Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292).

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.

Pilot Trial of Streamlined Genetic Education and Traceback Genetic Testing in Prostate Cancer Survivors.

BACKGROUND: Germline genetic testing is recommended for men with metastatic or high-risk prostate cancer to inform treatment and risk management for other cancers and inform genetic testing in at-risk relatives. However, relatively few patients with prostate cancer undergo genetic testing. Given the low rate of testing and increasing demands on genetic service providers, strategies are needed that reduce barriers to testing while conserving genetic counseling resources. The primary goal of this study was to determine whether a proactive and streamlined "traceback" approach could yield increased genetic testing participation among prostate cancer survivors. METHODS: We randomized 107 survivors of metastatic and high-risk prostate cancer to streamlined testing (ST) versus enhanced usual care (EUC). ST participants were proactively provided with print genetic education materials and the option to proceed to genetic testing without pre-test genetic counseling. EUC participants were sent a letter from their physician advising them of their eligibility for genetic testing and recommending they schedule genetic counseling. The primary outcome was genetic testing participation. Secondary outcomes were distress, knowledge, decision satisfaction, and regret. RESULTS: In the ST group, 41.5% of participants completed genetic testing compared with 27.8% in the EUC group. After adjusting for education and marital status, the odds of testing were more than twice as high for the ST group as for the EUC group (odds ratio, 2.57; 95% CI, 1.05-6.29). The groups did not differ on any of the psychosocial outcomes at the 3-month follow-up. CONCLUSIONS: Proactive outreach paired with streamlined genetic testing delivery may be a safe, effective, and resource-efficient approach to facilitate traceback genetic testing in prostate cancer survivors.

Acute Adverse Effects Related to Consumption of Nonnutritive and Low-Calorie Sweeteners.

Nonnutritive sweeteners (NNSs) and low-calorie sweeteners (LCSs) are commonly used as sugar substitutes. Many popular media Web sites caution against the use of these sweeteners because of their potential adverse effects such as inflammation; however, there are limited supporting data. A Medline search of articles published between 2010 and 2020 was conducted, resulting in 833 articles, of which 12 relevant studies were included in this review. Acute adverse effects associated with the consumption of NNSs and LCSs are rare. A few studies cite reports of acute adverse effects, including mild gastrointestinal disturbance, headaches, lightheadedness, hypersensitivity reactions, impaired spatial orientation, depression, and pain. Little scientific evidence has been reported in the literature since 2010 to support these warning statements to consumers about acute adverse effects to NNSs and LCSs.

Dermatology Residency Applicant Self-Reported Stressors and Coping Mechanisms by Sex, Race, and Geographic Region during the 2020-2021 Application Cycle.

OBJECTIVES: Our aim was to identify self-reported stressors and coping mechanisms during the 2020-2021 application cycle by dermatology residency applicants. We hypothesized that coronavirus disease 2019 (COVID-19) would be the most reported stressor. METHODS: During the 2020-2021 application season, the Mayo Clinic Florida Dermatology residency program sent a supplemental application to each applicant requesting that they describe a challenging life situation and how they handled it. Comparisons of self-reported stressors and self-expressed coping mechanisms according to sex, race, and geographic region were performed. RESULTS: The most common stressors reported were academic (18.4%), family crisis (17.7%), and COVID-19 (10.5%). The most frequent coping mechanisms expressed were perseverance (22.3%), seeking community (13.7%), and resilience (11.5%). The coping mechanism of diligence was observed more often in females than in males (2.8% vs 0.0%, P = 0.045). First in medicine was more often observed in Black or African American students (12.5% vs 0%, P = 0.001), immigrant experience was more often observed in Black or African American and Hispanic students (16.7% and 11.8% vs 3.1%, P = 0.021), and natural disaster was reported more often in Hispanic students (26.5% vs 0.5%, P < 0.001) as compared with White applicants. By geography, applicants in the northeastern United States were more likely to report the COVID-19 pandemic as a stressor (19.5%, P = 0.049), and the natural disaster stressor was more often reported by applicants from outside the continental United States (45.5%, P < 0.001). CONCLUSIONS: Stressors reported by dermatology applicants in the 2020-2021 cycle included academic, family crisis, and the COVID-19 pandemic. The type of stressor reported varied by race/ethnicity and geographic location of the applicant.

The Impact of a Group Telemedicine Program for Chronic Disease: A Retrospective Cohort Survey Study on Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder.

Background: We present an innovative care model for telehealth by creating a video conference group telemedicine program for patients with chronic disease and discuss findings from a post-program survey that was instrumental in understanding the response to telemedicine in a group setting. Methods: All patients who attended the group telemedicine program had a diagnosis of Hypermobile Ehlers-Danlos Syndrome or Hypermobility Spectrum Disorder and were requested to complete survey responses at the close of the program. Surveys were completed anonymously and electronically by REDCap. Elements of the Press Ganey, Consumer Assessment of Healthcare Providers and Systems, and Utah Telehealth Network patient satisfaction surveys were modified to construct the survey. Results: A total of 102 patients completed the post-telehealth program survey between August 20, 2021, and February 11, 2022. Around 93.1% stated that they gained a better understanding of the chronic condition, 88.3% stated that the program gave them the tools to improve, and 76.5% indicated the program addressed their specific needs. Approximately 92.1% found it easy to interact with the program facilitator and 79.4% found it easy to interact with program members. Around 93.1% said they would recommend the program to others. Discussion: We created a group telemedicine program for a complex chronic medical condition. The foundation of knowledge provided by the telemedicine program allowed more time during face-to-face encounters for individual assessment of the patient, and increased access to care. Overall, the program has improved the treatment process by reducing treatment burden and empowering patients with self-management skills to help reach our fundamental treatment goal of improving quality of life.

A Review of Oral Therapies for the Treatment of Skin Hyperpigmentation.

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.

Home Telemonitoring to Reduce Readmission of High-Risk Patients: a Modified Intention-to-Treat Randomized Clinical Trial.

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.

Cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate 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.

Discharge Summary Completion Timeliness and the Association of 30-Day Readmission.

OBJECTIVE: This study aimed to review the association between timeliness to completion of a discharge summary to 30-day readmission to the hospital. METHODS: This was a retrospective chart review of 109 patients discharged from Mayo Clinic Hospital. RESULTS: Twenty-four of these patients were readmitted within 30 days. The time to completion of discharge summary was categorized for these readmissions to <72 hours: 15 (20%), between 72 hours and 7 days: 2 (11.1%), and >7 days: 7 (43.7%). There was no statistical significance for readmission for discharge summaries completed between 72 hours and 7 days compared with <72 hours (P = 0.44). There was statistical significance correlating readmission within 30 days to the discharge summary completed >7 days compared with <72 hours (P = 0.04). CONCLUSIONS: This study found that discharge summaries completed >7 days have an increased association with 30-day readmission rate.

Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.

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.

Completion lymph node dissection in patients with sentinel lymph node positive cutaneous head and neck melanoma.

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.

Involuntary patient length-of-stay at a suburban emergency department.

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.

Patients on Involuntary Hold Status in the Emergency Department.

OBJECTIVES: Patients requiring involuntary holds are frequently seen in the emergency department (ED). Much of what is known comes from studies of patients at urban academic centers. Our aim was to describe the demographic and clinical characteristics of patients who were evaluated while on involuntary status at a suburban ED. METHODS: The medical records of patients seen in the ED requiring involuntary hold status between January 1, 2014 and November 30, 2015 were reviewed. Demographic and clinical variables including medical and psychiatric comorbidity were collected. A subanalysis was performed comparing patients who attempted suicide with all other involuntary patients. RESULTS: Two hundred fifty-one patient records were reviewed; 215 patients (85.3%) had psychiatric disorders-depression was the most common (57%)-and 108 patients (43%) had substance use disorders. Only 13 patients (5.2%) had neither a psychiatric disorder nor a history of substance use. Twenty-two patients (8.8%) were violent in the ED. Thirteen patients (5.2%) were readmitted, and 1 patient died within 30 days of discharge from the ED. One hundred twenty-four patients (49.4%) had medical disorders. Suicidal ideation was the most common reason for involuntary hold (n = 185, 73.7%); 63 patients (25.1%) attempted suicide. Compared with other involuntary patients, the patients who attempted suicide were less likely to use opiates (odds ratio 0.27, 95% confidence interval 0.08-0.94, P = 0.04) and to have medical disorders (odds ratio 0.52, 95% confidence interval 0.28-0.98, P = 0.04). CONCLUSIONS: Patients in this study differed from those in urban centers with respect to sex and psychiatric disorder; however, substance misuse was common in both settings. Suicidal ideation including suicide attempt was the most common reason for involuntary status. Patients who attempted suicide were similar to other patients on involuntary hold with respect to demographic and clinical variables.

Patients Threatening Harm to Others Evaluated in the Emergency Department under the Florida Involuntary Hold Act (Baker Act).

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.

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.

Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

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.

Opioid Use in Patients with Congestive Heart Failure.

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.

Violent behavior by emergency department patients with an involuntary hold status.

BACKGROUND: Violence against health care workers has been increasing. Health care workers in emergency departments (EDs) are highly vulnerable because they provide care for patients who may have mental illness, behavioral problems, or substance use disorders (alone or in combination) and who are often evaluated during an involuntary hold. Our objective was to identify factors that may be associated with violent behavior in ED patients during involuntary holds. METHODS: Retrospective review of patients evaluated during an involuntary hold at a suburban acute care hospital ED from January 2014 through November 2015. RESULTS: Of 251 patients, 22 (9%) had violent incidents in the ED. Violent patients were more likely to have a urine drug screen positive for tricyclic antidepressants (18.2% vs 4.8%, P=0.03) and to present with substance misuse (68.2% vs 39.7%, P=0.01), specifically with marijuana (22.7% vs 9.6%, P=0.06) and alcohol (54.5% vs 24.9%, P=0.003). ED readmission rates were higher for violent patients (18.2% vs 3.9%, P=0.02). No significant difference was found between violent patients and nonviolent patients for sex, race, marital status, insurance status, medical or psychiatric condition, reason for involuntary hold, or length of stay. CONCLUSION: Violent behavior by patients evaluated during an involuntary hold in a suburban acute care hospital ED was associated with tricyclic antidepressant use, substance misuse, and higher ED readmission rates.

Association of Anemia with Outcomes of Acute Heart Failure.

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 <10 g/dL on discharge from the hospital had higher mortality (3-year survival 46% vs 33%, P = 0.023) and 30-day readmission rates (23% vs 14%; P = 0.008) and increased LOS (4.8 vs 3.2 days, P < 0.001). Patients with admission HGB <10 g/dL had higher mortality rates (3-year survival 45% vs 32%, P = 0.019) and increased LOS (4.5 vs 3.4 days, P = 0.014). A lower admission HGB value was associated with higher 30-day readmission rates, but it was not statistically significant (P = 0.06). CONCLUSIONS: An HGB level <10 g/dL on admission or discharge in patients hospitalized with acute CHF is associated with a significantly worse outcome.

Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.

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 α 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%), IC1 (≥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. FUNDING: F Hoffmann-La Roche Ltd.