bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of first-line therapy with novel agents in multiple myeloma patients age 80 and above: A systematic review.
Authors: Rahman Sadaf , Sider Cody , Bahodi Fadi , Lam Selay , Louzada Martha , Phua Chai W.
Published: May 2020

e20532

Background: Novel therapeutic agents in multiple myeloma (MM) have demonstrated significant improvements in treatment outcomes. However, data remains scarce in newly diagnosed transplant-ineligible patients aged 80 and above as they are less represented in clinical trials. Optimal treatment of this population also proves challenging due to treatment-related adverse events. Methods: MEDLINE and EMBASE search concluded March 4, 2019. We included studies that evaluated first-line treatment of age ≥80 transplant-ineligible MM patients with novel agents. The primary outcomes assessed were OS and PFS. A qualitative analysis was undertaken due to the small number of included articles. Results: Of 1683 articles assessed for eligibility, 134 articles proceeded to full-text review. 6 articles with a total of 819 patients age ≥ 80 (range 80-96) were included for analysis (5 retrospective analyses and 1 phase II, non-randomized trial). Median OS were significantly shorter in age ≥80 in comparison to younger groups (reported median OS ranged from 19.5-31.9mo for age ≥80, 46-54.8mo for age 66-79, and 81-83.8mo or not reached for age ≤65). Shorter survival was associated with poorer performance status, advanced ISS stage, higher Charlson Comorbidity Index, anemia and elevated serum LDH. In one study, attaining a very good partial response or better (≥VGPR) was associated with improved median OS (30.4mo vs 18.8mo, p = 0.001). There was no difference between age groups for OS if ≥ VGPR was attained (53.4mo in age ≥80, vs not reached in age 66-79 or age ≤65; p = 0.184). In 1 of 3 studies that reported median PFS, a significant difference in one study was noted by age [age ≥80 = 19.1mo, age 66-79 = 26.3mo (p = 0.033), ≤65 = 54.3mo (p = 0.0009)]. Early mortality (at 2 or 6 months; in 3 studies) was significantly greater than in patients age < 80 and was primarily due to infection or renal failure, and more often in the frail. One study noted that despite reduced OS, the relative survival rate was higher in patients aged ≥85 at 2 years than in younger age groups. Conclusions: Our review excluded most RCTs as subgroup analyses of patients aged ≥80 were not available. Regardless, included articles are representative of the real-world experience. This systematic review suggests that while MM patients aged ≥80 experience shorter OS and PFS, treatment with a novel agent may offer comparable survival outcomes to younger groups in those able to attain ≥VGPR. Relative survival in elderly patients also favours active treatment in this age group, while balancing the risks of early mortality.
Adverse event and outcome patterns in patients with advanced multiple myeloma in the United States.
Authors: Richter Joshua Ryan , Yeaw Jason , Shah Drishti , Anupindi Ruthwik , Kudaravalli Suneel , Zavisic Stojan
Published: May 2020

e20544

Background: Multiple Myeloma (MM) is a hematologic malignancy with an estimated 5-year survival rate of just over 50%. Evolving paradigms arising from numerous FDA approvals continue to shape the treatment landscape for relapsed and refractory MM (RRMM) patients. As the number of approved drugs/regimens increases, the efficacy as well as toxicity profiles for the more heavily refractory patient change. The objective of this study was to evaluate adverse event rates and associated outcome patterns among RRMM patients treated with pomalidomide (poma) or daratumumab (dara). Methods: Adult patients with ≥1 claim of poma or dara (index) were identified between Jan 1, 2012 and Feb 28, 2018 using IQVIA’s Real-World Adjudicated US claims database. Patients were required to be continuously enrolled in the health plan ≥180 days prior and ≥360 days post index date, have a diagnosis or treatment claim for MM and a claim of any immunomodulatory drugs and proteasome inhibitors before index date. Mean time to new therapy and mean time to readmission were evaluated over the 1-year post-index period among RRMM patients. Overall survival (OS) was measured using Kaplan-Meier curves. Occurrences of adverse events (AEs) and mean length of stay for AE-related hospitalization were also reported. Results: There were 289 patients in the RRMM cohort with 67.8% of patients treated with combination therapy in the baseline period. Of index therapies, 81% of patients used poma and 40% used dara in post-index period. Overall, 42% of patients had a Charlson Comorbidity Score of ≥3. Among 258 patients with a new treatment post-index, mean (SD) time to a new treatment was 4.7(5.3) months. Median OS was 14.6 months. Post-index hematological AE were frequent such as anemia (72.0%), febrile neutropenia (52.6%), neutropenia (30.1%) and thrombocytopenia (36.0%, Table). Mean length of stay for AE-related hospitalizations was 10.1 days and mean time to readmission was 63.3 days. Conclusions: Low OS, high frequency of AEs and longer LOS for AE-related hospitalizations suggest that outcomes of these patients remain poor despite availability of newer treatment options. Further study is warranted to better manage the individual and system-wide toxicity in this clinical setting. [Table: see text]
Preclinical evaluation of TQB3602, a small molecule proteasome inhibitor clinical candidate.
Authors: Zhang Xiquan , Yang Ling , Tian Xin , He Lihua , Xiong Jian , Niu Xiaoxia , Xia Yuanfeng , Li Jian , Chen Shuhui , Chen Kevin
Published: May 2020

e20546

Background: Proteasome inhibitors, selectively inhibit the activity of proteasome in ubiquitin proteasome system, together with immunomodulatory drugs formed the basis of many treatment regimens for multiple myeloma in first-line therapy as well as for the treatment of relapsed disease. Bortezomib (Velcade), the first approved therapeutic proteasome inhibitor with a unique boronic acid as warhead, limited by its requirement for parenteral administration (intravenous or subcutaneous). The 2nd generation boronic acid – orally bioavailable Ixazomib (Ninlaro) was approved in 2015 by FDA greatly improved patient’s compliance. However, its adverse effect remained an issue in clinical application. The purpose of this study is to investigate the in vitro and in vivo antitumor activity of TQB3602, a novel orally bioavailable small molecule proteasome inhibitor, in preclinical models of multiple myeloma. Methods: The enzyme inhibition and anti-proliferative activity of TQB3602 was evaluated in 20S proteasome and MM.1S cell line. Oral administration of TQB3602 at 3 doses was used to evaluate the in vivo anti-tumor activity in MM.1S multiple myeloma xenograft (CDX) models. Results: TQB3602 displayed potent kinase inhibiting activity for 20S proteasome enzyme with IC50 15.3 nM. TQB3602 inhibited cell proliferation in MM.1S multiple myeloma cell line with IC50 10.1 nM. In the MM.1S multiple myeloma CB-17 CDX model, TQB3602 showed antitumor efficacy with TGI > 100% @7 mpk, BIW (tumor can’t be measured from day 17). Conclusions: We have identified a novel potent proteasome inhibitor TQB3602. Preclinical studies showed antitumor efficacy of TQB3602 in MM.1S multiple myeloma model. TQB3602 represents a promising clinical candidate for treating multiple myeloma and the First-in-human trial is expected in the middle of 2020.
Efficacy and tolerability of elotuzumab-based three-drug regimens for high-risk multiple myeloma: A meta-analysis.
Authors: Farooqui Arafat Ali , Nabeel Shaha , Tariq Muhammad , Ashraf Aqsa , Ahmed Zahoor , Faisal Muhammad Salman , Ammad Ud Din Mohammad , Shahab Zartashia , Setarehaseman Alireza , Anwer Faiz
Published: May 2020

e20550

Background: Efficacy of elotuzumab (E) 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 E based 3-drug regimens compared to non-E based regimens in high risk MM. Methods: A systematic review of literature was done to identify randomized controlled trials (RCTs) which reported overall response rates (ORR), progression free survival (PFS) and overall survival (OS) of MM patients (pts) with E based 3-drug regimens. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS and OS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using RevMan v.5.3 to report the efficacy of E 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: After screening 604 studies, 04 RCTs were included (n = 986 patients). E was evaluated with lenalidomide (L), pomalidomide (P), bortezomib (B) and dexamethasone (d). ELd regimen was studied in 359, EPd in 60 and EBd in 77 pts. Total 496 pts were evaluated with E. Pooled analysis of E based 3-drug regimens showed improved PFS (HR 0.69, 95% CI 0.59-0.81; p < 0.00001, I2 = 0%) and ORR (OR 1.92, 95% CI 1.33-2.78; p = 0.0005; I2 = 25%) as compared to non-E 2-drug regimens. Relapsed/refractory MM pts (n = 456) also showed improved ORR in E vs non-E groups (OR 1.88, 95% CI 1.19-2.97; p = 0.007; I2 = 47%). Sub-group analysis showed 30% reduction in progression in high risk MM pts (HR 0.70, 95% CI 0.53-0.94; p = 0.02; I2 = 0%) and 31% in standard risk pts (HR 0.69, 95% CI 0.53-0.88; p = 0.003, I2 = 0%). OS showed 25% reduction in risk of death with E based regimens (HR 0.75, 95% CI 0.62-0.91; p = 0.004, I2 = 0%). E proved to be clinically safe across all patients (OR 1.10, 95% CI 0.78-1.57; p = 0.58; I2 = 71%). Conclusions: Elotuzumab based 3-drug regimens appear to abrogate high risk features in MM compared to 2 drug regimens.
Mortality of multiple myeloma diagnosed peri-hospitalization.
Authors: Rubinstein Sam , Sigworth Elizabeth , Chaugai Sandip , Chen Qingxia M , Cornell Robert F. , Warner Jeremy Lyle
Published: May 2020

e20553

Background: Although modern therapeutics for multiple myeloma (MM) have resulted in improved overall survival (OS) in recent years, patients who present with an acute disease-related complication often have poor outcomes. We sought to compare the OS of patients diagnosed with MM in or shortly after hospitalization with those diagnosed in the outpatient setting. Methods: Patients treated for MM at Vanderbilt University Medical Center (VUMC) between 2000 and 2018 were included. OS was computed from date of diagnosis; patients still alive were censored at date last known alive or of last follow-up. Baseline laboratory and cytogenetic data were used to calculate Revised International Staging System (R-ISS) stage; age was also recorded. Dates of inpatient notes and encounter codes were identified and compared to date of diagnosis to identify patients diagnosed within 30 days of an inpatient stay; patients whose first encounter at VUMC was 30 days or more after their diagnosis date were excluded. Cox proportional hazards modeling was performed to investigate the effects of a diagnosis within 30 days of an inpatient encounter controlling for age and R-ISS on OS. Time-dependent coefficients were included to investigate the effects of a peri-hospitalization diagnosis on OS before and after 90 days. Mortality at 90 days for each group was compared using Fisher’s exact test. Results: A total of 681 patients were included, of whom 81 (11.8%) were diagnosed peri-hospitalization. Patients diagnosed peri-hospitalization had inferior OS within the first 90 days (adjusted HR 8.38, 95% CI 4.22-16.66, p < .001), but not after 90 days (Table). 90-day mortality for patients diagnosed peri-hospitalization was higher than for those not diagnosed peri-hospitalization (21.0% v. 3.3%, p < 0.001). Conclusions: Patients diagnosed with MM peri-hospitalization had high early mortality in this study, although patients surviving more than 90 days have similar mortality to those diagnosed as outpatients. Many factors could account for this finding, such as irreversible renal failure or immobility due to MM, hospital-related complications, or more aggressive MM phenotype. Predictive models of early mortality in MM should account for inpatient status at diagnosis. [Table: see text]
Impact of proteasome inhibitor vs. IMiD maintenance therapy on outcomes of patients with high-risk multiple myeloma (HRMM).
Authors: Tam Eric Leon , Iberri David Joseph , Liedtke Michaela , Muffly Lori S. , Shiraz Parveen , Frank Matthew Joshua , Lowsky Robert , Rezvani Andrew , Negrin Robert , Meyer Everett , Arai Sally , Johnston Laura J. , Shizuru Judith , Weng Wen-Kai , Miklos David Bernard , Sidana Surbhi
Published: May 2020

e20557

Background: The ideal choice of maintenance therapy in patients with HRMM high-risk multiple myeloma remains unknown. We analyzed the outcomes of patients with HRMM undergoing transplant receiving different maintenance approaches. Methods: Patients with MM undergoing their first ASCT from 2012-19 within 1 year of diagnosis were identified from the prospectively maintained database of patients undergoing ASCT. HRMM was defined as having t(4;14), t(14;16), t(14;20), del17p13, or gain 1q detected on fluorescent in situ hybridization (FISH). Results: Of the 412 patients undergoing ASCT within 1 year of diagnosis, 333 had FISH data available and of these, 37% (124/333) patients had high-risk cytogenetics. Distribution of HR cytogenetics was as follows: deletion 17p: 37% (n = 46), t(4;14): 27% (n = 34), t(14;16) or t(14;20): 12% (n = 26), gain1q: 31% (n = 41). 9% (n = 12) had more than one HR abnormality. In patients with HRMM, median age at transplant was 59 years (range: 39 to 73), and 61% (n = 103) were males. 64% (n = 107) of high-risk patients received post-transplant maintenance therapy. Maintenance therapy in this group included a proteasome inhibitor (PI) in 34% (n = 29), immunomodulatory drug (IMiD) in 59% (n = 51), or both in 7% (n = 6). There was no difference in baseline characteristics of HRMM patients receiving PI vs. IMiD maintenance, except that patients with del17p were more likely to receive PI maintenance therapy (55% vs 28%, p = 0.01). (Table) After a median follow-up of 3.1 years from diagnosis, patients with HRMM had inferior PFS compared to patients with standard risk disease, with median PFS of 3 vs. 4.8 years, p < 0.001. Amongst the 86 HRMM patients receiving maintenance therapy, median PFS in patients receiving PI vs. IMiD vs. both PI + IMiD maintenance was 3 vs. 3.2 vs. 2.2 years, respectively, log-rank p = 0.7. In the sub-group of patients with 17p deletion, median PFS in the three groups was 3 vs. 2.9 vs. 2.2 years, respectively, log-rank p = 0.7. Conclusions: Patients with HRMM have inferior PFS compared to patients with standard risk disease. We observed similar outcomes in HRMM patients post-transplant regardless of the choice of maintenance therapy. [Table: see text]
Use of treatment pathways reduce cost and increase entry into clinical trials in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: Weese James L. , Shamah Corey J. , Sanchez Federico Augusto , Singh Maharaj , Huibregtse Carol , Clement Kevin , Barry-Weers Anne Marie , Bock Amy L. , Mitchell Dorothy L. , Beres Amy
Published: May 2020

e21000

Background: VIA Oncology evidence-based pathways have been integrated into our medical oncology workflows since November 2014. Within 3 months, compliance was high for our 42 medical oncologists at 19 sites working with a common EHR with over 85% of pts treated on pathway. The aim of this study was to determine if there was a significant difference in the overall cost of treatment between pts treated on pathway versus off pathway, and whether on pathway pts had a lower rate of ED use and unplanned admissions within 30 days of chemotherapy as required in the new CMS directives. Methods: Newly diagnosed NSCLC pts diagnosed between January 1, 2017 to December 31, 2018 were identified from the tumor registry for the system. The VIA database was queried to separate these pts into two groups – those pts who were treated on pathway, and those who were off pathway. In addition, we divided pts into early diagnosis, advanced/curative, and advanced/non-curative. The data warehouse was utilized to determine the total charges of adjuvant medical oncology treatment for these pts. In addition, data was extracted for the same groups to determine those pts who sought ED evaluation and or hospital admission within 30 days of chemotherapy treatment (CMS-35). Statistical analysis was performed using Chi-square/Fisher’s exact test to compare proportions and t-test for independent samples to compare treatment costs and ED/hospitalizations between the on and off pathway groups. Results: During the 2 years, 407 (81.4%) NSCLC pts were treated on pathway (including clinical trials); 93 (18.6%) were off pathway. All patients undergoing treatment were ECOG 0-2 Performance Status. Mean cost for treating the on-pathway group was $104,436 compared to $183,717 for the off-pathway pts (p = 0.01). Since implementing pathways, clinical trial entry rose from 27 to 66/yr. 25.8% of on pathway compared to 29% of off pathway fell into the CMS 35 group. Conclusions: Standardized usage of evidence-based pathways can be used successfully across a large number of providers over wide geography. Adherence to pathways results in significant cost savings for each patient and significant rise in clinical trial entry.
Cancer-IgG upregulation of radioresistance in non-small cell lung cancer patients and cell lines.
Authors: Zhu Guangying , Yang Xiongtao , Guohui Wang , You Jing
Published: May 2020

e21013

Background: Immunoglobulin G (IgG) is produced by B lymphocytes which is an important effector molecule of human immunity. However,our collaborators in China Peking University have found that malignant tumor cells can also express IgG (cancer-IgG). This study was designed to investigate the relationship between cancer-IgG and radiosensitivity and to explore its possible mechanisms in NSCLC. Methods: First, the expression of IGHG1 (immunoglobulin heavy constant gamma 1, IGHG1) and cancer-IgG in NSCLC and their relationship with clinicopathological features and prognosis were analyzed by TCGA(The Cancer Genome Atlas, TCGA), GEO(Gene Expression Omnibus, GEO) databases and immunohistochemistry. Secondly, after silencing the expression of cancer-IgG, cell scratch test, transwell, clone formation and apoptosis experiments were performed to observe the changes of EMT and radiation sensitivity of tumor cells after irradiation. Finally, the key proteins of PI3K/Akt signaling pathway and EMT-related proteins were detected by western blot and real-time PCR. Results: 1. The expression levels of IGHG1 and cancer-IgG in NSCLC were significantly higher than those in normal lung tissues, and high expression of IGHG1 and cancer-IgG were factors of poor prognosis. And cancer-IgG was closely related to clinical stage (P = 0.042), T stage (P = 0.044) and metastasis (P = 0.007). 2. Cell scratches and transwell experiments showed that the cell migration and invasion ability of si-control+IR group were significantly enhanced, but in si-Cancer-IgG+IR group were significantly lower than si-control+IR group. 3. Cloning formation experiments showed that the number of cell clones formed in the si-cancer-IgG group was significantly less than that in the control group under 2-6 Gy irradiation. Apoptosis results showed that the apoptosis rates of si-control group, si-Cancer-IgG group, si-control+IR group and si-Cancer-IgG group were 6.36±1.69%, 21.33±1.21%, 23.31±0.96% and 52.69±2.33% respectively. The apoptotic cells in the Si-cancer-IgG group were significantly more than the si-control group. (P < 0.01). 4. Western blot results showed that p-AKT, p-GSK3β, bcl2 and Vimentin were significantly decreased in si-Cancer-IgG+IR group compared with si-control+IR, and the expression levels of BAD and E-cadherin were increased. Conclusions: Cancer-IgG may mediate radiation-induced EMT and radiotherapy resistance through the PI3K/AKT pathway.
Immunoscore classifier:A gene based prognostic tool in early non-small cell lung cancer.
Authors: Guo Meiying , Sun Xindong , Yu Jinming , Wang Linlin
Published: May 2020

e21030

Background: The clinical benefits of immunotherapy in patients with stage I non-small cell lung cancer (NSCLC) is still controversial. Immune status plays critical role in the development and progression of NSCLC, and is associated with the patient survival outcomes. The analysis of immune features is thus valuable for the determination of immunotherapy. However, one single immune feature cannot reflect the complex immune status, and its prognostic value is extremely limited. In this study, we aimed to construct an immunoscore classifier based on multiple immuno-genes to predict the prognosis of patients with early NSCLC. Methods: A total of 522 patients with stage I NSCLC were included in this study. All patients' follow-up records and gene expression data were completely preserved. A least absolute shrinkage and selection operator (LASSO) algorithm was used to screen immune-related genes, and a COX proportional hazard regression model was used to construct the immunoscore classifier based on multiple immune-genes. Besides, the net reclassification improvement (NRI) calculation and concordance index (C-index) were applied to quantify the improvement of usefulness added by the immunoscore classifier compared to TNM staging system. Results: The immunoscore classifier including CCL5, CD8A, CXCL9, HLA-DQA1, LAG3, STAT1, and CD276 was significantly correlated with OS (HR: 2.785 CI: 1.809-4.289 P < 0.001) in patients with stage I NSCLC. With the optimal cut-off value of 4.32, all patients can be divided into a low-risk immune group and a high-risk immune group. The 10-year survival rates of the two groups were 36.8% and 12.3%, respectively. Besides, the immunoscore classifier was superior to the traditional TNM staging system in terms of distinguishing ability (C-index improvement by 0.075) and net reclassification ability (NRI improvement by 11.29%), indicating that the immunoscore classifier plays an important role in improving prognostic value. Conclusions: Multiple immune-genes based immunoscore classifiers can effectively predict the prognosis of patients with stage I NSCLC, and is significantly superior to the traditional TNM staging system in terms of prediction effectiveness and accuracy. As a new assessment tool, the immunoscore classifier may be helpful for determining the immune status of patients with stage I NSCLC and screening patients suitable for subsequent immunotherapy.
Characterizing the molecular and immunological features of lung micropapillary adenocarcinoma.
Authors: Zhang Shirong , Xu Yang , Zhao Pan , Bao Hua , Wang Xiyong , Liu Rui , Xu Rujun , Xiang Jingjing , Jiang Hong , Yan Junrong , Wu Xue , Shao Yang , Liang Jiafeng , Wu Qiong , Zhang Zhihao , Lu Shun , Ma Shenglin
Published: May 2020

e21036

Background: Micropapillary adenocarcinoma (MPC) is one of the most aggressive histologic subtypes of lung adenocarcinoma (ADC). Although the incidence of MPC predominant ADC is low, nearly half of ADCs contain a minor proportion of MPC, which could contribute to poor prognosis in these patients. Comprehensive analysis of genetic and immunological features of ADC with different MPC contents would help better understand cancer biology of this ADC subtype and direct future treatments. Methods: We performed panel next-generation sequencing (NGS) of 425 cancer-related genes for a discovery cohort of 43 ADC patients whose tumors were microdissected to separate MPC and non-MPC regions and a reference cohort of 113 ADC patients with unknown ADC histologic subtypes. MPC-enriched mutations were identified by comparing tumors with different original MPC contents within these cohorts, which was then confirmed using a validation cohort of 183 ADC patients. Staining of immunological markers was also conducted for MPC samples from the discovery cohort to investigate their tumor microenvironment. Results: We found that ADC tumors with higher MPC contents/similarities tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). In addition, genetic alterations in transcription termination factor 1 ( TTF1), brain-specific angiogenesis inhibitor 3 ( BAI3), mammalian target of rapamycin ( MTOR), cyclin-dependent kinase inhibitor 2A ( CDKN2A), and CDKN2A were found to be enriched in MPC using the discovery and reference cohorts, which could then be cross-validated using the validation cohort. Tumors with higher MPC content were associated with elevated infiltration of CD4+, CD8+ and FOXP3+ T cells, especially at the peritumor regions. Higher percentage of PD-L1+ tumor cells were also found to be correlated with higher MPC content, suggesting of more immunosuppression in MPC predominant tumors than low MPC tumors. Conclusions: We identified multiple novel MPC-enriched genetic changes that could help understand the nature of MPC. MPC predominant tumors tended to have higher levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, making it a potential candidate for immunotherapy, especially the combination therapy of anti-PD-1/PD-L1 drugs and anti-CTLA-4 drugs, which could inhibit PD-1/PD-L1 pathway and FOXP3+ Treg cells simultaneously.
Liquid chromatography coupled to multiple reaction monitoring (LC-MRM) for quantification of PD-L1 and PD1-signaling proteins in non-small cell lung carcinoma (NSCLC).
Authors: Lacasse Vincent , Zahedi Rene , Richard Vincent , Wang Hangjun , Mitsa Georgia , Poetz Olivier , Redpath Margaret , Papadakis Andreas , Elchebly Mounib , Cohen Victor , Agulnik Jason Scott , Batist Gerald , Borchers Christopher , Spatz Alan
Published: May 2020

e21040

Background: Improving the predictive biomarkers arena of checkpoint inhibitors (CPIs) beyond PD-L1 immunohistochemistry (IHC) is one of the most important unmet need in NSCLC. Up to 50% of patients that show positive PD-L1 expression by IHC do not respond to anti-PD-L1 treatments, and patients with low/undetectable PD-L1 have significantly improved survival with CPI. Moreover, PD-L1 IHC is heterogeneous, can be affected by tissue fixation time and post-translational modifications like glycosylation. Also, multiple studies indicated that PD-L1 expression alone does not reliably reflect the immune status of the tumor, thus requiring the measurement of other members of the PD1 signalling pathway. Methods: To address these issues, we developed a multiplexed targeted mass spectrometry-based (MS) assay for the quantitation of protein members of the PD-1/PD-L1 axis in formalin fixed paraffin-embedded (FFPE) tissue.The effect of fixation time on protein recovery was determined using differentially fixed H1915 cells. Liquid chromatography (LC) coupled to MRM was used to develop a targeted assay for PD-L1, PD-1, PD-L2, NT5E, LCK and ZAP70. Results: After 30 minutes fixation 33.6 µg of protein were extracted per mg of FFPE H1915 cells, while protein recovery after 7 days was 55.8 µg/mg, with greater variability (18% and 28% CV, p-value = ns). The optimized LC-MRM method allows the quantitation of PD-L1 and PD-1 down to 23 amol on-column. We evaluated the utility of our MRM assays using the H1915 FFPE cells (PD-L1 3+ by IHC) and determined an endogenous concentration of PD-L1 and NT5E as being 33.2±0.1 amol/µg of total protein and 4.8±0.5 fmol/µg respectively. Noteworthy, a known glycosylation site of PD-L1 was quantified at 10.9±0.3 amol/µg of total protein (30% of total). As increases sensitivity was required, anti-peptide antibodies were generated against the 15 best peptides. We then evaluated this LC-MRM method using MDA-MB-436 cells with lower levels of PD-L1 protein assessed by IHC. Determination of endogenous PD-L1 concentration (3.0 amol/µg of total protein) was achieved using anti-peptide immuno-enrichment followed by MRM. Conclusions: We developed a fixation time independent extraction technique for FFPE and optimized a highly sensitive LC-MRM method that allows the absolute quantification of our targets. This proteomic workflow allows absolute quantification of the PD-1/PD-L1 axis from FFPE tissue using immuno-enrichment and a multiplexed LC-MRM method.
Changes of plasma GARP-LTGFβ1 complex during chemoradiotherapy may predict survival in non-small cell lung cancer (NSCLC).
Authors: Yu Yishan , Li Anqi , Wang Weili , Fu Pingfu , Jolly Shruti , Lawrence Theodore Steven , Machtay Mitchell , Li Zihai , Kong Feng-Ming Spring
Published: May 2020

e21042

Background: Glycoprotein-A repetitions predominant protein (GARP), a cell surface docking and activating receptor for latent transforming growth factor β1 (LTGFβ1), has been implicated in promoting oncogenesis. We report recently that GARP-LTGFβ can be clipped by thrombin but its clinical significance remains unclear. Herein, we hypothesized that 1) the baseline plasma GARP-LTGFβ1 complex is associated with clinical stage of cancers; 2) the baseline and/or changes of plasma GARP-LTGFβ1 complex during chemo-radiotherapy is associated with overall survival (OS) in patients with NSCLC. Methods: This is a correlative study for patients with stage I-III NSCLC receiving chemo-radiotherapy. Levels of GARP-LTGFβ1 complex in platelet-poor plasma were determined by a modified ELISA at pre-RT, 2,4 weeks during-RT and post-RT. Values were calculated based on the following formula: (ODtest-ODnegative control)/ODpostive control-ODnegative control). The primary endpoint was OS, analyzed using the Kaplan-Meier method and Cox proportional hazard model. Platelet-poor plasma samples from healthy subjects were used as normal controls. Results: A total of 155 patients were included: 41 stage I-II, 111 stage III. There were 115 male, 50 female with a median age of 66 years. Compared to 13 normal controls (0.638, 95% CI:0.477-0.799), NSCLC patients had a significantly higher plasma GARP-LTGFβ1 (0.965, 95%CI: 0.881-1.048, p = 0.014). The same trend was observed for stage, higher level in more advanced stage (1.037, 95%CI: 0.930-1.145) vs for stage I-II (0.854, 95%CI: 0.720-0.988) (p = 0.0375). Univariate analysis demonstrated that age, gender, clinical stage, smoking history, histology, KPS, and radiation dose were significantly associated with OS. Post/pre RT GARP-LTGFβ1 complex (high vs. low HR = 0.384, p = 0.043) instead of pre-RT (p = 0.538), during RT (p = 0.739 for 2 weeks, p = 0.570 for 4 weeks) or post-RT (p = 0.507) plasma GARP-LTGFβ1 complex during the course of radiation therapy correlated significantly with OS under univariate analysis. On multivariate Cox regression models after adjusting for above significant clinical factors, the changes of plasma GARP-LTGFβ1 level had significance in correlating with OS (HR = 0.359, p = 0.0087). Conclusions: Baseline plasma GARP-LTGFβ1 were significantly associated with presence of cancer and advanced stages in NSCLC patients. Changes of GARP-LTGFβ1 level in plasma could be useful to predict outcomes and reflect the changes of immune status after chemoradiation.
Association between homologous recombination deficiency and tumor mutational burden in lung cancer.
Authors: Jiang Yong , Dang Shiying , Yang Li , Han Yin , Zhang Yongshen , Mu Tianhao , Chen Shifu , Kong Feng-Ming
Published: May 2020

e21043

Background: Homologous recombination (HR) is an important repair method for DNA double-strand damage. HR is involved with complex signaling pathways and multiple steps, including BRCA1/2. Homologous Recombination Deficiency (HRD) can be caused by the loss of function of BRCA1/2 proteins due to gene mutation. Tumor mutational burden (TMB) was indicated to involved with HRD, which is critical to the guidance of immunotherapy. Methods: Patients available with tumor specimen genomic testing for lung cancer were enrolled in this study. The sequencing library was captured using a 605-gene panel. Homologous recombination (HR)-related gene list included 102 genes. Genomic alterations of HR-related genes were assessed by next-generation sequencing assay, including nonsense, nonstop, frameshift, splice site, damaging missense mutations in somatic variants and pathogenic germline variants. Then, TMB was calculated by dividing the total number of mutations counted by the size of the coding region. Results: A total of 741 patients was enrolled and 182 of them (25.6%) had at least one genomic alteration of the HR genes. The top mutant HR genes included ATM (4.1%), DNMT3A (2.8%), ATR (1.8%), CHEK2 (1.5%), BRCA2 (1.5%), ABL1 (1.4%), FANCA (1.2%), RIF1 (1.1%), FANCI (1.1%), RAD50 (0.9%), BRCA1 (0.9%), and MRE11A (0.9%). The most common mutational type was missense mutation (69.2%), followed by frameshift (15.6%), and nonsense mutation (15.2%). The median age was 62 in the HRD group (age < 45:5.4%, 45-65:59.6%, > 65:34.9%) compared to 60 in the rest of the patients (age < 45:11.3%, 45-65:61.3%, > 65:27.4%). There were overall 57.5% males and 42.5% females in terms of gender. HRD group had a significantly higher rate than Non-HRD group in males (72.1% vs 52.8%, p < 0.01). The occurrence of HRD mutations was significantly correlated with a high level of TMB (p < 0.01). The median TMB of HRD group (7.9 muts/Mb, 95%CI:7.1-9.2 muts/Mb) was significantly higher than that of Non-HRD group (3.8 muts/Mb, 95%CI:3.3-4.2 muts/Mb). In addition, the upper quantile value (7.5 muts/Mb) was used to identify patients with high TMB. HRD group had a significantly higher rate of TMB-high patients than Non-HRD group (51.1% vs 17.0%, p < 0.01). Conclusions: Our study demonstrated genomic alterations of the HR genes in about one fourth’s lung cancer. Besides, there was a significant positive correlation between HRD mutations and TMB level. The significance of HRD genomic mutation on predicting the efficacy of immunotherapy deserves further study.
Development and validation of a CT-based radiomic model combined with margin-related radiomic features to distinguish precancerous lesions from early-stage lung adenocarcinoma.
Authors: Huang Luyu , Zhou Haiyu , Yao Herui , Yu Yunfang , Zhu Hongyuan , Zheng Shaopeng , Lin Weihuan , Xie Daipeng , Zeng Fanjun , Liao Guoqing , Lin Zenan , Li Fasheng , Zhang Peirong , Xu Bin , Wu Shaowei , Yao Lintong , Li Wanshan
Published: May 2020

e21044

Background: The purpose of this study was to investigate whether the combined radiomic model based on tumor-associated and margin-related (5mm) radiomic features can effectively improve prediction performance of distinguishing precancerous lesions from early stage lung adenocarcinoma. Methods: 264 patients underwent preoperative chest CT in Guangdong Provincial People’s hospital from March 1, 2015 to December 31,2019 were sorted by three cohorts. All lesions were pathologically confirmed as precancerous lesions or Stage I lung adenocarcinoma and a total of 861 analyzable radiomic features were extracted from two segmented lesions including pulmonary lesions and margins, using PyRadiomics by two senior radiologists. In training cohort, 145 patients (70%) are selected randomly from the single-nodular patients (N = 207). As for the validation cohorts, the models were validated using the resting 62 patients from single-nodular cohort and multi-nodular cohort (n = 57) respectively. Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination were used for feature selection. ROC analysis and AUC were used to evaluate the performance of three models which were developed by multiple logistic regression on distinguishing the precancerous lesions from early stage lung adenocarcinoma. Results: Selected features from pulmonary lesions and pericarcinous tissue were developed into two independent radiomic models and a combined model. Margin-related radiomic model performs well in three validation cohorts. The AUC Brock of single-nodular cohort in training cohort was 0.912 (95% CI: 0.876-0.948), while in single-nodular validation cohort was 0.93 (95% CI: 0.862-0.966). Multi-nodular validation cohort in this model shows an AUC of 0.891 (95% CI = 0.824–0.943). Comparing combined model and tumor-associated radiomic model, it is found that the AUC of combined model was improved from 0.865 (95% CI: 0.767-0.963) to 0.94 (95% CI: 0.767-0.963) for single-nodular validation cohort. Respectively, this combined model also performs well in multi-nodular validation cohort. Conclusions: This study demonstrated the potential of margin-related radiomic features based on preoperative CT scans to distinguish precancerous lesions from early stage lung adenocarcinoma. The constructed radiomic model provided an easy-to-use, preoperative tool for surgeons to develop accurate therapeutic strategies for multi-nodular patients.
Epigenetic imprinted gene biomarkers significantly improve the accuracy of presurgical bronchoscopy diagnosis of lung cancer.
Authors: Zhou Jian , Cheng Tong , Li Xing , Pineda John P. , Lu Shaohua , Yu Hongyu , Ding Ming , Wang Xiaonan , Si Han , Shi Panying , Zhou Ning , Bai Chunxue
Published: May 2020

e21055

Background: The ability to diagnose earlier stages of carcinogenesis using less invasive presurgical tissue samples is especially desirable, but is often inconclusive because of insufficient morphological evidences of cancer. Many of the epigenetic biomarkers are involved in lung cancer, but are challenging to clinically evaluate. In this study, Quantitative Chromogenic Imprinting Gene In-Situ Hybridization (QCIGISH) was applied to directly visualize and quantitatively assess the biallelic and multiallelic alterations of imprinted gene expressions in order to characterize lung cancer carcinogenesis and progression. We updated an imprinted gene panel and developed an accurate lung cancer diagnostic grading model from minimally invasive biopsies using the QCIGISH method. Methods: 225 surgical (151 lung cancer, 74 benign lung lesion) and 95 pre-surgical samples (77 lung cancer, 18 benign lung lesion) were collected from 320 patients under clinical trial NCT03882684 involving five medical centers between 2015 and 2019. The QCIGISH method was applied to detect the allelic expression status of the GNAS, GRB10, SNRPN and HM13 imprinted gene panel. A diagnostic grading model for lung cancer progression was trained using 225 retrospectively collected surgical tissue set with known diagnosis, refined using 25 presurgical samples, and blindly validated using 70 presurgical samples. Results: The diagnostic grading model collectively achieved high sensitivity (98.7%) which is significantly higher than standard presurgical bronchoscopy diagnostic methods including transbronchial brushing (58-74%), transbronchial biopsy (61-75%), alveolar lavage (35-64%) and the combination of the aforementioned three methods (64-80%). Thus, epigenetic imprinted gene biomarkers significantly improve bronchoscopy diagnostic accuracy by 18.7% (98.7% vs 80%), while demonstrating even higher specificity (100% vs 94-96%). Conclusions: Epigenetic imprinted gene biomarkers are shown to be highly accurate in effectively differentiating benign lesions and malignant lung cancer cases. In addition, the improved accuracy demonstrated by QCIGISH over standard presurgical bronchoscopy diagnostic procedures makes it a viable and revolutionary epigenetics-based cancer detection method for practical clinical applications especially for small samples and less advanced grades of lung cancer.
Multiple immune features based signature for predicting recurrence and survival of inoperable la-NSCLC patients.
Authors: Guo Meiying , Li Wanlong , Fan Bingjie , Zou Bing , Sun Xindong , Yu Jinming , Wang Linlin
Published: May 2020

e21066

Background: The immune status of tumor microenvironment is extremely complex. One single immune feature cannot reflect the integral immune status and its prognostic value was limited. We postulated that the immune signature based on multiple immuno-features could markedly improve the prediction of post-chemoradiotherapeutic survival in inoperable locally advanced non-small-cell lung cancer (LA-NSCLC) patients. Methods: In this study, 100 patients who were diagnosed as inoperable LA-NSCLC between January 2005 and January 2016 were analyzed. A 5-immune feature-based signature was then constructed using the nested repeat 10-fold cross validation with LASSO Cox regression model. Nomograms were then established for predicting prognosis. Results: Immune signature combining 5 immuno-features were significantly associated with OS and PFS (P = 0.002 and P = 0.014, respectively) in patients with inoperable LA-NSCLC, and at a cutoff of -0.198 stratified patients into two groups with 5-year OS rates of 39.8% and 8.8%, and 2-year PFS rates of 22.2% and 5.5% for the high- and low-immune signature groups, respectively. Using immune signature, we proposed immune signature nomograms, which were better than the traditional TNM staging system in terms of discriminating ability (OS: 0.692 vs. 0.588; PFS: 0.672 vs. 0.586, respectively) or net weight classification (OS: 32.96%; PFS: 9.22%), suggesting that immune signature plays a complementary role in the prognosis prediction of patients with inoperable LA-NSCLC. Conclusions: Multiple immune features based immune signature could effectively predict recurrence and survival of inoperable LA-NSCLC patients, and complemented the prognostic value of the TNM staging system.
Prediction of lymph node metastasis using 5-point visual scale criteria of [18F]-fluoro-2-deoxy-D-glucose on positron emission tomography / computed tomography for early stage lung adenocarcinoma.
Authors: Kagimoto Atsushi , Tsutani Yasuhiro , Handa Yoshinori , Mimae Takahiro , Miyata Yoshihiro , Okada Morihito
Published: May 2020

e21084

Background: This study aimed to investigate the efficacy of the Deauville criteria, a 5-point visual scale criteria to assess the maximum standardized uptake value (SUVmax) of [18F]-fluoro-2-deoxy-D-glucose (FDG) on positron emission tomography (PET)/computed tomography (CT), in predicting lymph node metastasis and other pathological invasive characteristics of early-stage lung adenocarcinoma. Methods: In this retrospective study including 453 patients undergoing lobectomy or segmentectomy with lymph node dissection for clinical N0 lung adenocarcinoma with a whole size ≤ 3 cm between April 2011 and March 2019, the FDG-PET/CT scans were evaluated using the Deauville criteria to analyze the relationship of Deauville score with the clinicopathological characteristics and prognosis.The scoring method was as follows: Deauville score of 1, no FDG uptake by the primary tumor (same as background); Deauville score of 2, tumor FDG uptake that is the same as or weaker than that of mediastinum; Deauville score of 3, tumor FDG uptake that is stronger than that of mediastinum but same as or weaker than that of liver; Deauville score of 4, tumor FDG uptake that is moderately higher than that of liver; Deauville score of 5, tumor FDG uptake that is markedly stronger than that of liver. Results: The lymph node metastases were present in 0 (0%), 2 (1.1%), 6 (9.5%), 6 (15.8%), and 13 (15.7%) patients with Deauville scores of 1, 2, 3, 4 and 5, respectively. The pathological invasive characteristics (lymphatic, vascular, or visceral pleural invasion) were detected in 2 (2.4%), 17 (9.9%), 18 (28.6%), 23 (60.5%), and 54 (65.1%) patients, respectively. Similar results were found when the study cohort was analyzed according to the institutions where the FDG-PET/CT scans were performed. The 3-year recurrence-free survival was longer in the patients with a Deauville score of 1–2 (97.2%) than those with a Deauville score of 3 (86.2%, p < 0.001) or 4–5 (80.7%, p < 0.001). Conclusions: The 5-point-scale evaluation of the SUVmax on FDG-PET/CT using the Deauville score was useful in predicting not only lymph node metastasis but also other malignancy characteristics of early-stage lung adenocarcinoma.
Propensity score matching analysis of patients with inoperable stage III NSCLC treated with chemoradio- vs. chemoradioimmunotherapy.
Authors: Manapov Farkhad , Taugner Julian , Käsmann Lukas , Eze Chukwuka , Roengvoraphoj Olarn , Belka Claus
Published: May 2020

e21087

Background: Chemoradiotherapy (CRT) followed by consolidation treatment with the PD-L1 Inhibitor durvalumab is the new standard of care for inoperable stage III NSCLC. The present study compares outcome of patients treated with CRT alone to those treated with additional concurrent and/or sequential immune check-point inhibition (CRT-IO) using propensity-score matching analysis (PSM). Methods: PSM was performed with retro- and prospectively collected data of patients treated with CRT or CRT-IO (consolidation with durvalumab/concurrent and consolidation with nivolumab). Overall survival (OS), progression free survival (PFS) and time to loco-regional recurrence (defined as progression in the mediastinum and ipsilateral lung) were calculated from last day of thoracic irradiation. Results: Sixty-two (37%) of 166 treated patients were successfully matched; 31 received CRT and 31 CRT-IO. 18F-FDG-PET/CT for treatment planning was performed in 97% and cranial contrast enhanced MRI in 81% of patients. PSM was based on age, gender, PTV volume, histology, T- and N-stage. 36 and 51% vs. 42 and 46% of patients had T4- and N3-disease in the CRT and CRT-IO cohorts, respectively. All patients were irradiated to a total dose of at least 60Gy (EQD2). 90% of patients received two cycles of concomitant platinum-based chemotherapy (CRT: 82%, CRT-IO 96%). The median follow-up for 62 patients was 17.3 (range: 1.7-96.0) months. Median PFS was 7.1 (95%CI 2.2-12.1) months in CRT vs. 13.8 (95%CI 13.1-14.5) in CRT-IO patients (p = 0.004). Twelve-month PFS rates were 30% and 55% in the CRT and the CRT-ICI cohort, respectively. Median time to loco-regional recurrence was 15.3 months for CRT vs. not reached for CRT-IO patients (p = 0.050). 12-month loco-regional recurrence rates were 43% vs. 22%; 6- and 12-month brain metastases rates after completion of radiotherapy in the CRT vs. CRT-ICI cohort were 8% and 26% vs. 0% and 20%, respectively. Median OS was 19.1 (8.4-29.8 95%CI) months for CRT and not reached for CRT-IO patients (p < 0.001). 12-month survival rates were 62% and 93% in the CRT and CRT-IO cohort, respectively. Conclusions: The addition of concurrent and/or sequential IO to CRT led to an impressive improvement of loco-regional control, PFS and OS in the matching cohorts.