Data Driven Identification of Injury Risk Factors During Expansion on Irish Dairy Farms.

OBJECTIVES: This paper sought to determine risk factors of occupational injury in the Irish dairy farming sector and to estimate the roles of both dairying expansion and the discipline of agricultural extension in influencing reducing injury occurrence. METHODS: Data for this study was obtained via the Irish National Farm Survey (NFS). In total, 260 farm (83.6% of NFS dairy farm sample) workplace injury survey questionnaires were completed by NFS recorders by interviewing principal farm operators for year 2017. Injury survey data was analysed for 48 variables in conjunction with NFS core farm socio-economic, physical and financial data. Additionally, core data from 2010 for 78.5% of farms surveyed in 2017 was included in the study. Data were analysed using a three-step statistical testing process which met all Binary Logistic Regression assumptions. RESULTS: The study found that dairy farms had a higher farm workplace occupational injury level compared to a previous study. The study data indicates occurrence of elevated injury levels on farms which expanded and which were intensively managed from a milk production perspective. Farm expansion was associated with increased labor units used and increased investment per hectare. The study also found that use of extension services and farm discussion group participation were not associated with injury occurrence. CONCLUSIONS: This study demonstrates how a retrospective farm workplace occupational injury survey of Irish dairy farms, analysed in combination with farm business data can be used to identify injury risk factors, including those associated with production expansion. Irish dairy farms have a heightened farm workplace occupation injury level while dairy production expansion increased injury levels. Extension engagement did not influence on injury levels. Approaches to improve farm safety on dairy farms are outlined.

Incretins play an important role in FFA4/GPR120 regulation of glucose metabolism by GW-9508.

AIMS: To assess the role of GPR120 in glucose metabolism and incretin regulation from enteroendocrine L- and K-cells with determination of the cellular localisation of GPR120 in intestinal tissue and clonal Glucagon-Like Peptide-1 (GLP-1)/Gastric Inhibitory Polypeptide (GIP) cell lines. MAIN METHODS: Anti-hyperglycaemic, insulinotropic and incretin secreting properties of the GPR120 agonist, GW-9508 were explored in combination with oral and intraperitoneal glucose tolerance tests (GTT) in lean, diabetic and incretin receptor knockout mice. Cellular localisation of GPR120 was assessed by double immunofluorescence. KEY FINDINGS: Compared to intraperitoneal injection, oral administration of GW-9508 (0.1 µmol/kg body weight) together with glucose reduced the glycaemic excursion by 22-31 % (p < 0.05-p < 0.01) and enhanced glucose-induced insulin release by 30 % (p < 0.01) in normal mice. In high fat fed diabetic mice, orally administered GW-9508 lowered plasma glucose by 17-27 % (p < 0.05-p < 0.01) and augmented insulin release by 22-39 % (p < 0.05-p < 0.001). GW-9508 had no effect on the responses of GLP-1 receptor knockout mice and GIP receptor knockout mice. Consistent with this, oral GW-9508 increased circulating total GLP-1 release by 39-44 % (p < 0.01) and total GIP by 37-47 % (p < 0.01-p < 0.001) after 15 and 30 min in lean NIH Swiss mice. Immunocytochemistry demonstrated GPR120 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. SIGNIFICANCE: GPR120 is expressed on intestinal L- and K-cells and stimulates GLP-1/GIP secretory pathways involved in mediating enhanced insulin secretion and improved glucose tolerance, following oral GW-9508. These novel data strongly support the development of potent and selective GPR120 agonists as an effective therapeutic approach for diabetes.

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis.

PURPOSE: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. METHODS AND MATERIALS: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. RESULTS: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38). CONCLUSIONS: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Current and Future Therapies for Pancreatic Ductal Adenocarcinoma.

Pancreatic cancer is one of the leading causes of cancer-related death worldwide. This is due to delayed diagnosis and resistance to traditional chemotherapy. Delayed diagnosis is often due to the broad range of non-specific symptoms that are associated with the disease. Resistance to current chemotherapies, such as gemcitabine, develops due to genetic mutations that are either intrinsic or acquired. This has resulted in poor patient prognosis and, therefore, justifies the requirement for new targeted therapies. A synthetic lethality approach, that targets specific loss-of-function mutations in cancer cells, has shown great potential in pancreatic ductal adenocarcinoma (PDAC). Immunotherapies have also yielded promising results in the development of new treatment options, with several currently undergoing clinical trials. The utilisation of monoclonal antibodies, immune checkpoint inhibitors, adoptive cell transfer, and vaccines have shown success in several neoplasms such as breast cancer and B-cell malignancies and, therefore, could hold the same potential in PDAC treatment. These therapeutic strategies could have the potential to be at the forefront of pancreatic cancer therapy in the future. This review focuses on currently approved therapies for PDAC, the challenges associated with them, and future directions of therapy including synthetically lethal approaches, immunotherapy, and current clinical trials.

Circulating Nucleic Acids as Novel Biomarkers for Pancreatic Ductal Adenocarcinoma.

Despite considerable advancements in the clinical management of PDAC it remains a significant cause of mortality. PDAC is often diagnosed at advanced stages due to vague symptoms associated with early-stage disease and a lack of reliable diagnostic biomarkers. Late diagnosis results in a high proportion of cases being ineligible for surgical resection, the only potentially curative therapy for PDAC. Furthermore, a lack of prognostic biomarkers impedes clinician's ability to properly assess the efficacy of therapeutic interventions. Advances in our ability to detect circulating nucleic acids allows for the advent of novel biomarkers for PDAC. Tumor derived circulating and exosomal nucleic acids allow for the detection of PDAC-specific mutations through a non-invasive blood sample. Such biomarkers could expand upon the currently limited repertoire of tests available. This review outlines recent developments in the use of molecular techniques for the detection of these nucleic acids and their potential roles, alongside current techniques, in the diagnosis, prognosis and therapeutic governance of PDAC.

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

The risk of death from prostate cancer in men with Gleason score 3+4 prostate cancer treated using brachytherapy with or without a short course of androgen deprivation therapy.

OBJECTIVE: We evaluated whether intermediate-risk factors, in addition to age, were associated with risk of prostate cancer-specific mortality (PCSM) among men with Gleason 3+4 prostate cancer. MATERIALS AND METHODS: We conducted a prospective cohort study of 1,920 men with Gleason 3+4 adenocarcinoma of the prostate who received brachytherapy (BT) or BT and a median of 4 months of androgen deprivation therapy (ADT). Separate multivariable Fine and Gray competing risks regression models among men treated with BT or BT and ADT were used to assess whether percentage of positive biopsies (PPB), cT2b-T2c stage, prostate-specific antigen (PSA) of 10.1-20.0 ng/ml, and age >70 years (median) were associated with risk of PCSM after adjustment for comorbidity. RESULTS: After median follow-up of 7.8 years, 284 men (14.8%) had died (31 from prostate cancer). For BT alone, increasing PPB, PSA of 10.1-20.0 vs. 4.0-10.0 ng/mL, and age >70 vs. ≤70 were significantly associated with increased risk of PCSM (adjusted hazard ratio 1.015, 95% confidence interval 1.000-1.031, P = 0.048; 5.55, 2.01-15.29, P<0.001; and 3.66, 1.16-11.56, P = 0.03, respectively). The respective results for BT and ADT were 1.009, 0.987-1.031, P = 0.44; 4.17, 1.29-13.50, P = 0.02; and 3.74, 0.87-16.05, P = 0.08. CONCLUSION: Among men with Gleason score 3+4 prostate cancer treated with BT, the risk of PCSM was elevated in those with PSA of 10.1-20.0 ng/mL and possibly age >70 years, despite the addition of ADT. Should these findings be validated in future studies, then advanced imaging and targeted biopsy of suspicious areas should be investigated in an effort to personalize treatment and minimize the risk of PCSM in these men.

Performance of a Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Derived Risk-Stratification Tool for High-risk and Very High-risk Prostate Cancer.

Importance: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear. Objectives: To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools. Design, Setting, and Participants: This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021. Exposures: Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy. Main Outcomes and Measures: PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index. Results: Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database. Conclusions and Relevance: These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.

Long-term outcomes of a prospective randomized trial of 131Cs/125I permanent prostate brachytherapy.

PURPOSE: Iodine-125 (125I) is the most commonly used isotope for prostate brachytherapy (BT). Cesium-131 (131Cs) has a higher dose rate and shorter dose delivery time resulting in decreased duration of acute urinary morbidity. Long-term data suggest excellent oncologic outcomes; it is not known how outcomes compare. A prospective randomized trial comparing the two isotopes was initiated. MATERIALS AND METHODS: Patients with low- or intermediate-risk disease were treated with a BT in a single outpatient facility. Prescription dose was 144 Gy for 125I and 115 Gy for 131Cs. Androgen deprivation or supplemental EBRT was not allowed. The primary study objective was comparison of the mean EPIC Urinary Domain Score. Secondary objective was biochemical relapse-free survival (BRFS) comparison. Time-to-event for all outcomes of interest was measured from implant date. RESULTS: One hundred forty men were enrolled; 81.4% were low-risk and 18.6% were intermediate-risk. The median followup was 97 months. Urinary and sexual health-related quality of life did not differ between isotopes at any recorded time point. At 2 months after implantation, bowel health-related quality of life was worse with 125I; however, this difference was lost at subsequent time points. The 9-year BRFS was 87.2% and 84.0% for the 125I and 131Cs group, respectively (p = 0.897). There was no statistically significant difference in BRFS based on initial T stage, PSA, or Gleason score. CONCLUSIONS: Short- and long-term urinary, sexual, and bowel quality of life, as well as long-term biochemical control were comparable between 125I and 131Cs. This report therefore supports the continued use of 131Cs as an effective and comparable alternative isotope.

Pharmacy Services Reboot Roadmap: Resiliency During the COVID-19 Pandemic.

Description Planning for resumption of patient care services during and following the impact of novel coronavirus disease-2019 (COVID-19) while controlling costs are essential for pharmacy services resiliency. Implementation of a pharmacy services reboot roadmap across a 179 hospital health-system is described. The roadmap encompassed eight key areas: pharmacy leadership, staffing and scheduling, clinical pharmacy services, medication safety, medication supply, regulatory and compliance, team support opportunities, and financial stewardship. A supporting checklist and volume-based staffing plan are included as examples to assist pharmacy leaders in planning optimal pharmacy services support as patient volumes increase, particularly in the emergency department, surgical services and critical care areas. Resiliency strategies are provided as tangible planning considerations to assess the current status of, and prepare for, future operational and clinical pharmacy practice needs to support optimal patient care.

Long-term biochemical outcomes using cesium-131 in prostate brachytherapy.

PURPOSE: Long-term outcomes reveal equivalent biochemical outcomes with low-dose-rate (LDR) brachytherapy (BT) compared with radical prostatectomy and external-beam radiotherapy for the management of prostate cancer. Iodine-125, the most commonly used isotope, may be associated with long-term urinary consequences. Cesium-131 (131Cs) has a higher dose rate and shorter dose delivery time, predicting a shorter duration of urinary morbidity. We report our institution's high-volume experience and the most mature data to date on outcomes with 131Cs prostate BT. METHODS AND MATERIALS: 571 men (median age: 65.38 years) with low (55%)-, intermediate (36%)-, and high-risk disease (9%) received monobrachytherapy, dual-modality, or trimodality using 131Cs at a single institution. Risk groups were defined according to the National Comprehensive Cancer Network definition. Median prescription dose for definitive LDR-BT and LDR-BT boost was 115 Gy and 70 Gy, respectively. Median initial PSA was 6.1 ng/mL (IQR: 4.6-8.7). RESULTS: Median followup time was 5 years. 5/7-year overall survival for low-, intermediate-, and high-risk patients was 96.9%/96/9%, 92.8%/89.7%, and 95.8%/87.1%, respectively (p = 0.02). 5/7-year freedom from biochemical failure for low-, intermediate-, and high-risk patients was 98.5%/96.3%, 94.1%/86.4%, and 93.2%/74.5%, respectively (p < 0.01). 5/7-year prostate cancer -specific survival was 100%/100%, 99.3%/99.3%, and 98.0%/98.0% for low-, intermediate-, and high-risk patients, respectively (p < 0.01). CONCLUSIONS: 131Cs is a viable alternative isotope for prostate brachytherapy for organ-confined disease. Long-term biochemical control and survival outcomes are excellent and on par with those attained with the use of 125I or 103Pd. This report therefore supports the continued use of 131Cs as an effective and comparable alternative isotope.

Zinc-induced activation of GPR39 regulates glucose homeostasis through glucose-dependent insulinotropic polypeptide secretion from enteroendocrine K-cells.

The role of Zn2+-sensing receptor GPR39 on glucose homeostasis and incretin regulation was assessed in enteroendocrine L- and K-cells. Anti-hyperglycaemic, insulinotropic and incretin secreting properties of Zn2+ were explored in normal, diabetic and incretin receptor knockout mice. Compared to intraperitoneal injection, oral administration of Zn2+ (50 µmol/kg body weight) with glucose (18 mmol/kg) in lean mice reduced the glycaemic excursion by 25-34% (p < 0.05-p < 0.001) and enhanced glucose-induced insulin release by 46-48% (p < 0.05-p < 0.01). In diabetic mice, orally administered Zn2+ lowered glucose by 24-31% (p < 0.01) and augmented insulin release by 32% (p < 0.01). In glucagon like peptide-1 (GLP-1) receptor knockout mice, Zn2+ reduced glucose by 15-28% (p < 0.05-p < 0.01) and increased insulin release by 35-43% (p < 0.01). In contrast Zn2+ had no effect on responses of glucose-dependent insulinotropic polypeptide (GIP) receptor knockout mice. Consistent with this, Zn2+ had no effect on circulating total GLP-1 whereas GIP release was stimulated by 26% (p < 0.05) in lean mice. Immunocytochemistry demonstrated GPR39 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Zn2+ had a direct effect on GIP secretion from pGIPneo STC-1 cells, increasing GIP secretion by 1.3-fold. GPR39 is expressed on intestinal L- and K-cells, and stimulated GIP secretion plays an integral role in mediating enhanced insulin secretion and glucose tolerance following oral administration of Zn2+. This suggests development of potent and selective GPR39 agonists as a therapeutic approach for diabetes.

Surgery vs Radiotherapy in the Management of Biopsy Gleason Score 9-10 Prostate Cancer and the Risk of Mortality.

Importance: It is unknown how treatment with radical prostatectomy (RP) and adjuvant external beam radiotherapy (EBRT), androgen deprivation therapy (ADT), or both (termed MaxRP) compares with treatment with EBRT, brachytherapy, and ADT (termed MaxRT). Objective: To investigate whether treatment of Gleason score 9-10 prostate cancer with MaxRP vs MaxRT was associated with prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) risk. Design, Setting, and Participants: The study cohort comprised 639 men with clinical T1-4,N0M0 biopsy Gleason score 9-10 prostate cancer. Between February 6, 1992, and April 26, 2013, a total of 80 men were consecutively treated with MaxRT at the Chicago Prostate Cancer Center, and 559 men were consecutively treated with RP and pelvic lymph node dissection at the Martini-Klinik Prostate Cancer Center. Follow-up started on the day of prostate EBRT or RP and concluded on October 27, 2017. Exposures: Of the 559 men managed with RP and pelvic lymph node dissection, 88 (15.7%) received adjuvant EBRT, 49 (8.8%) received ADT, and 50 (8.9%) received both. Main Outcomes and Measures: Treatment propensity score-adjusted risk of PCSM and ACM and the likelihood of equivalence of these risks between treatments using a plausibility index. Results: The cohort included 639 men, with a mean (SD) age of 65.83 (6.52) years. After median follow-ups of 5.51 years (interquartile range, 2.19-6.95 years) among 80 men treated with MaxRT and 4.78 years (interquartile range, 4.01-6.05 years) among 559 men treated with RP-containing treatments, 161 men had died, 106 (65.8%) from prostate cancer. There was no significant difference in the risk of PCSM (adjusted hazard ratio, 1.33; 95% CI, 0.49-3.64; P = .58) and ACM (adjusted hazard ratio, 0.80; 95% CI, 0.36-1.81; P = .60) when comparing men who underwent MaxRP vs MaxRT, with plausibility indexes for equivalence of 76.75% for the end point of the risk of PCSM and 77.97% for the end point of the risk of ACM. Plausibility indexes for all other treatment comparisons were less than 63%. Conclusions and Relevance: Results of this study suggest that it is plausible that treatment with MaxRP or MaxRT for men with biopsy Gleason score 9-10 prostate cancer can lead to equivalent risk of PCSM and ACM.

Long-term outcomes analysis of low-dose-rate brachytherapy in clinically T3 high-risk prostate cancer.

PURPOSE: The available data demonstrating that superiority of LDR brachytherapy (LDR-BT) boost in high-risk prostate cancer patients under represents patients with extracapsular extension (T3a) and/or seminal vesicle invasion (T3b) have been limited. We report long-term clinical outcomes data for patients with cT3a/b disease receiving LDR-BT. METHODS AND MATERIALS: Ninety-nine men (median age: 69.4 years) with cT3a/bN0M0 high-risk prostate adenocarcinoma received definitive LDR-BT or LDR-BT boost after external beam radiation therapy (EBRT) at a single institution between 1998 and 2007. About 86% of patients received androgen deprivation therapy. Freedom from biochemical failure (FFBF), prostate cancer-specific survival (PCSS), and overall survival (OS) was calculated using the Kaplan-Meier method with the Phoenix definition used as definition of failure. Cox regression analysis was used to compare outcomes between clinical stage, initial PSA, Gleason Score, and percent core positive rate. RESULTS: With a median followup of 7 years, 7-year rate of FFBF, PCSS, and OS for the entire cohort was 65.2% (±5.6%), 90.1% (±3.6%), and 77.9% (±4.7%), respectively. LDR-BT boost patients achieved a 7-year FFBF rate of 73.5 (±6.5%). No significant difference in outcomes was present between T3a or T3b disease, Gleason score, iPSA stratification and percent core positive rates. CONCLUSIONS: LDR-BT, primarily as a boost in conjunction with ADT and EBRT, is not only feasible, but also highly effective in men with cT3a and cT3b high-risk prostate cancer resulting in excellent biochemical control and survival outcomes. LDR-BT boost implantation of patients should be strongly considered for cT3 patients given the merits of trimodality care.

Tissue expression of DPP-IV in obesity-diabetes and modulatory effects on peptide regulation of insulin secretion.

Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent an important class of glucose-lowering drug for type 2 diabetes. DPP-4 enzyme activity has been observed to be significantly altered in type 2 diabetes. Here, the role of DPP-4 was examined in a high fat fed (HFF) mouse model of insulin resistance. HFF mice had an increased bodyweight (p < .01), were hyperglycaemic (p < .01) and hyperinsulinaemic (p < .05). Compared to normal diet, HFF mice exhibited increased plasma DPP-4 activity (p < .01). Tissue distribution patterns in lean and HFF mice demonstrated highest levels of DPP-4 activity in lung (20-26 µmol/min/mg protein) and small intestine (13-14 µmol/min/mg protein), and lowest activity in the spleen (3.8 µmol/min/mg protein). Modulation of DPP-4 activity by high fat feeding was observed in several tissues with increases in the lung (p < .05), liver (p < .05), kidney (p < .05) and pancreas (p < .05). With a high fat diet, DPP-4 gene expression was upregulated in the liver (p < .001) and downregulated in the pancreas (p < 0.001) and small intestine (p < .001). Immunohistochemical analysis revealed increased DPP-4 immunostaining localised primarily in the pancreatic islets of HFF mice (p < .01) with no change in islet GLP-1 expression. Treatment of HFF mice with metformin for 21-days resulted in inhibition of circulating DPP-4 activity (p < .05), decreased blood glucose (p < .05) and increased GLP-1 gene expression (p < .001). These data indicate that DPP-4 is modulated in a tissue specific manner and is dependent on physiological conditions such as hyperglycaemia and insulin resistance, suggesting a significant role in disorders such as diabetes.

Comorbidity and the Receipt of Curative Therapy for Favorable-risk Prostate Cancer Prior to and Following the Publication of PIVOT.

The publication of the randomized Prostate Cancer Intervention Versus Observation Trial (PIVOT) in July 2012, in which men with favorable-risk prostate cancer (PCa) were not found to benefit from radical prostatectomy, had the potential to shift PCa practice patterns. Using a prospectively assembled database of 5398 men with low-risk or favorable intermediate-risk PCa selected for curative treatment with brachytherapy in the years preceding and the year following the publication of PIVOT, we evaluated the odds of receiving curative treatment after adjusting for risk group (favorable intermediate vs low), race (black, Hispanic, or other), number of cardiometabolic comorbidities, and age. Following publication, the receipt of curative treatment was significantly lower (adjusted odds ratio [AOR]: 0.40; 95% confidence interval [CI], 0.16-0.99; p=0.05) among men with at least two cardiometabolic comorbidities, in contrast to the increasing trend (p=0.02) noted prior to PIVOT. Among black men, a subgroup at risk for occult high-grade disease, the odds of receiving curative treatment increased after PIVOT (AOR: 1.55; 95% CI, 1.06-2.26; p=0.02). These observations suggest that PIVOT's publication appropriately contributed to decreasing the use of curative treatment in men unlikely to benefit. PATIENT SUMMARY: The Prostate Intervention Versus Observation Trial (PIVOT) showed that radical prostatectomy did not benefit men with favorable-risk prostate cancer. Following the publication of PIVOT, the selection of men with multiple medical issues for curative treatment declined, whereas treatment of men at high risk of having aggressive prostate cancer increased.

Brachytherapy monotherapy may be sufficient for a subset of patients with unfavorable intermediate risk prostate cancer.

PURPOSE/OBJECTIVE(S): Brachytherapy (BT) monotherapy is a well-established treatment modality for favorable intermediate risk (FIR) prostate cancer. However, patients with unfavorable intermediate risk (UIR) disease are often recommended trimodality therapy involving BT, androgen deprivation therapy (ADT), and external beam radiation therapy (EBRT). We sought to investigate the relative benefit of supplemental therapies (ADT and/or EBRT) for FIR and UIR prostate cancer in a large dataset. MATERIALS/METHODS: We identified 3,723 patients with intermediate risk prostate cancer treated with BT between 1997 and 2013, including 1,989 and 1,734 patients with FIR and UIR disease, respectively. For the FIR cohort, Fine and Gray's competing risks regression model was used to evaluate whether there was a difference in prostate cancer specific mortality (PCSM) between BT vs. BT + supplemental therapy (ADT, EBRT, or both). For the UIR cohort, this regression model was used to evaluate whether supplemental ADT, EBRT, or both decreased PCSM beyond BT alone. Both regression models were adjusted for clinical and treatment-related factors. RESULTS: The median follow-up periods were 7.7 years (interquartile range: 5.4-10.5) for the FIR cohort and 7.8 years (interquartile range: 5.3-10.6) for the UIR cohort. For the FIR cohort, there was no difference in PCSM between BT monotherapy vs. BT + supplemental therapy (adjusted hazard ratio [AHR] = 1.70; 95% CI: 0.46-6.29; P = 0.43). For the UIR cohort, supplemental EBRT (AHR = 2.66; 95% CI: 1.12-6.34; P = 0.03), ADT (AHR = 0.96; 95% CI: 0.38-2.43; P = 0.93), or both (AHR = 1.46; 95% CI: 0.42-5.01; P = 0.55) were not associated with improved PCSM compared with BT alone. CONCLUSION: In our analysis, supplemental therapies did not offer an improvement in PCSM compared with BT alone for FIR or UIR prostate cancers. Further prospective clinical trials are required to determine whether BT monotherapy may be sufficient for a subset of patients with UIR disease.

Infantile Epileptic Encephalopathy Associated With SCN2A Mutation Responsive to Oral Mexiletine.

BACKGROUND: Genetic alterations are significant causes of epilepsy syndromes; especially early-onset epileptic encephalopathies and voltage-gated sodium channelopathies are among the best described. Mutations in the SCN2A subunit of voltage-gated sodium channels have been associated with benign familial neonatal-infantile seizures, generalized epilepsy febrile seizures plus, and an early-onset infantile epileptic encephalopathy. METHOD: We describe two infants with medically refractory seizures due to a de novo SCN2A mutation. RESULTS: The first child responded to intravenous lidocaine with significant reduction in seizure frequency and was successfully transitioned to enteral mexiletine. Mexiletine was subsequently used in a second infant with reduction in seizure frequency. CONCLUSION: Class 1b antiarrhythmic agents, lidocaine and mexiletine, may be useful in infants with medically refractory early infantile epileptic encephalopathy secondary to mutations in SCN2A.