tbuckley/cabot-search huggingface dataset:
DASL-HiCAP (ANZUP1801): The impact of darolutamide on standard therapy for localized very high-risk cancer of the prostate—A randomized phase III double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation in very high-risk, clinically localized prostate cancer.
Authors: Tamim Niazi, Scott Williams, Ian D. Davis, Martin R. Stockler, Andrew James Martin, Wendy Hague, Karen Bracken, Margot Gorzeman, Felicia Roncolato, Sonia Yip, Lisa Horvath, Shomik Sengupta, Simon Hughes, Raymond S. McDermott, James WF Catto, Neha Vapiwala, Wendy R. Parulekar, Christopher Sweeney
Journal: Journal of Clinical Oncology (2020)

TPS385 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinising hormone releasing hormone analogue (LHRHA) for at least one year, is standard of care for men with very high-risk localised prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high risk features. Darolutamide is an androgen receptor antagonist with favourable tolerability. Our aim is to determine the efficacy of adding darolutamide to ADT and RT given in the setting of either primary definitive therapy (RP or RT), or adjuvant therapy for very high-risk PC. Methods: This study is a randomised (1:1) phase III placebo-controlled, double-blind trial for men planned for RT who have very high-risk localised PC, or very high-risk features with PSA persistence or rise within one year following RP. The trial will be stratified by: use of adjuvant docetaxel; pelvic nodal involvement; RP. 1100 participants will be randomised to darolutamide 600 mg or placebo twice daily for 96 weeks. Participants will receive LHRHA for 96 weeks, plus RT starting week 8-24 from randomisation. Participants are allowed nonsteroidal antiandrogen (up to 90 days) in addition to LHRHA up until randomisation. Early treatment with 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety and resistance to study treatment. Clinical trial information: NCT04136353.
TALAPRO-2: A placebo-controlled phase III study of talazoparib (TALA) plus enzalutamide (ENZA) for patients with first-line metastatic castration-resistant prostate cancer (mCRPC).
Authors: Neeraj Agarwal, Neal D. Shore, Curtis Dunshee, Lawrence Ivan Karsh, Arun Azad, Andre P. Fay, Joan Carles, Beth Sullivan, Nicola Di Santo, Mohamed Elmeliegy, Xun Lin, Ruben G.W. Quek, Akos Czibere, Karim Fizazi
Journal: Journal of Clinical Oncology (2020)

TPS264 Background: TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/2 and traps PARP on DNA, preventing DNA damage repair (DDR) and causing death of cells with DDR mutations (eg BRCA1/2). TALA is approved in multiple countries for germline BRCA1/2-mutated HER2- advanced breast cancer. ENZA is an established therapy for CRPC. PARP1 activity has been shown to support AR function, suggesting that co-blockade of PARP1 may synergize with AR-directed therapy, regardless of DDR deficiency. A combination of TALA with ENZA in mCRPC may improve clinical outcomes in patients with or without DDR-deficient tumors. TALAPRO-2 (NCT03395197) is a 2-part study to evaluate efficacy, safety, pharmacokinetics, and patient (pt)-reported outcomes (PROs) of the combination. Methods: Enrollment goal is 1037 pts (19 pts, part 1 dose-finding; 1,018 pts, part 2 placebo-controlled). Key eligibility criteria: age ≥18 y, asymptomatic/mildly symptomatic mCRPC, ECOG performance status ≤1, no brain metastases, and no prior life-prolonging systemic therapy in nonmetastatic CRPC or mCRPC state. Prior docetaxel or novel hormonal therapy (excluding novel AR inhibitors) in castration sensitive (CSPC) setting is allowed. The randomized double-blind portion will evaluate safety, efficacy, and PROs of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Randomization is stratified by prior NHT or docetaxel for CSPC (yes/no) and DDR mutation status (deficient vs nondeficient/unknown). The primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v.1.1 or in bone per PCWG3 criteria or death. The key secondary endpoint is overall survival (OS). Efficacy will be assessed by radiography every 8 weeks up to week 25 and every 8–12 weeks thereafter. rPFS will be compared between two arms by a 1-sided stratified log-rank test. Pt recruitment is ongoing in multiple regions including US, Europe/Eastern Europe, Israel, South America, South Africa, and Asia Pacific region. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03395197.
Association of metagene based on gene expression with response to atezolizumab (atezo) for metastatic urothelial carcinoma (mUC).
Authors: Arvind Ravi, Praful Ravi, Amin Nassar, Sarah Abou Alaiwi, Catherine Curran, Sanjeev Mariathasan, Daren Tayama, Xiaodong Shen, Romain Banchereau, Rich Price, Gad Getz, Guru Sonpavde
Journal: Journal of Clinical Oncology (2020)

569 Background: Despite the benefits of PD1/L1 inhibitors in metastatic urothelial carcinoma (mUC), the durable benefits accrue mostly to a minority of patients (pts) who attain ≥partial response (PR) by RECIST 1.1. There is a pressing need to identify pts with a low probability of response, who may be diverted to other regimens or trials. Biomarkers associated with response such as PD-L1 expression, intrinsic subtype and tumor mutational burden (TMB) are suboptimal. We studied the ability of agnostic gene expression analysis for association with response. Methods: A retrospective cohort of FFPE tumor samples that underwent RNAseq utilizing pts from the phase II IMvigor210 trial were analyzed. In this study, pts received atezo, a PD-L1 inhibitor, in either the post-platinum or first line cisplatin-ineligible setting. All reads were collapsed to gene level transcript per million (TPM) values, followed by feature selection based on enrichment observed in patients with PR vs progressive disease (PD) as well as complete response (CR) vs PD. A transcriptional biomarker was then designed based on these gene-level enrichment scores, followed by generation of a synthetic “metagene” reflecting a composite of the top single gene predictors. Results: A total of 298 pts were evaluable from the IMvigor210 dataset. The favorable and unfavorable composite biomarker ‘metagene’ was robustly associated with high or low probability of ≥PR, regardless of line of atezolizumab therapy (Table). Area Under the Curve (AUC) for this biomarker was 0.73. Notably, an indeterminate category of the metagene was associated with ≥PR in an intermediate proportion of pts, consistent with meaningful discrimination of response categories. Conclusions: A metagene based on tumor gene expression robustly identified pts with mUC who exhibited ≥PR with atezo. With validation across other PD1/L1 inhibitors and refinement in combination with clinical factors, the metagene may enable the selection of the most suitable pts with mUC for PD1/L1 inhibitors.[Table: see text]
A future for the world's children? A WHO–UNICEF–Lancet Commission
Authors: Helen Clark, Awa Marie Coll-Seck, Anshu Banerjee, Stefan Peterson, Sarah L Dalglish, Shanthi Ameratunga, Dina Balabanova, Maharaj Kishan Bhan, Zulfiqar A Bhutta, John Borrazzo, Mariam Claeson, Tanya Doherty, Fadi El-Jardali, Asha S George, Angela Gichaga, Lu Gram, David B Hipgrave, Aku Kwamie, Qingyue Meng, Raúl Mercer, Sunita Narain, Jesca Nsungwa-Sabiiti, Adesola O Olumide, David Osrin, Timothy Powell-Jackson, Kumanan Rasanathan, Imran Rasul, Papaarangi Reid, Jennifer Requejo, Sarah S Rohde, Nigel Rollins, Magali Romedenne, Harshpal Singh Sachdev, Rana Saleh, Yusra R Shawar, Jeremy Shiffman, Jonathon Simon, Peter D Sly, Karin Stenberg, Mark Tomlinson, Rajani R Ved, Anthony Costello
Journal: The Lancet (2020)
Renal tumor biopsy to reduce overtreatment of renal oncocytomas.
Authors: Joana B. Neves, John Withington, Rebecca Varley, Stefano Agnesi, Umberto Capitanio, Lee Grant, My-Anh Tran-Dang, Soha El-Sheikh, Miles Walkden, Yuigi Yuminaga, Prasad Patki, Ravi Barod, Faiz Mumtaz, Axel Bex, Maxine Gia Binh Tran
Journal: Journal of Clinical Oncology (2020)

623 Background: Up to 30% of renal masses are benign tumours, the most common of which is renal oncocytomas (RO). Our practice is to offer renal tumour biopsy (RTB) for small renal masses (SRM; ≤4cm) as part of a multi-disciplinary pathway. Our objective was to determine whether RTB influenced the management of RO. Methods: Retrospective descriptive analysis of the management of all sporadic cases with a histological diagnosis of RO (biopsy or surgical) at a high-volume tertiary centre from January/2012 to June/2019. Results: 170 patients (66% male; median age 67 years; median age-related Charlson comorbidity index 3) were diagnosed with 177 RO (median size 36mm). 70% (124) of RO were diagnosed using tumour biopsy (median size 33mm), of which 116 (93.4%) embarked on active surveillance (AS; 101) or watchful waiting (15). 53 (30%) RO were diagnosed after surgical excision (median size 50mm; 15 partial and 38 radical nephrectomies), of which 4 lesions were initially managed with AS. Median follow-up on AS was 20 months (2 to 84 months), with a median decrease in estimated glomerular filtration rate of 3 ml/min/1.73m 2 over this period. 79% of RO on AS were SRMs. Median overall lesion size change was 1.1mm/year during follow up. Overall 62.6% of lesions grew, a quarter of which at a rate &gt;5mm/year. Nine cases of RO on AS changed to intervention due to lesion growth or patient choice. No metastases were reported in the whole cohort. Three patients on AS died (stroke, respiratory arrest secondary to food inhalation, and unknown cause). One patient who had had surgical excision of RO died of unknown cause. Conclusions: Surgical risks for benign renal lesions are not different to those taken for renal cell carcinoma. RTB reduces the use of unnecessary surgery and its incumbent morbidity for benign renal lesions, such as RO. AS is a safe management option for patients with RO and can be used to reduce overtreatment-associated harm.
Effect of core needle biopsy number on intraductal carcinoma diagnosis in patients with metastatic castration-sensitive prostate cancer.
Authors: Masashi Kato, Toyonori Tsuzuki, Akiyuki Yamamoto, Takashi Fujita, Momokazu Gotoh
Journal: Journal of Clinical Oncology (2020)

243 Background: The number of core needle biopsies performed to diagnose metastatic prostate cancer are sometimes reduced in daily clinical practice. Intraductal carcinoma of the prostate (IDC-P) is associated with adverse prognostic parameters and has recently received attention as a valuable indicator for the prediction of disease severity. Currently, the relationship between IDC-P diagnosis and the number of core prostate biopsies is unclear. In the present study, we analyzed the effect of core needle biopsy number on IDC-P diagnosis in patients with metastatic castration-sensitive prostate cancer. Methods: We retrospectively evaluated data from 150 patients diagnosed with metastatic prostate cancer at our hospital between 2002 and 2012. Percentage of the core involved with cancer and the maximum cancer occupancy were 100% in median of all the patients. Subjects were allocated to three groups according to the number of core biopsies performed: ≤5, 6–9, and ≥10. The study endpoints were the cancer-specific survival (CSS) and overall survival (OS) rates. Results: Twenty-seven (18%) patients had ≤5 core biopsies, 67 (45%) patients had 6–9 core biopsies, and 56 (37%) patients had ≥10 core biopsies. For patients who underwent ≥10 core biopsies, a significant difference on CSS was detected between with or without IDC-P ( p = 0.002). On the other hand, the difference decreased as the number of core biopsies became smaller (6–9; p = 0.322 and ≤5; p = 0.815). A similar trend was identified for the OS outcome. A significant difference on OS was also found between with or without IDC-P in patients who underwent ≥10 and 6–9 core needle biopsies ( p = 0.0002 and 0.015, respectively), but not in those who underwent ≤5 core biopsies ( p = 0.3407). IDC-P served as a stronger prognostic marker for CSS and OS than did the other factors included in the multivariate analysis. ( p = 0.0024, and p = 0.0014, respectively). Conclusions: Given the IDC-P detection and its value as a prognostic marker, we recommend the performance of ≥10 core biopsy procedures in patients diagnosed with metastatic prostate cancer. Sampling error effects the IDC-P value in smaller number of core needle biopsies.
Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer
Authors: Farzin Khosrow-Khavar, Kristian B. Filion, Nathaniel Bouganim, Samy Suissa, Laurent Azoulay
Journal: Circulation (2020)

The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern.We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality).The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14-3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11-2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88-2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82-1.72]).In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.
Current evidence and future perspectives of immune-checkpoint inhibitors in unresectable malignant pleural mesothelioma
Authors: Katsuyuki Hotta, Nobukazu Fujimoto
Journal: Journal for ImmunoTherapy of Cancer (2020)

Platinum-based chemotherapy is commonly used as the standard first-line treatment for unresectable malignant pleural mesothelioma (MPM). However, in recent times, immune-checkpoint inhibitors (ICIs) have led to a paradigm shift. Herein, we review relevant literature and ongoing trials of ICIs used as both first-line and salvage therapies. Specifically, in the Japanese single-arm, phase II trial, the MERIT trial, nivolumab, an antiprogrammed cell death 1 (PD-1) antibody showed favorable efficacy when used as a salvage therapy. Currently, multiple ICI monotherapy or combination therapy trials have been conducted, which could provide further evidence. Among available ICIs, the anti-PD-1 antibody is promising for unresectable MPM, despite the limited efficacy of anti-CTLA4 monotherapy. Ongoing studies will further confirm the potential efficacy of ICIs for MPM, as observed across other malignancies. It is also crucial to identify any clinically useful predictive biomarkers that could reveal ICIs with maximal effects in MPM.
Intravesical anti-PD-1 immune checkpoint inhibition in urothelial bladder cancer in a mouse model.
Authors: Anne Rajkumar, Jian Wang, Kevin E. Neuzil, Austin Noah Kirschner, Sam S. Chang
Journal: Journal of Clinical Oncology (2020)

537 Background: Non-muscle-invasive bladder cancer is treated by resection within the bladder and bladder instillment with BCG or chemotherapy, but the majority of intermediate- and high-risk cases subsequently recur. Systemic administration of anti-PD-1 immune checkpoint inhibitors (anti-PD-1) are approved treatments for metastatic urothelial bladder cancer. We hypothesized that intravesical instillment with an anti-PD-1 inhibitor would treat localized bladder cancer. Methods: We investigated a syngeneic wild-type mouse model of orthotopic urothelial bladder cancer. We instilled MBT2 cells into wild-type C3H mice to compare treatments, which included weekly intravesical administration of chemotherapy and anti-PD-1 antibody alongside intraperitoneal administration of anti-PD1 antibody. Results: Anti-PD-1 antibody administered by bladder instillment (intravesical route) successfully treats the disease, similarly to anti-PD-1 by systemic route. Anti-PD-1 antibody by either route provides significant survival advantage over isotype control antibody given by bladder instillment. Treatment by immune checkpoint inhibitor increases CD8+ cell infiltration in tumors, particularly when administered intravesically. In addition, antibody treatment avoids toxicity observed for intravesical chemotherapy. Mice who cleared their tumors after initial treatment were rechallenged with tumor engraftment 3-9 months later without any additional treatment, showing initial-anti-PD-1 treated mice did not grow tumors but initial mitomycin-treated mice did grow tumors. Conclusions: Intravesical administration of anti-PD-1 is a promising avenue for treatment of localized bladder cancer, with comparable anti-tumor activity compared to systemic anti-PD-1 in this mouse model.
Hospital contacts due to hepatobiliary adverse events in &gt;5000 patients with inflammatory joint disease treated with originator or biosimilar etanercept (SB4): an observational nationwide study applying linkage between DANBIO and national registries
Authors: Bente Glintborg, Stylianos Georgiadis, Anne Gitte Loft, Asta Linauskas, Hanne Lindegaard, Oliver Hendricks, Dorte V Jensen, Birgitte Lange Andersen, Kamilla Danebod, Anders Villumsen, Grith Eng, Charlotte Wiell, Natalia Manilo, Salome Kristensen, Johnny Raun, Jolanta Grydehøj, Stavros Chrysidis, Mette Nørgaard, Frank Mehnert, Niels Steen Krogh, Merete Lund Hetland
Journal: Annals of the Rheumatic Diseases (2020)

Recent international guidelines recommend the use of biosimilar biological drugs on similar terms as their corresponding originators, including switching from a bio-originator to the biosimilar.1 However, the comparative safety of biosimilars in patients with inflammatory joint diseases (IJD) in routine care is still debated.2 In a phase 3 randomised trial among patients with rheumatoid arthritis, biosimilar etanercept (SB4) had slightly more hepatobiliary adverse events compared with the originator (ETN), possibly explained by differences in patients’ comorbid diseases and comedication use.3 The occurrence of, for example, hepatobiliary safety events is likely to differ across indications (due to differences in age, body weight, use of methotrexate, comedication, etc) and has not been explored in etanercept-treated patients with psoriatic arthritis or axial spondyloarthritis.4

In April 2016, a mandatory switch from ETN to SB4 was performed in Denmark to save costs and the 1-year clinical …
A pharmacometric approach to define target site-specific breakpoints for bacterial killing and resistance suppression integrating microdialysis, time–kill curves and heteroresistance data: a case study with moxifloxacin
Authors: K. Iqbal, A. Broeker, H. Nowak, T. Rahmel, A. Nussbaumer-Pröll, Z. Österreicher, M. Zeitlinger, S.G. Wicha
Journal: Clinical Microbiology and Infection (2020)

ObjectivesPharmacokinetic–pharmacodynamic (PK-PD) considerations are at the heart of defining susceptibility breakpoints for antibiotic therapy. However, current approaches follow a fragmented workflow. The aim of this study was to develop an integrative pharmacometric approach to define MIC-based breakpoints for killing and suppression of resistance development for plasma and tissue sites, integrating clinical microdialysis data as well as in vitro time–kill curves and heteroresistance information, exemplified by moxifloxacin against Staphylococcus aureus and Escherichia coli.MethodsPlasma and target site samples were collected from ten patients receiving 400 mg moxifloxacin/day. In vitro time–kill studies with three S. aureus and two E. coli strains were performed and resistant subpopulations were quantified. Using these data, a hybrid physiologically based (PB) PK model and a PK-PD model were developed, and utilized to predict site-specific breakpoints.ResultsFor both bacterial species, the predicted MIC breakpoint for stasis at 400 mg/day was 0.25 mg/L. Less reliable killing was predicted for E. coli in subcutaneous tissues where the breakpoint was 0.125 mg/L. The breakpoint for resistance suppression was 0.06 mg/L. Notably, amplification of resistant subpopulations was highest at the clinical breakpoint of 0.25 mg/L. High-dose moxifloxacin (800 mg/day) increased all breakpoints by one MIC tier.ConclusionsAn efficient pharmacometric approach to define susceptibility breakpoints was developed; this has the potential to streamline the process of breakpoint determination. Thereby, the approach provided additional insight into target site PK-PD and resistance development for moxifloxacin. Application of the approach to further drugs is warranted.
Abortion: US appeal court upholds Trump’s “gag rule” that stops doctors from facilitating provision
Authors: Owen Dyer
Journal: BMJ (2020)

A US federal appeal court has upheld a Trump administration rule that forbids doctors who provide federally funded reproductive health services from recommending abortion providers or referring patients to them.

An 11 judge panel of the US Ninth Circuit was split along party lines, as seven Republican appointed judges voted on the administration’s side and four judges appointed by Democrat presidents dissented.1

The ruling affects clinics that accept Title X (“Title 10”) funding, named after a federal programme that provides about $280m (£216m; €257m) in reproductive health services each year, mostly to women on low incomes.

Title X clinics have never been permitted to provide abortions, but …
Orsi Consensus Meeting on European Robotic Training (OCERT): Results from the First Multispecialty Consensus Meeting on Training in Robot-assisted Surgery
Authors: Aude E. Vanlander, Elio Mazzone, Justin W. Collins, Alexandre M. Mottrie, Xavier M. Rogiers, Henk G. van der Poel, Isabelle Van Herzeele, Richard M. Satava, Anthony G. Gallagher
Journal: European Urology (2020)