Publications by authors named "Matthew R Smith"

247 Publications

Darolutamide and health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: An analysis of the phase III ARAMIS trial.

Eur J Cancer 2021 Jul 14;154:138-146. Epub 2021 Jul 14.

Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Background: In the ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT significantly improved metastasis-free survival (MFS), overall survival (OS) and time to pain progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Herein, we present analyses of patient-reported health-related quality of life (HRQoL) outcomes.

Patients And Methods: This double-blind, placebo-controlled, phase III trial randomised patients with nmCRPC and prostate-specific antigen doubling time ≤10 months to darolutamide 600 mg (n = 955) twice daily or matched placebo (n = 554) while continuing ADT. The primary end-point was MFS; the secondary end-points included OS and time to pain progression. In this analysis, HRQoL was assessed by the time to deterioration using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) prostate cancer subscale (PCS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer Module (EORTC QLQ-PR25) subscales.

Results: Darolutamide significantly prolonged time to deterioration of FACT-P PCS versus placebo (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.70-0.91; P = 0.0005) at the primary analysis (cut-off date: 3rd September 2018). Time to deterioration of EORTC QLQ-PR25 outcomes showed statistically significant delays with darolutamide versus placebo for urinary (HR 0.64, 95% CI 0.54-0.76; P < 0.0001) and bowel (HR 0.78, 95% CI 0.66-0.92; P = 0.0027) symptoms. Time to worsening of hormonal treatment-related symptoms was similar between the two groups.

Conclusion: In patients with nmCRPC who are generally asymptomatic, darolutamide maintained HRQoL by significantly delaying time to deterioration of prostate cancer-specific quality of life and disease-related symptoms versus placebo.
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http://dx.doi.org/10.1016/j.ejca.2021.06.010DOI Listing
July 2021

Blood Biomarker Landscape in Patients with High-risk Nonmetastatic Castration-Resistant Prostate Cancer Treated with Apalutamide and Androgen-Deprivation Therapy as They Progress to Metastatic Disease.

Clin Cancer Res 2021 Jun 10. Epub 2021 Jun 10.

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.

Purpose: In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival (PFS2), and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation.

Experimental Design: In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or qRT-PCR. Circulating-tumor DNA (ctDNA) levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by the treatment group; genomic aberrations were summarized in ctDNA-positive samples. Association between detection of aberrations in all patients and outcomes was assessed using Cox proportional-hazards models and multivariate analysis.

Results: In 247 patients, the overall prevalence of ctDNA, AR aberrations, and inactivation increased from baseline (40.6%, 13.6%, and 22.2%) to EOST (57.1%, 25.4%, and 35.0%) and was comparable between treatment groups at EOST. In patients who received subsequent androgen signaling inhibition after study treatment, detectable biomarkers at EOST were significantly associated with poor outcomes: ctDNA with PFS2 or OS (HR, 2.01 or 2.17, respectively; < 0.0001 for both), any AR aberration with PFS2 (1.74; = 0.024), and or inactivation with OS (2.06; = 0.003; or 3.1; < 0.0001).

Conclusions: Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and inactivation at EOST were associated with poor outcomes in patients treated with first subsequent androgen signaling inhibitor.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0358DOI Listing
June 2021

Association of Molecular Subtypes With Differential Outcome to Apalutamide Treatment in Nonmetastatic Castration-Resistant Prostate Cancer.

JAMA Oncol 2021 Jul;7(7):1005-1014

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

Importance: There is a need to identify prognostic biomarkers to guide treatment intensification in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Objective: To examine whether molecular subtypes predict response to apalutamide, using archived primary tumor samples from the randomized, double-blind, phase 3 SPARTAN trial.

Design, Setting, And Participants: In this cohort study, gene expression data from 233 archived samples from patients with nmCRPC enrolled in the SPARTAN trial were generated using a human exon microarray. The present analysis was conducted from May 10, 2018, to October 15, 2020.

Interventions: Patients were randomized (2:1) to apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) or placebo+ADT.

Main Outcomes And Measures: Patients were stratified into high-risk and low-risk categories for developing metastases based on genomic classifier (GC) scores for high (GC >0.6) and low to average (GC≤0.6) and into basal and luminal subtypes; associations between these molecular subtypes and metastasis-free survival (MFS), overall survival (OS), and progression-free survival 2 (PFS2) were evaluated using Cox proportional hazards regression and Kaplan-Meier analysis.

Results: Median age of the 233 included patients was 73 (range, 49-91) years. A total of 116 of 233 patients (50%) in the SPARTAN biomarker subset had high GC scores. Although all patients receiving apalutamide+ADT had improved outcomes, having high GC scores was associated with the greatest improvement in MFS (hazard ratio [HR], 0.21; 95% CI, 0.11-0.40; P < .001), OS (HR, 0.52; 95% CI, 0.29-0.94; P = .03), and PFS2 (HR, 0.39; 95% CI, 0.23-0.67; P = .001) vs placebo+ADT. In total, 152 of 233 patients (65%) had the basal molecular subtype. Although there were no significant differences in MFS, PFS2, or OS between patients with the luminal vs basal subtype in the placebo+ADT arm, patients with the luminal subtype in the apalutamide+ADT arm had a significantly longer MFS (apalutamide+ADT: HR, 0.40; 95% CI, 0.18-0.91; P = .03; placebo+ADT: HR, 0.66; 95% CI, 0.33-1.31; P = .23) compared with patients with basal subtype; similar trends were observed for OS (apalutamide+ADT: HR, 0.50; 95% CI, 0.25-0.98; P = .04; placebo+ADT: HR, 0.78; 95% CI, 0.38-1.60; P = .50), and PFS2 (apalutamide+ADT: HR, 0.71; 95% CI, 0.42-1.22; P = .22; placebo+ADT: HR, 0.72; 95% CI, 0.38-1.39; P = .33). In regression analysis, the luminal-basal subtype score was significantly associated with MFS in patients receiving apalutamide+ADT (HR, 2.65; 95% CI, 1.15-6.08; P = .02), whereas GC score was significantly associated with MFS in placebo+ADT recipients (HR, 2.09; 95% CI, 1.02-4.27; P = .04).

Conclusions And Relevance: The findings of this study suggest that the GC score and basal-luminal subtype derived from archived tumor specimens may be biomarkers of response to apalutamide+ADT in the nmCRPC setting. Although overall, the addition of apalutamide to ADT was beneficial, higher-risk and luminal subtypes appeared to benefit most. Obtaining GC scores may be useful for identifying patients for early treatment intensification with apalutamide, and basal-luminal subtyping may be a beneficial approach for patient selection for further treatment intensification in trials combining novel therapies with apalutamide.
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http://dx.doi.org/10.1001/jamaoncol.2021.1463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176389PMC
July 2021

Apalutamide and Overall Survival in Prostate Cancer.

Eur Urol 2021 01 6;79(1):150-158. Epub 2020 Sep 6.

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.

Background: The phase 3 SPARTAN study evaluated apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and prostate-specific antigen doubling time of ≤10 mo. At primary analysis, apalutamide improved median metastasis-free survival (MFS) by 2 yr and overall survival (OS) data were immature.

Objective: We report the prespecified event-driven final analysis for OS.

Design, Setting, And Participants: A total of 1207 patients with nmCRPC (diagnosed by conventional imaging) were randomised 2:1 to apalutamide (240mg/d) or placebo, plus on-going androgen deprivation therapy. After MFS was met and the study was unblinded, 76 (19%) patients still receiving placebo crossed over to apalutamide.

Outcome Measurements And Statistical Analysis: OS and time to cytotoxic chemotherapy (TTChemo) were analysed by group-sequential testing with O'Brien-Fleming-type alpha spending function.

Results And Limitations: At median 52-mo follow-up, 428 deaths had occurred. The median treatment duration was 32.9 mo for apalutamide group and 11.5 mo for placebo group. Median OS was markedly longer with apalutamide versus placebo, reaching prespecified statistical significance (73.9 vs 59.9 mo, hazard ratio [HR]: 0.78 [95% confidence interval {CI}, 0.64-0.96]; p=0.016). Apalutamide also lengthened TTChemo versus placebo (HR: 0.63 [95% CI, 0.49-0.81]; p=0.0002). Discontinuation rates in apalutamide and placebo groups due to progressive disease were 43% and 74%, and due to adverse events 15% and 8.4%, respectively. Subsequent life-prolonging therapy was received by 371 (46%) patients in the apalutamide arm and by 338 (84%) patients in the placebo arm including 59 patients who received apalutamide after crossover. Safety was consistent with previous reports; when adverse events were adjusted for treatment exposure, rash had the greatest difference of incidence between the apalutamide and placebo groups.

Conclusions: Extension of OS with apalutamide compared with placebo conferred impactful benefit in patients with nmCRPC. There was a 22% reduction in the hazard of death in the apalutamide group despite 19% crossover (placebo to apalutamide) and higher rates of subsequent therapy in the placebo group.

Patient Summary: With data presented herein, all primary and secondary study end points of SPARTAN were met; findings demonstrate the value of apalutamide as a treatment option for nonmetastatic castration-resistant prostate cancer.
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http://dx.doi.org/10.1016/j.eururo.2020.08.011DOI Listing
January 2021

Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide.

N Engl J Med 2020 09;383(11):1040-1049

From Institut Gustave Roussy, University of Paris-Saclay, Villejuif (K.F.), and Bayer Healthcare SAS, Loos (M.-A.L.B.) - both in France; Carolina Urologic Research Center, Myrtle Beach, SC (N.S.); Tampere University Hospital and Tampere University, Tampere (T.L.T.), and Orion Pharma, Espoo (A.S., T.S.) - both in Finland; the National Cancer Institute, Vilnius (A.U.), and the Lithuanian University of Health Sciences, Medical Academy, Kaunas (M.J.) - both in Lithuania; Stradins Clinical University Hospital, Riga, Latvia (E.V.); N.N. Alexandrov National Cancer Center of Belarus, Minsk, Belarus (S.P.); Hospital Erasto Gaertner, Curitiba, Brazil (M.L.); the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow (B.A.); Clinical Statistics, Bayer, Berlin (I.K.); Bayer Healthcare, Whippany, NJ (O.P.); and the Massachusetts General Hospital Cancer Center, Boston (M.R.S.).

Background: Darolutamide is a structurally distinct androgen-receptor inhibitor that is approved for the treatment of nonmetastatic, castration-resistant prostate cancer. In the planned primary analysis of a phase 3 trial, the median metastasis-free survival was significantly longer with darolutamide (40.4 months) than with placebo (18.4 months). The data for the analysis of overall survival were immature at the time of the primary analysis.

Methods: In this double-blind, placebo-controlled trial, we randomly assigned 1509 men, in a 2:1 ratio, to receive darolutamide (955 patients) or placebo (554 patients) while they continued to receive androgen-deprivation therapy. After the results of the primary end-point analysis were found to be positive, unblinding of the treatment assignments occurred, and patients in the placebo group were permitted to cross over to receive open-label darolutamide treatment. At the time of this prespecified final analysis, which had been planned to be performed after approximately 240 deaths had occurred, overall survival and all other secondary end points were evaluated.

Results: The median follow-up time was 29.0 months. At the time of unblinding of the data, all 170 patients who were still receiving placebo crossed over to receive darolutamide; 137 patients who had discontinued placebo before unblinding had occurred received at least one other life-prolonging therapy. Overall survival at 3 years was 83% (95% confidence interval [CI], 80 to 86) in the darolutamide group and 77% (95% CI, 72 to 81) in the placebo group. The risk of death was significantly lower, by 31%, in the darolutamide group than in the placebo group (hazard ratio for death, 0.69; 95% CI, 0.53 to 0.88; P = 0.003). Darolutamide was also associated with a significant benefit with respect to all other secondary end points, including the time to first symptomatic skeletal event and the time to first use of cytotoxic chemotherapy. The incidence of adverse events after the start of treatment was similar in the two groups; no new safety signals were observed.

Conclusions: Among men with nonmetastatic, castration-resistant prostate cancer, the percentage of patients who were alive at 3 years was significantly higher among those who received darolutamide than among those who received placebo. The incidence of adverse events was similar in the two groups. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).
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http://dx.doi.org/10.1056/NEJMoa2001342DOI Listing
September 2020

Arthroscopic evaluation of the metacarpophalangeal and metatarsophalangeal joints in horses with parasagittal fractures of the proximal phalanx.

Equine Vet J 2021 Jul 24;53(4):746-751. Epub 2020 Sep 24.

Newmarket Equine Hospital, Newmarket, UK.

Background: Fractures of the proximal phalanx are one of the most common long bone fractures of Thoroughbred racehorses. Although the degree of disruption and damage to the articular surface is generally considered a major prognostic determinant, associated arthroscopic findings have not previously been reported.

Objectives: To describe the metacarpo/metatarsophalangeal (MCP/MTP) joint lesions associated with parasagittal fractures of the proximal phalanx arthroscopically identified at the time of fracture repair and compare radiographic and arthroscopic appearance of complete fractures.

Study Design: Retrospective case series.

Methods: Case records and arthroscopic images of horses with parasagittal fractures of the proximal phalanx admitted to Newmarket Equine Hospital from 2007 to 2017 were analysed.

Results: 81 MCP/MTP joints in 78 horses underwent arthroscopic evaluation concurrent to parasagittal fracture repair. Tears of the joint capsule and dorsal synovial plica were noted in 43 cases. Arthroscopy identified articular incongruity in three horses where fracture displacement was not predicted at all on pre-operative radiographs, and incongruity in additional plane(s) to the radiographic displacement in 14 horses. Concurrent osteochondral fragmentation and disruption of cartilage were present in some cases.

Main Limitations: As a retrospective study, the arthroscopic data available for review were variable. Arthroscopic assessment of fracture reduction and joint congruency was evaluated in all cases but there was variation in the completeness of evaluation of the entire dorsal joint space of the fetlock joint. This may have led to the underestimation of soft tissue lesions in these cases.

Conclusions: Some horses suffering from parasagittal proximal phalanx fractures have concurrent tearing of the joint capsule and/or dorsal plica, which may have relevance in the acute course of events resulting in the development of fractures. Fracture displacement and incongruency at the articular surface cannot confidently be excluded pre-operatively by radiographs alone.
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http://dx.doi.org/10.1111/evj.13343DOI Listing
July 2021

Efficacy and Safety Exposure-Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer.

Clin Cancer Res 2020 09 19;26(17):4460-4467. Epub 2020 Jun 19.

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.

Purpose: To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer.

Patients And Methods: An exploratory exposure-response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration-time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia.

Results: A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure.

Conclusions: The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure-safety analysis supports dose reductions in patients experiencing adverse events.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1041DOI Listing
September 2020

A Phase II Trial of Cabozantinib in Hormone Receptor-Positive Breast Cancer with Bone Metastases.

Oncologist 2020 08 18;25(8):652-660. Epub 2020 Jun 18.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Background: We assessed the antitumor activity of cabozantinib, a potent multireceptor oral tyrosine kinase inhibitor, in patients with hormone receptor-positive breast cancer with bone metastases.

Patients And Methods: In this single-arm multicenter phase II study, patients received an initial starting dose of 100 mg, later reduced to 60 mg, per day. The primary endpoint was the bone scan response rate. Secondary endpoints included objective response rate by RECIST, progression-free survival (PFS), and overall survival (OS).

Results: Of 52 women enrolled, 20 (38%) experienced a partial response on bone scan and 6 (12%) had stable disease. Prior to the first repeat bone scan at 12 weeks, 19 (35%) patients discontinued study treatment because of early clinical progression or unacceptable toxicity. RECIST evaluation based on best overall response by computed tomography revealed stable disease in extraosseous tissues in 26 patients (50%) but no complete or partial responses. In 25 patients with disease control on bone scan at 12 weeks, only 3 (12%) patients developed extraosseous progression. The median PFS was 4.3 months, and median OS was 19.6 months. The most common grade 3 or 4 toxicities were hypertension (10%), anorexia (6%), diarrhea (6%), fatigue (4%), and hypophosphatemia (4%).

Conclusion: Bone scans improved in 38% of patients with metastatic hormone receptor-positive breast cancer and remained stable in an additional 12% for a minimum duration of 12 weeks on cabozantinib. Further investigations should assess the activity of cabozantinib in combination with other hormonal and other breast cancer therapies and determine whether bone scan responses correlate with meaningful antitumor effects. ClinicalTrials.gov identifier. NCT01441947 IMPLICATIONS FOR PRACTICE: Most patients with metastatic hormone receptor-positive (HR+) breast cancer have bone involvement, and many have bone-only disease, which is difficult to evaluate for response. This phase II single-arm study evaluated the clinical activity of the small molecule MET/RET/VEGFR2 inhibitor cabozantinib in patients with metastatic HR+ breast cancer with bone metastases. This study met its primary endpoint, and cabozantinib treatment resulted in a significant bone scan response rate correlating with improved survival. This is the first study to use bone scan response as a primary endpoint in breast cancer. The results support further study of cabozantinib in HR+ breast cancer.
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http://dx.doi.org/10.1634/theoncologist.2020-0127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418363PMC
August 2020

Relationship Between Metastasis-free Survival and Overall Survival in Patients With Nonmetastatic Castration-resistant Prostate Cancer.

Clin Genitourin Cancer 2020 04 6;18(2):e180-e189. Epub 2019 Nov 6.

Division of Hematology and Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.

Background: Metastasis-free survival (MFS) has been shown to be predictive of overall survival (OS) in hormone-sensitive localized prostate cancer. We evaluated the relationship between MFS and OS in nonmetastatic castration-resistant prostate cancer (nmCRPC).

Patients And Methods: A retrospective analysis of 1207 high-risk patients with nmCRPC from the SPARTAN study (clinicaltrials.gov, NCT01946204) was undertaken. Landmark analyses of MFS status at several time points from randomization were performed to minimize guarantee-time bias. Hazard ratio (HR) of death as a function of MFS status was estimated based on a Cox proportional hazards model with 2-sided 95% confidence interval (CI). Estimated HRs were adjusted for stratification factors. Correlation analysis was performed using the Fleischer method.

Results: At all time points, MFS status strongly predicted OS. At landmark time points of 6, 9, and 12 months, risk of death was significantly higher for patients with metastases versus those without (adjusted HR at 6 months = 4.12; 95% CI, 2.60-6.54; P < .0001). MFS was positively correlated with OS based on the Fleischer method (HR, 0.69; 95% CI, 0.69-0.70; P < .0001). Approximately one-half of the variability in OS can be explained by MFS.

Conclusion: Metastasis development, regardless of time point, is associated with significantly greater risk of death in men with high-risk nmCRPC; hence, MFS is predictive of OS.
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http://dx.doi.org/10.1016/j.clgc.2019.10.030DOI Listing
April 2020

Exposure to Heptachlorodibenzo-p-dioxin (HpCDD) Regulates microRNA Expression in Human Lung Fibroblasts.

J Occup Environ Med 2019 12;61 Suppl 12:S82-S89

Department of Environmental Medicine (Dr Woeller, Dr Hopke, Dr Phipps, Dr Utell); Department of Medicine (Dr Thatcher, Dr Sime, Dr Utell); Microbiology and Immunology (Dr Thakar, Mr Cornwell, Dr Phipps), University of Rochester Medical Center, Rochester; Center for Air Resources Engineering and Science, Clarkson University, Potsdam (Dr Hopke), New York; Emory University, Atlanta, Georgia (Dr Smith, Dr Jones); Department of Preventive Medicine and Biostatistics, Uniformed Services University, Bethesda, Maryland (Dr Krahl, Dr Mallon).

Objective: Benzo(ghi)perylene (BghiP) and 1,2,3,4,6,7,8-Heptachlorodibenzo-p-dioxin (HpCDD) were elevated in serum from personnel deployed to sites with open burn pits. Here, we investigated the ability of BghiP and HpCDD to regulate microRNA (miRNA) expression through the aryl hydrocarbon receptor (AHR).

Methods: Human lung fibroblasts (HLFs) were exposed to BghiP and HpCDD. AHR activity was measured by reporter assay and gene expression. Deployment related miRNA were measured by quantitative polymerase chain reaction. AHR expression was depleted using siRNA.

Results: BghiP displayed weak AHR agonist activity. HpCDD induced AHR activity in a dose-dependent manner. Let-7d-5p, miR-103-3p, miR-107, and miR-144-3p levels were significantly altered by HpCDD. AHR knockdown attenuated these effects.

Conclusions: These studies reveal that miRNAs previously identified in sera from personnel deployed to sites with open burn pits are altered by HpCDD exposure in HLFs.
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http://dx.doi.org/10.1097/JOM.0000000000001691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058852PMC
December 2019

Metabolome-Wide Association Study of Deployment to Balad, Iraq or Bagram, Afghanistan.

J Occup Environ Med 2019 12;61 Suppl 12:S25-S34

Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory School of Medicine, Atlanta, Georgia (Drs Go, Smith, Walker, Uppal, Jones); Armed Forces Health Surveillance Center, Silver Spring (Dr Rohrbeck); Occupational and Environmental Medicine Residency Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University, Bethesda (Dr Krahl, Dr Mallon), Maryland; Center for Air Resources Engineering and Science, Clarkston University, Potsdam, New York (Dr Hopke, Dr Utell).

Objective: To use high-resolution metabolomics (HRM) to identify metabolic changes in military personnel associated with deployment to Balad, Iraq, or Bagram, Afghanistan.

Methods: Pre- and post-deployment samples were obtained from the Department of Defense Serum Repository (DoDSR). HRM and bioinformatics were used to identify metabolic differences associated with deployment.

Results: Differences at baseline (pre-deployment) between personnel deployed to Bagram compared with Balad or Controls included sex hormone and keratan sulfate metabolism. Deployment to Balad was associated with alterations to amino acid and lipid metabolism, consistent with inflammation and oxidative stress, and pathways linked to metabolic adaptation and repair. Difference associated with deployment to Bagram included lipid pathways linked to cell signaling and inflammation.

Conclusions: Metabolic variations in pre- and post-deployment are consistent with deployment-associated responses to air pollution and other environmental stressors.
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http://dx.doi.org/10.1097/JOM.0000000000001665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901093PMC
December 2019

Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial.

Target Oncol 2019 10;14(5):527-539

Institut Gustave Roussy, Université Paris-Sud, Villejuif, France.

Background: Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug-drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential-other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected.

Objective: Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC.

Patients And Methods: Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted.

Results: Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one comedication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of comedications with DDI potential, no significant effects on darolutamide pharmacokinetics were identified. Comedications included lipid-modifying agents (34.5%), β-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses.

Conclusions: These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614.
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http://dx.doi.org/10.1007/s11523-019-00674-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797643PMC
October 2019

Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline.

J Clin Oncol 2019 11 18;37(31):2916-2946. Epub 2019 Sep 18.

Medical College of Wisconsin, Milwaukee, WI.

Purpose: The aim of this work is to provide evidence-based guidance on the management of osteoporosis in survivors of adult cancer.

Methods: ASCO convened a multidisciplinary Expert Panel to develop guideline recommendations based on a systematic review of the literature.

Results: The literature search of the 2018 systematic review by the US Preventive Services Task Force in the noncancer population was used as the evidentiary base upon which the Expert Panel based many of its recommendations. A total of 61 additional studies on topics and populations not covered in the US Preventive Services Task Force review were also included. Patients with cancer with metastatic disease and cancer survival outcomes related to bone-modifying agents are not included in this guideline.

Recommendations: Patients with nonmetastatic cancer may be at risk for osteoporotic fractures due to baseline risks or due to the added risks that are associated with their cancer therapy. Clinicians are advised to assess fracture risk using established tools. For those patients with substantial risk of osteoporotic fracture, the clinician should obtain a bone mineral density test. The bone health of all patients may benefit from optimizing nutrition, exercise, and lifestyle. When a pharmacologic agent is indicated, bisphosphonates or denosumab at osteoporosis-indicated dosages are the preferred interventions.
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http://dx.doi.org/10.1200/JCO.19.01696DOI Listing
November 2019

Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer.

Clin Cancer Res 2019 12 11;25(24):7448-7454. Epub 2019 Sep 11.

University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany.

Purpose: Systemic androgen-signaling inhibition added to ongoing androgen-deprivation therapy (ADT) improved clinical outcomes in patients with nonmetastatic castration-resistant prostate cancer without detectable metastases by conventional imaging (nmCRPC). Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) detects prostate cancer with superior sensitivity to conventional imaging, but its performance in nmCRPC remains largely unknown. We characterized cancer burden in high-risk patients with nmCRPC using PSMA-PET.

Experimental Design: We retrospectively included 200 patients with nmCRPC, prostate-specific antigen (PSA) >2 ng/mL, and high risk for metastatic disease [PSA doubling time (PSADT) of ≤10 months and/or Gleason score of ≥8] from six high-volume PET centers. We centrally reviewed PSMA-PET detection rate for pelvic disease and distant metastases (M1). We further evaluated SPARTAN patients stratified by risk factors for PSMA-PET-detected M1 disease.

Results: PSMA-PET was positive in 196 of 200 patients. Overall, 44% had pelvic diseases, including 24% with local prostate bed recurrence, and 55% had M1 disease despite negative conventional imaging. Interobserver agreement was very high (κ: 0.81-0.91). PSA ≥ 5.5 ng/mL, locoregional nodal involvement determined by pathology (pN1), prior primary radiation, and prior salvage radiotherapy independently predicted M1 disease (all < 0.05).

Conclusions: PSMA-PET detected any disease in nearly all patients and M1 disease in 55% of patients previously diagnosed with nmCRPC, including subgroups with PSADT of ≤10 months and Gleason score of ≥8. The value of PSMA-PET imaging for treatment guidance should be tested in future studies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1050DOI Listing
December 2019

Cabozantinib for Progressive Metastatic Castration-resistant Prostate Cancer Following Docetaxel: Combined Analysis of Two Phase 3 Trials.

Eur Urol Oncol 2020 08 30;3(4):540-543. Epub 2018 Nov 30.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.

Two phase 3 trials, COMET-1 and COMET-2, have reported that cabozantinib did not significantly extend overall survival (OS) compared to prednisone and prednisone plus mitoxantrone, respectively, in post-docetaxel patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted a retrospective analysis of a combined data set from these trials to identify a benefit in subsets of patients according to prognostic risk factors. The prognostic ability of factors to predict survival was evaluated using Cox proportional hazards regression models. Evaluation of potential beneficial subsets was performed using interaction terms between factors and cabozantinib. All tests were two-sided and p≤0.05 was considered statistically significant. A total of 1147 post-docetaxel patients with mCRPC were available (1028 from COMET-1 and 119 from COMET-2). The following factors were prognostic for OS: age, disease-free interval, hemoglobin, prostate-specific antigen, alkaline phosphatase, albumin, bone scan lesion area, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, and pain (all p<0.05). There was no interaction effect on survival between cabozantinib versus comparator arms and any prognostic group. After adjusting for prognostic factors, cabozantinib was associated with better OS (hazard ratio 0.80, 95% confidence interval 0.67-0.95; p=0.012). Further investigation of cabozantinib in a better-powered trial or a rational patient population based on a molecular biomarker may be warranted. PATIENT SUMMARY: Two phase 3 trials have reported no survival benefit for cabozantinib, a multitarget oral drug, in metastatic castration-resistant prostate cancer. This analysis pooled 1147 patients from these trials to identify a survival benefit for cabozantinib. This study suggests that further rational development may be justified.
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http://dx.doi.org/10.1016/j.euo.2018.11.006DOI Listing
August 2020

Evaluation of Asymptomatic Microscopic Hematuria by Renal Ultrasound to Detect Upper Tract Malignancy: A 20-Year Experience in a Community Hospital.

Urology 2019 Nov 13;133:34-39. Epub 2019 Jul 13.

Departments of Urology, Gundersen Health System, La Crosse, WI.

Objective: To evaluate the sensitivity of ultrasound imaging in detecting upper urinary tract malignancy in patients with asymptomatic microscopic hematuria (AMH) in an outpatient community setting.

Materials And Methods: A list of all patients who received renal ultrasound for hematuria in our health care system between January 1, 1997 and July 1, 2015 was obtained, and electronic health records were retrospectively reviewed. Patients were excluded for age (<18 years), <3 years follow-up, prior upper tract malignancy, recent urinary tract catheterization, inpatient status, pregnancy, insufficient data, or gross hematuria. The initial ultrasound was considered positive if suspicious findings led to a subsequent diagnosis of an upper tract malignancy. False negatives were determined by electronic medical record follow-up for at least 3 years.

Results: Of the 2138 patients with AMH who met inclusion criteria, ultrasound imaging detected suspicious findings in 9 of 9 patients with renal cell carcinoma and 3 of 3 patients with upper tract urothelial cancer, indicating a sensitivity of 100% and 100%, respectively. Four additional malignancies were diagnosed more than 3 years after the initial evaluation for an incidence rate of 1.6 cases of upper tract malignancy per 10,000 person-years.

Conclusion: The prevalence of upper urinary tract malignancy was low in patients with AMH. Ultrasonography is an appropriate modality for upper tract imaging in the initial evaluation of patients with AMH. Practice guidelines should be updated to reflect the high sensitivity of ultrasound and low risk of upper tract malignancy in patients with AMH.
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http://dx.doi.org/10.1016/j.urology.2019.07.009DOI Listing
November 2019

Inadequate Zinc Intake in India: Past, Present, and Future.

Food Nutr Bull 2019 03;40(1):26-40

1 Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: India has made important strides in reducing nutritional deficiencies over the past several decades. However, for micronutrients such as zinc, previous studies have suggested a worsening situation, contrary to most other dietary indicators. Adding to this burden, higher carbon dioxide (CO) levels of 550 ppm, projected to potentially occur within decades, could reduce the zinc content of many staple crops.

Objective: To assess the historical prevalence of inadequate zinc intake, as well as to estimate the future prevalence attributable to rising CO.

Methods: Seven household food consumption surveys between 1983 and 2012 were used to calculate total dietary zinc, phytate, and absorbable zinc intakes and to assess the prevalence of historic inadequacy in zinc intake. The added nutritional effect of elevated CO on zinc intake is then modeled.

Results: Prevalence of inadequate absorbable zinc intake has increased from 17.1% (15.3%-19.0%) in 1983 to 24.6% (22.3%-27.1%) in 2011-12, corresponding to an additional 82 million people consuming inadequate zinc than would have otherwise if 1983 rates had persisted. These increases in inadequacy have been driven by a relatively constant zinc intake being increasingly insufficient to meet a 5% growth in zinc requirements due to the aging of the population. Reaching 550 ppm CO by 2050 could potentially increase the prevalence of inadequate zinc intake by another 3.9 percentage points (2.1-5.8), corresponding to 65 million additional people having inadequate zinc intake.

Conclusions: The persistently worsening trend for zinc-opposite most other measures of human nutrition-shows that it may pose an ongoing risk unless addressed.
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http://dx.doi.org/10.1177/0379572118825176DOI Listing
March 2019

Mitochondria in precision medicine; linking bioenergetics and metabolomics in platelets.

Redox Biol 2019 04 10;22:101165. Epub 2019 Mar 10.

Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, UK. Electronic address:

Mitochondria possess reserve bioenergetic capacity, supporting protection and resilience in the face of disease. Approaches are limited to understand factors that impact mitochondrial functional reserve in humans. We applied the mitochondrial stress test (MST) to platelets from healthy subjects and found correlations between energetic parameters and mitochondrial function. These parameters were not correlated with mitochondrial complex I-IV activities, however, suggesting that other factors affect mitochondrial bioenergetics and metabolism. Platelets from African American patients with sickle cell disease also differed from controls, further showing that other factors impact mitochondrial bioenergetics and metabolism. To test for correlations of platelet metabolites with energetic parameters, we performed an integrated analysis of metabolomics and MST parameters. Subsets of metabolites, including fatty acids and xenobiotics correlated with mitochondrial parameters. The results establish platelets as a platform to integrate bioenergetics and metabolism for analysis of mitochondrial function in precision medicine.
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http://dx.doi.org/10.1016/j.redox.2019.101165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436140PMC
April 2019

Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.

N Engl J Med 2019 03 14;380(13):1235-1246. Epub 2019 Feb 14.

From Institut Gustave Roussy, Université Paris-Sud, Villejuif, France (K.F.); Carolina Urologic Research Center, Myrtle Beach, SC (N.S.); Tampere University Hospital and University of Tampere, Tampere (T.L.T.), and Orion Pharma, Orion Corporation, Espoo (A.S., T.S.) - all in Finland; National Cancer Institute, Vilnius (A.U.), and Medical Academy, Lithuanian University of Health Sciences, Kaunas (M.J.) - both in Lithuania; Stradins Clinical University Hospital, Riga, Latvia (E.V.); N.N. Alexandrov National Cancer Center of Belarus, Minsk, Belarus (S.P.); Hospital Erasto Gaertner, Curitiba, Brazil (M.L.); National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow (B.A.); Bayer, Berlin (I.K., C.K.); and Massachusetts General Hospital Cancer Center, Boston (M.R.S.).

Background: Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer.

Methods: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks.

Results: In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P<0.001). Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo.

Conclusions: Among men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. The incidence of adverse events was similar for darolutamide and placebo. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).
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http://dx.doi.org/10.1056/NEJMoa1815671DOI Listing
March 2019

Predicting nutrient content of ray-finned fishes using phylogenetic information.

Nat Commun 2018 09 25;9(1):3742. Epub 2018 Sep 25.

Department of Nutrition, Harvard TH Chan School of Public Health, Harvard University, 665 Huntington Ave, Boston, MA, 02115, USA.

Human food and nutrition security is dependent on marine ecosystems threatened by overfishing, climate change, and other processes. The consequences on human nutritional status are uncertain, in part because current methods of analyzing fish nutrient content are expensive. Here, we evaluate the possibility of predicting nutrient content of ray-finned fishes using existing phylogenetic and life history information. We focus on nutrients for which fish are important sources: protein, total fat, omega-3 and omega-6 fatty acids, iron, zinc, vitamin A, vitamin B12, and vitamin D. Our results show that life history traits are weak predictors of species nutrient content, but phylogenetic relatedness is associated with similar nutrient profiles. Further, we develop a method for predicting the nutrient content of 7500+ species based on phylogenetic relationships to species with known nutrient content. Our approach is a cost-effective means for estimating potential changes in human nutrient intake associated with altered access to ray-finned fishes.
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http://dx.doi.org/10.1038/s41467-018-06199-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156416PMC
September 2018

Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2018 10 10;19(10):1404-1416. Epub 2018 Sep 10.

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.

Background: In the SPARTAN trial, addition of apalutamide to androgen deprivation therapy, as compared with placebo plus androgen deprivation therapy, significantly improved metastasis-free survival in men with non-metastatic castration-resistant prostate cancer who were at high risk for development of metastases. We aimed to investigate the effects of apalutamide versus placebo added to androgen deprivation therapy on health-related quality of life (HRQOL).

Methods: SPARTAN is a multicentre, international, randomised, phase 3 trial. Participants were aged 18 years or older, with non-metastatic castration-resistant prostate cancer, a prostate-specific antigen doubling time of 10 months or less, and a prostate-specific antigen concentration of 2 ng/mL or more in serum. Patients were randomly assigned (2:1) to 240 mg oral apalutamide per day plus androgen deprivation therapy, or matched oral placebo plus androgen deprivation therapy, using an interactive voice randomisation system. Permuted block randomisation was used according to the three baseline stratification factors: prostate-specific antigen doubling time (>6 months vs ≤6 months), use of bone-sparing drugs (yes vs no), and presence of local-regional nodal disease (N0 vs N1). Each treatment cycle was 28 days. The primary endpoint was metastasis-free survival. The trial was unblinded in July, 2017. In this prespecified exploratory analysis we assessed HRQOL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires, which we collected at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1-6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter. This study is registered with ClinicalTrials.gov, number NCT01946204.

Findings: Between Oct 14, 2013, and Dec 15, 2016, we randomly assigned 1207 patients to receive apalutamide (n=806) or placebo (n=401). The clinical cutoff date, as for the primary analysis, was May 19, 2017. Median follow-up for overall survival was 20·3 months (IQR 14·8-26·6). FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group; there were similar results for EQ-5D-3L. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for US adult men. Group mean patient-reported outcome scores over time show that HRQOL was maintained from baseline after initiation of apalutamide treatment and was similar over time among patients receiving apalutamide versus placebo. Least-squares mean change from baseline shows that HRQOL deterioration was more apparent in the placebo group.

Interpretation: In asymptomatic men with high-risk non-metastatic castration-resistant prostate cancer, HRQOL was maintained after initiation of apalutamide treatment. Considered with findings from SPARTAN, patients who received apalutamide had longer metastasis-free survival and longer time to symptomatic progression than did those who received placebo, while preserving HRQOL.

Funding: Janssen Research & Development.
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http://dx.doi.org/10.1016/S1470-2045(18)30456-XDOI Listing
October 2018

Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer.

Clin Genitourin Cancer 2018 10 24;16(5):332-340. Epub 2018 Jul 24.

Cliniques Universitaires Saint-Luc Université Catholique de Louvain Brussels, Woluwe-Saint-Lambert, Brussels, Belgium.

Prostate cancer (PC) is the second most common cancer in men and is the fifth leading cause of cancer-related deaths among men. Androgen receptor (AR) signaling plays a key role in PC tumor growth and progression, with androgens stimulating PC proliferation and survival. Castration-resistant PC (CRPC) is characterized by increasing levels of prostate-specific antigen or radiographic progression despite androgen-deprivation therapy (ADT). In most patients, castration resistance results from aberrations in AR or the AR signaling pathway. Up to one-third of patients with localized high-risk PC will have disease progression on local therapy and develop CRPC. This review summarizes the key clinical data, including ongoing trials, for hormonal therapies in CRPC and provides an overview of the clinical development of darolutamide, a novel, nonsteroidal AR antagonist currently in phase III development for the treatment of nonmetastatic CRPC and metastatic hormone-sensitive PC. In phase I/II trials, darolutamide has demonstrated a favorable safety profile, antitumor activity, and significant decreases in prostate-specific antigen in patients with metastatic CRPC. In the phase III ARAMIS (NCT02200614; A Multinational, Randomized, Double-Blind, Placebo-Controlled, Phase III Efficacy and Safety Study of Darolutamide [ODM-201] in Men With High-Risk Non-metastatic Castration-Resistant Prostate Cancer) study, metastasis-free survival is being evaluated in men with nonmetastatic CRPC who will receive ADT in combination with darolutamide or placebo. The ARASENS (NCT02799602; A Randomized, Double-Blind, Placebo Controlled Phase III Study of Darolutamide [ODM-201] Versus Placebo in Addition to Standard Androgen Deprivation Therapy and Docetaxel in Patients With Metastatic Hormone Sensitive Prostate Cancer) study is a placebo-controlled trial assessing whether the addition of darolutamide to ADT and docetaxel significantly prolongs overall survival in men with metastatic hormone-sensitive PC.
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http://dx.doi.org/10.1016/j.clgc.2018.07.017DOI Listing
October 2018

Impact of Historical Changes in Coarse Cereals Consumption in India on Micronutrient Intake and Anemia Prevalence.

Food Nutr Bull 2018 09 1;39(3):377-392. Epub 2018 Aug 1.

7 Harvard T.H. Chan School of Public Health, Harvard University, Cambridge, MA, USA.

Background: Production of rice and wheat increased dramatically in India over the past decades, with reduced proportion of coarse cereals in the food supply.

Objective: We assess impacts of changes in cereal consumption in India on intake of iron and other micronutrients and whether increased consumption of coarse cereals could help alleviate anemia prevalence.

Methods: With consumption data from over 800 000 households, we calculate intake of iron and other micronutrients from 84 food items from 1983 to 2011. We use mixed-effect models to relate state-level anemia prevalence in women and children to micronutrient consumption and household characteristics.

Results: Coarse cereals reduced from 23% to 6% of calories from cereals in rural households (10% to 3% in urban households) between 1983 and 2011, with wide variations across states. Loss of iron from coarse cereals was only partially compensated by increased iron from other cereals and food groups, with a 21% (rural) and 11% (urban) net loss of total iron intake. Models indicate negative association between iron from cereals and anemia prevalence in women. The benefit from increased iron from coarse cereals is partially offset by the adverse effects from antinutrients. For children, anemia was negatively associated with heme-iron consumption but not with iron from cereals.

Conclusions: Loss of coarse cereals in the Indian diet has substantially reduced iron intake without compensation from other food groups, particularly in states where rice rather than wheat replaced coarse cereals. Increased consumption of coarse cereals could reduce anemia prevalence in Indian women along with other interventions.
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http://dx.doi.org/10.1177/0379572118783492DOI Listing
September 2018

Possible Drug-nutraceutical Interaction leading to Unexpected Sequelae after Inguinal Hernia Repair.

Am J Case Rep 2018 Jul 17;19:836-838. Epub 2018 Jul 17.

Department of Surgery, Southern Illinois University (SIU) School of Medicine, Springfield, IL, USA.

BACKGROUND Nutraceutical formulations are an area in which physicians should be increasingly aware of their side effects. This case study shows the adverse effects that ginkgo biloba can have when combined with tadalafil following an inguinal hernia repair. CASE REPORT A 74-year-old male presented for repair of a recurrent inguinal hernia and for which the procedure was performed without complication. Upon follow-up, it was noted that he had significant ecchymosis not only in the inguinal region but in the ventral aspect of his penis. Upon further questioning, he reported that he had been taking ginkgo biloba that was stopped 5 days prior to the operation and restarted postoperative day 1. This, combined with tadalafil, was thought to be the reason for the unexpected induration and ecchymosis at the shaft of the penis. After discontinuing both medications, the ecchymosis and induration did resolve. CONCLUSIONS While ecchymosis and induration are expected in the inguinal region, the appearance of significant ecchymosis and induration down the shaft of the penis was unexpected in this case, and therefore we thought it could be due to nutraceutical use of ginkgo biloba combined with tadalafil, which were started postoperatively.
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http://dx.doi.org/10.12659/AJCR.908117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066968PMC
July 2018

Apalutamide and Metastasis-free Survival in Prostate Cancer.

N Engl J Med 2018 06;378(26):2542

University of California San Francisco, San Francisco, CA

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http://dx.doi.org/10.1056/NEJMc1806189DOI Listing
June 2018

Progress in Nonmetastatic Prostate Cancer.

Authors:
Matthew R Smith

N Engl J Med 2018 06;378(26):2531-2532

From the Massachusetts General Hospital Cancer Center, Boston.

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http://dx.doi.org/10.1056/NEJMe1805733DOI Listing
June 2018

Reply to C. Ren et al.

J Clin Oncol 2018 08 12;36(22):2354-2356. Epub 2018 Jun 12.

Glenn Heller, Memorial Sloan Kettering Cancer Center, New York, NY; Robert McCormack and Thian Kheoh, Janssen Research & Development, Raritan, NJ; Arturo Molina, Janssen Research & Development, Los Angeles, CA; Matthew R. Smith, Massachusetts General Hospital, Boston, MA; Robert Dreicer, University of Virginia Medical School, Charlottesville, VA; Fred Saad, University of Montreal, Montreal, Quebec, Canada; Ronald de Wit, Erasmus Medical Center, Rotterdam, Netherlands; Dana T. Aftab, Exelixis, South San Francisco, CA; Mohammed Hirmand, Medivation, San Francisco, CA; Ana Limon-Carrera, Takeda Oncology, Cambridge, MA; Karim Fizazi, Institut Gustave Roussy, Villejuif, and University of Paris Sud, Orsay, France; Martin Fleisher, Memorial Sloan Kettering Cancer Center, New York, NY; Johann S. de Bono, The Institute of Cancer Research, and The Royal Marsden Hospital, Sutton, Surrey, United Kingdom; and Howard I. Scher, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, NY.

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http://dx.doi.org/10.1200/JCO.2018.78.2672DOI Listing
August 2018

Integrative metabolomics and transcriptomics signatures of clinical tolerance to Plasmodium vivax reveal activation of innate cell immunity and T cell signaling.

Redox Biol 2018 07 11;17:158-170. Epub 2018 Apr 11.

Department of Medicine, School of Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322-1047, USA. Electronic address:

Almost invariably, humans become ill during primary infections with malaria parasites which is a pathology associated with oxidative stress and perturbations in metabolism. Importantly, repetitive exposure to Plasmodium results in asymptomatic infections, which is a condition defined as clinical tolerance. Integration of transcriptomics and metabolomics data provides a powerful way to investigate complex disease processes involving oxidative stress, energy metabolism and immune cell activation. We used metabolomics and transcriptomics to investigate the different clinical outcomes in a P. vivax controlled human malaria infection trial. At baseline, the naïve and semi-immune subjects differed in the expression of interferon related genes, neutrophil and B cell signatures that progressed with distinct kinetics after infection. Metabolomics data indicated differences in amino acid pathways and lipid metabolism between the two groups. Top pathways during the course of infection included methionine and cysteine metabolism, fatty acid metabolism and urea cycle. There is also evidence for the activation of lipoxygenase, cyclooxygenase and non-specific lipid peroxidation products in the semi-immune group. The integration of transcriptomics and metabolomics revealed concerted molecular events triggered by the infection, notably involving platelet activation, innate immunity and T cell signaling. Additional experiment confirmed that the metabolites associated with platelet activation genes were indeed enriched in the platelet metabolome.
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http://dx.doi.org/10.1016/j.redox.2018.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007173PMC
July 2018

Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.

N Engl J Med 2018 Apr 8;378(15):1408-1418. Epub 2018 Feb 8.

From the Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (M.R.S.); Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montreal (F.S.); Guy's, King's and St. Thomas' Hospitals, Great Maze Pond, London (S.C.); Georges Pompidou Hospital, Paris (S.O.); University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany (B.A.H.); Veterans Affairs Portland Health Care System, Portland, and Knight Cancer Institute, Oregon Health and Science University, Portland (J.N.G.); Spanish National Cancer Research Center, Madrid, and Hospitales Universitarios Virgen de la Victoria y Regional, Institute of Biomedical Research in Malaga, Malaga - both in Spain (D.O.); Centre for Personalised Nanomedicine, University of Queensland, Brisbane, Australia (P.N.M.); St. Mary's Hospital of Catholic University, Seoul, South Korea (J.Y.L.); Yokohama City University Medical Center, Yokohama, Japan (H.U.); Janssen Research and Development, Los Angeles (A.L.-G., G.C.T., B.M.E., Y.S., Y.C.P., W.R.R., M.K.Y.); and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco (E.J.S.).

Background: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis.

Methods: We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death.

Results: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%).

Conclusions: Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).
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http://dx.doi.org/10.1056/NEJMoa1715546DOI Listing
April 2018

An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer.

Cancer Discov 2018 03 4;8(3):288-303. Epub 2018 Jan 4.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTC score identifies a high-risk population with poor overall survival (HR = 6.0; = 0.01) and short radiographic progression-free survival (HR = 3.2; = 0.046). Expression of in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTC score predicts microscopic dissemination to seminal vesicles and/or lymph nodes ( < 0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer. There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342192PMC
March 2018
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