bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resource utilization and cost efficacy analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (DD-MVAC) versus gemcitabine-cisplatin (GC) as neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC).
Authors: Montazeri Kamaneh , Dranitsaris George , Curran Catherine , Thomas Jonathan David , Ingham Matthew D. , Preston Mark A. , Steele Graeme S. , Kilbridge Kerry L. , Wei Xiao X. , McGregor Bradley Alexander , Mossanen Matthew , Sonpavde Guru 
Published: May 2020

e19390 Background: DD-MVAC and GC are commonly used NAC regimens for MIBC. While efficacy across studies appears similar, resource utilization (RU) burden and cost efficacy have not been compared. Methods: We assessed RU and cost effectiveness of NAC with GC vs DD-MVAC among MIBC patients (pts) treated at Dana-Farber. Data on chemotherapy administered, supportive medications, relevant procedures, hospitalizations, clinic, infusion, and emergency room (ER) visits were collected retrospectively. Unit costs for each RU component were sought from the Centers for Medicare and Medicaid Website as well as relevant published sources. Utilization was compared between MVAC and GC using multivariate quantile regression (QR) analysis. Results: 147 pts were included; 51 received DD-MVAC and 86 GC. Baseline characteristics were similar, except lower mean age (59 vs 67 years, p < 0.001) and higher proportion of ECOG-PS = 0 (96.1% vs 60.5%, p < 0.001) for DD-MVAC. The mean cumulative cisplatin dosage was similar (DD-MVAC = 284 mg/m2, GC = 257 mg/m3). More DD-MVAC pts required G-CSF analogues (100% vs 32.6%, p < 0.001), central line placement (28.6% vs 11.8%, p = 0.017), and ER visits (35% vs 18%, p = 0.048). Infusion visits (12 vs 8/pt) and cardiac imaging (0.98 vs 0.58/pt, p < 0.001) were higher for DD-MVAC, whereas GC pts required more frequent clinic visits (mean of 9 vs 5/pt), chemotherapy cycle delays (30.2% vs 9.8%, p = 0.008) and hospitalization days (mean of 0.88 vs 0.49/pt). After adjusting for PS, the mean total cost/pt was higher for DD-MVAC ($17360 vs $12112, p < 0.001). Age was not statistically significant in the QR model (p = 0.628). Conclusions: DD-MVAC and GC exhibit different RU characteristics as NAC for MIBC. Although excess RU did not clearly favor one regimen, adjustment for PS indicated significant decrease in healthcare costs by approximately 30% using GC compared to DD-MVAC. Given that similar overall delivery of cumulative cisplatin dosage was feasible with both regimens, the values and costs affixed to different resources may impact the selection of DD-MVAC vs GC. Limitations were retrospective design and costs being specific to the US.
Predictors of increased episode expenditure and exceeding target price under the oncology care model.
Authors: Park Seojin , Waters Dexter , Thomas Ryan , Song Andrew Jehyun , Walsh Karen , Csik Valerie Pracilio , Leader Amy , Maio Vittorio 
Published: May 2020

e19403 Background: The Oncology Care Model (OCM) incentivizes participants to keep episode expenditure below target price; however, little is known about the adequacy of adjustments in target price calculation. This study investigates predictors of increased expenditures and explores how these predictors are associated with exceeding target price for hematologic and solid malignancies. Methods: Non-decedent OCM episodes, categorized as hematologic malignancies (HMs) or solid malignancies (SMs), from 7/1/2016 - 7/1/2018 attributed to our institute were analyzed. Multiple linear regression was used to identify factors associated with increased episode expenditure. Multiple logistic regression was used to evaluate whether such factors increased likelihood of expenditure exceeding target price. Results: Of 1,975 episodes, 499 (25.3%) were HMs and 1,476 (74.7%) were SMs. 54.3% of HMs and 35.2% of SMs had episode expenditure exceeding target price. In HMs, novel therapy use (NT), inpatient admission (INPT), Part B drug use (PB), Part D use (PD), and radiation therapy (XRT) were associated with increased episode expenditure. Of those, INPT and PD increased the likelihood of expenditure exceeding target price. XRT decreased the likelihood of expenditure exceeding target price (Table). In SMs, NT, INPT, emergency department visit, home health aides, durable medical equipment use, PB, PD, XRT, and surgery were associated with increased episode expenditure. Of those, NT, INPT, PB and PD increased the likelihood of expenditure exceeding target price. XRT and receipt of surgery decreased the likelihood of expenditure exceeding target price (Table). Conclusions: INPT and PD significantly increased episode expenditures in both HMs and SMs, leading to expenditures exceeding target prices determined by the OCM benchmark risk-adjustments in both cancer types. NT and PB were significant predictors of increased expenditure and the likelihood of exceeding target price in SMs, but not in HMs. Our findings suggest that there may be opportunities to improve the current model by refining the adjustment for these factors to better reflect real world expenditures. [Table: see text]
Role of epigenetic regulators in single-base substitution patterns in AML.
Authors: Paul Madhuri , Scarpa Frank J , Wolfson Wendy A , Weiss Lawrence , Funari Vincent Anthony , Blocker Forrest 
Published: May 2020

e19500 Background: Incidence of Acute Myeloid Leukemia (AML) increases with age, as does Clonal Hematopoiesis of indeterminate Potential (CHiP), wherein specific genes are mutated in healthy individuals. Single Base pair Substitutions (SBS) are associated with aging and AML, most commonly C>T. G>A transitions are found in a similar prevalence in all age groups, although the number of mutations are higher in older age groups and associated with therapy. Determining a pattern of SBS in leukemia that is distinct from aging has been a challenge. Methods: We performed mutational signature analysis on 10,152 mutations in 3,575 unique suspected AML patient bone marrow, peripheral blood, or FFPE tissue samples. Samples were evaluated using an all exon amplicon based 27 gene next generation sequencing panel. The cohort was divided into 5 groups based on age (0-14, 15-39, 40-54, 55-65, and >65 years), as well as into three gene mutation groups 1) TET2 WT (n=7,479 mutations), 2) TET2/DNMT3A WT (n=6,701) and 3) TET2/DNMT3A WT with chromatin regulators WT (ASXL1, ATRX, BCOR, BCORL1, EZH2, PHF6, RAD21, SMC1A, SMC3, STAG2; n=3627 mutations). Results: Predominant SBS were C>T (42.7%) and G>A (59.0%) transitions across all age groups. The percentage of C>T SBS increased with age: 0-14 years cohort (18.0% of cases; 1.5% of mutations) to >65 years cohort (58.8% of cases; 39.6% of mutations). There was no significant change in the prevalence of G>A mutations with age, however, the total number of mutations did increase with age (0-14 0.2% vs >65 39.6%). In each of the gene mutation groups, the number of C>T and G>A total mutations decreases as TET2 MT (42.7% and 59.0%), TET2 WT (27.0% and 45.1%), TET2/DNMT3A WT (20.8% and 34.3%), and TET2/DNMT3A WT with WT chromatin regulators (10.1% and 25.5%). Conclusions: In this study, both the prevalence and number of mutations in AML patients increases with age for C>T transitions, but for G>A transitions only the number of mutations increases with age, consistent with previously reported studies. In this data set, by removing mutations in TET2, TET2 and DNMT3A, TET2 and DNMT3A with genes that regulate chromatin accessibility, the number of C>T and G>A transitions decreases in order of effect, with the chromatin modifiers having the largest effect. The effect of removing these mutations suggests a mechanism driving leukemogenesis whereby DNMT3A methylates cytosine, TET2 deaminates this methylated cytosine, and finally chromatin modifiers regulate accessibility to these methylation sites, thereby modulating downstream oncologic pathways.
Diagnostic utility of bronchoscopy in newly diagnosed acute leukemia patients.
Authors: Curley Thomas , Koenig Kristin Lynn , Mani Shylaja , Lustberg Mark , Behbehani Gregory , Bhatnagar Bhavana , Blachly James Stewart , Haque Tamanna Zohra , Larkin Karilyn T.M. , Long Meixiao , Mims Alice S. , Vasu Sumithira , Wall Sarah Allison , Byrd John C. , Walker Alison R. , Grieselhuber Nicole Renee 
Published: May 2020

e19510 Background: Over 40% of newly diagnosed acute leukemia patients receiving induction therapy develop acute respiratory failure. Bronchoscopy is a valuable tool for evaluating airway disease, but its diagnostic yield in this setting has not been fully explored. Methods: We performed a retrospective chart review of 75 newly diagnosed acute leukemia patients who had bronchoscopies. Data recorded prior to bronchoscopy included age, diagnosis, induction treatment regimen, chest imaging, assisted ventilation, duration of neutropenia and antibiotic therapy and microbiological studies. Bronchoalveolar lavage (BAL) cultures were sorted by organism, as well as by other pathologic findings. The primary outcome was antibiotic change supported by culture data. Results: The study population is summarized in the table. Induction regimen backbones included 7+3 (51), 7+4+ATRA (2), decitabine (12), hyperCVAD (2), AYA (3), other (1) and none (4); 18 patients were treated on clinical trial. Average days of neutropenia was 10.92 and average days of antibiotic therapy was 10.57. Thirty-eight patients had chest infiltrates, 11 received NIPPV, and 17 were mechanically ventilated. We identified 24 patients with +BAL studies. Of these, 37.5% (9) had + blood, urine or sputum studies before bronchoscopy, but only 3 had cultures positive for the same organism as the BAL. Of 51 patients with –BAL studies, 33.3% (17) had prior negative cultures. Infections were most commonly bacterial (15, 62.5%), followed by viral (5, 20.8%) and fungal (4, 16.7%). The most common organisms were rhinovirus, vancomycin sensitive Enterococcus (4, 16.7% each) followed by VRE, Candida albicans and MRSA (2, 8.3% each). Five patients (6.7%) had alveolar hemorrhage. Of the 24 patients with +BAL cultures, bronchoscopy findings supported changing antibiotics in 18. In contrast, antibiotics were changed in 16 patients without +BAL cultures. Conclusions: We investigated the utility of bronchoscopy on AL patients during their initial admission. BAL cultures were positive in 32% of newly diagnosed AL patients undergoing bronchoscopy. However, +BAL cultures identified a new organism in 87.5% and guided antibiotic therapy in 75% of these patients. Further studies will be needed to establish predictors of bronchoscopy findings in this patient population. [Table: see text]
Genomic profile at diagnosis by targeted high throughput sequencing, and real-world clinical outcomes in patients diagnosed with acute myeloid leukemia at a tertiary care cancer center.
Authors: Radhakrishnan Vivek Sulekha , Bhaduri Arunima , Arora Neeraj , Nair Reena , Bhattacharya Shreya , Sanyal Somanka , Veldore Vidya , Parihar Mayur , Bhave Saurabh Jayanth , Kumar Jeevan , Ramprasad VL , Mishra Deepak Kumar , Chandy Mammen 
Published: May 2020

e19515 Background: Acute Myeloid Leukemia (AML) is a highly heterogeneous disease. High throughput sequencing (HTS) has led to the discovery of a number of recurrently mutated genes in AML & has provided a detailed molecular landscape of the disease. This information is now extensively utilised & interpreted in AML. Methods: Retrospective analysis of 47 patients with newly diagnosed AML for those who had both cytogenetic and targeted HTS information at diagnosis, [median age: 44y (12-80y); 24 females] & treated at Tata Medical Center, India between 2013-2019. HTS was performed using Illumina Trusight myeloid panel and/or Thermo Fisher Scientific Oncomine Myeloid panel, and mutation data from the common 28 genes were used. Patients were stratified by European Leukemia Net (ELN) 2010 and 2017 guidelines. Standard of care clinical outcome data was available for all patients. Results: 45 of 47 patients had mutations. The most frequently mutated gene was FLT3 (n = 13, 28.9%), followed by NPM1 (n = 8, 17.8%), and others [ IDH1, IDH2, TET2, CEBPA, and NRAS; n = 7, 15.6%). ELN-2010 classified 6 patients as Favourable (12.8%), 10 as Intermediate-I (21.3%), 25 as Intermediate-II (53.2%) and 6 as Adverse (12.8%) risk groups. One patient migrated to the adverse group from Intermediate-II when ELN-2017 was applied. ELN 2017 re-classification: Favorable (n = 6, 12.8%), intermediate (n = 34, 72.3%), and adverse risk groups (n = 7, 14.9%). Co-occurrence of driver gene mutations was found in NPM1 and FLT3 (8.2%) frequently. Patients with mutations in epigenetic modifiers ( ASXL1, IDH1, IDH2, DNMT3A) had high Variant Allele Frequency (VAF, 40-50%) while those with signaling pathway gene mutations ( NRAS, KRAS) had low VAF (9-25%). At a median follow up of 3.25 years, median overall survival in the three risk groups (favorable, intermediate, adverse) were 11.25 mons, 7 mons and 8 mons respectively, and relapse rates were 16%, 29% and 42% respectively. Conclusions: Early experience from a middle-income real-world setting suggests feasibility of integration of HTS information in practise, as additional prognostic/ predictive information. The pattern of a high VAF in epigenetic modifier gene mutations, potentially as a result of early acquisition during clonal development, needs further evaluation. This data set has helped us initiate a prospective multimodal omics study at our institution.
Myeloablative fludarabine and busulfan regimen in myelofibrosis: Long term outcomes and analysis of prognostic factors.
Authors: Joseph Jacinth , Milton Denai R. , Chen Julianne , Alatrash Gheath , Alousi Amin Majid , Bashir Qaiser , Ciurea Stefan O. , Daher May , Im Jin Seon , Mehta Rohtesh S. , Oran Betul , Olson Amanda Leigh , Saini Neeraj , Srour Samer Ali , Andersson Borje , Champlin Richard E. , Popat Uday R. 
Published: May 2020

e19520 Background: Scoring systems, such as DIPSS-plus, prognosticate outcomes of myelofibrosis (MF) at diagnosis and at transplant. In this study, we evaluated the impact of individual components of these scoring systems, along with other factors previously reported to significantly prognosticate transplant outcomes in patients with MF. Methods: We identified 65 consecutive patients conditioned uniformly with Fludarabine(40 mg/m2X4days)/Busulfan(AUC-4000X4days) and ATG(MUD), tacroliumus and methotrexate for GVHD prophylaxis for allo-SCT during 2007-2019 at MD Anderson Cancer Center, USA. Associations between factors of interest and overall survival(OS), cumulative-incidence-of-relapse(relapse) and non-relapse mortality(NRM) were evaluated. Results: At transpant, median age was 61(range = 27-73) years; 42% were transfusion-dependent, 31% had secondary MF and 53% patients were intermediate2 and 42% were high-risk by DIPSS-plus. Forty percent of the 35 patients who had 28-gene panel tested had atleast one high-molecular-risk mutation, per MIPSS. Median follow-up for survivors was 35.6 months(range = 0.5-123). One-year and 5-year rates for OS were 78% and 51%, for relapse were 21% and 30%, and for NRM were 16% and 28%, respectively. Our multivariate analysis shows the following significant prognostic factors: HCT-CI > 3[hazard ratio(95% CI):5.63(1.48-21.27)p = 0.011], peripheral-blood blasts≥5%[5.98(1.33-26.89)p = 0.020] and prior splenectomy[6.41(1.83-22.47)p = 0.004] were associated with worse OS. Matched-unrelated donor[4.07 (1.38-12.08)p = 0.011) and mismatched-unrelated donor[7.36 (1.36-39.83)p = 0.021] versus matched-related donor as well as peripheral blasts≥5%[4.10(1.00-16.83)p = 0.05] were associated with worse NRM. Diagnosis to transplant duration > 12months[5.81(1.33-25.420)p = 0.020] was associated with higher relapse. Presence of 2 or more poor-risk mutations [6.39(1.35-30.21)p = 0.019] predicted higher relapse on univariate analysis and was not included in multivariate analysis(as data was available in 35 patients only). Conclusions: Of the IPSS-components used at diagnosis, only peripheral-blood blasts(at threshold ≥5%) was associated with worse outcome(OS and NRM). Unrelated-donor source was associated with higher NRM. Diagnosis to transplant duration > 12months predicted higher relapse. The effect of mutations needs to be validated in a bigger study.
Ruxolitinib (RUX) retreatment in patients (Pts) with myelofibrosis (MF): Real-world evidence on pt characteristics and outcomes.
Authors: Pemmaraju Naveen , Yu Jingbo , Parasuraman Shreekant , Paranagama Dilan , Kish Jonathan , Visaria Jay , Singhal Mukul , Verstovsek Srdan , Gerds Aaron Thomas 
Published: May 2020

e19535 Background: RUX is a JAK1/JAK2 inhibitor FDA-approved for treatment (tx) of int/high risk MF. In the COMFORT studies, RUX reduced spleen volume in pts with MF (primary endpoint), with a median time to response of 3 mo. Case reports and clinical studies have shown some pts’ symptoms and/or splenomegaly improve upon RUX reinitiation after interruption. In the era of novel JAK inhibitors (JAKi), dose optimization and identifying indicators for tx changes remain major challenges. This study describes tx patterns and clinical outcomes of pts with MF with RUX interruption and retreatment in community-based clinical practices. Methods: Two independent patient care data sources were queried (not directly compared): (1) Cardinal Health Oncology Provider Extended Network (OPEN), (2) HealthCore Integrated Research Environment (HIRE); retrospective review of medical charts was conducted. Rigorous entry criteria for this analysis included: age ≥18 y; primary MF (PMF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF diagnosis between 1/1/2012–12/31/2016 (OPEN) or 1/2013–11/2017 (HIRE); use of RUX for MF; and documented physician-directed RUX interruption. MF-related symptoms, splenomegaly, and tx dose and patterns were analyzed. Results: 26 pts met entry criteria (Table). Pre-interruption median (IQR) RUX tx duration was 123 (57–391, OPEN) and 110 (37–148, HIRE) days; 50% had tx interruption within 3 mo. Most interruptions were for adverse events (AEs; 50% and 71%, respectively), followed by (in OPEN) alternative tx (17%), disease progression (8%), no response (8%), or loss of response (8%). After restarting RUX, median (IQR) retreatment duration was 196 (54–553) and 166 (108–262) days, respectively. Symptoms improved in 45% and 43% of evaluable pts, respectively, and spleen size improved in 40% and 33%. Conclusions: Consistent with previous reports, MF symptoms and spleen size improved with RUX retreatment in some pts. While RUX was discontinued for various reasons, one reason for clinical improvements upon reinitiation may be that tx was discontinued before deriving full JAKi benefit. Future studies are warranted investigating JAKi tx sequencing and reinitiation. [Table: see text]
Langerhans cell sarcoma: The Mayo Clinic experience with an extremely rare disease.
Authors: Alhaj Moustafa Muhamad , Jiang Liuyan , Tun Han W. 
Published: May 2020

e19543 Background: Langerhans cell sarcoma (LCS) is a very rare cancer with the reported incidence of 2 per 100,000,000. It originates from antigen presenting cells belonging to the dendritic cell/macrophage family. Methods: Following IRB approval, we identified LCS patients treated at the Mayo Clinic Cancer Center. Medical charts were reviewed to extract clinical data. Results: Our cohort consists of 5 patients with confirmed diagnosis of LCS. The median age at diagnosis was 34 years (range, 11-75) with 60% (3/5) females. One female was an African American and the rest were Caucasians. ECOG performance status at the time of diagnosis was 0 in 4 patients and 3 in 1 patient. Four patients had disseminated disease at diagnosis. 3/5 patients had moderate splenomegaly at diagnosis. 2/5 patients presented with a bulky mediastinal tumor and 1/5 patients presented with bulky intraabdominal disease. Predominant sites of disease are summarized in the table. BRAF mutation was negative in all 3 tested patients. The median follow up for the whole cohort was 25 months (range; 5, 41). Three patients relapsed after the initial treatment. Patient # 4 received allogeneic stem cell transplantation after the 4th relapse and is in CR 14 months later. Patient # 5 had PD-L1 expression > 95% and was started on pembrolizumab with sustained response for 1 year. Conclusions: LCS is extremely rare and is associated with unfavorable outcomes after currently available therapeutic interventions. More studies on the genetic and molecular basis of LCS are necessary to develop targeted therapies. [Table: see text]
Voruciclib plus venetoclax show high efficacy for CLL b cells on human stromal cells.
Authors: Lesnick Connie , Wood Jamie , Parikh Sameer Ashok , Kay Neil E. 
Published: May 2020

e20009 Background: Although treating B-Chronic Lymphocytic Leukemia (CLL) with small molecule inhibitors has shown promise, a lasting cure for this disease has yet to be found. Further treatments directed at key molecular targets in the CLL B cell need development for patients with adverse prognostic factors, and relapsed/refractory patients. We evaluated the impact of two novel drugs with non-overlapping mechanisms of action on CLL B cells: Voruciclib, a cyclin dependent kinase (CDK) inhibitor targeting CDKs 9, 6, 4, 1 and Venetoclax a BCL-2 inhibitor. To mimic the protective effect of the CLL micro-environment these experiments were done with CLL cells cocultured in the presence of bone marrow mesenchymal stromal cells (BMSC). Methods: Voruciclib, (MEI Pharma) and Venetoclax were tested for killing activity alone and in combination against CLL cells cocultured with healthy human bone marrow MSC. CLL B cells were from untreated patients stratified on risk of disease progression. Low risk had mutated and high risk patients had unmutated IVGH genetic status. CLL cells were cultured on BMSC’s with a series of escalating doses of individual drugs and drug combinations at fixed molar ratios then Annexin/PI stained for viability testing by flow cytometry. Killing curves generated for each drug/combination were analyzed by the combination index (C.I.) approach of Chou and Talalay with Calcusyn, characterizing interactions as synergistic, additive or inhibitory. C.I. value hierarchy classes synergy as moderate (0.7-0.9), synergistic (0.3-0.7), strong (0.1-0.3) and very strong (below 0.1). Results: CLL cells with unmutated IGVH status were more sensitive to Voruciclib than mutated IGVH both with and without BMSC’s. The combination Voruciclib +Venetoclax showed synergism for all patients regardless of risk; half strongly to very strongly (Table). Similar synergistic effects were seen with relapsed/refractory patients. Conclusions: Based on these preclinical data, Voruciclib + Venetoclax is a very promising combination to improve treatment of CLL patients. We speculate that CDK9 inhibition, which regulates transcription of Mcl-1, with Bcl-2 inhibition results in potent apoptosis induction in CLL B cells. [Table: see text]