tbuckley/cabot-search huggingface dataset:
Impact of single dose vial size availability on drug costs.
Authors: Kathleen Lokay, Peter G. Ellis
Journal: Journal of Clinical Oncology (2016)

6623 Background: Via Pathways’ Disease Committees request cost comparison data from the staff at Via Oncology (VIA) only when two drug regimens are considered comparable in efficacy and toxicity. For Medicare Part B drugs, VIA calculates cost to the payer and patient by assessing estimated units to be billed using current CMS allowables per billable unit. When a drug is available only in a single dose vial (SDV), VIA assumes that the residual drug within the smallest combination of vial sizes must be wasted and, therefore, billable to CMS. In 2015, the 50 mg SDV of pembrolizumab (PEM) was discontinued by the manufacturer, leaving only a 100 mg SDV available. Based on this change, VIA updated the cost calculation of PEM to determine whether the change in available vial size affected the cost of the drug. Methods: VIA calculated the cost of PEM assuming 2 mg/kg dose every two weeks. A total of 24 weeks of therapy were assumed. A range of weight assumptions from 70 mg to 95 mg was used to reflect expected patient weights. For the previous period when the 50 mg vial was available, VIA assumed 3 vials of 50 mg were used and billed for doses up to 150 mg, and that 4 vials were used and billed for doses of 150 mg or higher. For the period after the 50 mg vial was discontinued, VIA assumed 200 mg of drug were billed (using two 100 mg vials) for all weights between 70 kg and 95 kg. Results: The change in availability from a 50 mg vial size to a 100 mg vial size increased the average cost to Medicare and the patient by 6%, or approximately $4,000, over a 24-week course of therapy. Conclusions: Decisions by manufacturers about which vial sizes to manufacture can have a significant impact on the total cost to the patient and payer, particularly if the change leads to waste and the need to bill the patient and payer for the unused portion of a larger single dose vial.
Abstract 11078: Granzyme B Deficiency Protects Against Angiotensin II-induced Cardiac Fibrosis via a Perforin-independent Mechanism
Authors: Yue Shen, Fang Cheng, Mehul Sharma, Yulia Merkulova, Sheetal A Raithatha, Leigh G Parkinson, Hongyan Zhao, Kathryn Westendorf, Lubos Bohunek, Tatjana Bozin, Ivy Hsu, Lisa S Ang, Sarah J Williams, R C Bleackley, John E Eriksson, Michael A Seidman, Bruce M McManus, David J Granville
Journal: Circulation (2015)

Introduction: Granzyme B (GzmB) is a serine protease involved in immune cell-mediated apoptosis that is enabled through a mechanism involving the pore-forming protein, perforin that facilitates internalization. However, recent evidence suggests that GzmB contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. Hypothesis: GzmB contributes to cardiac fibrosis through a perforin-independent pathway involving extracellular proteolysis. Methods: Using a murine model of Angiotensin II (Ang II)-induced cardiac fibrosis, wild-type, GzmB deficient and Perforin deficient mice were treated with Ang II for 4 weeks, and were examined for the presence of cardiac fibrosis. Echocardiography was performed in these mice to examine the cardiac function. The level of Inflammation and inflammatory cells infiltration were examined by immunohistochemistry and RT-PCR analysis. The in vitro endothelial barrier function was measured by electric cell-substrate impedance sensing. Results: GzmB was highly up-regulated in both murine and human cardiac fibrosis. Genetic deficiency of GzmB markedly reduced Ang II-induced cardiac dysfunction, hypertrophy and fibrosis, independently of perforin. GzmB deficiency also decreases microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro studies identified VE-cadherin as a GzmB substrate. VE-cadherin is a key endothelial cell-cell junction protein. GzmB-mediated VE-cadherin cleavage resulted in increased endothelial permeability, and increased transcellular conductance. These results were also observed in vivo. Conclusions: GzmB contributes to the onset and progression of cardiac fibrosis through a perforin-independent process involving the cleavage of VE-cadherin.
Predicting 5-Fluorouracil related severe toxicity with DPD functional tests in plasma, fresh saliva and dried saliva samples.
Authors: Gilberto Schwartsmann, Maria Alice B Franzoi, Gustavo Vasconcelos Alves, Marina Venzon Antunes, Olavo Neto, Andiara Artmann, Suziane Raymundo, Mariane Tegner, Victoria Muller, Roberta Zilles Hahn, Rafael Linden
Journal: Journal of Clinical Oncology (2018)

e14563 Background: This project aimed to evaluate plasma and salivary uracil (U) to dihydrouracil (UH2) ratios as tools for predicting 5-Fluorouracil systemic exposure and drug-related severe toxicity, and clinically validate the use of dried saliva spots (DSS) as an alternative sampling strategy for dihydropyrimidine dehydrogenase (DPD) deficiency assessment Methods: Pre- chemotherapy plasma, fresh saliva and dried saliva samples were obtained from patients with gastrointestinal malignancies (N = 40) for measurement of endogenous U and UH2 concentrations by LC-MS/MS. A second plasma sample collected during 5FU infusion was used for the determination of 5FU area under the curve (AUC) by HPLC-DAD. Data on toxicity was reported according to CTCAE v. 4.0 Results: 15% of the patients developed severe 5FU-related toxicity, with neutropenia accounting for 67% the cases. U, UH2 and [UH2,]/[U] were highly correlated between fresh and dried saliva samples (rs = 0.960; rs = 0.828; and rs = 0.910, respectively). 5FU AUC ranged from 11.3 to 37.31 mg.h.L-1, with 46.2% of under-dosed and 10.3% over-dosed patients. The [UH2]/[U] ratios in plasma, fresh saliva and dried saliva samples were moderately correlated with 5FU AUC and adverse events grade, indicating a partial contribution of the variables to drug exposure (r = -0.412, rs = -0.373, rs = 0.377) and toxicity (r = -0.363, rs = -0.523, rs = 0.542). Median metabolic ratios were lower in patients with severe toxicity (P < 0.01 for salivary ratios, and P < 0.5 for plasma ratios), and 5FU AUC were in average 47% higher in this group than in moderate toxicity. The diagnostic performance of [UH2]/[U] ratios in fresh saliva and DSS for the identification of patients with severe toxicity were comparable. Conclusions: The [UH2]/[U] metabolic ratios in plasma, fresh saliva and DSS were significantly associated with 5FU systemic exposure and toxicity degree. This study also demonstrated the applicability of DSS as alternative sampling for evaluating DPD activity.
Burden of cytopenias among myelofibrosis patients.
Authors: Joseph Feliciano, Yoojung Yang, Mei Lu, Ellen Hooper, Ruben A. Mesa
Journal: Journal of Clinical Oncology (2016)

e18260 Background: Myelofibrosis (MF) patients often present with cytopenias related to disease progression or treatment. This retrospective study examined the prevalence and healthcare resource burden of cytopenias among MF patients in the United States. Methods: Adults ( ≥ 18 years) newly diagnosed with MF (ICD-9-CM: 289.83, 238.76) and continuously enrolled in a health plan for ≥ 6 months pre- and post- first MF diagnosis date were identified from the Truven Commercial Claims and Encounters and Medicare Supplemental Databases (01/2011 – 12/2014). The occurrence of any and each type of cytopenia, including anemia, thrombocytopenia, leukopenia, neutropenia, and lymphopenia, were examined from MF diagnosis to end of follow-up. Discrete cytopenia episodes (minimum gap of 14 days in between) and related healthcare resource use and costs were identified using specific ICD-9 diagnosis codes or treatments used for each cytopenia type (e.g., red blood cell [RBC] and platelet transfusions). Annualized all-cause and cytopenia-related costs were assessed. Results: In a cohort of 1,658 newly diagnosed MF patients (median age: 66 years; 50% male, 70% primary MF), 75% were identified with cytopenias during the follow-up period (median: 1.3 years, range: 0.5-3.1), with an average of 3 episodes per person-year. Anemia was the most common (68%), followed by thrombocytopenia (34%), leukopenia or neutropenia (19%), and lymphopenia (1%). About 1/3 and 1/4 of anemia and thrombocytopenia patients received RBC (34%) and platelet transfusions (23%), respectively. More than half of MF patients with hospitalizations (n = 801) had a diagnosis or treatment for cytopenias (68%), particularly anemia (56%). Approximately 18% of the total health care costs (annualized per person: $66,150) in MF patients were associated with cytopenias ($11,619). Inpatient costs were the major cost driver ($5,283), then outpatient care ($4,109), and therapy ($2,109). Transfusions ($1,568) accounted for 11% of total therapy costs ($14,087). Conclusions: High prevalence of cytopenias in MF, especially anemia and thrombocytopenia, impose a significant resource burden to the healthcare system. These findings highlight the need for safe and effective MF treatments for patients with cytopenias.
Abstract IA03: Functional lung cancer genomics through in vivo genome editing
Authors: Ian P. Winters, Zoë N. Rogers, Christopher D. McFarland, Pranav V. Lalgudi, Shin-Heng Chiou, Mark A. Kay, Dmitri Petrov, Monte M. Winslow
Journal: Clinical Cancer Research (2018)

Abstract Cancer genome sequencing has been instrumental in identifying the genomic alterations that occur in human tumors. However, the functional importance of the vast majority of these alterations, both alone and in combination, remains unknown. I will describe methods that integrate tumor barcoding with CRISPR/Cas9-mediated genome editing and ultradeep barcode sequencing to interrogate multiple tumor genotypes simultaneously in autochthonous mouse models of human cancer. We initially used this method to quantify the effects of eleven of the most frequently inactivated genes in human lung adenocarcinoma on tumor growth in vivo. We also investigated the in vivo fitness advantage conferred by inactivation of each of these eleven genes in combination with inactivation of p53 or Lkb1. This map of tumor-suppressive effects for &amp;gt;30 common lung adenocarcinoma genotypes revealed a complex landscape of context dependence and variability in effect strength. I will also describe a platform that integrates multiplexed Cas9-mediated homology-directed repair (HDR) with DNA barcoding and high-throughput sequencing to simultaneously investigate multiple oncogenic alterations in parallel. Using this approach, we introduced a library of nonsynonymous mutations into endogenous Kras in adult somatic cells to initiate tumors. High-throughput sequencing of barcoded Kras HDR alleles from bulk tumor-bearing lung uncovered surprising diversity in Kras variant oncogenicity. These in vivo approaches may redefine our ability to understand how diverse genomic alterations impact tumor initiation, growth, malignant transformation, and therapy responses. Citation Format: Ian P. Winters, Zoë N. Rogers, Christopher D. McFarland, Pranav V. Lalgudi, Shin-Heng Chiou, Mark A. Kay, Dmitri Petrov, Monte M. Winslow. Functional lung cancer genomics through in vivo genome editing [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA03.
Abstract 15149: Exosome-Mediated Anti-Aging Effects of Cardiosphere-Derived Cells
Authors: Lilian Grigorian, Soraya Fereydooni, Ryan Middleton, Weixin Liu, Michelle Kreke, Jackelyn Valle, Eduardo Marbán
Journal: Circulation (2016)

Introduction: Cell senescence underlies and/or exacerbates age-related cardiovascular pathologies. Cardiosphere -derived cell (CDC) therapy has demonstrated several favorable effects on heart struc...
TCT-306 Angiography-derived functional assessment of non-culprit stenoses with Quantitative Flow Ratio at the time of ST-elevation myocardial infarction
Authors: Fernando Macaya, Francesco Lauri, Hernan Mejia-Renteria, Nilesh Pareek, Sonoka Goto, Catherine Liontou, Pablo Salinas, Nieves Gonzalo, Carlos Macaya, Jonathan Byrne, Antonio Fernandez-Ortiz, Philip Maccarthy, Javier Escaned
Journal: Journal of the American College of Cardiology (2018)
Impact of clinical characteristics and unmet need on oncology combination pricing.
Authors: Priya Madhavan, Katherine Infante, Bryan Harris, John Thomas Lucas, Colin Nash
Journal: Journal of Clinical Oncology (2018)

e18941 Background: Combination therapy is the mainstay in oncology, where over the years branded combination therapies have become more widespread and expensive. This research aims to assess the impact of product characteristics and unmet need on pricing of combination therapies. Methods: The analysis focused on seven recently approved combination oncology therapies across various indications, which were evaluated by the European HTAs. After a deep dive analysis of the selected analogues, we identified clinical characteristics, unmet need, competition and ownership dynamics as key pricing considerations. The scope markets for this study included US, France, Germany, Italy, Spain, UK and Japan. Cost of therapy was presented as cost/course and cost/month in USD. Results: Clinical attributes such as efficacy and safety have the greatest impact on payer willingness to pay (WTP) for combination oncology therapies, where higher median progression-free survival (mPFS) was associated with higher combination prices. Among the combination analogues assessed, carfilzomib and lenalidomide indicated for multiple myeloma achieved the highest mPFS of 26.3 months and global average cost/course of $390,920. In contrast, fulvestrant and palbociclib in breast cancer had 9.5 months mPFS and the lowest cost/course of $87,630. Target patient population size also has an impact on pricing potential, where combination regimens initially targeting smaller patient populations were associated with higher prices. In the US, everolimus and lenvatinib indicated for renal cell carcinoma attained a price that was nearly 5-6 times higher vs. other markets, primarily driven by initial launch in a smaller indication (i.e., differentiated thyroid cancer). Conclusions: Payers want greater improvement in efficacy to justify high cost of combination therapies in oncology. While OS data is preferred, favorable PFS outcomes is sufficient to achieve high prices. In addition, lower disease incidence and smaller target patient populations will increase payer WTP. As more combination oncology regimens are developed and launch in the market, these considerations will continue to play an increasingly important role in their evaluation and pricing potential.
Survival of advanced cancer patients (ACP) receiving early inpatient palliative care (PC) compared to standard oncologic care (SOC) without palliative care.
Authors: Fay J. Hlubocky, Julie Johnson, Stacie K. Levine, Kristen Wroblewski, Bradford Lane, William Dale, Monica Malec, Christopher Daugherty
Journal: Journal of Clinical Oncology (2018)

10022 Background: Palliative care has been described as significantly enhancing ACP quality of life, symptom control, and reducing healthcare costs. Increasing evidence has shown improved outcomes for hospitalized ACP including discharge status, transitions to end-of-life care, and overall morality. Methods: An ACP cohort receiving either PC or SOC between Jan 2015-Dec 2015 were retrospectively analyzed for potential predictors associated with discharge and death. Demographics, diagnosis, discharge status, and survival from the time of discharge were compared between groups. Univariate and multivariate analyses were performed (e.g. log-rank survival and Cox proportional hazards regression). Results: Of a total of 810 patient encounters, 468 were admitted to PC and 342 to SOC. In comparison with SOC, PC were more likely to be: younger (61.1±13.2 v. 62.5±13.0, p = 0.02); AA (48% v. 36%, p = 0.0045); female (50% v. 40%, p = 0.005); shorter length of inpatient stay(5.7± 4.9 v. 6.2±6.5, p = 0.01). Compared with SOC, ACP receiving PC were more likely to be discharged to: home (55% v.45%, p = 0.01); healthcare facilities (e.g. skilled nursing, inpatient rehabilitation) (36.1% v. 20%, p = 0.04); and hospice (home and inpatient) (7.7% v 5.8%, p = 0.02). PC had overall greater median survival from the time of discharge (106.8±99.95 v. 73.8±61.93, p = 0.03) compared to SOC. PC were less likely to die during admission compared to SOC (4.7% v. 6.8%, p = 0.01) and 1.2 times more likely to be discharged home (p < 0.0001). Home discharge was associated with longer survival (ratio = 0.34; 95%CI, p = 0.002). For PC, multivariate logistic regression revealed younger age ( < 50) (p < 0.001); female gender (p = 0.004); and AA ethnicity (p = 0.003) was associated with home discharge. Primary cancer diagnosis (p = 0.0001) and disease severity (p = 0.0034) were independently associated with greater likelihood of death. Conclusions: Results from this simultaneous care program reveal a unique model of care such that early inpatient PC benefits younger and underserved ACP with distinct clinical characteristics and survival, with improved outcomes, compared to those receiving SOC.
Vismodegib in neoadjuvant treatment of locally advanced basal cell carcinoma: First results of a multicenter, open-label, phase 2 trial (VISMONEO study).
Authors: Laurent Mortier, Nicolas Bertrand, Nicole Basset-Seguin, Philippe Saiag, Alain Dupuy, Sophie Dalac-Rat, Bernard Guillot, Carole Templier, Eve Desmedt, Alain Duhamel, Pierre Guerreschi
Journal: Journal of Clinical Oncology (2018)

9509 Background: Surgery is the main treatment of basal cell carcinoma. In locally advanced basal cell carcinoma (laBCC), surgery may cause functional or aesthetic damages. Neoadjuvant administration of vismodegib in laBCC may reduce tumor size, facilitate resection and potentially reduce functional and aesthetic consequences of surgery. VISMONEO was conducted to assess efficacy and safety of vismodegib in the neoadjuvant treatment of laBCC. Methods: VISMONEO (NCT02667574) is an open-label, non-comparative, multicenter, phase II study. Patients with at least one histologically confirmed BCC of the face, inoperable or operable with functional or major aesthetic sequelae risk were included. Oral vismodegib 150 mg once-daily was administered for a period of 4 to 10 months, before surgery. Surgery was done once the best response under vismodegib was observed. Primary endpoint was the percentage of BCC patients with tumor down-staging following surgical resection after neoadjuvant vismodegib. Downstaging was defined according to a six-stage surgical classification related to the aesthetic and functional risk of the surgery. Results: 55 patients with laBCC were included. Median age of the patients was 73.1 years. At inclusion, 4 were inoperable, 15 were operable with a major functional risk and 36 were operable with a minor functional risk or a major aesthetic risk. Mean size of target lesion was 47.3 mm (SD = 27,2mm). 44 patients had a procedure after vismodegib treatment (80.0%, 95%CI [67 to 90]). Of these 44 responders, 27 had a complete response proved by biopsy. Main adverse events were dysgeusia, muscle spasms, alopecia, fatigue and weight loss (20 % of patients with grade ≥ 3) Conclusions: Neoadjuvant vismodegib allows a downstaging of surgical procedure for laBCCs in functionally sensitive locations. Final data will assess quality of long-term local control. Clinical trial information: NCT02667574.
Midcavitary Tako-Tsubo syndrome in cancer patients.
Authors: Dana Ionescu, Danielle Stone, James Stone, Jean-Bernard Durand, Juan Lopez-Mattei, Gloria Iliescu, Kaveh Karimzad, Cezar Iliescu
Journal: Journal of Clinical Oncology (2017)

e14011 Background:Variants of the classic Tako-tsubo syndrome or stress induced cardiomyopathy (SC) includes mid ventricular or basal left ventricular wall motion abnormalities. Midcavitary dyskinesia and ballooning is considered a unique presentation, and there is no published data showing midcavitary involvement in cancer patients. Methods: All cancer patients who fulfilled the diagnostic criteria for SC at MD Anderson Cancer Center over a 6–year period were included in the study. We selected and retrospectively reviewed the medical records of 8 patients who had midcavitary SC. Clinical presentation, ECG, laboratory data, transthoracic echocardiogram and left ventriculography results were reviewed. Results: Out of30 cancer patients who fulfilled the diagnostic criteria for SC, 8 patients (26.7%) (4 females, 4 men, mean age 57.37 yo) had midcavitary SC. 62,5 % patients were diagnosed with a solid malignancy. Trigger factors for midcavitary SC were: systemic infection (3 patients with neutropenia), emotional stress (2 patients), chemotherapy (1 patient undergoing treatment with Ibrutinib), and surgical interventions (3 patients). Clinical presentation included chest pain (37.5%), shortness of breath (50%) and non specific symptoms (12.5%). T wave inversion was the most common electrocardiographic presentation (37.5 %), followed by ST elevation (25 %). All patients had changes of the cardiac biomarkers (BNP mean 2224. 4 pg/dl, TN I mean 2. 8 ng/dl, CK-MB mean 14 ng/dl) and significant LV dysfunction (LVEF &lt; 50%). All patients underwent coronary angiography which showed no obstructive CAD; left ventriculography identified basilar and apical hyperkinesis and midventricular hypokinesia. Cancer therapy was interrupted; aspirin and beta blockers were initiated in all patients. The most common complications of midcavitary SC were: respiratory failure requiring intubation (37, 5%), pulmonary edema (25%), and hypotension (25%). No cardiac deaths were registered. None of the patients experienced recurrence of SC. Conclusions: Mid cavitary SC remains a rare entity, and raises further questions about the causal association between the mid cavitary involvement and cancer, and its impact on cancer therapy and overall survival in this cohort of patients.