Challenging the Urologist of the Future: Time for a Change?

Physicians need both medical expertise and diverse skills for effective patient care. Adaptability is also key in embracing advances in technology and new techniques. We outline six thought-provoking points to guide the new generation of urologists.

A unifying model for membrane protein biogenesis.

α-Helical integral membrane proteins comprise approximately 25% of the proteome in all organisms. The membrane proteome is highly diverse, varying in the number, topology, spacing and properties of transmembrane domains. This diversity imposes different constraints on the insertion of different regions of a membrane protein into the lipid bilayer. Here, we present a cohesive framework to explain membrane protein biogenesis, in which different parts of a nascent substrate are triaged between Oxa1 and SecY family members for insertion. In this model, Oxa1 family proteins insert transmembrane domains flanked by short translocated segments, whereas the SecY channel is required for insertion of transmembrane domains flanked by long translocated segments. Our unifying model rationalizes evolutionary, genetic, biochemical and structural data across organisms and provides a foundation for future mechanistic studies of membrane protein biogenesis.

Lean body mass in living kidney donors impacts postoperative renal function.

PURPOSE: A living donor kidney transplant is the optimal treatment for chronic renal impairment. Our objective is to assess if lean skeletal muscle mass and donor factors such as body mass index, hypertension, and age impact on renal function following donor nephrectomy. METHODS: Potential donors undergo CT angiography as part of their work-up in our institution. Using dedicated software (Horos®), standardized skeletal muscle area measured at the L3 vertebrae was calculated. When corrected for height, skeletal muscle index can be derived. Skeletal muscle mass index below predefined levels was classified as sarcopenic. The correlation of CT-derived skeletal muscle index and postoperative renal function at 12 months was assessed. Co-variables including donor gender, age, body mass index (BMI), and presence of pre-op hypertension were also assessed for their impact on postoperative renal function. RESULTS: 275 patients who underwent living donor nephrectomy over 10 years were included. Baseline pre-donation glomerular filtration rate (GFR) and renal function at one year post-op were similar between genders. 29% (n = 82) of patients met the criteria for CT-derived sarcopenia. Sarcopenic patients were more likely to have a higher GFR at one year post-op (69.3 vs 63.9 mL/min/1.73 m2, p < 0.001). The main factors impacting better renal function at one year were the presence of sarcopenia and younger age at donation. CONCLUSION: When selecting donors, this study highlights that patients with low skeletal mass are unlikely to underperform in terms of recovery of their renal function postoperatively at one year when compared to patients with normal muscle mass and should not be a barrier to kidney donation.

Secondary Analysis of the Rate of Second Primary Lung Cancer From Cancer and Leukemia Group B 140503 (Alliance) Trial of Lobar Versus Sublobar Resection for T1aN0 Non-Small-Cell Lung Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Patients with early-stage non-small-cell lung cancer (NSCLC) who undergo curative surgical resection are at risk for developing second primary lung cancer (SPLC). Cancer and Leukemia Group B 140503 (Alliance) was a multicenter, international, randomized, phase III trial in patients with stage T1aN0 NSCLC (using the TNM staging system seventh edition) and demonstrated the noninferiority for disease-free survival between sublobar resection (SLR) and lobar resection (LR). After surgery, patients underwent computed tomography surveillance as defined by the protocol. The determination of a SPLC was done by the treating physician and recorded in the study database. We performed an analysis of the rate of SPLC (per patient per year) and the 5-year cumulative incidence in the study population and within the SLR and LR arms. Median follow-up was 7 years. The rate per patient per year in the study population, in the SLR arm, and in the LR arm was 3.4% (95% CI, 2.9 to 4.1), 3.8% (95% CI, 2.9 to 4.9), and 3.1% (95% CI, 2.4 to 4.1), respectively. The estimated 5-year cumulative incidence of SPLC in the study population, SLR arm, and LR arm was 15.9% (95% CI, 12.9 to 18.9), 17.2% (95% CI, 12.7 to 21.5), and 14.7% (95% CI, 10.6 to 18.7), respectively.

The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout.

OBJECTIVES: Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase. METHODS: COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety. RESULTS: During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (-73.79% and -47.96%, P = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only. CONCLUSIONS: SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase. CLINICAL TRIAL REGISTRATION: NCT03905512.

Surgical management and post-operative functional outcomes of patients with a penile fracture-a single centre experience over 10 years.

BACKGROUND: Penile fractures are uncommon urological emergencies which occur when there has been a breach in the tunica albuginea of the corpora cavernosum that may be unilateral and bilateral and can extend to involve the urethra. AIM: To assess the management and outcomes of penile fractures in a single institution in Ireland. METHODS: A retrospective review of the emergency theatre logbooks was performed between 2011 and 2021 to identify patients who had undergone an exploration for a suspected penile fracture. OUTCOMES: Seventeen patients were initially identified on review of theatre logbooks as having an exploration for a suspected penile fracture. Two patients were excluded from the study due to a lack of clinical notes being available. A further 4 patients on chart review were found to not have a penile fracture at exploration. RESULTS: Eleven patients had a confirmed penile fracture intra-operatively, four of whom had an associated urethral injury. Nine (9/11) patients had preserved normal erections post-operatively documented on follow-up; two, however, reported erectile dysfunction requiring phosphodiesterase inhibitors. CLINICAL IMPLICATIONS: Our study supports urgent surgical exploration for penile fractures to ensure good functional outcomes. STRENGTHS AND LIMITATIONS: This is a retrospective review of theatre logbooks to identify patients with a suspected penile fracture. CONCLUSION: The results of our cohort show a good outcome of erectile function following surgical repair of a penile fracture (9/11; 82%). Four patients (4/11; 36%) had a urethral injury diagnosed intra-operatively, one of whom required a formal urethroplasty.

Surgical Approach for Partial Nephrectomy in the Management of Small Renal Masses: A Systematic Review and Network Meta-Analysis.

Background: A variety of surgical and nonsurgical management options for small renal masses (SRMs) now exist. Surgery in the form of partial nephrectomy (PN) has three different approaches. It is unclear which PN approach, if any, offers superior clinical outcomes. Aim: The aim of this study is to compare outcomes in patients with SRMs <4 cm undergoing PN through the open partial nephrectomy (OPN), laparoscopic partial nephrectomy (LPN), or robotic partial nephrectomy (RPN) approach and to establish the advantages and disadvantages of the various approaches. Methods: A systematic literature search was conducted for studies comparing at least two of the above techniques. Eighteen studies and 17,013 patients were included in our study. A network meta-analysis with a frequentist framework was performed. OPN was used as the baseline comparator. The prespecified primary outcome was R0 resection rates. Secondary outcomes included operating time, ischemia time, blood loss, transfusion rates, urine leak rates, significant morbidity, length of stay, and recurrence. Results: There was no significant difference between the techniques in terms of R0 rates, tumor recurrence, urine leak rates, renal function, and >3a Clavien-Dindo complications. LPN had a longer ischemic time and operating time. OPN had a longer length of stay and higher average intraoperative blood loss. RPN had lower blood transfusion rates. Discussion: All approaches are acceptable from an oncological perspective. The minimally invasive approaches (i.e., RPN and LPN) offer advantages in terms of morbidity; however, LPN may increase ischemic time and operative duration. Variations between perioperative outcomes may influence the choice of approach on a case-by-case and institutional basis.

Lobectomy, segmentectomy, or wedge resection for peripheral clinical T1aN0 non-small cell lung cancer: A post hoc analysis of CALGB 140503 (Alliance).

BACKGROUND: We have recently reported the primary results of CALGB 140503 (Alliance), a randomized trial in patients with peripheral cT1aN0 non-small cell lung cancer (American Joint Committee on Cancer seventh) treated with either lobar resection (LR) or sublobar resection (SLR). Here we report differences in disease-free survival (DFS), overall survival (OS) and lung cancer-specific survival (LCSS) between LR, segmental resection (SR), and wedge resection (WR). We also report differences between WR and SR in terms of surgical margins, rate of locoregional recurrence (LRR), and expiratory flow rate at 6 months postoperatively. METHODS: Between June 2007 and March 2017, a total of 697 patients were randomized to LR (n = 357) or SLR (n = 340) stratified by clinical tumor size, histology, and smoking history. Ten patients were converted from SLR to LR, and 5 patients were converted from LR to SLR. Survival endpoints were estimated using the Kaplan-Maier estimator and tested by the stratified log-rank test. The Kruskal-Wallis test was used to compare margins and changes in forced expiratory volume in 1 second (FEV1) between groups, and the χ2 test was used to test the associations between recurrence and groups. RESULTS: A total of 362 patients had LR, 131 had SR, and 204 had WR. Basic demographic and clinical and pathologic characteristics were similar in the 3 groups. Five-year DFS was 64.7% after LR (95% confidence interval [CI], 59.6%-70.1%), 63.8% after SR (95% CI, 55.6%-73.2%), and 62.5% after WR (95% CI, 55.8%-69.9%) (P = .888, log-rank test). Five-year OS was 78.7% after LR, 81.9% after SR, and 79.7% after WR (P = .873, log-rank test). Five-year LCSS was 86.8% after LR, 89.2% after SR, and 89.7% after WR (P = .903, log-rank test). LRR occurred in 12% after SR and in 14% after WR (P = .295). At 6 months postoperatively, the median reduction in % FEV1 was 5% after WR and 3% after SR (P = .930). CONCLUSIONS: In this large randomized trial, LR, SR, and WR were associated with similar survival outcomes. Although LRR was numerically higher after WR compared to SR, the difference was not statistically significant. There was no significant difference in the reduction of FEV1 between the SR and WR groups.

Factors Associated with Self-reported COVID-19 Infection and Hospitalization among Patients Seeking Care at a Comprehensive Cancer Center.

BACKGROUND: COVID-19 infection severity differs by race and ethnicity, but its long-term effect on cancer-related outcomes is unknown. Therefore, information on COVID-19 history is critical to ascertain among new cancer patients in order to advance research on its impact on cancer outcomes and potentially related health disparities. METHODS: A cross-sectional study was conducted among 16,025 new patients seeking care at Moffitt Cancer Center (MCC) between 2021 and 2022. Patient self-reported histories of COVID-19 infection and other pre-existing health conditions were obtained from electronic questionnaires administered to all new MCC patients. Associations between demographics and COVID-19 infection and hospitalization were examined. RESULTS: A total of 1,971 patients (12.3%) reported ever having COVID-19. Self-reported COVID-19 history was significantly more prevalent in Hispanic vs. non-Hispanic patients (OR = 1.24, 1.05-1.45) and less prevalent in Asian versus White patients (OR = 0.49, 95% 0.33-0.70). Among patients who ever had COVID-19, 10.6% reported a COVID-19-related hospitalization. Males had higher odds of a COVID-19 related hospitalization than females (OR = 1.50, 95% CI = 1.09-2.05), as did Black/African American patients (OR = 2.11, 95% CI = 1.18-3.60) and patients of races other than Black/African American and Asian (OR = 2.61, 95% CI = 1.43-4.54) compared to White patients. Hispanic patients also experienced higher odds of hospitalization (OR = 2.06, 95% CI-1.29- 3.23) compared with non-Hispanic patients of all races in a sensitivity analysis that combined race/ethnicity. Pre-existing lung and breathing problems were associated with higher odds of being hospitalized with COVID-19 (OR = 2.38, 95% CI = 1.61-3.48), but these and other health conditions did not explain the observed associations between race and COVID-19 hospitalization. CONCLUSIONS: Higher rates of COVID-19 hospitalization were observed among patients identifying as Black/African American or Hispanic independent of pre-existing health conditions. Future studies evaluating long-term effects of COVID-19 should carefully examine potential racial/ethnic disparities in cancer outcomes.

Salinity and total suspended solids control mercury speciation in a tidal river: Comparisons with a photochemical mercury model.

Daytime volatilization of gaseous elemental mercury (Hg(0)aq) is a significant mechanism for mercury removal from aquatic systems and potentially limits the production and bioaccumulation of methylmercury. Changes in incoming solar radiation (in the ultraviolet range), dissolved organic matter, salinity, and total suspended particles were investigated concurrently with several mercury species (Hg(0)aq, dissolved total mercury (THg), easily reducible mercury (ERM), and mercury associated with total suspended solids (THgTSS)) during daylight hours near the mouth of a hypertidal river. There were no predictable temporal changes observed for Hg(0)aq in unfiltered surface water. Hg(0)aq ranged from 0 to 12 pg L-1, THg ranged from 0 to 492 pg L-1, ERM ranged from 13 to 381 pg L-1, and THgTSS ranged from <1.58 ng g-1 to 261.32 ng g-1. The range of Hg(0)aq predicted by the empirical model was similar to measured ERM concentrations, but it was shown that ERM did not significantly predict in-situ photoreducible Hg(II) (Hg(II)RED). Production of Hg(0)aq appears to largely be suppressed by suspended solids, which limits ultraviolet radiation transmission through surface water. Comparison of these results to an empirical model developed for this site to predict Hg(0)aq indicates that significantly more mercury is available for photoreduction near the mouth of the tidal river, and that Hg(II) will likely photoreduce quickly when TSS levels decrease with ocean mixing.

Examining disparities in large-scale patient-reported data capture using digital tools among cancer patients at clinical intake.

BACKGROUND: Patient-reported data can improve quality of healthcare delivery and patient outcomes. Moffitt Cancer Center ("Moffitt") administers the Electronic Patient Questionnaire (EPQ) to collect data on demographics, including sexual orientation and gender identity (SOGI), medical history, cancer risk factors, and quality of life. Here we investigated differences in EPQ completion by demographic and cancer characteristics. METHODS: An analysis including 146,142 new adult patients at Moffitt in 2009-2020 was conducted using scheduling, EPQ and cancer registry data. EPQ completion was described by calendar year and demographics. Logistic regression was used to estimate associations between demographic/cancer characteristics and EPQ completion. More recently collected information on SOGI were described. RESULTS: Patient portal usage (81%) and EPQ completion rates (79%) were consistently high since 2014. Among patients in the cancer registry, females were more likely to complete the EPQ than males (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.14-1.20). Patients ages 18-64 years were more likely to complete the EPQ than patients aged ≥65. Lower EPQ completion rates were observed among Black or African American patients (OR = 0.59, 95% CI = 0.56-0.63) as compared to Whites and among patients whose preferred language was Spanish (OR = 0.40, 95% CI = 0.36-0.44) or another language as compared to English. Furthermore, patients with localized (OR = 1.16, 95% CI = 1.12-1.19) or regional (OR = 1.16, 95% CI = 1.12-1.20) cancer were more likely to complete the EPQ compared to those with metastatic disease. Less than 3% of patients self-identified as being lesbian, gay, or bisexual and <0.1% self-identified as transgender, genderqueer, or other. CONCLUSIONS: EPQ completion rates differed across demographics highlighting opportunities for targeted process improvement. Healthcare organizations should evaluate data acquisition methods to identify potential disparities in data completeness that can impact quality of clinical care and generalizability of self-reported data.

A Prospective Multi-institutional Study Using a Novel Safety Valve for the Prevention of Catheter Balloon Inflation Injury of the Urethra.

PURPOSE: We prospectively assessed the ability of a novel transurethral catheterization safety valve to prevent urethral catheter balloon injury in a multi-institutional clinical setting. MATERIALS AND METHODS: A prospective, multi-institution study was conducted. The safety valve was introduced for urinary catheterization in 6 hospital groups (4 in Ireland; 2 in the UK). The safety valve allows fluid in the catheter system to vent through a pressure relief valve if attempted intraurethral inflation of the catheter's anchoring balloon occurs. Device usage was studied over a 12-month period, with data recorded using a 7-item data sticker containing a scannable QR code. "Venting" through the safety valve during catheterization was indicative of prevention of a urethral injury. An embedded 3-month study was conducted in 3 centers, with any catheter balloon injuries occurring during catheterization without safety valve use referred to the on-call urology team recorded. Health economic analyses were also performed. RESULTS: During the overall 12-month device study phase, 994 urethral catheterizations were performed across study sites. Twenty-two (2.2%) episodes of safety valve venting were recorded. No urethral injuries occurred in these patients. In the embedded 3-month study, 18 catheter balloon injuries were recorded in association with catheterizations performed without the safety valve. Based on confirmed and device-prevented urethral injuries, the injury rate for urethral catheterization without safety valve use was calculated to be 5.5/1,000 catheterizations. CONCLUSIONS: The safety valve has the potential to eliminate catheter balloon injury if widely adopted. It represents a simple, effective, and innovative solution to this recurring problem applicable to all patient cohorts.

Lobar or Sublobar Resection for Peripheral Stage IA Non-Small-Cell Lung Cancer.

BACKGROUND: The increased detection of small-sized peripheral non-small-cell lung cancer (NSCLC) has renewed interest in sublobar resection in lieu of lobectomy. METHODS: We conducted a multicenter, noninferiority, phase 3 trial in which patients with NSCLC clinically staged as T1aN0 (tumor size, ≤2 cm) were randomly assigned to undergo sublobar resection or lobar resection after intraoperative confirmation of node-negative disease. The primary end point was disease-free survival, defined as the time between randomization and disease recurrence or death from any cause. Secondary end points were overall survival, locoregional and systemic recurrence, and pulmonary functions. RESULTS: From June 2007 through March 2017, a total of 697 patients were assigned to undergo sublobar resection (340 patients) or lobar resection (357 patients). After a median follow-up of 7 years, sublobar resection was noninferior to lobar resection for disease-free survival (hazard ratio for disease recurrence or death, 1.01; 90% confidence interval [CI], 0.83 to 1.24). In addition, overall survival after sublobar resection was similar to that after lobar resection (hazard ratio for death, 0.95; 95% CI, 0.72 to 1.26). The 5-year disease-free survival was 63.6% (95% CI, 57.9 to 68.8) after sublobar resection and 64.1% (95% CI, 58.5 to 69.0) after lobar resection. The 5-year overall survival was 80.3% (95% CI, 75.5 to 84.3) after sublobar resection and 78.9% (95% CI, 74.1 to 82.9) after lobar resection. No substantial difference was seen between the two groups in the incidence of locoregional or distant recurrence. At 6 months postoperatively, a between-group difference of 2 percentage points was measured in the median percentage of predicted forced expiratory volume in 1 second, favoring the sublobar-resection group. CONCLUSIONS: In patients with peripheral NSCLC with a tumor size of 2 cm or less and pathologically confirmed node-negative disease in the hilar and mediastinal lymph nodes, sublobar resection was not inferior to lobectomy with respect to disease-free survival. Overall survival was similar with the two procedures. (Funded by the National Cancer Institute and others; CALGB 140503 ClinicalTrials.gov number, NCT00499330.).

Mercury photoreduction and photooxidation kinetics in estuarine water: Effects of salinity and dissolved organic matter.

Net photoreduction of divalent mercury (Hg(II)) and volatilization of photoreduction products (i.e., elemental mercury (Hg(0))/dissolved gaseous mercury (DGM)) is a mechanism by which mercury burdens in ecosystems are lessened. The effects of salinity on mercury photoreactions were investigated while controlling the concentration of DOM (>1 kDa) using natural surface water from the tidal Jijuktu'kwejk (Cornwallis River) and processed with a tangential ultrafiltration-dilution technique. Pseudo first-order rate constants in estuarine water salinity dilutions ranged between 0.22 h-1 and 0.73 h-1. The amount of mercury available for photoreduction (Hg(II)RED) ranged between 67.2 and 265.9 pg. Pseudo first-order rate constants decreased with increasing salinity treatments (0-13.5 g L-1), with minimal change in rate constants occurring in higher salinity treatments (e.g. 20.3 or 26.8 g L-1), while Hg(II)RED increased with salinity. In lower salinity treatments, DOM was more photoactive. Taken together, results suggest changes in the mercury photoreduction mechanism from DOM-bound electron transfer to photochemically produced secondary reduction products with increasing salinity. Experiments examining photooxidation showed decreases in Hg (0) with longer exposure time, suggesting transformation of Hg(II)RED into a non-reducible form. This research highlights the importance of salinity and DOM interactions in estuarine surface water and their effects on mercury photochemistry.

Substrate-driven assembly of a translocon for multipass membrane proteins.

Most membrane proteins are synthesized on endoplasmic reticulum (ER)-bound ribosomes docked at the translocon, a heterogeneous ensemble of transmembrane factors operating on the nascent chain1,2. How the translocon coordinates the actions of these factors to accommodate its different substrates is not well understood. Here we define the composition, function and assembly of a translocon specialized for multipass membrane protein biogenesis3. This 'multipass translocon' is distinguished by three components that selectively bind the ribosome-Sec61 complex during multipass protein synthesis: the GET- and EMC-like (GEL), protein associated with translocon (PAT) and back of Sec61 (BOS) complexes. Analysis of insertion intermediates reveals how features of the nascent chain trigger multipass translocon assembly. Reconstitution studies demonstrate a role for multipass translocon components in protein topogenesis, and cells lacking these components show reduced multipass protein stability. These results establish the mechanism by which nascent multipass proteins selectively recruit the multipass translocon to facilitate their biogenesis. More broadly, they define the ER translocon as a dynamic assembly whose subunit composition adjusts co-translationally to accommodate the biosynthetic needs of its diverse range of substrates.

Mechanism of an intramembrane chaperone for multipass membrane proteins.

Multipass membrane proteins play numerous roles in biology and include receptors, transporters, ion channels and enzymes1,2. How multipass proteins are co-translationally inserted and folded at the endoplasmic reticulum is not well understood2. The prevailing model posits that each transmembrane domain (TMD) of a multipass protein successively passes into the lipid bilayer through a front-side lateral gate of the Sec61 protein translocation channel3-9. The PAT complex, an intramembrane chaperone comprising Asterix and CCDC47, engages early TMDs of multipass proteins to promote their biogenesis by an unknown mechanism10. Here, biochemical and structural analysis of intermediates during multipass protein biogenesis showed that the nascent chain is not engaged with Sec61, which is occluded and latched closed by CCDC47. Instead, Asterix binds to and redirects the substrate to a location behind Sec61, where the PAT complex contributes to a multipass translocon surrounding a semi-enclosed, lipid-filled cavity11. Detection of multiple TMDs in this cavity after their emergence from the ribosome suggests that multipass proteins insert and fold behind Sec61. Accordingly, biogenesis of several multipass proteins was unimpeded by inhibitors of the Sec61 lateral gate. These findings elucidate the mechanism of an intramembrane chaperone and suggest a new framework for multipass membrane protein biogenesis at the endoplasmic reticulum.

Evaluation of Antibody Response to SARS-CoV-2 mRNA-1273 Vaccination in Patients With Cancer in Florida.

Importance: Patients with cancer experience high rates of morbidity and mortality after SARS-CoV-2 infection. Immune response to mRNA-1273 vaccination across multiple cancer types and treatments remains to be established. Objective: To quantitate antibody responses after mRNA-1273 vaccination among patients with solid tumors and hematologic cancer and to assess clinical and treatment factors associated with vaccine response. Design, Setting, and Participants: This cohort study included patients with cancer who were aged 18 years or older, spoke English or Spanish, had received their first mRNA-1273 dose between January 12 and 25, 2021, and agreed to blood tests before and after vaccination. Exposures: Receipt of 1 and 2 mRNA-1273 SARS-CoV-2 vaccine doses. Main Outcomes and Measures: Seroconversion after each vaccine dose and IgG levels against SARS-CoV-2 spike protein obtained immediately before the first and second vaccine doses and 57 days (plus or minus 14 days) after the first vaccine dose. Cancer diagnoses and treatments were ascertained by medical record review. Serostatus was assessed via enzyme-linked immunosorbent assay. Paired t tests were applied to examine days 1, 29, and 57 SARS-CoV-2 antibody levels. Binding antibody IgG geometric mean titers were calculated based on log10-transformed values. Results: The 515 participants were a mean (SD) age of 64.5 (11.4) years; 262 (50.9%) were women; and 32 (6.2%) were Hispanic individuals and 479 (93.0%) White individuals; race and ethnicity data on 4 (0.7%) participants were missing. Seropositivity after vaccine dose 2 was 90.3% (465; 95% CI, 87.4%-92.7%) among patients with cancer, was significantly lower among patients with hematologic cancer (84.7% [255]; 95% CI, 80.1%-88.6%) vs solid tumors (98.1% [210]; 95% CI, 95.3%-99.5%), and was lowest among patients with lymphoid cancer (70.0% [77]; 95% CI, 60.5%-78.4%). Patients receiving a vaccination within 6 months after anti-CD20 monoclonal antibody treatment had a significantly lower seroconversion (6.3% [1]; 95% CI, 0.2%-30.2%) compared with those treated 6 to 24 months earlier (53.3% [8]; 95% CI, 26.6%-78.7%) or those who never received anti-CD20 treatment (94.2% [456]; 95% CI, 91.7%-96.1%). Low antibody levels after vaccination were observed among patients treated with anti-CD20 within 6 months before vaccination (GM, 15.5 AU/mL; 95% CI, 9.8-24.5 AU/mL), patients treated with small molecules (GM, 646.7 AU/mL; 95% CI, 441.9-946.5 AU/mL), and patients with low lymphocyte (GM, 547.4 AU/mL; 95% CI, 375.5-797.7 AU/mL) and IgG (GM, 494.7 AU/mL; 95% CI, 304.9-802.7 AU/mL) levels. Conclusions and Relevance: This cohort study found that the mRNA-1273 SARS-CoV-2 vaccine induced variable antibody responses that differed by cancer diagnosis and treatment received. These findings suggest that patients with hematologic cancer and those who are receiving immunosuppressive treatments may need additional vaccination doses.

Symptomatic Hydronephrosis and Ureteral Calculi in Pregnancy: A Narrative Review with a Proposed Management Protocol.

Introduction: Approximately 3% of pregnancies are complicated by symptomatic hydronephrosis and up to 0.8% with urolithiasis. Pain, coupled with the possibility of superimposed infection, increases the risks of premature labor and delivery, fetal loss, and caesarian sections. Surgical intervention as well as standard ionizing radiation imaging modalities are typically avoided making this a difficult, high-risk patient cohort to manage. In this study we propose a standardized contemporaneous approach to investigations and management in the pregnant population with acute upper tract pathology analysis. Methods: A literature search of PubMed, Cochrane, and EMBASE databases was performed to identify original, peer-reviewed articles from 2010 onward on the management of ureteral calculi and symptomatic hydronephrosis occurring during pregnancy. Search yielded 5636 articles and after exclusions, 24 full-text articles met inclusion criteria for analysis. Evidence Synthesis: Ultrasound remains the cornerstone of initial investigation with MRI in reserve if the diagnosis remains uncertain. Low-dose CT imaging can be used in limited cases. Conservative approaches for symptomatic hydronephrosis as well ureteral calculi is the preferred initial management option in the well patient. If intervention is required, ureteral stent and nephrostomy can be used with informed consent on the risks and benefits of each. Primary ureteroscopy with definitive stone management in centers with the appropriate expertise can safely deliver excellent stone-free rates and symptomatic improvement. Conclusions: Individualized investigation and management plans following a structured approach in pregnant women with symptomatic hydronephrosis or calculi are discussed. At all stages, the patient, obstetrician, anesthetist, and surgeon should be involved in a shared decision-making approach.

Pegloticase causes prolonged improvement in multiple disease parameters in patients with chronic refractory gout who maintain low serum urate levels.

OBJECTIVES: To assess the benefit of long-term urate-lowering with pegloticase. METHODS: The results from two, 6-month, randomised controlled trials (RCTs) and their 30-month open-label extension (OLE) were analysed. Efficacy was assessed in urate responders (patients with plasma urate <6.0 mg/dL for ≥80% of assessments around the 3- and 6-month time periods) to the approved regimen (8 mg every 2 weeks [q2w]) and responders to q4w treatment. Assessments included serum urate (sU), Patient Global Assessment (PtGA), tender and swollen joints (TJC and SJC), pain, Health Assessment Questionnaire Disability Index, bodily pain, the Arthritis-Specific Health Index, and reduction of target tophi. RESULTS: 34 responders to pegloticase in the RCTs were followed throughout the 2.5 years of the OLE. Of these, 20 received 8 mg pegloticase q2w and 14 q4w. The results for patients who received pegloticase q2w indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.0001), PtGA (p<0.0001), TJC (p=0.0001), and SJC (p=0.0014); 61.5%, had complete target tophus resolution. The results for patients treated monthly indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.001), PGA (p=0.0003), TJC (p=0.008), and SJC (p<0.0001);100% had complete target tophus resolution. CONCLUSIONS: There were significant sustained clinical benefits with long-term pegloticase treatment in patients with chronic refractory gout achieving a urate-lowering effect during the first 6 months of therapy and followed for up to 30 additional months.