Tumor downstaging as an intermediate endpoint to assess the activity of neoadjuvant systemic therapy in patients with muscle-invasive bladder cancer.

BACKGROUND: Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre-NAC cT stage) on the OS of patients with MIBC treated with NAC. METHODS: The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2-4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability-weighted regression adjustment. RESULTS: Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P < .001 for NCDB), and it yielded better discrimination (incremental C index, 4.2 for RISC and 1.6 for NCDB). The treatment effect of NAC in achieving pDS was 2.07-fold (P < .001) in comparison with cystectomy alone. CONCLUSIONS: A decrease of at least 1 stage from the cT stage to the pT stage is associated with improved OS in patients with MIBC treated with NAC.

Comparative patient-centered outcomes (health state and adverse sexual symptoms) between adjuvant brachytherapy versus no adjuvant brachytherapy in early stage endometrial cancer.

PURPOSE: To determine a relationship between sexual functioning and health state among survivors of stage I endometrial cancer, and to examine whether adjuvant intravaginal radiotherapy (IVRT) affects these measures compared to hysterectomy alone. METHODS: Two hundred five survivors (>1 year from surgery) completed questionnaires containing the EuroQol (EQ5D) and the Female Sexual Function Index (FSFI). A total of 136 (66.3 %) underwent surgery alone, and 69 (33.7 %) received IVRT. Pearson correlation was used to correlate FSFI and EQ5D-Health State scores. Multivariable regression was performed to measure the impact of IVRT on sexual functioning and health state. RESULTS: A majority of patients (80 %) met criteria for sexual dysfunction by FSFI < 26.5. A significant correlation was detected between FSFI and EQ5D scores (Pearson correlation = 0.21, p = 0.003). Compared to the IVRT group, the surgery group was younger (p = 0.001) and trended toward more frequent use of minimally invasive surgery versus laparotomy (p = 0.08). Otherwise, the two groups were well balanced with respect to demographics, comorbidities, and baseline sexual activity. Controlling for age and surgery type, IVRT was not associated with poorer health state or sexual function. Receipt of laparotomy was associated with both poorer health state and sexual function (p = 0.0156 and p = 0.0247, respectively). CONCLUSIONS: Sexual functioning was generally poor among endometrial cancer survivors; however, those with improved FSFI scores tended to have superior health states. IVRT was not a significant risk factor; however, receipt of laparotomy appeared to be associated with poorer sexual functioning and health state.

Risk factors for heterotopic ossification in operatively treated proximal humeral fractures.

AIMS: Heterotopic ossification (HO) is a potentially devastating complication of the surgical treatment of a proximal humeral fracture. The literature on the rate and risk factors for the development of HO under these circumstances is lacking. The aim of this study was to determine the incidence and risk factors for the development of HO in these patients. METHODS: A retrospective analysis of 170 patients who underwent operative treatment for a proximal humeral fracture between 2005 and 2016, in a single institution, was undertaken. The mean follow-up was 18.2 months (1.5 to 140). The presence of HO was identified on follow-up radiographs. RESULTS: The incidence of HO was 15% (n = 26). Our multivariate model revealed that male sex (odds ratio (OR) 3.57, 95% confidence interval (CI) 1.30 to 9.80 compared to female) and dislocation as the initial injury (OR 5.01, 95% CI 1.31 to 19.22) were significantly associated with the formation of HO (p < 0.05) while no significant associations were seen for the age of the patient, the characteristics of the injury, or the type of operative treatment. CONCLUSION: This retrospective radiological study is the first to investigate the association between the method of surgical treatment for a proximal humeral fracture and the formation of HO postoperatively. We found that male sex and dislocation as the initial injury were risk factors for HO formation, whereas the method of surgical treatment, the age of the patient, and the pattern of the fracture were not predictive of HO formation. While additional studies are needed, these findings can help to identify those at an increased risk for HO formation under these circumstances. Cite this article: Bone Joint J 2020;102-B(4):539-544.

"Lipase Only, Please": Reducing Unnecessary Amylase Testing.

BACKGROUND: Serum amylase testing is not recommended for the workup of acute pancreatitis; yet it is commonly ordered in acute care settings. METHODS: This was a student-led quality improvement initiative with application of a pre-post study design at two urban hospitals: Mount Sinai Hospital, a 1,134-bed academic hospital, and Mount Sinai Queens, a 235-bed community hospital. The multifaceted intervention combined a targeted educational and awareness campaign with the decoupling of amylase from electronic order sets (at the academic hospital only), as well as a nonintrusive electronic medical record (EMR) advisory statement (at both hospitals). Monthly amylase orders were tracked for all emergency department visits and hospital admissions between January 2016 and May 2018 for both hospitals RESULTS: There was a significant and sustained decrease in amylase ordering at both the academic hospital (from 3,214 orders per month to 2,348 orders per month; p = 0.011) and the community hospital (from 100 orders per month to 23 orders per month; p = 0.001). Specifically, the nonintrusive EMR order advisory statement was independently associated with a significant reduction in serum amylase ordering. There was an estimated net annual cost reduction of $44,999. CONCLUSIONS: This student-led initiative was successful in reducing unnecessary amylase ordering across two diverse institutions through a combination of education, publicity, and EMR changes.

The impact of pathologic response to neoadjuvant chemotherapy on conditional survival among patients with muscle-invasive bladder cancer.

PURPOSE: Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with a favorable prognosis. Patients with pathologic residual disease (pRD) generally have poor outcomes. However, prognosis after radical cystectomy (RC) improves with ongoing survivorship. Our objective was to determine whether the difference in prognosis of patients with pCR and pRD changes over time. MATERIALS AND METHODS: We queried the National Cancer Database for patients who received NAC and RC for localized MIBC (cT2-T4aN0M0) between 1998 and 2012. pCR was defined as ≤Tis disease. Kaplan-Meier analysis was used to estimate conditional survival to 5 years given survival to 1, 2, 3, and 4 years post-RC. Cox proportional hazard modeling was used to estimate the effect of pRD vs. pCR on overall survival. RESULTS: The cohort comprised 1,553 patients (pCR: 314 and pRD: 1,239). With median follow-up 2.65 years (range 0.01-9.97), median survival was 2.5 years (95% confidence interval 2.2-2.9) and not reached for pRD and pCR, respectively. All patients had improved conditional survival with each additional year of survivorship. Patients with pCR had improved overall survival relative to those with pRD. The effect of pRD vs. pCR on conditional survival did not differ over time (P = 0.7). CONCLUSIONS: MIBC patients with pCR after NAC have improved conditional survival relative to those with pRD post-RC. This survival advantage does not significantly change over time. These findings may inform patient counseling, surveillance intensity, and novel adjuvant approaches for patients with pRD.

Programmed Death-1 or Programmed Death Ligand-1 Blockade in Patients with Platinum-resistant Metastatic Urothelial Cancer: A Systematic Review and Meta-analysis.

CONTEXT: Several anti-programmed death-1 (anti-PD-1) and anti-programmed death ligand-1 (anti-PD-L1) antibodies have been approved by regulatory authorities for treatment of platinum-resistant metastatic urothelial cancer (mUC). The impact of these therapies on survival, and comparability of PD-1 versus PD-L1 blockade are unknown. OBJECTIVE: To determine the restricted mean survival time (RMST) of patients with platinum-resistant mUC treated with PD-1/PD-L1 inhibitors and to compare RMSTs in patients treated with PD-1 versus PD-L1 inhibitors. EVIDENCE ACQUISITION: We searched for phase 1, 2, and 3 clinical trials that assessed PD-1 or PD-L1 inhibition for patients with platinum-resistant mUC. Literature review and study selection, data abstraction, and risk of bias assessment were performed by two reviewers. Survival data were reconstructed using an algorithm that derives individual time-to-event data from published Kaplan-Meier curves. The RMST with 95% confidence interval (CIs) was calculated. EVIDENCE SYNTHESIS: From 836 references, six clinical trials were included. Survival data were reconstructed for 1315 and 736 patients treated with PD-1/PD-L1 inhibitors and chemotherapy, respectively. The RMSTs with PD-1/PD-L1 blockade up to 12 and 18mo of follow-up were 7.8mo (95% CI 7.6, 8.1) and 10mo (95% CI 9.7, 10.5), respectively. A network meta-analysis of two randomized trials revealed no significant difference in the RMST up to 18mo with PD-1 versus PD-L1 blockade (1.0mo; 95% CI -0.5, 2.3mo). Using reconstructed survival data from all six trials, the RMSTs with PD-1 versus PD-L1 blockade up to 12 and 18mo follow-up were 7.8mo (95% CI 7.7, 8.2) versus 7.8mo (95% CI 7.5, 8.2) and 10.1mo (95% CI 9.6, 10.7) versus 10mo (95% CI 9.5, 10.6), respectively. CONCLUSIONS: Our RMST estimates may be used as benchmarks to contextualize survival outcomes and inform future trial design with PD-1/PD-L1 inhibitors. PD-1 versus PD-L1 blockade in patients with mUC yields comparable survival outcomes. PATIENT SUMMARY: In this study, we found that outcomes for patients with metastatic bladder cancer treated with programmed death-1 and programmed death ligand-1 inhibitors, who received prior platinum-based chemotherapy, were similar.

Early Mortality in Patients With Muscle-Invasive Bladder Cancer Undergoing Cystectomy in the United States.

BACKGROUND: Although radical cystectomy (RC) is a standard treatment for muscle-invasive bladder cancer (MIBC), for many patients the risks versus benefits of RC may favor other approaches. We sought to define the landscape of early postcystectomy mortality in the United States and identify patients at high risk using pretreatment variables. METHODS: We identified patients with MIBC (cT2-T4aN0M0) who underwent RC without perioperative chemotherapy within the National Cancer Database (2003-2012). Using multistate multivariable modeling, we calculated time spent in three health states: hospitalized, discharged, and death more than 90 days postcystectomy. Cross-validation was performed by geographic region. Time spent in each state was weighted by utility to determine 90-day quality-adjusted life days (QALDs). RESULTS: Among 7922 patients, 90-day mortality was 7.6% (8.0% for lower and 6.7% for higher volume hospitals). Increasing age, clinical T stage, Charlson Comorbidity Index, and lower volume were associated with higher 90-day mortality and were included in the model. Cross-validation revealed appropriate performance (C-statistics of 0.53-0.74; calibration slopes of 0.50-1.67). The model predicted 25% of patients had a 90-day mortality risk higher than 10%, and observed 90-day mortality in this group was 14.0% (95% CI = 12.5% to 15.6%). Mean quality-adjusted life days (QALDs) was 63 (range = 44-68). CONCLUSIONS: RC is associated with relatively high early mortality risk. Pretreatment variables may identify patients at particularly high risk, which may inform clinical trial design, facilitate shared decision making, and enhance quality improvement initiatives.

Telemedicine-Enabled Clinical Trial of Metformin in Patients With Prostate Cancer.

PURPOSE: Clinical trials are critical to informing cancer care but often are hampered by slow accrual and lack of generalizability because of poor geographic accessibility. We tested the feasibility of replacing onsite study visits with telemedicine visits in a prospective clinical trial. METHODS: Castration-naïve patients with prostate cancer and a rising serum prostate-specific antigen after definitive local therapy were eligible. Patients were required to have a single onsite visit for enrollment. Study treatment consisted of oral metformin 850 mg daily for 1 month followed by 850 mg twice daily for 5 months. Telehealth video visits (televisits) were conducted monthly by using a Health Insurance Portability and Accountability Act-compliant smartphone application. The primary objective was to determine the feasibility of telemedicine-enabled study visits. Secondary objectives were defining safety, anticancer activity, quality of life, and patient satisfaction. RESULTS: Fifteen patients with a median age of 68 years (range, 57 to 83 years) and median one-way driving time to the study center of 71 minutes (range, 12 to 147 minutes) were enrolled. The patients completed 84 eligible televisits (completion rate, 100%; 95% CI, 0.80 to 1). Diarrhea was the most common adverse event but was limited to grade 1 in severity; a single patient experienced grade ≥ 3 adverse events. Seven patients (46.7%; 95% CI, 24.8% to 69.9%) had a ≤ 20% increase in prostate-specific antigen relative to baseline. Patients agreed or strongly agreed that they would participate in a telemedicine-enabled clinical trial in the future. CONCLUSION: To our knowledge, this interventional oncology clinical trial is the first to be conducted through telemedicine. Telemedicine-enabled trials are feasible and may overcome geographic barriers to trial participation. Metformin was generally well tolerated but associated with modest anticancer activity.

Comparison of automated platelet counts and potential effect on transfusion decisions in cancer patients.

OBJECTIVES: To evaluate the accuracy of platelet counts from various hematology analyzers using a reference immunologic method. METHODS: We tested 403 samples with platelet counts less than 50 × 10(9)/L with the Advia (Siemens, Tarrytown, NY), Sysmex (Mundelein, IL), and Abbott (Santa Clara, CA) analyzers. RESULTS: All methods showed a positive bias, especially at less than 20 × 10(9)/L and less than 10 × 10(9)/L. Undertransfusion risk ranged from 9.1% to 43.3 % in the groups below 20 × 10(9)/L and below 10 × 10(9)/L, respectively. For patients with optical counts more than 10 × 10(9)/L and CD61 less than 10 × 10(9)/L, 64.5% were transfused within 24 hours of the reported count, while 35.5% were transfused in more than 24 hours, after a subsequent optical platelet count of 10 × 10(9)/L or less was reported. CONCLUSIONS: Although optical and impedance methods were shown to be falsely increased in severely thrombocytopenic samples, further studies are needed to determine if more accurate methods would be clinically useful.