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Background Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer. Patients and Methods This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes’ B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes’ B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes’ B2 colon cancer with no additional chemotherapy. Results From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03–20.3 years). Among patients with Dukes’ B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes’ B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

differential rates of mutations in primary and metastatic prostate cancers

JAK1 mutation frequency across tumors

patient and tumor characteristics

characterization of frequently mutated genes in MSI-H

Purpose:In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance.Patients and Methods:In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate.Results:Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: n = 22; 300 mg: n = 12; 400 mg: n = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n = 1; 300 mg: n = 2, 400 mg: n = 2). No new or unexpected adverse events or evidence of drug–drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2–71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%.Conclusions:Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.

Treatment-Related Adverse Events Occurring in {greater than or equal to}1 Patient Treated With Pembrolizumab plus Ipilimumab

LLQ=15.6 mg/mL. LLQ shown by horizontal reference line. N=1 for 400 mg GSK2636771 plus 160 mg enzalutamide 160 mg escalation cohort. LLQ, lower limit of quantification.

Supplementary Table 1. PCWG2 criteria for progression.

Dashed lines represent 95% confidence intervals. PCWG2, Prostate Cancer Working Group 2; PSA, prostate-specific antigen.

Supplementary methods: PTEN screening

B: The dashed line represents 5 CTCs/7.5 mL. C: White circles indicate the location of the lymph node lesion with documented PR, demonstrating a 46% reduction in size from baseline. CT, computerized tomography; CTC, circulating tumor cells; PR, partial response; PSA, prostate-specific antigen.

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.

Supplementary Table 2. Summary of serious adverse events.

Purpose: In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance. Patients and Methods: In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate. Results: Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: n = 22; 300 mg: n = 12; 400 mg: n = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n = 1; 300 mg: n = 2, 400 mg: n = 2). No new or unexpected adverse events or evidence of drug–drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2–71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%. Conclusions: Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.

In a large academic medical center, patient requests from the community and internal referrals for evaluation of suspected hypermobility conditions were being denied consultation because services specific to this condition were not available. We identified this gap and developed a comprehensive evaluation for this unique patient population. The objective of this paper is to demonstrate a solution for improving outcomes in a neglected patient population by establishing an innovative outpatient clinic specifically tailored for patients with EDS.We describe the lessons learned on establishing a specialty clinic for treating patients with hypermobility syndromes including hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobile syndrome disorder (HSD). Findings were collected from a patient focus group that was instrumental in understanding common care gaps. We document the firsthand perspective of three patients presenting with hypermobility accompanied by joint pain and denote the complicated state of healthcare in recognizing and treating this condition. A summary of patient demographics and characteristics was collected from patients seen in the clinic from November 14, 2019 to April 13, 2021.The firsthand accounts illustrate the challenges faced in treating this condition and the need for, and success of, this clinic using a coordinated care model. Demographics reveal a primarily white female population under the age of 50 with many comorbidities. Genetic testing was largely negative, with more patients diagnosed with HSD than hEDS.Our shared experience of launching a successful EDS clinic may assist other clinicians in establishing similar care models.

BACKGROUND: Home telemonitoring has been used with discharged patients in an attempt to reduce 30-day readmissions with mixed results. OBJECTIVE: To assess whether home 30-day telemonitoring after discharge for patients at high risk of readmission would reduce readmissions or mortality. DESIGN: Prospective, randomized controlled trial. PATIENTS: We compared 30-day readmission rates and mortality for patients at high risk for readmission who received home telemonitoring versus standard care between November 1, 2014, and November 30, 2018, in 2 tertiary care hospitals. INTERVENTIONS: The intervention group received home-installed equipment to measure blood pressure, heart rate, pulse oximetry, weight if heart failure was present, and glucose if diabetes was present. Results were transmitted daily and reviewed by a nurse. Both groups received standard care. MAIN MEASURES: The primary outcome was a composite end point of hospital readmission or death within 30 days after discharge. The secondary outcome was an emergency department visit within 30 days after discharge. KEY RESULTS: A total of 1380 participants (mean [SD] age, 66 [14] years; 722 [52.3%] men and 658 [47.7%] women) participated in this study. Using a modified intention-to-treat analysis, the risk of readmission or death within 30 days among patients at high readmission risk was 23.7% (137/578) in the control group and 18.2% (87/477) in the telemonitoring group (absolute risk difference, − 5.5% [95% CI, − 10.4 to − 0.6%]; relative risk, 0.77 [95% CI, 0.61 to 0.98]; P = .03). Emergency department visits occurred within 30 days after discharge in 14.2% (81/570) of patients in the control group and 8.6% (40/464) of patients in the telemonitoring group (absolute risk difference, − 5.6% [95% CI, − 9.4 to − 1.8%]; relative risk, 0.61 [95% CI, 0.42 to 0.87]; P = .005). CONCLUSIONS: Thirty days of postdischarge telemonitoring may reduce readmissions of high-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02136186. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-020-06589-1.

Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer. Tumors from 1,027 patients with advanced prostate cancer that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27-gene panel) and co-occurring mutations in select canonical prostate cancer pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with antitumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA-repair pathways, (2) intrinsic prostate cancer signaling pathways that may prevent antitumor immunity, and (3) distinct genomic differences between localized and metastatic prostate cancer. These results lend support that genomic profiling for advanced prostate cancer may identify actionable targets not routinely used in the current metastatic paradigm.

Objectives This study describes the specific threats of harm to others that led to the use of the Baker Act, the Florida involuntary hold act for emergency department (ED) evaluations. The study also summarizes patient demographics, concomitant psychiatric diagnoses, and emergent medical problems. Methods This is a retrospective review of 251 patients evaluated while on involuntary hold from January 1, 2014 through November 30, 2015 at a suburban acute care hospital ED. The data that were collected included demographic information, length of stay, reason for the involuntary hold, psychiatric disorder, substance use, medical illness, and violence in the ED. The context of the homicidal threat also was collected. Results We found that 13 patients (5.2%) were homicidal. Three patients had homicidal ideations alone, whereas 10 made homicidal threats toward others. Of the 10 making homicidal threats, 7 named a specific person to harm. Ten of the 13 homicidal patients (76.9%) also were suicidal. Eleven patients (84.6%) had a psychiatric disorder: 9 patients (69.2%) had a depressive disorder and 8 patients (61.5%) had a substance use disorder. Eight patients had active medical problems that required intervention in the ED. Conclusions We found that three-fourths of patients expressing homicidal threats also were suicidal. The majority of patients making threats of harm had a specific plan of action to carry out the threat. It is important to screen any patient making homicidal threats for suicidal ideation. If present, there is a need to implement immediate management appropriate to the level of the suicidal threat, for the safety of the patient. Eighty-five percent of patients making a homicidal threat had a previously documented psychiatric disorder, the most common being a depressive disorder. This finding differs from previous studies in which psychosis predominated. More than 60% of homicidal patients had an unrelated medical disorder requiring intervention. It is important not to overlook these medical disorders while focusing on the psychiatric needs of the patient; most of our homicidal patients proved to be cooperative in the ED setting.

Background Limited data are available on the development of skin cancer and the associated risk factors for non-White liver transplant (LT) recipients. The aim of this study is to determine the incidence of newly diagnosed skin cancer postoperatively and to identify the risk factors for the development of skin cancer in non-White LT recipients. Methods We conducted an initial retrospective chart review of non-White LT patients who received a transplant at our center between January 1, 2011, and December 31, 2013. Results Of the 96 patients in the study cohort, 32% were Black, 17% were Asian, 15% were White Hispanic, and 10% were Black Hispanic. One patient had a history of nonmelanoma skin cancer before transplant. No skin cancers were diagnosed during follow-up (median, 1.3 years; range, 17 days to 8.6 years). Conclusion Our center's experience is consistent with the literature and suggests that the incidence of newly diagnosed skin cancer in non-White liver transplant recipients is low. Longer follow-up may provide additional insights into the specific risk factors for the posttransplant development of skin cancer.

Objective To evaluate the safety and efficacy of cabozantinib combined with docetaxel. Patients and methods This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m2 every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone. Results A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively). Conclusion Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.

Background In metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide). Patients and methods This randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR. Results Overall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline. Conclusions Technetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication., Highlights • Radium-223 is a targeted alpha therapy for bone-dominant metastatic castration-resistant prostate cancer. • Assessing bone lesions and treatment response with technetium-99m is limited by image resolution and subjectivity. • We used computer-aided detection (CAD) of bone scan lesion area (BSLA) to assess radium-223 ± abiraterone/enzalutamide. • On preliminary assessment, CAD-based BSLA demonstrated positive response to radium-223 ± abiraterone/enzalutamide therapy. • Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.

Objectives To determine the role of previous psychiatric disorders including substance use disorders on emergency department (ED) patients on involuntary holds and compare presentations, treatment, and outcomes based on cause. Methods We conducted a retrospective study of patients ≥ 18 years old on involuntary holds in the ED of a tertiary care center from January 1, 2013, to November 30, 2015. Demographic and clinical information were collected. Those with and without prior psychiatric disorder including substance use disorder were compared. Results We identified 251 patients of which 129 (51.4%) had a psychiatric disorder, 23 (9.2%) had a substance use disorder, and 86 (34.3%) had both. Thirteen patients (5.2%) had no psychiatric disorder or substance use disorder and the majority 10 (76.9%) were on involuntary holds due to suicidal threats related to pain or another medical problem. Patients without a psychiatric or substance use disorder were older (55 years [17.8] vs 42 [19]; P = 0.01), more likely to be married (10 [76.9%] vs 64 [26.9%]; P P = 0.049) compared with those without a psychiatric or substance use disorder. Conclusion Patients on involuntary holds most commonly have pre-existing psychiatric disorder including substance use disorder. Patients on involuntary holds without history of psychiatric disorder often have severe pain or other active medical conditions which may contribute to suicidal thoughts. Addressing these underlying medical issues may be crucial in preventing further psychiatric decompensation.

Summary Background Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma. Methods This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov , NCT01688999 . Findings Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8–70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9–34). The most common grade 3–4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths. Interpretation Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies. Funding National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.

Summary Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC.

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.

The opioid crisis that exists today developed over the past 30 years. The reasons for this are many. Good intentions to improve pain and suffering led to increased prescribing of opioids, which contributed to misuse of opioids and even death. Following the publication of a short letter to the editor in a major medical journal declaring that those with chronic pain who received opioids rarely became addicted, prescriber attitude toward opioid use changed. Opioids were no longer reserved for treatment of acute pain or terminal pain conditions but now were used to treat any pain condition. Governing agencies began to evaluate doctors and hospitals on their control of patients' pain. Ultimately, reimbursement became tied to patients' perception of pain control. As a result, increasing amounts of opioids were prescribed, which led to dependence. When this occurred, patients sought more in the form of opioid prescriptions from providers or from illegal sources. Illegal, unregulated sources of opioids are now a factor in the increasing death rate from opioid overdoses. Stopping the opioid crisis will require the engagement of all, including health care providers, hospitals, the pharmaceutical industry, and federal and state government agencies.

Objectives To determine whether use of a patient portal during hospitalization is associated with improvement in hospital outcomes, 30-day readmissions, inpatient mortality, and 30-day mortality. Materials and Methods We performed a retrospective propensity score–matched study that included all adult patients admitted to Mayo Clinic Hospital in Jacksonville, Florida, from August 1, 2012, to July 31, 2014, who had signed up for a patient portal account prior to hospitalization (N = 7538). Results Out of the admitted patients with a portal account, 1566 (20.8%) accessed the portal while in the hospital. Compared to patients who did not access the portal, patients who accessed the portal were younger (58.8 years vs 62.3 years), had fewer elective admissions (54.2% vs 64.1%), were more frequently admitted to medical services (45.8% vs 35.2%), and were more likely to have liver disease (21.9% vs 12.9%) and higher disease severity scores (0.653 vs 0.456). After propensity score matching, there was no statistically significant difference between the 2 cohorts with respect to 30-day readmission (P = .13), inpatient mortality (P = .82), or 30-day mortality (P = .082). Conclusion Use of the patient portal in the inpatient setting may not improve hospital outcomes. Future research should examine the association of portal use with more immediate inpatient health outcomes such as patient experience, patient engagement, medication reconciliation, and prevention of adverse events.

Objective To understand the relationship between opioid use in patients with congestive heart failure and outcomes, we compared length of stay (LOS), 30-day readmission rates, and 30- and 90-day mortality in patients discharged with a primary diagnosis of congestive heart failure (CHF) who were taking opioids. Design Retrospective study design. Setting Patients were seen at a 320-bed academic hospital. Subjects All patients not awaiting transplant who were discharged with a primary diagnosis of heart failure from January 1, 2011, through December 31, 2014. Methods Records were reviewed for demographic data, comorbidities, and opioid status at admission or discharge. The association of opioid use (at admission and discharge) with LOS, 30-day readmission, and 30- and 90-day mortality was examined. Results Six hundred eighty-two patients with a principle diagnosis of heart failure were admitted during the study period, with 168 (24.6%) taking opioids at admission. Opioid use at admission was not significantly associated with 30-day readmission (odds ratio [OR] = 1.24, 95% confidence interval [CI] = 0.80-1.93), 30-day mortality (hazard ratio [HR] = 0.91, 95% CI = 0.47-1.78), 90-day mortality (HR = 0.95, 95% CI = 0.58-1.54), or LOS (parameter estimate = -0.21, 95% CI = -0.91 to 0.48). One hundred ninety-three patients (28.3%) were prescribed opioids at discharge. No significant differences were observed between those who were and were not taking opioids at discharge for 30-day readmission (OR = 1.10, 95% CI = 0.72-1.69) or for 30- or 90-day mortality (HR = 0.51, 95% CI = 0.24-1.06, and HR = 0.67, 95% CI = 0.41-1.10, respectively). LOS was slightly shorter for patients not using opioids at discharge than for those who were (mean = 3.8 vs 4.6 days, respectively). Conclusions Opioid use at admission or discharge in patients with CHF did not appear to affect outcomes.

Abiraterone acetate (AA) and enzalutamide (ENZ) are oral therapies offering survival benefit to metastatic castration-resistant prostate cancer (mCRPC) patients. Despite the availability of multiple treatment options for mCRPC, there is a lack of information on the effect that being initiated on AA or ENZ has on the combined prostate cancer treatment duration.To compare the combined duration of prostate cancer treatments of patients initiated on AA with that of patients initiated on ENZ.Truven Health MarketScan Research Databases from March 2012 to December 2014 were used to identify males with prostate cancer initiated on AA or ENZ (index therapy). Baseline characteristics were assessed during the 6 months pre-index. Inverse probability of treatment weights (IPTWs) were used to reduce baseline confounding. Treatment duration spanned from the index date to the earliest of treatment discontinuation (defined as a60-day gap in treatment), 24 months post-index, health plan disenrollment, or end of data. Weighted Kaplan-Meier and Cox proportional hazard models were used to compare the combined duration of mCRPC treatments (AA, ENZ, chemotherapy, sipuleucel-T, and radium 223) and any prostate cancer treatments (mCRPC, hormonal, and corticosteroid treatments) between patients initiated on either AA or ENZ.A total of 2,591 patients initiated on AA and 807 patients initiated on ENZ were selected for the study. Patients' characteristics were generally well balanced after IPTW. At 3 months, patients initiated on AA were associated with fewer discontinuations of mCRPC treatments (hazard ratio [HR] = 0.73, P = 0.004) or of any prostate cancer treatments (HR = 0.61, P = 0.002), compared with patients initiated on ENZ. This result was maintained at 6, 9, 12, 18, and 24 months for mCRPC treatments (HR = 0.75, P0.001) and for any prostate cancer treatments (HR = 0.69, P0.001). Median duration of mCRPC treatments was 4.1 months longer for patients initiated on AA compared with those initiated on ENZ (18.3 vs. 14.2 months, P0.001) and similarly, the median duration of any prostate cancer treatment was longer for patients initiated on AA compared with those initiated on ENZ (not reached vs. 22.2 months, P0.001).In this study, patients initiated on AA, compared with those initiated on ENZ, had a longer combined duration of mCRPC or prostate cancer treatments.This research was funded by Janssen Scientific Affairs. Pilon, Emond, and Lefebvre are employees of Analysis Group, a consulting company that has received research grants from Janssen Scientific Affairs. Behl and Ellis are employees of Janssen Scientific Affairs and stockholders in JohnsonJohnson. Dawson is on the speakers bureau for Janssen, Astellas, and Sanofi Aventis. Emond reports grants from Regeneron, Bristol-Myers Squibb, GlaxoSmithKline, Aegerion, Bayer, Novartis, Allergan, Millenium, and Genentech. Pilon reports grants from Novartis, GlaxoSmithKline, Pfizer, and Bayer. Lefebvre reports grants from GlaxoSmithKline, Novartis, Bayer, Medtronic, Noven, and Novo Nordisk. Study concept and design were contributed primarily by Pilon and Lefebvre, along with the other authors. Pilon, Emond, and Lefebre collected the data, and data interpretation was performed by Behl, Lefebvre, and Dawson, along with Pilon, Ellis, and Emond, The manuscript was written by Pilon, Emond, and Lefebvre and revised by Behl, Ellis, and Dawson.

Objectives Canine-assisted therapy (CAT) has been used in many settings with much success, yet no study has assessed its feasibility and receptiveness in hospitalized patients awaiting heart transplantation. Methods Patients admitted to our institution with a status I for heart transplantation during a 12-month period (April 2014-April 2015) were prospectively included in a feasibility pilot study. Patients were included if there was no history of transmittable disease or active infectious process and consented for study participation. Each patient was visited daily by a canine and quantitative and qualitative data regarding the visit were obtained. Results A total of 11 patients were included in the study. Most patients were men (n = 8, 72.7%) and the average age was 51.1 years. A total of 146 individual therapies took place, totaling 2718 minutes of CAT during the study period. Each patient had an average of 13.3 visits and each visit had an average duration of 14.7 minutes. Patient receptiveness, as measured by the CAT volunteer, averaged 9.9 (scale 0-10). No reports of infection transmission occurred. Conclusions Our study found that CAT among hospitalized pre-heart transplant patients is feasible and is a welcomed adjunct to usual medical care.

Purpose Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] ≥ 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA > 10 ng/mL plus biopsy GS > 6. Patients with PSA ≤ 0.2 ng/mL after radical prostatectomy were stratified by pT/N stage, GS, and adjuvant radiation plan and randomly assigned to ADT (bicalutamide and goserelin for 2 years) or ADT plus six cycles of MP. The primary end point was overall survival (OS). Median OS was projected to be 10 years in the ADT arm, requiring 680 patients per arm to detect a hazard ratio of 1.30 with 92% power and one-sided α = .05. Results Nine hundred sixty-one eligible intent-to-treat patients were randomly assigned to ADT or ADT + MP from October 1999 to January 2007, when the Data Safety Monitoring Committee recommended stopping accrual as a result of higher leukemia incidence with ADT + MP. Median follow-up was 11.2 years. The 10-year OS estimates were 87% with ADT (expected 50%) and 86% with ADT + MP (hazard ratio, 1.06; 95% CI, 0.79 to 1.43). The 10-year estimate for disease-free survival was 72% for both arms. Prostate cancer was the cause of death in 18% of patients in the ADT arm and 22% in the ADT + MP arm. More patients in the MP arm died of other cancers (36% v 18% in ADT alone arm). Conclusion MP did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm.

Background Ra-223 demonstrated improvements in overall survival (OS) and time to symptomatic skeletal events (SSEs) in patients (pts) with mCRPC and bone metastases in the ALSYMPCA study (Parker C et al. N Engl J Med 2013; 369:213–223). The current study investigated antitumor activity of Ra-223 alone or in combination with abiraterone (abi) or enzalutamide (enza). Methods In this multicenter, open-label phase 2a study, pts with mCRPC and bone-only metastases were randomized (1:1:1) to: six injections of Ra-223 (55 kBq/kg, q4w), Ra-223+abi (1000mg qd + prednisone 5mg bid), or Ra-223+enza (160mg qd). The primary endpoint was bone scan lesion area response rate (BSLA RR) at Week 24 based on the quantified technetium-99 bone scan. BSLA RR, defined as>30% decrease from baseline (BL), was evaluated centrally. The hypothesis of a BSLA RR≥5% at Week 24 was tested in each arm separately. No cross-arm comparisons were planned. Secondary endpoints are shown in the table. Results 68 pts were randomized; 63 received treatment. The most common reason for treatment discontinuation was disease progression (50.0%). Approximately 36.5% of pts used bone health agents (BHAs) at BL. The primary endpoint of BSLA RR at Week 24 was 57.9%, 50.0%, and 22.2% for the Ra-223+abi, Ra-223+enza, and Ra-223 groups, respectively. Median SSE-free survival (SSE-FS) was not reached, 19.91, and 11.93 months and median OS was 37.55, 29.86, and 35.81 months, for the Ra-223+abi, Ra-223+enza, and Ra-223 groups, respectively. Fracture rates were lower in pts with vs without BL BHAs; 3/23 (13.0%) vs 10/40 (25.0%), respectively. 17, 18, and 8 pts receiving Ra-223+abi, Ra-223+enza, and Ra-223 experienced related treatment-emergent adverse events, respectively.Table870PTableRa-223 + abi (n=22)Ra-223 + enza (n=22)Ra-223 (n=19)BL, median (min, max)Age, years68 (56, 86)73 (56, 86)71 (54, 91)PSA, µg/L19.0 (0.90, 1500.0)19.3 (1.2, 805.9)23.1 (0.05, 617.0)ECOG 0/1, n (%)13 (59.1)/9 (40.9)11 (50.0)/11 (50)10 (52.6)/9 (47.4)Time since PC diagnosis, months51.4 (2.6, 196.0)48.3 (5.1, 198.0)38.34 (6.6, 252.9)Extent of disease, n (%) 20 lesions Superscan6 (27.3) 10 (45.5) 5 (22.7) 06 (27.3) 12 (54.5) 4 (18.2) 09 (47.4) 7 (36.8) 2 (10.5) 1 (5.3)Prior therapies, n (%)* Sipuleucel-t Docetaxel Cabazitaxel6 (25.0) 3 (12.5)3 (13.6) 5 (22.7) 1 (4.5)5 (22.7) 4 (18.2)EfficacyBSLA RR, % (80% CI)**57.9 (40.8–73.7); p Conclusions The primary endpoint of BSLA response was met in each treatment arm. Overall, OS does not appear to correlate with BSLA RR in this small study population. Clinical trial identification NCT02034552. Editorial acknowledgement Jenny Feehan of OPEN Health Medical Communications (London, UK), with financial support from Bayer. Legal entity responsible for the study Bayer HealthCare Pharmaceuticals. Funding Bayer HealthCare Pharmaceuticals. Disclosure D.P. Petrylak: Advisory / Consultancy, Research grant / Funding (institution): Ada Cap (Advanced Accelerator Applications); Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Endocyte; Advisory / Consultancy: Incyte; Research grant / Funding (institution): Innocrin; Advisory / Consultancy: Incyte; Research grant / Funding (institution): Genentech; Advisory / Consultancy: Janssen, Pharmacyclics, Urogen; Research grant / Funding (institution): MedImmune, Merck; Research grant / Funding (institution): Novartis, Progenics, Sanofi Aventis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer, Roche Laboratories, Seattle Genetics; Shareholder / Stockholder / Stock options: Bellicum, Tyme. U.N. Vaishampayan: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer Inc. C.S. Higano: Advisory / Consultancy, Research Grant / Funding (Institution): Aptevo; Advisory / Consultancy: Asana; Advisory / Consultancy, Research Grant / Funding (Institution): Astellas; Advisory / Consultancy, Research Grant / Funding (Institution): AstraZeneca; Advisory / Consultancy, Research Grant / Funding (Institution), Travel/Accommodation/Expenses: Bayer; Advisory / Consultancy, Travel/Accommodation/Expenses: Blue Earth Diagnostics; Advisory / Consultancy: Churchill Pharma; Advisory / Consultancy, Travel/Accommodation/Expenses: Clovis Oncology; Advisory / Consultancy, Research Grant/Funding (Institution): Dendreon; Advisory / Consultancy: Endocyte; Advisory / Consultancy, Travel/Accommodation/Expenses: Ferring; Advisory / Consultancy, Travel/Accommodation/Expenses: Hinova; Advisory / Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory / Consultancy, Travel/Accommodation/Expenses: Myriad; Advisory / Consultancy, Travel/Accommodation/Expenses: Orion Corporation; Advisory / Consultancy, Research Grant / Funding (Institution), Travel/Accommodation/Expenses: Pfizer, Research Grant / Funding (Institution), Travel/Accommodation/Expenses: Genentech, Research Grant / Funding (Institution): Hoffmann-La Roche Research Grant / Funding (Institution): Medivation, Research Grant / Funding (Institution): Sanofi; Research Grant / Funding (Institution): Aragon Pharma. C. Albany: Speaker Bureau / Expert Testimony: Sanofi. N. Dawson: Speaker Bureau / Expert Testimony: Astellas/ Pfizer, Speaker Bureau / Expert Testimony: Janssen. B. Mehlhaff: Honoraria (self), Advisory / Consultancy, Research Grant / Funding (Institution), Travel/ Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research Grant / Funding (Institution), Travel/ Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research Grant / Funding (Institution), Travel/ Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Research Grant / Funding (Institution), Travel/ Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Travel/ Accommodation / Expenses: Amgen. D. Quinn: Research Grant/Funding (Institution): Seattle Genetics. Research Grant/Funding (Institution), Advisory / Consultancy, Travel/Accommodations/ Expenses: MSD. Research Grant/Funding (Institution), Advisory / Consultancy: Novartis. Advisory/Consultancy: Astellas. Advisory/Consultancy, Travel / Accommodations/ Expenses: AstraZeneca. Advisory/Consultancy: Bayer. Advisory/Consultancy, Travel / Accommodations/ Expenses: BMS. Advisory/Consultancy: Dendreon. Advisory/Consultancy: Exelixis. Advisory/Consultancy, Travel / Accommodations/ Expenses: Roche. Advisory/Consultancy: Janssen. Advisory/Consultancy, Travel / Accommodations/ Expenses: Pfizer. Advisory/Consultancy: Sanofi.V.J. Wagner: Full / Part-time employment: Bayer Pharmaceuticals. J. Shen: Full / Part-time employment: Bayer Pharmaceuticals. L. Trandafir: Full / Part-time employment: Bayer Pharmaceuticals. O. Sartor: Advisory/Consultancy: Advanced Accelerator Applications (AAA); Advisory/Consultancy: Astellas; Advisory/Consultancy, Research Grant/Funding (Institution): AstraZeneca; Advisory/Consultancy, Research Grant/Funding (Institution): Bayer; Advisory/Consultancy: Blue Earth; Advisory/Consultancy: Board of Scientific Counselors; Advisory/Consultancy: Diagnostics, Inc; Advisory/Consultancy, Research Grant/Funding (Institution): Constellation; Advisory/Consultancy, Research Grant/Funding (Institution): Dendreon; Advisory/Consultancy: EMD Serono; Advisory/Consultancy, Research Grant/Funding (Institution): Endocyte; Advisory/Consultancy: Hinova; Advisory/Consultancy, Research Grant/Funding (Institution): Johnson & Johnson; Advisory/Consultancy: Myovant; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research Grant/Funding (Institution): Progenics; Advisory/Consultancy, Research Grant/Funding (Institution), Speaker Bureau/Expert Testimony: Sanofi; Research Grant/Funding (Institution): Innocrin; Research Grant/Funding (Institution): Invitae; Research Grant/Funding (Institution): Merck; Research Grant/Funding (Institution): SOTIO; Leadership Role: Co-Chairman of GU Committee. All other authors have declared no conflicts of interest.

Central nervous system (CNS) events are frequently reported among patients with advanced prostate cancer as a consequence of the treatments used in this patient population.To assess the incidence of CNS events in patients with advanced prostate cancer who initiated treatment with abiraterone acetate, bicalutamide, enzalutamide, or chemotherapy.The Truven Health MarketScan Research databases were used to retrospectively identify patients with prostate cancer who initiated treatment with abiraterone acetate, enzalutamide, bicalutamide, or chemotherapy after September 1, 2012 (ie, the index date). The chemotherapy agents included cabazitaxel, docetaxel, mitoxantrone hydrochloride, and estramustine, and were used as monotherapy or as combination therapy. Patients were followed until December 31, 2014, the end of exposure to treatment, or until loss to follow-up. Kaplan-Meier rates and adjusted Cox proportional hazard models were used to compare the incidence of CNS events between the abiraterone acetate cohort and the other cohorts. A sensitivity analysis of patients with a diagnosis of metastasis was also conducted.A total of 1067 patients receiving abiraterone acetate, 5524 receiving bicalutamide, 592 receiving enzalutamide, and 256 receiving chemotherapy were identified. After 12 months, patients who received abiraterone acetate were less likely to have a CNS event than patients who received enzalutamide (39.5% vs 46.0%, respectively;The results of this large observational study suggest that among patients with metastatic prostate cancer, treatment with abiraterone acetate is associated with a significantly lower likelihood of having a CNS event compared with treatment with enzalutamide or chemotherapy, but not with bicalutamide, even when controlling for metastatic disease.

Background: Physician discharge instructions are critical to patient care because they are the link transitioning the hospital care plan to the home. We hypothesize that physician perception of discharge instructions communication is better than patient perception. Objective: In a preliminary study, to compare patient and physician perception of communication at discharge. Design: Observational, survey-based. Setting: 330-bed adult teaching hospital. Participants: Surveys were mailed to 100 patients discharged home and 49 internal medicine physicians responsible for those patients’ care. Each physician had between 1 and 4 patients surveyed. Measurements: Patients and physicians received anonymous 5-item questionnaires concerning physician communication at discharge. Patient surveys inquired about their physicians’ communication at the specific physician encounter, while physician surveys asked about the physicians’ overall self-perception of discharge communication skills. Results: Completed questionnaires were returned by 59 patients and 40 physicians. Physicians reported a noticeably better perception of communication than their patients regarding spending adequate time reviewing the discharge plan (83% vs. 61%, P = 0.027), speaking slowly enough to understand (98% vs. 80%, P = 0.013), using wording that could be easily understood (100% vs. 68%, P < 0.001) and taking time to answer questions before discharge (85% vs. 59%, P = 0.008). Perception of discharge communication improved with physician experience for several survey items. Conclusions: This study provides evidence suggesting that physician perception of communication at discharge is better than patient perception. Future studies of larger sample size and direct patient-physician pairing focusing on patient satisfaction and outcomes are needed.

BackgroundCastration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.MethodsMen with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.ResultsA total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P

TRC105 is a chimeric monoclonal antibody that targets CD105 (endoglin). Heavily pretreated patients with metastatic urothelial carcinoma received TRC105 at 15 mg/m(2) every 2 weeks on a 28-day cycle. Treatment was not associated with significant toxicities, but did not improve 6-month progression-free survival. Exploratory analyses suggest interplay between immunosuppressive subsets and TRC105, which warrants further study. BACKGROUND: In this trial we assessed the efficacy and tolerability of TRC105, a chimeric monoclonal antibody that targets CD105 (endoglin) in patients with advanced, previously treated urothelial carcinoma (UC). PATIENTS AND METHODS: Patients received TRC105 15 mg/kg every 2 weeks on days 1 and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) at 6 months. Secondary end points included safety, toxicity, and overall survival (OS). CD105 expression was evaluated using immunohistochemistry (IHC) in a separate cohort of 50 UC patients. Biomarker studies included immune subsets, circulating tumor cells (CTCs), circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and osteopontin. RESULTS: Of 13 patients enrolled, 12 were evaluable for OS and PFS. The 3-month PFS probability was 18.2% (median PFS, 1.9 months [95% confidence interval (CI), 1.8–2.1 months). This met the criterion for ending accrual on the basis of the 2-stage design. Median OS was 8.3 months (95% CI, 3.3–17.0 months). IHC for CD105 scores was not associated with T stage (P = .26) or presence of lymph nodes (P = .64). Baseline levels of regulatory T and B cells, CEPs, and changes in CEC level after TRC105 exhibited trends toward an association with PFS or OS. CTCs pre- and post-TRC105 were detected in 4 of 4 patients. CONCLUSION: Although TRC105 was well tolerated, it did not improve 6-month PFS in heavily pretreated patients with advanced UC. CD105 staining was present in 50% of UC tumors at different intensities. Our observations on the pharmacodynamic significance of immune subsets, CECs, and CTCs warrant further study.

Background Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population. Methods For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged >= 18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an a level of 0.05. This study is registered with ClinicalTrials.gov, number NCT02108652. Findings Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (= 1% but < 5%), and IC2/3 (>= 5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p< 0.0001; IC1/2/3: 18% [13-24], p= 0.0004) and in all patients (15% [11-20], p= 0.0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11.7 months (95% CI 11.4-12.2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study. Interpretation Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma.

Quality problem or issue: Medication errors related to reconciliation processes. Initial assessment: Even though most US medical centers utilize medication reconciliation processes to reduce medical errors, adverse events related to medications continue to occur causing extra burden on the US healthcare system. New strategies toreduce medication errors are being implemented, including pharmacy-based medication reconciliations. Case report: An 86-year-old female was admitted for symptomatic bradycardia in the setting of a fall. During her hospitalization, she was evaluated for pacemaker implantation until her thyroid-stimulating hormone blood test revealed severe hypothyroidism. Medication reconciliation had been performed twice with the patient, and her family adamantly affirmed the patient was complianton her levothyroxine. Upon further investigation, she had changed pharmacies nine months prior to her hospitalization andwas obtaining her thyroid replacement hormone from an online Canadian pharmacy. Once restarting Synthroid, her symptomsimproved allowing her to forego the procedure. Lessons learned: Physicians must understand common pitfalls with rapidly verifying home medications against electronicmedical records as patient knowledge of their home therapies is often inaccurate in combination with non-updated electronicdata. Hospitals are evaluating strategies such as pharmacy-based medication reconciliations to reduce adverse events related tomedication errors, which can decrease hospital costs and improve patient outcomes. Knowing which pharmacy is dispensing themedications can prove useful as discounted medications from online pharmacies may lack efficacy.

Clinical data suggest that large radiation fractions are biologically superior to smaller fraction sizes in prostate cancer radiotherapy. The CyberKnife is an appealing delivery system for hypofractionated radiosurgery due to its ability to deliver highly conformal radiation and to track and adjust for prostate motion in real-time. We report our early experience using the CyberKnife to deliver a hypofractionated stereotactic body radiation therapy (SBRT) boost to patients with intermediate- to high-risk prostate cancer. Twenty-four patients were treated with hypofractionated SBRT and supplemental external radiation therapy plus or minus androgen deprivation therapy (ADT). Patients were treated with SBRT to a dose of 19.5 Gy in 3 fractions followed by intensity modulated radiation therapy (IMRT) to a dose of 50.4 Gy in 28 fractions. Quality of life data were collected with American Urological Association (AUA) symptom score and Expanded Prostate Cancer Index Composite (EPIC) questionnaires before and after treatment. PSA responses were monitored; acute urinary and rectal toxicities were assessed using Common Toxicity Criteria (CTC) v3. All 24 patients completed the planned treatment with an average follow-up of 9.3 months. For patients who did not receive ADT, the median pre-treatment PSA was 10.6 ng/ml and decreased in all patients to a median of 1.5 ng/ml by 6 months post-treatment. Acute effects associated with treatment included Grade 2 urinary and gastrointestinal toxicity but no patient experienced acute Grade 3 or greater toxicity. AUA and EPIC scores returned to baseline by six months post-treatment. Hypofractionated SBRT combined with IMRT offers radiobiological benefits of a large fraction boost for dose escalation and is a well tolerated treatment option for men with intermediate- to high-risk prostate cancer. Early results are encouraging with biochemical response and acceptable toxicity. These data provide a basis for the design of a phase II clinical trial.