The dendritic ERGIC: Microtubule and actin cytoskeletons participate in stop-and-go movement of mobile carriers between stable structures.

The endoplasmic reticulum (ER)-to-Golgi intermediate compartment (ERGIC) is a membranous organelle that mediates protein transport between the ER and the Golgi apparatus. In neurons, clusters of these vesiculotubular structures are situated throughout the cell in proximity to the ER, passing cargo to the cis-Golgi cisternae, located mainly in the perinuclear region. Although ERGIC markers have been identified in neurons, the distribution and dynamics of neuronal ERGIC structures have not been characterized yet. Here, we show that long-distance ERGIC transport occurs via an intermittent mechanism in dendrites, with mobile elements moving between stationary structures. Slow and fast live-cell imaging have captured stable ERGIC structures remaining in place over long periods of time, as well as mobile ERGIC structures advancing very short distances along dendrites. These short distances have been consistent with the lengths between the stationary ERGIC structures. Kymography revealed ERGIC elements that moved intermittently, emerging from and fusing with stationary ERGIC structures. Interestingly, this movement apparently depends not only on the integrity of the microtubule cytoskeleton, as previously reported, but on the actin cytoskeleton as well. Our results indicate that the dendritic ERGIC has a dual nature, with both stationary and mobile structures. The neural ERGIC network transports proteins via a stop-and-go movement in which both the microtubule and the actin cytoskeletons participate.

Real-time estimation of nephron activity with a linear measurement system (RENAL-MS) predicts postoperative estimated glomerular filtration rate.

OBJECTIVE: To determine whether a simple point-of-care measurement system estimating renal parenchymal volume using tools ubiquitously available could be used to replace nuclear medicine renal scintigraphy (NMRS) in current clinical practice to predict estimated glomerular filtration rate (eGFR) after nephrectomy by estimating preoperative split renal function. PATIENTS AND METHODS: We performed a retrospective review of patients who underwent abdominal cross-sectional imaging (computed tomography/magnetic resonance imaging) and mercaptoacetyltriglycine (MAG3) NMRS prior to total nephrectomy at a single institution. We developed the real-time estimation of nephron activity with a linear measurement system (RENAL-MS) method of estimating postoperative renal function via the following technique: renal parenchymal volume of the removed kidney relative to the remaining kidney was estimated as the product of renal length and the average of six renal parenchymal thickness measurements. The utility of this value was compared to the utility of the split renal function measured by MAG3 for prediction of eGFR and new onset Stage 3 chronic kidney disease (CKD) at ≥90 days after nephrectomy using uni- and multivariate linear and logistic regression. RESULTS: A total of 57 patients met the study criteria. The median (interquartile range [IQR]) age was 69 (61-80) years. The median (IQR) pre- and postoperative eGFR was 74 (IQR 58-90) and 46 (35-62) mL/min/1.73 m2 , respectively. [Correction added on 29 December 2023, after first online publication: The data numbers in the preceding sentence have been corrected.] Correlations between actual and predicted postoperative eGFR were similar whether the RENAL-MS or NMRS methods were used, with correlation using RENAL-MS being slightly numerically but not statistically superior (R = 0.82 and 0.76; P = 0.138). Receiver operating characteristic curve analysis using logistic regression estimates incorporating age, sex, and preoperative creatinine to predict postoperative Stage 3 CKD were similar between RENAL-MS and NMRS (area under the curve 0.93 vs. 0.97). [Correction added on 29 December 2023, after first online publication: The data numbers in the preceding sentence have been corrected.] CONCLUSION: A point-of-care tool to estimate renal parenchymal volume (RENAL-MS) performed equally as well as NMRS to predict postoperative eGFR and de novo Stage 3 CKD after nephrectomy in our population, suggesting NMRS may not be necessary in this setting.

Pathological and Clinical Outcomes in a Large Surveillance and Intervention Cohort of Radiographically Cystic Renal Masses.

PURPOSE: We evaluated oncologic risks in a large cohort of patients with radiographic cystic renal masses who underwent active surveillance or intervention. MATERIALS AND METHODS: A single-institutional database of 4,340 kidney lesions managed with either active surveillance or intervention between 2000-2020 was queried for radiographically cystic renal masses. Association of radiographic tumor characteristics and high-grade pathology was evaluated. RESULTS: We identified 387 radiographically confirmed cystic lesions in 367 patients. Of these, 247 were resected (n=240) or ablated (n=7; n=247, 203 immediate vs 44 delayed intervention). Pathologically, 23% (n=56) demonstrated high-grade pathology. Cystic features were explicitly described by pathology in only 18% (n=33) of all lesions and in 7% (n=4) of high-grade lesions. Of the intervention cohort, African American race, male gender, and Bosniak score were associated with high-grade pathology (P < .05). On active surveillance (n=184), Bosniak IV lesions demonstrated faster growth rates than IIF and III lesions (2.7 vs 0.6 and 0.5 mm/y, P ≤ .001); however, growth rates were not associated with high-grade pathology (P = .5). No difference in cancer-specific survival was identified when comparing intervention vs active surveillance at 5 years (99% vs 100%, P = .2). No difference in recurrence was observed between immediate intervention vs delayed intervention (P > .9). CONCLUSIONS: A disconnect between "cystic" designation on imaging and pathology exists for renal lesions. Over 80% of radiographic Bosniak cystic lesions are not described as "cystic" on pathology reports. More than 1 in 5 resected cystic renal lesions demonstrated high-grade disease. Despite this finding, judiciously managed active surveillance ± delayed intervention is a safe and effective management option for most radiographic cystic renal masses.

Clinical Performance of Technetium-99m-Sestamibi SPECT/CT Imaging in Differentiating Oncocytic Tumors From Renal Cell Carcinoma in Routine Clinical Practice.

PURPOSE: Technetium-99m-sestamibi single-photon emission CT/x-ray CT is an emerging clinical tool to differentiate oncocytic tumors from renal cell carcinomas. We report data from a large institutional cohort of patients who underwent technetium-99m-sestamibi scans during evaluation of renal masses. MATERIALS AND METHODS: Patients who underwent technetium-99m-sestamibi single-photon emission CT/x-ray CT between February 2020 and December 2021 were included in the analysis. Scans were defined as "hot" for oncocytic tumor when technetium-99m-sestamibi uptake was qualitatively equivalent or higher between the mass of interest and normal renal parenchyma, suggesting oncocytoma, hybrid oncocytic/chromophobe tumor, or chromophobe renal cell carcinoma. Demographic, pathological, and management strategy data were compared between "hot" and "cold" scans. For individuals who underwent diagnostic biopsy or extirpative procedures, the concordance between radiological findings and pathology was indexed. RESULTS: A total of 71 patients (with 88 masses) underwent technetium-99m-sestamibi imaging with 60 (84.5%) patients having at least 1 "cold" mass on imaging and 11 (15.5%) patients exhibiting only "hot" masses. Pathology was available for 7 "hot" masses, with 1 biopsy specimen (14.3%) being discordant (clear cell renal cell carcinoma). Five patients with "cold" masses underwent biopsy. Out of 5 biopsied masses, 4 (80%) were discordant oncocytomas. Of the extirpated specimens, 35/40 (87.5%) harbored renal cell carcinoma and 5/40 (12.5%) yielded discordant oncocytomas. In sum, 20% of pathologically sampled masses that were "cold" on technetium-99m-sestamibi imaging still harbored oncocytoma/hybrid oncocytic/chromophobe tumor/chromophobe renal cell carcinoma. CONCLUSIONS: Further work is needed to define utility of technetium-99m-sestamibi in real-world clinical practice. Our data suggest this imaging strategy is not yet ready to replace biopsy.

Diabetes, Obesity, and Pathological Upstaging in Renal Cell Carcinoma: Results From a Large Multi-institutional Consortium.

PURPOSE: We sought to determine whether clinical risk factors and morphometric features on preoperative imaging can be utilized to identify those patients with cT1 tumors who are at higher risk of upstaging (pT3a). MATERIALS AND METHODS: We performed a retrospective international case-control study of consecutive patients treated surgically with radical or partial nephrectomy for nonmetastatic renal cell carcinoma (cT1 N0) conducted between January 2010 and December 2018. Multivariable logistic regression models were used to study associations of preoperative risk factors on pT3a pathological upstaging among all patients, as well as subsets with those with preoperative tumors ≤4 cm, renal nephrometry scores, tumors ≤4 cm with nephrometry scores, and clear cell histology. We also examined association with pT3a subsets (renal vein, sinus fat, perinephric fat). RESULTS: Among the 4,092 partial nephrectomy and 2,056 radical nephrectomy patients, pathological upstaging occurred in 4.9% and 23.3%, respectively. Among each group independent factors associated with pT3a upstaging were increasing preoperative tumor size, increasing age, and the presence of diabetes. Specifically, among partial nephrectomy subjects diabetes (OR=1.65; 95% CI 1.17, 2.29), male sex (OR=1.62; 95% CI 1.14, 2.33), and increasing BMI (OR=1.03; 95% CI 1.00, 1.05 per 1 unit BMI) were statistically associated with upstaging. Subset analyses identified hilar tumors as more likely to be upstaged (partial nephrectomy OR=1.91; 95% CI 1.12, 3.16; radical nephrectomy OR=2.16; 95% CI 1.44, 3.25). CONCLUSIONS: Diabetes and higher BMI were associated with pathological upstaging, as were preoperative tumor size, increased age, and male sex. Similarly, hilar tumors were frequently upstaged.

Female sexual function evaluation and intraoperative vaginal reconstruction in bladder cancer.

RC significantly negatively impacts sexual function (SF) in both men and women. While significant research resources have been allocated to examine the deleterious effects of post prostatectomy erectile dysfunction, little attention has been directed towards female sexual function and organ preservation post cystectomy. These academic shortcomings often result in poor provider awareness and inadequate preoperative assessment. As such, it is crucial for all providers involved in female RC care to understand the necessary and available tools for preoperative evaluation, in addition to the anatomic and reconstructive techniques. This review aims to summarize the current preoperative evaluation and available tools of SF assessment and describe in detail the varying operative techniques in the preservation or restoration of SF in women after RC. The review explores the intricacies of preoperative evaluation tools, and intraoperative techniques for organ- and nerve-sparing during radical cystectomy in females. Particular emphasis on vaginal reconstruction after partial or complete resection is provided, including split-thickness skin (STF) graft vaginoplasy, pedicled flaps, myocutaneous flaps and use of bowel segments. In conclusion, this narrative review highlights the importance of understanding anatomic considerations and nerve-sparing strategies in promoting postoperative SF and quality of life. Furthermore, the review describes the advantages and limitations of each organ- and nerve-sparing technique and their impact on sexual function and overall well-being.

Injecting Alone: Practices and Preferences among People Who Inject Drugs in New York City.

Injecting alone is a suspected risk factor for opioid overdose death among people who inject drugs (PWID). Better understanding of PWID's injecting practices and preferences could guide pragmatic harm reduction and overdose prevention interventions. We investigated injection practices and preferences among PWID attending syringe services programs (SSPs). We surveyed 108 PWID with opioid use disorder from 3 New York City SSPs between November 2020 and August 2021 to ascertain harm reduction service preferences. This secondary analysis examined injection behavior preferences, reasons for these preferences, and self-reported non-fatal lifetime overdoses. Slightly more participants preferred injecting alone (56%) than with someone present (44%), but most in both groups inject alone most of the time (97% vs 52%, p < 0.01). Commonly reported reasons for preferring to inject alone were privacy (82%) and not wanting to be judged (78%), whereas many preferred to inject with others to have someone present in case of overdose (92%), for camaraderie (69%), and to share drugs (65%). Those preferring to inject alone (vs. with someone present) self-reported higher mean number of lifetime overdoses (3.1 vs 2.6), but differences were not statistically significant. In conclusion, most participants injected alone regardless of preference. While not associated with prior non-fatal overdose, injection preference likely carries risk for future overdose. Participants preferred injecting alone to avoid shame or injecting with others in case of overdose, which can inform public health interventions that support both preferences. Reducing stigma while facilitating rapid overdose response can mitigate the risk of fatal overdose.

Differences in Survival Associated with Performance of Lymph Node Dissection in Patients with Invasive Penile Cancer: Results from the National Cancer Database.

PURPOSE: Inguinal lymphadenectomy remains under performed in patients with invasive penile cancer. Using a large national cancer registry we assessed temporal trends in inguinal lymphadenectomy performance and evaluated the impact of the procedure on survival in patients in whom inguinal lymphadenectomy was an absolute indication (T1b-4 N0/x-1) according to NCCN® (National Comprehensive Cancer Network®) Guidelines®. MATERIALS AND METHODS: We queried the National Cancer Database for all cases of nonmetastatic, T1b-4 N0/x-1 squamous cell carcinoma of the penis from 2004 to 2014. Multivariable logistic regression models adjusting for patient, demographic, and clinicopathological characteristics were used to examine the association between available covariates and receipt of inguinal lymphadenectomy. Cox proportional hazards regression analysis was then done to assess the impact of clinical and pathological variables on overall survival. Propensity score weighted analysis was performed to assess the effect of inguinal lymphadenectomy on overall survival. RESULTS: A total of 2,224 patients met analysis criteria, of whom 606 (27.2%) underwent inguinal lymphadenectomy. Following adjustment the procedure was more likely in younger patients, those who presented with palpable adenopathy (cN1), those treated at an academic facility and those with a more contemporary diagnosis. On survival analysis controlling for all known and measured confounders inguinal lymphadenectomy was associated with improved overall survival (HR 0.79, 95% CI 0.74-0.84, p <0.001). CONCLUSIONS: At hospitals that report to the National Cancer Database the overall rate of inguinal lymphadenectomy in patients with invasive penile cancer was only 27.2%. Inguinal lymphadenectomy was associated with increased overall survival, justifying the procedure as an important quality metric for performance reporting in patients with invasive penile cancer.

Comparison of functional outcomes of robotic and open partial nephrectomy in patients with pre-existing chronic kidney disease: a multicenter study.

BACKGROUND: We compared renal functional outcomes of robotic (RPN) and open partial nephrectomy (OPN) in patients with chronic kidney disease (CKD), a definite indication for nephron-sparing surgery. METHODS: A multicenter retrospective analysis of OPN and RPN in patients with baseline ≥ CKD Stage III [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2] was performed. Primary outcome was change in eGFR (ΔeGFR, mL/min/1.73 m2) between preoperative and last follow-up with respect to RENAL nephrometry score group [simple (4-6), intermediate (7-9), complex (10-12)]. Secondary outcomes included eGFR decline > 50%. RESULTS: 728 patients (426 OPN, 302 RPN, mean follow-up 33.3 months) were analyzed. Similar RENAL score distribution (p = 0.148) was noted between groups. RPN had lower median estimated blood loss (p < 0.001), and hospital stay (3 vs. 5 days, p < 0.001). Median ischemia time (OPN 23.7 vs. RPN 21.5 min, p = 0.089), positive margin (p = 0.256), transfusion (p = 0.166), and 30-day complications (p = 0.208) were similar. For OPN vs. RPN, mean ΔeGFR demonstrated no significant difference for simple (0.5 vs. 0.3, p = 0.328), intermediate (2.1 vs. 2.1, p = 0.384), and complex (4.9 vs. 6.1, p = 0.108). Cox regression analysis demonstrated that decreasing preoperative eGFR (OR 1.10, p = 0.001) and complex RENAL score (OR 5.61, p = 0.03) were independent predictors for eGFR decline > 50%. Kaplan-Meier analysis demonstrated 5-year freedom from eGFR decline > 50% of 88.6% for OPN and 88.3% for RPN (p = 0.724). CONCLUSIONS: RPN and OPN demonstrated similar renal functional outcomes when stratified by tumor complexity group. Increasing tumor age and tumor complexity were primary drivers associated with functional decline. RPN provides similar renal functional outcomes to OPN in appropriately selected patients.

Symptomatic and functional recovery after transurethral resection of bladder tumor: Data from ecological momentary symptom assessment.

OBJECTIVES: To quantitatively describe the nature, severity, and duration of symptoms and functional impairment during recovery from transurethral resection of bladder tumors. MATERIALS AND METHODS: All patients scheduled for transurethral resection were approached for enrollment in a text-message based ecological momentary symptom assessment platform. Nine patients reported outcomes were measured 7 days before surgery and on postoperative days 1, 2, 3, 5, 7, 10, and 14 using a 5-point Likert scale. Self-reported degree of hematuria was collected using a visual scale. Clinical data was collected via retrospective chart review. RESULTS: A total of 159 patients were analyzed. Postoperative symptoms were overall mild, with the largest differences from baseline to postoperative day 1 seen in dysuria (median 0/5 vs. 3/5) and ability to work (median 5/5 vs. 4/5). Recovery was generally rapid, with 76% of patients reporting ≥4/5 agreement with the statement "I feel recovered from surgery" by postoperative day 2, although 15% of patients reported persistently lower levels of agreement on postoperative day 10 or 14. Patients undergoing larger resections (≥2cm) did take longer to return to baseline in multiple symptom domains, but the difference of medians vs. those undergoing smaller resections was less than 1 day across all domains. Multivariable analysis suggested that receiving perioperative intravesical chemotherapy was associated with longer time to recovery. 84% of patients reported clear yellow urine by postoperative day 3. CONCLUSION: In this population, hematuria and negative effects on quality of life resulting from transurethral resection of bladder tumors were generally mild and short-lived, although a small number of patients experienced longer recoveries.

High Interest in Injectable Opioid Agonist Treatment With Hydromorphone Among Urban Syringe Service Program Participants.

BACKGROUND: Injectable opioid agonist treatment with hydromorphone (iOAT-H) is effective for persons who inject drugs (PWID) with opioid use disorder (OUD) but remains unavailable in the United States. Our objective was to determine interest in iOAT-H among syringe services program (SSP) participants. METHODS: We recruited PWID with OUD from SSPs in New York City. Interest in iOAT-H was assessed on a 4-point scale. We compared participants who were and were not interested in iOAT-H regarding sociodemographic characteristics and self-reported variables (past 30 days): heroin use, public injection practices, and participation in illegal activity other than drug possession. Participants reported their preferred OUD treatment and reasons for these preferences. RESULTS: Of 108 participants, most were male (69%), Hispanic (68%), and median age was 42 years. The median number of prior OUD treatment episodes was 6 (interquartile range: 2-12). Most (65%) were interested in iOAT-H. Interested participants (vs not interested) reported, over the prior 30 days, greater heroin use days (mean, 26.4 vs 22.3), injecting in public more times (median, 15 vs 6), and a higher percentage having participated in illegal activity (40% vs 16%). Preferences for OUD treatment were: iOAT-H (43%), methadone (39%), and buprenorphine (9%). Participants who preferred iOAT-H to conventional OUD treatments reported preferring injection as a route of administration and that available OUD treatments helped them insufficiently. CONCLUSIONS: SSP participants with OUD reported high interest in iOAT-H. Participants had attempted conventional treatments but still used heroin almost daily. We identified PWID at risk for opioid-related harms who potentially could benefit from iOAT-H.

Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-institutional Prospective Cohort Evaluation.

Neoadjuvant chemotherapy (NAC) is linked with clinical advantages in urothelial carcinoma for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive research into the influence of tumor mutation expression profiles and clinicopathologic factors on chemotherapy response, the role of the gut microbiome (GM) in bladder cancer chemotherapy response remains poorly understood. This study examines the variance in the GM of patients with bladder cancer compared with healthy adults, and investigates GM compositional differences between patients who respond to chemotherapy versus those who exhibit residual disease.Our study reveals distinct clustering, effectively separating the bladder cancer and healthy cohorts. However, no significant differences were observed between chemotherapy responders and nonresponders within community subgroups. Machine learning models based on responder status outperformed clinical variables in predicting complete response (AUC 0.88 vs. AUC 0.50), although no single microbial species emerged as a fully reliable biomarker.The evaluation of short chain fatty acid (SCFA) concentration in blood and stool revealed no correlation with responder status. Still, SCFA analysis showed a higher abundance of Akkermansia (rs = 0.51, P = 0.017) and Clostridia (rs = 0.52, P = 0.018), which correlated with increased levels of detectable fecal isobutyric acid. Higher levels of fecal Lactobacillus (rs = 0.49, P = 0.02) and Enterobacteriaceae (rs = 0.52, P < 0.03) correlated with increased fecal propionic acid.In conclusion, our study constitutes the first large-scale, multicenter assessment of GM composition, suggesting the potential for a complex microbial signature to predict patients more likely to respond to NAC based on multiple taxa. SIGNIFICANCE: Our study highlights results that link the composition of the GM to the efficacy of NAC in MIBC. We discovered that patients with higher levels of Bacteroides experienced a worse response to NAC. This microbial signature shows promise as a superior predictor of treatment response over traditional clinical variables. Although preliminary, our findings advocate for larger, more detailed studies to validate these associations.

A Description and Safety Overview of Irreversible Electroporation for Prostate Tissue Ablation in Intermediate-Risk Prostate Cancer Patients: Preliminary Results from the PRESERVE Trial.

The PRESERVE study (NCT04972097) aims to evaluate the safety and effectiveness of the NanoKnife System to ablate prostate tissue in patients with intermediate-risk prostate cancer (PCa). The NanoKnife uses irreversible electroporation (IRE) to deliver high-voltage electrical pulses to change the permeability of cell membranes, leading to cell death. A total of 121 subjects with organ-confined PCa ≤ T2c, prostate-specific antigens (PSAs) ≤ 15 ng/mL, and a Gleason score of 3 + 4 or 4 + 3 underwent focal ablation of the index lesion. The primary endpoints included negative in-field biopsy and adverse event incidence, type, and severity through 12 months. At the time of analysis, the trial had completed accrual with preliminary follow-up available. Demographics, disease characteristics, procedural details, PSA responses, and adverse events (AEs) are presented. The median (IQR) age at screening was 67.0 (61.0-72.0) years and Gleason distribution 3 + 4 (80.2%) and 4 + 3 (19.8%). At 6 months, all patients with available data (n = 74) experienced a median (IQR) percent reduction in PSA of 67.6% (52.3-82.2%). Only ten subjects (8.3%) experienced a Grade 3 adverse event; five were procedure-related. No Grade ≥ 4 AEs were reported. This study supports prior findings that IRE prostate ablation with the NanoKnife System can be performed safely. Final results are required to fully assess oncological, functional, and safety outcomes.