tbuckley/cabot-search huggingface dataset:
Assessing the value of day 8 blood tests in patients treated with a doublet platinum-vinorelbine.
Authors: Rocio Vazquez Sanchez, Raul Diez-Fernandez, Santos Enrech-Frances, Ana Sanchez-Pena, Teresa Molina-Garcia
Journal: Journal of Clinical Oncology (2015)

e17749 Background: The combination of platinum drugs (carboplatin, cisplatin), given on day 1, and vinorelbine, given on days 1 and 8, every 3 weeks is one of the standard regimens in several cancers, mainly non-small-cell lung cancer. One study (Provencio et al, 2009) showed that the hemogram on day 8 (intravenous vinorelbine) could potentially be avoided in the subgroup of patients that received cisplatin. However, carboplatin is considered to be more myelotoxic than cisplatin. We aim to quantify the incidence of thrombocytopenia, neutropenia and impaired liver blood tests on the day 8 in patients receiving the doublet platinum-vinorelbine (intravenous and oral). Methods: A retrospective and observational study (January 2004-December 2014) was made. All patients who had received at least one course of the doublet platinum, both cisplatin and carboplatin, and vinorelbine were included. Data was extracted from the chemotherapy electronic prescription and laboratory database. According to blood analysis results, patients were considered deemed well to receive treatment when neutrophils were > 1.5 x109/L, platelets were > 75 x109/L, ALT < 10xULN and bilirubin < 1.25xULN. Results: A total of 86 patients were included (80.26% men, mean age: 62.43±9.57 years). 90% of patients had non-small-cell lung cancer. Carboplatin and cisplatin were given to 40% and 60 % of patients respectively. The median number of cycles administered per patient was 3.6 (range, 1–6). 27.9% of patients had received previous chemotherapy treatment (1.5 treatment lines per patient). Grade 2 CTC neutropenia occurred in only one day 8 administration (1.4 x109/L) and no grade 3 or 4 neutropenia was observed. Thrombocytopenia and increased blood bilirubin of any grade were not seen in any course of treatment on day 8 and ALT levels were always below 10xULN. Only one dose modification was made on day 8 and it was not caused by an analytical disorder. No delays occurred on day 8. Conclusions: The incidence of impaired blood tests is extremely low on day 8 when vinorelbine was given with cisplatin or carboplatin, suggesting that blood tests might be spared on that day of the cycle. Dose modifications and treatment delays were incidental making medical visit unnecessary.
Results from a phase I expansion cohort of the first-in-class oral HIF-2α inhibitor PT2385 in combination with nivolumab in patients with previously treated advanced RCC.
Authors: Brian I. Rini, Leonard Joseph Appleman, Robert A. Figlin, Elizabeth R. Plimack, Jaime R. Merchan, Keshi Wang, Sanjay Thamake, Naseem J. Zojwalla, Toni K. Choueiri, David F. McDermott
Journal: Journal of Clinical Oncology (2019)

558 Background: The transcription factor hypoxia-inducible factor (HIF)-2α has been established as an oncogenic driver in clear cell renal cell carcinoma (ccRCC) due to underlying VHL deficiency. Activation of HIF-2α can also promote immunosuppression. In preclinical models, HIF-2α inhibition demonstrated increased efficacy in combination with checkpoint inhibitors (Han et al. AACR 2016). In a Phase 1 dose escalation/expansion trial in heavily pre-treated advanced ccRCC patients, PT2385 monotherapy was associated with variability in drug exposure with higher therapeutic exposure associated with improved anti-tumor activity (Courtney et al. JCO 2018). Methods: In the current Phase 1 expansion cohort, patients with advanced ccRCC who had received 1-3 prior therapies (including at least one VEGF(R)-targeting agent) were treated with PT2385 (800 mg PO BID) in combination with nivolumab (3 mg/kg IV Q2Weeks) to evaluate safety, efficacy, and pharmacokinetics. Results: 50 patients were enrolled. Median age was 62 with 58% ECOG 1 and 42% ECOG 2. Median number of prior therapies was 1; 42% of patients received ≥2 prior lines of therapy. The most common all-grade AEs were anemia (46%), fatigue (46%), nausea (36%), and arthralgia (30%). The most common Grade 3 AE’s were anemia (4%), fatigue (4%), and hypoxia (4%). Two Grade 4 events of elevated ALT and increased lipase/amylase were observed. As of August 31, 2018, ORR = 22% (1 CR, 10 PR). At a median follow up of 12.4 months (m), median PFS was 7.3 m for all patients. Patients who had sub-therapeutic exposures ( &lt; 300 ng/ml) of PT2385 (n = 17) had a median PFS of 4.7 m compared to patients with therapeutic exposures of PT2385 (n = 33), who had a median PFS of 10.0 m. Conclusions: The combination of PT2385 + nivolumab was well tolerated and demonstrated promising anti-tumor activity in advanced ccRCC patients, most notably in patients who achieved therapeutic exposure of PT2385. Single agent and combination studies with PT2977, a second-generation HIF-2α inhibitor with an improved PK profile, are ongoing. Clinical trial information: NCT02293980.
Selective enhancement of cytarabine toxicity to AML blasts by differentiating agents.
Authors: Jonathan Harrison, Timothy J Hoffman, Xeuning Wang, George P. Studzinski
Journal: Journal of Clinical Oncology (2015)

e18063 Background: Cytarabine (AraC) is one of the mainstays of AML therapy, but, like other DNA damaging therapeutic agents it is rarely curative. Even high dose AraC regimens cannot in general be used at concentrations which eliminate sufficient numbers of malignant blasts to allow the immune system to eradicate the remaining cells. Here we report that with the addition of a differentiating agent combination immediately following AraC damage to AML blasts, the cell kill is selectively increased. Methods: The experiments were performed using cultured cells freshly obtained from patients with AML, or from established cell lines of AML (HL60 and U937), and compared with the effects of the drugs on cells from normal human bone marrow. The cells were exposed to AraC at concentrations which produced approximately 50% cell kill, followed by a combination of 10 nM 1alfa- hydroxyvitamin D2 (1-D2) and 10 uM carnosic acid (CA), which together serve as a powerful differentiating agent for AML cells, but are not toxic. Results: Increased cell death, measured by Annexin V, as compared to treatment using AraC alone, was selective for malignant cells, occurs by both necrosis and apoptosis, and is due to increased DNA damage and higher levels of DNA damage response (DDR) markers. We also observed that the levels of the pro-apoptotic SH3-only member of BCL family, BIM, are prominently increased by the addition of 1-D2/CA to cells previously exposed to AraC. The increase BIM expression occurs at both mRNA and protein levels. Conclusions: The data indicate that attempted differentiation of cells with activated DDR interacts with apoptotic pathways, and results in improved leukemia cell kill as compared to AraC alone.( Supported by grants R01CA044722-25 from the National Cancer Institute, NIH, and 10A049 from American Institute for Cancer Research, both to GPS, and by the Nellie B. Smith endowment at the University of Missouri to JSH
Randomized phase I trial of pembrolizumab with neo-adjuvant versus concomitant stereotactic body radiotherapy in metastatic urothelial carcinoma: Clinical and translational results.
Authors: Gillian Vandekerkhove, Nora Sundahl, Karel Decaestecker, Annabel Meireson, Pieter De Visschere, Valerie Fonteyne, Daan Joost De Maeseneer, Dries Reynders, Els Goetghebeur, Jo Van Dorpe, Sofie Verbeke, Matti Annala, Lieve Brochez, Kim Van der Eecken, Alexander William Wyatt, Sylvie Rottey, Piet Ost
Journal: Journal of Clinical Oncology (2019)

422 Background: Preclinical data indicates that stereotactic body radiotherapy (SBRT) works synergistically with pembrolizumab, but the effect and potential toxicity might depend on the timing of SBRT. The current study assessed the safety of two different SBRT schedules in combination with pembrolizumab for metastatic urothelial carcinoma (mUC), and explored correlative biomarkers including circulating tumor DNA (ctDNA). Methods: An open-label phase 1 trial was conducted at Ghent University Hospital in patients with mUC to assess the dose-limiting toxicity (DLT) of the combination of pembrolizumab (200mg intravenously, 3-weekly) and SBRT (3x8Gy to the largest lesion). Patients were randomized (1:1) to receive SBRT either prior to the first (arm A) or the third (arm B) cycle of pembrolizumab. Blood was collected throughout the trial for biomarker analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Secondary endpoints included best overall response measured per Response Evaluation Criteria in Solid Tumors v1.1 (RECISTv1.1). The trial was approved by the Ethical Committee of Ghent University Hospital and is registered on ClinicalTrials.gov (NCT02826564). Funding was provided by Merck Sharp &amp; Dohme. Results: Eighteen patients were randomized (nine to each arm) and started trial treatment. No DLT occurred. Treatment-related AEs grade 1-2 occurred in 6/9 and 9/9 patients in arm A and B respectively. One patient in arm B experienced lymphopenia grade 3, unrelated to SBRT. No treatment-related AEs grade 4-5 occurred. An objective response rate as per RECISTv1.1 of 0% and 44·4% was noted in arm A and B respectively. Targeted sequencing of tissue DNA and ctDNA revealed high genomic concordance. A decline in ctDNA was observed in responding patients. Conclusions: Neo-adjuvant and concomitant SBRT combined with pembrolizumab is safe, with potentially superior responses in the latter. ctDNA monitoring is feasible during disease evolution and suggests a shared driver gene status throughout disease progression. Clinical trial information: NCT02826564.
Abstract P109: Genetic Correlates of Resilience Among African American Families From the Jackson Heart Study
Authors: La’Shaunta’ Glover, Mario Sims, Kari North, Keith Norris, Jennifer Smith, Jacquelyn Taylor, Abanish Singh, Solomon Musani
Journal: Circulation (2019)

Background: Research has reported that measures of resilience, such as optimism, social support, and religious coping are positively associated with longevity, but there are limited studies on the genetic contribution of resilience among African Americans. Utilizing Jackson Heart Study (JHS) data, we examined the heritability estimates of markers of resilience and their association with proportion of West African genetic ancestry (pAfr) in order to understand familial patterns of resilience among African Americans. Hypothesis: We hypothesized that genetic variation would contribute significantly to variation in indicators of resilience, and that pAfr will be positively associated with greater resilience in African Americans. Methods: Resilience measures (optimism, social support, social networks, religious experiences, and religious practices and coping) were obtained from validated questionnaires. Scores were created for each resilience measure and then all measures were summed to create a total resilience score among 1,200 related and 1,456 unrelated individuals of the JHS cohort. We then analyzed the subset of related individuals to estimate polygenic heritability for resilience measures using Sequential Oligogenic Linkage Analysis Routines (SOLAR), and evaluated the subset of unrelated participants for the association between resilience and pAfr using a multiple linear regression model. The pAfr was estimated from more than 1,400 ancestry informative markers that differentiate West African genetic ancestry from European ancestry using HAPMIX genetic software. In both analyses, we controlled for age, sex, age-by-sex interaction, education, physical activity, smoking and depressive symptoms. Results: In related individuals, we found a significant proportion of variation (h 2 ±SE; p-value) due to familial correlation on religious practices and coping (0.15±0.09; p=0.0371); religious experience (0.26±0.09; p&lt;0.001); social networks (0.32±0.07; p&lt;0.001); and optimism (0.21±0.08; p&lt;0.001). Heritability estimates for total resilience and social support were not significant. In the subset of unrelated individuals, we found that pAfr was significantly associated (beta±SE; p-value) with total resilience (3.08±1.44; p=0.0327), religious experience (5.16±2.55; p=0.0437), and religious practices and coping (3.77±1.23; p=0.0023) in men but not in women. Conclusion: In this sample of African Americans, we found evidence that variation in markers of resilience are influenced by genetic ancestry and sex. West African genetic background was associated with markers of resilience in men only. Due to lack of household effects we could not account for influence of the common environment, which is a limitation of these findings. However, because we found genetic influences of resilience, future studies that explore associations with longevity loci are warranted.
Abstract 18625: Mismatch Between Right and Left Sided Filling Pressures in Heart Failure Patients With Preserved and Reduced Ejection Fraction
Authors: Yu Horiuchi, Shuzou Tanimoto, Hiroshi Kadowaki, Taishi Okuno, Toshio Kinoshita, Mika Izumo, Jiro Aoki, Hiroyoshi Nakajima, Kazuhiro Hara, Kengo Tanabe
Journal: Circulation (2016)

Introduction: Elevated jugular venous pressure (JVP) is one of the most important physical signs of elevated left-sided filling pressure in patients with congestive heart failure (HF). However, tre...
The Clinical and Biological Implications of Early Clearance of Peripheral Blood Blasts after Induction Chemotherapy in Acute Myeloid Leukemia
Authors: Ming-Kai Chuang, Yu-Chiao Chiu, Hsin-An Hou, Wen-Chien Chou, Jih-Luh Tang, Hwei-Fang Tien
Journal: Blood (2018)
Activation of Hottip lncrna Perturbs HSC Function Leading to AML like Disease in Mice
Authors: Huacheng Luo, Ganqian Zhu, Jie Zha, Bowen Yan, Ying Guo, Jianfeng Xu, Qian Lai, Bing Xu, Feng-Chun Yang, Wei Li, Yi Qiu, Mingjiang Xu, Suming Huang
Journal: Blood (2018)
Analysis of T-Cell Receptor Beta-Constant Region Expression for Rapid Assessment of T-Cell Clonality
Authors: Paul Maciocia, Margarida Neves, Shimobi Onuoha, Patrycja Wawrzyniecka, Giuseppe Gritti, Manuela Tosi, Alessia Moioli, Martin Pule, Teresa Marafioti
Journal: Blood (2018)
Early Accountable Care Organization Results in End-of-Life Spending Among Cancer Patients
Authors: Miranda B Lam, Jie Zheng, E John Orav, Ashish K Jha
Journal: JNCI Journal of the National Cancer Institute (2019)

Spending on cancer patients is substantial and has increased in recent years. Accountable care organizations (ACOs) are arguably the most important national experiment to control health-care spending. How ACOs are managing patients with cancer at the end of life (EOL) is largely unknown. We conducted this study with the objective of determining whether becoming an ACO is associated with subsequent changes in EOL spending or utilization among patients with cancer.Using national Medicare claims from 2011 to 2015, we identified patients who died in 2012 (pre-ACO, n = 12 248) and 2015 (post-ACO, n = 12 248), assigning each decedent to a practice. ACOs were matched to non-ACOs within the same geographic region. We used a difference-in-difference model to examine changes in EOL spending and utilization associated with becoming an ACO in the Medicare Shared Savings Program for beneficiaries with cancer.We found that the introduction of ACOs had no meaningful impact on overall EOL spending in cancer patients (change in overall spending in ACOs = -$1687 vs -$1434 in non-ACOs, difference = $253, 95% confidence interval = -$1809 to $1304, P= .75). We found no changes in total patient spending by cancer type examined or by spending categories, including cancer-specific categories of radiation, therapy, and hospice services. Finally, emergency department visits, inpatient hospitalization, intensive care unit admissions, radiation therapy, chemotherapy, and hospice use did not meaningfully differ between ACO and non-ACO patients.The introduction of ACOs does not appear to have had any meaningful effect on EOL spending or utilization for patients with a cancer diagnosis.
Evaluation of clinical practice among urologists caring for patients with early stage prostate cancer.
Authors: John Williamson Peabody, Trever Bradley Burgon, Diana Tamondong-Lachica, Lisa DeMaria
Journal: Journal of Clinical Oncology (2015)

e16115 Background: Of the 240,000 men in the US diagnosed annually with prostate cancer, the majority have indolent tumors. Treatment choices for the indolent cases, however, are difficult and range from surveillance to procedural interventions each with significant clinical and economic consequences. This study measures the variation in the management of early-stage prostate cancer cases among urologists using a simulation strategy. Methods: 63 board-certified urologists each cared for 3 of a total of 9 possible simulated patients using Clinical Performance and Value (CPV) vignettes—a validated method to assess practice variation. The cases had either a Gleason 3 + 3 and 3 + 4 prostate cancer on biopsy with varying clinico-pathologic risk profiles (e.g., age, PSA). Treatment for the 9 cases was grouped into 3 categories: those for whom active surveillance (AS) was recommended; those for whom active treatment (AT) was indicated; and patients where the treatment plan was uncertain. Responses were scored as a percentage of explicit care criteria determined for each case from the literature, NCCN guidelines and national experts. Results: The median score for diagnosis and treatment was 33% (c/w established norms of 45-50%); significantly there was a wide range of practice exhibited by interquartile ranges (IQR) of 16.7-50.0% (c/w norms of 10-15%). In cases where AT was the recommended treatment, this course was chosen 74% of the time. In cases where the literature suggested that treatment was indeterminate, AT was done 59% and AS 41% of the time. In AS-indicated cases, AT was still recommended 59% of the time. (Table 1). Conclusions: These findings suggest that care variation in prostate cancer, especially treatment, is significant even after controlling for case mix. Cases where treatment is clinical uncertain or where AS is recommended still predominantly receive AT. Additional diagnostics tests on disease status would serve to improve patient care. Overall CPV vignettes scores, and by case type. Diagnosis and Treatment Score % AT % AS Median IQR Freq. Freq. All Cases 33.3 16.7-50.0 58.7 41.3 By Case Type Case A: AS 41.2 16.7-66.7 42.8 57.2 Case B: AT 33.0 25-42.9 73.5 26.5 Case C: Indeterminate 38.0 16.7-50 58.9 41.1
Incidence, prevalence, and risk factors of malignancy in lung transplant recipients.
Authors: Vikas Kumar Singh, Vipin Das Villgran, Lavaniya Beesley, Alycia Petraglia, Kevin M. Kane, Cynthia Gries, M. Patricia George
Journal: Journal of Clinical Oncology (2015)

1581 Background: Solid organ transplant is associated with post-transplant malignancy (PTxM) due to chronic immunosuppression, but data is limited in lung transplant recipients (LTRs). Our goal was to analyze the Organ Procurement and Transplant Network (OPTN) database to determine the incidence, prevalence and risk factors for developing PTxM in LTRs. Methods: All LTRs in the OPTN database from May 4, 2005 to March 3, 2014 were included in this study. LTRs aged <18 years and those without malignancy follow up data were excluded. Prinary endpoint was the development of PTxM. Multivariate logistic regression was done for non-skin PTxM with variables age, sex, smoking history, previous history of malignancy and pre-transplant diagnosis. Results: A total of 10,894 subjects were included. Diagnoses among LTRs were COPD (27%), Idiopathic Pulmonary Fibrosis (IPF) (38%), Cystic Fibrosis (CF) (12%) and others (23%). 791 (7.3%) had history of pre-transplant malignancy. Recurrence rate of pre-transplant malignancy as PTxM was 2.3%. Median follow up time was 4.7 years (IQR 2.0-8.0). Incidence and prevalence are provided in table-1. Post-transplant lymphoproliferative (PTLD) disorder prevalence was 1.3%, of which 50% occurred within one year of transplant. Prevalence of any PTxM was highest in patients with IPF (16%) and lowest among patients with CF(6%). Significant risk factors (p<0.001) for non-skin PTxM included: history of previous cancer (Odds Ratio, OR 1.52), age (OR 1.03), smoking history (OR 1.2), male gender (OR 2), and pre-transplant diagnoses of COPD (OR 1.5) or IPF (OR 1.6). Conclusions: Prevalence of PTLD was comparable to published prevalence in renal transplant recipients. Prevalence of any type of cancer is significantly higher in LTRs as compared to 0.19% in the general adult population reported by CDC in 2014. Lower prevalence in CF group could be explained by younger median age of 29 in this diagnostic group. Malignancy incidence and prevalence in adult lung transplant recipient. Malignancy Type 1-Year follow up Entire follow up period Prevalence N (%) Incidence* Prevalence N (%) Incidence* All types combined 247 (2.3%) 2.03 1,471 (13.5%) 25.3 Other than Skin 174 (1.6%) 1.4 1,321 (12.1%) 22.7 * per 1,000 person-year.
Birch pollen allergen‐specific immunotherapy with glutaraldehyde‐modified allergoid induces <scp>IL</scp>‐10 secretion and protective antibody responses
Authors: Michèle Myriam Rauber, Hoi Ka Wu, Britta Adams, Julia Pickert, Barbara Bohle, Mohamed H. Shamji, Wolfgang Pfützner, Christian Möbs
Journal: Allergy (2019)

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Addressing lack of US insurance coverage of Cancer Hereditary Multiplex Testing (CHMT).
Authors: Julia Rachel Trosman, Christine B. Weldon, Allison W. Kurian, Michael P Douglas, Robin Kate Kelley, Kathryn A Phillips
Journal: Journal of Clinical Oncology (2015)

e17515 Background: CHMT is emerging in US clinical practice, but is debated and lacks insurance coverage. Payers’ coverage affects access and clinical practice, and their requirements impact research. Methods: Using qualitative research, we interviewed 12 clinical experts to identify arguments for CHMT insurance coverage; and executives from 10 major US private payers covering > 120 million lives on how they view these arguments. Results: Payers generally disagree with the experts’ 3 main arguments for CHMT coverage. (1) “Syndrome heterogeneity warrants CHMT coverage.” Payers note a lack of evidence on how heterogeneity impacts clinical management (100%); state that CHMT use leads to broad genetic screening vs. careful patient selection for testing (70%) and counters the standard coverage framework for hereditary testing based on well-defined pedigree / phenotype (60%). (2) “Combining clinical CHMT with research may be the only feasible way to advance novel variant research.” Payers worry that this approach may not uphold research rigor and transparency, especially by commercial labs (80%), and inappropriate use of patient and employer insurance premiums to fund research (50%). (3) “Dropping CHMT prices facilitate coverage.” Payers note that low prices will not impact coverage because they are more concerned with downstream care costs (80%) and the potential for inappropriate use and higher test volumes due to low pricing (30%). Payers suggest how researchers can address their concerns: i) clearly characterize and quantify heterogeneous syndrome populations and clinical pathways for CHMT (90%); ii) develop a novel but rigorous, transparent model for research to be done in conjunction with clinical use, that clearly delineates clinical vs. research funding (70%); and iii) establish best practices and infrastructure for patient re-contact as understanding of CHMT results evolves (80%). 60% of payers indicate that standardizing the definition of “actionable” across medical societies is necessary for coverage. Conclusions: Our findings outline tangible opportunities for researchers and clinicians to address barriers to CHMT insurance coverage by developing relevant evidence, medical consensus and best practices.