bluuebunny/crossref_metadata_2025 huggingface dataset:
Daratumumab-based three drug regimens for high-risk multiple myeloma: A meta-analysis.
Authors: Farooqui Arafat Ali , Tariq Muhammad , Nabeel Shaha , Ashraf Aqsa , Ahmed Zahoor , Faisal Muhammad Salman , Ammad Ud Din Mohammad , Shahab Zartashia , Setarehaseman Alireza , Anwer Faiz
Published: May 2020

e20549

Background: Efficacy of daratumumab (D) based regimens in high risk multiple myeloma (MM) (i.e, ISS stage II/III and t(4;14) or (del17p)) has not been thoroughly investigated. The aim of this study was to assess the efficacy of D based 3-drug regimens compared to non-D based regimens in high risk MM. Methods: A systematic review of literature was performed to identify randomized controlled trials (RCTs) which reported overall response rates (ORR) and progression free survival (PFS) of MM patients (pts) with D based 3-drug regimens. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using RevMan v.5.3 to report the efficacy of D based 3-drug regimens. A random effects model was employed only when there was significant heterogeneity among studies ( > 40%, as assessed by I-squared). Results: Screening of 604 studies yielded 04 RCTs (n = 2,234 pts). D was evaluated with lenalidomide (L), carfilzomib (C), bortezomib (B) and dexamethasone (d). DLd regimen was studied in 649, DCd in 312 and DBd in 240 pts. Total 1201 pts were evaluated with D. D based 3-drug regimens proved to be of improved efficacy versus non-D 2-drug regimens in the pooled analysis i.e., PFS (HR 0.46, 95% CI 0.33-0.63; p < 0.00001; I2 = 81%) and ORR (OR 2.83, 95% CI 2.06-3.88; p < 0.00001; I2 = 44%). Relapsed/refractory MM (n = 833) also showed improved ORR (OR 2.79, 95% CI 1.78-4.36; p < 0.00001; I2 = 62%). In high risk group, addition of D decreased the risk of progression to 42% (HR 0.58, 95% CI 0.39-0.85; p = 0.005; I2 = 3%). In standard risk pts, D decreased the risk of progression/death to 66% (HR 0.34, 95% CI 0.23-0.51; p < 0.00001; I2 = 74%). D increased the risk of neutropenia (OR 1.88, 95% CI 1.54-2.31; p < 0.00001; I2 = 0%), respiratory tract infections (OR 1.87, 95% CI 1.49-2.35; p < 0.00001; I2 = 0%) and diarrhea (OR 1.83, 95% CI 1.46-2.29; p < 0.00001; I2 = 23%) in the study population. Conclusions: Daratumumab based 3-drug regimens appear to abrogate high risk features in MM compared to 2 drug regimens.
Retrospective review of chronic pain causes and management in multiple myeloma patients.
Authors: Dave Ami Atulkumar , Lewis Jaime K , Paner Agne
Published: May 2020

e20552

Background: The survival of patients with multiple myeloma has improved dramatically since the introduction of proteasome inhibitors such as bortezomib, which can have the adverse effect of peripheral neuropathy. This study retrospectively examines causes of chronic pain in myeloma patients and the modalities and duration of treatments used for pain control. Methods: Rush University Medical Center multiple myeloma patients who were diagnosed and treated between 2000-2019 were included. Outcome measures were abstracted from the medical record and included: classes of pain medication used, duration of treatment, prevalence of peripheral neuropathy symptoms, and use of adjunct treatment modalities. Descriptive statistical models including Chi-square and Fisher’s exact test were used for categorical variable analysis. Results: In all, 134 patients were included, of which 75.4% (N = 101) patients received at least one cycle of bortezomib. 42.5% (N = 57) patients were seen in palliative clinic. 72.9% (N = 97) reported bone pain symptoms. A total of 73.7% (N = 98) patients experienced peripheral neuropathy symptoms. 86.1% (N = 87) of patients who received bortezomib reported neuropathy, as compared to 34.4% (N = 11) of patients who did not have bortezomib therapy (OR 11.8, p < 0.0001). 66.4% (N = 67) patients who received bortezomib took anticonvulsants as compared to 31.3% (N = 10) of those who did not receive bortezomib (OR 4.3, p < 0.0005). Patients were on anticonvulsant therapy for a mean of 32.6 months (SD = 26.7) with no significant difference in the bortezomib group. 79.7% (N = 106) patients took opioid medications. Norco was the most commonly used opioid (N = 55) and average duration of use was 36.6 months (SD = 34). 18.8% (N = 25) took antidepressant medications such as TCAs or SNRIs for pain, and all of these patients received bortezomib therapy (p = 0.0003). 36.6% (N = 45) of patients received radiation and 16.5% (N = 22) underwent kyphoplasty. 70.7% (N = 94) patients attended at least one physical therapy session. There was no statistically significant difference in radiation or kyphoplasty utilization between patients who had received bortezomib and those who had not, but there was a significant difference in physical therapy (OR 4.9, p < 0.0001). Conclusions: Patients who received bortezomib as part of their myeloma treatment were more likely to experience peripheral neuropathy and required anticonvulsant therapy more frequently. It is important to better understand and define the health burden of chronic pain and use of pain medications in patients with multiple myeloma.
Impact of autologous stem cell transplant utilization in a vulnerable multiple myeloma population.
Authors: Othman Tamer , Wang Yingyu , Gupta Shelly , Wu Daniel , Gupta Rohan , Celles Larissa , Lane Gregorianna , Mei Matthew Genyeh , Yeh James , Tomassetti Sarah
Published: May 2020

e20556

Background: Despite improvements in the survival of multiple myeloma (MM) patients, disparities in outcomes persist in underserved populations, in part due to variable access to treatments including autologous stem cell transplant (ASCT), a standard treatment for fit patients. Harbor-UCLA Medical Center (HUMC) is a safety net hospital in Los Angeles with a population of socially and medically vulnerable patients, many of whom possess limited English proficiency. Historically, access to ASCT at tertiary centers has been challenging for patients at HUMC. We present the outcomes for 160 newly diagnosed MM patients between 1998 and 2019 during which our referral process for ASCT markedly improved. Methods: We retrospectively analyzed 160 MM patients evaluated at HUMC between 1998 and 2019. The cohort was divided into 2 groups based on year of diagnosis: 1998-2013 and 2014-2019. Referral for and utilization of ASCT, and 5-year survival rates were recorded. Survival rates were calculated through a Kaplan-Meier analysis. Results: 160 MM patients were included in the analysis. 93 patients were diagnosed in 1998-2013 and 64 in 2014-2019. Three patients had an unknown diagnosis date. Patient characteristics are described in Table. ASCT referrals increased from 23% to 59% (P<0.001) after designating a nurse practitioner to coordinate referrals, and implementing a standardized referral template and an electronic medical record system to send and track requests. With an increased referral rate, ASCT utilization showed an increasing trend from 15% between 1998-2013 to 27% between 2014-2019 (P=0.11). Five-year survival rate was 49% (95% CI, 37.8%-62.5%) from 1998-2013 and 70% (95% CI, 57.5%-84.6%) from 2014-2019, and was greater in patients who received ASCT compared to those who did not, 95% (95% CI, 85.2%-100.0%) versus 55% (95% CI, 40.2%-75.1%) (P=0.01). Conclusions: Increased ASCT utilization was associated with improved survival in our underserved MM population, suggesting that adherence to the most evidence-based treatments, such as ASCT utilization, may help overcome the disadvantages of a resource-limited setting. Continued refinements in our referral process will likely increase ASCT utilization. [Table: see text]
HORIZON (OP-106): An exploratory analysis of time-to-next treatment (TTNT) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) who received melflufen plus dexamethasone (dex).
Authors: Mateos Maria-Victoria , Oriol Albert , Larocca Alessandra , Blade Joan , Cavo Michele , Rodríguez Otero Paula , Leleu Xavier , Hiemenz John W. , Hassoun Hani , Touzeau Cyrille , Alegre Adrian , Paner Agne , Maisel Christopher , Mazumder Amitabha , Raptis Anastasios , Harmenberg Johan , Zavisic Stojan , Thuresson Sara , Öhman Oskar , Richardson Paul G.
Published: May 2020

e20570

Background: Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. Melflufen + dex showed efficacy and a manageable safety profile in pts with poor-risk, heavily pretreated RRMM in the phase 2 HORIZON study (Mateos et al. ASH 2019. Abs. 1883). For pts with RRMM, longer TTNT is indicative of disease stabilization and clinical benefit and is associated with lower costs (Chen et al. J Manag Care Spec Pharm. 2017). This report of TTNT after melflufen + dex from HORIZON is, to our knowledge, the first report from a trial population with such advanced RRMM. Methods: Pts with RRMM who had received ≥2 prior lines of therapy, including an IMiD and a proteasome inhibitor (PI), and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody (mAb), received melflufen 40 mg (IV on d1 of each 28-d cycle) + dex 40 mg/wk until disease progression or unacceptable toxicity. The primary endpoint was overall response rate. Secondary endpoints included progression-free survival (PFS) and safety. TTNT was defined as the time from start of melflufen + dex to first subsequent therapy. Results: Overall, 154 pts were treated (data cutoff, Oct 1, 2019); median age was 64.5 y (range, 35-86), 32% had International Staging System stage 3 disease, 38% had high-risk cytogenetics, 32% had extramedullary disease (EMD), the median number of prior therapies was 5 (range, 2-12), and 71% had triple-class refractory MM (IMiD + PI + anti-CD38 mAb). Treatment discontinuation occurred in 108 pts (70%), most commonly due to disease progression (47%) and adverse events (14%). Among 125 pts evaluable for response, with a median follow up of 15.3 mo, the median TTNT was 8.0 mo (95% CI, 7.2-8.9) and the median PFS was 4.2 mo (95% CI, 3.7-4.9). TTNT and PFS were similar in subgroups of pts with triple-class refractory MM and EMD (Table). Subsequent therapies after melflufen + dex will be presented. Conclusions: TTNT in HORIZON (median 5 prior lines) was consistent with previous reports of TTNT in pts with RRMM who received melflufen + dex or other therapies (median 2-4 prior lines) (Bringhen et al. J Clin Oncol. 2019. Abs. 8043). Melflufen + dex is being further evaluated in the phase 3 OCEAN study (NCT03151811) in pts with RRMM who are refractory to lenalidomide. Clinical trial information: NCT02963493. [Table: see text]
The impact of programmed death-ligand 1 expression on the prognosis of early-stage resected non-small cell lung cancer: A meta-analysis of literatures.
Authors: Zhu Shuai , Li Xiongfei , Zhao Shikang , Wang Yanye , Lei Xi , Huang Dingzhi , Chen Jun , Li Ziming , Xu Song
Published: May 2020

e21004

Background: Previous studies have demonstrated that programmed cell death-ligand 1 (PD-L1) serves as a poor prognostic biomarker for the survival in advanced-stage non-small-cell lung cancer (NSCLC) patients. However, the value of PD-L1 expression for the prognosis of early-stage NSCLC patients after complete resection remains controversial. Here, we conduct a meta-analysis to investigate the relationship between PD-L1 expression and prognosis in resected NSCLC. Methods: Electronic databases, including PubMed, EMBASE, and the Cochrane Library, were searched up until June 30 2019, for studies evaluating the expression of PD-L1 and prognosis of the resected NSCLC. Hazard ratios (HRs) with 95% confidence interval (CI) of overall survival (OS) and disease-free survival (DFS) were pooled and analyzed. Heterogeneity and publication bias analyses were also performed. Results: A total of 15 studies involving 3501 patients were enrolled. The pooled hazard ratio (HR) showed that PD-L1 expression was related to a much shorter DFS (HR = 1.63, 95% CI: 1.26-2.12, P = 0.022), as well a significantly worse OS (HR = 1.68, 95% CI: 1.32-2.14, P = 0.000). Furthermore, our analysis indicated that PD-L1 expression was significantly associated with gender (male vs. female: HR = 1.25, 95% CI:1.02-1.52, p = 0.028), tumor stage (III/IV vs. I/ II: HR = 2.39, 95% CI:1.85-3.08, p = 0.000), lymph node metastasis (N+ vs N-: HR = 3.54, 95%CI:2.56-4.88, p = 0.000) and smoking status (Yes vs No: HR = 1.37,95% CI:1.20-1.560, p = 0.000). Conclusions: The results of this meta-analysis suggest that PD-L1 expression predict an unfavorable prognosis in early-stage resected NSCLC. The role of individualized anti-PD-L1/PD-1immunotherapy in the adjuvant settings of resected NSCLC is worthy of being further investigated.
The role of adjuvant chemotherapy in the management of surgically resected primary pulmonary salivary gland-type carcinomas.
Authors: Younis Moustafa , Rakhra Sunpreet , Kennedy Kevin F , Heimes Jessica K , Davis John Russell , Kujtan Lara , Subramanian Janakiraman
Published: May 2020

e21009

Background: Primary pulmonary salivary gland-type carcinomas (PSGC) are rare tumors. There are limited data on the role of adjuvant chemotherapy after surgical resection of these tumors. Here, we examine the role of adjuvant chemotherapy in the management of resected PSGC. Methods: The National Cancer Database was queried to identify patients with PSGC who underwent surgical resection. Histology codes 8200- adenoid cystic carcinoma (ACC), 8430- mucoepidermoid carcinoma (MEC), 8550- acinic cell carcinoma (AIC) and 8551- adenocarcinoma, acinar predominant were used. Patients were divided based on chemotherapy status. Summary and univariate analysis was performed. Multivariable proportional hazard regression analyses were used to obtain hazard ratios (HR). Results: A total of 6685 patients, with a mean (±SD) age of 66.1 ± 11.0 years, were included; 4148 (62%) were females. Most patients were Caucasian (84%). Chemotherapy was administered in 1141 patients (17%); multiagent chemotherapy: n = 1034 (91%). AIC was the most common subtype (n = 6302, 94%) followed by MEC (n = 304, 4.6%) and ACC (n = 73, 1.1%). Patients who received chemotherapy were younger (64.0 ± 9.0 vs 66.5 ± 11.3; p < 0.001), otherwise, there was no significant difference in baseline demographics. Unadjusted 5-year survival for stage I PSGC was significantly lower in the chemotherapy arm (60.5% vs 72%, p < 0.001). Chemotherapy did not improve survival in resected stage II or III PSGC. Overall survival was inferior with chemotherapy on multivariable analysis (adjusted HR: 1.32, 95%CI (1.13-1.55), p = 0.0006). Older age, male gender, positive margins, higher clinical stage, comorbidities, rural population and pneumonectomy were associated with lower overall survival (Table). Conclusions: Contrary to previous studies AIC is the most common tumor type among PSGC. Adjuvant chemotherapy is associated with worse survival in resected PSGC and current guidelines for administering adjuvant chemotherapy in resected lung cancer is inadequate for this population. [Table: see text]
Dynamic changes of lymphocyte subsets during multimodal treatment of patients with inoperable stage III NSCLC.
Authors: Hofer Thomas Philipp , Käsmann Lukas , Pelikan Carolyn , Mathur Saloni , Eze Chukwuka , Karin Monika , Taugner Julian , Roengvoraphoj Olarn , Belka Claus , Noessner Elfriede , Manapov Farkhad
Published: May 2020

e21011

Background: Lymphocytopenia is associated with deterioration of patient survival in solid cancers treated with concurrent chemo/radiotherapy (cCRT). A prospective analysis of peripheral blood mononuclear cells during cCRT in inoperable stage III NSCLC patients was performed to determine dynamic changes of individual lymphocyte subsets. Methods: Twenty-one patients were prospectively enrolled in this study. Eighteen patients received platinum-based cCRT, seven of them received, additionally, concurrent and/or sequential immune checkpoint-inhibition (ICI). Thoracic irradiation (TRT) was delivered with median total dose of 62Gy (31 daily fractions of 2Gy) in all patients. Peripheral blood was collected 5-10 days before treatment (A1), three weeks after start of cCRT (A3), on the last day of TRT (RTend) and during follow-up. Samples were analyzed using polychromatic flow cytometry. Results are reported for time-points A1, A3 and RTend. Results: Sixteen patients met final analysis criteria, 50% of them received concurrent and/or sequential ICI. All patients developed severe lymphocytopenia; in 81% of them lymphocyte nadir was documented at A3. Lymphocyte subsets, B cells, T cells (CD4, CD8), regulatory T cells, and NK cells, decreased with medians between 99.9% and 59%. Lymphocyte nadir was independent of the absolute numbers of immune cells that a patient had before start of cCRT or whether additional ICI was applied. From A3 to RTend, all lymphocyte subsets started to recover in patients treated with cCRT alone, while they remained low in patients who received additional ICI. The ratios of CD4/CD8 and CD8/Treg cells did not change during treatment (A1 to RTend) and was not different between the patients treated with or without ICI. However, the fraction of PD-1 cells among CD8 T-cells decreased in patients treated with ICI and remained low until RTend (range 0.55%-13.8%). In contrast, in 50% of patients treated with cCRT alone, PD-1 T-cell among CD8 T-cells increased and remained high (range 6.8%-46.3%) until RTend. Conclusions: Delayed recovery of lymphocyte subsets in peripheral blood was observed in patients treated with cCRT combined with concurrent or sequential ICI. A decrease of PD-1 T-cells among CD8 T-cells was described exclusively in patients treated with additional ICI.
Clinical and genomic features of high tumor mutation burden in patients with non-small cell lung cancer.
Authors: Qiu Yuan , Yang Haihong , Chen Hanzhang , Deng Qiuhua , Liu Liping , Xiao Dakai , Shao Di , Li Weiwei , Jiang Wenxi , Zhu Changbin , Lin Yongping , He Jianxing
Published: May 2020

e21023

Background: TMB is associated with mono-immunotherapy efficacy for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). For early-stage NSCLC or EGFR mutated non-resectable NSCLC, TMB-H predicted better prognosis or poor response to TKIs. This research might develop potential predictive parameters for distinguishing NSCLC with high or low TMB. Methods: Samples of surgically resected, cancer tissues were collected from 499 patients with NSCLC: 29 (5.8%) lung squamous cell carcinoma (LUSC) and 468 (94.2%) lung adenocarcinoma (LUAD). The mutations and TMB were confirmed by target region capture sequencing (Oseq™-508). Results: According to the median value (3.08), TMB is divided into high (N = 244) and low (N = 255). Interactions between TMB and sex, age, location, histology, pathological subtype, lymph node, parabronchial lymph node, LVI, neuro-invasive, stage and mutation status were evaluated. The distribution of TMB-H was significantly (p < 0.001) correlated with sex, age, histology, pathological subtype, stage (TN stage) and partial mutations. Among all mutations, 6 genes (TP53 / FAT3 / KMT2D / TSHZ3 / NAV3 / EPHA3) were confirmed to be significantly related to TMB-H in NSCLC. We also found that TMB-H was significantly affected by mutation status of KRAS gene (P. G12X, p < 0.001) and missense mutations in FAT3 (p < 0.001). The Kruskal–Wallis H test results showed that the mutation types of FAT3, KRAS, TP53 and PIK3CA were closely related to TMB-H. Lasso linear regression analysis was applied and resulted the better predictors of TMB status including TSHZ3, KMT2D, TP53, gender and T stage. Conclusions: Instead of comprehensive genomic profiling to evaluate TMB, clinical characteristics and special mutation types may help to effectively screen and predicate patients with TMB-H status. [Table: see text]
Characterization of the tumor microenvironment landscape and deep learning-guided prediction of prognosis in lung adenocarcinoma with bulk RNA sequencing data.
Authors: Gui Philippe , Wu Wei , Yu Elizabeth , McCoach Caroline Elizabeth , Doebele Robert Charles , Bivona Trever G.
Published: May 2020

e21025

Background: The tumor microenvironment (TME) plays an important role in tumor progression and treatment response, therefore profoundly affecting patient outcomes. Efforts to characterize the TME in lung adenocarcinoma are emerging but have been limited by the sample size and lack of treatment timepoints. Methods: We characterized changes in lung TME using the xCell algorithm to distinguish 64 immune and stroma cell types from bulk RNA sequencing data. The correlation between subtype cell population in lung TME and various clinical and biological characteristics was analyzed from over 500 lung adenocarcinoma (LUAD) samples from The Cancer Genome Atlas and an independent cohort of 48 advanced LUAD patients with treatment annotations (treatment-naive, residual disease, and progressive disease). In addition, we used key features in lung TME to predict prognosis using deep learning algorithms. Results: We found significant changes in both immune and stroma cell populations according to various clinical parameters such as smoking history, cancer stage, and treatment status. Specific sub-populations within lung TME correlate with survival outcomes based on Kaplan-Meier survival analyses. CD4- and CD8-positive T-cells are enriched in early stage disease and depleted in late stage disease, suggesting evolution of the TME during cancer progression. Consistent with previous reports, scores of immune cell populations associated with worse survival, such as T helper type 2 cells, are increased in late stage disease. Smoking history also reshapes the lung TME as populations correlated with better survival are decreased in smokers. We also found variations in sub-populations according to the driver oncogenes, with a less abundant lymphoid compartment in EGFR mutant samples compared to KRAS driven samples. Interestingly, we found higher scores of macrophage populations in residual disease following targeted-therapy treatment compared to pre-treatment. Finally, using machine and deep learning methods we identified a panel of 12 key features within the lung TME which could be used to predict prognosis. Conclusions: We comprehensively characterized immune and stroma cell type changes in the lung TME utilizing bulk RNA-seq data, and evaluated the association of sub-type cell populations with different clinical and biological features. Key features in lung TME could be used to predict prognosis.
The effect of different dose and sites of irradiation on lymphocyte subsets in peripheral blood of patients with lung cancer.
Authors: Duan Xiaotong , Zhu Xiaoxia
Published: May 2020

e21032

Background: To explore the effect of different radiation doses and sites on systemic immunity in patients with lung cancer by detecting the changes in the percentage of lymphocyte subsets in peripheral blood before and after radiotherapy. Methods: Peripheral blood in 48 patients with lung cancer receiving radiotherapy were collected (before, during and after radiation), and the lymphocyte subsets as follow were examined: total T cell (CD3+), CD4+T cell, CD8+T cell, CD3+CD4+/CD3+CD8+, NK cell, memory T-helper cell subpopulation (CD4+ CD45RO+), CD4+ naïve T-cell subset (CD4+CD45RA+), cytotoxic T cell (CD8+CD28+), IL-2 receptor α(CD25+), B cells (CD3-CD19+), regulatory T cells (CD4+CD25+). The results were statistically analyzed with unpaired Student's t-test using GraphPrism6 software. Results: Among non-small cell lung cancer (NSCLC) patients treated with thoracic radiation (n = 21), B cells in patients receiving 20Gy/10F (P = 0.0072), 40Gy/ 20F (P = 0.0001), 60Gy/30F (P = 0.0002) irradiation were significantly lower than that before radiotherapy. However, CD4+ naïve T-cells decreased significantly at each dose point compared with that before radiotherapy, P values were 0.0394, 0.0081 and 0.0007, respectively. NK cells after completion of 60Gy/30F irradiation were distinctly lower than those after receiving 20Gy/10F of radiotherapy (P = 0.0278), and no significant difference was found in other immune cell subsets. Patients with small cell lung cancer (n = 6) who underwent thoracic radiation showed a similar trend of changes in B cells. However, the CD4+CD45RA+ subset decreased evidently after completing radiation compared with that after 10 fractions of irradiation (P = 0.0390). The NSCLC patients (n = 4) who received radiation for bone metastases (regimen: 36Gy/12F) had evidently lower B cells (CD3-CD19+) at the end of radiotherapy than that at the start of radiotherapy (P = 0.0286). Patients with NSCLC (n = 10) who received brain radiation (regimen: 40Gy/20F for whole brain, 54-56Gy/20F for multiple brain metastases) had a significantly reduced CD4+CD45RA+ subsets after finishing radiation (20F) compared with those after 10 fraction of radiation (P = 0.0497). The changes of other subsets were not statistically significant. Conclusions: The effect of radiation in different sites and doses on peripheral blood lymphocyte subsets is not identical.It is urgent to expand the sample size to explore the law for the optimization of radiation combined with immunotherapy.Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033
Prognostic value of the TGFß1 rs4803455 single nucleotide polymorphism and its association with prophylactic cranial irradiation in small cell lung cancer.
Authors: Ayala de Miguel Pablo , Enguix-Riego María Valle , Cacicedo Jon , Delgado Blas David , Pérez Marco , Praena-Fernández Juan Manuel , Quintana Cortés Laura , Borrega Pablo , Rivin del Campo Eleonor , Lopez Guerra Jose
Published: May 2020

e21038

Background: Small cell lung cancer (SCLC) is one of the greatest therapeutic challenges of oncology. Potential associations between single-nucleotide polymorphisms (SNP) in Heat shock protein beta- 1 (HSPB1) and Transforming growth factor (TGFß1) and survival have been investigated. Methods: A prospective multicenter study of 94 SCLC patients treated between 2013 and 2016 was conducted. Several variables clinical, tumour-related, therapeutic, and genetic (9 SNPs of TGFß1 gene and 5 of HSPB1 gene) variables were analyzed. Results: The cohort included 77 men and 17 women with a median age of 61 years. Eighty percent presented with limited stage at diagnosis and received thoracic radiation with a median dose of 45 Gy (BID in 42%). Forty-seven percent received concomitant platinum-based chemotherapy and 57% received prophylactic cranial irradiation (PCI). Overall survival (OS) was 34% at 2 years and 16% at 3 years. In multivariate analysis PCI and the TGFß1 SNP rs4803455 showed a statistically significant association with OS and local control. Patients with the CA genotype of the TGFß1 SNP rs4803455 showed worse OS (HR 2.53; IC 1.22-5.21; p = 0.012) and higher local recurrence (HR 2.26; IC 1.01-5.08;p = 0.048). A combined analysis showed that those patients receiving PCI and carrying the rs4803455:CA genotype had a statistically significant lower OS (p < 0.001) and disease-free survival (p < 0.001) than patients receiving PCI and carrying the rs4803455:AA genotype. Conclusions: Genetic analysis showed that the CA genotype of TGFß1 SNP rs4803455 was associated with worse prognosis in SCLC patients and could be considered as a potential biomarker for OS.
Association of higher EGFR mutation in the primary lesions with lymph node metastasis in early lung adenocarcinoma.
Authors: Zhang Yi , Wang Jinjin , Yuan Yuwei
Published: May 2020

e21039

Background: Prognosis of early stage lung adenocarcinoma after surgery are usually affected by whether the patients had lymph node metastasis along with the primary lesions. The pathological stage of operable lung adenocarcinoma without or with lymph node metastasis were ⅠA/B or ⅡB/ⅢA, respectively, which related to different clinical outcomes, especially 5 years survivors (90% vs 50%). Due to the high tumor heterogeneity, it is difficult to trace which genes lead to tumor metastasis. We hypothesis that the genetic mutations in the smaller tumor might discover the key genetic changes associated with metastasis. Methods: 47 NSCLC patients with the primary lesion diameter less than or equal to 3cm were enrolled for genotyping with multiple cancer-related genes. Among them, 20 were lymph node metastasis and 27 were non-metastasis. Fisher test was used to analyze the difference between the two primary tumors. Results: EGFR amplification in all patients with lymph node metastasis is higher than the non-metastasis group (0.250 vs 0.037, P = 0.043), shown in the following table. This tendency was also found when the tumor diameter thresholds were configurated as < 2.5cm and < 2cm, even more prominently in the latter, (0.400 vs 0, P = 0.020). The CNV value of EGFR increased while the tumor diameter threshold value decreased. The difference of EGFR VAF between the two groups showed the same pattern. The metastatic patients had higher VAF values than the non-metastatic patients (each P-value was lower than 0.05). Conclusions: Based on the above results, it is speculated that EGFR mutations plays an important role in tumor early metastasis, and the genetic mutations in the smaller tumor might discover the key genetic changes associated with metastasis more notably. [Table: see text]
Identification of a prognostic immune-related signature for small cell lung cancer.
Authors: WANG JUN , Zhang Bicheng , Sun Jianguo , Liang Jing , Liu Xiaolin , Li Yan , Wang Baocheng
Published: May 2020

e21041

Background: As a subgroup of lung cancer, small cell lung cancer (SCLC) is characterized by a short tumor doubling time, high rates of early occurred distant cancer spread, and poor outcome. Despite its exquisite sensitivity to chemotherapy and radiotherapy, acquired drug resistance and tumor progression was impossibly avoided. This study aimed to develop a robust signature based on immune-related genes to predict the outcome of patients with SCLC. Methods: The expression data of 77 SCLC patients from George’s cohort were divided into training and testing set, and 1,534 immune-related genes from ImmPort database were used to generate and validate the signature. The Cox proportional hazards model was developed to determine the best gene model and construct the signature. The Kaplan-Meier survival analysis and Cox proportional hazards were used to test the prognostic significance of the signature. Results: A 10-genes model comprising NR3C1, NR1D2, TANK, ARAF, HDGF, INHBE, LRSAM1, PLXNA1, PML and SP1 with the highest frequency after 1,000 interactions, was chosen to construct an immune-related signature. This signature showed robust predictive value for SCLC patients’ survival in both training and testing set. This signature was closely associated with the activation of immune signal pathways, but not TNM stage. Furthermore, patients with high immune risk score presented with poor survival, whereas had high specific tumor-infiltrating immune cells such as NK CD56 bright cells. Conclusions: The present developed immune-related signature could predict the prognosis of SCLC patients, which to some extent reflect individual immune microenvironment phenotype in this highly lethal cancer type.
Stereotactic body radiotherapy for early-stage non-small cell lung cancer in patients with subclinical interstitial lung disease.
Authors: Hu Min , Sun Xiaojiang , Liu Yuanjun , Zhu Yaoyao , Xu Qinghua , Li Fangjuan , Liu Hui , Xu Yaping , Weng Denghu , Lin Qingren
Published: May 2020

e21050

Background: Stereotactic body radiotherapy (SBRT) is a highly focused radiation treatment, which is now recommended to treat non-small cell lung cancer (NSCLC) patients with early stage disease. The purpose of this study is to evaluate the efficacy and toxicity of SBRT for early stage NSCLC patients with subclinical interstitial lung disease (ILD). Methods: One hundred and nine patients with early stage NSCLC were treated with SBRT between December 2011 and August 2016 in our institution; patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD (post- or under treatment) were not. The median SBRT dose was 50 Gy in 5 fractions and the median biologically effective dose (BED; α/β = 10) was 100 Gy (range:72-119 Gy). The presence of subclinical ILD in the pre-SBRT CT findings was reviewed by two chest radiologists. The relationships among the efficacy, radiation pneumonitis (RP) and clinical factors were investigated. Results: Subclinical ILD was recognized in 38 (35%) of 109 patients. Grade 2–4 RP was recognized in 48 (44%) of 109 patients, no Grade 5 RP was happened. Grade 2–4 RP was observed in 17 (45%) of 38 patients with subclinical ILD. Subclinical ILD was not found to be a significant factor influencing Grade 2–4 RP; however, extensive RP beyond the irradiated field, including the contralateral lung, was recognized in only two patients who were both suffering from subclinical ILD, and the rate of extensive RP was significantly high in the patients with subclinical ILD. Dosimetric factors of the lungs (V5, V10, V20, MLD, V12.5, V13.5) were significantly associated with Grade 2–4 RP. The three-year overall survival and progression-free survival rates of all patients were 82.8% and 62.5%, respectively. No significant differences were seen in either overall survival or progression-free survival rates among the patients with ILD and those without ILD, or with RP and those without RP. Conclusions: Subclinical ILD was not found to be a significant factor for Grade 2–5 RP or clinical outcomes in early stage NSCLC treated with SBRT; however, uncommon extensive RP can occur in patients with subclinical ILD.
Thermal ablation versus stereotactic body radiotherapy for stage I non-small cell lung cancer: A cost-effectiveness analysis.
Authors: Wu Xiao , Uhlig Johannes , Blasberg Justin , Gettinger Scott N. , Suh Robert , Solomon Stephen Barnett , Kim Kevin
Published: May 2020

e21061

Background: Stereotactic body radiotherapy (SBRT) and thermal ablation are increasingly used to treat medically inoperable patients with non-small cell lung cancer (NSCLC). The purpose of this study is to assess the cost-effectiveness of microwave (MWA) and stereotactic body radiotherapy (SBRT) for patients with stage I NSCLC. Methods: A decision-analysis model was constructed over a 5-year of Medicare billing data from a health care sector’s perspective using TreeAge Pro Suite 2019 (TreeAge Software LLC, Cambridge, MA). The two evaluated strategies were SBRT and MWA. All clinical, cost and health utility parameters were derived from the literature with preference to long-term prospective trials and assigned appropriate statistical distributions. Costs and health utilities (quantified by quality-adjusted life years (QALY)) associated with procedure, short-term complications, long-term surveillance and disease progression were incorporated. A willingness-to-pay (WTP) threshold of $100,000/QALY was used. One QALY is equivalent to 1 year of life in perfect health. Strategies were compared using incremental cost-effectiveness ratio (ICER). Base case calculations, Monte Carlo Simulations with 10,000 iterations drawing parameters from their respective distributions, and multiple sensitivity analyses were performed. Results: Literature review and interpolation showed that average annual recurrence risk of SBRT and MWA were 4.64% and 10.4% respectively. SBRT yielded 2.33 QALY and MWA yielded 2.31 QALY. The difference in health benefit is equivalent to 1 week of life in perfect health. The overall costs were $225,271 and $195,331. The ICER of MWA in reference to SBRT was $1,480,597/QALY, which is more than 10 times of the WTP threshold currently used in the US, indicating that MWA is the more cost-effective strategy. MWA was the optimal strategy in 99.84% of the Monte Carlo simulations. One-way sensitivity analyses showed that MWA is more cost-effective than SBRT if recurrence risk of MWA is < 18.4% per year or recurrence risk of SBRT is > 1.44% per year, or cost of MWA is lower than or at most $7,500 more than SBRT. One-way sensitivity analysis showed that MWA would achieve a higher health benefit than SBRT if the overall survival after MWA was > 76.9% per year or after SBRT was < 75.6% per year. Conclusions: Our study showed that MWA is more cost-effective than SBRT for medically inoperable stage I NSCLC patients with comparable health benefits based on multiple robust probabilistic and deterministic sensitivity analyses.
Targeted sequencing analysis of predominant histological subtypes in resected stage I invasive lung adenocarcinoma.
Authors: Li Chong , Li Yan , Tan Yan , Yan Zhantao , Xie Jun , Zhang Xian , Hu Song , Zong Yun , Li Qing , Ye Junyi , Li Xi , Han-Zhang Han
Published: May 2020

e21067

Background: Lung adenocarcinoma (LADC) is classified into 5 main histological subtypes with distinct clinicopathologic characteristics: lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary component (MPC) and solid-predominant adenocarcinoma (SPA). However, the mutational profiles of predominant histological subtypes have not been well defined. In this study, we aimed to reveal the genomic landscape of the 5 main histological subtypes. Methods: Surgically resected tumor samples were obtained from 86 patients with pathological stage I invasive lung adenocarcinoma who underwent surgery between January 2015 and December 2018. No patient had received preoperative chemotherapy or radiotherapy. Capture-based targeted sequencing was performed in a cohort of 86 stage I invasive adenocarcinoma (IAC) patients spanning 5 subtypes using a panel consisting of 168 lung cancer-related genes. Results: Our analysis identified a total of 302 genomic alterations. Five subtypes showed distinct mutation profiles with LPA, APA, PPA, MPC and SPA had an average mutation rate of 1.95 (range: 0–5), 2.56 (range: 1–6), 3.5 (range: 1–7), 3.75 (range: 1-8) and 6.05 (range: 2-12), respectively (p = 4.17e-06). In this cohort, 96.55% (83/86) of all patients had mutations in classic lung cancer drivers with EGFR (73.3%), KRAS (9.3%), ALK (4.7%) and MET (4.7%) being the most commonly mutated drivers. TP53 is the top mutated tumor suppressor gene. It has been reported that SPA and MPC have unfavorable prognosis comparing to the rest subtypes. Interestingly, LRP1B mutations, which has been reported to be associated with high tumor mutation burden and better response to immunotherapy, were only detected from 5 SPA patients (p = 0.001). No MPC patients from this cohort harbored LRP1B mutations. Conclusions: We revealed distinctive mutation landscape of the 5 major histological subtypes of LADC, evident by distinctive average mutation rate with SPA and PLA having the highest and lowest average mutation rate, respectively. Furthermore, we also showed that SPA patients harboring LRP1B mutations may benefit from immunotherapy.
An exploratory study of PD-1 inhibitor for high-risk multiple ground-glass nodules (mGGNs) in synchronous stage I non-small cell lung cancer patients.
Authors: Xu Lin , Shi Meiqi , Li Ming , Xia Wenjia , Shen Wenrong , Zhang Jingyuan , Zhu Jun , Shao Yang , Yin Rong
Published: May 2020

e21068

Background: Surgical resection is recommended for the stage I NSCLC patients. However it is lack of standard therapies for synchronous mGGNs. This study aims to explore the feasibility of a PD-1 inhibitor (sintilimab) in high-risk residual mGGNs in post-surgery synchronous stage I NSCLC patients. Methods: This is a single arm phase I trial intending to recruit 20 subjects. Eligible patients contained at least one high-risk residual mGGN (confirmed by MDT discussion) after surgical resection of stage I NSCLC. Patients received sintilimab (200mg i.v., Q3W) for 10 cycles since 6 weeks post-surgery. Radiological evaluations were performed at every 3 cycles in treatment period and every 3 months during follow-up. Whether re-operation is needed depends on MDT evaluation. The primary endpoints were safety and ORR. The secondary endpoints included DOR, MPR of re-operated GGNs, and the one-year PFS. Results: As data cutoff (23 Jan 2020), 20 patients (9 males and 11 females) were enrolled. The pathological results revealed that all were lung adenocarcinoma. The median treatment cycles was 6 (range 3 to 10). All lesions were evaluated as stable disease by RECIST 1.1. Six patients underwent re-operation safely and12 GGNs were resected. Pathology showed that 1 had no tumor cells residue, 4 had 20-35%, and 7 had over 80% residues. Whole-exome sequencing of 12 GGNs showed 6 harboring EGFR and 2 harboring KRAS mutations. Interestingly, 3 out of 6 with EGFR-mut showed less tumor cells residues (23.3%, 30%, and 80%). The highest TMB (15.7 mut/Mb) was observed in the complete response GGN. 65% patients experienced treatment-related 1-2 grade AEs. Conclusions: The PD-1 inhibitor showed well tolerability and a certain degree anti-tumor activity was seen from the pathologic results of re-operated GGNs. Radiological evaluation using RECIST 1.1 might be unsuitable for mGGNs. Further studies are needed to demonstrate the clinical benefits. ChiCTR: 1900022159 Clinical trial information: 1900022159 .
Prognostic and predictive effect of KRAS gene copy number and mutation status in early stage non-small cell lung cancer (NSCLC) patients.
Authors: Fung Andrea S. , Karimi Maryam , Michiels Stefan , Seymour Lesley , Brambilla Elisabeth , Le Chevalier Thierry , Soria Jean-Charles , Kratzke Robert Arthur , Graziano Stephen L. , Devarakonda Siddhartha , Govindan Ramaswamy , Tsao Ming-Sound , Shepherd Frances A.
Published: May 2020

e21080

Background: The prognostic and predictive role of KRAS mutations and gene copy number aberrations (CNA) in early stage NSCLC is unclear. In this study, we characterize the prognostic effect of KRAS mutation status and concomitant CN gain in early stage NSCLC, and determine the ability to predict survival benefit from adjuvant chemotherapy. We hypothesize that concomitant KRAS mutations and CN gain will be prognostic of worse survival compared to KRAS mutations alone. Methods: Clinical and genomic data from The LACE (Lung Adjuvant Cisplatin Evaluation)-BIO consortium was utilized. CNA were categorized as Gain or Neutral (Neut)/Loss; mutation status was defined as wild type (WT) or mutant (MUT). WT+Neut/Loss (reference), WT+Gain, MUT+Gain and MUT+Neut/Loss groups were compared in all patients and the adenocarcinoma subgroup. Primary endpoint was lung-cancer-specific survival (LCSS); secondary endpoints were DFS and OS. Survival curves were assessed using Kaplan-Meier and log-rank tests. Concomitant KRAS CNA and mutation status was correlated to endpoints using a Cox proportional hazards model stratified by trial and adjusted for treatment, age, gender, histology, WHO performance status, surgery type, tumor and nodal stage. A treatment-by-variable interaction was added to evaluate predictive effect. Results: 946 (399 adenocarcinoma) patients had complete KRAS mutation, CNA and clinical data: 41 (30) MUT+Gain, 145 (99) MUT+Neut/Loss, 125 (16) WT+Gain, 635 (254) WT+Neut/Loss. There was a negative prognostic effect of KRAS MUT+Neut/Loss for LCSS (HR = 1.32 [1.01-1.71]) on univariable analysis, and to a lesser extent after adjusting for covariates (HR = 1.28 [0.97-1.68]). A similar non-significant trend was observed in KRAS MUT+Gain patients for LCSS (HR = 1.34 [0.83-2.17]), DFS (HR = 1.34 [0.86-2.09]) and OS (HR = 1.59 [0.99-2.54]). There was no significant predictive effect in the overall population; however, a potential predictive effect of KRAS for OS was seen in the adenocarcinoma subgroup (interaction p = 0.046). KRAS MUT+Gain was associated with a beneficial effect of chemotherapy on DFS (HR = 0.33 [0.11-0.99], p = 0.048), with a non-significant trend also seen for LCSS (HR = 0.41 [0.13-1.33]) and OS (HR = 0.40 [0.13-1.26]). Conclusions: A small prognostic effect of KRAS mutation was identified for LCSS. A potential predictive effect of concomitant KRAS mutation status and CNA was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require further validation.
Management of medical inoperable and tyrosine kinase inhibitor-naive early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: A retrospective multi-institutional analysis.
Authors: Sun Yue Mei , Zhou Ming Xiu , Zeng Ming
Published: May 2020

e21082

Background: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) and for medical inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations is not yet determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI alone and combined radiation and TKI on the survival outcomes in this patient subgroup. Methods: 132 cases of medical non-operable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among the patients, 65 cases received combined radiation and EGFR-TKI therapy (R+TKI) (49.2%), while 67 cases had EGFR-TKI (50.8%) treatment alone. All patients were followed until death. Results: For R+TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < .001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups were 24 months and 14.7 months respectively (log-rank p < .001). Multivariate analysis showed that R+TKI was independently associated with improved OS (adjusted HR: 0.420; 95% CI, 0.287 to 0.614; p < .001) and PFS (adjusted HR: 0.420; 95% CI, 0.291 to 0.605; p < .001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. Conclusions: Upfront radiation to primary sites with TKI to follow was a feasible option for patients with EGFR-mutant medical inoperable non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with TKI alone
Reconstruction of the superior vena cava in patients with thymic malignancies.
Authors: Yu Lei
Published: May 2020

e21116

Background: Thymoma is a kind of mediastinal tumors usually with an indolent growth pattern but malignant because of potential for local invasion, pleural dissemination, and even systemic metastases. Different from other malignant tumors, thymoma is often associated with autoimmune disorder s, the most common one being myasthenia gravis (MG). Complete surgical excision has been regarded as the standard of care for patients with thymoma, esp. locally advanced thymoma. The aim of this study was to investigate the effectiveness of reconstruction (Y-shaped bypass) of the superior vena cava (SVC) to treat locally advanced thymoma with SVC syndrome. Methods: We retrospectively studied data from 24 consecutive patients with locally advanced thymoma and SVC syndrome, operated on from October. 2015 to Dec. 2018 in Beijing Tongren Hospital. Their clinical data including clinical presentation, operation procedure, postoperative drug, adjuvant radiochemotherapy and follow-up were documented. 18 cases had MG, one having dermatomyositis, and two having interstitial pneumonia. Results: There were no perioperative deaths. All patients underwent complete resection and replacement with a GORE-TEX Vascular Graft (Y-shaped bypass) of SVC. The number of typeAB, B1, B2, B3 thymoma, and thymic carcinoma in this data were 2, 2, 7, 7, and 6, respectively. 7 patients had postoperative complications: 3 (with MG) experienced myasthenia crisis, 3 had pneumonia, and one had pulmonary embolisms, respectively. Both unfractionated heparin and Warfarin were routinely used the second or third day after surgery to maintain INR (International Normalized Ratio) between 1.8 and 2.5. All patients received mediastinal radiation therapy within one month after surgery. All patients were followed up for 2 months to 42 months. There were no patients dying and recurring. Conclusions: Reconstruction of SVC (Y-shaped bypass) is an effective way to treat locally advanced thymoma with SVC syndrome. After surgery, postoperative anti-thrombotic agents should be applied to prevent acute graft occlusion.