bluuebunny/crossref_metadata_2025 huggingface dataset:
Parameters of cellular immunity in patients with lymphomas after COVID-19.
Authors: Kamaeva Inna A. , Lysenko Irina B. , Sagakyants Aleksandr B. , Bondarenko Elena S. , Shulgina Oksana G. , Nikolaeva Nadezhda V. , Kapuza Elena A. , Pushkareva Tatiana F. , Gaysultanova Yakha S. , Kit Oleg I. , Dmitrieva Viktoria V. , Velichko A. V.
Published: June 2021

e19572

Background: The development of lymphomas is accompanied by disorders in the structural and functional organization of the immune system leading to immune deficiency. Such patients are at greater risk of severe SARS-CoV infection. Our purpose was to assess the parameters of cellular immunity in patients with lymphomas with a history of multi-course chemotherapy, therapy with anti-CD20+ antibodies and PCR-confirmed COVID19. Methods: The study included 12 adult patients with lymphoproliferative diseases (non-Hodgkin's large B-cell lymphomas (NHL) - 7, Hodgkin's lymphomas (HL) - 5) with a history of PCR-confirmed COVID-19. All patients underwent 4 to 6 chemotherapy cycles. The relative numbers of the main populations of leukocytes, T- and B-lymphocytes, as well as subpopulations of T-lymphocytes, were assessed in the whole blood collected in K2EDTA anticoagulant using the BD FACSCanto II flow cytometer with a panel of antibodies according to the manufacturer's instructions (Becton Dickinson, USA). Results: Patients with HL showed a number of changes in the parameters of cellular immunity. The content of total lymphocytes and monocytes was reduced in comparison with patients with NHL by 34% and 56%, respectively: 14.3 (11; 17) vs. 21.7 (15.2; 32), and 6.0 (4.8; 7.1) vs. 13.5 (12.9; 13.7), respectively. An increase in granulocytes by 30% was revealed in patients with HL. No differences were found in the content of both general and main populations (CD3+, CD3+CD4+, CD3+CD8+, central and effector memory cells). However, the content of naive CD3+CD4+ and CD3+CD8+ lymphocytes in patients with HL increased by 43% and 62%, respectively. While the number of CD3+CD4-CD8- lymphocytes was 47% lower, the number of CD3+CD4+CD8+, on the contrary, exceeded the values in patients with NHL by 4.6 times. Patients with HL also showed a tendency towards a decrease in the number of NK and NKT-lymphocytes. Conclusions: The increased levels of naive lymphocytes and both populations of memory cells and a sharp increase in double-negative T-lymphocytes and B-lymphocytes in patients with HL could indicate certain characteristics of the disease course affected by COVID-19. The data require additional research and can be used to assess the condition of patients and to predict the therapy efficacy.
Retrospective study to assess the impact of hepatitis C virus infection on the prognosis and management of multiple myeloma.
Authors: Kaldas David , Wahba Andrew , Azab Radwa Hamdy , Elnakoury Ehab Mostafa , Abdel Karim Nagla Fawzy , Abdel-Malek Raafat
Published: June 2021

e20001

Background: Multiple Myeloma (MM) is a neoplasm of the post-germinal center, terminally differentiated B-cells. MM accounts for 1% of all types of cancer and 10% for all hematologic malignancies. Chronic hepatitis C virus (HCV) is an infection that affects over 71 million patients worldwide. Cytotoxic agents and immunosuppressive therapy as steroids are the main line of therapy in lymphoid malignancies, but these drugs may exacerbate chronic viral hepatitis and cause uncontrolled replication of hepatitis viruses. The impact of HCV infection on MM patients remains unclear. Objective: To assess the impact of HCV infection on the prognosis and management of MM patients. Methods: A 10-year retrospective study of MM patients was conducted at Cairo University Clinical Oncology Department from January 2009 to April 2019. Results: During this time, 150 patients were diagnosed with MM, 109 (72.7%) were HCV negative, 24 (16%) were HCV positive, and 17 (11.3%) with unknown HCV status. The median age was 51 and 54 years for HCV negative and positive groups respectively, with a statistically insignificant difference (p-value > 0.2). In the multivariate analysis, HCV infection was not an independent factor related to overall survival (OS), however age, creatinine and hemoglobin levels correlated significantly with OS (p < 0.009, 0.008, 0.031 respectively). The median OS for the HCV negative group was 31.11 months (95% CI: 22.62 - 39.61) compared to 37.66 months (95% CI: 7.19 - 68.13) for the HCV positive group. The median progression-free survival (PFS) for all patients was 18.9 months, for HCV positive patients was 15.36 months (95% CI: 13.18 – 17.54), and for HCV negative patients was 20.49 months (95% CI: 14.13 – 26.85). Age below 60 years and creatinine level less than 2 mg/dL were statistically significant for favorable disease-free survival (DFS) (p < 0.030, 0.034 respectively). Conclusions: Age, creatinine and hemoglobin levels are significant prognostic factors in MM but HCV status doesn’t affect the overall survival or progression-free survival. HCV infection should not contraindicate MM therapy.
Profile and management of toxicity of selinexor and belantamab mafodotin for the treatment of relapsed/refractory multiple myeloma: A systematic review.
Authors: Neupane Karun , Ehsan Hamid , Wahab Ahsan , Masood Adeel , Ahmed Tehniat Faraz , Bahram Saman , Hannan Abdul , Haider Mobeen Zaka , Shahzad Moazzam , Mushtaq Muhammad Umair , Anwer Faiz
Published: June 2021

e20014

Background: Selinexor (Sel) and belantamab mafodotin (belamaf) were recently approved by the US FDA for treatment of relapsed/refractory multiple myeloma on July 2019 and August 2020 respectively. The toxicity profile of these drugs is a concern since these are approved for use in patients who have already undergone multiple lines of treatment. Methods: Six studies for Sel and two for belamaf were included after a systematic search of PubMed, Embase, Cochrane, and Clinicaltrials.gov. Results: The most common hematological toxicity associated with these two drugs is thrombocytopenia. The common G-3/4 hematological AEs of Sel were thrombocytopenia (39%-71%), anemia (16%-33%), leukopenia (8%-33%) and neutropenia (9%-33%) whereas common G-3/4 non-hematological AEs were hyponatremia (5%-26%), fatigue (13%-15%), diarrhea (5%-10%), eye disorders (9%-10%), musculoskeletal disorders (4%-10%), elevated liver enzymes (10%), peripheral neuropathy (5%) and vomiting (2-4%). Keratopathy and anemia were the major toxicities of belamaf. Most of these toxicities are manageable. Treatment modifications and dose interruption are usually needed when AEs are more than grade II. REMS program guidelines is recommended for close monitoring and evaluation of Sel and belamaf toxicities and early ophthalmological intervention. Conclusions: As these are newer drugs with limited data, continuous surveillance and monitoring is warranted during the treatment course with early mitigation strategies. The physician should be aware of thrombocytopenia and its management as well as belamaf ocular toxicity which is manageable but if missed could have serious complications.[Table: see text]
Management of light chain deposition disease: A systematic review.
Authors: Masood Adeel , Shahzad Moazzam , Wahab Ahsan , Pachika Pranali Santhoshini , Ahmed Tehniat Faraz , Khanam Razwana , Ehsan Hamid , Neupane Karun , Amin Saher Nasir , Mushtaq Muhammad Umair , Anwer Faiz
Published: June 2021

e20042

Background: Light-chain deposition disease (LCDD) is part of a wide spectrum of plasma cell proliferation disorders. LCDD predominantly affects kidneys by systemic deposition of congo red negative non-fibrillar light chains. Due to the rarity of disease, no prospective data is available, and clear guidelines don’t exist for the treatment. We reviewed data to summarize effective treatment strategies. Methods: A literature search was conducted on PubMed, Cochrane, and ClinicalTrials.gov with final update in November 2020 using terms ‘light chain deposition disease’, ‘therapy,’ and ‘disease management’. Library was manually screened to remove articles on LCDD in transplant kidneys. We identified 63 case reports/series and 11 retrospective studies n=365. Results: Retrospective Studies: 9 studies (n=283) identified various combinations of LCDD and plasma cell dyscrasias given the rarity of idiopathic LCDD. Lorenz et al. reported 6 patients (pts) that received ASCT with MEL preconditioning with 92% improved proteinuria and 95% improved eGFR. Pozzi et al. reported 63 pts (32% idiopathic LCDD, 65% concurrent MM and 3% concurrent CLL) where all pts received a combination of vincristine, doxorubicin, dexamethasone/methylprednisolone. 5/63 patients received ASCT. The median survival was 4.1 years. Bortezomib (V) based regimens: Most experts favor V based regimens to treat LCDD, but no dedicated trials exist. 26 case reports/case series (37 pts) included; 23 pts with idiopathic LCDD and rest with a concurrent disorder. Daratumumab: Milani et al. treated 8 pts with LCDD and concurrent MM with single agent daratumumab who failed at least one regimen. Autologous stem cell transplant (ASCT): 13 case reports/case series (20 pts) identified who received ASCT with melphalan (MEL) conditioning with/without various combinations of chemotherapies before and after ASCT. 14 pts had LCDD, and 6 pts had concurrent clonal cell dyscrasia. Miscellaneous regimens: Various other regimens showed promising results with improved renal functions but not well studied e.g., thalidomide and dexamethasone (Haruyuki et al.). Conclusions: Dedicated clinical trials are difficult given rarity of LCDD but needed. Bortezomib based regimens seem to be good options, ASCT with MEL conditioning is a suitable choice for younger and fit pts.[Table: see text]
Weekly osimertinib dosing to prevent EGFR mutant tumor cells destined to home mouse lungs.
Authors: Butle Ashwin , Joshi Asim , Noronha Vanita , Prabhash Kumar , Dutt Amit
Published: June 2021

e20504

Background: The recent ADAURA trial concludes daily dosing of adjuvant osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), improves disease-free survival with stage IB/II/IIIA EGFR-mutated non-small cell lung cancerpatients in comparison to placebo. We have developed a preclinical orthotopic mouse model, using luciferase tagged lung adenocarcinoma cells harboring EGFR TKI sensitive exon 19 deletion, to model and extend trial implications comparing a weekly vs daily dosing outcome of osimertinib to a first-generation TKI- erlotinib. Methods: We present an assessment of the homing of PC9-luciferase cells to the lungs of mice injected through mouse tail vein. Thirty NOD-SCID mice were divided into five groups as follows: two groups each for daily and weekly treatment and one group for vehicle control. For all the mice in the respective groups, erlotinib (25 mg/kg) and osimertinib (15 mg/kg) was orally administered. Homing of cells in the lungs of mice was assessed by bioluminescence imaging regularly. Results: In the control group, 100% of the mice showed homing and retention of cells in the lungs of mice 18 days post-injection. In mice receiving erlotinib daily, homing of the cells in lungs was absent in all four mice, except in one mouse where emergence was observed after day eight post-injection. In the case of erlotinib weekly group, out of four only one mouse showed absence of homing of cells in the lungs of mice. Interestingly, 100% of the mice in both the groups receiving osimertinib daily or weekly showed complete absence of homing of cells in the lungs of mice from day 3 onwards post-injection (Table). The tumors observed in the lungs, when dissected at day 30, confirmed the colonization of the injected cells homing to the organ. Conclusions: Based on the complete absence of the homing of cells in lungs of osimertinib treated mice, in both weekly and daily regimens, adjuvant osimeritinib may represent a viable treatment option in delaying the onset of disease post resection of early stage tumors or among patients with pre-disposition to EGFR mutant lung cancers harboring germline EGFR mutations. In addition, low-dose once-a-week osimertinib could potentially have several advantages over daily dosing, including lower toxicity, affordability, ease of administration and delaying or preventing acquired resistance that remains to be explored. [Table: see text]
Relationship between loss-of-function mutation of the stromal antigen 2 gene and treatment in non-small cell lung cancer.
Authors: Zhuo Minglei , Liu Xin , Chen Rongrong , Xu Xiong , Ni Bin
Published: June 2021

e20509

Background: The protein encoded by Stromal Antigen 2 ( STAG2) gene is a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Loss-of-function (LOF) mutations of STAG2 gene are commonly detected in different tumors including non-small-cell lung cancer. However, there is no relevant research on the impact of STAG2 alterations on lung cancer treatment. Here we explored the correlation between the LOF of STAG2 and clinical features, concomitant genetic alterations and treatment in NSCLC pts. Methods: A total of 2882 NSCLC pts were enrolled. All the tissue samples were detected by DNA based next generation sequencing (NGS) with a 1021 gene panel. Clinical information was obtained synchronously from physicians and surgeons. According to whether LOF of STAG2 is detected, pts were divided into LOF subgroup and wild type (WT) group. Results: All pts enrolled are Chinese, and median age at diagnosis of them is 63±11.21. Compared to the WT subgroup, a higher average TMB was observed in the LOF group (12.64muts/Mb vs. 6.66mut/Mb, P＜0.05). Between the LOF group and the WT group, there were no significantly difference in all clinical baseline characteristics including age at diagnosis, gender, tumor stage and pathological type. At the time of sample collection, there was no significant difference between the two groups of pts whether they had received systemic treatment (chemotherapy, targeted therapy or immunotherapy) and systemic treatment, and the number of systemic treatment lines received. Neither significant differences in driver gene alteration and other accompanying mutations were observed in the two groups. Conclusions: In NSCLC pts, LOF of STAG2 is not a change after drug resistance, but it may lead to an increase in TMB, which indicates that these pts may have more benefits from immunotherapy. But the influence on prognosis of NSCLC pts needs further research to clarify.
Overexpression of LILRB2 (ILT4) is correlated with immunosuppressive immune infiltration in lung adenocarcinoma.
Authors: Li Butuo , Jiang Chao , Wang Shijiang , Li Xuanzong , Xu Yiyue , Fan Xinyu , Yu Jinming , Wang Linlin
Published: June 2021

e20519

Background: Immune checkpoint inhibitors have revolutionized the patterns of tumor treatment with significantly improved survival. However, it’s worth noting that the objective response rate of PD-1/PD-L1 inhibitors monotherapy is just 20% in non-small cell lung cancer (NSCLC) patients, and biomarkers for the prognosis of patients receiving PD-1/PD-L1 inhibitors are urgently needed. LILRB2 (ILT4) is known as an immunosuppressive molecule and promotes the development and progression of NSCLC. However, the relationship between LILRB2 expression and immune microenvironment remains unclear in patients with lung adenocarcinoma. Methods: Expression profile and corresponding clinicopathological data of patients with lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) database. TIMER 2.0 was used to investigate the relationship between LILRB2 expression and immune infiltrates, including T cell subset, macrophage and so on. Cox proportional hazard model was also performed to evaluate the role LILRB2 expression and immune infiltrations in prognostic prediction of patients with lung adenocarcinoma. Results: 515 patients with lung adenocarcinoma were included in analysis from TCGA dataset. LILRB2 expression was found to have significant negative correlation with CD8+ T cell infiltration (P = 0.0012), and positive correlation with CD4+ T cell infiltration (P < 0.001). There were also significant positive correlations between LILRB2 expression and Treg (P = 0.0083), cancer associated fibroblast (P < 0.001), monocyte (P < 0.001), M2 macrophage (P < 0.001) infiltration, which was regarded as the marker of immunosuppressive microenvironment. Notably, there were also significant association between the expression of LILRB2 and PD-1 (P < 0.001) and PD-L1(P < 0.001). In terms of survival analysis, high level of Treg (HR = 0.86, P = 0.03) and M2 macrophage (HR = 0.84, P = 0.017) infiltration was associated with poor prognosis of patients with lung adenocarcinoma. However, the level of CD8+T cell (HR = 0.93, P = 0.298), CD4+ T cell (HR = 0.933, P = 0.321), and LILRB2 expression (P = 0.56) was not associated with the survival of patient with lung adenocarcinoma. Conclusions: The overexpression of LILRB2 is significantly correlated with immunosuppressive immune infiltration and microenvironment in lung adenocarcinoma and might be the potential predictive biomarkers for the PD-1/PD-L1 inhibitors.
Predictors of early hospice or death in patients with inoperable lung cancer treated with curative intent.
Authors: Laucis Anna Mary Brown , Hochstedler Kimberly A. , Boike Thomas Pence , Movsas Benjamin , Stevens Craig William , Kestin Larry Llyn , Dominello Michael M. , Wilkie Joel , Grills Inga S. , Matuszak Martha , Hayman James , Paximadis Peter Alexander , Schipper Matthew J. , Jolly Shruti ,   on behalf of the Michigan Radiation Oncology Quality Consortium
Published: June 2021

e20525

Background: Treatment for inoperable stage II-III non-small cell lung cancer (NSCLC) involves aggressive chemo-radiotherapy (CRT). While outcomes have improved with immunotherapy, some patients transition to hospice or die early in their treatment course. To help identify these patients, we developed a predictive model for early poor outcomes in NSCLC patients treated with curative intent. Methods: In a statewide consortium involving 27 sites, information was collected prospectively on stage II-III NSCLC patients who received curative CRT from April 2012 to November 2019. We defined an early poor outcome as termination of treatment due to hospice enrollment or death within 5 months of initiating radiation therapy. Potential predictors included clinical characteristics and patient reported outcomes (PROs) from validated questionnaires. Logistic regression models were used to assess potential predictors and build predictive models. Multiple imputation was used to handle missing data. We used Lasso regularized logistic regression to build a predictive model with multiple predictor variables. Results: Of the total of 2267 included patients, 128 patients discontinued treatment early due to hospice enrollment or death. The mean age of the 128 patients was 71 years old (range 48-91) and 59% received concurrent chemotherapy. Significant uni-variable predictors of early hospice or death were advanced age, worse ECOG performance status, high PTV volume, short distance to normal tissue critical structures, high mean heart dose, uninsured status, lower scores on the Functional and Physical Well-Being scale and the Lung Cancer Symptoms sub-scale of the FACT-L quality of life instrument, as well as higher levels of patient-reported lack of energy, cough, and shortness of breath. The best predictive model included age, ECOG performance status, PTV volume, mean heart dose, patient insurance status, and patient-reported lack of energy and cough. The pooled estimate of area under the curve (AUC) for this multivariable model was 0.71, with a negative predictive value of 95%, specificity of 97%, positive predictive value of 23%, and sensitivity of 16% at a predicted risk threshold of 20%. Conclusions: Our models identified a combination of clinical variables and PROs that may help identify individuals with inoperable NSCLC undergoing curative intent chemo-radiotherapy who are at a high risk of early hospice enrollment or death. These preliminary results are encouraging and warrant further evaluation in a larger cohort of patients.
Real-world treatment patterns in stages IA-IIIB non-small cell lung cancer.
Authors: Lee Jay M. , Wang Rongrong , Abbass Ibrahim M. , Sheinson Daniel , Kent Matthew , Johnson Ann , Lee Janet
Published: June 2021

e20528

Background: Given the rising number of immunotherapy or targeted therapy trials, a call for real-world treatment (Tx) data among resectable non-small cell lung cancer (NSCLC) patients is needed. We describe Tx patterns and timelines to Tx. Methods: Retrospective data were collected from the SEER Medicare database. Patient inclusion criteria: newly diagnosed NSCLC stages IA to IIIB between 2010 and 2015, ≥65 years of age, and continuously enrolled in Medicare Part A and B and no HMO enrollment for ≥7 months prior to diagnosis (Dx) date. A subset of patients with a follow-up of ≥12 months after Dx or ≥6 months after surgery were evaluated for Tx patterns. Results: Among 31,921 NSCLC patients identified, the mean (SD) age was 76 (7) years and 51% were female. AJCC (7th edition) stages included IA (25%), IB (21%), II (8%), IIIA (17%), and IIIB (30%). Among the 6,559 (21%) patients identified with a solitary pulmonary nodule (SPN) prior to Dx, the median [IQR] time from SPN to Dx was 29 [13, 67] days. Among the 24,952 (78%) patients who received Tx, the median [IQR] time from Dx to Tx was 31 [14, 54] days. Among 19,304 patients included in the Tx pattern analysis, 63% did not undergo surgery. Among resected patients with lymph node metastasis, only 64% (stage II), 74% (stage IIIA), and 52% (stage IIIB) of patients received chemotherapy (CT) before or after surgery (Table). Median [IQR] time in days between Dx and neoadjuvant or adjuvant CT was 29 [14, 48] and 84 [56, 119], respectively. Median [IQR] time in days between Dx and surgery was longer for patients with neoadjuvant Tx (Table). Median [IQR] time between surgery to adjuvant CT was 46 [33, 63] days, with 59% of patients receiving their adjuvant CT ≥ 6 weeks after surgery and 33% of patients receiving their adjuvant CT ≥ 8 weeks after surgery. Conclusions: A significant proportion of lymph node positive stage II or III NSCLC patients did not receive perioperative systemic therapy despite standard of care guidelines. This finding suggests a patient population with unmet need notwithstanding recommendations for systemic therapy. [Table: see text]
Spatial analysis of the T-cell repertoire in non-small cell lung cancer reveals a clonality gradient from the tumor to the distal lung.
Authors: Frank Meredith , Yu Fenglei , Reuben Alexandre , Peng Muyun , Yang Gao , Chen Xiaofeng , Ji Liyan , Li Pansong , Xia Xuefeng , Guan Yan-Fang , Zhang Jianjun
Published: June 2021

e20544

Background: The immunomodulatory effects of the tumor microenvironment (TME) significantly impact the T cell repertoire resulting in different anti-tumor immune responses. Previous work by our group and others has highlighted intratumor heterogeneity in T cell clonality, spatial distribution, and diversity, as well as infiltration of bystander T cells in early-stage non-small cell lung cancer (NSCLC). However, little is known about how the TME impacts the T cell repertoire in distant or surrounding adjacent uninvolved lung tissue. Methods: We investigated the interplay between tumor and surrounding lung tissues by investigating the T cell repertoire at the tumor site, tumor margin, and 1cm, 2cm, 5cm, and 10cm away from the tumor as well as in peripheral blood in 21 NSCLC patients with a total of 123 samples undergoing T cell receptor (TCR) CDR3b sequencing using the Geneplus technology. Differences in regional T cell repertoires were analyzed based on clonality, diversity, and Morisita Overlap Index (MOI). GLIPH was utilized to identify motifs associated with pathogen specificity in each region. Results: Clonality was lowest within the tumor and progressively increases from tumor margin to tumor adjacent lung toward distant lung with “hot spot” regions of T cell expansion located in adjacent lung tissue proximal to the tumor, namely 2cm away (p = 0.0025). Dominant T cell populations were better conserved between the tumor margins and “hot regions” of high clonality compared to the tumors (p = 0.0009) highlighting the differences between these environments and possible T cell exclusion in immunosuppressive TME. GLIPH analysis revealed an inverse correlation between clonality and the proportion of pathogen-associated TCR motifs (r = -0.83, p = 0.0195). Interestingly, tumor tissue contained the highest proportion of predicted pathogen TCRs whereas regions of high clonality contained the lowest (p < 0.0001), suggesting the antigen-independent nature of T cell trafficking. Conclusions: Combined, these results highlight isolated pockets of T cell expansion in the lungs outside the tumor and potential immune evasion mechanisms in NSCLC.
The genomic and transcriptomic characteristics of early recurrence patients in stage IA non-small cell lung cancer.
Authors: Zhang Shirong , Jiang Hong , Chen Xueqin , Zhu XiuLi , Bai Jing , Wu Qiong , Hu Runlei , Zhu Chenchen , Xia Xuefeng , Xun Yanping , Zhang Jing , Ma Shenglin
Published: June 2021

e20547

Background: Lung cancer is the leading cause of cancer-related death worldwide. The mortality risk is still high in early stage because of the high relapse rates about 30–45% within 5 years after surgery. The main purpose of this study was to depict the genomic and transcriptomic characteristics in stage IA non-small cell lung cancer (NSCLC) patients and elucidate the recurrence risk factors for providing more postoperative intervention management and treatment. Methods: We prospectively enrolled 60 patients with stage IA NSCLC from 2012 to 2018 including 29 non-relapse patients and 31 early-relapse patients within 5 years. A total of 60 primary tumor specimens and 10 relapse tumor specimens were obtained. The paired adjacent non-tumor tissues for each patient were collected as negative control. DNA and RNA were co-extracted and performed with whole exon and transcriptome sequencing. The immune cell infiltration scores were estimated using ssGSEA algorithm. Results: The most frequently mutated genes in our cohort were EGFR (46.4%), TP53 (38.0%), TTN (35.2%) and USH2A (21.1%). Notably, USHA was enriched in relapse patients (32.3% vs 3.4%, p = 0.006). The median tumor mutation burden of the post-relapse group was 6.14/Mb, significantly higher than the pre-relapse group (Median: 2.63/Mb, p = 0.047) and the non-relapse group (1.91/Mb, p = 0.025). Among the early-relapse patients, copy number amplification at 2q31.1 was prevalent in the pre-relapse group (p < 0.05). Two patterns of clonal evolution were identified during the recurrence, including autonomous clonal evolution and acquired clonal evolution. Compared with non-tumor tissues, differentially expressed genes in pre-relapse affected the metabolism-associated pathways. Furthermore, post-relapse samples down-regulated antigen processing and presentation signaling pathway compared to non-relapse group. Interestingly, lower plasma dendritic cell infiltration was detected in post-relapse (p = 0.0078), indicating the defect of antigen presentation in recurrence. Concentrating on the primary tumor specimens, samples from relapse patients showed higher infiltration of CD8+T cell (p = 0.019), Helper T cells (p = 0.0036) and Treg cells (p = 0.0071) than that from non-relapse patients. Conclusions: This study elucidated the recurrence risk molecular and immune microenvironment in stage IA NSCLC patients. Findings in our research may help find out the subset of patients with early stage at high risk for recurrence who have the urgent need for postoperative intervention and guide therapeutic strategies.
Single institution toxicity of definitive chemoradiation and maintenance durvalumab in locally advanced non-small cell lung cancer.
Authors: Prodduturvar Pranitha , Leventakos Konstantinos , Potter Ashley , Gao Robert W. , Dimou Anastasios , Marks Randolph , Garces Yolanda I. , Olivier Kenneth R. , Molina Julian R. , Merrell Kenneth , Mansfield Aaron Scott , Adjei Alex A. , Schwecke Anna , Hocum Craig , Moffett Jenesse Nicole , Park Sean Sunghun , Owen Dawn
Published: June 2021

e20554

Background: The paradigm for locally advanced non-small cell lung cancer has been markedly altered to include maintenance durvalumab (D) post completion of definitive chemoradiation (CRT) following the publication of the Pacific trial in 2018. The toxicity of this treatment has not been well evaluated in the real-world setting. Methods: We identified 42 patients (pts) with Stage IIB-IIIC NSCLC treated at Mayo Clinic Rochester between 6/1/2018 and 10/1/2020 who received definitive CRT followed by maintenance D. Data were abstracted by retrospective chart review under an IRB approved protocol. Results: Median age was 66 yrs (range 47-90) and 62% were women. Primary lung cancer histology included 19 adenocarcinoma, 20 squamous cell, and 3 adenosquamous. The distribution of stages was: IIB (4/42), IIIA (15/42), IIIB (19/42), IIIC (4/42). Approximately half of patients had PDL1 expression > 25% (20/42). With a median follow up of 12.2 months (calculated from first cycle of D; range 4.2-30.5 months), 14 had completed one year of maintenance D, 16 were receiving ongoing D, and 10 stopped D early with 6/12 discontinuing due to disease progression (4/6 local progression, 2/6 distant progression). Other reasons for discontinuation (5/10) included grade 3 colitis, grade 2 hepatitis, aspergillus lung infection, and flare of autoimmune disorders. One quarter of patients experienced grade 2 radiation pneumonitis (RP; 10/42) with median time to development of RP 78 days from end of CRT and 45 days from start of D. RP was determined by multidisciplinary review of imaging and treatment fields. 17/42 patients developed immune related adverse events (see Table for details). There was minimal overlap between the patients who experienced pneumonitis and immune related toxicity; 2/17 had both pneumonitis and immune related toxicity (hepatitis, thyroiditis). Conclusions: In our early experience with the Pacific regimen, 29% of patients did not complete D due to either toxicity or progression during D administration. Pneumonitis was common (10/42 patients) although there were no grade 3 events. Nearly half of the patients developed an immune-related adverse event. Further analysis is needed to evaluate the real-world toxicity of this treatment as well as oncologic outcomes.[Table: see text]
Validation of National Comprehensive Cancer Network Guidelines (NCCN) at a single institution.
Authors: Dolan Daniel Powell , Polhemus Emily , Lee Daniel N. , Gentilella Chris , Tsukada Hisashi , Bueno Raphael , Khalil Hassan , White Abby , Swanson Scott James
Published: June 2021

e20556

Background: Invasive mediastinal staging is necessary to identify locally advanced non-small cell lung cancer (NSCLC). We sought to validate NCCN guidelines for invasive mediastinal staging. Methods: We retrospectively reviewed all patients who had curative lung resection for pathologically confirmed NSCLC from October 2018 to December 2019. We excluded patients who had induction therapy without undergoing invasive mediastinal staging first. We evaluated methods of mediastinal staging, staging results, and final pathology. Indications for staging were one or more of the following; mediastinal lymph nodes > 1.0cm in short axis, Standardized Uptake Value of > 3.0 on Positron Emission Tomography, > 50% of tumor on medial side of mid-clavicular line (central vs peripheral), or peripheral lesion > 3.0cm in diameter. Staging methods were mediastinoscopy, endobronchial ultrasound (EBUS), and video-assisted thoracoscopic surgery (VATS) ipsilateral mediastinal staging before resection of main tumor. Results: In total, 457 lung resections were performed. Staging was done in 144/275 indicated cases (52.4%). Mediastinoscopy was completed in 49 patients, with 20.4% (n = 10) N2-positive. The false negative rate of mediastinoscopy was 4.1% (n = 2 at station 7). EBUS was performed in 64 patients and 21.9% (n = 14) were N2 positive. The false negative rate for EBUS was 3.1% (n = 2 at station 7). Two mediastinoscopy and 9 EBUS patients had 0 N2 stations sampled. None of the patients were ultimately N2 positive. Staging of three mediastinal stations (4L, 4R, and 7) was done in 26/49 mediastinoscopies and 15/64 EBUS. Of 20 patients who had VATS ipsilateral mediastinal staging, none were N2 positive and there were 0 false negatives. This left 131 patients who did not received indicated staging. The most common indication in this group was central location, 83.2% (n = 109). Four of these unstaged patients were N2 positive at resection (3.1%). The sole indication for these 4 patients was a centrally located tumor. Clinical tumor sizes were 1.2 cm, 1.3 cm, 1.5 cm, and 1.9 cm. Overall, the N2-positive rate of the staged group was 24/144 (16.7%) vs 4/131 (3.1%) N2 positive in the unstaged group, p < 0.001. Conclusions: The current NCCN staging guidelines accurately reflect the risk of N2 disease for NSCLC. The indication of central location for tumors may benefit from being reevaluated in a larger cohort, particularly given efficacy of adjuvant therapy.
Analysis of chemotherapy efficacy according to histology in malignant pleural mesothelioma (MPM) patients (p).
Authors: Cedres Perez Susana , Assaf Pastrana Juan David , Iranzo Patricia , Callejo Ana , Pardo Nuria , Navarro Alejandro , Martinez-Marti Alex , Marmolejo Castañeda David Humberto , Lostes Julia , Gonzalo Javier , Frigola Joan , Carbonell Caterina , Amat Ramon , Pedrola Anna , Dienstmann Rodrigo , Felip Enriqueta
Published: June 2021

e20563

Background: MPM is a highly aggressive pleural tumor associated with asbestos exposure and with limited survival despite systemic therapy. Histology is a prognostic factor and recently CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line with some differences in the efficacy of chemotherapy according to histology. However, randomized trials who led to the approval of antifolate in mesothelioma did not include analysis of outcomes by histology. The objective of this study is to characterize the impact of chemotherapy according to histology in p with MPM at our institution. Methods: We review 189 MPM p diagnosed at Vall d´Hebron University Hospital between November 2002 and April 2020. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: Patient’s characteristics: median age 68 years (y) (45-88 y), males: 70%, performance status (PS)1: 69%, asbestos exposure: 75%, epithelioid subtype: 76%. First line chemotherapy was offered to 85% of p (66% cisplatin-pemetrexed and 27% carboplatin-pemetrexed). Median overall survival (OS) in overall population was 21.3 m (95%CI17.2-24.3). Epithelioid histology, PS 0, neutrophil-lymphocyte ratio <5 and treatment with cisplatin vs carboplatin were associated with significant improvements in OS (p<0.001). When we analyzed the survival of patients who received first line chemotherapy according to histology, we found that patients with epithelioid tumors had better PFS and OS. Median PFS for p with epithelioid tumors treated with chemotherapy in first line was 4.8 m versus 3.6 months non-epithelioid (HR1.5 CI95% 1.1-2.3; p=0.03). OS of epithelioid p treated with first line chemotherapy was 26.7 m versus 15.0 m non-epithelioid patients (HR2.25 CI95% 1.4-3.4; p<0.001). We analyzed if the differences in survival according to histology were due to type of systemic treatment received (Table). Conclusions: In our series, p with non-epithelioid tumors presented worse prognosis. We confirmed histology is a prognostic factor with better OS for p with epithelioid tumors. Moreover, we demonstrated better efficacy of chemotherapy in epithelioid tumors, although histology is not a predictive factor for the platinum agent sensitivity (p of interaction PFS=0.09, p of interaction OS= 0.65).[Table: see text]
Multivalent state transitions regulate the intratumoral composition of small cell lung carcinoma.
Authors: Gopal Priyanka , Petty Aaron , Bareja Rohan , Bera Titas , Rogacki Kevin , Patel Jyoti D. , Peacock Craig , Abazeed Mohamed E.
Published: June 2021

e20587

Background: Small cell lung carcinoma (SCLC) is an aggressive, tobacco-associated tumor with neuroendocrine features characterized by rapid growth, metastatic progression, and initial response followed by almost invariable resistance to therapy. Studies to date have not resolved the extent that diverse transcriptional programs drive SCLC and contribute to its lethality. Methods: We combined one of the largest and most diverse inventories of patient-derived xenograft models of SCLC with an ex vivo culture system that maintains transcriptional fidelity with matched primary SCLC tumor to identify transcriptional state heterogeneity. Using the expression of the Ascl1, NeuroD1, and Yap1 as markers of well-conserved SCLC states, we developed a state-of-the-art fluorescent platform that can directly measure single-cell state transitions in a multi-layered ecosystem using tandemly integrated reporters. We modeled population dynamics using a discrete time Markov chain and directly measure single-cell state transitions. Results: We show significant cell-state heterogeneity in several SCLC primary tumors, patient-derived xenografts (PDX), and ex vivo cultures. These states comprise distinct subpopulations marked by the master regulatory transcription factors (TFs) Ascl1, NeuroD1, and Yap1. Ex vivo, the 3 TFs are associated with suspension aggregates of small neuroendocrine cells, pre-suspension (loosely adherent) aggregates, and large mesenchymal cells with visible cytoplasm and spindle-like membrane extensions, respectively. We have observed equilibria in cell-state proportions in SCLC tumors both in vivo (PDX) and ex vivo. In addition, we have shown that the “elasticity” of SCLC responses, measured as the extent of clinical response during chemotherapy followed by the time to relapse from the end of therapy, is dependent on tumor TF levels. These observations suggest that mechanistic modeling of intra-tumoral state dynamics is of high clinical relevance. Conclusions: Our integrative approach is poised to formulate and validate a unified model of cellular states and program diversity in SCLC. If successful, the characterization of malignant cell ontogenic programs, their plasticity, and the advancement of new therapies designed to combat plasticity by epigenetic reprogramming will create a new scientific canvas for the study of this highly lethal disease.
Exploring the applicability of immunotherapy in different EGFR mutation subgroups based on data analysis of 9,659 Chinese patients with NSCLC.
Authors: Peng Hao , Zhang Hushan , Zhang Libin , Wang Yang , Shen Xudong , Huang Depei , Xu Zheyuan , Wang Han
Published: June 2021

e21020

Background: Here we assessed TMB level, PD-L1 expression, and their correlation in 9649 Chinese NSCLC patients with or without EGFR mutation, and different subtypes of EGFR mutations, to find out the underlying mechanisms that different outcomes of ICI for EGFR wild type and EGFR mutation NSCLC patients, and the possibility of ICI therapy for NSCLC patients of different EGFR mutation subtypes. Methods: Tumor tissue samples of 9649 NSCLC patients were collected from Janary 2018, expression of PD-L1 were detected by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. Gene mutation was detected by means of next generation sequencing (NGS). Performed Whole-Exome Sequencing (WES) on 70 tissue samples and corresponding White Blood Cells (WBCs) as matched control. Other samples were detected with panel covering whole exon regions of 733 cancer related genes. All these detections were performed in a College of American Pathologists (CAP)-certified and Clinical Laboratory Improvement Amendments (CLIA)-accredited lab for gene mutation analysis (3D Medicines Inc.,Shanghai, China). Statistical analysis was performed using GraphPad Prism (version 7.01) and SPSS version 21.0 (SPSS,Inc.). Results: Results showed that the proportion of EGFR mutation in Chinese patients with NSCLC was 51.3%, and the proportion of EGFR mutation subtypes were 42.6% L858R, 39.5% exon 19del, 2.3% exon 20in, 4.3% T790M. These samples were divided into different groups according to EGFR mutation, both WES based and panel-based results showed that EGFR wild type group displayed higher TMB level than EGFR mutation group (P < 0.05). However, except for exon 19del, L858R, exon 20in, no significant differences were found between wild type and other EGFR mutation subtypes. Furthermore, results of IHC revealed that, higher proportion of strong positive PD-L1 expression (TPS≥50) were found in EGFR wild type than exon 19del, L858R and exon 20in, no significant correlation was found between TMB level and PD-L1 expression. Conclusions: EGFR mutations account for half of Chinese NSCLC patients. The biomarkers of immune checkpoint inhibitors (such as TMB and PD-L1) are different in various EGFR mutation subtypes, which may indicate that for some NSCLC patients with EGFR mutation subtypes, they may also respond to ICI treatment as wild-type.
Real-world experience of dacomitinib in EGFR mutated advanced NSCLC: A single center experience from India.
Authors: Biswas Bivas , Ganguly Sandip , Ghosh Joydeep , Roy Somnath , Bakshi Rupsa , Dabkara Deepak
Published: June 2021

e21043

Background: Dacomitinib is an irreversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) approved in advanced non-small cell lung cancer (NSCLC) with mutated EGFR. Literature on real world experience of dacomitinib is lacking, especially in patients (pts) with brain metastasis and uncommon EGFR mutation. Methods: This is single center retrospective study of EGFR mutated advanced NSCLC patients treated with dacomitinib between July’19 and Dec’20. All patients received dacomitinib at 45 mg once oral dose except few with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-3 and elderly received 30 mg once daily. Clinicopathologic features, treatment details, toxicity and treatment outcome were recorded. Progression free survival was calculated from start date of dacomitinib till date of progression. All pts underwent re-biopsy with evaluation for EGFR T790M at progression. Results: Total 43 pts were treated with median age of 63 years (range:43-81) and M: F ratio of 22:21. 26 pts accessed the drug through early access program, 6 pts through clinical trial and rest through commercially available product. ECOG PS was 1 in 29 pts, 2 in 13 pts and 3 in 1 patient. Ten patients had brain metastasis (out of evaluated 38) and 9 received whole brain radiotherapy. Type of mutations was Del 19 in 27 pts, L858R in 12 pts, G719X in 2pts, and Del 19 + L858R, L861Q in one patient each. Histopathology types were – adenocarcinoma in 39 pts, adenosquamous in 2 pts, NSCLC-not otherwise specified and squamous histology in one patient each. Starting dose of dacomitinib was 45 mg in 34 pts and 30 mg in 9 pts. 39 pts had any grade of toxicity and 20 pts (47%) had any grade 2 & 3 toxicity- mostly diarrhea and acneiform skin rash. Total 18 pts (42%) required dose modification (all from 45 mg to 30 mg). 38 pts have evaluable response: complete response in 2, partial response in 34 and stable disease in 2 pts. 8 out of 10 pts with brain metastases had partial response. All three pts with uncommon EGFR mutation had partial response. Five pts underwent re-biopsy on subsequent progression (4 had Del 19 and one had L861Q) and two developed EGFR T790M mutation. Six patients died (5 died of infection and one died of acute myocardial infarction). After a median follow-up of 13.8 months (range: 1.2-20.1), the median PFS not reached (95% confidence interval [CI]: 17.9, not reached) and 2-yr PFS was 57.5%. Conclusions: This is the largest experience of dacomitinib in EGFR mutated advanced NSCLC from Indian subcontinent. This is first reported activity of dacomitinib in pts with brain metastasis and uncommon EGFR mutation. Response rate was high and durable. 42% pts on 45 mg oral daily dose required dose modification due to toxicity. 30 mg once daily may be an optimum dose of dacomitinib in Indian pts.
Efficacy of stereotactic body radiotherapy for oligoprogression on PD-1 axis inhibitors in advanced non-small cell lung cancer: A single-center retrospective study.
Authors: Wang Zhen , Li Jing , Zhou Han , Li Si , Zhu Xi-xu
Published: June 2021

e21065

Background: Immunotherapy has brought considerable benefit for patients with advanced non-small cell lung cancer (NSCLC), while acquired resistance could occur, of which most were oligoprogression. Adding locoregional therapy into the current systematic treatment could significantly improve the survival of oligoprogressed group. One of the conventional locoregional therapy for oligoprogression is stereotactic body radiotherapy (SBRT), however efficacy of combing SBRT to the ongoing PD-1 axis inhibitors was unclear in oligoprogressive NSCLC. Methods: In this study, we retrospectively reviewed data of patients with advanced NSCLC, who received SBRT on oligoprogressive lesions after acquired resistance to PD-1 axis inhibitor (First line or more) in our hospital, between June 2015 and June 2019. Acquired resistance was defined as initial CR/PR (by RECIST) followed by progression/death. Oligo patterns of acquired resistance were defined as progression in ≤ 3 sites of disease. We summarized the locoregional control rate (LR), progression-free survival (PFS) and overall survival (OS) after SBRT. Results: A total of 18 patients were included, 5 females and 13 males. The median age was 63 years (range: 37-82). 10 (55.6%) patients had a PD-L1 expression > 1%, 13 (72.2%) received combination therapy (anti-PD-1+chemo/antivascular), duration of immunotherapy was longer than 24 months in 9 (50%) patients. After acquired resistance, 25 sites of oligoprogressive lesions were identified (11 in brain, 5 in lung, 3 in lymph node, 3 in bone, 2 in adrenal, 1 in liver), the median maximum dimension was 14.8 cm (range, 10 to 79 cm). The SBRT dose were 30-55 Gy/2-6 fx, with the median biological effective dose at 60 Gy (range: 45-124.8). At a median follow-up of 28.5 months (range: 15-60), 12 (48%) lesions achieved complete response, 7 (28%) had a partial response, 4 (16%) remains stable and 2 (8%) developed progressive disease. The 1 and 2 years’ LR were 100% and 77.8% respectively. The median PFS was 10 months (range: 7-18). Among them, 44.4% and 14.8% had a 1 and 2 years of PFS, and 87.5% and 60% achieved 1-year and 2-year survival respectively. Conclusions: We observed that SBRT for oligoprogression can improve disease control and bring survival benefit, suggesting that SBRT could be considered in patients with oligoprogression after required resistance on immunotherapy in NSCLC. Meanwhile, prospective evaluation or stratified analysis with larger sample size was needed to verify its efficacy and safety in specific group.