bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of high-dose melphalan followed by autologous stem cell transplant in producing MRD negative complete response in newly diagnosed multiple myeloma.
Authors: Ebraheem Mohammad , Cook Joselle , Kumar Shaji , Jevremovic Dragan , Dispenzieri Angela , Dingli David , Buadi Francis , Kapoor Prashant , Lacy Martha , Kourelis Taxiarchis , Warsame Rahma M. , Binder Moritz , Muchtar Eli , Hayman Suzanne R. , Go Ronald S. , Leung Nelson , Rajkumar S. Vincent , Kyle Robert A. , Gonsalves Wilson I. , Gertz Morie A.
Published: June 2022

e20001

Background: High dose melphalan followed by autologous stem cell transplant (HDM-ASCT) remains the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) despite advances in treatments. Achievement of complete response (CR) is associated with improved overall survival (OS) and progression-free survival (PFS); Minimal Residual Disease (MRD) negativity (-) using next generation flow cytometry with a sensitivity of 10-5 is strongly associated with improved PFS and OS. We investigated the rates of conversion to MRD(-), especially MRD(-) CR following HDM-ASCT in patients with NDMM. Methods: We retrospectively reviewed patients with NDMM who underwent early HDM-ASCT at Mayo Clinic Rochester from May 2018 to July 2019. Response assessment was conducted after induction and within 100 days post-ASCT based on 2016 IMWG criteria, except for using Mass-Fix instead of immunofixation. MRD was assessed in bone marrow using the established Euro Flow protocol with sensitivity of 10-5. The FISH assay was used to risk-stratify patients as high-risk (HR) and standard risk (SR) cytogenetics as per the mSMART guidelines. Primary outcome measure was the conversion to MRD(-) CR after ASCT. Secondary outcomes include the overall conversion to MRD(-) irrespective of IMWG response, the impact of HR cytogenetics and pre-ASCT IMWG response on conversion to MRD(-) CR. Results: Two-hundred and ten patients were included; 126 (60%) were male and median age 62 years (range 32–77 years). There were 78 (44%) patients with HR cytogenetics. Pre-ASCT, 23 patients (11%) achieved MRD(-) CR, and 66 (31%) patients achieved MRD(-) CR post ASCT. Of 187 patients not in MRD(-) CR pre-ASCT, 45 (24%) converted to MRD(-) CR. Table provides a breakdown of the conversion rate of pre-ASCT IMWG response category to MRD(-) CR post ASCT and patients with MRD(+) CR had the highest rate (78%) of conversion. The presence of HR cytogenetics did not impact rates of MRD(-) CR achievement post ASCT irrespective of pre-ASCT IMWG response (p = 1.0). Overall, irrespective of IMWG response, 43 (20%) patients were MRD(-) pre-ASCT (19 in VGPR, 24 in CR or better) and 102 (49%) patients were MRD(-) post-ASCT (36 in VGPR, 66 in CR or better). Among 85 patients in VGPR post-ASCT, 36 were MRD(-) of which 8 (22%) progressed, while 49 were MRD(+) of which 24 (49%) progressed (p = 0.014). Conclusions: Upfront HDM-ASCT in patients with NDMM leads to deeper responses with 24% converting to MRD(-) CR and more than doubling of the total rate of MRD(-) irrespective of IMWG response. [Table: see text]
Addition of carfilzomib as a third agent in lenalidomide-refractory multiple myeloma: Switching from doublet to triplet.
Authors: Cerchione Claudio , Nappi Davide , Catalano Lucio , Ronconi Sonia , Cangini Delia , Ceccolini Michela , Musuraca Gerardo , Martinelli Giovanni
Published: June 2022

e20002

Background: Carfilzomib is an epoxyketone proteasome inhibitor of second generation, proved to be effective and safe in relapsed and refractory Multiple Myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone. In this retrospective observational trial, it has been evaluated efficacy and safety of carfilzomib, in combination with lenalidomide-dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, where lenalidomide-based regimens have no proven efficacy. Methods: 41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7 years (r. 43-82), median age at start of treatment 67 years (r. 48-84) previously treated with several lines of treatments (median 3, r. 2-11), underwent to KRD regimen (ASPIRE trial schedule) for a median treatment cycles of 8 (r 2-18). ISS was equally distributed, and all patients had previously been treated with bortezomib and IMIDs, and were refractory to this agents. 61% (19/31) of them had undergone at least to a single ASCT. Results: According to IMWG criteria, after a median follow-up of 9 months (r. 2-18), ORR was 68,2% (28/41: 9 CR, 12 VGPR, 7 PR) with 5 progressive diseases (PD) and 8 patients in stable disease (SD): this can be considered as an impressive result in this subset of rrMM patients, refractory to lenalidomide. In particular, for 11 patients, KRD was, after having achieved at least a PR, a bridge to second/third autologous SCT. Median time to response was 1.3 months (r.1-4), median OS from diagnosis was 62 months (r. 9-170), median OS from start of Carfilzomib was 11 months (r. 2-18). Carfilzomib was well tolerated, with grade 2 anemia in 39%(16/41) of patients, successfully managed by ESAs, without necessity of blood transfusions; 29% (12/41) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no ospedalization was required, no septic shocks were observed); 34% (14/41) grade 2, 21% (9/41) grade 3 and 12% (5/41) grade 4 thrombocytopenia, without hemorrhagic events and transfusion-dependency. Moreover, it was observed pneumonia in 39% (16/41) of patients, treated by common antibiotic drugs and always solved. A cardiac monitoring was performed for all patients: hypertension (grade 2-3) in 34% (14/41) of patients; fatigue in 39% (16/31) of patients. Conclusions: Carfilzomib-Lenalidomide-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, also lenalidomide, and it could be considered as a bridge to a second autologous or allogenic SCT. Clinical trial information: A108.
Body mass index and overall survival in multiple myeloma.
Authors: Wang Bei , Derman Benjamin Avi , Langerman Spencer , Stepniak Elizabeth , Johnson Julie , Zhang Wei , Jakubowiak Andrzej J. , Chiu Brian C
Published: June 2022

e20007

Background: Elevated body mass index (BMI) is associated with a higher risk of multiple myeloma (MM), but its influence on survival is unclear. Studies evaluating BMI and mortality of MM have reported conflicting findings and most have limited data on clinical prognostic factors. We evaluated the associations between BMI at different life stages up to the time of diagnosis and overall survival (OS) in a cohort of newly diagnosed patients with MM. Methods: A total of 583 newly diagnosed MM patients were prospectively enrolled between 2010-2019 at the University of Chicago Medical Center. Epidemiology questionnaire and blood samples were collected at the time of diagnosis. We collected baseline clinical, laboratory, cytogenetic, and treatment data from electronic medical records. Vital status was ascertained using the National Death Index. Patients were followed through 31 December 2020 with an average follow-up length of 77.8 months. BMI was calculated using height and weight information collected from electronic health records and questionnaires. OS was defined as time from diagnosis until death from any cause. Chi-squared test and t-test were used to compare characteristics of patients by vital status. Hazard Ratios (HR) and 95% confidence intervals (CI) were derived from Cox proportional hazards models to examine the associations between BMI at different times and OS, adjusting for potential confounders. Stratified analyses were done to examine sex- and race-specific associations. Results: The median age at diagnosis was 63 years, 45% (n = 258) were female, and 27% (n = 150) were African Americans. Of the 572 MM patients, 176 (31%) deaths were identified during the follow-up. There was no significant association between elevated BMI at different time points (i.e., at diagnosis, 5 years before diagnosis, age 20, and maximum adulthood BMI) and OS after adjusting for age, race, sex, and prognostic variables (e.g., stage, serum lactate dehydrogenase levels). No association was found for both African Americans and European Americans. However, for women, obesity (BMI > = 30) at the time of diagnosis was associated with a better OS (HR = 0.25; 95% CI = 0.12-0.54 for obese vs. normal weight) whereas in men, obesity at the time of diagnosis was associated with worse OS (HR = 2.54; 95% CI = 1.18-5.49). Conclusions: We found no association between BMI and OS in MM, irrespective of race. Our data showed that, compared to subjects with normal BMI at the time of diagnosis, female patients with elevated BMI had better survival, whereas a higher BMI was associated with inferior OS among male patients. Our findings of an effect modification by sex are novel and warrant further investigations. These findings might have clinical significance because BMI is amenable to lifestyle modification.
Incidence and risk factors for bacterial infection in newly diagnosed multiple myeloma patients undergoing treatment with bortezomib, lenalidomide, and dexamethasone (RVD).
Authors: Pianko Matthew James , Bici Anisa , Nachar Victoria
Published: June 2022

e20008

Background: Infection is an important cause of morbidity and mortality in newly diagnosed multiple myeloma (NDMM), but the risk of infection using novel treatment regimens is incompletely described in the literature. There are mixed trial results for antibacterial prophylaxis to reduce infection risk in newly diagnosed multiple myeloma and its use remains controversial. Methods: To evaluate the incidence of bacterial infection and early mortality in patients receiving bortezomib, lenalidomide, and dexamethasone (RVD) for NDMM, we performed a retrospective single-center cohort study of patients treated between 01/2014-01/2020. Demographic and clinical data were collected. Two cohorts were generated for those patients with or without bacterial infection during the follow-up period. A multivariate logistic regression was utilized to determine risk factors for bacterial infection. Variables with a P-value <0.2 on univariate analysis were considered for the model. For co-linear variables with a P-value <0.2 on univariate analysis, only one variable was included in the multivariable model. A receiver operating characteristic (ROC) curve was generated to assess the sensitivity and specificity of the model. Results: Of 144 patients, 21 patients (14.5%) experienced a bacterial infection of any grade. 11% of patients received pneumocystis prophylaxis, and 1 patient received levofloxacin prophylaxis. 11 (7.6%) patients experienced grade 3 (G3) or higher infection. One patient died in our cohort; there were no deaths from infection. G3 neutropenia occurred in 11% of patients with 2% experiencing any grade febrile neutropenia. Pneumonia and urinary tract infections were common, affecting 8(5.5%) and 6 (4.2%) patients, respectively. On multivariable analysis (Table), age, smoking history, history of diabetes, antibiotic use in the 60 days preceding 1st cycle of RVD, and high-risk cytogenetics (HR CG) were associated with a greater likelihood of experiencing a bacterial infection. The area under the ROC curve of the multivariable model was 0.829 (95% CI 0.729-0.934). Conclusions: The overall incidence of bacterial infection in NDMM patients receiving induction with RVD was low despite minimal use of antibacterial prophylaxis. Early mortality was uncommon and not attributable to infection. Clinical features may identify a subgroup of patients at greater risk of infection during induction therapy for MM and may impact clinical decisions to utilize antibacterial prophylaxis.[Table: see text]
Short- and long-term outcomes of multiple myeloma patients undergoing modern treatments proceeding to ASCT: A retrospective analysis.
Authors: Awada Hussein , Hajj Ali Adel , Ali Muhammad Faizan , Kumar Ashish , Adroja Shubham , Mahalwar Gauranga , Babar Arslan , Anwer Faiz
Published: June 2022

e20012

Background: Multiple Myeloma (MM) accounts for approximately 10% of all hematological malignancies. MM patients have heterogeneous outcomes that depend on several demographic, genetic and clinical factors. Here, we report the demographics along with the short and long-term outcomes in a cohort of patients who underwent Autologous Stem Cell Transplant (ASCT) over a period of 5 years. Methods: In this retrospective cohort, we assessed all MM patients who underwent ASCT at the Cleveland Clinic during the period between January 1, 2016 and January 15, 2021. Demographic characteristics, ISS staging, Cytogenetic risk categorization, Pre-ASCT treatment, short-term in-hospital complications, response (defined per IMWG response criteria) before and up to12 months after ASCT, as well as maintenance therapy were collected by reviewing electronic health records. Continuous variables are presented as mean with standard deviation, while categorical variables are presented as percentages. Categorical variables are compared using the chi-squared test while continuous variables are compared using the ANOVA and t-tests. Results: 379 patients who underwent ASCT within the studied time period were identified (Table). Most common cytogenetic abnormalities were del(13) (RB) 25.07%, t(11;14) 17.94% and gain(1q) 16.62%. A Lenalidomide, Bortezomib and dexamethasone (RVd) regimen was the most common to elicit response pre-ASCT (59.05%). Complete response (CR) was achieved in 27.82%, very good partial response (VGPR) in 34.71% and partial response (PR) in 37.47% of all patients pre-ASCT as compared to CR in 43.05%, VGPR in 28.05%, PR in 24.73% and progressive disease (PD) in 4.17% 3 months post-ASCT. All patients received intermediate (140 mg/m2) or high-dose (200 mg/m2) Melphalan conditioning. Average length of hospital stay was 14.56 ± 2.11. Of all patients, thrombotic events were seen in 1.3%, bleeding in 1.8%, neuropathy in 5.34%, mucocutaneous toxicities in 47.99%, cytopenias in 98.39% and infections in 32.25%. RBC and platelet transfusions were required in 36.1% and 88.9% of patients, respectively. Progression-free survival (PFS) was 96.89% at 3 months, 93.77% at 6 months, 92.55% at 9 months, and 88.47% at 12 months post-ASCT. PFS up to 12 months was not statistically different across ISS stages (p = 0.881) or cytogenetic risk categories (p = 0.347). Most common cause of death was progressive MM (73.47%). Conclusions: Responses in MM are boosted by ASCT. Its most common complications are transfusion-dependent thrombocytopenia and infections. Most patients survive beyond 1 year with PD rate of only 11.53%. Advanced ISS stage and high-risk cytogenetics do not confer higher PD in the 1st 12 months post-ASCT.[Table: see text]
A retrospective study of the association of pre-autologous stem cell transplantation disease status with outcomes in patients with multiple myeloma: A single-center study.
Authors: Gutta Radhika , Balanchivadze Nino , Wani Kashmira , Sweidan Aroob , Springer Kylie , Kuriakose Philip
Published: June 2022

e20013

Background: Autologous stem cell transplantation (ASCT) has improved long-term survival for many patients with multiple myeloma (MM), but not all patients respond to ASCT favorably, and many experience disease relapse. Our goal was to explore various disease parameters in patients with MM that might be associated with adverse outcomes after receiving ASCT. Methods: We performed a retrospective medical record review of adult patients with MM who underwent ASCT at Henry Ford Hospital between January 1, 2010 and November 1, 2020. Age, sex, international staging system stage, type of induction therapy, bone marrow cytogenetics and/or fluorescence in situ hybridization, International Myeloma Working Group (IMWG) treatment response criteria categories before ASCT, and the use of maintenance therapy were collected. Outcomes analyzed were time to relapse (TTR) and overall survival (OS). Cox regression analysis was performed. Results: A total of 321 patient records were analyzed: 194 (60.4%) patients were < 65 years old; 185 (57.6%) were men; 162 (50.5%) were Black, and 140 (43.6%) were White. IMWG treatment response categories before ASCT included 250 (78.2%) patients with partial response (PR) and very good partial response (VGPR) combined, and 40 (12.5%) with complete response (CR). There were 69 (21.4 %) patients classified with high-risk cytogenetics. Commonly used induction therapies included 96 (29.9%) patients receiving bortezomib/lenalidomide/dexamethasone, 21 patients (9%) receiving lenalidomide/dexamethasone, 80 patients (24.9%) receiving bortezomib/dexamethasone, and 30 patients (9.3%) receiving cyclophosphamide/bortezomib/dexamethasone, while other patients received a combination of other induction therapies. Mean time from ASCT and last follow-up date was 3.94 years. The overall mean TTR was 29.4 months and OS was 44.8 months. Univariate analysis showed that pre-ASCT treatment response status of combined PR/VGPR was associated with higher hazard of dying than CR (hazard ratio 3.03; 95% CI, 1.23-7.46); however, multivariate analysis showed that PR/VGPR status before ASCT was not significantly associated with increased TTR compared to CR (hazard ratio 1.29; CI, 0.65-2.59). Patients with pre ASCT CR status had longer OS than those with PR/VGPR status (hazard ratio 2.75; CI, 0.995-7.61; p < 0.05). No other variables, including cytogenetic risk were associated with a difference in OS or TTR. Conclusions: Being at CR status before receiving ASCT may indicate a reduced risk of death in MM patients compared to PR and VGPR status, regardless of upfront therapies. Since multiple factors, including treatment type, impact CR status in patients with MM, we believe that studying evolving risk-adapted front-line therapies will help guide optimized treatment strategies to improve overall survival.
Implications of 18F-FDG PET/CT findings before autologous stem cell transplant in patients with multiple myeloma.
Authors: Khan Muhammad Azeem , Markabawi Danny , Alberti Matthew , Burton Jeffrey , Maini Ruby , Catalfamo Vince , Badari Ambuga
Published: June 2022

e20023

Background: The IMWG recommends using 18F-FDG PET/CT (PET) to monitor response to therapy in multiple myeloma (MM). Prior studies in patients who received chemotherapy before autologous stem cell transplant (ASCT) found that severe FDG uptake on PET was associated with inferior event free survival. However, novel agents and monoclonal antibodies have changed the landscape of MM and chemotherapy is no longer used as initial treatment making the role of PET before ASCT unclear. This study explores findings on pre-ASCT PET that may predict shorter remissions after ASCT. Methods: This was a retrospective cohort study. Patients were included if they had a PET at least 60 days before ASCT between 2014 and 2021. All patients achieved at least a partial response (PR) prior to ASCT. The primary endpoint, PFS was defined as time to progression on labs, imaging or bone marrow biopsy necessitating change in therapy or resulting in death after ASCT. The cytogenetic risk category (CG), number of bone lesions at diagnosis, presence of severe FGD uptake on PET (defined as SUV max ≥ 4.2) and persistence of lesions on PET was recorded. Patients who did not experience the event of interest were censored at their last date of clinic follow up. Hazard ratios (HR) for disease progression were estimated using Cox proportional hazards models. Results: 151 patients were included in our study. All patients underwent induction with a 3-drug regimen containing a proteasome inhibitor (PI) and/or an immunomodulatory agent (IMiD). 32% had high risk CG, 44% had > 3 bone lesions at diagnosis, 24% had severe FDG uptake and 29% had > 3 lesions on pre-ASCT PET. The presence of high-risk CG [HR 2.08 (1.03 – 4.17)] and severe FDG uptake on diagnostic PET [HR 6.43 (2.58 – 16.07)] was associated with more aggressive disease and shorter PFS. Patients with > 3 lesions in their pre-transplant PET had a statistically significant decreased PFS [HR 2.01 (1.02 – 3.96)] compared to those with ≤ 3 lesions. Conclusions: This study found that that persistence of > 3 lesions on pre-ASCT PET were an adverse finding associated with an increased risk of progression. To our knowledge these findings have not previously been shown in patients treated with PIs and IMiDs before ASCT. Significantly shorter PFS was observed in patients with high-risk CG and severe FDG uptake on initial PET, consistent with our knowledge of MM. In addition to established risk factors for aggressive disease, persistence of > 3 bone lesions on PET/CT could be used to identify a high-risk group of patients who may benefit from more intensive surveillance or therapy after ASCT. [Table: see text]
Economic evaluations of adjunctive osimertinib treatment in surgically resected epidermal growth factor receptor positive (EGFR+) non-small cell lung cancer (NSCLC): Analysis for stage 3A disease.
Authors: Obeng-Kusi Mavis , Choi Briana M , Abraham Rachel B , Aqel Osama , Calamia Matthias , Halawah Hala , Tugay Deniz , Alamer Ahmad , McBride Ali , Abraham Ivo
Published: June 2022

e20505

Background: Patients with surgically resected EGFR+ NSCLC remain at risk of recurrence after surgery. Osimertinib, a tyrosine kinase inhibitor, had been assessed clinically as adjunctive therapy in surgically resected EGFR+ NSCLC including stage 3A. We conducted a cost effectiveness/utility analysis of adjunctive osimertinib therapy in stage 3A surgically resected EGFR+ NSCLC. Methods: We specified a two state partitioned survival model of disease free survival (DFS) versus disease recurrence and death in a), with a 5 year time horizon (US payer perspective). DFS and overall survival curves were extrapolated per parametric functions. A 3% discount rate was utilized to costs and utilities beyond year 1. Costs of therapies (wholesale acquisition cost), adverse events (AE; grade 3/4; all grades for immunotherapy related AEs), and monitoring costs were based on Redbook, publications, and Physician Fee Schedules, respectively (US $2021). Costs, DFS life years (DFSLY) and DFS quality adjusted life years (DFSQALY) were used to determine the incremental cost effectiveness/utility ratios (ICER/ICUR) of the additional cost needed to gain (g) a DFSLY and DFSQALY in base case (BSA) and probabilistic sensitivity analyses (PSA). Results: Exponential regression was used to extrapolate the Kaplan-Meier curves of osimertinib and placebo,. As shown in the table, the BCA (PSA) estimated the incremental cost at $669,369 ($670,274). The incremental DFSLY was 1.895 (1.899), yielding ICER of $353,125/DFSLYg ($352,963/DFSLYg). The incremental DFS QALY was 1.35, yielding an ICUR of $497,905/DFSQALYg ($497,676/DFSQALYg). Conclusions: In stage 3A surgically resected EGFR+ NSCLC, adjunctive osimertinib therapy showed incremental benefits of 1.895 (1.899) DSFLYg and 1.344 (1.349) QALYg compared to placebo, however at marked incremental cost. As adjunctive osimertinib treatment is indicated in EGFR+ NSCLC disease stages1B and 2, the present stage 3A cost effectiveness/utility results should be compared to those for stages 1B and 2.[Table: see text]
The age-adjusted rates and treatment of typical carcinoid tumors of the lung.
Authors: Valluri Anisha P , Voland Rick , Varlotto John M. , Shweihat Yousef Michael , Cooper Mark Michael , Zander Dani
Published: June 2022

e20507

Background: Pulmonary typical carcinoid tumors(TC) are rare and the treatment of these tumors has not been well studied. The purpose of our investigation is to find whether or not these tumors are increasing in frequency and to assess the value of different treatment options. Methods: The National Cancer Database was queried from the years 2004-2015 for those patients who underwent a surgical resection((bi)lobectomy(L+) or sub-lobar resection(L-)) of TC. Multi-variate analysis for overall survival (OS) in surgical patients was used for propensity matching to determine the benefits of (L-) vs (L+) and to assess the role of chemotherapy or radiation in node positive disease(N+). SEER-18 was used to estimate the age-adjusted rates of TC and the percentage of N+ tumors during the years of our study. Results: With a median follow-up of 62.1 months, 16337 patients underwent surgical resection of TC of which 7846, 7538, 644, 302, and 7 patients had NX, N1, N2, and N3 disease. The rate of TC per 100,000 population progressively and significantly increased from 3.2 to 5.4 while the rate of node positivity remained flat at 0.3-0.4/100,000 population. Adjuvant therapy was given to 155 patients with radiation and 945 with chemotherapy. In the total population, a significant OS benefit was noted in those undergoing a L+ compared to L- (HR = 1.35 p < 0.0001), which was not seen in patients with node negative tumors < 2cm, but was seen in node negative tumors > 2cm (HR = 2.00, p 0.0088) and N1(HR = 3.2, P < 0.0001) and N2 disease(HR = 4.2, p < 0.0001. N2(HR = 2.25, p < .0001 and N1 disease(HR = 1.53 p = 0.0021) had a significant lower OS than N0 disease which were not improved not with radiation therapy(p-value 0.4055) and worsened with both adjuvant chemotherapy(median OS HR p value = < 0.0001). Conclusions: Typical carcinoid tumors are increasing in the US population and should undergo a lobectomy when the size > 2cm or when node positive disease is present. Despite the worse prognosis of patients with node positive disease, radiation did not improve and chemotherapy worsened OS.
The critical role of histone modifications in lung adenocarcinoma based on novel molecular subtypes.
Authors: Wang Bo , Zhang Lianbin , Tang Wei , Deng Jianqing , Mu Tianhao
Published: June 2022

e20510

Background: Studies revealed the pathogenesis and exploring the treatment of lung adenocarcinoma (LUAD), but overall survival (OS) of LUAD patients still remains low in the recent years. Methods: This study analyzed the relationship between gene expression and histone modifications, and discussed the prognostic value of these findings in patients with LUAD. Four types of histone modifications including H3K9me3, H3K27me3, H3K27ac and H3K4me3 were included. Promoters and enhancers in protein coding genes (PCGs) were selected as targeted analyzing regions. Unsupervised consensus clustering was performed to identify molecular subtypes. Cox regression analysis and stepwise Akaike information criterion (stepAIC) were applied to construct a prognostic model. Results: A large number of epigenetic abnormal genes in lung adenocarcinoma were found by comparing the histone modifications and methylation regions on the elements including. We identified 699 epigenetic dysregulated genes specific to LUAD. Finally, based on these epi-PCGs, we constructed three molecular types of LUAD and identified 5 epi-PCGs as prognostic markers for LUAD patients. Conclusions: Our research provided a better understanding that the abnormal epigenetic regulation of PCG expression contributes a lot for the progress of gene regulation in LUAD. These novel molecular subtypes and the prognostic model could serve as guiders to assist decision-makings for LUAD treatment.
The gain of somatic copy number alteration in both primary and lymph node metastases predict poor prognosis of non-samll cell lung cancer.
Authors: Wan Renping , Jing Zhongying
Published: June 2022

e20511

Background: Lung cancer is the leading cause of cancer-related mortality among the world, and distant metastases is still the main cause of poor prognosis and cancer-related deaths. Lymph nodes nearby primary tumor is the most commonly metastases. More than 90% NSCLC patients were diagnosed at II or higher stage. Although more and more prognosis molecular biomarkers have been identified, it’s still hard to completely understand the metastases mechanism of NSCLC. Here we work on evaluation whether molecular divergence or common mutational characters in matched primary and lymph node metastases of NSCLC could predict patient’s prognosis. Methods: Within MSKCC(MSK-IMPACT-2017) datasets, 12 matched primary and lymph node metastatic samples were gotten. Molecular divergence and similarity were analyzed between matched samples, including SNVs, fusion mutations, CNA, TMB, signature, concordance between primary and metastatic lymph nodes and relate it to patient’s overall survival. Results: Cox survival analysis results proved that the gain of CNA in both primary and lymph node metastases would be a poor prognosis biomarker for NSCLC. 3/3 NSCLC patients with CNA in both primary and metastases occurred death within 10 months, median OS was 7.76 month. Only 1/9 of the others occurred death at 14 months, other NSCLC patients did not reach the end point of this study. HR for OS with CNA in both matched samples versus the others was 0.07 (95% CI 0.0067-0.67), log-rank p value was 0.0028. Conclusions: The gain of CNA in both primary and lymph node metastases could be a poor prognosis predictor for NSCLC patients.
EGFR gene aberrations in non-small cell lung cancer patients in the Crimea Republic.
Authors: Timoshkina Natalya N. , Petrusenko Natalia A. , Rashed Al-Nsour , Gvaramiya Astanda K. , Gappoeva Madina A. , Savchenko Dmitriy A. , Kit Oleg I. , Kutilin Denis S.
Published: June 2022

e20514

Background: Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and remains the most commonly diagnosed human neoplasm with a poor prognosis. Significantly improving the clinical course of NSCLC, EGFR tyrosine kinase inhibitors are effective only against tumors carrying activating mutations in the EGFR gene, and their frequency varies depending on the patient population. The aim of the study was to analyze a retrospective group of Crimean patients with advanced NSCLC for the presence of EGFR gene aberrations and association with clinical outcome. Methods: We used DNA samples from FFPE blocks of tumor and non-tumor tissues of 72 European-type patients (aged 46-78 years, median 64 years, 82% - men, 18% - women) diagnosed with lung cancer (T1-1aN0-2M0-1, stage I-IV). The relative copy number of the EGFR gene was assessed by RT-qPCR using GAPDH and B2M as reference genes. Mutations (9 deletions in exon 19, L858R, T790M, L861Q, G719S/A/C, 3 insertions in exon 20, S768I) in the EGFR gene were determined using the Therascreen EGFR RGQ PCR Kit (Qiagen, Germany). Results: For Crimean population patients, the squamous subtype of NSCLC was more common (57%). EGFR copy number evaluation in patients with adenocarcinoma showed locus amplification in 9 patients (30%), no loss of copy number was recorded. In the squamous cell carcinoma group, locus amplification prevailed in 25 of 42 samples (59.6%) and a decrease in copy number was noted in 4 samples (9.5%). Differences in the frequency of aberrant changes in the relative copy number of EGFR in adenocarcinoma and squamous cell lung cancer groups were statistically significant (χ2 = 11.04 at p = 0.003). The activating mutation frequency in adenocarcinoma samples was 9.7% (ex19del), which was lower than the frequency recorded in European adenocarcinoma patient populations (14.4%, p = 0.036). No EGFR mutations were found in cases of squamous cell lung cancer. The presence of mutations and/or changes in EGFR copy number were associated with shorter overall survival in patients who did not receive targeted and immune therapy (p = 0.034). Conclusions: The ex19del activating mutation of the EGFR gene frequency in adenocarcinoma samples was 9.7%. A more frequent EGFR alteration was detected when assessing the locus copy number in the tumor relative to the non-tumor tissue: changes were recorded for 30% of adenocarcinoma cases and 69.1% of squamous cell lung cancer.
Experimental photodynamic therapy in the treatment of lung tumor.
Authors: Komarova Ekaterina Fedorovna , Engibaryan Marina A. , Ulianova Yulia V. , Volkova Viktoriya L. , Bauzhadze Mamuka V. , Pustovaya Irina V. , Chertova Natalia A. , Goncharova Elena G. , Gvaramiya Astanda K. , Maldonado Mary L. , Cherkes Maria A. , Komarova Elizaveta , Goncharova Anna S. , Kurbanova L. Z.
Published: June 2022

e20515

Background: Study of the effect of photodynamic therapy (PDT) with Photoditazine using a high-energy laser at various periods after tumor transplantation on the dynamics of growth of experimental Lewis lung carcinoma in mice. Methods: The study included 176 male C57Bl6 mice weighing 18-20 g with Lewis lung carcinoma (LLC) transplanted subcutaneously. The animals received experimental PDT sequential overlapping of fields of influence (662 nm, 3 W, Photoditazine 25 mg/kg, 300 J/cm2). Animals received PDT on day 11 after the transplantation (experimental series I) and on day 21 (experimental series II). Experimental groups were divided in dependence on the exposure area (to the primary tumor -1gr, thorax (area of metastases)-2 gr and to both zones-3 gr). Animals with tumors without PDT were used as controls. Results: PDT with Photoditazine using the 3W laser stimulated the growth of primary tumor node. The degree of stimulation depended on the time of PDT. Increase in tumor sizes differed already on day 7 after PDT at various periods of the LCC growth. During PDT on the 11th day from the moment of tumor inoculation, the percentage of growth on the 7th day after the end of treatment was 60.7; 69.6 and 86.7% in groups 1, 2 and 3, respectively. In the groups of animals that underwent PDT on the 21st day of the growth of the grafted tumor on the 7th day after the end of treatment, the percentage of tumor growth was 20; 35.6 and 24.4% in groups 1, 2 and 3, respectively. Increase in the median survival was registered in experimental animals with PDT on 22.6% compared to control. A smaller increase in tumor volume was observed in animals receiving PDT to the primary tumor, and the group receiving therapy to both areas was in between. Conclusions: The study was shown that with an earlier initiation of PDT, a greater stimulation of tumor growth was revealed than with therapy at a later date. The revealed characteristics of the development of experimental LLC at PDT exposure allows further selection of parameters for photodynamic therapy regimens.
Clinical analysis of patients (pts) with Lung cancer treated with anti-PD1/PDL1 therapy.
Authors: Tian Kaihua , Wang Xintong
Published: June 2022

e20522

Background: Characterization of Lung cancer treated with anti-PD1/PDL1 therapy was an approach to predict the clinical benefit. this research is a prospective and observational study of long-term immunization therapy safety in routine clinical practice in lung cancer. Methods: This study obtained 395 Chinese patients lung cancer patients who underwent surgical resection or biopsies from January 2020 to January 2022. It is aimed to evaluated the value of TMB,MSI,and PD-1 expression in the pts subset that was therapy at anti-PD1/PDL1 therapy(n = 47),other anticancer therapies (n = 348) included chemoradiation therapy(55%), docetaxel(18%), EGFR-TKIs (16%), pemetrexed (5%) etc. Results: In this cohort, lung cancer pts treated with anti-PD1/PDL1 therapy had a higher proportion of MSI-H than others (7.7% vs 3.4%). PD-L1 High expression in two groups (anti-PD1/PDL1 therapy vs others) about in 19.1%(n = 9) vs 10.6% (n = 37), and low expression in 8.9% (n = 31) vs 10.6% (n = 5) pts. Median TMB was 13 mut/Mb from anti-PD1/PDL1 therapy and 9.6 mut/Mb from other therapy. Conclusions: Lung cancer pts were integrated after immunotherapy vs other therapy, most pts received multiple subsequent anticancer therapies. In this study, immune-related biomarker analysis of lung cancer populations with multiple treatment methods may help improve the efficacy of precise treatment in lung cancer.[Table: see text]
The prognostic value of Sprouty2 protein in nonsmall cell lung cancer.
Authors: Acikgoz Yusuf , Yildirim Fatma Unal , Ergun Yakup , Ucar Gokhan , Aktürk Esen Seli̇n , Bal Oznur , Uncu Dogan
Published: June 2022

e20524

Background: We represent Sprouty 2 (Sprty2) protein expression analysis and its association with key pathological and clinical features of pts with NSCLC as the largest ex-vivo data series. Methods: All IHC stainings were performed using a fully automated IHC staining device (Ventana BenchMark XT, Ventana Medical Systems, Tucson, AZ). Sprouty2 (Clone: AB_2720609, Cat. Number: PA5-7688; Dilution:1/100, ThermoFisher-Invitrogen) primer antibodies were used in IHC examination. Lung alveolar epithelium and bronchial mucosa were used as positive controls. Staining intensity [0 (no reaction), 1+ (weak reaction), 2+ (moderate reaction), 3+ (strong reaction)] and percentage of positively (PP) stained cells [0 (0%), 1 (< 10%), 2 (11-50%), 3 (51-90%), 4 (> 90%)] were analyzed together to calculate immunreactivity score (IRS) values ranging from 0 to 12. Results: 41 pts' sample were analyzed in this study. Sprty2 staining intensity and percentage were statistically significantly lower in tumor tissue (p < 0.0001). The number of pts with positive Sprty2 expression was 17 (42%) and negative was 24 (58%). The ratio of smoking status, brain and lypmh node metastasis were higher in Sprty2 positive group (Table). OS for patients with Sprty2 positive was lower than those with Sprty2 negative in metastatic patients (6.9 mo vs 13.6 mo, p = 0.023). Sprty2 positive pts had inferior survival compared to Sprty2 negative pts among those with AC histology (7.0 mo vs NR, p = 0.003). Conclusions: Sprty2 expression was decreased in tumor tissue compared to normal lung parenchyma. Paradoxically, Sprty2 positive patients had lower survival in certain subgroups (metastatic disease, AC) compared to those with negative pts. Sprty2 protein may be a new target especially for pts without druggable targets. [Table: see text]
Caloric restriction ketogenic diets (KR) in relation to radiotherapy responses in lung cancer xenografts
Authors: Lyu Jiahua , Xiao Ling , Liu Yudi , Wang Yuan , Zhang Rongke , Chen Taiyu , Zhang Hangyue , Tang Chunhan , Pan Shiyi , Nie Xinyu , Zhang Min , Li Tao
Published: June 2022

e20528

Background: Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth. Caloric restriction (CR) and ketogenic diet (KD) are often thought to limit tumour progression. The current study tests the hypothesis that caloric restriction ketogenic diets (KR) enhance radiotherapy responses in lung cancer xenografts. Methods: Mice bearing Lewis Lung Carcinoma xenografts were randomly divided into ad libitum diet group (AL), radiation group (RT), KR diet group (KR), or KR + RT group (KT). Mice in KR and KT group were fed a KR (KetoCal 4:1 fats: proteins+carbohydrates;70% of total energy). Mice in RT and KT group were treated with radiation (4Gy*3f). Mice weights, tumor size, blood ketone levels and survival were monitored. Results: Blood ketone levels were significantly higher for the mice consuming a KR diet compared to standard diet (3.2 mmol/L vs 0.8 mmol/L at week 3, P < .001). Some mice with KR diet lost a significant amount of weight (10%～15% of starting weight) by the end of the treatment.The KR diets combined with radiation resulted in slower tumor growth in Lewis Lung Carcinoma xenografts and longer survival time (P < 0.05), relative to radiation alone. The KR diet also slowed tumor growth and prolonged survival (P < 0.05), relative to control. Hematological and pathological examinations indicated that the KR diet was safe and well tolerated, and no significant cardiac, hepatic and renal toxicity was observed. Conclusions: These results showed that a KR diet enhanced radiotherapy responses in lung cancer xenografts. Further studies are needed to address the mechanism of this diet intervention.
High homology of carcinomatous component and sarcomatous component in pulmonary carcinosarcoma and heterogeneity of gene expression among different patients.
Authors: Wu Haixia , Xue Yingbo , Huang Ping , Wu Xiaoliang , Peng Xueqin , Liu Xin
Published: June 2022

e20534

Background: Pulmonary carcinosarcoma (PCS) is a rare subtype of non-small-cell lung cancer (NSCLC) which is highly aggressive and currently has no optimal treatment. Previous studies have shown that some potential markers for targeted therapy and immunotherapy have been detected in PCS patients. A few studies and cases have used microdissection to separate the carcinomatous component (CaC) and sarcomatous component (SaC) component of PCS and performed DNA-based next-generation sequencing (NGS) and confirmed that the two components are highly homologous. There are no studies yet to analyze the differences between CaC and SaC in PCSs from multiple aspects including DNA, RNA, and protein expression assays. Methods: 10 tumor tissues from 5 PCS patients were divided into CaCs and SaCs by microdissection, DNA-based NGS with a 520 gene panel, RNA-based NGS with a 115 gene panel, and Immunohistochemistry (IHC) were performed on these samples. The same type of detection results for different components of the tumors were used for comparative analysis, and the overall DNA test results of the two components were used to compare with detection data of NSCLC and lung sarcoma in the TCGA database respectively. Results: No significant differences were found between CaC and SaC at both DNA, RNA, and IHC assays. The most commonly mutated genes in this cohort of patients were TP53 (10/10, 100%), KRAS (6/10, 60%), LRP1B (5/10, 50%), RBM10, PTPRT, AKT2 (both are 4/10, 40%). Notably, all the mutated genes detected were more similar to those detected in NSCLC rather than mutated genes commonly found in sarcomas. In addition, regardless of DNA or RNA sequencing, no landmark fusion variants were detected in the four available sarcoma tissues. Single sample gene set enrichment analysis (ssGSEA) was used to analyze the RNA results of the matched CaC and SaC of the three patients, no difference in RNA expression among different types of tissues in the same patient was found, but gene expression heterogeneity among the 3 patients was very high. IHC results showed that the positive rates of PD-L1, CD3 and CD8 in the 5 CaCs were 40%, 100% and 100%, while this value was 80%, 100% and 100% in the 5 SaCs. PD-L1 showed a trend of high expression rate in SaC tissues of PCS patients. Conclusions: This study showed that the CaC and SaC tissues of the same PCS patient were both highly homologous in terms of DNA, RNA and protein expression, but the RNA expression was highly heterogeneous among different patients. The landscape of genetic alterations revealed that PCSs are molecularly more likely to arise from NSCLC rather than lung sarcomas, which suggests that for these patients, it may be suitable to choose a treatment plan for the pathological type of the carcinomatous component.
Driver mutations and air pollution in advanced non-small cell lung cancer (NSCLC) at two reference hospitals in Mexico City.
Authors: Sanchez Eduardo , Trejo Rosales Raul Rogelio , Remolina Bonilla Yuly Andrea , Sánchez Hernández Juan José , Vélez Martínez Amairany Guadalupe , De Jesus Hernandez Dulce Angelica , Najar Miriam , Lizcano Aguilar Nestor Javier , Hernandez Castillo Marco Antonio , Cruz Andrea , Zarroca Palacio Santiago
Published: June 2022

e20545

Background: Currently, precision medicine has allowed the classification of NSCLC according to the profile of driver mutations and the development of highly effective treatments. There is evidence to support the relationship between outdoor air pollution, particularly particulate matter (PM) in outdoor air, with lung cancer incidence and mortality. Smoking is a negative predictor of EGFR mutation, but the effect of air pollution has not been stablished. Methods: We perform a retrospective study in two referral hospitals in Mexico City between 2015 to 2020 to determinate the frequency of key driver mutations in patients with advanced NSCLC and the relation with smoking habit, wood smoke exposure and pollution indexes (PM2.5, PM10, SO2, O3, NO2) according to their place of residence. We used WHO air quality thresholds for air pollutants to classify cases with high or low exposure. Results: A total of 1277 cases were analyzed. The median age at diagnosis was 66 years (range 18-97 years), 53% were females and 49.6% had history of smoking habit. According to histology, 61.6% of cases corresponded to adenocarcinoma, 11.7% were squamous, 1.3% large cell, and 25.4% indeterminate. Wood smoke was assessed in 83.1% of cases and 28.5% had exposure history. Air pollutants were measured in half of cases, high level of exposure for PM2.5, PM10, NO2 and SO2 occurred in 63.2%, 30.8%, 15.6%, 53.4%, respectively. EGFR, ALK and KRAS mutations were evaluated in 85%, 16.7% and 8.6% of patients, respectively. The presence of these mutations was: EGFR 17.1%, ALK 11.1%, and KRAS 16.5%. Patients with EGFR-positive NSCLC were more frequently female (65.1% vs 34.9%, OR 1.8 95%CI 1.4-2.5, p < 0.001) and had no history of tobacco use (35% vs 65%, OR 0.49 95%CI 0.36-0.67, p < 0.001). Wood smoke was not statistically significant. High exposure to PM2.5 was most common in patients with non-mutated EGFR NSCLC (65.3% vs 34.7%, OR 1.7 95%CI 1.2-2.5, p = 0.006). Relationship with other air pollutants were not statistically significant. ALK-positive NSCLC patients tend to be females (68% vs 32%, p = 0.07) and had no history of smoking habit (20.8% vs 79.2% OR 0.28 95%CI 0.1-0.78, p = 0.01). High exposure to SO2 was common (78.6% vs 21.4% p = 0.05). Association in KRAS-positive NSCLS patients were not found. Conclusions: A low rate of key driver mutations assessment was found in this Mexican cohort. Clinical profile of NSCLC EGFR positive is according with previous reports in the literature. Exposure to PM2.5 and SO2 were found associated with EGFR and ALK status in this retrospective study and are hypothesis generating information.