bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.