bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution and influencing factors of tumor mutational burden in different lymphoma subtypes.
Authors: Zhou Hui , Du Xinhua , Zhao Tingting , Ouyang Zhou , Liu Wei , Deng Mingyang , He Qian , Yi Yuting , Dai Lian , Yang Ling , Xia Xuefeng
Published: March 2020

e19053

Background: Tumor mutational burden (TMB) has emerged as a promising biomarker in melanoma, NSCLC, glioma, and likely across types of solid cancers. However, TMB distribution and influencing factors in non-Hodgkin's lymphoma are still unknown. Methods: In this study, we focused on tumor (tTMB) and peripheral blood TMB (bTMB) in different lymphoma subtypes and conducted a hybridization-capture methodology and targeted 1.1Mb or 1.7 Mb of genomic coding sequence. Analysis of 188 tumors and 98 plasma samples matching oral epithelial normal samples was performed to characterize the landscape of somatic mutations between the TMB high (TMB-H) and TMB low (TMB-L) groups. Results: In our cohort, tTMB and bTMB ranged from 0 to 42.48, and 0.59 to 37.17, respectively. The top quartile TMB distribution (tTMB:12.34, bTMB:13.20) was used as the cut-off value to define TMB-H. DLBCL had significantly higher tTMB than small B cell lymphoma and peripheral T-cell lymphoma (p < 0.0001). 34.09% of DLBCL had TMB-H, and minority of patients had TMB-H in small B cell lymphoma (3.70%), and peripheral T-cell lymphoma (3.85%). The bTMB had the similar distribution to tTMB. Among all the tumor and plasma samples we detected 8 gene mutations having a significant correlation with high TMB including BTG2, PIM1, DUSP2, HIST1H1E, BTG1, SOCS1, HIST1H1C, CD70 ( p< 0.05) . Table TMB distribution of different lymphoma subtypes Conclusions: Compared to other lymphoma subtypes, DLBCL had higher TMB. Particular gene mutation had correlation with high TMB.[Table: see text]
Impact and influence of PET on imaging related endpoints in patients with Lymphoma using IWG-NHL or Lugano classification.
Authors: Sharma Manish , Bohnsack Oliver , Clark Daniel , O'Connor Michael , Singareddy Anitha , Narang Jayant , Jarecha Rudresh
Published: March 2020

e19061

Background: Positron Emission Tomography (PET) scans were applied to lymphoma as early as in 1990s. Revised criteria for lymphoma assessment was published in 2007 by International Working Group (IWG). The criteria for PET into response assessment were added due to better sensitivity and superiority of PET over CT and its ability to distinguish between viable tumor and necrosis or fibrosis in residual mass after treatment. PET was primarily recommended for patients with FDG avid curable lymphomas such as Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) and later for the post-treatment assessment of DLBCL and HL. The Lugano Classification 2014 regarded FDG PET/CT to be the standard for staging and assessment of all FDG-avid histologies. Methods: A retrospective review of 10 Lymphoma studies with a total of 1,537 subjects and 17,394 time points was carried out using PET in addition to CT as per imaging schedule. There were 5 clinical trials with a total of 1,169 subjects with 15,480 time points using IWG-NHL classification 2007 while 5 clinical trials with a total of 729 subjects and 1,914 time points using Lugano classification 2014. The number of subjects and time points with PET where PET had an impact on the overall assessment was calculated. Results: PET was available for a total of 1,159 subjects (out of 1,537) and 4,688 time points (out of 17,394) across all 10 studies. Out of 4,688 visits with PET, 956 (20.4%) visits had an impact on overall assessment due to additional metabolic findings. Out of 1,159 subjects with PET, 462 (39.9%) subjects had an impact on overall assessment and study endpoints due to additional uptake related findings. The impact across different studies was between 7% to 59% possibly due to difference in indication, line of therapy and blinded independent review design. The most common impact due to PET was related to complete response and disease progression. Conclusions: It can be concluded that PET significantly impacts assessments and imaging endpoints for lymphoma clinical trials using IWG-NHL classification or Lugano classification. Thus, addition of PET improves the outcome of the response not only in lymphoma treatment and diagnosis, but also clinical trial outcomes. [Table: see text]
Prognostic factors and nomogram for survival prediction in patients with primary pulmonary lymphoma: A SEER population-based study.
Authors: Low Soon Khai , Tawfik Gehad Mohamed , Zayan Ahmad Helmy , Istanbuly Obaida , Nguyen Tran Minh Duc , Ebied Amr , Lee Shin Yin , Huy Nguyen Tien
Published: March 2020

e19069

Background: The prognostic factors influencing survival and optimal management of primary pulmonary lymphomas (PPLs) have not been clearly defined due to rarity of the disease. This study sought to characterize the significant prognostic factors of PPL and develop a prognostic nomogram for individualized prediction of survival outcomes in patients with PPL. Methods: Patients diagnosed with PPL between 1983 and 2010 were identified using the Surveillance, Epidemiology, and End Results (SEER) Program database. Kaplan-Meier survival analysis and Cox proportional hazards regression model were performed to identify significant independent prognostic factors for overall survival (OS) in patients with PPL. A nomogram was constructed for the prediction of 5-year OS probability based on these variables. Results: The study cohort of 2325 PPL patients has a 5-year OS rate of 52% and a median OS of 67 months. Older age at diagnosis (HR 1.031; 95% CI, 1.026-1.036; p<0.001], males (HR 1.434; 95% CI, 1.267-1.622; p<0.001), Hispanic race (HR 1.370; 95% CI, 1.113-1.687; p=0.003), non-marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT) histology (p<0.001), primary site at main bronchus (HR 1.326; 95% CI, 1.014-1.735; p=0.039), Ann Arbor stage IV (HR 1.542; 95% CI, 1.324-1.795; p<0.001) were significantly associated with worse OS. All treatment modalities, including chemotherapy (HR 0.615; 95% CI, 0.536-0.706; p<0.001), surgery (HR 0.666;95% CI, 0.577-0.769; p<0.001) and radiotherapy (HR 0.829; 95% CI, 0.693-0.992; p=0.041) were independent predictors of survival. The nomogram constructed using these variables has a higher concordance index of 0.716 (95% CI, 0.699-0.734) compared to that of Ann Arbor staging system [0.571 (95% CI,0.552-0.591); p<0.001]. Conclusions: Older age, male sex, Hispanic race, non-MALT histology, primary site at main bronchus, advanced Ann Arbor stage, not receiving treatment were independent prognostic factors that are associated with worse OS in patients with PPL. The nomogram demonstrated good agreement between the predicted probabilities and actual observations on calibration plots.
Concordance and discordance in myeloma bone marrow studies.
Authors: Mendiola Vincent Louie , Kesireddy Meghana , Jana Bagi RP
Published: March 2020

e19508

Background: Multiple myeloma (MM) diagnostic costs, including bone marrow (BM) studies: (flow (F), aspirate (manual differential) (A) and biopsy (Bx)) are increasing. BM studies already have underlying discordance issues that may lead to repetitive studies. Thus, elucidation of characteristics associated with concordant/discordant BM studies in identifying plasma cell percentage (PC%) of ≥10, a key MM diagnostic criteria, arises. Methods: A retrospective chart review (total of152 patients diagnosed with MM and managed at UTMB through 1/2016-1/2018) was completed. 56 subjects met inclusion, PC ≥10% in any BM study, and exclusion criteria. Subjects were grouped into BMA vs BMBx and BMF vs BMBx groups and subdivided into MM subtypes for exploratory review. Two-sample Independent t-test (CI 95%) and descriptive statistics were used for comparison of variables. Two-sided p value ≤ 0.05 was considered significant. Results: Sensitivities in identifying BM PC≥10% were as follows: BMA (66.1%), BMF (39.3%) and BMBx (96.4%) (Gold standard: BMA+BMF+BMBx (100%)). Concordance rates were at 60.7% between BMA and BMBx and 35.7% between BMF and BMBx. Larger BMBx spicule size (mean(cm) = 1.3(1.1-1.48) x 0.27(0.22- 0.31) x 0.21(0.19-0.22), p = 0.037) and higher B2 microglobulin (B2m) levels (mean(mcg/mL) = 11.92 (8.04- 15.79), p = 0.003) were associated with BMA and BMBx concordance in typical/secretory MM types but not in oligo-secretory and non-secretory subtypes of MM, nor is associated with BMF and BMB concordance or discordance. Meanwhile, # of BM acquisition attempts, tool types (hand trochar vs drill) for BM acquisition, LDH and CRP levels had no significant associations with concordance or discordance in any BM study groups. Conclusions: BMF is the least sensitive in identifying PC≥10% likely due to PC damage during flow cytometry, and it may be prudent to just perform BMA with BMBx to save on costs. The associations between larger spicule sizes and higher B2m levels to BMA and BMBx concordance are likely due to an increase in the chance of identifying monoclonal PCs in bigger samples, and greater monoclonal PC tumor burden, respectively, and may have predictability benefits.
Efficacy and mechanism of action of NKTR-255, a polymer-conjugated IL-15 receptor agonist in hematological tumors.
Authors: Madakamutil Loui
Published: March 2020

e19512

Background: NKTR-255 is a polymer-conjugated IL-15 receptor agonist that accesses the IL-15 signaling pathway, and enhances the function and numbers of natural killer (NK) cells and CD8 memory T cell populations. Many hematological malignancies are treated with targeted antibodies that utilize effector mechanisms to recruit NK cells and macrophages. Most patients with hematological malignancies experience a progressive decline of NK cell immunity, a phenomenon termed as an “immunological desert”. We evaluated the hypothesis that a combination of NKTR-255 with a targeted antibody such as an anti-CD38 monoclonal antibody (mAb) or an anti-CD20 mAb, when evaluated in a preclinical hematological tumor model, would provide enhanced efficacy. Methods: Human PBMCs were stimulated with NKTR-255 and/or daratumumab for in vitro NK cell characterization. Using a B cell lymphoma model, SCID mice were inoculated i.v. with 107 Daudi cells and treated with a single dose of daratumumab or rituximab two weeks after tumor cell injection. NKTR-255 was administered s.c. concurrently on a q7dx3 dosing schedule. Survival of treated animals was measured using hind limb paralysis and morbidity as surrogate endpoints. Tumor cell depletion and phenotyping of immune cells in bone marrow were conducted by flow cytometry. Results: NKTR-255, when combined with daratumumab, enhanced NK cell degranulation and decreased NK cell death, leading to enhanced antibody-dependent cellular cytotoxicity (ADCC) activity for the daratumumab - NKTR-255 combination over the single agents. NKTR-255 demonstrated synergistic activity and provided a long-term survival benefit when combined with daratumumab or rituximab in the CD38 and CD20-expressing lymphoma mouse models. Mechanistic studies conducted in tumor-bearing mice treated with a combination of NKTR-255 and daratumumab showed effective clearance of lymphoma cells from the bone marrow and increased expansion of effector NK cells and other immune cells. Depletion experiments confirmed the role of NK, CD8 and other monocyte lineage immune cells in the observed anti-myeloma activity. Conclusions: These studies indicate that administration of NKTR-255, when combined with a monoclonal antibody such as daratumumab and rituximab, significantly increases NK cell numbers and activates their tumor killing capacity by virtue of an enhanced ADCC effect. Combinatorial approaches of NKTR-255 with these targeting agents could lead to novel and effective clinical applications in hematology.
Real-world use of carfilzomib among multiple myeloma patients with at least one prior therapy.
Authors: Terpos Evangelos , Gamberi Barbara , Caers Jo , Söhne Maaike , Heibl Sonja , Suzan Florence , Szabo Zsolt , Mohammad Abeera , Wetten Sally , Leleu Xavier
Published: March 2020

e19515

Background: To understand how novel therapies approved in relapsed multiple myeloma, e.g. carfilzomib (CFZ), are used in real-life, we describe the results of a planned interim analysis from a large observational study (NCT03091127). Methods: The study enrolled adult patients (pts) who received ≥1 prior line of therapy and ≥1 CFZ dose in routine care. Pts were followed until 30 days after last CFZ dose or up to 18 months (mos) from initiation. Results: As of 22 Oct 2018, 293 pts from 10 included EU countries were observed for a median time of 7 mos. At CFZ initiation, pts who received CFZ, lenalidomide and dexamethasone (KRd) were younger than pts treated with CFZ and dexamethasone alone (Kd): 64 vs 70 years (median), respectively. Over half of KRd pts had received 1 prior line of therapy while nearly half of Kd pts had ≥4 prior lines. Hypertension (30%), cardiac disorder (14%), diabetes (12%) and renal disorder (9%) were reported at CFZ initiation. A best response (see Table) was achieved in 3-4 mos. The total dose received relative to EU label on average was 95% and 74% by KRd (20/27 mg/m2 for K) and Kd pts (20/56 mg/m2 for K), respectively. The Kaplan-Meier median estimate of treatment duration was 16.6 mos for KRd and 7.7 mos for Kd pts. Among the 138 pts who discontinued, disease progression/refractoriness was the most frequent reason (40%). Gr3+ AEs were reported in 37% pts, including hypertension (2%) and cardiac failure (1%). Conclusions: In this real-life setting, KRd pts are younger and receive CFZ in earlier lines than Kd pts and the benefit-risk profile is consistent with published trials. The estimated treatment duration was longer than observed in other real-life data. [Table: see text]
Clinical significance of CXCR5-CXCL13 signaling in multiple myeloma.
Authors: Adebayo Olayinka omoyitola , Young Corey , Griffen Tiara , Carey Kaylin , Nunez Sha'Kayla , Jain Sanjay R , Lillard James
Published: March 2020

e19517

Background: Multiple myeloma (MM) is characterized by the neoplastic proliferation of plasma cells resulting in monoclonal immunoglobulins in the blood, bone marrow, and urine (1). According to a 2019 American Cancer Society (ACS) report, MM is now classified as subtypes of non-Hodgkin lymphoma (NHL). ACS expects there will be ~32,110 new MM cases (18,130 in men and 13,980 in women) and ~12,960 (6,990 in men and 5,970 in women) anticipated deaths in 2019. MM is a heterogenous disease; characterizing its molecular phenotypes is important for effective treatment of MM and predicting relapse. CXCL13-CXCR5 interactions are involved in malignancy cell homing, adhesion, signal transduction, and calcium flux, all of which promote MM progression. Methods: We analyzed RNA-sequence data from matched normal, primary and relapsed MM cases. Patient control mRNA samples matched primary tumor and relapse samples were acquired from dbGap (database of Genotypes and Phenotypes) to evaluate the mRNA expression patterns of CXCL13, CXCR5 and associated genes in MM. A bioinformatics strategy was used to integrate published genomic data from MM patients (n = 480) and identify genes associated with CXCL13-CXCR5 signaling. DESeq analysis was used to determine differentially expressed genes between normal tissues, primary tumor and relapse groups. Weighted gene co-expression network analysis (WGCNA) identified clusters of genes significantly associated with the molecular phenotypes of MM. Results: Notably, gene expression driven by NFAT and JUN, known to be activated by the CXCL13-CXCR5 axis, and plasma cell signaling pathways significantly correlated with select MM molecular phenotypes and patient survival. Ingenuity pathway analysis (IPA) was performed to analyze upstream regulators, gene interaction networks and canonical pathways. Taken together, our data show CXCR5-CXCL13 signaling networks are significantly expressed and associated with MM pathogenesis and plasma clonality. Conclusions: This study provides a better understanding of the heterogeneous nature of MM and the role of the CXCL13-CXCR5 axis in MM.
Cost-effectiveness of next-generation sequencing minimal residual disease testing during maintenance treatment for multiple myeloma.
Authors: Carlson Josh John , Eckert Benjamin , Zimmerman Marita
Published: March 2020

e19529

Background: MRD testing is part of the response evaluation criteria for MM, and clinical guidelines recommend MRD testing with technologies that detect malignant cells at a level of at least 1/100,000. Deep MRD negativity correlates with improved health outcomes for MM pts, and MRD status may inform treatment (tx) continuation decisions during MM maintenance therapy. We evaluated the potential cost-effectiveness of NGS MRD (clonoSEQ) vs. no MRD testing in the maintenance MM setting. Methods: We developed a Markov model with 6 health states: MRD+ or MRD- on or off tx, relapsed, or dead and compared yearly NGS MRD to no MRD testing over a lifetime horizon. The model assumed tx stops after an MRD- result; otherwise, tx continued until disease progression. Progression-free survival (PFS) and overall survival (OS) data for MRD- and MRD+ and hazard ratios for on/off tx were applied based on peer-reviewed literature. MRD- pts were assumed to have the same PFS/OS rates on and off tx, which were varied in sensitivity analyses. On tx, 2%/month of MRD+ pts became MRD-. Health state utilities were based on peer-reviewed literature and included an adverse event (AE) disutility. The cost of NGS MRD was $1,800 + $1,836 for specimen collection, with maintenance tx at $21,168/month and tx for relapsed pts at $27,422/month. We used a US health system perspective and a 3% discount rate. Results: MRD testing saved $1,156,600 over patients remaining lifetime. Health outcomes were similar and slightly favored MRD testing vs no testing (0.01 quality-adjusted life-years [QALYs]) from lower AE risk over time, suggesting a potentially dominant strategy, i.e., less costly with improved health outcomes. This result was most sensitive to the probability of MRD+ to MRD- transition and the cost of maintenance tx. Conclusions: NGS MRD testing is cost-saving, with potential QALY gains due to avoidance of tx-related AEs compared with no testing for MM patients on maintenance therapy. Further studies are needed to determine the health outcomes of MRD testing during MM maintenance tx. [Table: see text]
TTF1 negative in non small cell lung cancer adenocarcinoma: A prognostic factor.
Authors: Cordoba Juan Felipe , Morales Serafin , Veas Rodriguez Joel , Rodriguez Galindo Álvaro , Salud Antonia
Published: March 2020

e20004

Background: Patients with thyroid transcription factor 1 (TTF1) negative lung adenocarcinoma (ADC) have been reported to have a worse prognosis and to lack epidermal growth factor receptor (EGFR) mutations. This study describes a series of sample tumors from patients with clinically confirmed lung cancer. Methods: In all lung cancer patients diagnosed in the University Hospital of Lleida from January 2011 to December 2016, a real world data study of TTF1-negative ADC was performed, using TTF1 clone 8G7G3/1(DAKO). Each patient’s clinical history, pathology specimens and molecular results were noted. Two hundred and thirty one patients with TTF1 positive lung ADC formed the control group. Results: Twenty seven (27) patients were identified with ADC TTF1 negative (74% males). The media age was 66 years. The smoking history was as follows: 55,5% former, 29,6% ex smokers and 14,8% never smokers. The clinical stages were as follows: stage I or II (n = 3 [11%]), stage III (n = 4 [14,8%]) and stage IV (n = 20 [74%]). Patients’ mean survival was 7,6 vs 24,4 months in ADC TTF1 negative patients (P = 0,00001). Three hundred and thirty four (334) patients with ADC were found, TTF1 results were available in 258 (77,2%) cases, of them twenty-seven cases (10,4%) had TTF1 negative; when they were compared with the control group, TTF1 negative patients had overall shorter survival (P = 0,00001), regardless of whether patients were treated with radical or palliative intent: 34,4 vs 10, months P = 0,00001 (radical treatment) and 14,6 vs 6,7 months P = 0,007 (palliative intent). EGFR mutations were less frequent (P = 0,046) in TTF-negative tumors 5,5% vs 25,3%. Conclusions: Patients with TTF1 negative NSCLC ADC, have worse overall survival regardless of treatment intention and a lower frequency of EGFR mutations.
Value of precision medicine in advanced NSCLC: Real-world outcomes associated with the use of companion diagnostics.
Authors: John Ani , Shah Roma , Wong William Bruce , Schneider Charles , Gari Hamid H. , Johnson Marliese
Published: March 2020

e20015

Background: Five-year survival rates as low as 2.8% have been reported in patients with non-small cell lung cancer (NSCLC), highlighting the need for individualized diagnosis and treatment. Companion diagnostic testing (CDx) identifies patients with molecular targets likely to respond better to particular therapies; however, not all cancer patients receive CDx in the real-world setting. This study evaluated the clinical value of CDx in the real world with respect to overall survival among patients with non-squamous advanced (Stage IIIB/IV) NSCLC (aNSCLC). Methods: Patients were from the Flatiron Health electronic health-derived database, treated with systemic therapy, and diagnosed with aNSCLC between January 1, 2011 and May 31, 2018; those who received CDx with their first line of treatment were compared with those who did not. Logistic regression using components of the modified Lung Cancer Prognostic Index (LCPI; age, sex, stage, actionable mutation(s), smoking, respiratory comorbidity; Alexander et al. Br J Cancer. 2017) and other factors were used to predict characteristics associated with receiving CDx. Overall survival was evaluated using Kaplan-Meier analysis. Unadjusted and adjusted Cox proportional hazards regression models were used to evaluate the association between CDx and overall survival. Results: A total of 17,143 patients with aNSCLC (CDx, n = 14,389; no CDx, n = 2754) and a mean (SD) age at diagnosis of 67.2 (10.0) years (CDx, 67.1 [10.1]; no CDx, 67.5 [9.2]) were included. There were more nonsmokers in the CDx group (17.4%) than the no CDx group (5.5%). Patients who were female, diagnosed after 2014, receiving multiple lines of therapy or had advanced stage at diagnosis were more likely to receive CDx. Patients receiving CDx had decreased mortality risk (unadjusted HR [95% CI] = 0.54 [0.52-0.57]) and lived longer than those not receiving CDx (median survival = 14 vs 7 months). The significant reduction in mortality associated with CDx remained after adjusting for factors included in the modified LCPI (adjusted HR [95% CI] = 0.78 [0.75-0.82]) as well as a model without actionable mutations (adjusted HR [95% CI] = 0.70 [0.66-0.73]). Conclusions: Among patients with non-squamous aNSCLC, use of CDx was associated with reduced risk of mortality compared with no CDx.
DIPNECH: The Mayo experience.
Authors: Almquist Daniel , Cabrera Arriana , Sonbol Mohamad Bassam , Kosiorek Heidi E. , Halfdanarson Thorvardur Ragnar , Ross Helen J. , Paripati Harshita , Jaroszewski Dawn E.
Published: March 2020

e20029

Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pulmonary disorder with neuroendocrine cell proliferation with potential progression to lung neuroendocrine tumor (Lu-NET). Optimal diagnostic and treatment strategies have yet to be well defined. Herein, we aim to describe the Mayo Clinic experience with DIPNECH. Methods: A retrospective analysis was performed of patients diagnosed with DIPNECH within Mayo Clinic between January 2000-Febuary 2019. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, disease characteristics, time of diagnosis, surgery, and last follow up date were extracted. Extent of symptom burden, treatment approaches, disease progression, and disease-free survival (DFS) were evaluated by chart review. Results: A total of 59 patients were identified with a median age of 63(43-81) years. The cohort was predominantly female (93.2%) and non-smoking (76.3%). Most patients (86.4%) had symptomatic disease with chronic cough being the most common (71.2%) followed by exertional dyspnea (44.1%). Imaging typically showed bilateral lung nodules (93.2%) with mosaic attenuation noted 69.5% of the time. Surgical resection was frequently completed to confirm diagnosis (94.9%). Most patients received inhaled glucocorticoids combined with a beta agonist (79.7%). Oral steroid use was seen in 49.2% of patients whereas a somatostatin analog was used in 15.3% following the diagnosis of DIPNECH. These medical interventions led to symptom relief in 23.7% of the patients. The median follow up for all patients was 19.5 months. Progression of tumorlets was seen in 48.7% of patients with only 7(17.9%) patients progressing to a diagnosis of Lu-NET. The 3-year DFS was 90.5%. Conclusions: This is amongst the largest studies completed evaluating DIPNECH patients. DIPNECH remains a rare disease more commonly diagnosed in women in their early 60’s. DIPNECH appears to have an indolent course with obstructive symptoms being the most common finding. A minority of patients experienced symptom relief with therapy. Overall, DIPNECH appears to have a low risk of progressing to Lu-NET based on the observation of this study.
Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.
Authors: Cedres Susana , Ponce Aix Santiago , Callejo Ana , Pardo Nuria , Navarro Alejandro , Martinez Marti Alex , Sansano Irene , Enguita Ana Belen , Rodriguez Gisela , Monton Victor , Miquel Josep M , Viaplana Cristina , Dienstmann Rodrigo , Felip Enriqueta
Published: March 2020

e20062

Background: The increasing incidence and poor outcome associated with MPM demand identification of effective treatment options. Promising results have been reported with immunotherapy (IO) in a small proportion of MPM patients (p). MMR deficiency (dMMR) has been well described in several malignancies and was recently approved as a tumor biomarker for IO with anti-PD-1 checkpoint inhibitor. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM p. Methods: Tumors of 159 MPM p from Vall d´Hebron University Hospital and October 12th University Hospital diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR when any MMR protein expression was negative and MMR intact when all MMR proteins were positively expressed. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: P characteristics: median age: 69 years (29-88 years), males: 71%, performance status (PS) 1:69%, asbestos exposure: 52%, stage III at diagnosis: 42%, epithelial subtype: 65%, systemic treatment 81% (57% chemotherapy with cisplatin plus pemetrexed in first line), 50% received second line and 28% third line. MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8m). In a multivariate model factors associated to improved mOS were PS 0 vs PS2 (13 v 2 m, HR 12.8, p < 0.01), neutrophil-lymphocyte ratio (NLR) < 5 (18 v 9 m in NLR ≥5,HR 1.5, p < 0.05) and epitheliod vs sarcomatoid histology (18 vs 4 m HR 4.7, p < 0.01). Thirteen p received IO with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1m). Conclusions: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate novel predictive biomarkers benefit from IO in MPM.
Treatment outcomes in malignant pleural mesothelioma: A single center experience of systemic therapies and biomarkers.
Authors: Balasubramanian Adithya , Pick Adrian , Kumar Beena , Prodanovic Zdenka , Joshi Prashant , Alamgeer Muhammad
Published: March 2020

e20070

Background: Malignant Pleural Mesothelioma (MPM) is a rare but fatal disease related to asbestos exposure, with historic survival in the order of 9 to 17 months. Chemotherapy is associated with only a modest benefit. The advent of immunotherapy has heralded significantly improved outcomes using checkpoint inhibitors in an as yet ill-defined cohort. We aim to identify predictive and prognostic biomarkers in a series of patients (pts) with MPM and describe survival data. Methods: A retrospective audit was undertaken of pts with MPM diagnosed between 2013 and 2017 at a single tertiary centre in Melbourne, Australia (Monash Health). Data relating to patient outcomes and clinicopathological features were obtained through medical reports. Further immunostains are being performed on archived tissue for PDL-1 status. Results: 65 pts were identified, of whom 52 (80.0%) were male. Median age was 73 years (range 44-90). 52 pts were noted to be ECOG 0-1. 42 pts (64.6%) were noted to have suspected asbestos exposure. Epithelioid MPM was the most common subtype, noted in 41 pts (63.1%) (table 1). 8 pts (12.3%) presented with stage IV disease. 16 pts (24.6%) received checkpoint inhibitor therapy, with 10 (63 %) in the second/third line setting. Median overall survival (OS) was 19.8 months (95% CI 13.3-26.3) in the whole cohort.Patient characteristics associated with poor OS were: presence of weight loss (P = 0.001), chest pain (p = 0.08) and ECOG 2 (p = 0.04). Pts with sarcomatoid histology who received immune checkpoint inhibitors in any line of treatment had significantly prolonged OS compared to other histologies. 3-year survival was 80% in this group while median OS was not reached (p = 0.04). This difference was not seen with other histologies. Conclusions: The evolving landscape of treatment in MPM appears to show promise in improving OS. In this unselected case series, our data is consistent with historic controls in terms of survival and prognostic factors. The finding of significantly improved survival with immune checkpoint inhibitors in the sarcomatoid histology is exciting and warrants further exploration. Further data on PDL1 status will be presented.
Identifying small cell lung cancer resistance mechanisms to cytotoxic T cells in vitro using whole genome CRISPR screening.
Authors: Hiatt Joseph , MacPherson David
Published: March 2020

e20075

Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine neoplasm associated with high tumor mutation burden (TMB), a paucity of compelling therapeutic options, and very poor survival. In comparison to other malignancies with high TMB, SCLC patients tend to experience lower response rates and shorter response durations with immune checkpoint blockade (ICB) targeting the PD-1 and/or CTLA-4 axes, and chemotherapy with ICB in first line does not exhibit the dramatic synergy seen in non-small cell lung cancer. To identify additional immunosuppressive mechanisms that could serve as novel biomarkers and therapeutic targets in SCLC, we adapted a recently described method to screen for genes that alter the sensitivity of cancer cells to killing by cytotoxic CD8+ T cells. Methods: We introduced Cas9 nuclease and a genome-wide gene inactivation library of ~80,000 single guide RNA (sgRNA) templates into a cell line derived from a genetically engineered murine model of SCLC (mSCLC). In parallel, we isolated and stimulated CD8+ T cells from the OT-I transgenic mouse, which express a rearranged T cell receptor with very high avidity for the ovalbumin (OVA) SIINFEKL peptide presented on H2-K(b) class I MHC. mSCLC cells were loaded with OVA peptide or vehicle and co-cultured with T cells for 24 hours. We collected surviving cells, isolated DNA, and used next-generation DNA sequencing to tabulate the relative representation of sgRNAs in each experimental condition. From these data, we inferred which gene knockouts were protective from, or sensitizing to, killing by CD8+ T cells. Results: We observed expected mediators, including resistance via knockout of antigen presentation machinery and sensitization via knockout of pro-survival pathways ( e.g. NF-kB), and unexpected hits spanning diverse cellular functions. Conclusions: Genome-wide screening for mediators of in vitro killing by CD8+ T cells in a murine model of SCLC is feasible and reveals that both expected and novel pathways may contribute to resistance to immunotherapy in SCLC. Future studies are directed at validating these hits in vitro and in vivo, incorporating new complex gene perturbation libraries, and scaling to additional cell lines.
Precision medicine and actionable alterations in lung cancer.
Authors: Mambetsariev Isa , Nadaf Sorena , Wang Yingyu , Chen Chen , Hewelt Blake , Pharaon Rebecca , Massarelli Erminia , Koczywas Marianna , Reckamp Karen L. , Salgia Ravi
Published: March 2020

e20707

Background: In recent years, healthcare centers have become more reliant on the advent of new technology, testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians, researchers, and the medical community. This aggregate of information stands to be a powerful tool that can enable one to perform highly complex investigations more easily, as well as aid physicians in their efforts to provide personalized medicine to patients. However, in order to take advantage of vital clinical and research data, we must initially make an effort to create an effective infrastructure for the collection, storage, utilization, and protection of this information with uniquely designed disease-specific registries that have adequate informatics support to allow for the collection of a large number of patients. Methods: In this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry. Results: Of the 415 patients in the analysis, 59% (n = 245) were female; the median age was 64 (range, 22-92) years with a median OS of 33.29 months (95% CI, 29.77-39.48). The frequency of the most commonly occurring oncogenes was 50% EGFR (n = 207/415), 28% KRAS (n = 97/352), and 7% ALK rearrangement (n = 28/377), while the most commonly occurring tumor suppressor genes consisted of TP53 (n = 140/283 [49%]), LRP1B (n = 63/228 [28%]), and STK11 (n = 39/278 [14%]). The most common actionable alterations were identified in EGFR L858R/exon 19 deletion (n = 177/415 [42.7%]), ALK rearrangement (n = 28/377 [7.4%]), ROS1 rearrangement (n = 3/257 [1.2%]), BRAF V600E (n = 7/288 [2.4%]) and MET exon 14 splice site/deletion (n = 7/287 [2.4%]). While there were no median OS differences in patients who were tested under a broad-panel vs small-panel (33.4 months vs 33.5 months; 95% CI; P = 0.36), there was a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 patients who were wild-type with a median OS of 26.0 months (95% CI; P < 0.001). In addition, we identified an unprecedented number of patients with actionable alterations [53.5% (222/415)], including distinct individual alteration rates, as compared with 15.0% and 22.3% in TCGA and GENIE respectively. Conclusions: The use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes.
Effect of a multi-disciplinary approach and incorporation of reflex testing on genomic profiling of non-squamous lung cancer in a community oncology practice.
Authors: Gupta Niraj K. , Toney Brent , Uprety Sajeev , Mastrodicasa Mark , Ascioti Anthony , Nuthakki Vijay , Leagre Christopher A. , Mahidhara Raja , Freeman Richard K , Jhajria Sunil , Schroeder Ryan , Mintz Ed , Schmidt Kristen , Tumati Vas , Liebross Robert H.
Published: March 2020

e20719

Background: Genomic profiling of advanced non-squamous lung cancer is integral for appropriate management. Appropriate testing and timeliness in getting the results often pose a challenge in a community setting. We share our experience in a community setting and the importance of an integrated approach to improve outcomes. Methods: Retrospective review of the charts of patients with stage- III-B/IV was conducted to gather data. Effect of Multi-disciplinary meetings to improving coordination among treating physicians and Incorporation of reflex testing for complete mutational profiling on diagnosis was studied. Results: Between 04/2016 and 10/2018, 127 patients charts were reviewed. 83% were stage-IV and 17% stage-III-B. Males (61%), Females (49%). Median age was 62 yrs. 76% had smoking history.There were 53% core biopsies, 42% FNAs and 5% resections. Mutational profiling panel was based on the NCCN guidelines. Adequate specimen for complete profiling was available in 111/127 (87%) of the patients. Two/16 (12%) of pts with in-adequate sample had a repeat biopsy and 12/16 ( 75%) had liquid biopsies done. Remaining 2 pts didnot have further w/u due to declining PS. Complete mutational profile (EGFR/ALK/ROS-1/MET/RET/BRAF/PDL-1) was available in 100% of pts. after re-biopsy/liquid bx. Incorporation of reflex testing decreased the reporting time from an average of 11.6 days to 6.9 days. The results of mutational profiling were available in 94% of pts. before starting the treatment. Prevalence of mutations were, EGFR:14%, ALk:3%, BRAF:1%, MET:0%, RET:1%, ROS-1:2%. Conclusions: Multi-disciplinary integrated approach and reflex testing upon diagnosis is essential for appropriate and timely genomic profiling of locally advanced/ metastatic non-squamous lung cancer patients to deliver appropriate treatment in a community setting.
Real-world (rw) clinical outcomes for advanced/metastatic non-small cell lung cancer (aNSCLC) patients (pts) treated with second line (2L) ramucirumab plus docetaxel (R+D) post frontline (1L) platinum based chemotherapy plus immune checkpoint inhibitors (Pt + ICI).
Authors: Clarke Jeffrey Melson , Mathur Raina , Molife Cliff , Batus Marta , Stefaniak Victoria Jennifer , Winfree Katherine B. , Baxi Shrujal , Cui Zhanglin Lin , Lenis David , Bonomi Philip D.
Published: March 2020

e20727

Background: R+D is approved for use in pts with aNSCLC after Pt chemotherapy. With recent approvals, ICI can now be added to Pt chemotherapy (Pt + ICI) in 1L. This retrospective observational study provides an exploratory view of baseline characteristics and rw clinical effectiveness outcomes for pts receiving 2L R+D post 1L Pt + ICI. Methods: All adult pts treated with 2L R+D after 1L Pt + ICI therapy between 03/01/2015 and 06/30/2018, with ≥ 3 months follow up, were selected from the Flatiron Health EHR-derived de-identified database (n = 15). Rw clinical endpoints during R+D therapy included rw objective response rate (rwORR), rw disease control rate (rwDCR), rw best response, as well as Kaplan-Meier estimates of rw time to first response & rw duration of response. Results: Median age was 62 years, 10 pts (66.6%) were aged < 65 years, 11 (73.3%) were men, 3 (20.0%) had no history of smoking, 14 (93.3%) had non-squamous histology, 4 (26.7%) were EGFR positive, 3 (20.0%) were KRAS positive and 6 (85.7%) were PD-L1 negative. Of the 8 pts with a documented rw tumor response assessment, 3 (37.5%) had partial response (PR), 3 (37.5%) had stable disease (SD), & 2 (25.0%) had progressive disease as their rw best response. The rwORR (PR or complete response [CR]) & rwDCR (PR, CR, or SD) were 37.5% and 75.0%, respectively. Among responding pts, median time to first response was 2.2 months (95% CI, 1.3 - not reached [NR]) & median duration of response was 2.3 months (95% CI, 1.5 - NR). Patient numbers were too small (n = 15) and duration of follow-up was too short (3.4 months [IQR, 0.7 - 5.4]) to make robust estimation of overall survival or rw progression free survival. Conclusions: Data from this small patient cohort in US community practice are not conclusive and should be considered exploratory, but do show high rates of rw objective response and rw disease control rates during 2L R+D following 1L Pt + ICI. Data with larger sample sizes and additional follow-up are needed to better understand outcomes of R+D following the addition of ICI to 1L Pt chemotherapy regimens.
MET second-site mutations in EGFR-mutant, MET-amplified non-small cell lung cancer after resistance to combinatorial targeted therapy.
Authors: Cheng Jia-Tao , Yang Jinji , Wu Yilong
Published: March 2020

e20730

Background: MET second-site mutations were previously reported in a few cases of MET-amplified or exon 14-mutant advanced non-small-cell lung cancer (NSCLC) treated with MET inhibitors. However, both the frequency of MET second-site mutations and clinical outcome of patients with such genetic alterations have not been investigated, particularly in EGFR-mutant, MET-amplified advanced NSCLC treated with combinatorial targeted therapy. Methods: Retrospectively, from November 2016 to January 2019, 22 patients with EGFR-mutant, MET-amplified advanced NSCLC had sufficient tumor samples after resistance to a combinatorial therapy with both EGFR and MET inhibitors. All tissue samples were detected using Next-generation sequencing (NGS). The progression-free survival (PFS) was calculated the start of subsequent treatment to progressive disease or death from any cause. The overall survival (OS) was calculated from the start of subsequent treatment to death from any cause. Last follow-up was on January 31, 2019. Results: Five kinds of MET second-site mutations were found in 7 patients: D1246N D1228N, D1228H, D1231Y and Y1230H. The frequency of MET second-site mutations was 31.8% (7/22). The median PFS and OS were 3.7 (95%CI: 1.13-6.3) months and 6.9 (95%CI: 0.2-13.7) months respectively. The ORR of EGFR TKIs plus cabozantinib for suchsecond-site mutaant patients was 50% (2/4). However, the ORR of other treatments was 0% (0/3), Two of them received single agent cabozantinib, and PFS was 0.7 and 1.7 months respectively. One had a PFS of 2.5 months with pemetrexed/carboplatin plus bevacizumab. Conclusions: MET second-site mutation might be one of the commonly-seen molecular mechanisms of acquired resistance to combinatorial targeted therapy in EGFR-mutant, MET-amplified advanced NSCLC. Patients with such mutations could respond to cabozantinib plus EGFR TKI. Further more investigations are warranted to improve the efficacy.
Evaluation of outcome and prognostic factors in paediatric extraskeletal ewings sarcoma: A single institution experience.
Authors: Srinivasalu Vijay Kumar , Sankaran Hari , Subramaniam Narayana , Philip Arun , Jose Wesley Mannirathil , Keechilat Pavithran
Published: March 2020

e21507

Background: Ewing's sarcoma (ES) represent the most frequent small and round cell bone tumors of childhood and adolescence. Data on extraskeletal ewings sarcoma (EES) with uniform chemotherapy protocol are very minimal. We aimed to assess this aspect in our patients and identify prognostic factors in patients with extraskeletal ewings sarcoma. Methods: A retrospective analysis of data was done between January 2005 and January 2016. These paediatric EES patients who received chemotherapy with VAC-IE regimen were evaluated for their response, overall survival (OS) and Event free survival (EFS). The prognostic factors which influenced their overall survival were also analysed. Results: Fourty one paediatric EES patients were diagnosed at our institute out of which 31 patients received treatment at our hospital. 25.8% (8) were metastatic at presentation. The mean age was 12.37 years (1-18 years) with a predominant female preponderance 54.8%. The commonest site at presentation was presacral mass (7) and mass in the brain parenchyma (8). Rare sites of presentation as a nasal mass and parotid mass was seen in one patients each. 78% received chemotherapy with VAC-IE regimen. The ORR was 71% (8 CR + 9 PR). Toxicity was grade III neutropenia in 5 (20.8%). 8 patients received local RT. The 3 year OS and EFS in the localized EES were 55% and 39% and in metastatic EES were 35% and 24% respectively. Low hemoglobin (P = 0.05) and high LDH (P = 0.01) predicted inferior OS for the entire EES cohort on multivariate analysis. Conclusions: High LDH and low hemoglobin is associated with poor OS for patients with EES ewings sarcoma. VAC-IE is a very effective and a safe chemotherapy regimen and should be considered in patients with extraskeletal ewings sarcoma.
Shared dysregulation of long non-coding RNA and developmental gene networks in histone H3 K27M gliomas and PF-A ependymomas.
Authors: Sanders Lauren , Cheney Allison , Beale Holly , Kephart Ellen , Bjork Isabel , Pfeil Jacob Joseph , Salama Sofie R. , Haussler David , Morozova Olena
Published: March 2020

e21523

Background: Diffuse pediatric gliomas harboring a Histone-H3 K27M mutation are more aggressive than H3-wild type gliomas and demonstrate global hypomethylation at the K27 residue1. As a result, these tumors show global aberrant gene expression, resulting in a stem-like proliferative cell population2. Posterior fossa (PF) ependymomas, on the other hand, harbor few significantly recurrent somatic mutations, but PF-A and PF-B subgroups have been defined on the basis of epigenetic differences3. Compared to PF-B, the PF-A subgroup demonstrates H3K27 hypomethylation, aberrant gene expression and aggressive tumor growth4,5. Methods: We recently identified a set of long non-coding RNA (lncRNA) that are transiently expressed in early brain development6, and hypothesized that H3K27M gliomas and PF-A ependymomas may share methylation-related dysregulation of lncRNA networks responsible for maintaining normal differentiation programs. Results: Here we describe a network of regulatory lncRNA with increased expression in both H3K27M gliomas and PF-A ependymomas, as compared to H3-WT gliomas and PF-B ependymomas. We demonstrate that increased expression of this lncRNA network correlates with the over-expression of signaling pathways involved in maintaining a non-differentiated, proliferative phenotype and driving tumorigenesis. Conclusions: We hypothesize that in both H3K27M gliomas and PF-A ependymomas, aberrant global methylation may be driving lncRNA to activate and maintain stem-like states in early neural development, suggesting similarities in epigenetically driven, developmental origins for both tumor types. References: 1. Chan KM, Fang D, Gan H, et al. Genes Dev. 2013;27(9):985-90; 2. Filbin MG, Tirosh I, Hovestadt V, et al. Science. 2018;360(6386):331-5; 3. Witt H, Mack SC, Ryzhova M, et al. Cancer cell. 2011;20(2):143-57; 4. Bayliss J, Mukherjee P, Lu C, et al. Sci. Transl. Med. 2016;8(366):366ra161; 5. Mack SC, Witt H, Piro RM, et al. Nature. 2014;506(7489):445; 6. Field AR, Jacobs FM, Fiddes IT, et al. bioRxiv. 2017:232553.