tbuckley/cabot-search huggingface dataset:
A phase II study of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: David Johnson Einstein, Atish Dipankar Choudhury, Philip James Saylor, Lillian Werner, Mark G. Erlander, Maya Ridinger, Glenn Bubley
Journal: Journal of Clinical Oncology (2020)

TPS266 Background: Metastatic CRPC remains a leading cause of cancer-related deaths worldwide. Although abiraterone (abi) in either the castration-sensitive or castration-resistant setting increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that regulates mitotic functions and progression, and it is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models and patient-derived tumor xenografts via several mechanisms. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In phase 1 testing, onvansertib demonstrated a manageable safety profile, with transient and reversible hematologic effects. Methods: The goal of this phase 2 study (NCT03414034) is to observe the effects of onvansertib in combination with abi + prednisone on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients will be enrolled at time of PSA progression while on standard abi. A safety lead-in phase has been completed at one dosing schedule (24 mg/m 2 on days 1-5 of a 21-day cycle) and is ongoing at a second dosing schedule (18 mg/m 2 on days 1-5 of a 14-day cycle). Expansion phases are ongoing on both arms. In addition, a more continuous dosing schedule has been proposed (12 mg/m 2 on days 1-14 of a 21-day cycle). With 32 patients in each arm, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if &lt;2 of the first 13 patients achieve disease control. Exploratory analyses include evaluation of the presence of the androgen receptor variant 7 (AR-V7) and other genomic alterations in circulating tumor cells and circulating tumor DNA that may be associated with response to treatment. Clinical trial information: NCT03414034.
Abstract MP43: Monounsaturated Fatty Acids From Plant or Animal Sources and Risk of Type 2 Diabetes in Three Large Prospective Cohorts of Men and Women
Authors: Frank Qian, Geng Zong, Yanping Li, Qi Sun
Journal: Circulation (2019)

Background: Existing evidence on the relationship between intakes of monounsaturated fatty acids (MUFAs) and risk of developing type 2 diabetes (T2D) is conflicting. Few studies have examined whether MUFAs from plant or animal sources exhibit differential associations with T2D. Aims: To examine the association of intake of total, plant-based (MUFA-Ps), and animal-based MUFAs (MUFA-As) with T2D risk. Methods: We used data from three prospective cohorts which included 54,518 women in Nurses’ Health Study (1990-2012), 88,613 women in Nurses’ Health Study II (1991-2013), and 29,520 men in Health Professionals Follow-up Study (1990-2012). Using validated food-frequency questionnaires and food composition tables, we calculated the average MUFA-Ps and MUFA-As intake in every 4-year period and modeled their association with T2D using Cox regression models. Results: During 3,682,622 person-years of follow-up, we documented 13,077 incident cases of T2D. After multivariate adjustment, total MUFA intake was not associated with risk of T2D. In contrast, MUFA-Ps were associated with a lower risk of T2D, whereas MUFA-As were associated with a higher risk. In iso-caloric substitution analyses, the pooled hazard ratios (HRs) and 95% confidence intervals (CI) were 0.99 (0.88, 1.12; P =0.89) for saturated fat (SFAs, 5% of energy), 0.91 (0.85, 0.98; P =0.01) for refined carbohydrates (5% of energy), and 0.87 (0.80, 0.94; P =0.0006) for trans fats (2% of energy), when replaced by MUFA-Ps ( Table 1 ). Additionally, the HRs (95% CIs) were 0.67 (0.61, 0.73; P &lt;0.0001) and 0.78 (0.73, 0.83; P &lt;0.0001), respectively, for replacing 5% of energy in MUFA-As or the sum of SFAs and MUFA-As with MUFA-Ps. Conclusion: In three large prospective cohort studies, higher intakes of MUFA-Ps were associated with a lower risk of T2D, whereas increased intakes of MUFA-As was associated with higher risk. Replacing refined carbohydrates, trans fats, and MUFA-As with MUFA-Ps may be beneficial for the prevention of T2D.
Contribution of clinical pharmacy services integrating into the outpatient oncology unit: Single institution experience in Mexico.
Authors: Saul Campos Gomez, Marlen Morales Perez, Karen Angelica Campos Gomez, Irvin Sanchez Rodriguez, Marciela Garcia Garces, Eva Maria Gomez Garcia, Marlid Cruz Ramos, Estefani Toledo Vigueras, Paula Cabrera, Gabriel Tellez Trevilla, Armando Carlos Gomez Sanchez
Journal: Journal of Clinical Oncology (2015)

e17531 Background: Clinical pharmacists are contributing to the safe medication use by providing comprehensive management to patients and medical staff. Care efforts remain undocumented, resulting in underestimation of the importance of the pharmacy staff interventions and missed opportunities to find new directions for quality improvement regarding their impact in oncology. Methods: The purpose of this prospective study was to document and evaluate the services of clinical pharmacists and care interventions in a oncology outpatient setting. Medication reviews concerning outpatient adult cancer patients were performed daily during a 5-month period (aug-dec 2014), in an outpatient oncology unit of the State Oncology Center ISSEMYM. Medications problems, interventions and acceptance rate by the oncologists were recorded by 2 pharmacists. Results: Medications problems (n = 255) included inappropriate medications (18%), inappropriate administrations (1.7%), underdosing (4.3%), lack of monitoring (4.3%), drug-drug interactions (10%), overdosing (6%), administration omissions (2 %), side effects (1.2%). Interventions (n = 232) led to drug dosing adjustments (28%), treatment discontinuations (5%), drug additions (5%), alternate routes of administration (1%), therapeutic drug monitoring (1.7%), replacement of a drug by another one (2%). Most (97 %) of the interventions were accepted and implemented by the medical staff. Conclusions: A significant amount of pharmaceutical care was documented by pharmacy staff. The integration of clinical pharmacy services resulted in drug specific interventions in 5.7% of the prescriptions of outpatient adult cancer patients. Medication problems mostly concerned wrong dosage error on prescription. The pharmacy staff intervention had a high rate of acceptance by oncologists and nursing staffs. The outcome of care in the oncology outpatient and medication cost avoidance remains to be measured. To the best of our knowledge, this is the first report describingthe contribution of a Clinical Pharmacy Services Integrating into the Outpatient Oncology Unit in México.
The influence of hospital and surgeon factors on the prevalence of axillary evaluation in ductal carcinoma in situ.
Authors: Ellie J. Coromilas, Jason Dennis Wright, Yongmei Huang, Sheldon M. Feldman, Alfred I. Neugut, Ling Chen, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2015)

6529 Background: Axillary lymph node evaluation (LND) is standard of care in the surgical management of invasive breast cancer, but benefit has not been demonstrated in ductal carcinoma in situ (DCIS). We aimed to determine the incidence of LND in women with DCIS undergoing breast conserving surgery (BCS) and mastectomy, and to identify clinical, hospital, and surgeon-related factors associated with LND. Methods: Perspectives database was used to identify women ages 18-90 with DCIS who underwent BCS or mastectomy between 2006-2012. Analyses were stratified by surgery type, and multivariable regression analysis was used to identify factors associated with LND. Results: Of 35,591 women identified with DCIS, 26,580 (74.7%) underwent BCS and 9,011 (25.3%) underwent mastectomy; 17.7% undergoing BCS and 63% undergoing mastectomy had LND. Rates increased over time with mastectomy (2006: 56.6%, 2012: 67.4%) and were relatively stable with BCS (2006: 18.5%, 2012: 16.2%). In a multivariable analysis, Medicaid insurance (RR 1.17, CI 1.05-1.30) and treatment in a non-teaching hospital (RR 1.13, CI 1.06-1.21) or urban location (RR 1.30, CI 1.09-1.55) were associated with LND with mastectomy. Among women undergoing BCS, Hispanic race (RR 1.32, CI 1.00-1.74) and treatment in a non-teaching hospital (RR 1.17, CI 1.03-1.33) influenced LND. Surgeon volume was the most significant predictor of LND with BCS (mid vs. low: RR 0.87, CI 0.70-0.94; high vs. low: RR 0.54, CI 0.44-0.65). Low volume surgeons performed LND in 26.4% of patients undergoing BCS, compared to 20.4% by mid volume and 10.4% by low volume surgeons. Conclusions: Despite guidelines recommending against LND in women with DCIS undergoing BCS and lack of evidence for its use with mastectomy, it is frequently performed. Given the additional morbidity and cost of these procedures, alternative surgical approaches or prospective evaluation of the clinical benefit of LND in women with DCIS is needed.
How to ensure access to innovative cancer treatment in times of health technology assessment and comparative effectiveness research?
Authors: Michael Opel, Amanda McDonell, Ashley Woolmore, Josh Hiller, Stephen Deitch, Karin Berger
Journal: Journal of Clinical Oncology (2015)

e17501 Background: In the light of increasing budget pressures, access to optimal treatment is a growing challenge for oncologists. As the gold standard of clinical evidence, RCT data is used to inform decision making. However, payer are also keenly aware that RCTs do not answer all questions in oncology / hematology. Real world data (RWD) might provide some of those answers, researchers are unclear what exactly payers need to ensure access to innovative cancer treatment. The aim of our project was to understand how RWD is used today,how it might be used to support access and reimbursement decisions. Methods: Delphi panel discussions with payers, clinicians, ethics experts in Germany, France and the UK. Results: Pre-launch, only the UK saw a clear role for RWD. Post launch, all three countries saw utility. Defining standard of care (SoC) and quantifying resource use were seen as the applications with the most pronounced access benefit. Germany and the UK highlighted willingness to develop RWD usage further. France intends on maintaining the status quo. Future RWD uses identified include supporting risk share agreements, monitoring health care delivery and complementing RCT data as part of adaptive licensing. In order for these uses to become reality, 4 key hurdles will need to be overcome: Quality, Privacy, Trust and Relevance. These were identified unanimously across countries, with trust seen as the primary hurdle by payers. Approaches identified to address these hurdles include, unrestricted research by a third party, publication in a peer reviewed journal and ensuring population comparability.Conclusions: The highest value RWD use for access lies in SoC definition, resource use quantification and monitoring healthcare delivery. Associated quality concerns should be addressed by use of established datasets and building dataset credibility prior to employing them for access support. Trust concerns should be addressed primarily via publication in peer reviewed journals and joint pharma/payer study definition. Transparency on payers needs for oncological RWD is essential for future study panning, health care providers and patients access to innovative drugs and reimbursement.
Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor (ICI) response in metastatic renal cell carcinoma (mRCC).
Authors: Jason Zhu, Sarabjot Pabla, Matthew Labriola, Rajan T. Gupta, Shannon McCall, Daniel J. George, Devin Dressman, Sean Glenn, Saby George, Carl Morrison, Tian Zhang
Journal: Journal of Clinical Oncology (2019)

2595 Background: ICIs are now standard of care for mRCC; however, there are few biomarkers to predict ICI response. Recent data from atezolizumab/bevacizumab trials in mRCC suggest tumors with high T eff high /PD-L1+ are more likely to respond to ICI. Here, we use two gene panels as well as other inflammation markers in the tumor microenvironment to correlate with ICI responses. Methods: This multicenter study evaluated 86 patients (pts) with mRCC treated with ICIs. FFPE tumor samples were evaluated by RNA sequencing for T eff status. Two gene panels were analyzed: a T eff Gene Panel (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, TAP1) and a 5-Gene panel (FOXP3, CCR4, KLRK1, ITK, and TIGIT) based on the gene expression pattern of tumors in our cohort. Objective response rates (ORRs, defined as CRs and PRs) were correlated with PD-L1 status (positivity was defined as ≥1% TPS based on Dako 22C3 IHC assay), and TMB (0-10, 10-20, ≥20 mut/Mb), and tumor inflammation (high CD8 expression compared to a large reference population). Best responses to ICI was determined by an expert radiologist using RECIST 1.1 criteria. Inflamed tumor status, T eff gene panel, 5-gene panel, PD-L1 status, and TMB were associated with ORR and tested using a chi-squared test with Yates’s continuity correction. Results: ORR was 50% (4/8) for PD-L1 positive pts and 14% (9/65) for PD-L1 negative pts (p = 0.042). The majority of tumors (95%, 82/86) had TMB &lt; 10 mut/mb. 43 pts (50%) were classified as T eff high and 43 pts were classified as T eff low . ORR was 23% (10/43) in the T eff high cohort and 12% (5/43) in the T eff low cohort (p = 0.256). ORR was 31% (14/45) in the 5-Gene high cohort and 2% (1/41) in the 5-Gene low cohort (p = 0.001). Conclusions: TMB and tumor inflammation based on CD8 did not reliably predict for objective responses in this study of mRCC pts treated with ICIs. Gene expression signatures provide a more comprehensive evaluation of the tumor microenvironment and may lead to better predictive biomarkers for ICI response than individual biomarkers such as PD-L1, TMB, or CD8 expression.
Systemic PPARγ deletion in mice provokes lipoatrophy, organomegaly, severe type 2 diabetes and metabolic inflexibility
Authors: Federica Gilardi, Carine Winkler, Laure Quignodon, Jean-Gael Diserens, Barbara Toffoli, Mariano Schiffrin, Chiara Sardella, Frédéric Preitner, Béatrice Desvergne
Journal: Metabolism (2019)

BackgroundThe peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response and development. Numerous studies relying on tissue-specific invalidation of the Pparg gene have shown distinct facets of its activity, whereas the effects of its systemic inactivation remain unexplored due to embryonic lethality. By maintaining PPARγ expression in the placenta, we recently generated a mouse model carrying Pparg full body deletion (PpargΔ/Δ), which in contrast to a previously published model is totally deprived of any form of adipose tissue. Herein, we propose an in-depth study of the metabolic alterations observed in this new model.MethodsYoung adult mice, both males and females analyzed separately, were first phenotyped for their gross anatomical alterations. Systemic metabolic parameters were analyzed in the blood, in static and in dynamic conditions. A full exploration of energy metabolism was performed in calorimetric cages as well as in metabolic cages. Our study was completed by expression analyses of a set of specific genes.Main findingsPpargΔ/Δ mice show a striking complete absence of any form of adipose tissue, which triggers a complex metabolic phenotype including increased lean mass with organomegaly, hypermetabolism, urinary energy loss, hyperphagia, and increased amino acid metabolism. PpargΔ/Δ mice develop severe type 2 diabetes, characterized by hyperglycemia, hyperinsulinemia, polyuria and polydispsia. They show a remarkable metabolic inflexibility, as indicated by the inability to shift substrate oxidation between glucose and lipids, in both ad libitum fed state and fed/fasted/refed transitions. Moreover, upon fasting PpargΔ/Δ mice enter a severe hypometabolic state.ConclusionsOur data comprehensively describe the impact of lipoatrophy on metabolic homeostasis. As such, the presented data on PpargΔ/Δ mice gives new clues on what and how to explore severe lipodystrophy and its subsequent metabolic complications in human.
Abstract 2536: Transapical Valve in a Valve Concept for Minimally Invasive Redo Xenograft Replacement
Authors: Thomas Walther, Todd Dewey, Volkmar Falk, Jörg Kempfert, Michael Mack, Friedrich W Mohr
Journal: Circulation (2006)

Objective: Aim of this study was to test the feasibility of minimally invasive transapical redo valve-in-a-valve (VinV) placement surgery as a treatment option for degenerated xenografts usually associated with an increased perioperative risk. Methods: In 7 pigs the VinV concept was evaluated. On routine cardiopulmonary bypass (CPB) commercially available conventional Carpentier Edwards porcine aortic (n=5) and mitral (n=2) valve prostheses were implanted. The Ascendra™ valve replacement system, consisting of a pericardial xenograft fixed within a 23 mm stainless steel, balloon expandable stent (Edwards Lifesciences, Irvine, CA, USA) was then implanted using a subxiphoid minimally invasive incision and a transapical approach. Deployments were performed under fluoroscopic and echocardiographic visualization on the beating heart with ventricular unloading using CPB and rapid ventricular pacing. Results: The transapical approach was relatively easy and safe in all experiments. Visualization was good and valv...
PRINT: Prostate cancer intensive, non-cross reactive therapy for CRPC—Early observations of feasibility and efficacy.
Authors: Bobby Chi-Hung Liaw, Che-Kai Tsao, Matt D. Galsky, Richard Lorne Bakst, Robert Stewart, Richard Stock, William K. Oh
Journal: Journal of Clinical Oncology (2019)

310 Background: Optimal sequencing of approved therapeutic agents in mCRPC is not known. The standard approach, is to treat until resistance then switch. The PRINT trial explores the efficacy of treating mCRPC with a rapidly-cycling, non-cross reactive regimen as a way to more effectively treat an intrinsically heterogeneous disease, to delay or prevent drug resistance, and minimize treatment toxicity. Methods: Patients were treated with 3 consecutive treatment modules, each of 12 weeks' duration: 1. abiraterone acetate 1000 mg PO daily and prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV and carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily and radium-223 50 kBq/kg IV q4 weeks (in those with bone metastases). After completion of this 9 month regimen, patients are followed on ADT alone. Primary endpoint is PSA or radiographic time to disease progression. Results: From 3/2017 to 10/2018, 28 of 40 planned men with mCRPC were enrolled, 19 (67.9%) with bone metastases. PSA response rates ( &gt; 90%/ &gt; 50%), compared to baseline, following each treatment module: 1. 50%/78.6%; 2. 50%/92.7%; 3. 64.39%/92.7%. Currently, 14 patients have completed the study regimen with median follow up of 3.6 months, 8 of whom continue without any additional therapy. Of the patients evaluable for primary endpoint, median time to PSA progression is 96+ days (95% CI 82-110+ days). The regiment was well tolerated, grade 3/4 adverse effects include: hyperglycemia (17.9%), diarrhea (7.1%), anemia (3.6%), fatigue (3.6%), neutropenia (3.6%), thrombocytopenia (3.6%). Measurable response and molecular correlate data will be presented. Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross reactive regimen is feasible, demonstrates significant antitumor benefits, and is well tolerated. Further follow up will determine if PRINT delays progression compared with standard approaches. Clinical trial information: NCT02903160.
Abstract MP65: Maternal Vascular Lesions in the Placenta May Identify Women Susceptible to Masked Hypertension a Decade After Pregnancy
Authors: Janet M Catov, Vanessa Assibey-Mensah, Matthew Muldoon, Baiyang Sun, W. Tony Parks
Journal: Circulation (2019)

Introduction: Women with placentally mediated pregnancy complications such as preeclampsia have excess hypertension and cardiovascular disease later in life, but the underlying pathophysiology linking these conditions is unknown. Hypothesis: We considered that histological examination of the placenta may reveal maternal vascular impairments that identify a group susceptible to blood pressure (BP) elevations a decade after delivery, including elevations that may only be detectable using out of office BP measurement. Method: Women with a singleton live birth at Magee-Womens Hospital (Pittsburgh, PA) during 2008-2009 were enrolled 8-10 years after delivery (n=248). Pregnancy features and placental pathology were abstracted from medical records. Women with placental vasculopathy (several related lesions arising from impaired remodeling of maternal myometrial and decidual arteries, n=24) or infarcts (n=32) were compared to women with neither lesion (n=192). Clinic BP was measured three times by trained research staff using a standard protocol and a validated home BP device. Women were trained to measure their BP twice daily for 7 days using the same device mentioned above. Subsequently, time and date stamped BP measures were downloaded (mean 12.2 measures ± 4.5). BP status (elevated, stage 1, stage 2) was identified using the 2018 ACC/AHA guidelines for clinic and home BP measures. Sustained normotensive, white coat, masked, and sustained hypertension status were classified. Results: Women were, on average, 37 years of age at measurement. In analysis controlled for age and race (p-value &lt; 0.05) those with placental vasculopathy had higher mean diastolic BP in clinic and at home (80.5 ± 13.3 mmHg, 79.9 ± 10.4, respectively) than women without vascular lesions in the placenta (75.4 ± 9.8 mmHg and 74.3 ±8.6, respectively). In addition, women with placental vasculopathy had a higher prevalence of masked hypertension (higher elevated BP status measured at home vs. in clinic; 37.5% vs. 14.1%) that persisted after accounting for maternal age and race (adjusted OR 4.7, 95% confidence interval 1.6, 13.8). Vasculopathy associations were similar after excluding women with preeclampsia (n=42), the pregnancy complication most strongly associated with placental vascular pathology. There were modest, non-significant associations between placental infarcts and all measures of maternal blood pressure. Conclusions: Irrespective of prior preecclampsia, women with placental evidence of vasculopathy have excess hypertension and particularly masked hypertension in the decade after pregnancy. Our results emphasize the value of out of office blood pressure measurement, and indicate that placental vasculopathy may be pathophysiologically related to development of hypertension before age 50.