bluuebunny/crossref_metadata_2025 huggingface dataset:
A matching-adjusted indirect treatment comparison of elranatamab in patients with triple-class exposed relapsed/refractory multiple myeloma: Comparisons with belantamab mafodotin, selinexor plus dexamethasone, and real-world physician’s choice of treatment.
Authors: Hlavacek Patrick , Mol Isha , Hu Yannan , Cappelleri Joseph C. , Chu Haitao , Aydin Didem
Published: June 2023

e20038

Background: Elranatamab, a bispecific antibody targeting B-cell maturation antigen on multiple myeloma (MM) cells and CD3 on T cells, is being evaluated as a monotherapy in the MagnetisMM-3 trial (MM3; NCT04649359) in patients with triple-class exposed (TCE) relapsed/refractory MM. While there is no standard of care for TCE MM, belantamab mafodotin (belamaf) and selinexor plus dexamethasone (sel-dex) are treatment options. LocoMMotion is a prospective, non-interventional study investigating real-world physician’s choice of treatment (PCT) in patients with TCE MM. In the absence of head-to-head trials, unanchored matching-adjusted indirect comparisons (MAIC) were conducted to compare the relative efficacy across comparators. Methods: Individual patient-level data were obtained for elranatamab from MM-3 (data cut Oct 2022). Aggregated data for belamaf, sel-dex, and PCT were obtained from DREAMM-2 (NCT03525678), STORM (NCT02336815), and LocoMMotion (NCT04035226). Unanchored MAICs were conducted to compare the relative treatment effect on objective response rate (ORR) accounting for potential different distributions of prognostic variables (PVs) and effect modifiers (EMs). In the base case, PVs identified via logistic regressions based on MM-3 data were adjusted. In sensitivity analyses, PVs/EMs identified from the literature were added. Relative treatment effects were measured by rate differences and odds ratios. Results: After MAIC adjustments, the selected PVs/EMs were balanced in each comparison. The table presents the results from the naïve comparison with no MAIC adjustment plus the MAIC base case. The ORR of elranatamab was statistically higher than belamaf, sel-dex, and PCT in LocoMMotion. Results were consistent across all sensitivity analyses. Conclusions: Elranatamab had a significantly higher ORR than belamaf, sel-dex, and real-world PCT in LocoMMotion for patients with TCE MM, demonstrating its clear clinical benefit for this population. [Table: see text]
The efficacy of autologous hematopoietic cell transplantation in standard risk multiple myeloma refractory to multiple therapies.
Authors: Awada Hussein , Hajj Ali Adel , Tabaja Chadi , Khouri Jack , Anwer Faiz
Published: June 2023

e20039

Background: Patients with multiple myeloma (MM) of standard risk (SR) cytogenetics generally experience better outcomes compared to high risk (HR) disease. However, it remains poorly understood why outcomes amongst SR MM patients are highly variable, especially after autologous hematopoietic cell transplant (AHCT). Here, we investigated the outcomes of AHCT in SR MM patients who failed multiple therapies pre-AHCT. Methods: We reviewed all MM patients who underwent AHCT at the Cleveland Clinic between January 1, 2011 and January 15, 2021. Demographic characteristics, comorbidities, International Scoring System (ISS) stages, serum and bone marrow studies, pre-AHCT treatments, and maintenance therapy were obtained from electronic medical records. SR MM was considered in patients without t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Patients were divided into 4 groups of 1, 2, 3 or ≥4 therapies pre-AHCT. The primary outcome studied was median time to either progression or death, reported as time to event (TTE) and determined by Kaplan Meier analysis. Results: We reviewed a total of 517 patients, among whom 279 were determined as SR MM and hence were included in our analysis. Of this cohort, 188 patients received a single line of therapy, 63 patients received 2 lines, 32 patients received 3 lines, and 10 patients received ≥4 lines pre-AHCT. The baseline demographic and clinical characteristics were then compared between the groups and they showed similar age at AHCT (61 vs 60.6 vs 59.6 vs 59.9 years, P=0.8), albumin levels (<3.5 g/dL 22.4 vs 22.8 vs 16.7 vs 50%, P=0.2), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score (≥3 40.4 vs 47.6 vs 65.6 vs 60%, P=0.1), Male preponderance (54.8 vs 65.1 vs 65.6 vs 50%, P=0.4), ethnicity (White 82.4 vs 84.1 vs 78.1 vs 90%, P=0.8), ISS stages (P=0.7), MM immunoglobulin subtype (IgG 28.7 vs 20.6 vs 18.8 vs 30%, P=0.6), on single agent maintenance (8.9 vs 19 vs 13.8 vs 0%, P=0.1), respectively. The only significant differences between the four groups were smoking history (34.9 vs 53.2 vs 40.6 vs 60%, P=0.045) and time from diagnosis to transplant (>12 months 21.3 vs 44.4 vs 75 vs 100%, P<0.0001) reflecting resistance to therapies. Kaplan-Meier analysis for median TTE revealed a significantly shorter median TTE for the ≥4 therapies group at 8 months vs 54.5, 55.9 and 67.7 months for the 1, 2, and 3 pre-AHCT therapies groups. Conclusions: SR MM patients who require ≥4 therapies pre-AHCT have poor outcomes post-transplant. We suggest the use of AHCT early in the course of myeloma treatment given the shorter time to progression as also shown in randomized trials.
In hospital outcomes and mortality predictors of multiple myeloma on stroke hospitalizations: A multivariable logistic regression study on the National Inpatient Sample Database.
Authors: Shah Zunairah , Younas Hafiz Muhammad Waqar , Rehman Mohammad Ebad Ur , Taha Amro , Baloch Ali Shahbaz Shehbaz , Khir Fadi , Badu Irisha , Basit Jawad , Sandhyavenu Harigopal , Ali Shehzad , Anwer Faiz
Published: June 2023

e20048

Background: Multiple Myeloma (MM) patients have a higher risk of stroke due to a hypercoagulable state. A study by Liu et al. 2014 reported a 1.23 times higher incidence of stroke in MM patients compared to the matched cohort. Another study by Lee et al. 2016 reported a 5-year estimated cumulative incidence rate of 7.45%. Bortezomib therapy is an independent risk factor for stroke. However, data on the inpatient outcomes of MM on stroke hospitalizations is limited. Therefore, we conducted a nationwide population-based study investigating in-hospital outcomes and mortality predictors of MM in stroke hospitalizations. Methods: The national inpatient sample database from 2016-2019 was queried to identify patients with a primary diagnosis of stroke and stratified based on the presence of MM as a secondary diagnosis. The adjusted odds ratios (aOR) of in-hospital outcomes were calculated using multivariable logistic regression using STATA v.17 software. The primary outcome was in-hospital mortality. Results: A total of 2,028,240 weighted hospitalizations with stroke were identified between 2016-2019, of which 4,240 were associated with MM. On adjusted analysis, stroke-MM patients have statistically significant higher odds of in-hospital mortality (aOR 1.33, CI 1.01-1.40, P<0.001). Furthermore, the presence of fluid and electrolyte imbalance, complicated diabetes mellitus, and coagulopathy were found to be independent predictors of mortality. However, the odds of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), and cardiac arrest were similar between stroke patients with and without MM. Bleeding risk was not assessed, given the low sample size. Additionally, no significant statistical difference was found between the two cohorts regarding the length of hospital stay and cost of hospital stay. Conclusions: Stroke patients with MM have significantly higher odds of in-hospital mortality than those without MM. Given the increased mortality risk, physicians should pay particular attention to optimizing the modifiable risk factors of stroke. Large-scale prospective trials are needed to identify the patients at the highest risk. [Table: see text]
Identifying associations between race and gender in the incidence and mortality of patients with multiple myeloma.
Authors: Ghosh Aditya Kumar , McGuire Nicole , Ruiz Vega Ruben , Alaws Hossny , Adewunmi Comfort , Abidoye Oluseyi , Caton Andria P , Johnson Andrew Thomas
Published: June 2023

e20052

Background: Multiple Myeloma (MM) is a plasma cell malignancy due to proliferation of malignant clonal plasma cells. Prior studies have shown that overall incidence of MM was 8.47 per 100,000 individuals. It has also been seen that the incidence of MM has trended upwards in non-Hispanic white (NHW) males and non-Hispanic blacks (NHB) across all age groups. This retrospective, database-driven population study sought to further assess racial and gender-based differences in the trends of the incidence of MM and mortality from MM. Methods: Data obtained from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry 17 were available to assess trends of multiple myeloma incidence and mortality from 2000 to 2019. Trends were described as average annual percentage change (APC) rates. Results: A total of 102,467 MM patients were identified in this data set; 56,508 (55.1%) were males and 45,949 (44.8%) were female. The distribution of MM by race was as follows (in order from highest to lowest): Non-Hispanic White [NHW] patients was 63.2% (N = 64,776), Non-Hispanic Black [NHB] patients was 18.6% (n = 19,099), Hispanic patients was 11.6 % (11,841), Non-Hispanic Asian [NHA] patients was 5.6% (5,769), and Non-Hispanic American Indian [NHAI]/Alaska Native patients was 0.5% (523). Incidence of MM (cases per 100,000 persons) was highest in males (7.5; 95% CI: 7.5, 7.6) and blacks (13; 95% CI: 12.8, 13.2). Overall trend in the incidence of MM has increased significantly for all gender and ethnicity groups over the period from 2000-2019, except for NHA patients. The incidence-based mortality of MM was highest in male (5.2; 95% CI: 5.2, 5.3) and black (8.7; 95% CI: 8.5, 8.8) patients. The overall incidence-based mortality increased significantly in males APC 4.1% (95% CI: 2.2,5.9; p < 0.001), females APC 3.6% (95% CI, 1.8,5.5; p < 0.001) and all ethnicities - NHW patients APC 4.1%, (95% CI, 2.2,6.0; p < 0.001), NHB (APC 4.2%, 95% CI, 2.1,6.3; P < 0.001), NHAI (APC 4.7%, 95% CI, -2.2,7.2; p < 0.001), NHA (APC 3.0%, 95% CI: 0.8,5.2; P = 0.009) and Hispanic (APC 2.9, 95% CI:1.1,4.7; P = 0.003). Conclusions: Population-based trends in MM incidence and mortality, as reported in this study, were increased commensurate with prior reports. Of note, mortality was noted to be highest amongst the NHB and male populations, indicating a need for further research focused efforts in this potentially high-risk population.
Clinicopathologic features and outcomes associated with induction regimen intensity among older veterans with myeloma.
Authors: Kirby Conor , Atweh George , Rosko Ashley Elizabeth , Friedman Daphne Ruth , Yellapragada Sarvari , Vashistha Vishal
Published: June 2023

e20054

Background: More than one third of patients diagnosed with multiple myeloma (MM) are 75 years or older. Though registries and clinical trials have conveyed the disease features across myeloma patients and have confirmed improvement in outcomes with increasing number of frontline induction agents, older patients are disproportionately excluded from these studies. We sought to evaluate the disease characteristics and frontline (FL) induction treatment patterns among older Veterans. Methods: The VA’s Corporate Data Warehouse was queried to identify patients who (1) were diagnosed with MM between January 1, 2016 and December 31, 2019, (2) were 75 years or older at the time of diagnosis, and (3) received at least 1 induction regimen within the VA. Each unique record was reviewed in the VA’s Joint Legacy Viewer, an online platform collectivizing Veteran electronic charts nationwide. Data abstraction was performed to ascertain disease type, cytogenetics, stage, and characteristics of treatment regimen(s) by reviewing provider progress notes and treatment notes. Presence of del(17p), t(4;14), t(14;16), t(14;20), or gain 1q by FISH defined high-risk cytogenetics. Median composite progression-free survival (PFS), defined as the interval between date of FL induction initiation and the earliest date of second induction or death, was computed for Veterans based upon number of drugs in their FL induction regimens. Results: A total of 199 Veterans met selection criteria, with a mean age of 83.0 (SD 4.8) years at start of treatment. Of the 84 patients with documented cytogenetics, 44 (52.3%) had high-risk disease, and 6 (7.1%) had 2 or more deleterious cytogenetic findings. The majority (52.8%) of patients received only 1 induction regimen, and only 44 (22.1%) patients received maintenance therapy following frontline induction. 1 patient underwent autologous stem cell transplant, and 1 was referred for chimeric antigen receptor T-cell therapy. Within FL induction regimen, 104 (52.3%) received 2 drugs and 88 (44.2%) received 3 drugs. Induction therapy selection was unrelated to disease stage (p = 0.556) or cytogenetic risk (p = 0.335), but patients 80 years or older were more likely to receive 2-drug therapy (p = 0.012) than those between 75 and 79 years. No difference in median composite PFS was observed between patients receiving 2 drugs (10.1 [4.5 – 21.7] months) and those receiving 3 drugs (10.7 [5.0 – 20.3] months) (p = 0.733) in FL induction regimen. Conclusions: In a real-world study of older Veterans with MM bearing a high rate of high-risk cytogenetics, the median PFS with FL induction is only 10 months, but a more intensive FL 3-drug induction regimen is not more beneficial than a 2-drug. Less intense treatment planning is most reasonable for geriatric patients. Larger investigations evaluating cytogenetic results across Veterans with MM should be considered.
Impact of time period of diagnosis, race, and military exposures on the survival of US military veterans with multiple myeloma and/or plasmacytoma.
Authors: Mahmood Sharmeen , Gupta Pankaj , Ma Helen
Published: June 2023

e20061

Background: The aging veteran population represents a unique demographic with potential exposures to carcinogens. Multiple myeloma has been linked to exposure to Agent Orange, burn pits, radiation, and water contamination. There have been remarkable advances in the management of multiple myeloma. We investigate whether the survival of veterans diagnosed with multiple myeloma and/or plasmacytoma has changed over time. Methods: Using ICD-O criteria we identified 14,026 veterans diagnosed with multiple myeloma and/or plasmacytoma between 1/1/2000 and 12/31/2020 in the national electronic Veterans Administration (VA) medical records. Variables including age and date of diagnosis, race, gender, branch of military service, tobacco use, military exposures, cause of death and survival were analyzed. Patients were subdivided into 4 time periods for analysis based on date of diagnosis: Group 1 (1/1/2000-12/31/2005), Group 2 (1/1/2006-12/31/2010), Group 3 (1/1/2011-12/31/2015), Group 4 (1/1/2016-12/31/2020). Results: Of the 14,026 cases, 98% of patients were male, 58% were white and 28% black; 57% were current or previous tobacco users, 26% were never users. The table summarizes military exposures and causes of death. Median overall survival (OS) for Group 1 was 0.9 years [95% CI, 0.8-1], Group 2 was 2 years [95% CI, 1.8-2.9], Group 3 was 2.8 years [95% CI, 2.6-2.9], and Group 4 was 3.5 years [95% CI, 3.3-3.6]. These differences in OS were statistically significant (p<0.0001). Deaths attributed to myeloma accounted for 67%, 65%, 63%, and 56% of patients in Group 1, 2, 3, and 4, respectively. On multivariable analysis of 6023 cases where selected variables were consistently available, tobacco use, exposure to Agent Orange or burn pits, older age and earlier time period of diagnosis were significantly associated with shorter survival. However, race did not significantly impact survival. Conclusions: In US military veterans diagnosed with multiple myeloma and/or plasmacytoma, survival has significantly improved over the past two decades. Survival was adversely impacted by tobacco use and military exposures, but not impacted by race. Advances in diagnosis, therapies and supportive care may have contributed to the observed improvement in survival over time. Future research should investigate if differences exist in the pathophysiology of malignancies developing in veterans with military exposures, and whether novel treatments can improve their outcomes. [Table: see text]
Peripheral pre-existing cancer-antigen specific T-cell immunity as predictive biomarker for immunotherapy in NSCLC patients.
Authors: Xagara Anastasia , Fortis Sotirios P. , Goulielmaki Maria , Koinis Filippos , Chantzara Evangelia , Kokkalis Alexandros , Samaras Ioannis , Papadopoulos Vasileios , Georgoulias Vasileios , Baxevanis Constantin N , Kotsakis Athanasios
Published: June 2023

e20504

Background: Pre-existing Tumor Antigen specific T-cells describe the endogenous adaptive immunity before any treatment that may represent a valuable novel predictive biomarker for ICI treatment. We investigate the potential value of pre-existing cancer-antigen specific CD8+ T-cells as a circulating predictive biomarker. Additionally, we analyze the major differences of known immune-cell phenotypes between Pre-existing positive (PreI+) and Pre-existing negative immunity (PreI-) NSCLC patients. Here, we present the preliminary results of this study. Methods: Blood was collected from 24 patients with NSCLC, stage III PD-L1+, after completion of radical chemoradiation, before initiation of maintenance durvalumab. PBMCs were isolated with Ficoll density gradient centrifugation from patients and 10 healthy donors (HD). PreI was calculated by detecting endogenous IFNg expressing cells with FACS after in-vivo co-cultures of PBMCs with mixes of hTERT, MAGEA1, NY-ESO-1 και Survivin cancer-associated antigens. Immunophenotyping was performed by multi-color flow cytometry using antibodies against CD3, CD4, CD8, CD45RA, CD45RO, CCR7, PD-1, PD-L1 for T-cells. Results: From 24 patients receiving Durvalumab, 10/24 (41.6%) had peptide specific T-cells (PreI + patients), 60% (6/10) had detectable peptide specific T cells for all (4/4) antigens tested. Survival analysis revealed better PFS in PreI+ than PreI – patients (Log-rank = 0.06, median 333.5 and 185 days ) and better OS (p = 0.032, median not reached and 254 days). The levels of CD3CD4PD-1 were higher in patients compared to HD (p = 0.019) but there was not a difference between PreI+ and PreI- patients (p = 0.25). PreI+ patients had significantly higher numbers of CD3CD8PD-1 cells compared to PreI- (p = 0.024) but not CD3CD8PD-L1. Prei+ patients had high numbers of Teff (CD3+CD8+CD45RA+CD45RO-CCR7) compared to both HD (p = 0.0039) and PreI- (p = 0.032). Conclusions: Pre-existing tumor antigen specific immunity before initiation of ICI in NSCLC patients could serve as a good predictive factor of response. The study is ongoing.
Clinical and molecular Characterization of NSCLCs with MET exon 14 skipping mutation coexist MET amplification.
Authors: Tian Huimin , Tan Yuan , Zhang Qin , Duan Qianqian , Sun Tingting , Qi Chuang
Published: June 2023

e20506

Background: MET exon 14 skipping mutation (METex14) and MET amplification are the most prevalent molecular alterations associated with MET carcinogenesis in non-small cell lung cancer, with respective frequencies of 3-4% and 1-5%. Recent research indicates that patients with METex14 may also carry MET amplification, and that MET-TKI therapy has a higher response rate in this patient population. We evaluated the clinical and molecular characteristics of patients with altered or co-altered MET using NGS data of non-small cell lung cancer cases from Jiangsu Simcere diagnostic Co., ltd. Methods: During 2019-2021, samples from 33074 NSCLC patients underwent comprehensive genomic profiling (CGP) using hybrid-capture technology at the Simcere diagnostic laboratory (Nanjing, China). To detect gene mutations in tumor tissue or blood samples of patients, next-generation sequencing (NGS) was performed. MET amplification was defined as MET copy number greater than 2.25. Results: MET exon 14 skipping was found in 325 pts (0.98%), MET amplification was found in 136 pts (0.41%), and the co-alter population consisted of only 36 pts (0.11%). Receptor, Donor, D1010, Y1003, and other METex14 subtypes represented 12.0%, 36.6%, 24.6%, 0.2%, and 26.2%, respectively, of the population. Then, we divided MET-altered NSCLC patients into three groups: MET14 (carrying only METex14), AMP (carrying only MET amplification), and MET14& (MET14 concomitant MET amplification). The differences in age, gender, TMB copy number, and MET copy number were then compared between these groups. Patients with AMP were considerably younger than those with METex14& or AMP. (MET14&: 69.0±9.27 vs AMP: 63.5±10.6, P = 0.032; MET14: 70.0±10.9, P < 0.001). The AMP group contained significantly more male patients than the MET14 group (68.0% vs. 54.5%, P = 0.019), but there were no significant differences between the remaining groups. In contrast to tissue-based TMB, the AMP group was significantly higher than the other two (AMP:17.059.5 vs MET 14: 2.945.79; P0.001; MET14&: 3.650.63, P = 0.005). In spite of this, there was no statistically significant difference between the AMP and MET14 & AMP groups in terms of MET copy number or percentage of MET CN > = 10. Conclusions: In general, AMP pts are younger and have a higher TMB than co-alteration pts; however, there is no significant difference in MET CN between AMP and co-alteration pts; whether the coexisting group is sensitive to MET-TKI is unknown, and future research should focus on the treatment of co-alteration and AMP pts.
Comparing the prognostic implications of spread through airspaces versus lymphovascular invasion in non-small cell lung cancer.
Authors: Epstein Rebecca Elizabeth , Seetharamu Nagashree , Esposito Michael J.
Published: June 2023

e20509

Background: Risk stratification for patients with non-small cell lung cancer (NSCLC) has historically been evaluated using TNM staging, but there are several other pathological features that have been identified as poor prognostic factors such as lymphovascular invasion, visceral pleural invasion, micropapillary pattern, and more recently, spread through airspaces. There is considerable data linking lymphovascular invasion to poor prognosis and emerging data suggesting spread through airspaces as a poor prognostic factor, but there is limited data comparing the prognostic power of lymphovascular invasion to spread through airspaces. This study aims to distinguish lymphovascular invasion from spread through airspaces as a prognostic factor and to further investigate the correlation of these to other pathologic markers. Methods: Retrospective review of the histopathologic diagnosis, recurrence, and survival status of 720 patients who underwent surgical excision of NSCLC between 2015 and 2019 was conducted. The relationships between pathological factors and prognosis were evaluated with chi square tests and a binary logistic regression was performed. Patients with stage V disease and those treated with neoadjuvant chemotherapy were excluded. Prognosis was assessed using documentation of recurrence of the primary tumor and survival status at the time of chart review. Results: Of the 720 patients, 61 patients had lymphovascular invasion (7.2%) and 56 patients had spread through airspaces (7.1%). Lymphovascular invasion was associated with a statistically significant increase in recurrence and patient mortality across stages I-III collectively, and stage I disease independently. Spread through airspaces was not associated with a statistically significant increase in recurrence or patient mortality in stage I-III or in stage I disease independently. Lymphovascular invasion was also significantly correlated to a greater number of nodal metastases, higher frequency of a micropapillary component, higher frequency of visceral pleural invasion, and increased tumor size. Spread through airspaces was significantly correlated to each of the same pathological risk factors except increased frequency of visceral pleural invasion and increased tumor size. Conclusions: The presence of lymphovascular invasion increases risk of recurrence and mortality and is associated with all of the additional pathological risk factors measured making it more relevant pathologically and prognostically than spread through airspaces.
Tumor immune microenvironment (TIME) analysis of stage I lung adenocarcinoma with micropapillary pattern.
Authors: Han Yun , Yu Yue , Xu Chongyuan , He Qianru , Zhang Qin , Sun Tingting , Qi Chuang
Published: June 2023

e20510

Background: Micropapillary is one of the most aggressive histologic subtypes of lung adenocarcinoma, which is considered a poor prognostic marker. Comprehensive analysis of tumor immune microenvironment (TIME) features of micropapillary of early invasive lung adenocarcinoma may provide better insight and facilitate the development of novel strategies for early detection and intervention. Methods: A total of 15 patients who underwent anatomical resection and were pathologically diagnosed with stage I micropapillary adenocarcinomas were included in this study. Gene expression profiles (GEPs) of tumor immune-related 289 genes were analyzed using NanoString nCounter. Differentially expressed genes(DEGs), estimation of TIME cell infiltration, and TIME signatures between micropapillary and non-micropapillary were assessed. Results: The number of micropapillary and non-micropapillary patients was 5 and 10. The comparison revealed CD69, IL6, CXCL8, CXCL2, POLR2A and so on were significantly upregulated in the micropapillary group compared with the non-micropapillary group, while HLA-DPA1, IFIT2, and other seven genes were down-regulated in the micropapillary group. These DEGs were mostly enriched in “positive regulation of cytokine production”， “T cell activation”， “receptor ligand activity，” and “signaling receptor activator activity” pathways according to GO enrichment analysis. The results of the KEGG analysis revealed that genes were significantly enriched in “IL-17 signaling pathway”, “TNF signaling pathway”, “cytokine-cytokine receptor interaction”, and so on. Meanwhile, different immune infiltration of the two groups was analyzed. Totally, there was a better TIME cell infiltration in the micropapillary group compared with the non-micropapillary group. Especially, the score of DCs and mast cells was significantly higher in micropapillary group. However, TIME signature scores were similar in both groups. Conclusions: Our study demonstrated that the TIME between micropapillary and non-micropapillary of stage I lung adenocarcinoma was different. Increased mast cells explained poor prognosis in lung adenocarcinoma with micropapillary pattern. A high level of DCs infiltration indicated that micropapillary adenocarcinoma might benefit from immunotherapy.
Association of CAR-T cell secreting CD47 blocking protein with an enhanced antitumor activity in small cell lung cancer.
Authors: Guo Fuchun , Ma Qizhi , Wang Yongsheng
Published: June 2023

e20512

Background: Notch ligand family DLL3 has been considered a therapeutic target for small cell lung cancer. CD47/SIRPa is an important immunosuppressive factor in the tumor microenvironment and is considered to be a "checkpoint" of innate immune cells. Here, we described an DLL3 targeting CAR-T cells secreting CD47/SIRPa signal blocking protein. We hypothesized that the armored CAR-T cells, by blocking the CD47/SIRPa signal with specific antibodies may promote macrophages to engulf tumor cells and induce anti-tumor immune response, thus addressing a clinical need of cell therapy in SCLC. Methods: Bioinformatics analysis of immune cell composition in the microenvironment of small cell lung cancer, focusing on macrophage content and phenotypic characteristics. The CAR genes were cloned into the lentiviral vector pWPXLd, the expression, phenotype, activation, proliferation, killing and cytokine release of CAR-T cells were detected by flow cytometry, Western blot, RTCA and ELISA; NSG mice were injected subcutaneously with H446-DLL3 cells or H446-DLL3(+/-) combined with CAR-T cells or armored CAR-T cells. Tumor size was measured every 3rd day. The number and phenotype of macrophages in tumors were detected by FCM. Results: Bioinformatics analysis showed that tumors with high expression of DLL3 were often accompanied by downregulation of antigen presentation-related genes; there is a large amount of macrophage infiltration in SCLC, and the later the stage, the more the infiltration. CAR-T cells co-cultured with target cells could effectively activate T cells, promote CAR-T cell proliferation, secrete IL-2, IFN-γ and TNF-α cytokines, and specifically kill DLL3 positive tumor cells. We have established a solid tumor model with heterogeneous antigen expression. CAR-T cells can effectively inhibit the growth of tumors with positive DLL3 expression in vivo, but the inhibition on tumors with heterogeneous antigens is not obvious. Blocking CD47 can promote phagocytosis of tumor cells by macrophages. Western blot analysis revealed the presence of CD47 blocking protein CV1-Fc in the supernatant of secreted CAR-T cells, which can effectively promote the phagocytic effect of macrophages; Armored CAR-T cells have a better anti-tumor effect in antigen heterogeneous tumor model in vivo, delays tumor progression, and promotes the aggregation of M1 type macrophages. Conclusions: CAR-T cells that specifically target DLL3 can effectively kill antigen-positive tumor cells in vivo and in vitro. Blocking CD47 can promote the non-specific anti-tumor effect of macrophages. CAR-T cells secreting CD47 blocking protein have dual anti-tumor effects, not only killing antigen-positive tumor cells, but also recruit and activate macrophages to exert phagocytosis, and have better anti-tumor effects in antigenic heterogeneous solid tumors.
Using next-generation sequencing for RET fusion detection in Chinese cancer patients.
Authors: Dang Huashao , Nguyen Thi Phuong Anh , Kai Zhentian , He Hongsheng , Luo Peng
Published: June 2023

e20516

Background: Approval Selpercatinib of FDA for lung and thyroid cancer patients harboured RET mutations or fusions attracts the investigation RET fusion partners and their ability for RET‐based targeted therapy. Here, we presented a genomic characteristics of RET fusion in six cancer type among 24,087 Chinese cancer patients. Methods: Tumor samples (including tissues, formalin-fixed paraffin-embedded or plasma) obtained from patients between March 2021 and February 2023 were used for RET fusion detection. Customed probes were designed to covered all exonic and intronic regions of 6, 10 and 11 for RET. GeneFuse and Delly softwares were used for analyzing RET fusion. To ensure both sensitivity and accuracy of fusion calling, RET fusions were only reported to fuse with a set of 600 cancer-related genes and require at least two individual supporting reads. Results: A total of 233 cases with RET fusion was identified among 24,087 patients with the given six cancer types including lung cancer, thyroid cancer, coloretal cancer, pancreatic cancer, oesophageal cancer and cancer of unknown primary site. A total of 6 fusion patterns were identified in the study cohort with KIF5B, CCDC6, NCOA4 and ERC1 being the most common RET fusion partners. Notably, two novel fusion partners (i.e. GOPC and VCL) were first reported in this study. RET variants frequencies were the highest in thyroid carcinoma (13/210, 6.19%), lung cancer (212/20,402; 1.04%), esophageal cancer (1/156, 0.64%), cancer of unknown primary site (2/374, 0.53%) , pancreatic cancer (1/337, 0.29%) and colorectal cancer (5/2,608, 0.19%). The results of the analysis revealed that different tumor types tend to have preferred fusion partners. For instance, KIF5B is highly specific in lung cancer, account for 72% of cases. Meanwhile, CCDC6 and NCOA4 are both enriched in thyroid cancer (both 46%). NCOA4 also present frequently in colorectal cancer, with 80% of cases displaying this partner. Conclusions: Detection of co‐occurrence of partner and RET fusions provide a guide to clinicians in deciding tumors as candidates for RET targeted therapies.
Comparative analysis of the mutation detection using malignant pleural effusion and blood cell-free DNA samples in lung cancer.
Authors: Lin Yaobin , Ji Sunwen , Jiang Yiling , Wang Tao
Published: June 2023

e20518

Background: Malignant pleural effusion (MPE) is an abnormal amount of fluid to collect between the chest wall and the lung, and it denotes an advanced malignant disease process. MPE presents a severe medical condition which can result in breathlessness, pain, cachexia and reduced physical activity. MPE is considered to bear cancer signatures because it contains tumor cells released from malignancies, thus can be applied in high-throughput sequencing for cancer screening. Cell-free DNA (cfDNA) in blood consists of small fragments released from apoptotic cells or cancer cells, and pathological conditions can influence this process. Therefore, detection of cfDNA in peripheral blood can identify abnormalities of individuals in a noninvasive manner. Here, we wonder the difference of MPE and cfDNA in lung cancer-related mutation detection. Methods: In this study, MPE and blood samples from 216 patients with late-stage lung cancer were collected and applied to library construction and next-generation sequencing. All samples were collected during August 2018 to December 2022. We focused on the key mutations in cancer-causing genes and drug treatment-related genes (e.g., EGFR, KRAS, BRAF, ERBB2, etc.). Statistical analysis was conducted to compare the detection results between MPE and cfDNA samples by Fisher’s exact test. Results: Among the 216 patients, 60 patients (60/216 = 27.8%) were identified as negative detection with no mutation detected in cancer-causing genes in MPE and blood samples. Of the remaining 156 pairs of samples, there were 118 (118/216 = 54.6%) pairs showing the positive detection in both MPE and blood samples. 12 patients (12/216 = 5.6%) demonstrated the positive detection in blood samples while negative detection in MPE samples. The other 26 patients (26/216 = 12%) demonstrated the positive detection in MPE but negative detection in blood samples. There is no significant difference in detection rates between two types of samples (p = 0.194). Similarity, we next focused on the mutations in drug treatment-related genes and identified 91 patients (91/216 = 42.1%) as negative detection. There were 85 patients (85/216 = 39.4%) showing the same positive detection both in MPE and blood samples. 13 patients (13/216 = 6%) demonstrated the positive detection in blood samples but negative detection in MPE samples. The other 27 patients (27/216 = 12.5%) demonstrated the positive detection in MPE but negative detection in blood samples. No significant difference in detection rates was observed between two types of samples (p = 0.211). Conclusions: The mutation detection results in MPE and blood samples turned out to be consistent in most conditions, suggesting an alternative application of MPE or blood samples in cancer screening. Nonetheless, it is still valuable to integrate the information in both MPE and blood samples for a higher detection sensitivity.
Prospective evaluation of cell-free DNA fragmentation profiles for lung cancer detection.
Authors: Wong Kwok-Kin , Mazzone Peter J. , Tsay Jun-Chieh , Pass Harvey I. , Vachani Anil , Thompson Jeffrey C. , Ryan Allison , Carey Jacob , Jakubowski Debbie , Wu Tony , Zong Yuhua , Portwood Carter , Lumbard Keith , Catallini Joseph , Arjungi Kavita , Birch Ashley , Leal Alessandro , Bach Peter Brian , Scharpf Robert B. , Velculescu Victor E.
Published: June 2023

e20521

Background: Annual lung cancer screening can save lives, but fewer than 10% of eligible persons participate each year. More widespread screening is hindered by cost, inaccessibility, and uncertainty over individual-level benefit vs risk. Screening rates could be raised by a simple, inexpensive initial blood test, if it were sensitive for cancer detection. The DELFI (DNA evaluation of fragments for early interception) technology uses low-coverage, whole-genome sequencing and machine learning to identify patterns of cell-free DNA (cfDNA) fragmentation associated with cancer. Here we report preliminary cfDNA analysis results from DELFI-L101 (NCT04825834), a prospective, observational, multistate case-control study to train and test DELFI classifiers for lung cancer detection. Methods: Enrollees were ≥50 years old with current or previous smoking histories of ≥20 pack-years and recent or planned chest CT imaging. Medical history was recorded at enrollment, and blood samples were collected for DELFI analysis. Repeated 10-fold cross-validation was used to develop a classifier for lung cancer detection. A split study approach is planned for independent validation of the classifier. Results: At this time, 242 individuals with lung cancer and 652 without cancer have enrolled. Most participants were ≥65 years old, and the proportions of men and women were similar. Lung cancer risk factors were present among both cases and controls. Like the lung cancer screening population, approximately half of lung cancer cases were stage I. Median DELFI scores were higher among individuals with lung cancer than no cancer, overall and across groups stratified by age or body mass index (BMI). Cross-validated area under the receiver operator characteristic curve was 0.81 for lung cancer detection. Clinically meaningful sensitivity to detect lung cancer was attained across all disease stages, with sensitivity increasing stepwise with stage. Conclusions: We developed a classifier based on cfDNA fragmentome patterns analyzed using DELFI that could differentiate between lung cancer cases and controls with cross-validated performance across age groups, BMI categories, and cancer stages. A blood-based DELFI fragmentome test could serve as a low-cost, high-performance blood test with potential to improve lung cancer screening efficiency. Clinical trial information: NCT04825834 .
CD73/adenosine pathway-related gene signature for intratumor heterogeneity and immune infiltration in prognosis of lung adenocarcinoma.
Authors: Luo Wang , Zhang Shuhua
Published: June 2023

e20524

Background: Adenosine is an immunosuppressive molecule that can inhibit the activity of immune cells, particularly T cells, and promote tumor growth. CD73, also known as ecto-5'-nucleotidase, is a cell-surface enzyme that plays a role in the adenosine pathway can catalyzes the conversion of AMP to adenosine. Establish and evaluate a prognosis model based on CD73/ Adenosine pathway will help to understanding of the biological mechanisms in lung adenocarcinoma (LUAD) and providing more accurate predictions for patients' treatment. Methods: The RNA sequencing (RNA-seq), whole exome sequencing (WES) and clinical data were obtained from LUAD cohorts of the Cancer Genome Atlas (TCGA). CD73/ Adenosine pathway-related genes were identified by screening for genes that were in both the CD73 STRING network (confidence = 0.9, 1st shell ≤50 interactors) and the KEGG purine metabolism pathway gene list(map00230). Least absolute shrinkage and selection operator (LASSO) regression was conducted to develop a CD73/ Adenosine pathway-related risk score (CD73RS). Time-dependent ROC curve and survival analysis were conducted in LUAD-TCGA cohort to verify the predictive performance of CD73RS. The MATH (Mutant-Allele Tumor Heterogeneity) ITH scores were calculated to evaluate intratumor heterogeneity (ITH) in LUAD-TCGA WES "maf" files using the R package "maftools" and the "math.score" function. TIMER 2.0 database(http://timer.cistrome.org/) was conducted to estimation of tumor microenvironment to further understand the molecular features of CD73RS. An independent cohort (GSE72094) was used to verify the prognostic effect of CD73RS. Results: A prognosis prediction model based on 21 CD73/ Adenosine pathway-related genes was established using LASSO regression. Kaplan-Meier survival analysis of the risk model from LUAD-TCGA cohort showed that the high-risk group had a significantly worse prognosis (HR = 3.298, P = 1.26e-08). The area under the curve (AUC) in time-dependent ROC curve at 1, 3 and 5 years were turn out to be 0.794, 0.722 and 0.686, respectively. The validation set also showed worse prognosis in high-risk group(HR = 1.473,p = 0.0403). In the high-risk group, there was a higher ITH score compared to the low-risk group (p = 0.0094), along with lower infiltration levels of B cells(p = 7.23e-15), CD4+ T cells(p = 0.003), macrophage cells(p = 0.016), and myeloid dendritic cells(p = 0.037). Conclusions: We established and validated a CD73/ Adenosine pathway risk model that exhibits a robust predictive performance for the outcome of patients with LUAD. The CD73/Adenosine pathway has been shown to play a role in both self-driven genomic changes, such as intra-tumor heterogeneity (ITH), as well as non-autonomous processes, such as immune microenvironment adaptation, which contribute to tumor plasticity and development.
Use of immune checkpoint gene (ICG) signatures to identify selective enrichment of FGL1 and CEACAM1 in histologic subtypes of lung cancer.
Authors: Puthanmadhom Narayanan Susrutha , Huang Yufei , Owonikoko Taofeek K.
Published: June 2023

e20527

Background: Immune checkpoint blockade has changed the management paradigm for lung cancer. Identification of vulnerable subsets using reliable predictive biomarkers is an area of unmet need. We systematically compared the pattern of expression of validated mediators of adaptive and innate immune response in clinical and histologic subsets of lung cancer using publicly available datasets. Methods: Gene expression data for lung adenocarcinoma (LUAD, N = 501) and and lung squamous cell carcinoma (LUSC, N = 491) was obtained from The Cancer Genome Atlas. We compared the expression of ICGs between LUSC and LUAD using DESeq2 and estimated the proportion of different immune cells in the tumor microenvironment by CIBERSORT. An expanded panel of ICG signatures from MSigDB was compared between LUSC and LUAD using gene set variation analysis (GSVA). Weighted gene co-expression network analysis (WGCNA) identified modules of immune checkpoint inhibitor genes with significant correlation with histology, which were further investigated for biologic pathway involvement and survival analysis using Ingenuity Pathway Analysis and Gene Expression Profiling Interactive Analysis (GEPIA2), respectively. Results: Majority of the ICGs had a higher expression in LUAD than LUSC with the strongest differential expression recorded for FGL1 (LogFC = 6.2, FDR = 1.2E-239) and CEACAM1 (LogFC = 1.4, FDR = 2E-71). Treg cells and monocytes were higher in LUAD while NK cells and macrophages were higher in LUSC. There was no difference in CD8(+) T cell population by histology. Genesets related to PD1 signaling from MSigDB had significantly higher GSVA scores in LUAD than LUSC. WGCNA identified 2 modules containing immune checkpoint genes – one module containing 15 of the 23 ICGs involved in allograft rejection, interferon gamma response, interferon alpha response, IL6-signaling, IL2-signaling and TNF-alpha signaling showed moderate correlation with LUAD (module-trait correlation = 0.3, P = 8e-26). A second module with 4 ICGs ( FGL1, LGALS3, CEACAM1, PVRL2) enriched in pathways related to carbohydrate and lipid metabolism (galactose degradation, gamma-linolenate biosynthesis) showed very strong correlation with LUAD (module-trait correlation = 0.85, P = 5e-278). Additional comparison by gender and smoking status along with external validation using independent dataset is ongoing. Conclusions: ICG expression profile differs between LUAD and LUSC with a stronger expression profile in LUAD than LUSC.
Influence of increase in hospital costs on mortality for pleural mesothelioma in teaching hospitals: A nationwide analysis.
Authors: Guevara Nehemias , Francis-Morel Garry , Perez Esmirna , Bustamante Alvarez Jean Gabriel
Published: June 2023

e20533

Background: Rural and non-teaching hospitals are known to have a lower budget compared to urban-teaching hospitals. Pleural mesothelioma is an aggressive and rare malignancy, and it remains unknown whether treatment in institutions with higher revenue or reimbursement rates impacts outcomes. This study sought to elucidate if such a difference in outcomes exists. Methods: A retrospective cohort analysis of adults admitted from 2016 to 2020 with the primary diagnosis of pleural mesothelioma was conducted. Data was extracted from the National Inpatient Sample Database. We compared outcomes such as mortality, length of stay (LoS), and total charges in teaching versus non-teaching hospitals. Results: We identified 7,320 patients that met inclusion criteria; 84% were admitted to teaching hospitals, and the remaining 16% to non-teaching facilities ( p < 0.001). Elderly patients were the most afflicted group, with a mean age of 72 to 74 years ( p 0.009). No differences in sex, race, or primary insurance distribution were noted ( p 0.067; p 0.731; p 0.801, respectively). The mean hospital LoS was 6.4 days in non-teaching hospitals compared to 7.7 days in teaching hospitals ( p 0.0061). In addition, Asians ( p 0.016), those with a median household income of 65,000 to 85,999 ( p 0.021), higher Charlson index ( p < 0.001), and those admitted to large to medium size hospitals ( p 0.011; p 0.001, respectively) had a positive linear relation to LoS. Moreover, total hospital charges were greater in teaching hospitals (120,100 USD) in comparison to non-teaching hospitals (73,883 USD) ( p < 0.001). Mortality did not differ based on teaching status ( p 0.643). However, Native Americans and those with higher Charlson comorbidity index were more likely to die ( aOR 21, p 0.004; aOR 1.32, p < 0.001, respectively). Conclusions: Hospital teaching status does not impact mortality in patients admitted with malignant pleural mesothelioma, even though teaching hospitals incur higher expenses on average. It does not come as a surprise due to this condition's known high mortality rate, late presentation in advanced stages, and resistance to current therapies. Prevention is key in a deadly disease, and more research is needed to offer a better prognosis; even though current regimens have shown improvement in survival, curative therapies are still unavailable. Even though asbestos is subject to strict regulations in the United States, it is not banned. We should revisit the idea of a complete ban; those most affected tend to have the least access to healthcare and need a safer work environment. Decreasing exposure to known carcinogens should also be a priority, as there is no better medicine than preventive medicine. Interestingly, mortality was greater in Native Americans compared to other races; the underlying causes are broad and need more research and better characterization of MM.