bluuebunny/crossref_metadata_2025_split huggingface dataset:
TALAPRO-1: An open-label, response rate phase II study of talazoparib (TALA) in men with DNA damage repair (DDR) defects and metastatic castration-resistant prostate cancer (mCRPC) who previously received taxane-based chemotherapy (CT) and progressed on greater than or equal to one novel hormonal therapy (NHT).
Authors: De Bono Johann S. , Higano Celestia S. , Saad Fred , Miller Kurt , Chen Hsiang-Chun , Czibere Akos , Healy Cynthia , Fizazi Karim 
Published: March 2019

TPS342 Background: There are no approved therapies for mCRPC that has progressed on taxane and NHT. Preclinical studies showed that DDR-positive prostate tumors may be sensitized to PARP inhibition. TALA inhibits PARP, causing cell death in BRCA1/2-mutated cells. Methods: This study (NCT03148795) is enrolling patients (pts) (N ≈ 100) with measurable soft tissue disease per RECIST v1.1, progressive mCRPC, DDR likely to sensitize to PARP inhibition, ECOG performance status ≤ 2, and no brain metastases, who received 1-2 CT regimens (including ≥ 1 taxane-based CT) and progressed on ≥ 1 NHT (enzalutamide/abiraterone acetate). Prior use of PARP inhibitors, cyclophosphamide, mitoxantrone, or platinum-based CT ≤ 6 mos before study or progression on a platinum-based CT at any time are excluded. Pts will receive TALA 1 mg/d orally (pts with moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or withdrawal of consent. TALA should not be discontinued based on increased prostate specific antigen (PSA) or circulating tumor cell (CTC) count alone. Primary endpoint is best objective response (OR) rate (complete/partial soft tissue response; exact 2-sided 95% confidence interval). Responses must be confirmed ≥ 4 wks later by computed tomography/magnetic resonance imaging with no evidence of bone progression ≥ 6 wks later per PCWG3 criteria. Secondary endpoints include time to OR, duration of response, PSA decrease ≥ 50%, CTC count conversion (to CTC = 0 and < 5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival, overall survival, safety, pt-reported outcomes, and pharmacokinetics of TALA. Efficacy will be assessed every 8 wks for the first 24 wks, then every 12 wks thereafter. An initial safety and efficacy analysis will be performed on 20 pts after ≥ 8 wks of treatment. An interim efficacy analysis is planned when 60 pts have completed ≥ 6 mos of treatment. This study was sponsored by Pfizer Inc. Previously presented at ESMO 2018, FPN 859TiP, De Bono JS et al. Reused with permission. Clinical trial information: NCT03148795.
Genetic counseling processes and outcomes among prostate cancer patients (ProGen).
Authors: Vatnick Donna Rachel , Aktar Sandjida , Stopfer Jill E. , Kipnis Lindsay , Culver Samantha K. , Koeller Diane R. , Husband Alexander E. , Allen Kyle , Kilbridge Kerry L. , McGregor Bradley Alexander , Sweeney Christopher , Speare Virginia , Tippin Davis Brigette , Dolinsky Jill S. , Garber Judy Ellen , Rana Huma Q. , Taplin Mary-Ellen , Pomerantz Mark 
Published: March 2019

TPS343 Background: Prostate cancer (PC) is among the leading causes of cancer mortality in males. Recent studies found 8-12% of advanced PC cases may be hereditary. Germline mutations have been reported in BRCA1/2, other DNA repair genes including ATM, CHEK2, PALB2 and DNA mismatch repair genes. Genetic testing can inform treatment decisions including drug targeting, such as PARP inhibitors for men with BRCA mutations, and checkpoint inhibitors for those with pathogenic mutations in mismatch repair genes2. Discovering a pathogenic mutation associated with increased cancer risk also prompts dissemination of this information to family, where subsequent testing can lead to risk stratification and impactful opportunities for cancer screening and prevention. It is critical that men with high risk and potentially lethal prostate cancer routinely be offered genetic testing as a component of their cancer care. Genetic counseling services are limited, and more efficient services are needed. Methods: We are investigating video education prior to genetic testing compared with in-person pretest counseling with a licensed genetic counselor (GC). ProGen is an ongoing randomized trial evaluating two distinct models of cancer genetics service delivery in 450 PC cases over a two-year period. The study is conducted in collaboration with Ambry Genetics utilizing a 67-gene cancer panel. The primary aim is analysis of the proportion and type of germline mutations identified. Secondary aims include testing uptake by arm, evaluation of distress, knowledge, satisfaction with testing services, family communication, and impact on cancer care. Results are communicated by telephone with a GC. Inclusion criteria are: potentially lethal PC (metastatic, localized with Gleason score ≥8, rising/persistent PSA after local therapy), early diagnosis (≤ 55 years), prior malignancy, and/or family history potentially indicating a hereditary cancer risk. Enrollment is 74% completed at a single institution. (NCT03328091). 1 Pritchard CC, et al. Inherited DNA‐repair gene mutations in men with metastatic prostate cancer. NEJM. 2016;375:443 2 Mateo J, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. NEJM . 2015;373(18):1697-1708 Clinical trial information: NCT03328091.
A phase II, randomized study of nivolumab (nivo) or nivo plus BMS-986205 with or without intravesical Bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC): CheckMate 9UT.
Authors: Hahn Noah M. , Chang Sam S. , Meng Maxwell , Shore Neal D. , Konety Badrinath R. , Steinberg Gary D. , Gschwend Juergen E. , Nishiyama Hiroyuki , Palou Redorta Juan , Taylor John Arthur , Elegbe Ayanbola , Lambert Alexandre , Zhu Li , Ishii Yuko , Maeda Toshiki , Raybold Bradley , Grossfeld Gary , Fischer Bruce S. , Rutstein Mark , Witjes Alfred 
Published: March 2019

TPS493 Background: Immune checkpoint inhibitors, including nivo (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment (tx) paradigm for advanced bladder cancer (advBC). However, an unmet need exists for new effective tx options in earlier stages of disease, specifically for patients (pts) with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors (Inman, et al. Cancer 2007; Hudolin, et al. Anticancer Res 2017), support the combination of anti–PD-1 and IDO1 inhibition in NMIBC. BMS-986205, a selective, potent, once-daily IDO1 inhibitor that works early in the IDO1 pathway, has demonstrated clinical activity in combination with nivo in pts with immunotherapy-naive advBC who received ≥ 1 prior line of therapy (objective response rate, 37%; Tabernero, et al. J Clin Oncol 2018;36(suppl) [abstr 4512]). These findings provide a rationale for investigation of nivo + BMS-986205 ± intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. Here we describe a phase 2, randomized, open-label study assessing the safety and efficacy of nivo ± BMS-986205 ± intravesical BCG in pts with BCG-unresponsive, high-risk NMIBC. Methods: Pts aged ≥ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Pts must have urothelial carcinoma as the predominant histological component (>50%). Key exclusion criteria include locally advanced or metastatic BC, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Using a novel adaptive-type design, pts will be randomized to 1 of 4 tx arms with nivo ± BMS-986205 ± BCG. Primary endpoints include proportion of pts with CIS with complete response (CR), duration of CR in pts with CIS, and event-free survival for all pts without CIS. Secondary endpoints are progression-free survival and safety. This global study in 13 countries is underway, with a target enrollment of 436 pts. ( Clinical trial information: NCT03519256.
EV-301: Phase III study to evaluate enfortumab vedotin (EV) versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial cancer (la/mUC).
Authors: Petrylak Daniel Peter , Rosenberg Jonathan E. , Duran Ignacio , Loriot Yohann , Sonpavde Guru , Wu Chunzhang , Gartner Elaina M , Melhem-Bertrandt Amal , Powles Thomas 
Published: March 2019

TPS497 Background: Standard first-line treatment for patients (pts) with la/mUC is cisplatin-based chemotherapy or carboplatin-based chemotherapy for pts unfit for cisplatin. Immune checkpoint inhibitors (CPIs) are standard treatment options for pts who progressed during or after platinum-based chemotherapy. While some pts with la/mUC achieve durable responses with CPIs, less than 25% of pts respond. Following failure of a CPI, no therapies are approved. Enfortumab vedotin is a fully humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is expressed in 97% of mUC pt samples (Petrylak et al. ASCO, 2017). In a phase 1 study (EV-101; NCT02091999), single-agent EV 1.25 mg/kg was generally well tolerated and demonstrated a confirmed objective response rate (ORR) of 42% across the overall population of pts with mUC; in pts with prior CPI therapy or liver metastasis at baseline confirmed ORRs of 42% and 36% were observed. A pivotal phase 2 study of EV in la/mUC pts with prior CPI treatment (EV-201; NCT03219333) is ongoing. Methods: EV-301 is a global, multicenter, open-label phase 3 trial (NCT03474107) enrolling adult pts with la/mUC and an ECOG performance status score ≤1, who have received a prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with a CPI. Approximately 550 pts will be randomized (1:1) to receive EV (1.25 mg/kg) administered by IV infusion over approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle ( Arm A), or investigator choice of IV docetaxel, paclitaxel, or vinflunine (EU only) on Day 1 of each 21-day cycle ( Arm B). Treatment with the study drug will continue until radiological disease progression, intolerance, or other discontinuation criterion is met. Radiological assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint is overall survival; secondary endpoints include progression-free survival, duration of response, and overall response rate, as well as assessment of safety/tolerability, and quality-of-life parameters. Clinical trial information: NCT02091999.
A phase III, randomized, open-label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SoC) chemotherapy and durvalumab in combination with tremelimumab and soc chemotherapy versus soc chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC).
Authors: Galsky Matt D. , Necchi Andrea , Sridhar Srikala S. , Ogawa Osamu , Ruscica Dario , Angra Natasha , Bellmunt Joaquim 
Published: March 2019

TPS499 Background: Despite high response rates to 1L SoC for locally advanced or metastatic UC chemotherapy (gemcitabine +cisplatin or gemcitabine + carboplatin for patients who are cisplatin-ineligible [poor performance status, impaired renal function, comorbidities]), most patients experience disease progression. Novel strategies like combining chemotherapy and immunotherapy offer hope for improving clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a human IgG2 mAb directed against CTLA-4. The mechanisms of action of PD-1 and CTLA-4 are nonredundant, so targeting both checkpoint pathways may have additive or synergistic efficacy compared to monotherapy. Studies in other tumor types of platinum-based chemotherapy combined with checkpoint blockade have yielded improved efficacy with acceptable safety and support exploration of this approach for 1L locally advanced or metastatic UC. Methods: NILE is a randomized, open-label, multicenter, global trial that will enroll approximately 1265 patients who will be randomized (1:1:1) to durvalumab + SoC chemotherapy, durvalumab + tremelimumab + SoC chemotherapy, or SoC chemotherapy as 1L-line therapy in patients with histologically or cytologically documented, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium. Primary endpoints are progression-free survival using blinded independent central review assessments per RECIST 1.1 and overall survival (OS). Secondary endpoints include objective response rate, OS at 24 months, proportion of patients alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, and HRQoL. Safety, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. The study opened for enrollment in September 2018. Clinical trial information: NCT03682068.
P3BEP (ANZUP 1302): An international randomized phase III trial of accelerated versus standard BEP chemotherapy for adult and pediatric male and female patients with intermediate and poor-risk metastatic germ cell tumors (GCTs).
Authors: Zhang Alison Yan , Toner Guy C. , Lawrence Nicola Jane , Stockler Martin R. , Martin Andrew James , Ford Kate , Stevanovic Amanda Gwendolyn , Wyld David , Walpole Euan Thomas , Troon Simon , Hanning Fritha J. , Mallesara Girish , Weickhardt Andrew James , Birtle Alison Jane , Davis Ian D. , Grimison Peter S. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Published: March 2019

TPS539 Background: Bleomycin, etoposide, cisplatin (BEP) given 3-weekly x 4 remains standard 1st line chemotherapy for metastatic GCTs. Acceleration of standard regimen with shorter cycle lengths has improved cure rates in other cancers. This is the first international randomised clinical trial for intermediate and poor-risk metastatic extracranial GCTs involving both adult and paediatric age group males and females. We aim to determine if accelerated BEP is superior to standard BEP. Methods: DESIGN: Open label, randomised, stratified multicentre, 2 stage, phase 3 trial. Primary endpoint for stage I (n = 150) is the achievement of a complete response (CR), and for entire trial (n = 500) is progression free survival (PFS). SAMPLE SIZE: 150 and 500 patients gives > 80% power to detect a 20% improvement in achieving a CR and 7% absolute improvement in 2yr PFS, respectively. POPULATION: Males and females aged 11-45 years with intermediate or poor-risk metastatic GCTs of the testis, ovary, retroperitoneum or mediastinum for 1st line chemotherapy. TREATMENT: Randomisation 1:1 to 4 cycles of “standard BEP” or “accelerated BEP”: cisplatin 20mg/m2 IV D1-5; etoposide 100mg/m2 IV D1-5; bleomycin 30000 IU IV weekly; and pegylated G-CSF SC D6 or Filgrastim daily; given every 3 weeks or every 2 weeks respectively. Accelerated BEP arm receives 4 additional weekly doses of bleomycin. ASSESSMENTS: Response assessments at 30 day safety assessment, and 6 months from randomisation or after all post-chemotherapy intervention is completed. Regular follow-up up to 5 years, then annually. Archival tumour tissue and baseline blood collected for translational substudies. STATUS: 25 sites open in ANZ, 11 sites open in UK (led by Cambridge Clinical Trials Unit), 19 sites open in the USA (led by Children’s Oncology Group). As of 23rd October 2018, 59 patients have been recruited. Clinical trial information: NCT02582697.
An open-label phase II study to evaluate PT2977 for the treatment of von Hippel-Lindau disease-associated renal cell carcinoma.
Authors: Jonasch Eric , Park Eric Kristopher , Thamake Sanjay , Hirmand Mohammad , Linehan W. Marston , Srinivasan Ramaprasad 
Published: March 2019

TPS680 Background: In von Hippel-Lindau (VHL), renal cell carcinomas (RCC) are of clear cell histology (ccRCC). HIF-2α has been established as an oncogenic driver in ccRCC, where VHL deficiency is the underlying genomic alteration. In this setting, HIF-2α accumulates under normoxic conditions, driving the expression of genes associated with progression of ccRCC, including vascular endothelial growth factor A ( VEGFA), cyclin D1 and other factors that contribute to tumor growth and proliferation. Management of VHL-associated renal tumors most often involves active surveillance until surgery is recommended for tumors larger than 3 cm to reduce the risk of metastasis. Repeated surgical procedures, which are often required, can carry significant morbidity. Systemic therapy options that can delay or obviate the need for surgery by reducing tumor size are needed. Methods: This open-label Phase 2 study will evaluate the efficacy and safety of PT2977, a highly selective small molecule inhibitor of HIF-2α, in VHL patients who have at least 1 measurable ccRCC (per RECIST 1.1). PT2977 will be administered orally at 120 mg once daily. Key inclusion criteria include a germline VHL alteration and at least 1 measurable solid ccRCC but no tumor > 3.0 cm requiring immediate surgical intervention. Patients may have VHL-associated tumors in other organ systems. Key exclusion criteria include prior systemic therapy for VHL, evidence of metastatic disease, and history of a non-VHL-associated invasive malignancy in the past 2 years. The primary endpoint is objective response rate (ORR) of ccRCC tumors per RECIST 1.1. Secondary endpoints include duration of response (DOR), time to response (TTR), progression-free survival (PFS), time to surgery (TTS) for ccRCC tumors, and efficacy evaluations for non-ccRCC tumors. Safety and pharmacokinetics of PT2977 will also be evaluated. Patient recruitment is ongoing. Funding: Peloton Therapeutics, Inc. Clinical trial information: NCT03401788.
High-Intensity Interval Training Improves Left Ventricular Contractile Function
Authors: HUANG YU-CHIEH , TSAI HSING-HUA , FU TIEH-CHENG , HSU CHIH-CHIN , WANG JONG-SHYAN 
Published: March 2019

ABSTRACT

Introduction
Improved myocardial contractility is a critical circulatory adaptation to exercise training. However, the types of exercise that enhance left ventricular (LV) contractile and diastolic functions have not yet been established. This study investigated how high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) influence LV mechanics during exercise.

Methods
Fifty-four healthy sedentary men were randomized to engage in either HIIT (3-min intervals at 40% and 80% of V˙O2max, n = 18) or MICT (sustained 60% of V˙O2max, n = 18) for 30 min·d−1, 5 d·wk−1 for 6 wk or to a control group (n = 18) that did not engage in exercise intervention. LV mechanics during semiupright bicycle exercise tests were measured by two-dimensional speckle-tracking echocardiography.

Results
Before the interventions, acute bicycle exercise increased (i) peak basal/apical radial and circumferential and peak longitudinal strains and strain rates, (ii) peak basal/apical rotations and torsion, and (iii) peak systolic twisting and early diastolic untwisting velocities in the LV. After the interventions, the HIIT group exhibited greater LV mass and diastolic internal diameter as well as higher ratio of E wave to A wave and early diastolic propagation velocity than did the MICT group. Despite decreased peak apical rotation and torsion, HIIT enhanced peak apical radial strain and strain rate as well as shortened the time to reach peak untwisting velocity in the LV during exercise. However, the LV mechanics during exercise were unchanged in the control group.

Conclusion
HIIT but not MICT induces eccentric myocardial hypertrophy. Moreover, HIIT effectively improves the LV mechanics during exercise by increasing contractile and diastolic functions.
Friedewald’s equation for calculating LDL-cholesterol: Is it the time to say “Goodbye” and adopt direct LDL cholesterol methods?
Authors: Khan Sikandar Hayat , Niazi Najmusaqib Khan , Sobia Farah , Fazal Nadeem , Manzoor Syed Mohsin , Nadeem Ahmed 
Published: March 2019

Objectives: To measure correlation and concordance between measured LDL cholesterol (mLDLc) and Friedewald’s calculated LDL cholesterol (cLDLc). To compare the mLDLc and cLDLc values for various anthropometric measures and biochemical indices including insulin resistance, nephropathy, glycated hemoglobin and triglycerides.
Methods: Two hundred thirty two subjects were included in this cross-sectional analysis from Jan-2016 to July-2017 from a target population visiting PNS HAFEEZ hospital. Mean age of the subjects was 46.56(±11.95) years (n=232). These subjects underwent clinical evaluation including measurement of anthropometric measurements, biochemical testing for fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipid profile, urine albumin creatinine ratio (UACR), and insulin. Correlation and concordance between mLDLc and Friedewald’s cLDLc were measured. Finally, Comparison of risk evaluation for mLDLc and cLDLc between groups formulated based upon UACR (Based upon a cut off of 2.5 mg/g) and fasting triglycerides (Group-1 :< 1.0 mmol/L, Group-2: 1.0-1.99 mmol/L and Group-3 :> 1.99 mmol/) was carried out.
Results: There was significant positive linear correlation between mLDLc and cLDLc [r=0.468, <0.001]. Kendall’s Coefficient of concordance between mLDLc and cLDLc was 0.055 (p<0.001). Differences evaluated by one way ANOVA analysis for mLDLc between various triglycerides groups were only significant between group-1 and group-2 [{Group-1:Mean=2.40, (2.19-2.61), n=43}, {Group-2:Mean=2.81, (2.69-2.92),n=136}, [{Group-3:Mean=2.59,(2.37-2.81), n=53}],(p=0.004) in comparison to cLDLc [{Group-1:Mean=2.63, (2.43-2.84), n=43}, {Group-2:Mean=2.85, (2.76-2.93), n=136}, [{Group-3:Mean=2.75, (2.60-2.90),n=53}]. Calculated method for LDLc showed higher UACR than mLDLc. (p=0.021)
Conclusion: cLDLc over estimates LDL-cholesterol in comparison to mLDLc. The correlation between cLDLc and mLDLc was only moderate. However, cLDLc provided better degree of risk prediction for nephropathy and glycated hemoglobin than mLDLc.
How to cite this:Khan SH, Niazi NK, Sobia F, Fazal N, Manzoor SM, Nadeem A. Friedewald’s equation for calculating LDL-cholesterol: Is it the time to say “Goodbye” and adopt direct LDL cholesterol methods? Pak J Med Sci. 2019;35(2):388-393. doi: https://doi.org/10.12669/pjms.35.2.679
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