tbuckley/cabot-search huggingface dataset:
Real-world outcomes with immuno-oncology (IO) therapies: A prospective, observational cohort study in patients (pts) with advanced melanoma (OPTIMIzE).
Authors: John M. Kirkwood, Lisa A. Kottschade, Robert R. McWilliams, Nikhil I. Khushalani, Sekwon Jang, Sigrun Hallmeyer, David F. McDermott, Hussein Abdul-Hassan Tawbi, Yin Wan, Rosa Wang, Corey Ritchings, Sumati Rao, Scott Ramsey
Journal: Journal of Clinical Oncology (2019)

e14144 Background: There is little real-world evidence evaluating treatment patterns and outcomes with IO therapies for pts with advanced melanoma (aMEL). We present results from the OPTIMIzE (NCT02780089) study in pts with aMEL receiving IO therapies. Methods: OPTIMIzE is a US-based multisite (150 sites), community-based study of adult pts with aMEL. Pts receiving first-line (1L) nivolumab (NIVO)+ipilimumab (IPI), anti-PD-1 (NIVO/pembrolizumab), or IPI between 2011-2018 with a minimum 1 y of follow-up were included. Baseline characteristics, objective response rate (ORR), overall survival (OS), treatment-related adverse events (TRAEs), and quality of life (QoL) were analyzed. QoL assessments included the Functional Assessment of Cancer Therapy–Melanoma (FACT-M), EQ-5D index, and visual analog scale (VAS). Results: Cohort size: 81 NIVO+IPI, 147 anti-PD-1, and 16 IPI (IPI arm not included in the analysis). Overall, mean age was 64.5 y; 42% had BRAF mutation. Mean follow-up was 14.1 mo. Pts in the NIVO+IPI group were younger, had better ECOG performance status, and a higher likelihood of M1c disease and elevated LDH vs the anti-PD-1 group. ORR was higher for pts treated with NIVO+IPI vs anti-PD-1 (48% vs 33%, P= 0.08). Unadjusted 1-y OS was 78.4% for NIVO+IPI and 73.1% for anti-PD-1. In multivariate Cox model analysis, the hazard ratio for OS for NIVO+IPI vs anti-PD-1 was 0.78 (95% CI, 0.46–1.33; P= 0.36). Grade 3/4 TRAEs occurred in 53% and 22% of pts in the NIVO+IPI and anti-PD-1 groups, respectively ( P˂0.001). QoL changes from baseline were clinically meaningful for EQ-5D VAS and FACT-M in the NIVO+IPI group at 12 mo (Table). After adjusting for baseline covariates, the difference at 12 mo between NIVO+IPI vs anti-PD-1 was 6.7 ( P= 0.04) for EQ-5D VAS and 8.8 ( P= 0.02) for FACT-M. Conclusions: Safety and efficacy outcomes from this prospective real-world study are consistent with those reported in prior clinical trials in treatment-naive aMEL pts. No clinically meaningful deterioration in QoL measures was observed in either group. Clinical trial information: NCT02780089. [Table: see text]
A process to reduce hospital admissions in the OCM population through focused intervention of super-utilizers.
Authors: Manuel Perry, Katie Rudy-Tomczak, Joanne Lalanne, Allison Whalen, Shannon Shah, Scott Hines
Journal: Journal of Clinical Oncology (2019)

6505 Background: A small number of patients (super-utilizers) are responsible for much of the cost in healthcare. In several studies, 5% of patients are responsible for 50% of the cost. Healthcare hot-spotting is the strategic use of data to deliver enhanced resources to selected super-utilizers in an effort to improve the quality of care and to reduce costs. Methods: Patients enrolled in the Oncology Care Model (OCM) who were scheduled to receive cytotoxic, targeted therapy or immunotherapy beginning in the fall of 2017 were screened by nurse practitioners prior to initiating treatment in an effort to identify super-utilizers. Risk factors included high risk disease (stem cell transplant, myelodysplastic syndrome, acute leukemia, stage IV disease), significant co-morbidities (CHF, COPD, renal failure, Insulin Dependent Diabetes , presence of a gastrostomy tube), or an admission to the hospital in the past 6 months. Such patients were provided with enhanced services which included twice weekly outreach by a nurse practitioner between 8am and 10am for a telephonic evaluation of their health status. If the patient was found to have either a new problem that required intervention or a worsening chronic problem, then a same-day appointment was made with the nurse practitioner, oncologist, primary care provider or appropriate specialist. Results: Inpatient admissions decreased from 21.3 per 100 OCM beneficiaries to 18.7 per 100 OCM beneficiaries representing a 12.2% decrease. Inpatient costs were reduced from $979 per beneficiary per month (PBPM) to $885 PBPM representing a decrease of $94 PBPM (9.6% decrease). Conclusions: Targeting oncology super-utilizers based on the nature of their diagnosis, co-morbidities, or history of a recent hospital admission and offering telephonic evaluation reduced hospitalizations and decreased cost resulting in a savings of nearly $600,000 per year for our OCM cohort of 600 beneficiaries. [Table: see text]
Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to brain tissue using drug-embedded biodegradable nanofibers.
Authors: Shih-Jung Liu, Yuan-Yun Tseng
Journal: Journal of Clinical Oncology (2019)

e13501 Background: Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor cell resistance to chemotherapy. Methods: We developed bilayered poly[(d,l)-lactide- co-glycolide] nanofibrous membranes that enable the sequential and sustained release of carmustine [or bis-chloroethylnitrosourea (BCNU)], irinotecan, cisplatin, and combretastatin by employing an electrospinning technique. An elution method and a high-performance liquid chromatographic assay were employed to characterize the in vitro release behaviors of pharmaceuticals from the nanofibers. Results: The experimental results showed that the drug-eluting nanofibers exhibited a sequential drug release behavior, with the release of high concentrations of BCNU, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then placed into the cerebral cavity of rats after operative craniectomy was performed, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. A histological examination revealed the progressive atrophy of brain tissues without inflammatory reactions. Conclusions: Biodegradable drug-eluting nanofibers can be manufactured for the long-term sequential delivery of various chemotherapeutic and antiangiogenic agents in the cerebral cavity, which can potentially enhance the therapeutic efficacy of glioblastoma multiforme treatment and prevent toxic effects resulting from systemic administration.
Correlation of circulating EBV-targeted cytotoxic T lymphocyte precursors (EBV-CTLp) and clinical response following tabelecleucel (tab-cel) infusion in patients with EBV-driven disease.
Authors: Blake T. Aftab, Daniel Munson, Kevin Rasor, Philippe Foubert, Donald Edward Tsai, Wen-Kai Weng, Armin Ghobadi, Koen Van Besien, Yan Sun, Minoti Hiremath, Willis H. Navarro, Susan Prockop
Journal: Journal of Clinical Oncology (2019)

2532 Background: EBV is implicated in a variety of diseases. Tab-cel is an investigational off-the-shelf, allogeneic T-cell immunotherapy utilizing endogenous T cell receptors targeting EBV antigens. We hypothesized the clinical activity of tab-cel is mediated by expansion and persistence of EBV-specific T cells. Therefore, we quantified circulating EBV- CTLp after tab-cel administration and examined the correlation between expansion and clinical response. Methods: Samples from 10 patients with EBV + post-transplant lymphoproliferative disease (PTLD) and other EBV-associated diseases enrolled in an multicenter expanded access protocol (EAP) study ( NCT02822495 ) were analyzed. To evaluate CTLp frequencies, limited dilution analysis was performed on samples taken at baseline and day 34 post first tab-cel dose (end cycle 1). The day 34 persistence of circulating EBV-CTLp from best overall response to initial tab-cel product was tested using the two-tailed Mann-Whitney test. Changes in inflammatory cytokines were also measured. Results: Responders represented in this sampling (n=6; 2 PR and 4 CR) showed a median 5.8-fold increase in circulating CTLp between baseline and day 34 (range: 0.8 to 133-fold). Five of 6 responders showed an increase in EBV-CTLp at day 34 of ≥ 3.8-fold while 1 pt showed no change in CTLp (0.8-fold change). In contrast, the 4 non-responders (3 SD; 1 PD) showed a median 0.3-fold decrease in EBV-CTLp from baseline (range: 1.2 to 0.02-fold; ns). Cumulative analyses revealed a statistically significant correlation between the fold-change of circulating CTLp at day 34 and clinical response (p=0.038) which did not appear to correlate with the type of the EBV-associated disease. Inflammatory cytokines showed no meaningful change from baseline. The safety profile remains consistent with previously reported data. Conclusions: These data support the correlation of clinical activity of tab-cel with the expansion and persistence of EBV-specific T-cells at day 34 post-treatment, as well as the use of circulating CTLp as a biomarker for response in clinical studies. Clinical trial information: NCT02822495.
A real-world study of recombinant human endostatin continuous intravenous infusion combined with chemotherapy in the treatment of advanced mucosal melanoma.
Authors: Xin Liu, Jun Cao, Yanchun Meng, Xiaowei Zhang, Yu Xu, Chunmeng Wang, Yong Chen, Huijuan Yang, Yunyi Kong, Zhiguo Luo
Journal: Journal of Clinical Oncology (2019)

e21019 Background: There is no standard treatment for patients with advanced mucosal melanoma (AMM). Recombinant human endostatin (Endostar) combined with chemotherapy had been showed to improve the efficacy of advanced melanoma. This real world study was aimed to observe the efficacy and safety of endostar continuous intravenous infusion (Civ) combined with chemotherapy in patients with AMM. Methods: 23 patients with AMM treated with endostar plus dacarbazine or temozolomide plus cisplatin between April 2017 and December 2018 were collected. Endostar was given 105mg/m 2 Civ168h (unlike the usual use of 7.5mg/m 2 /d d1-14) . 5 patients with local advanced disease received concurrent radiotherapy. Results: There were 11 males (48%) and 12 females (52%), with a median age of 58 years (30-72 years). Primary lesions were located in the nasal cavity and paranasal sinuses in 9 cases (39%), anorectum in 9 cases (39%), vagina in 3 cases (13%), esophagus in 1 case (4%), and choroid in 1 case (4%). There were 7 patients with local advanced disease and 16 patients with metastatic disease. 1 patient received prior anti-PD1 therapy, 1 patient received prior chemotherapy, the other 19 patients received no prior systemic therapy. A total of 21 patients underwent gene detection, there were 2 patients (10%) with BRAF mutation (one with V600E mutation, one with G606E mutation), 7 patients (33%) with NRAS mutation (3 with exon 2 mutation, 4 with exon 3 mutation), and 1 patient (5%) with KIT exon 11 mutation. Overall, 4 patients (13%) had CR, 4 patients (22%) had PR, 10 patients had SD (43%), and 5 patients (22%) had PD, resulting in a RR of 35% and a DCR of 78%. The 4 patients with CR were with localized disease and received concurrent radiotherapy. The RR were 44%, 33%, 33%, 0% and 0%, and the DCR were 100%, 67%, 67%, 0%, and 100% in patients with melanoma of the nasal cavity, anorectum, vagina, esophagus and choroid respectively. The median PFS was 7.5 months (95% CI: 1.0-14.0months). The median OS was 14.7 months (95% CI: 5.0-24.4months). Grade III/IV adverse events were leucopenia (13%), thrombocytopenia (13%), anemia (4%), nausea and vomiting (4%), elevated transaminase (4%), nasal hemorrhage (4%) and intestinal obstruction (4%). Conclusions: Endostar combined with chemotherapy is effective and safe in the treatment of AMM, especially for patients with melanoma of the nasal cavity and paranasal sinuses. For mucosal melanoma patients with local advanced disease, concurrent chemoradiotherapy may be a good choice. It deserves further study.
Phase 2 study of brigatinib in patients (pts) with anaplastic lymphoma kinase (ALK)−positive, advanced non–small cell lung cancer (NSCLC) that progressed on alectinib or ceritinib.
Authors: Edward S. Kim, Sai-Hong Ignatius Ou, Fabrice Barlesi, Tony S. K. Mok, Myung-Ju Ahn, Veronica Bunn, Pingkuan Zhang
Journal: Journal of Clinical Oncology (2019)

TPS9115 Background: Second-generation ALK tyrosine kinase inhibitors (TKIs) alectinib and ceritinib have demonstrated efficacy and acceptable safety in ALK TKI-pretreated and TKI-naive NSCLC. However, as with crizotinib, resistance to alectinib and ceritinib eventually develops, with secondary resistance mutations detected in approximately 50% of pts. Brigatinib is a next-generation ALK TKI designed to have potent and broad activity against ALK mutants. Post-crizotinib, brigatinib demonstrated high systemic and CNS objective response rates (ORR) and the longest reported median progression-free survival (PFS) of any ALK inhibitor in this setting (16.3–16.7 mo) (Huber. J Clin Oncol 2018;36; Bazhenova. Ann Oncol 2017;28); efficacy was demonstrated regardless of mutations. Based on nonclinical and clinical data, brigatinib may show efficacy in ALK+ NSCLC that has developed resistance or failed to respond to alectinib/ceritinib. This trial was designed to assess efficacy and safety of brigatinib in pts with ALK+ NSCLC that has progressed on alectinib or ceritinib. Methods: This is a phase 2, open-label, single-arm, multicenter, international trial (NCT03535740) in pts (≥18 y) with locally advanced/metastatic NSCLC and disease progression on alectinib or ceritinib (± prior crizotinib; ≤3 different systemic regimens for locally advanced/metastatic disease). Pts receive oral brigatinib 180 mg QD with 7-day lead-in at 90 mg QD. Treatment beyond progression or escalation to brigatinib 240 mg QD is permitted. Primary endpoint: independent review committee (IRC)−assessed confirmed ORR (cORR) per RECIST v1.1. Secondary endpoints: investigator (INV)-assessed cORR, duration of response (INV- and IRC-assessed), PFS, disease control rate, and time to response; in pts with baseline brain metastases: IRC-assessed intracranial cORR, duration of intracranial response, and intracranial PFS; OS; safety/tolerability; and HRQoL. Exploratory endpoints include biomarker analyses. The study was initiated in Dec 2018 at 78 sites (North America, Europe, Asia), with a planned sample size of 103 pts. Accrual is ongoing. Clinical trial information: NCT03535740.
Abstract P041: New Biomarkers for Detecting and Subtyping Insulin Resistance
Authors: David P Cistola, Ina Mishra, Vipulkumar Patel, Rinkal Patel, Sneha Deodhar
Journal: Circulation (2017)

Introduction: The metabolic abnormalities that precede type 2 diabetes progress slowly and in stages. Current evidence-based diabetes prevention programs target individuals in Stage 2 (impaired glucose tolerance or prediabetes). However, by that stage, 70% of pancreatic beta-cell insulin secretory capacity has been lost irreversibly. Thus, it is imperative to identify individuals in Stage I (early insulin resistance syndrome) in order to preserve pancreatic insulin secretion and prevent both diabetes and prediabetes. Early insulin resistance syndrome is characterized by compensatory hyperinsulinemia, dyslipidemia, sub-clinical inflammation and acid-base abnormalities. The nature of the association between these elements is unclear, and different subtypes of insulin resistance syndrome may exist. Hypothesis: We have developed two novel and unconventional biomarkers for characterizing insulin resistance in non-diabetic subjects. One approach is based on dynamic light scattering (DLS) of human serum. The second approach measures the T 2 relaxation time of water in human plasma using compact time-domain NMR relaxometry (TD-NMR). We hypothesize that these methods can detect subtypes, i.e. , insulin resistance with or without inflammation, hypercholesterolemia, or acid-base abnormalities. Methods: Seventy-two asymptomatic non-diabetic human subjects were recruited through an IRB-approved biomarker discovery protocol. Medical histories, anthropomorphic measurements and fasting blood samples were obtained, and over 1300 blood biomarkers were measured on each subject along with DLS and TD-NMR parameters. Bi-variate correlation analyses and multiple regression models were used to analyze continuous variables, and categorical variables were established for insulin resistance, inflammation, acid-base abnormalities and lipid abnormalities. Multiple means comparisons were performed using one-way ANOVA and Tukey-Kramer testing. Results: Plasma water T 2 from TD-NMR was strongly correlated with markers of early insulin resistance syndrome. Multiple regression analysis showed independent contributions from markers of hyperinsulinemia, hypercholesterolemia and inflammation. Multiple means comparisons showed significant differences for insulin resistance with and without inflammation. By contrast, DLS parameters were strongly correlated with insulin markers, but could not distinguish the inflammatory subtypes. Conclusions: Both TD-NMR and DLS are able to detect early insulin resistance in individuals who do not meet the criteria for prediabetes or metabolic syndrome. However, TD-NMR has the unique ability to distinguish inflammatory vs. non-inflammatory subtypes of insulin resistance. Subtyping and risk stratification are important for the design of personalized interventions to prevent diabetes, prediabetes and cardiovascular disease.
Impact of reactive gastrostomy tube placement on clinical course of oropharynx cancer patients treated with chemoradiation.
Authors: Ami A Dave, Marisa A Mozer, Yanyu Zhang, Neilayan Sen, Monica Bojko, Amanda A Huff, Samer Al-Khudari, Kerstin Stenson, Mary J. Fidler
Journal: Journal of Clinical Oncology (2019)

e17540 Background: Prophylactic percutaneous gastrostomy tube (PEG) insertion reduces toxicity from chemoradiation to the head and neck but is thought to increase long term feeding tube dependence. This study retrospectively examines incidence and risk factors for treatment related complications of oropharynx cancer patients with and without prophylactic PEGs. Methods: Rush University Medical Center oropharynx cancer patients who received definitive chemoradiation treatment between 2007-2018 were included. Classifications were: “therapeutic” PEG (pretreatment for immediate use due to inability to swallow), prophylactic PEG, reactive PEG (patient/physician preference or 10% weight loss from baseline), and no PEG inserted on treatment. We compared patients with reactive or no PEG to (1) patients with prophylactic PEG, and (2) patients with prophylactic PEG and therapeutic PEG. Multivariate linear and logistical regression models were used to test PEG effect on weight loss, hospital admission, and incidence of acute kidney injury (AKI). Models were adjusted for covariates (age, gender, race, HTN, CAD, DM, other comorbidity). Acute kidney injury (AKI) was creatinine 1.5-2x above baseline. Results: In all, 104 patients were included with mean age 60.1 (SD = 8.65) and baseline BMI 29.6 (SD = 5.62). 53.4% (N = 55) had a prophylactic PEG, 38.8% (N = 40) had reactive or no PEG, 7.8% (N = 8) had a therapeutic PEG. 80 (76.9%) were treated with cisplatin. For all patients, analyses showed that reactive PEG or no PEG patients were more likely to develop AKI during treatment compared to patients with a prophylactic PEG (OR:3.2, p = 0.03), and to patients with prophylactic PEG and therapeutic PEG combined (OR:3.5, p = 0.02). There were no statistically significant differences between PEG groups for weight loss and hospital admission rate. In cisplatin treated patients, reactive PEG or no PEG patients were more likely to be admitted to the hospital compared to prophylactic PEG patients (OR:3.8, p = 0.04). Compared to patients with prophylactic and therapeutic PEG combined, however, there was no statistically significant difference. Patients with reactive or no PEG were more likely to have AKI than prophylactic PEG (OR:5.2, p &lt; 0.01), and as compared to patients with therapeutic or prophylactic PEG (OR:4.4, p = 0.02). Conclusions: Reactive PEGs were associated with increased AKI and hospitalizations compared with prophylactic PEG. With a reactive PEG model, patients may need to have routine lab work and monitoring adjusted to reduce treatment complications.
An Essay on the Nature and Consequences of Anomalies of Refraction.
Journal: JAMA (1899)

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Translational Research of PT-112, a Clinical Agent in Advanced Phase I Development: Evident Bone Tropism, Synergy In Vitro with Bortezomib and Lenalidomide , and Potent Efficacy in the Vk*MYC Mouse Model of Multiple Myeloma
Authors: Tyler D Ames, Meaghen E Sharik, Gulam M Rather, Guillaume Hochart, David Bonnel, Stefan Linehan, Jonathan Stauber, Richard A Wing, Jose J Jimeno, Daniel Medina, Joseph R Bertino, Marta Chesi, P. Leif Bergsagel
Journal: Blood (2017)