet Eduardo , Acosta Luciana Paola , Magi Ignacio , tello Alfonso Rocio , Peruchin Rita Vanessa , Perea Pablo , Molina Matias , Richardet Martin
Published: June 2022

e21041

Background: The tumor microenvironment TME is a heterogeneous mixture of different tumor cells, necrotic cells and immune infíltrate.Furthermore nerves and vasculature immersed in the surrounding stroma. The TME cells have different immunological phenotypes. The infiltrating lymphocytes of the tumor stroma (tils) and neutrophil lymphocyte ratio (NLR) are a reflection of the state of “inflammation” in the TME and his systemic repercussion. In our institution we have carried out several research studies studying different markers of inflammation, such as BMI, TILs and NLR in different solid tumors. We conclude that these markers of inflammation have a role in tumor behavior, prognosis and response to treatment. The main objective was investigated the relationship between as NLR and progression-free survival (PFS).in patients with NSCLC who received immunotherapy. The secondary objective was to analyze if there is a relationship between ORR and NLR in patients with NSCLC. Methods: Retrospective and analytical study of patients of Instituto Oncológico de Córdoba. Patients with stage IV NSCLC were analyzed. Were included patient who performed IT alone or in combination with another immunomodulator or platinum-based chemotherapy. The cut-off value for NLR > or < 3 was taken. ORR was evaluated by RECIST criteria. For the statistical analysis of survival, Chi-Square test and Kaplan-Meyer test were used. Results: 52 pts with NSCLC were selected, the average age was 67 years. Of the total number of subjects analyzed, 75% (39) presented non-squamous histology and 25% (13) presented squamous histology. All performed IT (anti PD1) alone or in combination with another immunomodulator (Ipilimumab) or platinum-based CT. Of total patients analized, 27 pts had a NLR < 3; and 25 pts NLR > 3. The median overall survival (OS)was 8.5 months for general population. Patients with an NLR < 3, the median PFS was 14.9 months and those with an NLR > 3 was 5.5 months (p: 0.01). When analyzed the ORR in pts with NLR < 3 it was 21% and those with NLR > 3 the ORR was 4% with statistically significant differences (p:0.02). All patients had follow-up of at least 1 year4 patients (8%)with NLR < 3 had disease progression at 6 months in differencies with patients with NLR > 3 that had progression 13 pts (25%)(p:0.01) and these differences were maintained when we evaluated the PFS at year. Conclusions: Patients with NLR < 3 had better progression-free survival and ORR. It is possible that NLR is a very useful and easily accessible predictive factor in patients with NSCLC undergoing immunotherapy.
Signature based on B cells-related gene pairs could predict prognosis and immunotherapeutic response in NSCLC.
Authors: Li Xuanzong , Fan Xinyu , Wang Linlin
Published: June 2022

e21051

Background: Tumor-infiltrating B cells accompanying several widely used B cell-related biomarkers, such as CD19 and CD20, have inconsistent clinical prognostic values in non-small-cell lung cancer (NSCLC) patients. Considering only one B cell-related biomarker could not distinguish the anti-tumor and pro-tumor B cell subsets in tumor, we aimed to construct a more accurate B-cells related gene pairs (BRGPs) prognostic model and evaluate its potential predictive ability to immunotherapy in NSCLC patients. Methods: Using public single-cell RNA sequencing data, the B cells-related genes (BRGs) in NSCLC samples were identified. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were utilized to construct the BRGPs model which was not affected by the technical bias of different platforms. With no dependence upon specific gene expression levels, a novel signature based on BRGPs was established in this study. In addition, the prognostic value and immunotherapeutic response for this signature with regard to the TME components and potential molecular mechanism were explored. Results: Based on the TCGA database, we built a novel prognostic signature of 23 BRGPs comprising 28 unique BRGs. This risk model showed significant power in distinguishing good or poor prognosis and could serve as an independent prognostic factor for NSCLC patients in the TCGA cohort. The prognostic accuracy of the model was further verified in the GSE31210 dataset from the GEO database. Likewise, the prognostic value of the risk score for the BRGPs model was demonstrated in the GEO cohorts by the univariate and multivariate cox regression analysis. In addition, the risk model was significantly associated with sex, TNM stage, immune score, tumor purity and various tumor-infiltrating immune cells. GSEA analysis indicated that low-risk group enriched with several immune-related pathways, such as activation of immune response, antigen receptor mediated signaling pathway, B cell activation and B cell mediated immunity, whereas several proliferation-related pathways, such as nuclear chromosome segregation, sister chromatid segregation and mitotic sister chromatid segregation were most enriched in high-risk group. Besides, the tumor mutational burden (TMB) score rather than CD274(PD-L1 mRNA) expression was positively correlated with the risk score (P＜0.001; P = 0.94, respectively). NSCLC patients with high-risk exhibited significantly higher TMB score compared with low-risk patients (P < 0.001). Correspondingly, we demonstrated that immune checkpoint blockade therapy may be more efficacious in high-risk group NSCLC patients according to TIDE method (P＜0.01). Conclusions: This novel BRGPs model can assess the prognosis of patients with NSCLC, and may be helpful to guide immune checkpoint inhibitors treatment in our clinical practice.
Weight loss affects outcome in KrasG12C non-small cell lung cancer first line treated patients.
Authors: Fancelli Sara , Caliman Enrico , Pillozzi Serena , Napolitano Brunella , Pieroni Edoardo , Mazzoni Francesca , Paglialunga Luca , Gatta Michelet Marta Rita , Roviello Giandomenico , Castiglione Francesca , Bartoli Caterina , Antonuzzo Lorenzo
Published: June 2022

e21054

Background: Cachexia is a syndrome characterized by weight loss (WL), reduction of muscle mass, systemic inflammation and is an independent criteria of worse clinical outcomes in cancer. Patients with KRASmut non-small cell lung cancer (NSCLC) experience a higher rate of WL than KRASwt patients. However no data about the prognostic value of each Kras mutation subtype for WL and/or BMI status are available. Methods: We reviewed the clinicopathological data of 110 NSCLC patients harboring KRAS G12 mutation who were treated at Clinical Oncology Unit, Careggi University Hospital in Florence, from March 2016 to March 2020. Patients received either chemotherapy or anti-PD1 pembrolizumab or a combination of chemo-immunotherapy as first-line treatment. The prognostic value of basal BMI and WL (< and > 5%) was analyzed according to each mutation subtype. Results: In the study population, 49.1% of patients harbor the KRAS G12C mutation, 20.9% G12V, 18.2% G12D and 11.2% of patients have other subtypes of KRAS mutations. Overall, our data confirm the better prognostic value of G12C mutation. At a median follow-up of 18 months, median OS for G12C patients was 17.5 months, longer compared to any other mutation subtype ( p = 0.113), whereas G12V mutation was associated with significantly worse outcomes than in the whole population (mOS 9.5 months IC 95% 6.0-17.0, p = 0.018). WL within 6 months of first-line therapy was observed in 29.7% and 35.3% of G12C and G12V-mutated patients, respectively. WL statistically decreased survival outcomes both in G12C (mPFS 4.0 months vs NR, p < 0.001; mOS 12.0 months vs NR, p = 0.009) and in G12V patients (mPFS 3.0 months vs NR, p = 0.073; mOS 8.0 vs 12.0 months, p = 0.994), compared to patients who do not lose weight during treatment. Conclusions: WL significantly worsens clinical outcomes in G12C patients, with a similar trend in G12V. Further analyses in a larger population including a representative sample of less frequent mutations are needed.
ICI in combination with chemotherapy or anti-angiogenic agents as second-line or beyond treatment for advanced non-small cell lung cancer: A retrospective study.
Authors: Wu Lin , chen bolin , Wang Jingyi , Pu Xingxiang , Li Jia , Wang Qianzhi , Liu Liyu , Xu Yan , Xu Li , Kong Yi , Li Kang , Xu Fang , Liang Shuzhi
Published: June 2022

e21057

Background: Immune checkpoint inhibitors (ICIs), which are currently used in the standard second-line treatment for non-small cell lung cancer (NSCLC), have largely improved the prognosis of advanced NSCLC. However, patients treated with ICI monotherapy have low response rates; hence, there is an urgent need to expand the population responding to immunotherapy treatment. This study aimed to explore the efficacy and safety of the combination of ICI with chemotherapy or anti-angiogenic therapy compared to ICI monotherapy in patients previously treated for advanced NSCLC. Methods: Data was collected from previously treated patients with NSCLC who further received ICI monotherapy or combination therapy. The distribution of clinical variables was assessed using the chi-square test or Fisher's exact test. The relationship between descriptive variables and survival was described using Kaplan–Meier curves and compared by log-rank test. Cox proportional-hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to confirm survival differences. Results: A total of 145 patients were included in this study, of which 63 were in the ICI monotherapy group, 57 were in the ICI with chemotherapy group, and 25 were in the ICI with anti-angiogenic therapy group. Compared with the ICI monotherapy group, the ICI with chemotherapy group had significantly higher ORR (31.6% vs. 11.1%, P = 0.006), DCR (84.2% vs. 61.9%, P= 0.006), PFS (mPFS: 6.37 vs. 3.47 months, P< 0.0001; HR = 0.42, 95% CI: 0.29–0.63, P< 0.0001), and OS (mOS: 18.60 vs. 8.47 months, P< 0.0001; HR = 0.40, 95% CI: 0.25–0.64, P= 0.0001). In addition, the ICI with anti-angiogenic therapy group also had significantly elevated DCR (88% vs. 61.9%, P= 0.02), PFS (mPFS: 8.17 vs. 3.47 months, P< 0.0001; HR = 0.30, 95% CI: 0.17–0.53, P< 0.0001), and OS (mOS: 19.20 vs. 8.47 months, P= 0.006; HR = 0.44, 95% CI: 0.24–0.80, P= 0.007) compared with the ICI monotherapy group. There was no significant difference between the ICI with chemotherapy group and the ICI with anti-angiogenic therapy group. Meanwhile, the addition of chemotherapy or anti-angiogenics did not increase immune-related adverse events and had a good safety profile. Conclusions: For previously treated patients with advanced NSCLC, treatment with ICI in combination with chemotherapy led to enhanced ORR, DCR, PFS, and OS compared to treatment with ICI monotherapy. Moreover, treatment with ICI combined with anti-angiogenic therapy led to enhanced DCR, PFS, and OS compared to treatment with ICI monotherapy. The combination of immunotherapies is a promising second-line treatment option for some of the patients in this study, and the findings of this study necessitate the need for further exploration.
Promising efficacy of immune-checkpoint inhibitor with chemotherapy for SMARCA4-deficient thoracic sarcomatoid tumors.
Authors: Lin Ying , Zhang Yao , Hu Zhihuang , Wu Xianghua , Wang Jialei , Wang Huijie
Published: June 2022

e21074

Background: SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) is a rare and highly aggressive disease that lack clear treatment guidelines. This research reports the clinicopathological features of SD-TSTs and the promising efficacy of immune-checkpoint inhibitor with chemotherapy in SD-TSTs. Methods: A total of 16 patients were diagnosed and treated with SD-TSTs in Fudan University Shanghai Cancer Center (FUSCC) from January, 2017 to December, 2021. Clinicopathologic, genomic characteristics and treatment information were obtained and analyzed. Results: SD-TSTs were diagnosed at median age of 64.5 years old, and predominantly affected male (100%) with heavier smoking history (≥20 pack-year). Many patients were diagnosed at advanced stages (Stage I 18.8%, Stage II 25%, Stage III 25% and Stage IV 43.8%). The most often metastatic sites were adrenal gland, lymph nodes, bone and liver, while brain metastasis was not found. For patients underwent radical therapy, median disease-free survival is 4.8 months, indicating a rapid relapse pattern even for early-stage patients. 8 patients with Stage IV SD-TSTs were treated in FUSCC. As for first-line therapy, 3 patients received chemotherapy, whose regimen included gemcitabine plus cisplatin, doxorubicin plus ifosfamide, and vincristine, doxorubicin plus cyclophosphamide alternating with ifosfamine and etoposide. 5 patients received immune-checkpoint inhibitor plus chemotherapy as first-line therapy, including 3 patients treated with pembrolizumab plus nab-paclitaxel and carboplatin, 1 patient treated with tislelizumab plus nab-paclitaxel and carboplatin and 1 patient treated with sintilimab plus paclitaxel and carboplatin. Median progression-free survival (PFS) of first line was 6.53 months for all patients. First-line median PFS was significantly higher for patients with immune-checkpoint inhibitor plus chemotherapy than those treated with only chemotherapy (not reach vs. 2.73 months, p = 0.07). This result suggested that SD-TSTs were irresponsive to chemotherapy, including those used for sarcomas, and better responded to immune-checkpoint inhibitor included regimen. Conclusions: SD-TSTs is a highly aggressive disease. Immune-checkpoint inhibitor combined with chemotherapy showed promising efficacy in metastatic SD-TSTs than traditional chemotherapy. Considering the low incidence of SD-TSTs, our research contains the largest sample size by far to report the efficacy of immune-checkpoint inhibitor plus chemotherapy in this deadly disease.
The prognosis of EGFR complex mutation or co-mutation with tyrosine kinase inhibitor treatment in non-small cell lung cancer.
Authors: Jiang Da , Fu Yuhui , Zhou Xinliang , Li Ying , Cui Yanzhi , Hong Lei , Jin Hui , Shi Ke , Huang Fang , Zhang Xue , Fan Shaoshuang , Song Wenya , Deng Ruoying
Published: June 2022

e21086

Background: To compare the prognoses of EGFR complex mutation, co-mutation and single mutation with first-line TKI treatment in NSCLC patients. Methods: A retrospective study of 215 patients with EGFR-mutated NSCLC who were admitted to the Department of Medical Oncology, the Fourth Hospital of Hebei Medical University from January 2015 to January 2021, all received first-line EGFR-TKI therapy. According to the type of mutation, they were divided into 48 cases (22.3%) of EGFR single mutation group, 48 cases (22.3%) of complex mutation group, and 142 cases (66.0%) of co-mutation group, of which 23 cases (10.6%) both had complex mutation and co-mutation. The prognoses of the latter two groups were compared with that of the single mutation group respectively. SPSS 26.0 was used to analyze the data, and P < 0.05 indicated the difference was statistically significant. Results: Progression-free survival (PFS): the co-mutation group was shorter than the single mutation group (11.0m vs 13.5m; HR = 1.492, 95%CI: 1.036-2.149; P= 0.030), especially the co-mutation was occurred in TP53 (10.5 m vs 13.0m; HR = 1.665, 95%CI: 1.234-2.248; P= 0.001) or HER family (9.0m vs 12.0m; HR = 2.435, 95%CI: 1.492-3.974; P< 0.001). Overall survival (OS): compared with the single mutation group, complex mutation group (36.5m vs 52.0m; HR = 1.480, 95%CI: 0.821-2.668; P= 0.193), co-mutation group (41.0m vs 52.0m; HR = 1.418, 95%CI: 0.901-2.231; P= 0.131) were not statistically different, but the co-mutation of PTEN pathway significantly reduced OS (24.0m vs 46.0m; HR = 1.884, 95%CI: 1.137 -3.120; P= 0.014). Objective response rate (ORR) and disease control rate (DCR) of first-line EGFR-TKI: single mutation group separately compared with complex mutation group and co-mutation group (ORR: 64.6% vs 6.2% vs 27.4%, P< 0.001; DCR: 100% vs 70.8% vs 91.5%, P < 0.001 and 0.007 respectively). After the first-generation EGFR-TKI treatment and secondary EGFR E20 T790M mutation, the presence or absence of the original sensitive mutation affects the PFS of the first-generation TKI (12.0m vs 11.0m; HR = 1.109, 95%CI:0.739-1.664 ; P= 0.616), PFS of the third-generation TKI (10.0m vs 8.0m; HR = 1.130, 95%CI: 0.717-1.781; P= 0.599) and OS (34.0m vs 44.5m; HR = 0.834, 95%CI: 0.505-1.377; P= 0.478) were not statistically different. Conclusions: EGFR co-mutation is a predictor of poor prognosis in NSCLC patients treated with EGFR-TKI; after first-generation EGFR-TKI resistance, the disappearance of the original sensitive mutation cannot predict the prognosis.
Immunotherapy in Hispanic patients with advanced non-small cell lung cancer: A real-world data.
Authors: Lujan Mauricio , Lema Mauricio , Preciado Beatriz , Lema Camila , Egurrola Jorge , Cardona Zorrilla Andres Felipe , Gonzalez Diego Mauricio , Mantilla William Armando , Pino Luis , Rojas Gustavo , Gomez-Abreo Diego Andres , Munevar Isabel , Manneh Raimundo , Manneh Kopp Ray , Lobaton Jose F. , Calle Esteban , Borras Mariana , Triana Ivan Camilo , Pineda Mateo , Moran Ortio Diego
Published: June 2022

e21094

Background: Nivolumab is a human programmed death receptor-1 (PD-1) blocking antibody, used as treatment option in patients with advanced non-small cell lung cancer (NSCLC). We assessed the nivolumab efficacy in terms of survival and response to treatment as second- or third-line therapy in patients with advanced NSCLC. Methods: This is a multicentric observational study. Data of patients with advanced NSCLC who received nivolumab as second (2L) or third-line (3L) treatment were analyzed retrospectively. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness, and safety of nivolumab treatment were collected. The outcomes evaluated were overall survival (OS), progression-free survival (PFS), and objective reponse rate to treatment (ORR). OS and PFS were estimated with the Kaplan-Meier method. Statistical analysis was carried out using SPSS version 21.0. Results: Eleven centers distributed across the country (Colombia) participated. Data from 178 patients were included. The median follow-up was 26.8 months (IQR 20.3 - 40.4). Women represented 51.7% of the population, and the median age was 63 years (IQR 56-72 years). Nivolumab was commonly used as a 2L treatment. The ORR with nivolumab as 2L treatment was 21.0%. The median PFS and OS were 5.5 months (95%CI: 4.5 – 6.5) and 12.4 months (95%CI: 10.8 – 14.0), respectively. In 3L the ORR with nivolumab was 15.0%. The overall incidence of adverse events was 1.7%. Conclusions: Nivolumab effectiveness and safety in this scenario was consistent with than reported by previous trials and other real world data.
Pan-immune-inflammation value as a predictive biomarker for survival in advanced non-small cell lung cancer patients treated with immunotherapy.
Authors: Sooi Kenneth , Low Jia Li , Miow Qing Hao , Kumarakulasinghe Nesaretnam Barr , Sundar Raghav , Huang Yiqing
Published: June 2022

e21095

Background: It is well known that chronic inflammation can enable immune escape by suppressing immune surveillance. This promotes cancer growth and development, which forms the basis of immune checkpoint inhibitors use. Pan-Immune-Inflammation Value (PIV), a type of immune-inflammatory biomarker, has shown predictive value in various cancer patient populations (colorectal, melanoma, breast, oesophagus, ALK-positive lung cancer) and patients with ANCA-associated vasculitis. We aimed to evaluate the role of PIV as a predictive biomarker in advanced non-small cell lung cancer (NSCLC), whereby immune checkpoint inhibitor therapy is frequently used. Methods: We conducted a retrospective review of advanced NSCLC patients who received immunotherapy in the National University Hospital, Singapore between January 2015 and January 2022. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count, with the median value used to distinguish between high and low PIV. Kaplan–Meier method and Cox proportional hazards regression models were used for survival analyses. Results: 203 patients were included in the study. The median age was 63, 70% were males, 76% were Chinese, 83% had ECOG Performance Status ≤1 and 70% had adenocarcinoma histology. The immunotherapy agents used were Pembrolizumab (82%), Nivolumab (13%) and Atezolizumab (5%). Chemotherapy was given in conjunction with immunotherapy in 37% of the population. The median PIV value derived was 790 and patients with a low baseline PIV experienced better progression-free survival (PFS) and overall survival (OS). The median PFS was 249 days in PIV-low vs 145 days in PIV-high cohorts (hazard ratio for progression or death from any cause [HR] 0.58, 95% Confidence Interval [CI] 0.40-0.86, p < 0.01) and the median OS was 794 days in PIV-low vs 420 days in PIV-high cohorts (HR 0.69, 95% CI 0.49-0.96, p = 0.03). Patients who had higher PIV, ECOG performance status ≥2, liver metastases, immunotherapy exposure in 2nd line or later, use of immunotherapy alone without chemotherapy had worse OS in univariate analysis, but only PIV (HR = 1.61, 95% CI 1.08-2.40, p < 0.02) was an independent prognostic factor in multivariate analysis. Amongst the patients with known PD-L1 status (n = 158), univariate analysis showed that PD-L1 ≥1 and PD-L1 ≥50 were not prognostic for OS whereas PIV remained an independent prognostic factor in both univariate and multivariate analyses. Conclusions: PIV appears to be a strong predictor of survival outcomes for patients with advanced NSCLC receiving immunotherapy as part of their cancer treatment. Prospective clinical trials are required to validate the predictive value of PIV in NSCLC patients receiving immunotherapy, as well as evaluating PIV’s performance against PD-L1.
Tumor neutrophil extracellular traps and pretreatment neutrophils in association with progression-free survival in patients with metastatic non-small cell lung cancer receiving pembrolizumab alone or with chemotherapy.
Authors: Petrova Mila , Parvanov Dimiter , Ganeva Rumiana , Metodiev Dimiter , Bachurska Svitlana , Eneva Mariyana , Penkova Polya , Popov Teodor , Nikolov Krasimir , Taushanova Margarita , Kraleva Petya , Ruseva Rossitza Krasteva , Zhelev Kiril , Donev Ivan
Published: June 2022

e21099

Background: Background: In this multicentric retrospective study, we evaluated the relationship between pre- treatment blood neutrophils and neutrophil extracellular traps (NET) in biopsy samples and their predictive value for progression progression-free survival (PFS) in patients with non-small-cell lung cancer (NSCLC) receiving immunotherapy alone or in combination with chemotherapy as a first-line treatment. Methods: Patients with metastatic NSCLC (n = 100) were retrospectively analyzed between Apr 2018 and Sep 2021; 77.5% of the patients received platinum-containing chemotherapy with Pembrolizumab, and 22.5% – Pembrolizumab only as a first-line treatment. Pre-treatment blood neutrophils were counted. Tissue sections were stained immunohistochemically for Neutrophil elastase (NE) and Histone H3. Both NE and Histone H3 stained tissue areas were calculated manually and determined by Image-J software. We considered the extracellular components that were double-positive for NE and H3 to be NET. Results: In correspondence analysis, patients with low levels (< 33rd percentile) of pre-treatment neutrophils were grouped with low amounts (< 33rd percentile) of NET-positive tumor areas (p = 0.02). The amounts of NET-positive tumor areas were not related to other clinicopathological characteristics of the patients. Patients with an intermediate/high amount of NET-positive areas had significantly shorter mean PFS, 10.7 (95% CI: 9.6–11.8) than those with low NET-positive areas, 14.8 (95% CI: 11.5–18.1) (log-rank test p = 0.003). Moreover, in a multivariate Cox regression model, the presence of an intermediate/high amount of NET-positive areas was an independent predictive factor for shorter PFS, HR 2.1 (95% CI: 1.2–3.7; p = 0.005). Conclusions: Our study suggests that tumor formation of NETs is related to the numbers of pre-treatment neutrophils and may mediate neutrophil-induced antitumor resistance. Excessive NET formation in tumor tissue is a potential negative predictive marker for shorter PFS.
Actionable insights for managing inter-reader variability of RECIST overall response in lung clinical trials: A retrospective analysis.
Authors: Beaumont Hubert , Iannessi Antoine
Published: June 2022

e21102

Background: To assess drug efficacy in clinical trials with imaging endpoints, the FDA recommends blinded independent central review (BICR) with double reads to ensure robust image interpretation. However, discordance created by double-reading adds burden and costs that stakeholders strive to minimize. Given that selection of tumors at baseline is reported to cause one third of adjudications, we tested a set of risk factors arising from baseline evaluations and trained models likely to predict discrepancies in RECIST responses. Methods: We pooled and retrospectively analyzed data from five lung cancer clinical trials that used RECIST with BICR and double reads including a total of 1720 patients. Firstly, we analyzed the distribution of four kinds of response discrepancies (KoD): progression or date of progression (PD), response or date of response (OR), progression or response (ANY) and best response (BR). We derived discrepancy rates, average time-point of the first occurrence of KoD and the proportion of time-points before KoD out of total time-point number (compared using Marascuilo procedure) as key indicators of the at-risk period of discordance. Secondly, from the baseline evaluations performed by readers, we computed the odds ratios of 32 risk factors for discrepancies including differences in measurements, tumor selection and disease locations. Finally, based on 77 features, we trained a Random Forest (RF) and a deep learning (DL) model to predict KoDs. Results: On average, respectively for PD, OR, ANY and BR, discrepancy rates were 41.5%, 49.1%, 66.3% and 28.7%; number of time-points for first occurrence were 4.6, 2.7, 2.7 and 4.8; and the proportion of time-points before KoD were 30.7%, 24.7%, 33.1% and 23.2% (significantly different). The main risk factors for discrepancies were miss-detection of measurable disease, completely different disease selection, miss-selection of lung tumors and when readers’ difference in sum of diameters was between 10% and 20%. However, associations were weak, with no association when one of the readers selected infrequent diseases (e.g., skin, gastric). DL outperformed RF. Classification performances were generally poor. PD was not predictable. BR performances were positive predictive value: 81.0 [95% CI: 78.8; 83.2], negative predictive value: 73.3 [95% CI: 72.8; 73.8]. Conclusions: The KoDs have different distributions, but all occur in the first third of the patient evaluation defining a risk period. We confirmed the reported association of selection and measurement at baseline with responses' variabilities. However, the associations were weak and did not allow good prediction of the variability in responses. For BICR of lung cancer trials using RECIST, our results support the implementation of a monitoring of variability focusing on the baseline and the beginning of the evaluation of the patients.
Integrated analysis of transcriptome profiles in lung adenocarcinoma with spread through air spaces.
Authors: Pan Bo , Jia Dexin , Geng Jianxiong , Cui Chengwei , Yu Yan
Published: June 2022

e21103

Background: Spread through air spaces (STAS) is a recently described invasive pattern of lung cancer with a relatively poor prognosis. The current study aims to evaluate and compare the transcriptome patterns and tumor microenvironment (TME) of STAS positive and negative lung adenocarcinoma (LUAD) cases. Methods: Nineteen LUAD patients who underwent radical surgery were enrolled in the current study, of which 11 were STAS-positive and 8 were STAS-negative. We performed RNA sequencing and data analyzes of the patient’s resected primary tumor tissue samples in a College of American Pathologists accredited laboratory (Genecast Biotechnology Co., Ltd, Wuxi). Results: A total of 841 differently expressed genes (DEGs) were identified between STAS positive and negative groups, including 442 up-regulated and 399 down-regulated DEGs in STAS positive tumors. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that the 841 DEGs were significantly enriched in humoral immune response, cell adhesion molecules, and IL-17 signaling pathways, and so on. Moreover, hypoxia VHL targets up was exceedingly up-regulated in STAS positive tumors through gene set enrichment analysis (GSEA). In addition, the abundance of regulatory T cells (Tregs) showed a borderline significant trend to be higher in STAS positive cases. Conclusions: Our study is the first to report the transcriptome profiles and TME of LUAD patients with STAS. These novel findings may add to further understanding underlying biological mechanisms of STAS occurrence and help developing rationale treatments to deliver more survival benefits for STAS positive LUAD patients.
Neoadjuvant Toripalimab plus chemotherapy in patients with stage IIB-IIIB NSCLC: A single-center, prospective, single-arm, phase 2 trial (Renaissance Study).
Authors: Yan Shi , Chen Jinfeng , Wang Jia , Lv Chao , Bi Jiwang , Yang Xin , Li Shaolei , Wang Yuzhao , Li Xiang , Yang Yue , Wu Nan
Published: June 2022

e21128

Background: Neoadjuvant treatment of a programmed cell death protein 1 (PD-1) inhibitor plus chemotherapy has been shown to be promising in treating resectable non-small cell lung cancer (NSCLC). The current study aimed to investigate the efficacy and safety of toripalimab plus double platinum-based chemotherapy as neoadjuvant treatment for stage IIB-IIIB NSCLC. Methods: Study eligibility involved stage IIB-IIIB, wildtype EGFR/ALK NSCLC pts with ECOG PS 0-1 status. Pts received 2-4 cycles of toripalimab (240mg, q3w) plus cisplatin-based chemotherapy. All pts were assessed by imaging/surgical indication after the second cycle of treatment. Pts who cannot undergo surgery will be reassessed after another 1-2 cycles of neoadjuvant therapy. Primary endpoints were major pathological response (MPR), complete pathological response (pCR). Secondary endpoints were objective response rate (ORR), R0 resection rate and safety. Results: A total of 52 eligible pts (median age: 62, IQR: 45-76; female: 4, 7.7%) were enrolled and received 2-4 cycles neoadjuvant treatment since Mar 2021. 42 pts had squamous cell carcinoma and 10 pts had non-squamous cell carcinoma. Disease distribution in stage IIB, IIIA and IIIB consisted of 14, 30 and 8 pts, respectively. 15 pts were undergoing preoperative treatment or preparing for surgery, 32 pts underwent resection (median interval between neoadjuvant treatment and surgery: 67 days, IQR 39-113), 5 pts were unsuitable for surgery (1 pt had immune-related pneumonia; 2 pts who had stable disease were considered radical radiotherapy and immunotherapy for maintenance due to the difficulty of surgery induced by tumor location and lymph node metastasis; 2 pts continued toripalimab plus chemotherapy or radiotherapy due to high surgical risk induced by old age and poor performance status). 20 pts (20/32, 62.5%) achieved MPR, including 16 pts (16/32, 50%) with pCR. 6 pts (6/8, 75%), 12 pts (12/18, 66.7%), and 2 pts (2/6, 33.3%) with stage IIB, IIIA and IIIB achieved MPR respectively. R0 resection was achieved for all 32 pts (100%). 23 pts underwent surgery with cN2/N1 at baseline (23/24, 95.8%) achieved nodal downstaging. For pts who finished radiological reassessment (45 pts finished the treatment schedule and only 43 pts finished radiological reassessment), ORR was 83.7% (36/43). Grade 1-2 TRAEs were reported in 33 patients (33/45, 73.3%). Grade 3-4 TRAEs were reported in 6 pts (6/45, 13.3%). Conclusions: Toripalimab plus platinum-based doublet as neoadjuvant treatment yields a high MPR rate, manageable toxicity and feasible surgical resection in stage IIB-IIIB NSCLC. Clinical trial information: NCT04606303.
Insights into the advanced non-small cell lung cancer patient journey: Treatment decision-making, preferences, and quality of life considerations.
Authors: Wheatley-Price Paul , Ferris Andrea Stern , Barros Luciana Holtz De Camargo , Mancera Font Adriana , Ornstein Carly , Saez Daniel , Szmytke Ewelina , Vallone Stefania , May Suepattra Grace , Konidaris Gerasimos , Shaddock Hampton
Published: June 2022

e21129

Background: Individuals with advanced non-small-cell lung cancer (aNSCLC) who have undergone multiple lines of prior therapy face a poor prognosis and limited treatment options, significantly impacting quality of life (QoL). This exercise explored European, North, and South American patient advocate perspectives on QoL and its relation to treatment decision-making and preferences in aNSCLC. Methods: A global aNSCLC patient advocacy advisory board was convened with organizations from Europe, US, Canada, and Brazil, asking participants about QoL and treatment side effects, and how these relate to subsequent care and treatment decision-making. The discussion was moderated by an oncologist, transcribed, and analyzed using thematic analysis. Results: Preserving one’s independence was highlighted as a key component of QoL, with advocates noting that tumor-related symptoms and treatment toxicities have a substantial negative impact on an individual’s ability to engage in daily activities. Fatigue – both physical and psychological – is especially burdensome, particularly for those who have undergone multiple lines of therapy. Participants also noted the need for more accessible care (e.g., telehealth appointments, oral therapies) that fits into the routines of individuals and caregivers. The importance of palliative care and its ability to improve QoL was noted, showing the need for health systems to better integrate palliative care into treatment regimens. Finally, participants noted that treatment priorities change as individuals undergo subsequent lines of therapy, with participants noting the importance of independence and QoL in later stages of therapy, and thus must be assessed regularly by the care team. Conclusions: Individuals with aNSCLC place importance on consideration of QoL when making treatment decisions, particularly those related to maintaining independence. While there remains a need for additional and more effective therapies, an integrated and accessible care approach, with patient-provider communication focusing on maintaining QoL and independence, should be a priority.
The impact of population-based EGFR testing in metastatic non-small cell lung cancer in Alberta.
Authors: Brenner Darren R , O'Sullivan Dylan E. , Jarada Tamer N. , Yusuf Amman , Boyne Devon J , Mather Cheryl A , Box Adrian , Morris Donald , Cheung Winson Y. , Mirza Imran
Published: June 2022

e21139

Background: While Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors have been shown to be effective in phase III randomized trials, the value of targeted therapies have been challenging to evaluate at the population level. We examined the impact of population-level EGFR testing and treatment on survival outcomes among metastatic Non-Small Cell Lung Cancer (NSCLC) patients. Methods: Real-world, population-level data were collected from all de novo metastatic non-squamous NSCLC patients in Alberta, Canada from 2004 to 2020. EGFR testing data were collected through Alberta Precision Laboratories using various text mining approaches. Differences in survival rates and overall survival (OS) pre (2004-2012) and post-initiation (post) (2013-2019) testing periods were evaluated using interrupted time series analyses. The impact of testing and subsequent treatment weas evaluated using multivariable Cox Proportional Hazards models. Results: In total, 4,578 metastatic NSCLC patients with a confirmed non-squamous cell carcinoma histology were diagnosed pre- EGFR testing and 4,457 patients were diagnosed post- EGFR testing (2013-2019). Among patients diagnosed in the pre- EGFR testing period, the 6-month, 1-year, and 2-year survival probabilities were 0.39 (95% CI: 0.38-0.41), 0.22 (95% CI: 0.21-0.23), and 0.09 (95% CI: 0.08-0.10), while the survival probabilities for patients diagnosed in the post- EGFR testing period were 0.45 (95% CI: 0.43-0.46), 0.29 (95% CI: 0.27-0.30), and 0.16 (95% CI: 0.15-0.1 7), respectively. After adjusting for baseline patient and clinical characteristics, OS in the post- EGFR period was significantly improved compared to the pre- EGFR period (HR: 0.81; 95% CI: 0.78-0.85). In the post-EGFR period, among patients who were treated with systemic therapy, those tested for an EGFR mutation had significantly greater survival than patients who were not tested HR of 0.81 (95% CI: 0.70-0.95). Conclusions: These results show the considerable impact of population-based molecular testing and subsequent targeted therapies on survival among advanced NSCLC patients. The estimates here can be used in future studies to evaluate the population-level cost-effectiveness of testing and treatment.
Anlotinib combined with pemetrexed and carboplatin as first-line treatment in driver-gene negative advanced non-squamous non-small cell lung cancer: ALTER L012.
Authors: Wang Qiming , He Zhen , Yang Xiuli , Ma Tianjiang , Yang Qiumin , Zhang Chenghui , Chen Yunfang
Published: June 2022

e21147

Background: Anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients. The study aimed to explore the efficacy and safety of anlotinib combined with carboplatin and pemetrexed followed by anlotinib combined with pemetrexed maintenance in advanced EGFR/ALK wild-type non-squamous non-small-cell lung cancer (nsq-NSCLC). Methods: This multicenter (n = 6), single-arm clinical trial recruited patients with wild-type EGFR/ALK advanced nsq-NSCLC who received first-line therapy between March 2019 and February 2021. Patients received anlotinib (12 mg p.o., QD d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m, iv, d1, Q3W) + carboplatin (AUC = 5, iv, d1, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints are OS, objective response (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Feb 2021, 44 patients were enrolled and 38 of them have received at least one tumor assessment. The median age was 62 (range: 33-75) years. Most of the patients were non-smoker (68.4%). The median follow-up was 13.6 (range: 12.3-14.9) months. Median PFS was 10.5 (95%CI: 4.1, 17.0) months, and median OS was 23.4 (95%CI: NE, NE) months. The DCR and ORR were 94.7% and 60.5%, respectively. Twelve participants had treatment-related adverse events (TEAEs) of grade > 3. The most common Grade 3 AEs were hypertension (23.7%), neutropenia (19.4%), and bone marrow hypocellular (10.5%). Seven patients discontinued treatment, including two during induction and five during maintenance. No grade 5 TRAE was recorded. In the non-smoker participants, the median PFS was 14.5 (95%CI: 4.0-25.0) months. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin followed by anlotinib plus pemetrexed maintenance therapy might be a promising treatment for patients with wild-type EGFR/ALK advanced nsq-NSCLC. The combination was well tolerated, and the AEs were manageable. Clinical trial information: NCT03790228.
Characterization of molecular subtypes of melanoma and development of prognostic and immunotherapy-related genetic characteristics by ferroptosis gene analysis.
Authors: Xu Libin , Mu Tianhao , Wang Weiyu , Yu Sheng Ji , Zhang Yu , Liu Ting , Luqiang Wang , Zhao Zhenguo , Xinxin Zhang , Xiaoyang Li , Wu Wence
Published: June 2022

e21508

Background: The heterogeneity is a major problem in clinical treatment of skin cutaneous melanoma (SKCM). Objective and reproducible classification systems may help decode SKCM heterogeneity. Methods: Based on ferroptosis-related genes, this study used unsupervised clustering to identify two molecular subtypes of SKCM C1 and C2. A ferroptosis-related prognosis risk score (FPRS) model was constructed through analyzing the differences between C1 and C2 subtypes. Results: C1 showed a poor prognosis, with low infiltration degree of immune cells and TIED score were lower and higher homologous recombination defects, fraction altered, number of segments and copy number amplification and deletion. These characteristics of C2 were the opposite of C1. SKCM patients were divided into two risk groups based on FPRS. There were significant differences in the infiltration and proportion of immune cells, expression of immune checkpoint genes, and response to immune checkpoint therapy and sensitivity to chemotherapeutic drugs between high-risk group and low-risk group. Conclusions: In summary, we have identified two subtypes of SKCM with different molecular and immune characteristics based on ferroptosis-related genes, further developed and verified a FPRS model, which can be used as an independent prognostic indicator for SKCM. This study may provide a new insight for the development of personalized management of patients with SKCM.
Relationship between IL-1β and IL-8 serum concentrations in patients with metastatic melanoma taking checkpoint inhibitors.
Authors: Orlova Rashida , Malkova Anna , Zhukova Natalia V. , Kaledina Ekaterina , Demchenkova Alexandra , Naymushina Polina , Sharoyko Vladimir
Published: June 2022

e21510

Background: Melanoma is a disease that is most often treated with immune checkpoint inhibitors (ICI). The principle mechanism of ICI is based on the activation of the antitumor immune response. This therapy is not effective in all patients, which may be due to the immunosuppressive effect of tumor microenvironment (TME). IL-1β is one of the most important participants in the TME, however, it is difficult to determine it in blood serum, in contrast to IL-8, the synthesis of which is induced by IL-1β. The study aims to determine the relationship between IL-1β and IL-8 in patients with metastatic (mts) melanoma and to reveal their diagnostic significance. Methods: The study involved 28 patients (pts) with mts melanoma taking ICI. The level of IL-1β and IL-8 in blood serum was determined using the ELISA method. Statistical analysis was performed in GraphPad Prism 6 (Graph Pad Software, USA) using Fisher, Mann-Whitney, ROC, Wilcoxon matched-pairs signed rank test, Spearman statistical analysis. Results: IL-1β was detected in 35.5% (11/31) of patients before therapy, while an elevated level was recorded in only one patient. IL-8 was found in all patients, an elevated level before therapy was observed in 64.5% (20/31) of cases, after 2-3 months - in 35.5% (11/31). During ICI therapy, a statistically significant decrease in the concentration of IL-1β (p = 0.0498) and IL-8 (p = 0.0002) were observed. In the presence of IL-1β, the level of IL-8 was statistically higher (139.6±65.26 pg/ml), p = 0.024, while a mean positive correlation was found between IL-1β and IL-8 concentrations (R = 0.6469, p = 0.035). According to ROC analysis (Area = 0.76), with an increase in the concentration of IL-8 more than 42.31 pg/ml with a diagnostic sensitivity of 66.67% and a specificity of 90.00%, it can be assumed that the level of IL-1β will be detected in the patient (p = 0.025). Conclusions: According to the study, with an IL-8 concentration of more than 42.31 pg/ml in patients with mts melanoma, the presence of IL-1β in the blood serum can be expected. At the same time, the level of IL-8 correlated with the level of IL-1β. It can be assumed that high level of IL-8 may indicate the overexpression IL-1β in TME and it`s high activity, which may be associated with the possible risk of low ICI efficacy.
Two checkpoint inhibitor combinations in patients with cutaneous melanoma: A systematic review of clinical trials.
Authors: Aiman Wajeeha , Dad Ullah Mati Ullah , Ali Mukarram Jamat Jamat , Khan Iman Waheed , Choudhry Mina , Chaudry Hafsa , Anwar Aqsa , Avula Sreekant , Anwer Faiz , Ali Muhammad Ashar
Published: June 2022

e21530

Background: Melanoma is a cancer of melanocytes and has the potential to metastasize to distant organs. Immune checkpoint inhibitors (ICI) enhance the immune response against cancer cells. Programmed cell death protein-1 (PD-1), PD-ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene (LAG-3) are the common targets of ICI. Blocking two pathways can have an additive/synergistic effect. This systematic review will assess the efficacy of two ICI combinations in cutaneous melanoma. Methods: A search was performed on PubMed, Embase, and clinicaltrials.gov. We used the following mesh and Emtree terms, “Melanoma” AND “Immune checkpoint inhibitors,” from the inception of literature till 01/15/2022. We screened 11,287 articles and included 4 randomized clinical trials (N = 1,948) and 6 single-arm clinical trials (N = 438) in this review. We excluded preclinical trials, case reports, case series, review articles, observational studies, meta-analysis, and irrelevant clinical trials. Results: In 10 clinical studies (N = 2,386), two ICI combinations were assessed in adult patients with melanoma. Nivolumab (nivo) + ipilimumab (ipi), relatlimab (rela) + nivo, pembrolizumab (pemb) + ipi, lag525 + spartalizumab (spa), fianlimab (fian) + cemiplimab (cem) and single drug/placebo were used to treat 560, 365, 223, 42, 48, and 1,148 patients, respectively. 2,119, 70, and 197 patients had advanced untreated, PD-1/L1 refractory, and resectable stage III/IV melanoma. The response rates (RR) and survival rates are given in table. Conclusions: Two ICI combinations of nivo, ipi, and rela were more effective than monotherapy in patients with untreated advanced melanoma. In early phase trials, combinations of ipi, nivo, pemb, lag525, spa, fian, and cem were effective in advanced melanoma. Nivo, ipi, and rela were effective in patients with resectable melanoma. Pemb+ipi was effective in patients with PD-1/L1 refractory melanoma. More randomized double-blinded clinical trials are needed to confirm these results.[Table: see text]