bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutropenia and neutropenic fever with polatuzumab vedotin for diffuse large B-cell lymphoma: Meta-analysis of randomized clinical trials.
Authors: Gupta Varsha , Singh Vinit , Khalid Farhan , Eltoukhy Hussam , Meghal Trishala
Published: June 2022

e19576

Background: Polatuzumab vedotin (POLA) is an antibody–drug conjugate composed of an anti-CD79b monoclonal antibody conjugated by a protease-cleavable linker to monomethyl auristatin E, a microtubule inhibitor. POLA has shown efficacy in patients with relapsed or refractory Diffuse large B-Cell lymphoma (DLBCL) and recently shown better progression free survival in previously untreated DLBCL as well. We conducted a meta-analysis of randomized controlled trials (RCTs) to determine the relative risk of neutropenia and febrile neutropenia associated with use of POLA regimens for DLBCL. Methods: We conducted a systematic search at PUBMED, EMBASE, and meeting abstracts as per PRISMA guidelines from 2010 until December 2021. Randomized controlled trial utilizing POLA for DLBCL were included. We used the Mantel-Haenszel (MH) method utilizing random effects model to calculate pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value. All statistical analyses were performed with Review Manager Version 5.4. Results: A total of 1073 patients from 3 RCT (1 Phase III and 2 Phase II Studies) were included in this study. The study arm used POLA-R-CHP (Rituximab, Cyclophosphamide, Doxorubicin, Prednisone), POLA-Rituximab, and POLA-BR (Bendamustine-Rituximab). The control arm used R-CHOP, Pinatuzumab-R, and BR respectively The overall incidence of neutropenia was 31.54% in POLA Group vs 32.94% in control group with RR 0.99 (95% CI: 0.69 – 1.42, P=0.97, I2=16%) whereas grade 3-4 neutropenia incidence was 29.24 vs 30.82 with RR 0.95 (95% CI: 0.79 – 1.16, P=0.65, I2=2%). The overall febrile neutropenia incidence was 12.87% in Polatuzumab group vs 7.90% in the control group with RR 1.62 (95% CI: 1.12 – 2.35, P = 0.01, I2=0%). Conclusions: Our study demonstrated that there was no statistical difference in risk ratio of any grade neutropenia (including grade 3-4) in both the arms. However, there was significantly increased risk of febrile neutropenia among patients who received Polatuzumab vedotin based treatment compared to those who did not. Further studies and long term follow up are necessary to define the actual relation and definitive incidence.[Table: see text]
Geographic disparity between patients with multiple myeloma (non-Whites and Whites).
Authors: Cheung Christian S. , Sweeney Nathan W. , Molina Thomas H. , Ahlstrom Jennifer M.
Published: June 2022

e20003

Background: People that live in rural areas experience significant health disparities from higher incidences of disease and disability, increased mortality rates, and lower life expectancies. Rural risk factors for health disparities include geographic isolation, lower socioeconomic status, limited access to healthcare specialists and sub-specialists, and limited job opportunities. Interestingly, we often see other, non-white, races experience delays in care, are under-treated, and lack of access to MM specialists. We, therefore, investigated whether there was a relationship between race and where one lives geographically. Methods: Validated real-world (RW) MM patient data was collected through HealthTree Cure Hub for Multiple Myeloma (healthtree.org). We examined the patient’s race which was either Caucasian American (White) or any other race (Black American, Asian, American Indian, East Indian, Middle Eastern, or Native Hawaiian) which was categorized as “non-White” and where they lived geographically (Rural, Urbanized Cluster, or Urban Areas). The association between race and geographic classification was compared by using a chi-squared test. Results: In this retrospective analysis of 2,687 MM patients, we compared the geographical classification of Whites (n = 2403) and non-Whites (n = 284). Our analysis revealed a significant association between the two groups and where they lived with a chi-square value of 20.455 (2, n = 2,687, p < 0.001). We found that Whites are 1.9 times more likely to live in urbanized cluster areas and 2.7 times more likely to live in a rural area compared to non-Whites. Conclusions: The results of this RW analysis identified a disparity among races and where one lives geographically. While there is strong evidence of health disparities our findings revealed that where one lives geographically is not a probable reason why non-Whites experience delays in care, are under-treated, or lack access to MM specialists.
Smoldering multiple myeloma progression to multiple myeloma in a community-based population.
Authors: Fatoki Raleigh Ayoolu , Carpenter Diane M. , Ramalingam Nirmala D. , Khan Adnan Ahmed , Nair Bijay P. , Stevenson Ryan Lloyd , Green Michael M. , Lo Joan C. , Baer David M.
Published: June 2022

e20015

Background: Few studies have characterized patients with smoldering multiple myeloma (SMM) in ethnically diverse settings and data regarding progression to multiple myeloma (MM) in real-world clinical populations is limited. Using data from a large healthcare system, we examined a contemporary cohort of adults with confirmed SMM and their progression to MM. Methods: We conducted a retrospective cohort study of SMM cases from 2010-2017 in Kaiser Permanente Northern California (KPNC). We used the KPNC SEER-based Cancer Registry to identify potential SMM cases by ascertaining MM cases with either: 1) “asymptomatic, evolving, or smoldering myeloma” status in the Cancer Registry or 2) mention of “smoldering” in clinical records. Chart review was conducted for potential SMM cases and confirmed SMM status was assigned using the 2014 IMWG criteria. SMM cases were followed for progression to MM and myeloma-directed therapy, excluding those with KPNC membership <1 year after diagnosis. Time to MM progression (or treatment) was examined. SMM cases were classified during follow-up as: a) SMM, no progression to MM (and no receipt of myeloma-directed therapy); b) SMM, progression to MM (and receipt of myeloma-directed therapy); and c) SMM, receipt of myeloma-directed therapy without frank progression to MM (follow-up was censored at treatment). Results: During 2010-2017, we identified 152 adults with confirmed SMM. The median age at diagnosis was 71 years (IQR, 62-78), 56% were male, and 55% were non-Hispanic White, 17% Black, 9% Hispanic, and 18% Asian. During follow-up, 28% of patients progressed to MM, with a median time to progression of 1.2 years (IQR 0.8-2.0). Over half (58%) did not progress during a median follow-up time of 3.4 years, and an additional 14% received treatment before a MM-defining event. Progression data by demographic group is shown in Table. Conclusions: This is one of the first studies to examine SMM progression in an ethnically diverse cohort using the 2014 IMWG criteria. Although follow-up time was limited, we found that over half of the identified SMM cases did not progress to MM. However, patients who did progress to MM generally required treatment within 2 years of SMM diagnosis. These findings support efforts to identify high-risk patients with SMM who may benefit from early initiation of therapy. [Table: see text]
Using electronic health records to derive a synthetic control arm for a historical trial on relapsed/refractory multiple myeloma.
Authors: Bisquera Alessandra , Wallis Jamie , Valencia Ray , Ruau David , Scott-Ram Nicholas , Carpenter Lewis
Published: June 2022

e20025

Background: It is increasingly challenging and ethically questionable to recruit patients on control arms when a vast body of information is readily available through electronic health records (EHR). Synthetic Control Arms (SCA) may reduce the time and cost of running a trial, and ultimately alleviate patient burden. This study explores the potential of SCAs derived from EHR to provide additional support for trials investigating treatment efficacy in multiple myeloma (MM). Methods: De-identified EHR from a UK NHS trust were matched with patients from a historical, Phase III randomised control trial investigating the efficacy of elotuzumab therapy in combination with lenalidomide and low-dose dexamethasone in relapsed/refractory MM (ClinicalTrials.gov Identifier: NCT01239797). Trial specific eligibility criteria were applied to the EHR dataset to derive 94 patients for the SCA. The primary outcome was progression free survival (PFS), as defined by the International Myeloma Working Group based on relative and absolute changes in serum M protein or kappa/lambda free light chain assay. The observation period was defined as time from randomisation (Trial) or treatment initiation (SCA) to death or disease progression. Results: In the SCA, the median age was 72 years [range 41, 93], 44% female, 76% white ethnicity, between 1 to 3 prior therapies, and between 0 to 6.3 years since diagnosis. This is in comparison to the trial control arm (n = 325) with a median age of 66 years [range 38, 91], 41% female, 86% white ethnicity, 1 to 4 prior therapies, and 0 to 16.2 years since diagnosis. Median PFS in the SCA was 14.4 months (95% Confidence Interval (CI) 9.5, 22.2), compared to 14.9 months (95% CI 12.1, 17.2) in the trial control arm. The hazards of progression or death in the trial treatment arm (when compared to trial control) was 0.70 (95% CI 0.57, 0.85) and 0.71 (95% CI 0.54, 0.95) when compared to the SCA. Additional sensitivity analysis using Multiple Imputation of missing ECOG values in the SCA yielded similar results, with a median PFS of 16.5 months (95% CI 10.4, 24.0) and hazards that is 0.77 (95% CI 0.57, 1.05) lower in the treatment arm. Conclusions: These results show that SCA can generate valuable additional evidence of efficacy supporting regulatory submission with considerable benefits in term of budget and time. Future work on SCAs aim to further refine the precision of estimates by applying the best performing confounder adjustment techniques.
A systematic review on smoldering multiple myeloma: Whether treatment is beneficial.
Authors: Sathe Sanjivani , Selene Insija Ilyas , Jose Jemin , Adhikari Biplov , Waqar Syed Hamza Bin , Shah Zunairah , Haider Mobeen Zaka , Anwer Faiz
Published: June 2022

e20029

Background: Smoldering multiple myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells. There are multiple early intervention strategies investigated in the last ten years, including single v/s combination therapy, which can either delay progression or be used as an aggressive therapy to cure SMM. This study aims to summarize the reported outcomes of interventions in SMM within the past decade. Methods: We performed a literature search following PRISMA guidelines and used the following bibliographic databases: PUBMED, EMBASE, Cochrane Library, Web of Science, and clinical trials.gov. A total of 1474 articles were found from the above-mentioned databases and a total of seven articles were included in the final analysis. Results: Seven clinical trials were finalized, which included 599 patients, gender was specified in five studies and constituted 51 percent female patients, and the remaining were males. The median age of patients ranges from 61 (21-89) years. In progression evaluation, four studies, 440 patients were considered. However, significant heterogeneity existed with treatments and the survival analysis hence cumulative PFS was not obtained. PFS greater than 90% was obtained in two studies; 95.5% was obtained with Carfilzomib (K), lenalidomide (R), and dexamethasone(d) regimen after a follow-up period of 31.9 months. PFS of 91% was obtained with Lenalidomide alone for a follow-up of 35 months. Three studies, including 200 patients, were evaluated for response rate. MRD negative CR of 70.4% was obtained with the use of the KRd regimen. Overall response (ORR) of intense and intermediate use of Daratumumab showed a rate of 56.7% and 53.1%, while the complete response in the respective arms was 4.9% and 9.8%. CR, stringent CR of 17.4% and 4.3% was obtained with the use of Isatuximab with Lenalidomide. Conclusions: No definite conclusion can be made due to variability in the data. However, based on the data analyzed from the seven clinical trials, we advocate for early therapeutic intervention in high-risk SMM patients. There are multiple ongoing clinical trials to answer whether we should treat SMM or not.[Table: see text]
Retrospective analysis of vaccine antibody titers in patients with different stages of monoclonal plasma cell disorders.
Authors: Taneja Alankrita , Parker Sarah , Ba Aqeel Sheeba Habeeb , Attwood Kristopher , Hillengass Jens
Published: June 2022

e20031

Background: Infections occur with up to twofold increased risk in patients with monoclonal gammopathy of undetermined significance (MGUS) and tenfold increased risk in multiple myeloma (MM). To reduce risk, revaccination following autologous hematopoietic cell transplantation (AHCT) is recommended to restore humoral immunity. We have previously shown that vaccine titers after AHCT have prognostic significance. In the COVID era, reliable clinical data about antibody titers is relevant yet scarce. We investigated the significance of different vaccine titers in newly diagnosed patients in different stages of the disease. Methods: The study population comprised of 77 patients with MGUS, smoldering multiple myeloma (SMM) and MM who were seen at a tertiary cancer center from 2018-2022. All patients had antibody titers (B. pertussis, Diptheria, H. Influenzae B, Hepatitis, Influenza, Meningitis, Mumps, Rubeola, Rubella, Poliovirus, S. pneumoniae, Varicella Zoster and Tetanus) tested at the time of diagnosis, prior to start of treatment if indicated. Titers were interpreted in accordance with the manufacturers’ recommendations. Patient characteristics were compared using the Kruskal-Wallis and Fisher’s exact tests. Associations with % titer positivity were evaluated using the Kruskal-Wallis test. Results: There was significant difference in antibody titer positivity between the different patient groups (51.4% in MGUS, 40.5% in SMM and 34.2% in MM) (p < 0.001). There was no difference in antibody titer positivity depending on age, sex or race. Among individual pathogens, there was a significant difference between the three groups in regards to titers for Diphtheria, Mumps, Poliovirus 3, Strep pneumoniae 19, Strep pneumoniae 56 and Varicella Zoster. Conclusions: Antibody titers for vaccine preventable diseases are significantly different between patients with MGUS, SMM and MM at the time of diagnosis, with MGUS having the highest and MM having the lowest positivity. Patient related factors such as age, sex or race were not associated with antibody titer positivity. Current guidelines for revaccination are not extended to patients with MGUS and SMM and can be considered in prospective trials.[Table: see text]
Extended neoadjuvant therapy in NSCLC achieved remarkable pathological complete response (pCR) rate and prolonged disease-free survival.
Authors: Fan Zhaohui , Wang Xiaojunn , Xu Youtao , Li Si , Chen Dong-sheng , Xiao Mingzhe
Published: June 2022

e20500

Background: Over 50% early stage NSCLC patients would suffer from recurrence and distant metastasis. Neoadjuvant TKI therapy had been explored aiming to reduce recurrence and metastasis. Erlotinib neoadjuvant therapy (NAT) significantly improved ORR, PFS and major pathologic response (MPR) rate in trial EMERGING/CTONG1103. In our hospital, some patients received extended neoadjuvant treatment because of continued lesion remission. These patients eventually received surgery when the lesions stopped remission and achieved remarkable pathologically complete remission (pCR) rate. Herein we analyzed the efficacy of extended NAT. Methods: 9 NSCLC patients who received extended neoadjuvant therapy in Department of Thoracic Surgery, Jiangsu Cancer Hospital from 2013-2020 were enrolled in this study. Extended neoadjuvant therapy was defined as duration of treatment longer than standard regimens (for TKI, longer than 42 days; for chemotherapy, longer than 2 cycles or 6 weeks). Pathological complete response, progression free survival (PFS), overall survival (OS) were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Standard statistical methods, including descriptive statistics, x2 test, two-sided 95% CI were used. Results: Up to 9 patients were enrolled in this study. There were 5 patients in TKI group, 1 (20%) was male and 4 (80%) were female. There were 4 patients in chemo group, 2 (50%) were male and 2 (50%) were female. The median age of TKI and chemotherapy groups were 59 (47-70) and 62 (30-75), respectively. The median duration of treatment (DOT) were 185 (163-248) and 82 (29-98) days, respectively. Among TKI group, 4 patients were EGFR L858R positive and 1 was ALK rearrangement positive and they all received relative TKI treatment based on genetic feature. In the TKI group, all 5 patients achieved pCR, the pCR rate was 100%. In chemotherapy group, 1 out of 4 patients achieved pCR and the other 3 achieved major pathological response (MPR). The pCR rate was 25% and MPR rate was 100%. The pCR rate of TKI group was significantly higher than chemotherapy group (100% vs 25%, p < 0.01). The pCR rate or MPR rate was higher than historical data. For instance, in trial CTONG 1103, neither TKI (Erlotininb) or chemotherapy (Gemcitabine) group achieved pCR, and the MPR rate was only 45% in TKI group and 51% in chemotherapy group. Extended NAT regimen in our study achieved much higher pCR rate (100% vs 0% for TKI and 25% vs 0% for chemotherapy) and MPR rate (100% vs 45%̃51%) than standard 42 days regimens used in CTONG-1103. Conclusions: Extended NAT resulted in better pCR rate and MPR rate than the standard 42-days duration of NAT. For patients with good response to TKI in the neoadjuvant stage, extending the duration neoadjuvant TKI treatment until lesions stopped remission might result in better pCR rate and might extend PFS and OS.
Economic evaluations of adjunctive osimertinib treatment in surgically resected epidermal growth factor receptor-positive (EGFR+) non-small cell lung cancer (NSCLC): Analysis for stage 2 disease.
Authors: Choi Briana M , Aqel Osama , Abraham Rachel B , Obeng-Kusi Mavis , Calamia Matthias , Halawah Hala , Alamer Ahmad , McBride Ali , Abraham Ivo , Tugay Deniz
Published: June 2022

e20506

Background: Following surgical resection, patients with NSCLC require monitoring due to the risk of recurrence. Studies have demonstrated the clinical benefit of osimertinib, a tyrosine kinase inhibitor, as adjunctive therapy in surgically resected EGFR+ NSCLC, including in stage 2 disease. We performed a cost effectiveness/utility analysis of adjunctive osimertinib therapy in stage 2 disease following surgical resection. Methods: A two state partitioned survival model differentiating disease free survival (DFS) from disease recurrence and death was specified (US payer perspective). Parametric functions were fit to digitized overall survival (OS) and DFS curves. A 5 year time horizon was specified, with a 3% discount rate applied to costs and utilities beyond year 1. Costs of treatment (wholesale acquisition cost), adverse events (grade 3/4 except all grades for immunotherapy related AEs), and monitoring were sourced from, respectively, Redbook, literature, and Physician Fee Schedules (US $2021). DFS life years (DFSLY) and quality adjusted life years (DFSQALY), incremental cost effectiveness/utility ratios (ICER/ICUR) in terms of DFSLY and DFSQALY gained (g) were estimated in base case analyses (BSA) and probabilistic sensitivity analyses (PSA). Results: Exponential regression was used to extrapolate osimertinib and placebo Kaplan-Meier curves. As detailed below, in BCA (PSA) the incremental cost of osimertinib over placebo was $778,315 ($778,202). The incremental DFSLY was 1.740 (1.738), which yielded ICER of $447,349/DFSLYg ($447,768/DFSLYg). The incremental DFS QALY was 1.234 (1.232), yielding ICUR of $630,910/DFSQALYg ($631,498/DFSQALYg). Conclusions: As to disease recurrence in stage 2 surgically resected EGFR+ NSCLC, our model associated adjunctive osimertinib therapy with incremental clinical gains of 1.740 (1.738) DFSLY and 1.234 (1.232) DFSQALY compared to placebo, however at marked incremental cost. As adjunctive osimertinib treatment is indicated in EGFR+ NSCLC disease stages 1B and 3A, the present stage 2 cost effectiveness/utility results should be compared to those for stages 1B and 3A.[Table: see text]
Desmocollin 3 (DSC 3) expression in different subtypes of non-small cell lung cancer.
Authors: Ulianova Elena P. , Stateshny Oleg N. , Sagakyants Aleksandr B. , Kharagezov Dmitry A. , Leyman Igor A. , Milakin Anton G. , Gappoeva Madina A. , Iozefi Kristian D. , Chernyak Maksim N. , Shulgina Oksana G. , Lazutin Yuriy N. , Dzhenkova Elena A. , Novikova Inna A. , Popova Natalia N. , Rozenko Lyudmila Ya
Published: June 2022

e20513

Background: Currently, an active search is underway for additional markers that predict the risk of tumor progression based on the epithelial-mesenchymal transition (EMT). Desmocollin 3 (DSC 3), a member of the Cadherin superfamily and a cell adhesion marker, is one of the markers for this transition. The aim of our study was to evaluate the expression of DSC 3 as a prognostic factor in different subtypes of non-small cell lung cancer. Methods: The study included 12 patients with squamous cell lung cancer and 8 patients with lung adenocarcinoma, aged 49 to 76 years. Immunohistochemical study was performed on sections from paraffin blocks of tumors using polyclonal rabbit antibodies to Desmocollin 3 (Invitrogen) at a dilution of 1:300 and the UltraVision Quanto Detection System HRP DAB. The expression of DSC 3 was semiquantitatively analyzed according to the percentage of cells and the intensity of staining: 0; 1+ (weak); 2+ (moderate); 3+ (high). Expression was considered positive if the score was ≥2. The Mann-Whitney U-test, Pearson's χ² distribution, and Spearman's correlation coefficient were used for statistical analysis of the results. Results: The predominance of patients with DSC3+ tumors was noted in the group with squamous cell carcinoma (64%), while the majority of patients with adenocarcinoma had DSC3- tumors (71%). However, Pearson's χ² was not statistically significant. Differences in DSC 3 expression values by 1.3 times were insignificant (p = 0.082): Me = 40 [0-80] in squamous cell carcinoma, Me = 30 [0-65] in adenocarcinoma. The correlation analysis between the expression of this marker and the survival rate of patients also had no statistical significance (rs = 0.061 for squamous cell carcinoma and rs = 0.196 for adenocarcinoma, p > 0.05). Conclusions: The immunohistochemical study revealed some specific features in the expression of DSC 3 in different subtypes of non-small cell lung cancer.
Dissecting transcriptional heterogeneity in multiple primary lung cancer by single cell RNA sequencing.
Authors: Guo Wei , Tan Fengwei , Xue Qi , Gao Shugeng , He Jie
Published: June 2022

e20516

Background: The progression of multiple primary lung cancer has been involved in complex cell changes in composition and metabolic function. However, the role of immune related cells proliferation and epithelial cells differentiation during the synchronous multiple primary lung cancer development is still understudied. Methods: In this study, we performed scRNA sequencing of 167,397 cells from six patients with multiple primary lung cancer, combined with bulk RNAseq and whole exome sequencing. Results: We firstly revealed that both naïve and memory T cells participated in the differentiation of CD8+ T cells. One end state of CD8+ T cells is exhausted T cells and they response to stimulus and positive regulated the cell death. The Other end state is cytotoxic T cells which mainly implicated in regulation of cytokine production included positive regulation of myeloid leukocyte cytokine production involved in immune response, immune effector process, macrophage cytokine production and positive regulation of cytokine production involved in immune response. Multiple functional Treg cells and naïve T cells contributed to the CD4+ T cells origin. In addition, B cells with two main kinds of function also plays an important role in immune response. One is that the regulation and activation of innate immune response have been highly activated. The other were enriched in pathways that antigen binding, processing and presentation including MHC class II Antigen Presentation. We also revealed the cellular metabolic functions during the tumor invasion. The positive regulation of blood vessel diameter has been observed in endothelial cells, while angiogenesis has not been found in early glandular neoplasia of the lung. The development of epithelial cells mainly consists of two function states. One is that some cells response to the stress from immune, and the other is that some will die programmatically and begin to cell circle due to selective pressure with the development of tumor in multiple primary lung cancer. Conclusions: Our study showed a complete landscape of different dynamic cellular changes which might pinpoint the key cellular mechanisms of synchronous multiple primary lung cancer and therefore provided new clues for pathogenesis of tumors.
Clonal hematopoiesis in lung cancer and its impact on liquid biopsy based on targeted deep sequencing.
Authors: Yang Xue , Wang Youyu , Li Yingmei , Liu Danni , Shao Mengqi , Liu Lei , Liao Yida , Huang Tanxiao , Zhang Jing , Mu Tianhao , Chen Shifu , Feng Gang , Jia Kegang
Published: June 2022

e20532

Background: Blood-based liquid biopsy has proved its potential in enormous clinical applications, such as cancer screening, diagnosis, treatment guidance, disease tracking and monitoring. In certain scenarios (e.g., molecular residual disease), it requires the technique to be able to detect mutation with very low frequency (0.001% ̃ 1%). The major hurdle of ultra-sensitive circulating tumor DNA sequencing is the high background noise of plasma cell-free DNA (cfDNA) and clonal hematopoiesis (CH). Here in this study, we investigated the prevalence of CH in lung cancer patients and its interference with liquid biopsy. Methods: We retrospectively analyzed cfDNA and blood cell genomic DNA (gDNA) sequencing data sets (n = 1,261) from a group of Chinese lung cancer patients. Threshold (1%) and subthreshold (0.2%) for variant allele frequency were set and compared. We focused on 23 clonal hematopoiesis genes that were selected based on previous publications. Results: CH mutations were detected in 27.68% of all the patients at the threshold and 62.01% at the subthreshold, and the detection rate increased with age. DNMT3A was the most frequently mutated CH gene, accounting for more than half of the CH mutations. The CH mutations had a higher detection rate in smokers (72%) than non-smokers (59.4%) at subthreshold. VAFs of CH mutations in cell-free DNA strongly correlated with their VAFs in gDNA (Pearson’s R = 0.92, p < 2.2x10-16), while tumor-derived somatic mutations didn’t have such correlation. Conclusions: Our study showed that clonal hematopoiesis is very common in lung cancer patients, especially when examining low-frequency mutations. Sequencing of gDNA at equivalent depth is very important to filter out CH mutation in cancer liquid biopsy.
ZFHX4 mutation as a novel predictive biomarker for immune checkpoint blockade in non-small cell lung cancer.
Authors: Shen Peng , Zeng Di , Lin Zhenzi , Lin Pei , Luo Mingyang , Zhao Lele , Chai Huizi , Huang Lingli , Xiao Mingzhe
Published: June 2022

e20535

Background: ZFHX4 mutation as a novel predictive biomarker for immune checkpoint blockade in non-small cell lung cancer. Methods: 165 NSCLC patients treated with ICIs from independent public cohorts(Rizvi2015; Hellmann2018; Miao 2018) were included to assess immunotherapeutic predictive performance of ZFHX4 mutation. The genomic, mRNA profile and its corresponding survival data were retrieved from The Cancer Genome Atlas (TCGA) database for prognostic analysis. Results: In public cohorts 43 (26.06%) NSCLC patients harbored ZFHX4 mutations. Longer PFS was detected in NSCLC patients with ZFHX4 mutation (ZFHX4-mut) compared with those with wildtype ZFHX4 (ZFHX4-wt) (median PFS 22.1 months vs 4.2 months, HR 0.37; 95% CI 0.22 to 0.61; p < 0.001). Higher ORR and DCR were also observed in patients with ZFHX4-mut compared with ZFHX4-wt (ORR: 62.8% vs 21.3%, p＜0.001; DCR: 86.0% vs 60.7%, p＜0.001, respectively). In the multivariable Cox proportional hazards regression model adjusted by PD- L1 expression and tumor mutational burden (TMB) and other confounding factors, ZFHX4-mut remained an independent predictor (HR 0.43; 95% CI 0.22 to 0.83; p = 0.01). ZFHX4-mut was associated with significantly higher TMB compared to ZFHX4-wt (P＜0.001). According to ZFHX4 status and TMB level, we stratified patients into four subgroups: ZFHX4mut-TMB high, ZFHX4mut-TMB low, ZFHX4wt-TMB high, and ZFHX4wt-TMB low. As expected, ZFHX4mut-TMB high patients achieved the longest PFS 23 months (HR 0.21 95% CI 0.10 to 0.43; p < 0.01) among all groups. The combination of ZFHX4 mutation and TMB-H had a better predictive effect. Conclusions: Our results suggested that ZFHX4 mutation might be a potential predictor for ICIs therapy in NSCLC. Prospective studies to further understand the mechanism are warranted.
Co-occurring mutations in the DDR pathway and tumor-associated genes for predicting immunotherapeutic efficacy in non-small cell lung cancer patients.
Authors: Zhang Louqian , Fu Zhichao
Published: June 2022

e20539

Background: In recent years, the advent of immunotherapy had provided a new approach for non-small cell lung cancer (NSCLC) patients. However, only a small subset of patients can benefit from immune checkpoint inhibitors (ICIs) and the majority of patients still show poorly durable responses. Although some biomarker for predicting clinical efficacy of immunotherapy has been reported, the more proper predictive biomarker is required to screen dominant populations for ICI efficacy. Methods: A total of three publicly available datasets of NSCLC patients treated with immunotherapy were collected for analysis. The discovery contained 57 NSCLC patients sequenced by WES from Miao et al. and another cohort of 75 patients with clinical data and WES data download from Hellman et al. studies. We collected two MSK-IMPACT cohorts including 240 and 350 NSCLC immunotherapy patients used as validation set from cBioPortal(www.cbioportal.org). Results: We detected 79 mutation genes (mutation frequency > 5% cases) associated with a better progressive free survival PFS (HR < 1, P value < 0.05) by univariate Cox regression analysis in the discovery cohort. The survival analysis results indicated that patients who carried co-occurring mutations of GRIN2A, FAT1, FLT1, ASXL2, PTPRS , and DDR pathway showed a longer PFS (p = 0.004, HR = 0.37, 95% Cl 0.235-0.644). Notably, comparing with the non-co-mutation group, the higher tumor mutation burden (TMB)(P < 0.01) and more durable clinical benefit(P < 0.05) have been detected in the co-mutations group. Next, we validated our findings using two independent validation cohorts who received ICI therapies from MSKCC, the results showed that PFS was significantly prolonged in the co-mutation group (p = 0.036, HR = 0.67, 95%CI 0.47-0.97), and with no significant difference in overall survival. Additionally, the TMB was significantly higher in the co-mutation group than that harbored non-co-mutation in two validation cohorts(p < 0.01). Conclusions: In this study, we found that co-occurring mutations in five genes and DDR pathways can predict a better immunotherapy efficacy of NSCLC. Therefore, the co-mutation signature may have great potential as a biomarker for guiding immunotherapy of NSCLC.
S100A7 as a founder of immunosuppressive tumor microenvironment shed light on immunotherapy in lung squamous cell carcinoma.
Authors: Liu Chengming , Zheng Sufei , Lu Zhiliang , Sun Nan , He Jie
Published: June 2022

e20541

Background: The application of immune checkpoint inhibitors (ICIs) has revolutionarily improved the prognosis of patients with lung squamous cell carcinoma (LUSC) with limited treatment options, yet only certain patients can benefit from ICIs. S100A7 has been reported to accelerate tumor progression by activating oncogenic pathway in LUSC. Here, we aimed to deepen in the role played by S100A7 in the tumor immune microenvironment (TIME) and immunotherapeutic efficacy. Methods: Immunohistochemical analysis of PD-L1 expression and CD8+ tumor infiltrating lymphocytes (TILs) was applied to investigate the correlation between S100A7 expression and TIME. The mechanism of S100A7 regulating PD-L1 expression and infiltration of CD8+ TILs was then explored. Based on a mouse model and a clinical cohort, the association between S100A7 expression and the efficacy of ICIs was also analyzed. Results: Immunohistochemical analysis of 102 LUSC specimens revealed that S100A7 expression negatively corelated with PD-L1 expression and the infiltration of CD8+ TILs. The in vitro studies showed that S100A7 deregulated PD-L1 expression by activating the p-AKT pathway. Notably, a negative correlation between S100A7 expression and CXCL9 expression in tumor cell and CD68+ macrophage was observed in LUSC samples, which may lead to a decrease in CD8+ TILs. Results of murine models of LUSC revealed that dysregulation of S100A7 exerted an impact on anti-tumor response of immunotherapy. Further analysis showed that targeting S100A7 may enhance the efficacy of immunotherapy by yielding an inflammatory phenotype. In addition, baseline plasma level of S100A7 was higher in patients with progressive disease ( p = 0.0393) based on our cohort of LUSC patients treated with ICIs. The potential predictive value of baseline plasma level of S100A7 for immunotherapy response was then confirmed with area under curve up to 0.869. Multivariate Cox regression analyses revealed that baseline S100A7 level in plasma samples was an independent prognostic factor. Conclusions: This study deepened in the understanding of the role played by S100A7 in the TIME, offering a novel insight of its mechanism of action on immunotherapy resistance. Our results indicated that S100A7 may emerge as a powerful predictive tool for immunotherapy and the treatment targeting S100A7 may be beneficial for immunotherapy in LUSC.
Effects of high-fat and low-carbohydrate diet combined with radiation therapy on tumor microenvironment in LLC tumor-bearing mice.
Authors: Xiao Ling , Li Tao
Published: June 2022

e20543

Background: Metabolic reprogramming of tumor immune cells can regulate immune function. To add a sentence linking tumor metabolism with radioimmunity. In this study, the high heterogeneity and reprogramming of tumor cell metabolism were utilized to explore the effects of high fat and low carbohydrate diet combined with radiotherapy on tumor immune microenvironment of tumor mice bearing LLC from the perspective of tumor microenvironment. Methods: Lewis lung cancer (LLC) model was established in female C57BL/6J mice aged 6 to 8 weeks and around 18g, and they were given a high fat and low carbohydrate diet (45F, fat 45.00% of energy) combined with radiotherapy. The body weight, tumor growth, blood glucose and blood ketone (βHB) values, survival time, median survival time and treatment safety of tumor-bearing mice were observed. Immunohistochemistry, multiple immunofluorescence and flow cytometry were used to detect the expression of tumor-associated microangiogenesis molecules (CD34), lymphatic microvessels (LYVE-1), collagen fibers and immune cell phenotypes (CD3, CD4, CD8, Treg and PD1). Results: High fat and low carbohydrate diet combined with radiotherapy (45F+RT) group had the best tumor control, and the tumor volume was significantly smaller than the control group (p < 0.001), and tumor weight in the combined treatment group (45F+RT) was significantly lower than that in the normal diet (PT, fat 12.11% of energy) and 45F group (p < 0.001); The blood glucose in 45F group was lower than that in PT group, but there was no statistical difference (p < 0.05); It was found that the βHB value in the high-fat and low-carbohydrate diet group was higher than that in the normal diet group. There were statistically significant differences in the second and third weeks (1.00±0.20mmol/L vs 0.63±0.06mmol/L, 0.90±0.17mmol/L vs 0.70±0.10mmol/L, p < 0.05). The median survival time of mice in each group was 38 days in the PT group, 55 days in the PT+RT group and 41 days in the 45F group, but not in the 45F+RT group. Immunohistochemistry and Multiple immunofluorescence showed that CD8 expression was up-regulated and PD1, CD34, LYVE-1 and collagen fiber expression were down-regulated in 45F+RT group. Flow cytometry showed that the proportion of CD8+T cells in 45F+RT group was higher than that in PT group and PT+RT group (p < 0.05) and higher than 45F group, but the difference was not statistically significant (p < 0.05); The proportion of CD4+T cells in PT+RT and 45F+RT groups was higher than that in PT and 45F groups (p < 0.05); The proportion of Treg in T cells in 45F+RT group was lower than that in PT+RT group, but the difference was not statistically significant (p < 0.05). Conclusions: High fat and low carbohydrate diet combined with radiotherapy can enhance the recruitment and function of immune effector cells in tumor microenvironment and inhibit tumor microangiogenesis, thereby inhibiting tumor growth.
Better tumor immune microenvironment in patients with older lung adenocarcinoma.
Authors: Wang Yongjie , Yang Ronghua , Wang Dong , Xuan Yunpeng , Yu Yi , Qi Yingxue , Ge Minghui , Luo Ningning , Zhu Xiaofeng , Li Mengmeng
Published: June 2022

e20544

Background: Lung adenocarcinomas (LUAD) is the most common histological subtype of lung cancers. Immunotherapies (ICIs) have been confirmed to improve the clinical outcomes of LUAD patients. Efficacies of ICIs are considered strongly associated with tumor immune microenvironments (TIME). Age-related immune dysfunction might induce difference on the efficacy of ICIs between younger and older patients. However, the potential effect of age on TIME remains little known and controversial. Herein, we aimed to analysis the association between age and TIME based on The Cancer Genome Atlas (TCGA) database. Methods: We screened out 582 LUAD patients with complete information, whose tumors underwent next-generation sequencing (NGS) detection in TCGA. All patients were divided into two groups according to age, the younger group (age < 50-year old) and the older group (age≥50-year old). The differences of immune-related signatures between the two groups were calculated according to previous reports. We also analyzed the differences in immune-related signature between different clinical stages. P-values were calculated via the T.Test. Results: In total 582 patients with LUAD in our study, 115 (19.76%) patients in younger group and 467 (80.24%) patients in older group were found. Many immune-related signatures were found significantly higher in older group than in younger group, including cytolytic activity (CYT) (p = 0.0352), expanded immune signature (p = 0.0065), T cell inflamed gene expression profile (GEP) (p = 0.0048), IFN-γ-related response genes (p = 0.0346), immune signature (p = 0.0022), immunosuppression (p = 0.0065), major histocompatibility complex class I (MHC class I) (p = 0.0319), T-cell survival (p = 0.0235), tertiary lymphoid structures (TLS) signature (p = 0.0001) and total_TILs_scores (p = 0.0020). In addition, tertiary lymphoid structure (p = 0.0355) and TLS_signature (p = 0.0243) were found significantly difference in different clinical staging, which decreased as the staging get later. On the contrary, cell cycle score (p = 0.0001) increased as the staging get later. Conclusions: Our study evaluated the impact of age and clinical stage on the TIME in patients with LUAD using a threshold of 50 years old for the first time. We founded that LUAD patients in older group had better TIME than in younger group and some immune-related signatures were significantly related with clinical staging.
Prevalence and clinical significance of pathogenic germline mutations in homologous recombination repair genes in Chinese lung cancer patients.
Authors: Jiang Yanxia , Han Liying , Wang Yan , Wu Nuoting , Peisu Suo , Huang Tanxiao
Published: June 2022

e20547

Background: There is accumulating evidence indicating that pathogenic germline mutations may contribute to lung cancer susceptibility besides environmental factors. The prevalence and clinical significance of pathogenic germline mutations in homologous recombination repair genes on lung cancer susceptibility has not been systematically investigated. Methods: We used real-world HaploX genomic data from patients (pts) with lung cancer to determine the prevalence of pathogenic germline mutations in homologous recombination repair genes from July 2020 to January 2022. Results: Out of the 766 patients screened, 5.5% (42/766) of the patients harbored the pathogenic germline mutations：12 with ATM, 12 with FANCA, 8 with ATR, 7 with BRCA1, and 3 with BRCA2. Conclusions: A proportion of 5.5% of patients carrying germline mutations in homologous recombination repair genes may be potentially linked to increased susceptibility to lung cancer. Our study has demonstrated that pathogenic germline mutations in homologous recombination repair genes are a risk factor for lung cancer.
Association of DDR1 with immune exclusion and outcomes in non-small cell lung cancer.
Authors: Zhang Lei , Lou Ning , Yu Qingxiang , Ma Rui
Published: June 2022

e20553

Background: Discoidin domain receptor 1 (DDR1) is a collagen receptor with tyrosine kinase activity. Although DDR1 has been reported to implicated in cancer progression and metastases, the underlying mechanism remains poorly characterized and its prognostic value is also contradictory in non-small cell lung cancer (NSCLC). Methods: Clinical and DDR1 mRNA expression data of 1925 patients with NSCLC were obtained from 14 publicly available datasets utilizing an online tool KM-plotter. All patients were split into 2 groups by median expression of DDR1. The Kaplan-Meier curve and log-rank test, and Cox regression analyses were used to examine the association between DDR1 expression and overall survival (OS). The table shows 48 immune-regulatory genes classified into 4 signatures associated with activated T cells, immune cytolytic activity, and antitumor immunity. Expression data of these genes for 994 patients with NSCLC were gathered from the TCGA Pan-Cancer Atlas. Abundance data of various immune cell types in tumor microenvironment for the TCGA patients were inferred using xCell, and then immune infiltration extent was calculated as immune score. Associations of DDR1 with immune genes expression and immune score were determined with Spearman rank correlation. Results: DDR1 overexpression was significantly associated with inferior OS in this large-scale cohort (median, 62 vs 78.5 months; hazard ratio [HR], 1.16; 95% CI, 1.02-1.31; P = .02). Of note, multivariable Cox model indicated DDR1 overexpression was an independent risk factor for OS (HR, 1.41; 95% CI, 1.01-1.98; P = .046), controlling for potential confounders (histology, stage, sex, and smoking history). Of the 48 immune-regulatory genes, 44 (92%) showed significant negative correlations with DDR1 expression (all P < .05), implying the role of DDR1 in decreasing immune infiltration into tumor microenvironment. Further, higher immune score was observed in tumors underexpressing DDR1 (correlation coefficient, -0.44; P < .001), more directly demonstrating the link between DDR1 and immune infiltration. Conclusions: To our knowledge, this is the largest study to evaluate the prognostic role of DDR1 expression in NSCLC. Our results suggest that DDR1 overexpression may predict poor outcomes and a possible mechanistic explanation regarding this role may be immune exclusion instigated by DDR1. Thus, targeting DDR1 expression to abrogate immune exclusion warrants further investigation.[Table: see text]
Pattern of failure in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy with/without immune checkpoint inhibition.
Authors: Taugner Julian , Käsmann Lukas , Eze Chukwuka , Nieto Alexander , Guggenberger Julian , Flörsch Benedikt , Kenndoff Saskia , Tufman Amanda , Reinmuth Niels , Belka Claus , Manapov Farkhad
Published: June 2022

e20570

Background: We compared pattern of failure in patients treated with chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (IO, immuno-oncology therapy) and CRT alone for inoperable stage III NSCLC. Methods: Prospective data of thirty nine consecutive patients who completed CRT-IO with sequential durvalumab (72%, 28 patients) or concurrent and sequential nivolumab (28%, 11 patients) and a sensitive propensity score matched (PSM adjusted for patients age, gender, T- and N-status, PTV, histology) cohort of 39 patients treated with CRT alone were analyzed. First site of failure was compared between the CRT-IO and the CRT alone subgroup. Results: All patients were treated with conventionally fractionated thoracic irradiation to a total dose of at least 60Gy (range: 60-66Gy), all patients received either sequential or simultaneous chemotherapy while 95% (74 patients; CRT-IO: 38/39; CRT alone: 36/39) received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 33.3 (range: 1.5-102.9) months; median overall survival (OS) was 34.9 (95%CI: 10.7-59.1) months (CRT-IO: not reached; CRT alone: 24.4, p = 0.003); median progression-free survival (PFS) was 13.6 (95% CI: 10.5-6.7) months (CRT-IO: 26.3; CRT alone: 8.3; p < 0.001). At the time of evaluation 21 (53.8%) vs. 7 (17.9%) patients of the CRT-IO vs. CRT alone subgroup were progression free and alive (p = 0.003); 4 (10.3%) vs. 3 (7.7%) had brain metastases as first site of failure; 7 (17.9%) vs. 6 (15.4%) had ≤ 3 extracranial metastasis and 3 (7.7%) vs. 4 (10.3%) had multi-organ progression. Local-regional recurrence (LRR) as first site of failure was significantly less frequent in patients treated with CRT-IO vs. CRT alone, namely 3 (7.7%) vs. 12 (30.8%) patients (p = 0.001); median time to LRR was not reached vs. 15.0 (95%CI: 0.9-33.7) months. Conclusions: Pattern of failure differ significantly in patients treated with CRT-IO vs. CRT alone; CRT-IO patients are significantly less likely to develop a LRR. No differences in the prevalence of brain metastases as first site of failure could be detected.