bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality-of-life (QOL) analyses in patients with multiple myeloma: Results from the selinexor (KPT-330) treatment of refractory myeloma (STORM) phase IIb study.
Authors: Jagannath Sundar , mehta jyotsna , Breeze Janis , Tremblay Gabriel , Li Lingling , Biran Noa , Shacham Sharon , Kauffman Michael G. , Shah Jatin J.
Published: May 2020

e20522

Background: Selinexor, a novel oral selective inhibitor of nuclear export, was recently approved for use in relapsed/refractory multiple myeloma (MM). The efficacy and safety of selinexor and dexamethasone was evaluated in a phase 2b, single-arm, open-label, multicenter trial in patients with penta-exposed, triple-class refractory MM. Patient-reported outcomes were measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM) assessment. While minimal clinically important differences (MCID) have been established for other FACT scales, there is no known, validated definition of MCID for the FACT-MM. This study reports results of QoL analyses in patients with MM enrolled in the STORM phase 2b trial and examines two approaches to calculate MCID for the FACT-MM. Methods: FACT-MM data were collected at baseline, on day 1 of each 4-week cycle, and at end of treatment (EOT) during the STORM phase 2b trial. Change from baseline was analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain. Two approaches for evaluating MCID were explored: the first based on patient-reported assessment of meaningful change, defined as 10% of the instrument range (Ringash 2007), and the second based on mean baseline differences between ECOG groups (0 vs 1 to 2) based on patient level data. Additional analyses were performed to identify trends among treatment responders and non-responders, including a difference-in-difference (DID) analysis to compare changes between baseline and EOT. Results: Eighty patients had sufficient data to be included in longitudinal QOL analyses. MCID analyses demonstrated that most patients did not experience decline during the first six cycles of treatment; this pattern was consistent with MCID defined either as 10% of the instrument range (range 54% to 75% of patients), or as an ECOG-based anchor (range: 54% to 73% of patients). The DID analysis found that the mean change in QoL of non-responders decreased significantly between baseline and EOT, while responders had no significant change. This difference between responders and non-responders was significant for the FACT-G. Conclusions: Most patients did not experience QoL decline during the early cycles of selinexor treatment during the STORM 2b trial. The MCID decline, evaluated by two approaches, was greater among treatment non-responders than responders. A DID approach demonstrated greater decline between baseline and EOT for non-responders. Clinical trial information: NCT02336815.
DREAMM-2: Assessing efficacy via indirect comparison of single-agent belantamab mafodotin versus selinexor plus dexamethasone combination in anti-CD38 exposed relapsed/refractory multiple myeloma (RRMM).
Authors: Popat Rakesh , Suvannasankha Attaya , Kapetanakis Venediktos , Prawitz Thibaud , Sarri Grammati , Hughes Rachel , Wang Feng , Hogea Cosima , Ferrante Shannon Allen , Willson Jenny
Published: May 2020

e20527

Background: Single-agent belantamab mafodotin (GSK2857916) is a first-in-class immunoconjugate targeting B-cell maturation antigen that demonstrated deep and durable responses in heavily pretreated patients with RRMM in the pivotal DREAMM-2 study (NCT03525678; Lancet Oncol 2020). Methods: DREAMM-2 included patients with late-line RRMM treated with ≥3 prior lines of therapy, refractory to an immunomodulatory agent and a proteasome inhibitor, with prior exposure to an anti-CD38 antibody. Evidence from Phase II/III trials in a similar patient population was systematically identified following PRISMA guidelines. Based on the specificity of the DREAMM-2 population, selinexor plus low-dose dexamethasone (sel+dex) was identified as the only feasible comparator (STORM Part 2, NCT02336815). Matching-adjusted indirect comparisons (MAIC) were used to investigate the efficacy of single-agent belantamab mafodotin vs. sel+dex. Populations were matched for all clinically validated effect modifiers and prognostic factors with available data. MAIC were performed for overall response rate (ORR), time to response (TTR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS), as per NICE guidelines. Results: Single-agent belantamab mafodotin was more efficacious than sel+dex in terms of OS and DoR (Table). Results for ORR, TTR, and PFS showed no statistical difference between the two regimens. Conclusions: MAIC of single-agent belantamab mafodotin vs. sel+dex in this patient population with RRMM showed significantly improved efficacy on OS and DoR for belantamab mafodotin. Further validation is required owing to limited data availability. Additional safety analyses will further inform comparisons of the two. Clinical trial information: NCT03525678; NCT02336815. Funding: GlaxoSmithKline (207145). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. [Table: see text]
Daratumumab-induced lymphopenia predicts adverse events and outcomes in patients with myeloma.
Authors: Cottini Francesca , Williams Nita , Bumma Naresh , Khan Abdullah Mohammad , Chaudhry Maria , Devarakonda Srinivas S. , Efebera Yvonne Adeduni , Benson Don M. , Rosko Ashley Elizabeth
Published: May 2020

e20534

Background: Daratumumab, a monoclonal antibody against CD38, is very effective in patients with Multiple Myeloma (MM). CD38 is expressed on MM cells but also on normal lymphocytes. Therapy-induced lymphopenia has been reported in 30-40% of patients; however its clinical significance is vastly unexplored. Methods: Here, we report the baseline characteristics and clinical course of 100 relapsed/refractory MM patients treated at the Ohio State University with Daratumumab as single agent or in combination. Data pertaining to patient demographics, MM characteristics, absolute lymphocyte count-ALC, infections, and hospital stays were collected. ALC of less or equal to 500 cells/µL is considered severe lymphopenia. Results: Fifty-nine percent of patients who completed treatment with Daratumumab (59%) developed severe lymphopenia. MM type (LLC and IgA), combination with immunomodulatory drugs (IMIDs), and lower baseline ALC count were statistically associated with severe lymphopenia, while stage, age, cytogenetics, number of prior lines of treatment, and autologous stem cell transplant were not. Patients with severe lymphopenia had higher rates of infections (52.5% versus 41.4%) and required hospital stays more frequently (83.8% versus 52.9%) than patients without severe lymphopenia. Upper respiratory tract infections and pneumonias were the most common infections. Sixty-one percent of severely lymphopenic patients recovered to ALC > 500 lymphocyte/μL while on therapy. The median time to recover was 14 days (average 43 days). Older patients have longer ALC recovery time (average: 52 days versus 24 days). No statistically significant difference in progression-free survival (PFS), overall survival (OS), or overall response rate (ORR) was noted between patients who did or did not develop severe lymphopenia. However, when the severe lymphopenic group was stratified based on ALC recovery, those with persistent lymphopenia had worst OS (p = 0.0019) and PFS (p < 0.0001), possibly due to better immune-mediated anti-tumoral effects. Conclusions: In our patient population, we discovered an elevated rate of severe lymphopenia, hospital utilization, and infections. Persistent severe lymphopenia is associated with shorter PFS and worst OS. Combination with IMIDs and low baseline ALC count are risk factors for severe lymphopenia while patients older than 65 has a longer ALC recovery time. These findings underline the importance of monitoring lymphocyte count and considering prophylactic measures in high-risk patients treated with Daratumumab.
Real-world stem cell mobilization (PBSC) patterns in MM pts receiving autologous transplant (ASCT).
Authors: Hari Parameswaran , Davila Omar , Pope Andrea , Hamadani Mehdi
Published: May 2020

e20536

Background: PBSC mobilization (MOB) and apheresis is mandatory prior to ASCT and pose clinical, logistical, and financial challenges at transplant centers. This has resulted in considerable practice variation and a variety of local algorithms. Traditionally MOB was performed using G-CSF in the recovery phase after administration of chemotherapeutic agents such as cyclophosphamide (CTX). G-CSF alone (G) or G-CSF w/plerixafor (G+P) are other options. We compared the current US patterns of mobilization in a prospective observational study between OCT2017 and SEP2019. Methods: Consecutive pts (n = 690) undergoing MOB for upfront MM ASCT were prospectively enrolled from 20 participating centers. Specially designed data collection forms were used to collect resource utilization and complications in the peri-mobilization period. Based on a presurvey of center practices, 4 patterns of MOB were identified: CTX, G, G+P, or P Rescue of suboptimal G MOB. Results: CTX was the least common strategy (n = 52) followed by G (95) or G+P (252) or P Rescue (291). Presumed disease control and center preference were reasons for using CTX. Pt and disease characteristics were similar among groups with notable exceptions: CTX was less common in pts with higher SCr and more in those with higher beta2 microglobulin. CTX group had fewer pts in ≥VGPR status (31% vs. 60-71%). Triplet induction was used in 83% (RVD in 73% of pts) and resulted in ≥VGPR status in 61%. CTX was associated with 26% incidence of complications including a 4% hospitalization rate. Blood/platelet transfusions were needed in 15 and 12% respectively in CTX group but < 3% in other groups. A median of 8 million/kg CD34 cells were collected across all groups. Apheresis was completed in 2 days in 89% of G+P group vs. 70-75% of pts in the other groups. MOB was successful in 99% of cases overall with only 10 pts needing remobilization. 33% of CTX MOBand 63% of P Rescue group needed P resulting in 66% overall P use. With 98% pts still alive,clinical results of ASCT are not mature. Conclusions: CTX MOB is less used in clinical practice in the US for MM while P use was 66% in this large prospective study. CTX MOB seems to be preferred in some centers in those with suboptimal induction responses but was associated with higher complication rate. Planned G+P approach resulted in the fastest time to goal and less apheresis sessions. These data should inform overallMOB decision-making in the era of increasing apheresis needs for cellular therapies. [Table: see text]
Clinicopathologic profile of extramedullary plasmacytoma in Central Valley.
Authors: Valliani Salimah , Barakat Mohamad , Gill Harinder , Okudo Jerome , Abdulhaq Haifaa , Bukari Mohammed SANI
Published: May 2020

e20551

Background: Extramedullary Plasmacytoma (EMP) occurs when neoplastic plasma cells cross the bone cortex to the surrounding soft tissue or spread hematogenously to other organs. The incidence rate of isolated plasmacytoma is reported to be 2-5% of plasma cell neoplasm. The skeletal system, head and neck are common organs involved. Our study evaluates the clinicopathologic characteristics of patients with EMP, with or without multiple myeloma (MM) in Central Valley, California. Methods: This is a retrospective review of 354 patients diagnosed with plasma cell dyscrasias, from January 2000 to January 2018. 33 patients had pathologically confirmed EMP and were evaluated for clinicopathologic data. Results: The incidence rate of EMP during the study period was 9%. Of the 33 patients diagnosed with EMP, 26 (78%) were associated with MM. The mean age at diagnosis was 62.6 years with no significant difference in mean age at diagnosis between patients with isolated EMP and EMP with MM (p = 0.23). Of the 33 patients, 11 (36.7%) were Hispanic, 11 (36.7%) were Caucasian whilst the rest constitute other minorities. This mirrored the 2010 population profile of the county. There are no statistically significant ethnic differences in the incidence of EMP with OR of 1.96 (p = 0.84). Compared to isolated EMP where aerodigestive system is most common site, bone with soft tissue (21%) is the most frequent site of involvement in EMP with MM [Table]. 9 (37%) patients were found to have IgG kappa as most common serum immunofixation finding in EMP with MM. FISH displayed high risk cytogenetics in 11 (45%) patients in the group. 91% of patients with EMP and MM were treated with chemotherapy alone or in combination with surgery or radiation. The median overall survival of patients with isolated EMP and EMP with MM was 46 months [95% CI: 11.2-80.9] and 55 months [95% CI: 16.3-93.7] respectively. Conclusions: The number of patients with isolated EMP is small for comparison with patients with EMP and MM. EMP occurs frequently with MM either at diagnosis or with disease progression. It tends to have high risk cytogenetics and may signify more aggressive disease. [Table: see text]
Comprehensive immune cell analysis from lung cancer patients with PD-1 inhibitor neoadjuvant immunotherapy using single cell sequencing.
Authors: Hui Zhenzhen , Zhang Jiali , Xiao Shanshan , Pu Yue , Lin Rui , Wang Tao , You Jian , Ren Xiubao
Published: May 2020

e21001

Background: Single-cell RNA sequencing (scRNA-seq) is a powerful tool to investigate the tumor microenvironment including infiltration of different types of immune cells. However, there is limited study utilizing scRNA-seq technology to investigate patient response to immunotherapy using a comprehensive set of samples. In this study, we used scRNA-seq approach to study tumor infiltrating immune cells in lung cancer patients receiving PD-1 inhibitor neoadjuvant immunotherapy. Methods: CD45 cells were collected from the tumor tissues, the adjacent normal tissues, peripheral blood, lymph nodes, and normal lung tissues for three lung cancer patients receiving PD-1 inhibitor neoadjuvant immunotherapy and four treatment naive lung cancer patients, followed by single cell library construction using 10x Genomics technology and sequenced on Illumina HiSeq X-Ten platform. CellRanger was used to generate expression matrices, and Seurat was used to identify cell subpopulations. Results: From a total of 62,970 single cells, we identified 23 clusters that belonged to different types of immune cells including myeloid cells, T cells, NK cells, mast cells, and B cells. Compared with the adjacent normal tissues, the tumor tissues had lower proportion of NK cells and higher percentage of B cells in all but one patient, and higher percentage of Treg cells for all the seven patients. We observed that patients treated with neoadjuvant immunotherapy had higher proportion of tumor-infiltrating T cells and lower percentage of myeloid cells compared with the treatment naive patients. Patients in the two groups showed differential gene expression in categories including leukocyte cell-cell adhesion, and cell-cycle arrest. Furthermore, the three patients undergoing immunotherapy had different response; the gene expression pattern for the patients differed in functional groups including regulation of inflammatory response, leukocyte migration, and regulation of immune effector process. These results support the potential application for scRNA-Seq in monitoring patient response to neoadjuvant immunotherapy. Conclusions: scRNA-Seq technology can detect the composition of tumor-infiltrating immune cells after neoadjuvant immunotherapy, which provides new tool for predicting the efficacy of treatment. We will next focus on the gene expression of tumor-infiltrating Treg cells and its effect on the therapeutic response.
Contribution of DNA damage repair gene mutations and concomitant TP53 variations to the efficacy of platinum-based chemotherapy as initial therapeutic option in Chinese NSCLC patients.
Authors: Ma Ke , Peng Jun , Zhang Huachuan , He Jintao , Xiao Bo , Zhu Jiang , Zhu Changbin , Rong Hao
Published: May 2020

e21002

Background: Though targeted, immune-, even combinational therapies have been applied widely, platinum-based chemotherapy still plays irreplaceable role as initial management for patient with either resected or advanced NSCLC without actionable target. Platinum is sought to increase DNA damage burden inducing cell death, especially in cells with intrinsic DNA damage repair (DDR) dysfunction. This study aims to explore impact of DDR genes as well as co-occurrence of TP53 mutations on prognosis of NSCLC patients. Methods: 110 NSCLC patients were consecutively recruited from 2016-2018. 508 cancer related genes were sequenced by BGI-seq 500. COX regression was used to evaluate risk of disease progression as well as cancer-related death among patients with various DDR/TP53 status. Results: 61 NSCLC patients with stage II-IV (median age of onset: 55 years) were recruited who received platinum-based therapy as adjuvant or 1st line systemic therapy. Till 15th.Oct.2019, median follow-up time was 24 months. 21 patients (34.4% of 61) carried DDR mutations. TP53 mutations were detected in 36 patients (59% of 61). 11 patients (18% of 61) displayed TP53/DDR co-mutations. COX regression analysis indicated NSCLC patients with DDR mutation would have lower risk of disease progression (HR:0.37, P = 0.19) as well as superior overall survival time (HR:0.35, P = 0.035). Patients with DDR co-mutations had no superior survival benefit. Patients with HRR mutations presented similar result. Patients with TP53 mutations had similar risk as ones with other mutations. While those with DDR concomitant mutations showed significantly improved clinical benefit (HR for PFS:0.28, P = 0.05; HR for OS:0.22, P = 0.023). Conclusions: DNA damage repair genes in Chinese NSCLC patients may play vital roles in predicting efficacy of platinum-based chemotherapy even in the context of TP53 co-mutation. Further, combination of BRCA2 and PALB2 may be better associated with patients’ prognosis. Large cohort should be set up to validate this finding in near future. [Table: see text]
The mutation frequency of HPD related genes in different lung cancer stages.
Authors: Wan Yanhui , Fang Fuyuan , Wu Guodong , Zhang Xing , Song Chao , Tian Minqi , Tang Jiyu
Published: May 2020

e21006

Background: Clinical detections of hyper-progressive disease (HPD) gene mutations in advanced lung cancer should be considered to avoid the inappropriate immunotherapy, and recently neoadjuvnat and adjuvant immunotherapy also proved to be efficacy in early stage of lung cancer. Nevertheless, it still remains poorly understanding of the distribution of HPD related mutations in early stage lung cancer. Methods: In this study, according to information of patient specimens from public database TCGA, Ⅰ and Ⅱ stages were defined as early stage, Ⅲ and Ⅳ stages were defined as advanced stage. The mutations in HPD related genes were evaluated including CNVs of CCND1, FGF19, FGF3, FGF4, MDM2 and MDM4, and SNVs of DNMT3A. Chi-square test was performed to analyze the differences of HPD related gene mutation frequency in early and advanced stages. Results: Based on the statistics of clinical data from TCGA, we found 399 early stage cases and 110 advanced stage cases in patients with lung adenocarcinoma (LUAD), 402 early stage cases and 91 advanced stage cases in patients with lung squamous cell carcinoma (LUSC). In early stage, we found 76, 76, 76, 75, 89, 201 cases of CNVs of CCND1, FGF19, FGF3, FGF4, MDM2 and MDM4, 10 cases of SNVs of DNMT3A, respectively. In advanced stage, we counted 32, 32, 32, 29, 21, 37 cases of CNVs of CCND1, FGF19, FGF3, FGF4, MDM2 and MDM4, 4 cases of SNVs of DNMT3A, respectively. No significant differences of mutation frequency HPD related gene between early and advanced stages were found via χ2 test. CNVs frequencies of CCND1, FGF19, FGF3, FGF4 and MDM4 in LUAD were significantly lower than them in LUSC. No significant differences of CNVs frequency of MDM2 and SNVs frequency of DNMT3A beween patients with LUAD and patients with LUSC were found. Conclusions: Our analysis indicated that immunotherapy for patients with early stage lung cancer also needed to test these mutations. LUSC patients required paying more attentions on HPD related mutations of which frequencies were significantly higher than LUAD patients. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
Management of bronchopulmonary carcinoid: NCDB database analysis.
Authors: Zhu Mojun , Fuentes Harry E , Westin Gustavo Figueiredo Marcondes , Sonbol Mohamad Bassam , Leventakos Konstantinos , Wigle Dennis A. , Jaroszewski Dawn E. , Molina Julian R. , Halfdanarson Thorvardur Ragnar
Published: May 2020

e21007

Background: There is a lack of data to guide the management of resectable bronchopulmonary carcinoid tumors (BCTs). Methods: The NCDB database was retrospectively reviewed to analyze the roles of surgery, chemotherapy and radiation. Patients with a diagnosis of clinically staged T1-2/N0-1 typical carcinoid (TC) and atypical carcinoid (AC) between 2004-2012 were included. Kaplan-Meier methods and multivariable analysis were performed. Results: A total of 2148 patients (TC 1874 & AC 274; T1/1648 & T2/500) were identified. The median age was 59 (range 18-89). There was a female (69.7%) and right lung (56.9%) predominance. Fifty-three patients received pneumonectomy, 68 chemotherapy, and 84 radiation therapy. The impact of age, histology (TC vs. AC), medical comorbidities (Charlson/Deyo score 0 vs. ≥1) and type of surgery [sublobar resection (SR) vs. lobectomy vs. lobectomy with mediastinal lymph node dissection (L/MLND)] were subsequently examined. AC, older age, and comorbidities were associated with shorter overall survival (OS) by both univariate and multivariable analysis. Patients who underwent lobectomy had longer OS (119 months) than those with SR (109 months) or L/MLND (115 months). However, this association was not significant by multivariable analysis with age incorporated as either a categorical ( < 60 vs. ≥60) or a continuous variable (Table). In the subgroup analysis of patients with T1, T2, TC and AC respectively, type of surgical resection was not significantly associated with OS by multivariable analysis. Conclusions: Patients with resectable BCTs have excellent OS. Atypical histology, older age, and comorbidities predicted inferior OS. There were insufficient data to support the use of perioperative chemotherapy or radiation therapy. Lobectomy was associated with prolonged OS by univariate analysis but this was not significant in the multivariable model, suggesting that SR is a reasonable approach for patients who cannot tolerate lobectomy. MLND did not seem to provide additional survival benefits. [Table: see text]
Stereotactic body radiation therapy (SBRT) in a developing country: Patterns of failure and response rates.
Authors: Przybysz Daniel
Published: May 2020

e21010

Background: Surgery remains the treatment of choice for early stage lung cancer. For patients without clinical conditions or those who refuse to this procedure, Stereotactic Body Radiation Therapy (SBRT) is the treatment of choice. It is important to understand the patterns of treatment response and toxicities within this practice. Therefore, we aim to analyze and review our data on lung SBRT for Non-Small Cell Lung Cancer (NSCLC) treated in our institution. Purpose: To describe response and toxicity patterns for NSCLC treatment with SBRT in a single third world country private institution. Methods: We retrospectively collected and analyzed data from patients treated at a single private institution in Rio de Janeiro between January 2017 and May 2019. Inclusion criteria were histopathological diagnosis of NSCLC, 18 years old or older, SBRT treatment, who were closely followed-up according to international guidelines. All data was analyzed and reviewed by the radiation oncologist and medical oncologist responsible, as well as kept in a reliable way for future comparisons. Results: 121 patients were analyzed. 77 were excluded. Only patients diagnosed with NSCLC from 2017 to 2019 who received SBRT as primary treatment. The average age was 74 (56-94). The highest prevalence among patients were females 68% (n = 30). 26 patients were smokers (59%), 4 non-smokers (9%) and 14 patients were not recorded in the medical records. Molecular assessment for non-smokers will not be described in this study. Adenocarcinoma was the most common subtype (77%, n = 35), 15% were squamous cell carcinoma subtype (n = 7), 4.4% poorly differentiated (n = 2). The patients were distributed between early stage lung cancer and metastatic disease - foreseeing oligometastatic disease being continuously treated as potentially curable. 11 patients are not classified in the medical record. Twelve patients had metastasis: central nervous system (33%), lung (41%), bone (8.3%) and patients with more than two metastases 16.6% (bone and CNS, bone and lung). Eleven patients had adjuvant chemotherapy (QT) 25%. Ten of the patients (22%) had toxicities, all with different doses and SBRT fractions. Among them, cough was the most prevalent (40%); nausea / vomiting and rash accounted for 30%; pneumonitis accounted for 17%; and mucositis in 10% of patients. Of the 44 patients, 7 died. Conclusions: The study data corroborates the worldwide published literature. SBRT in treating early stage lung cancer is a safe and effective treatment modality, with acceptable low-grade toxicities and high response rates.
Peripheral blood leukocytes-related early diagnosis for lung cancer.
Authors: Mei Qi , Li Jian , Cheng Weiting , Mansmann Ulrich Robert , Hu Guangyuan , Yuan Xianglin
Published: May 2020

e21020

Background: Early diagnosis of lung cancer is critically important to reduce disease severity and improve overall survival. For patients with suspicious lung lesions, a definitive diagnosis of malignant cancer currently requires surgical biopsy. Newer, minimally invasive biopsy procedures often fail to provide adequate specimens for accurate tumor subtyping or staging which is necessary to inform appropriate use of molecular targeted therapies and immune checkpoint inhibitors. Thus newer approaches to diagnosis and staging in early lung cancer are needed. Methods: In order to address this need, peripheral blood samples from 99 individuals with clinically evident pulmonary nodules (benign and malignant), as well as ten healthy persons, were obtained. Average RNA sequencing (RNAseq) data from these samples were integrated into an artificial intelligence (AI) model in order to perform a pathway flux analysis at the system level. The AI model utilized the biological knowledge derived from the literature and publicly available databases and possessed four layers with following relationship: (1) gene→ (2) RNA→ (3) protein/complex/compound → (4) pathway. The last layer (pathway) was connected back to the first layer (gene) via diverse feedback mechanisms. Based on these results, an immune index system, IM-Index, was defined and tested for early lung cancer diagnosis and staging. Results: The leukocyte-based IM-Index correctly identified the malignancy status of lung cancer patients with high accuracy (specificity 93.5%, sensitivity 70.5%), and was able to differentiate between the three accepted phases of the cancer immunoediting concept (i.e., elimination, equilibrium, escape) (odds ratio: 1.17 [95% CI: 1.1-1.25, p< 0.001). Further, the IM-Index clearly differentiated between adenocarcinoma and squamous cell carcinoma (OR: 1.2 [95% CI 1.14-1.35, p = 0.019]). In addition, tumor- and host-specific signaling pathways and metabolic profiles were identified that fully distinguished between tumor and host immunity (p < 0.05). Conclusions: Taken together, these findings suggest that our rapid, non-invasive peripheral blood leukocyte-based AI approach may be useful for early definitive cancer diagnosis and staging.
Correlation of gene expression profile to identify tumors with extreme sensitivity to the alkylating agent LP184.
Authors: Kathad Umesh , Kulkarni Aditya , Bhatia Kishor , Barnhart Kerry , Sharma Panna
Published: May 2020

e21021

Background: Lantern Pharma is advancing LP184, a next generation alkylating acylfulvene class prodrug. LP184 damages DNA that is subject to preferential repair by Transcription-Coupled Nucleotide Excision Repair. LP184 efficacy in 35 cell lines from solid tumor origin with known transcriptomic profiles identifies gene expression patterns that strongly correlate with response in cell lines. This gene expression profile allows the interrogation of clinical transcriptomics datasets to identify tumors that would potentially be highly responsive to LP184. Methods: LP184 cytotoxicity in cell lines was tested in a concentration range from 14 nM to 10 uM. Cell viability readout using CellTiter Fluor reagent was measured 72h post drug addition, and IC50 value was generated using GraphPad Prism. Bioinformatic analyses were run using the Morpheus tool from the Broad Institute. CCLE microarray expression data were used for gene signature findings and TCGA patient data were used for gene signature validation. Results: LP184 showed broad anti-tumor cytotoxicity in solid tumor cell lines including liver, NSCLC, prostate, ovarian, kidney and thyroid cancers (median IC50: 358.9 nM). Across this spectrum, LP184 sensitivity was found to be most highly correlated with high transcript levels of PTGR1, and with low transcript levels of KDM4A. Analysis of top 10 sensitive cell lines showed that NSCLC cell lines had the highest representation (5 of 10). Differential sensitivity and gene expression pattern analyses on NSCLC cell lines correlated with high relative expression of PTGR1, CASP6, NAMPT, SMARCD3 and GLRX genes along with low relative expression of KMD4A, HPGD, PTPRF and KRT14 genes in the highly sensitive cell lines. The oxidoreductase activity of PTGR1 is likely involved in bioactivation of LP184 and CASP6 mediates drug-induced apoptosis. HPGD acts upstream of PTGR1 in the prostaglandin metabolism pathway in turn modulating the turnover of endogenous PTGR1 substrate. Assessing relative expression of these genes in selected clinical NSCLC data indicates that around 37% of such tumors would potentially respond with high sensitivity to LP184. Conclusions: Overall, LP184 is a novel alkylating agent with nanomolar potency in solid tumor cell lines, especially NSCLC, and can serve as a molecularly guided therapy option in multiple tumors. The correlated genes KDM4A/ HPGD that impart high sensitivity at low expression levels, suggest potential synergistic combinations of their respective inhibitors in development PKF118-310/ ML147 with LP184.
The impact of estrogen receptor status on EGFR/TP53/CTNNB1 axis in the evolution of non-small cell lung cancer.
Authors: Tani Yoko , Koh Yasuhiro , Tamiya Akihiro , Isa Shun-ichi , Kubo Akihito , Ando Masahiko , Saka Hideo , Izumi Motohiro , Ogawa Koichi , Matsumoto Yoshiya , Sawa Kenji , Yoshimoto Naoki , Suzumura Tomohiro , Watanabe Tetsuya , Kaneda Hiroyasu , Mitsuoka Shigeki , Asai Kazuhisa , Kawaguchi Tomoya
Published: May 2020

e21035

Background: The role of estrogen receptor status in the carcinogenesis of lung cancer remains elusive. A census of clonal and sub-clonal mutations has been defined through the analyses of evolutionary histories of cancers. We previously reported a prospective multicenter molecular epidemiology study (JME study; Kawaguchi T, J Clin Oncol 2016), which included the expression levels of estrogen receptors β (ER) using immunohistochemistry(IHC) and the mutational profile using next generation sequencing as well as solid smoking information and reproductive/ hormonal risk factors from the detailed questionnaire. Methods: Utilizing the data of the JME study, the impact of ER in lung cancer development was explored. All the patients underwent surgery. In 441 ever- and 435 never-smokers, ER were observed in 46.4% and 53.5%, respectively. The cancer-associated 72 gene mutations and 5 gene amplifications examined in this study included EGFR, SMAD4, APC, FBXW7, BRAF, STK11, PIK3CA, TP53, PTEN, KRAS, CTNNB1, NFE2L2, NF1, and MET. ALK fusion was detected by IHC. Patients were enrolled between July 2012 and December 2013, with follow up until November 30th, 2017.Cox proportional hazards models were used to assess the ER expression on relapse free survival (RFS) and overall survival (OS). A logistic regression model was applied to assess the impact of ER (positive vs. negative) on gene alterations, using sex, smoking history, age and stage as independent variables. Results: ER expression was significantly higher in never smokers (vs. ever smokers; p = 0.022) and earlier stage (stage I vs. II-IV; p = 0.002). Patients with ER positive tumors had a longer RFS than those with negative tumors (RFS rate at 4 years: 33.7 vs. 26.5%; p = 0.021), however, there was no significant difference in OS between the two groups (p = 0.108). In the impact of ER status on the gene alterations, mutations in EGFR (p = 0.003), TP53 (p = 0.007) and CTNNB1 (p = 0.027) were significantly associated with ER expression. Multivariate analysis showed that EGFR mutations (OR = 1.394, 95%CI: 1.029-1.890, p = 0.032) and CTNNB1 mutations (OR = 0.272, 95%CI: 0.087-0.853, p = 0.026) were significantly associated with ER expression, while there was a trend for significance with TP53 mutations (OR = 0.737, 95%CI: 0.537-1.011, p = 0.059). Conclusions: ER positive status triggered the clonal EGFR mutations and suppressed the sub-clonal mutations of TP53 and CTNNB1. It is suggested that ER plays a critical role in the alterations of EGFR/TP53/ CTNNB1 axis in lung cancer evolution.
Deciphering molecular characters of multiple lung lesion using comprehensive genomic profiling and its association of histology.
Authors: Zhu Changbin , Qiu Yuan , Deng Qiuhua , Yang Haihong , Chen Hanzhang , Liu Liping , Xiao Dakai , Shao Di , Li Weiwei , Jiang Wenxi , Lin Yongping , He Jianxing
Published: May 2020

e21051

Background: Differentiating multiple pulmonary lesions as multiple primary lung cancer (MLC) or intra-pulmonary metastasis (IPM) is critical for clinics. Radiological or histological (dis)concordance may be informative, while, genetic information may aid tracing lineage information on multiple lung lesions. This study aims to apply comprehensive genomic profiling deciphering intrinsic genetics of multiple lung lesions. Methods: 32 patients, 69 FFPE samples were applied to perform high-through put sequencing. 636 cancer-related genes were captured and sequenced by MGI-seq 2000. Raw data was processed via in-house developed pipeline. Unsupervised clustering was applied to cluster samples based on genetic characters after variant calling and annotation. Patients were categorized into “Genomic related” and “Genomic unrelated” groups. Another cohort consisting of 402 patients with mono-lesion was used as control cohort. Results: No difference of age of onset was found between 32 patients and 403 patients with mono lesion (60.5 versus 60 years). Male had relatively lower incidence of multiple lung lesions (RR:0.46,95%CI: 0.20-0.93, P = 0.04). Eight patients were classified as “Genomic related” by presenting same mutation in driver or tumor suppressor genes. Six of eight patients were characterized to carry EGFR L858R, in addition, two patients presented co-mutation of RB1(c.1814+1G > T, p.E48Kfs*18) and TP53 mutations (p.H193R, p.R249S). Another two patients carried EGFR 19 Deletion. Two lesions from one patient with predefined diagnosis of intra-pulmonary metastasis showed biallelic loss of function mutations in same loci of NF1 gene (p.S2311*/ p.Q1360*) together with same KRAS mutation (p.G13C). Radiologically, no same lobe as well as left-right preference were revealed between “Genomic related” and “Genomic unrelated” groups. Histologically, there was no enrichment of patients with same histology subtype in “genomic related” group, verse visa. While, patients in “genomic related” group had higher ages at initial diagnosis (median age 69.5 vs 56.5 years, P = 0.04). Conclusions: Comprehensive genomic profiling should be applied to clinics distinguishing the nature of multiple lung lesion irrespective of radiological and histological diagnosis. [Table: see text]
Salvage radiotherapy after chemotherapy for unresectable locally advanced non-small cell lung cancer in real world.
Authors: Xu Qinghua , Hu Min , Yuan Xiaoshuai , Li Fangjuan , Liu Hui , Xu Yaping
Published: May 2020

e21052

Background: For patients with unresectable stage III disease, combined modality therapy (chemoradiation) is superior to radiation alone, and concurrent chemoradiotherapy (CCRT) is superior to sequential chemoradiotherapy (SCRT). The current standard of care for unresectable stage III disease is CCRT. Consequently, CCRT is commonly given to patients with minimal or no comorbidities, a good general condition, and who are relatively young. SCRT may be a valuable alternative for patients who are not eligible for CCRT. However, the role of salvage radiotherapy (SRT) after chemotherapy for patients with unresectable stage III disease without CCRT or SCRT is currently unknown. Methods: Patients with unresectable stage III disease receiving chemoradiotherapy were enrolled. All patients were treated with CCRT, SCRT or SRT. Overall survival (OS) was estimated by Kaplan-Meier curves. Results: From May 2014 to September 2018, 216 patients were enrolled, including 65 (30.1%) who received CCRT, 80 (37.0%) who received SCRT, and 71 (32.9%) who received SRT. No significant difference in gender, age, performance status, TNM stage, or EGFR gene status among the three groups. The median OS for the entire cohort was 22.1 (range: 18.4–25.8) months. The median OS in CCRT, SCRT, and SRT group were 29.7, 21.3, and 19.1 months, respectively (P = 0.011). The difference was statistically significant between CCRT group and SCRT or SRT group but was not between SCRT and SRT group. The 1-year survival rate in CCRT, SCRT, and SRT group were 89.2%, 75.0%, and 75.2%, respectively. However, the 3-year survival rate in CCRT, SCRT, and SRT group were 42.7%, 32.7%, and 9.6%, respectively. However, CCRT also has a higher rate of Grade 3 or 4 acute esophagitis and pneumonitis . Conclusions: The current study demonstrated compared with CCRT and SCRT, SRT had reduced patient survival survival time significantly.
The genomic landscape of immune-related genes and its correlations with TMB and PD-L1 expression in Chinese NSCLC.
Authors: Zheng Linxin , Li Weifeng , Xie Wenzhuan , Huang Mengli
Published: May 2020

e21056

Background: Understanding the genomic landscape of immune-related genes (IRGs) of patient with Non-Small Cell Lung Carcinoma (NSCLC) may provide critical insight and facilitate development of novel strategies for cancer therapy. Methods: Targeted next generation sequencing (NGS) was performed on tissue obtained from patients with NSCLC using a 381-gene panel. The IRGs were mainly based on a published article that summarized the genes related to activated T cells, immune cytolytic activity and IFN-γ release. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations (CNV) and gene fusions were assessed. Mutational profiles of IRGs and its correlations with Tumor mutation burden (TMB) and PD-L1 expression in NSCLC patients were analyzed from the 3D Medicine database. Results: Genomic data of 2,510 patients with NSCLC were analyzed via tissue detection [median age 62 years, (IQR: 54 - 69 years)]. 4.26% (107 / 2,510) of the patients had at least one characterized altered IRGs. The most frequently mutated IRGs identified for all genomic alternations occurred in PDCD1LG2 (40%), FAS (27%), LCK (23%), CD274 (21%), CD74 (3%), and missense mutations were the mainly mutant types of PDCD1LG2 and LCK, and copy number gains were showed in PDCD1LG2 and CD274. TMB levels in NSCLC patients with IRGs mutations were higher than in wild-type patients (mean TMB: 14.17 mut/MB vs 9.27 mut/MB, P < 0.001). 65.42% (70/107, 9.35% for PD-L1 > = 1% and < 5%, 28.97% for PD-L1 > = 5% and < 50%, 27.10% for PD-L1 > = 50%) of patients harboring PD-L1-positive ( > = 1%), and the proportion of patients with mutations in IRGs does not exceed 10% in each subgroup. Results of Pearson Chi-square test showed that the PD-L1 expression had different between two groups ( Χ2 = 13.3774, P = 0.0038), patients harboring IRGs mutation had a significantly higher level of PD-L1 than those wide-type patients (P = 0.001). Conclusions: Genomic landscape of IRGs significantly correlated with that of PD-L1 expression. Further analyses using more precisely IRGs and different stage NSCLC samples are requisite to support a role for IRGs as an target to immune therapy of cancers.
Study of immune regulatory receptor expression upon combination of chemotherapy and immune checkpoint blockade in a murine lung cancer model.
Authors: Ho James C. M. , Yan Sheng , Lam Sze Kwan
Published: May 2020

e21083

Background: Blockade of inhibitory immune checkpoints namely the programmed cell death protein 1 (PD-1) and the PD-1 ligand (PD-L1) achieved remarkable clinical outcomes in multiple malignant diseases including lung cancer. However, as the dynamic interactions between the cancer cells and the tumor-associated microenvironment evolves, acquired resistance arises. Thus exploration on alternative strategies would be necessary in order to reach long-term tumor suppression. Methods: Murine lung cancer model was established by inoculation of Lewis lung carcinoma cells subcutaneously on the flank of C57BL/6J mice. Chemotherapy (cisplatin or pemetrexed) or anti-PD-1 alone, or in combination started at 7 days post-inoculation as tumor growth was established. Digital caliper was used to measure tumor sizes and survival rates were recorded. Mice were sacrificed upon humane endpoint (tumor size > 17 mm in diameter). Splenocytes and tumor cells were harvested and expression of immune regulatory markers (including PD-L1, PD-1, Tim-3, OX-40, GITR, LAG-3 and CTLA-4) was analyzed by flow cytometry. Results: While PD-1 blockade delayed tumor growth ( p< 0.001), there was no significant difference in overall survival. Systemically, anti-PD-1 immunotherapy induced upregulation of Tim-3, OX-40 and GITR; cisplatin alone and in combination with anti-PD-1 induced upregulation of GITR; OX-40 is upregulated in combinations of chemotherapy and anti-PD-1. Population of tumor-infiltrating T cells were increased in anti-PD-1-treated mice, while combination of pemetrexed and anti-PD-1 prompted augmented expression of co-stimulatory receptors including GITR and OX-40 within tumor. Conclusions: Cisplatin and pemetrexed triggered different systematic and intratumoral immune responses when used alone or in combination with anti-PD-1 treatment. Increased expression of co-stimulatory receptors in the tumor in response to combination therapy provide insights for investigation of synergism on anti-PD-1 and alternative therapeutic targets.
Developing post-treatment PET/CT volumetric prognostic index for non-small cell lung cancer.
Authors: Liu Liu , Zhang Jingmian , Ferguson Mark K. , Appelbaum Daniel E. , Pu Yonglin
Published: May 2020

e21085

Background: The aim of this study is to model and validate a post-treatment PET/CT volumetric prognostic (ptPVP) index for risk assessment after definitive therapy for NSCLC. Methods: This IRB-approved retrospective cohort study included 1028 NSCLC patients diagnosed between 2004 and 2017. Variables included: pre-treatment whole-body metabolic tumor volume (MTVwb) measured on baseline FDG PET/CT, patient age, clinical TNM stage, ECOG performance status (PS), gender, tumor histology, treatment type, and survival outcomes. Patients were assigned to a modeling cohort (531 patients) for modeling ptPVP index and a clinical index with a multivariate Cox regression model. The ptPVP index was validated with a separate validation cohort (497 patients) by comparing the prognostic value of ptPVP index against its individual independent variables and the clinical index. Results: The ptPVP index generated from the modeling cohort was comprised of 5 variables including treatment type (surgery, no surgery, and no therapy), age, clinical TNM stage (stage I or II, III, and IV), PS ( 0, 1, and ≥ 2) and MTVwb. The clinical index was comprised of above 4 clinical variables without MTVwb. Univariate Cox models showed significant association of the ptPVP index with OS with Hazard ratio (HR) of 2.72 (95% CI = 2.39-3.09, p < 0.001). The C-statistic of ptPVP index (0.71) was significantly greater than that of clinical index (0.68) (p = 0.001). In the validation cohort, univariate Cox models showed significant association of the ptPVP index with OS (HR = 3.09, 95% CI = 2.64-3.61, p < 0.001). The ptPVP index showed greater prognostic power (C-statistic = 0.72) than that of the clinical index (C-statistic = 0.70, p = 0.001), treatment type (C-statistic = 0.66, p < 0.001), MTVwb (C-statistic = 0.67, p < 0.001), age (C-statistic = 0.58, p < 0.001), clinical 9-group TNM staging (C-statistic = 0.66, p < 0.001), and PS (C-statistic = 0.57, p < 0.001). Multivariate Cox regression analysis demonstrated a significant association of ptPVP index with OS (HR = 3.06, 95% CI of 2.60-3.61, p < 0.001) after adjusting gender and NSCLC histology. A better separation of Kaplan-Meier curves of patients grouped by ptPVP index than those grouped by clinical index, MTVwb, or clinical TNM stage was evident. Conclusions: The ptPVP index developed for NSCLC patients demonstrated moderately prognostic power and better prognostic ability than its individual independent variables and clinical index without MTVwb. It provides a practical quantitative risk assessment for the patient follow-up and management after initial treatment.
Role of the total mutation burden (TMB) and tumor-infiltrating lymphocytes (TILs) on the development of second primary cancer after complete resection of non-small cell lung cancer (NSCLC).
Authors: Gauthier Marie-Pier , Karimi Maryam , Michiels Stefan , Seymour Lesley , Brambilla Elisabeth , Le Chevalier Thierry , Soria Jean-Charles , Kratzke Robert Arthur , Graziano Stephen L. , Govindan Ramaswamy , Tsao Ming-Sound , Shepherd Frances A.
Published: May 2020

e21092

Background: Risk of developing SPC after complete surgical resection of NSCLC has been reported to be 3-6% per person-year. We hypothesized that genomic instability, as assessed by high TMB, and the absence of TILs in the primary tumor might be associated with SPC. Methods: The LACE [Lung Adjuvant Cisplatin Evaluation])-BIO database was used, which includes 3 randomized trials. TMB and TILs were analyzed on FFPE specimens. TMB was categorized into tertiles (high > 7.8 mutations/MB, moderate i.e. > 4 and < = 7.8, low < 4) and TILs as marked vs. other. Associations on competing time-to-event endpoints (SPC, and death without developing SPC) were evaluated using the Fine and Gray model stratified by trail and adjusted on treatment, age, gender, tumor stage, nodal stage, histology, performance status and surgery type. Results: TMB and TILs assessments were available for 879 patients without missing clinical covariates; 85 patients had marked TILs. During follow-up, 47 SPCs had been observed and 392 deaths without developing SPC. Regarding TMB, a significant association was found between low TMB and death without SPC (sub-distribution hazard ratio SHR = 1.36(1.06-1.74), see Table), suggesting a higher risk of death without SPC among patient with low TMB compared to those with moderate TMB; no strong effect was observed for SPC. Regarding TILs, a trend was observed between marked TILS and a lower risk of death (SHR = 0.70 [0.47-1.04]) but to a lesser extent for SPC (SHR = 0.80 [0.28-2.28]). Conclusions: This is the first study of the effect of genomic instability (measured by TMB) and host immune response (measured by TILs) in completely resected NSCLC on competing events of SPC and death, suggesting associations between TMB, TILs and death-without-SPC . There was no statistically significant association with SPC. However, the number of SPCs was small; these findings requires validation in other early stage lung cancer cohorts. [Table: see text]