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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.

This review article examines evidence supporting the use of oral therapies in treating idiopathic, actinic, and metabolically induced skin hyperpigmentation. A thorough review of the literature regarding oral treatments for hyperpigmentation was systematically conducted through PubMed. Keywords used in the primary search include “Hyperpigmentation,” “Melanosis” or “Melasma,” “Lightening,” “Oral,” and “Therapeutics.” The search was limited to the English language, and no timeframe restrictions were implemented. Numerous orally administered therapies have been proposed for the treatment of skin hyperpigmentation. There is an abundant body of literature demonstrating the efficacy of orally administered tranexamic acid, glutathione, isotretinoin, and proanthocyanidin. It is reasonable to expect that the most effective oral therapies will address known underlying causes of hyperpigmentation such as thyroid disease, diabetes, and hormonal imbalance. Improvement due to oral therapy of otherwise unresponsive skin hyperpigmentation or hyperpigmentation of unknown cause is less predictable. This review is limited by the strength of evidence contained within the available studies. Clinical studies investigating the treatments discussed within this article are limited in number, at times lack blinding in the study design, and are based on small sample sizes. Based on existing research, the most promising oral remedies for hyperpigmentation appear to be tranexamic acid, glutathione, isotretinoin, and proanthocyanidin. Additional studies to better establish safety and efficacy are necessary.

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.

Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over 220 countries and territories have been affected by this virus, and the infection rate has continued to rise. As patients recover from the virus, many are experiencing lingering symptoms. Understanding the impact of demographics and comorbidities on symptom prevalence, manifestations, and severity is not only relevant during acute infection, it is critical to the clinical management of patients with post-acute sequelae of COVID-19, also known as PASC. Herein, we provide a comprehensive review on the most recent research related to PASC. Specifically, we focus on the description of the disorder itself, compared to acute COVID-19, and which types of patients are most affected by long-term sequelae. Further, we share recommendations for management of the most common complications of PASC.

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.

Background Patients who may be a danger to themselves or others often are placed on involuntary hold status in the Emergency Department (ED). Our primary objective was to determine if there are demographic and/or clinical variables of involuntary hold patients which were associated with an increased ED LOS. Methods Records of ED patients evaluated while on involuntary hold from January 1, 2014 through November 30, 2015 at a suburban acute-care hospital ED were reviewed. Data collected included demographics information, LOS, suicidal or homicidal ideation, suicide attempt, blood alcohol concentration (BAC), urine drug test (UDT), psychiatric disorder, substance use, medical illness, violence in the ED, and hospital admission. Linear regression based on the log of LOS was used to identify factors associated with increased LOS. Results Two-hundred and fifty-one patients were included in the study. ED LOS (median) was 6 h (1, 49). Linear regression analysis showed increased LOS was associated with BAC (p = 0.05), urine drug test (UDT) (p = 0.05) and UDT positive for barbiturates (p = 0.01). There was no significant difference in ED LOS with respect to age, gender, housing, psychiatric diagnosis, suicidal or homicidal ideation, suicide attempt, violence, medical diagnosis, or admission status. Conclusions Involuntary hold patients had an increased ED LOS associated with alcohol use, urine drug test screening, and barbiturate use. Protocol development to help stream-line ED evaluation of alcohol and drug use may improve ED LOS in this patient population.

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.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.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.

This study aimed to review the association between timeliness to completion of a discharge summary to 30-day readmission to the hospital.This was a retrospective chart review of 109 patients discharged from Mayo Clinic Hospital.Twenty-four of these patients were readmitted within 30 days. The time to completion of discharge summary was categorized for these readmissions to72 hours: 15 (20%), between 72 hours and 7 days: 2 (11.1%), and7 days: 7 (43.7%). There was no statistical significance for readmission for discharge summaries completed between 72 hours and 7 days compared with72 hours (This study found that discharge summaries completed7 days have an increased association with 30-day readmission rate.

Background: The total cost of healthcare for patients with castration-resistant prostate cancer (CRPC) is an important component for assessing value of treatment options. The need for real-world ev...

This prospective cohort study aimed to improve hospital outcomes through geographic location of hospitalist patients and conducting daily multidisciplinary team rounds—Goal-directed Achievements through Geographic Location (GAGL). Patients were admitted to a geographic (GAGL) study unit where daily multidisciplinary rounds took place among nursing, case management, a hospitalist, pharmacy, physical and occupational therapy, respiratory therapy, and nutrition services. A total of 985 (56.4%) patients were admitted to the GAGL study unit and 760 patients (43.6%) were admitted to non-GAGL units. Patients admitted to the GAGL study unit had a shorter average length of stay (3.64 days vs 4.35 days, P = .0001) and a lower number of risk events (91 [9.2%] vs 93 [12.2%], P = .038). There was no significant difference in 30-day readmissions, avoidable day events, or code blue team activations. GAGL provides a framework for hospital organizations to improve provider communication, hospital efficiency, and patient safety.

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.

287 Background: RCC has a distinct pattern of metastatic spread with common sites of metastasis including the lung, bone, and liver. Less common sites include the brain, adrenal gland, and pancreas. While the pattern of metastatic spread has prognostic significance, the biology driving tropism to specific organ sites has not been fully characterized. We utilized a multi-institutional real-world dataset to examine genomic alterations and transcriptional signatures across the spectrum of metastatic sites in patients with RCC. Methods: RCC tissue specimens derived from the kidney and distant metastatic sites were sequenced utilizing a commercially available Clinical Laboratory Improvement Amendments (CLIA)-certified assay by Caris Life Sciences. Whole exome and transcriptome sequencing was performed. Molecular subgroups were defined according to the IMmotion151 metastatic RCC subtypes, with subgroups determined by a weighted average of gene expression levels. Molecular analysis and PD-L1 expression (SP142) were described by metastasis site. Results: 657 RCC samples from 653 patients underwent molecular profiling. The median age was 62 years (range 14-90) and the majority were male (70.6%). The most common histology was clear cell RCC (n = 509, 77.5%), followed by papillary (n = 63, 9.6%), chromophobe (n = 30, 4.6%), medullary (n = 8, 1.2%), collecting duct (n = 6, 0.9%), and mixed (n = 41, 6.2%). Specimen source included the kidney (n = 340, 51.8%), lung (n = 75, 11.4%), bone (n = 45, 6.8%), lymph nodes (n = 34, 5.2%), liver (n = 28, 4.3%), endocrine glands (adrenal, pancreas, and thyroid; n = 23, 3.5%), brain/CNS (n = 16, 2.4%), and other metastatic sites (n = 96, 14.6%). Compared to kidney, several genes were mutated at higher rates for select metastatic sites, including PBRM1 (59.5% bone, 59.1% endocrine, and 45.9% lung vs 33.8% kidney, p< 0.05) and KDM5C (27.8% endocrine, 29.2% lymph nodes, and 35.3% soft tissue vs 9.3% kidney, p< 0.05). When evaluating metastatic specimens versus kidney specimens, bone metastases had a significantly higher proportion of tumors classified as ‘Angio/stromal’ (n = 19, 42.2%; vs n = 52, 15.4%; p< 0.0001), while liver metastases had a higher proportion of the ‘complement/Ω-oxidation’ subgroup (n = 17, 60.7%; vs n = 48, 14.1%; p< 0.0001). PD-L1 expression in metastatic sites (range 6.8%-21.7%, with exception of 0% in GI; p= 0.09 to 0.99) was not significantly different from the kidney (16.6%). Conclusions: In our contemporary real-world analysis, we demonstrate differential patterns of molecular alterations among sites of metastasis in RCC. Our observations elucidate the biology underlying heterogeneous disease outcomes associated with site of metastasis. Application of predictive signatures by site of metastasis may help inform personalized therapy strategies in advanced RCC. Further studies are warranted to validate our findings.

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.

Men with castration-resistant prostate cancer (CRPC) experience disease progression at different rates. The purpose of this study was to quantify the strength of patient preferences for delaying prostate cancer progression utilizing a discrete choice experiment (DCE) and valuing 3 health states in the continuum of CRPC.Men with CRPC, recruited from US patient panels, completed a cross-sectional web-based survey. The survey consisted of vignette-based time trade-off and a DCE designed to quantify patients' willingness to pay to delay metastatic CRPC. Three health states were presented: (1) living with non-metastatic castration-resistant prostate cancer (nmCRPC) (2) living with metastatic CRPC (mCRPC) before chemotherapy, and (3) living with mCRPC either on or after chemotherapy. The DCE consisted of 15 hypothetical choices with attributes characterizing CRPC (pain, fatigue, out of pocket cost, dosing, and time until cancer metastasizes). Patients' willingness to pay for changes in each attribute were derived.A total of 176 patients with CRPC were surveyed (mean age: 64.2 years; 74% nmCRPC). Patients valued the nmCRPC health state (0.865) significantly higher than mCRPC before chemotherapy (0.743) or mCRPC on or after chemotherapy (0.476), both P0.001. In the DCE, patient treatment valuation was most affected by increasing the number of months until cancer metastasized; patients were willing to pay an additional $682 per month to delay time to metastases from 6 to 24 months (95% Confidence Interval: $387-$977) and additional $1,041 per month to delay time to metastasis to 48 months (95% Confidence Interval: $591-$1,490).The results of this study demonstrated men with CRPC place significant value on delaying metastases. This study represents the first time 2 stated preference methods, time trade-off and DCE, were used together to understand patients' preferences and valuation of health states in CRPC.

Background Relatively few cutaneous head and neck melanoma (CHNM) patients with were included in the multicenter selective lymphadenectomy trial II (MSLT-II). Our objective was to investigate whether immediate completion lymph node dissection completion of lymph node dissection (CLND) was associated with survival benefit for sentinel lymph node (SLN) positive CHNM using the National Cancer Database. Methods SLN positive patients with CHNM from 2012 to 2014 were retrospectively analyzed. Patients were divided into two groups: those who underwent SLN biopsy (SLNB) only versus those who underwent SLNB followed by CLND (SLNB + CLND). The primary outcome was 5-year overall survival (OS). Results Among 530 SLNB + patients, 342 patients underwent SLNB followed by CLND (SLNB + CLND). The SLNB only group had fewer positive SLN, less advanced pathologic stage, and a lower rate of adjuvant immunotherapy. There was no significant difference in 5-year OS between the two groups (51.0% vs 67%; P = .56). After adjusting for pathologic stage, there remained no difference in 5-year OS among patients with stage IIIA (63.0% vs. 73.6%, P = 0.22) or IIIB/IIIC disease (39.1% vs 57.8%; P = .52). Conclusions Using a large nationwide database, CLND was not shown to be associated with improved OS for patients with SLNB positive CHNM, validating the results of MSLT-II.

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 Anemia is common in patients presenting with acute congestive heart failure (CHF); when hemoglobin (HGB) declines to low levels, it can result in worse outcomes. The aim of this study was to determine a level of HGB on admission or discharge that affects outcomes in patients with CHF and then to evaluate the effect of the low HGB levels on these outcomes. METHODS We conducted a retrospective cohort study of 756 patients admitted with acute CHF during the period January 1, 2011-December 31, 2014. We used multivariable regression analysis to evaluate the relation among HGB levels and three major outcomes: 3-year mortality, 30-day readmission rate, and length of stay (LOS). RESULTS Compared with patients with HGB ≥10 g/dL, patients with HGB

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.