Limitations of Parenchymal Volume Analysis for Estimating Split Renal Function and New Baseline Glomerular Filtration Rate After Radical Nephrectomy.

PURPOSE: Accurately predicting new baseline glomerular filtration rate (NBGFR) after radical nephrectomy (RN) can improve counseling about RN vs partial nephrectomy. Split renal function (SRF)-based models are optimal, and differential parenchymal volume analysis (PVA) is more accurate than nuclear renal scans (NRS) for this purpose. However, there are minimal data regarding the limitations of PVA. Our objective was to identify patient-/tumor-related factors associated with PVA inaccuracy. MATERIALS AND METHODS: Five hundred and ninety-eight RN patients (2006-2021) with preoperative CT/MRI were retrospectively analyzed, with 235 also having NRS. Our SRF-based model to predict NBGFR was: 1.25 × (GlobalGFRPre-RN × SRFContralateral), where GFR indicates glomerular filtration rate, with SRF determined by PVA or NRS, and with 1.25 representing the median renal functional compensation in adults. Accuracy of predicted NBGFR within 15% of observed was evaluated in various patient/tumor cohorts using multivariable logistic regression analysis. RESULTS: PVA and NRS accuracy were 73%/52% overall, and 71%/52% in patients with both studies (n = 235, P < .001), respectively. PVA inaccuracy independently associated with pyelonephritis, hydronephrosis, renal vein thrombosis, and infiltrative features (all P < .03). Ipsilateral hydronephrosis and renal vein thrombosis associated with PVA underprediction, while contralateral hydronephrosis and increased age associated with PVA overprediction (all P < .01). NRS inaccuracy was more common and did not associate with any of these conditions. Even among cohorts where PVA inaccuracy was observed (22% of our patients), there was no significant difference in the accuracies of NRS- and PVA-based predictions. CONCLUSIONS: PVA was more accurate for predicting NBGFR after RN than NRS. Inaccuracy of PVA correlated with factors that distort the parenchymal volume/function relationship or alter renal functional compensation. NRS inaccuracy was more common and unpredictable, likely reflecting the inherent inaccuracy of NRS. Awareness of cohorts where PVA is less accurate can help guide clinical decision-making.

Practical Prediction of New Baseline Renal Function After Partial Nephrectomy.

BACKGROUND: Partial nephrectomy (PN) is generally preferred for localized renal masses due to strong functional outcomes. Accurate prediction of new baseline glomerular filtration rate (NBGFR) after PN may facilitate preoperative counseling because NBGFR may affect long-term survival, particularly for patients with preoperative chronic kidney disease. Methods for predicting parenchymal volume preservation, and by extension NBGFR, have been proposed, including those based on contact surface area (CSA) or direct measurement of tissue likely to be excised/devascularized during PN. We previously reported that presuming 89% of global GFR preservation (the median value saved from previous, independent analyses) is as accurate as the more subjective/labor-intensive CSA and direct measurement approaches. More recently, several promising complex/multivariable predictive algorithms have been published, which typically include tumor, patient, and surgical factors. In this study, we compare our conceptually simple approach (NBGFRPost-PN = 0.90 × GFRPre-PN) with these sophisticated algorithms, presuming that an even 90% of the global GFR is saved with each PN. PATIENTS AND METHODS: A total of 631 patients with bilateral kidneys who underwent PN at Cleveland Clinic (2012-2014) for localized renal masses with available preoperative/postoperative GFR were analyzed. NBGFR was defined as the final GFR 3-12 months post-PN. Predictive accuracies were assessed from correlation coefficients (r) and mean squared errors (MSE). RESULTS: Our conceptually simple approach based on uniform 90% functional preservation had equivalent r values when compared with complex, multivariable models, and had the lowest degree of error when predicting NBGFR post-PN. CONCLUSIONS: Our simple formula performs equally well as complex algorithms when predicting NBGFR after PN. Strong anchoring by preoperative GFR and minimal functional loss (≈ 10%) with the typical PN likely account for these observations. This formula is practical and can facilitate counseling about expected postoperative functional outcomes after PN.

Thermal Ablation Versus Partial Nephrectomy for cT1 Renal Mass in a Solitary Kidney: A Matched Cohort Comparative Analysis.

BACKGROUND: Nephron-sparing approaches are preferred for renal mass in a solitary kidney (RMSK), with partial nephrectomy (PN) generally prioritized. Thermal ablation (TA) also is an option for small renal masses in this setting; however, comparative functional/survival outcomes are not well-defined. METHODS: A retrospective study of 504 patients (1975-2022) with cT1 RMSK managed with PN (n = 409)/TA (n = 95) with necessary data for analysis was performed. Propensity score was used for matching patients, including age, preoperative glomerular filtration rate (GFR), tumor diameter, R.E.N.A.L. ((R)adius (tumor size as maximal diameter), (E)xophytic/endophytic properties of tumor, (N)earness of tumor deepest portion to collecting system or sinus, (A)nterior (a)/posterior (p) descriptor, and (L)ocation relative to polar lines), and comorbidities. Functional outcomes were compared, and Kaplan-Meier was used to analyze survival. RESULTS: The matched cohort included 132 patients (TA = 66/PN = 66), with median tumor diameter of 2.4 cm, R.E.N.A.L. of 6, and preoperative GFR of 52 ml/min/1.73 m2. Acute kidney injury occurred in 11%/61% in the TA/PN cohorts, respectively (p < 0.01). After recovery, median GFR preserved was 89%/83% for TA/PN, respectively (p = 0.02), and 5-year dialysis-free survival was 96% in both cohorts. Median follow-up was 53 months. Five-year recurrence-free survival (RFS) was 62%/86% in the TA/PN cohorts, respectively (p < 0.01). Five-year local recurrence (LR)-free survival was 74%/95% in the TA/PN cohorts, respectively (p < 0.01). Five-year cancer-specific survival (CSS) was 96%/98% in the TA/PN cohorts, respectively (p = 0.7). Local recurrence was observed in nine of 36 (25%) and five of 30 (17%) patients managed with laparoscopic versus percutaneous TA, respectively. For TA with LR (n = 14), nine patients presented with multifocality and/or cT1b tumors. Twelve LR were managed with salvage TA, and seven remained cancer-free, while five developed systemic recurrence, three with concomitant LR. CONCLUSIONS: Functional outcomes for TA for RMSK were improved compared with PN. Local recurrence was more common after TA and often was associated with the laparoscopic approach, multifocality, and large tumor size. Improved patient selection and greater experience with TA should improve outcomes. Salvage of LR was not always possible. Partial nephrectomy remains the reference standard for RMSK.

PADRES: a phase 2 clinical trial of neoadjuvant axitinib for complex partial nephrectomy.

OBJECTIVE: To report the results of PADRES (Prior Axitinib as a Determinant of Outcome of Renal Surgery, NCT03438708), a study investigating neoadjuvant axitinib for tumours of high complexity with imperative indication for partial nephrectomy (PN). METHODS: We conducted a single-arm phase II clinical trial of localized (cT1b-cT3M0) clear-cell renal cell carcinoma (RCC) patients with imperative indications for nephron preservation, where PN is a high-risk procedure due to complexity (RENAL score 10-12). Axitinib 5 mg was administered twice daily for 8 weeks with repeat imaging at completion, followed by surgery. The primary outcome was successful completion of planned PN following axitinib treatment. Secondary objectives included changes in tumour diameter, RENAL nephrometry score, renal function and Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and surgical complications. RESULTS: Twenty-seven patients were enrolled (median age 69 years). Prior to therapy, twenty patients (74.0%) had ≥ clinical T3a staged tumours. Axitinib resulted in reductions in tumour diameter (7.5 vs 6.2 cm; P < 0.001) and RENAL score (11 vs 10; P < 0.001). Nine patients (33.3%) had partial response based on RECIST and nine (33.3%) were clinically downstaged. PN was performed in twenty patients (74.0%); twenty-five patients (96.2%) had negative margins. Six patients (22.2%) had Clavien III-IV complications. The median change in estimated glomerular filtration rate (preoperative to last follow-up) was 8.5 mL/min/1.73 m2 . CONCLUSION: Neoadjuvant axitnib resulted in reductions in tumour size and complexity, enabling safe and feasible PN and functional preservation in patients with complex renal masses and imperative indication.

Parenchymal volume preservation during partial nephrectomy: improved methodology to assess impact and predictive factors.

OBJECTIVE: To rigorously evaluate the impact of the percentage of parenchymal volume preserved (PPVP) and how well the preserved parenchyma recovers from ischaemia (Recischaemia ) on functional outcomes after partial nephrectomy (PN) using an accurate and objective software-based methodology for estimating parenchymal volumes and split renal function (SRF). A secondary objective was to assess potential predictors of the PPVP. PATIENTS AND METHODS: A total of 894 PN patients with available studies (2011-2014) were evaluated. The PPVP was measured from cross-sectional imaging at ≤3 months before and 3-12 months after PN using semi-automated software. Pearson correlation evaluated relationships between continuous variables. Multivariable linear regression evaluated predictors of ipsilateral glomerular filtration rate (GFR) preserved and the PPVP. Relative-importance analysis was used to evaluate the impact of the PPVP on ipsilateral GFR preserved. Recischaemia was defined as the percentage of ipsilateral GFR preserved normalised by the PPVP. RESULTS: The median tumour size and R.E.N.A.L. nephrometry score were 3.4 cm and 7, respectively. In all, 49 patients (5.5%) had a solitary kidney. In all, 538 (60%)/251 (28%)/104 (12%) patients were managed with warm/cold/zero ischaemia, respectively. The median pre/post ipsilateral GFRs were 40/31 mL/min/1.73 m2 , and the median (interquartile range [IQR]) percentage of ipsilateral GFR preserved was 80% (71-88%). The median pre/post ipsilateral parenchymal volumes were 181/149 mL, and the median (IQR) PPVP was 84% (76-92%). In all, 330 patients (37%) had a PPVP of <80%, while only 34 (4%) had a Recischaemia of <80%. The percentage of ipsilateral GFR preserved correlated strongly with the PPVP (r = 0.83, P < 0.01) and loss of parenchymal volume accounted for 80% of the loss of ipsilateral GFR. Multivariable analysis confirmed that the PPVP was the strongest predictor of ipsilateral GFR preserved. Greater tumour size and endophytic and nearness properties of the R.E.N.A.L. nephrometry score were associated with a reduced PPVP (all P ≤ 0.01). Solitary kidney and cold ischaemia were associated with an increased PPVP (all P < 0.05). CONCLUSIONS: A reduced PPVP predominates regarding functional decline after PN, although a low Recischaemia can also contribute. Tumour-related factors strongly influence the PPVP, while surgical efforts can improve the PPVP as observed for patients with solitary kidneys.

Every decade counts: a narrative review of functional recovery after partial nephrectomy.

OBJECTIVE: To provide a narrative review of the major advances regarding ischaemia and functional recovery after partial nephrectomy (PN), along with the ongoing controversies. METHODS: Key articles reflecting major advances regarding ischaemia and functional recovery after PN were identified. Special emphasis was placed on contributions that changed perspectives about surgical management. Priority was also placed on randomized trials of off-clamp vs on-clamp cohorts. RESULTS: A decade ago, 'Every minute counts' was published, showing strong correlations between duration of ischaemia and development of acute kidney injury (AKI) and chronic kidney disease after clamped PN. This reinforced perspectives that ischaemia was the main modifiable factor that could be addressed to improve functional outcomes and helped spur efforts towards reduced or zero ischaemia PN. These approaches were associated with strong functional recovery and some peri-operative risk, although they were generally safe in experienced hands. Further research demonstrated that, when parenchymal volume changes were incorporated into the analyses, ischaemia lost statistical significance, and percent parenchymal volume saved proved to be the main determinant. Cold ischaemia was confirmed to be highly protective, and limited warm ischaemia also proved to be safe. The reconstructive phase of PN, with avoidance of parenchymal devascularization, appears to be most important for functional outcomes. Randomized trials of on-clamp vs off-clamp PN have shown minimal impact of ischaemia on functional recovery. CONCLUSIONS: The past decade has witnessed great progress regarding functional recovery after PN, with many lessons learned. However, there are still unanswered questions, including: What is the threshold of warm ischaemia at which irreversible ischaemic injury begins to develop? Are some cohorts at increased risk for AKI or irreversible ischaemic injury? and Which patients should be prioritized for zero-ischaemia PN?

Parenchymal volume analysis to assess longitudinal functional decline following partial nephrectomy.

OBJECTIVE: To identify factors associated with longitudinal ipsilateral functional decline after partial nephrectomy (PN). PATIENTS AND METHODS: Of 1140 patients managed with PN (2012-2014), 349 (31%) had imaging/serum creatinine levels pre-PN, 1-12 months post-PN (new baseline), and >3 years later necessary for inclusion. Parenchymal-volume analysis was used to determine split renal function. Patients were grouped as having significant renal comorbidity (CohortSRC : diabetes mellitus with insulin-dependence or end-organ damage, refractory hypertension, or severe pre-existing chronic kidney disease) vs not having significant renal comorbidity (CohortNoSRC ) preoperatively. Multivariable regression was used to identify predictors of annual ipsilateral parenchymal atrophy and functional decline relative to new baseline values post-PN, after the kidney had healed. RESULTS: The median follow-up was 6.3 years with 87/226/36 patients having cold/warm/zero ischaemia. The median cold/warm ischaemia times were 32/22 min. Overall, the median tumour size was 3.0 cm. The preoperative glomerular filtration rate (GFR) and new baseline GFR (NBGFR) were 81 and 71 mL/min/1.73 m2 , respectively. After establishment of the NBGFR, the median loss of global and ipsilateral function was 0.7 and 0.4 mL/min/1.73 m2 /year, respectively, consistent with the natural ageing process. Overall, the median ipsilateral parenchymal atrophy was 1.2 cm3 /year and accounted for a median of 53% of the annual functional decline. Significant renal comorbidity, age, and warm ischaemia were independently associated with ipsilateral parenchymal atrophy (all P < 0.01). Significant renal comorbidity and ipsilateral parenchymal atrophy were independently associated with annual ipsilateral functional decline (both P < 0.01). Annual median ipsilateral parenchymal atrophy and functional decline were both significantly increased for CohortSRC compared to CohortNoSRC (2.8 vs 0.9 cm3 , P < 0.01 and 0.90 vs 0.30 mL/min/1.73 m2 /year, P < 0.01, respectively). CONCLUSIONS: Longitudinal renal function following PN generally follows the normal ageing process. Significant renal comorbidities, age, warm ischaemia, and ipsilateral parenchymal atrophy were the most important predictors of ipsilateral functional decline following establishment of NBGFR.

Functional recovery after partial nephrectomy: next generation analysis.

OBJECTIVES: To provide a more rigorous assessment of factors affecting functional recovery after partial nephrectomy (PN) using novel tools that allow for analysis of more patients and improved accuracy for assessment of parenchymal volume loss, thereby revealing the potential impact of secondary factors such as ischaemia. PATIENTS AND METHODS: Of 1140 patients managed with PN (2012-2014), 670 (59%) had imaging and serum creatinine levels measured before and after PN necessary for inclusion. Recovery from ischaemia was defined as the ipsilateral glomerular filtration rate (GFR) saved normalised by parenchymal volume saved. Acute kidney injury was assessed through Spectrum Score, which quantifies the degree of acute ipsilateral renal dysfunction due to exposure to ischaemia that would otherwise be masked by the contralateral kidney. Multivariable regression was used to identify predictors of Spectrum Score and Recovery from Ischaemia. RESULTS: In all, 409/189/72 patients had warm/cold/zero ischaemia, respectively, with median (interquartile range [IQR]) ischaemia times for cold and warm ischaemia of 30 (25-42) and 22 (18-28) min, respectively. The median (IQR) global preoperative GFR and new baseline GFR (NBGFR) were 78 (63-92) and 69 (54-81) mL/min/1.73 m2 , respectively. The median (IQR) ipsilateral preoperative GFR and NBGFR were 40 (33-47) and 31 (24-38) mL/min/1.73 m2 , respectively. Functional recovery correlated strongly with parenchymal volume preserved (r = 0.83, P < 0.01). The median (IQR) decline in ipsilateral GFR associated with PN was 7.8 (4.5-12) mL/min/1.73 m2 with loss of parenchyma accounting for 81% of this loss. The median (IQR) recovery from ischaemia was similar across the cold/warm/zero ischaemia groups at 96% (90%-102%), 95% (89%-101%), and 97% (91%-102%), respectively. Independent predictors of Spectrum Score were ischaemia time, tumour complexity, and preoperative global GFR. Independent predictors of recovery from ischaemia were insulin-dependent diabetes mellitus, refractory hypertension, warm ischaemia, and Spectrum Score. CONCLUSIONS: The main determinant of functional recovery after PN is parenchymal volume preservation. A more robust and rigorous evaluation allowed us to identify secondary factors including comorbidities, increased tumour complexity, and ischaemia-related factors that are also independently associated with impaired recovery, although altogether these were much less impactful.

Predicting GFR after radical nephrectomy: the importance of split renal function.

PURPOSE: To evaluate a conceptually simple model to predict new-baseline-glomerular-filtration-rate (NBGFR) after radical nephrectomy (RN) based on split-renal-function (SRF) and renal-functional-compensation (RFC), and to compare its predictive accuracy against a validated non-SRF-based model. RN should only be considered when the tumor has increased oncologic potential and/or when there is concern about perioperative morbidity with PN due to increased tumor complexity. In these circumstances, accurate prediction of NBGFR after RN can be important, with a threshold NBGFR > 45 ml/min/1.73m2 correlating with improved overall survival. METHODS: 236 RCC patients who underwent RN (2010-2012) with preoperative imaging (CT/MRI) and relevant functional data were included. NBGFR was defined as GFR 3-12 months post-RN. SRF was determined using semi-automated software that provides differential parenchymal-volume-analysis (PVA) from preoperative imaging. Our SRF-based model was: Predicted NBGFR = 1.24 (× Global GFRPre-RN) (× SRFContralateral), with 1.24 representing the mean RFC estimate from independent analyses. A non-SRF-based model was also assessed: Predicted NBGFR = 17 + preoperative GFR (× 0.65)-age (× 0.25) + 3 (if tumor > 7 cm)-2 (if diabetes). Alignment between predicted/observed NBGFR was assessed by comparing correlation coefficients and area-under-the-curve (AUC) analyses. RESULTS: The correlation-coefficients (r) were 0.87/0.72 for SRF-based/non-SRF-based models, respectively (p = 0.005). For prediction of NBGFR > 45 ml/min/1.73m2, the SRF-based/non-SRF-based models provided AUC of 0.94/0.87, respectively (p = 0.044). CONCLUSION: Previous non-SRF-based models to predict NBGFR post-RN are complex and omit two important parameters: SRF and RFC. Our proposed model prioritizes these parameters and provides a conceptually simple, accurate, and clinically implementable approach to predict NBGFR post-RN. SRF can be easily obtained using PVA software that is affordable, readily available (FUJIFILM-Medical-Systems), and more accurate than nuclear-renal-scans. The SRF-based model demonstrates greater predictive-accuracy than a non-SRF-based model, including the clinically-important predictive-threshold of NBGFR > 45 ml/min/1.73m2.

Identification of Somatic Gene Signatures in Circulating Cell-Free DNA Associated with Disease Progression in Metastatic Prostate Cancer by a Novel Machine Learning Platform.

PURPOSE: Progression from metastatic castration-sensitive prostate cancer (mCSPC) to a castration-resistant (mCRPC) state heralds the lethal phenotype of prostate cancer. Identifying genomic alterations associated with mCRPC may help find new targets for drug development. In the majority of patients, obtaining a tumor biopsy is challenging because of the predominance of bone-only metastasis. In this study, we hypothesize that machine learning (ML) algorithms can identify clinically relevant patterns of genomic alterations (GAs) that distinguish mCRPC from mCSPC, as assessed by next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA). EXPERIMENTAL DESIGN: Retrospective clinical data from men with metastatic prostate cancer were collected. Men with NGS of cfDNA performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory at time of diagnosis of mCSPC or mCRPC were included. A combination of supervised and unsupervised ML algorithms was used to obtain biologically interpretable, potentially actionable insights into genomic signatures that distinguish mCRPC from mCSPC. RESULTS: GAs that distinguish patients with mCRPC (n = 187) from patients with mCSPC (n = 154) (positive predictive value = 94%, specificity = 91%) were identified using supervised ML algorithms. These GAs, primarily amplifications, corresponded to androgen receptor, Mitogen-activated protein kinase (MAPK) signaling, Phosphoinositide 3-kinase (PI3K) signaling, G1/S cell cycle, and receptor tyrosine kinases. We also identified recurrent patterns of gene- and pathway-level alterations associated with mCRPC by using Bayesian networks, an unsupervised machine learning algorithm. CONCLUSION: These results provide clinical evidence that progression from mCSPC to mCRPC is associated with stereotyped concomitant gain-of-function aberrations in these pathways. Furthermore, detection of these aberrations in cfDNA may overcome the challenges associated with obtaining tumor bone biopsies and allow contemporary investigation of combinatorial therapies that target these aberrations. IMPLICATIONS FOR PRACTICE: The progression from castration-sensitive to castration-resistant prostate cancer is characterized by worse prognosis and there is a pressing need for targeted drugs to prevent or delay this transition. This study used machine learning algorithms to examine the cell-free DNA of patients to identify alterations to specific pathways and genes associated with progression. Detection of these alterations in cell-free DNA may overcome the challenges associated with obtaining tumor bone biopsies and allow contemporary investigation of combinatorial therapies that target these aberrations.

Tumor Frameshift Mutation Proportion Predicts Response to Immunotherapy in Mismatch Repair-Deficient Prostate Cancer.

BACKGROUND: Genomic biomarkers that predict response to anti-PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti-PD1 therapy in prostate cancer. METHODS: To enrich for response to anti-PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair-deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti-PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort. RESULTS: Nineteen of 65 patients with dMMR metastatic castration-resistant prostate cancer were treated with anti-PD1 therapy. The PSA50 response rate was 65%, and the median progression-free survival (PFS) was 24 (95% confidence interval 16-54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti-PD1 treatment and with density of CD8+ tumor-infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti-PD1 therapy in a validation cohort. CONCLUSION: Tumor FSP correlated with prolonged efficacy of anti-PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity. IMPLICATIONS FOR PRACTICE: Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair-deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti-PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti-PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti-PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts.

Preincision adjunctive prophylaxis for cesarean deliveries a systematic review and meta-analysis.

OBJECTIVE: This study aimed to systematically review the relative effectiveness of preincision cefazolin with or without adjunctive prophylaxis (macrolides or metronidazole) vs cefazolin alone in decreasing the incidence of postcesarean delivery surgical site infections. DATA SOURCES: We performed a systematic search on PubMed, Ovid EMBASE, Google Scholar, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials from October 25, 2020, to November 25, 2020, to identify studies comparing cefazolin with adjunctive macrolides or metronidazole with cefazolin alone. The reference lists were reviewed, and a manual search of articles published after the last database search was performed. STUDY ELIGIBILITY CRITERIA: Overall, 3 randomized controlled trials and 1 prospective observational study of reproductive-age women undergoing cesarean deliveries were included in the study. We excluded studies of women who were immunocompromised (eg, patients who were HIV positive) or women with a diagnosis of chorioamnionitis before cesarean delivery. All patients received first-line cefazolin (either cefazolin 1 g or 2 g). We compared preincision cefazolin alone with preincision cefazolin plus adjunctive therapy (500 mg, oral or intravenous formulations of azithromycin, metronidazole, or clarithromycin). METHODS: A total of 6 review authors independently assessed the risk of bias for each study, using the Cochrane Risk of Bias criteria. Synthesis and further appraisal were done using the Grading of Recommendations, Assessment, Development, and Evaluation levels and the American College of Obstetricians and Gynecologists appraisal guidelines. Disagreements were resolved by discussion. Treatment effects were evaluated using meta-analysis, and pooled relative risks and 95% confidence intervals were generated using random-effects models using the Review Manager 5 software (version 5.4.1). RESULTS: Overall, 3 randomized controlled trials and 1 prospective observational study representing 2613 women met the criteria for inclusion. Significant reductions in surgical site infections (relative risk, 0.46; 95% confidence interval, 0.34-0.63; 3 randomized controlled trials) and the duration of hospital stay (weighted mean difference, -1.46; 95% confidence interval, -2.21 to -0.71; 2 randomized controlled trials) were observed with preincision cefazolin and adjunctive prophylaxis compared with cefazolin alone. No significant difference was observed in maternal febrile morbidity (relative risk, 0.38; 95% confidence interval, 0.11-1.25; 2 randomized controlled trials). CONCLUSION: Our findings have provided evidence for the use of preincision adjunctive extended-spectrum prophylaxis with cefazolin over cefazolin alone. However, future investigations are required to establish the relative efficacies of different adjunctive antibiotic options.

Up-front Treatment With Romiplostim in Children With Acquired Bone Marrow Failure: A Single Institutional Pediatric Case Series.

BACKGROUND: Thrombopoietin receptor agonists are emerging as a therapeutic option for patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). We report our experience of treating children with AA/MDS with romiplostim, thrombopoietin receptor agonist. OBSERVATIONS: Three children (AA, 2; MDS, 1) received romiplostim treatment at a median dose of 10 µg/kg/week (starting dose: 5 µg/kg/wk; 2.5 µg/kg/wk increment). Trilineage hematopoietic recovery occurred at a median of 13 weeks (range: 13 to 16 wk) without adverse events. Hematopoiesis continued to improve after therapy discontinuation (median follow-up: 2.8 y; range: 0.5 to 3.0). CONCLUSION: Our experience supports the short-term safety and efficacy of romiplostim in children with AA/MDS.

Novel androgen axis systemic therapies for metastatic hormone-sensitive prostate cancer.

PURPOSE OF REVIEW: Upfront docetaxel and androgen deprivation therapy (ADT) has improved outcomes over ADT alone in men with metastatic hormone-sensitive prostate cancer (mHSPC). Here in, we review the emerging role of novel androgen axis inhibitors in the treatment of men with mHSPC. RECENT FINDINGS: Recently two studies, LATITUDE and STAMPEDE arm G, showed improved survival with addition of abiraterone acetate with prednisone or prednisolone to ADT in men with hormone-naïve advanced prostate cancer. SUMMARY: Upfront docetaxel in addition to ADT has been shown to improve survival outcomes in men with high-volume mHSPC. Recently, abiraterone acetate and prednisone or prednisolone and ADT have been shown to improve survival outcomes compared with ADT alone in men with mHSPC. Multiple other novel androgen axis inhibitors are being investigated in this setting, and expected to garner regulatory approval in the near future. Biomarkers predicting response to these agents are urgently needed to optimize treatment selection, not only to improve outcomes but to also minimize cost and toxicities.

Reducing False-Positives Due to Urinary Stagnation in the Prostatic Urethra on 18 F-DCFPyL PSMA PET/CT With MRI.

PURPOSE: Prostate-specific membrane antigen (PSMA)-targeting PET radiotracers reveal physiologic uptake in the urinary system, potentially misrepresenting activity in the prostatic urethra as an intraprostatic lesion. This study examined the correlation between midline 18 F-DCFPyL activity in the prostate and hyperintensity on T2-weighted (T2W) MRI as an indication of retained urine in the prostatic urethra. PATIENTS AND METHODS: Eighty-five patients who underwent both 18 F-DCFPyL PSMA PET/CT and prostate MRI between July 2017 and September 2023 were retrospectively analyzed for midline radiotracer activity and retained urine on postvoid T2W MRIs. Fisher's exact tests and unpaired t tests were used to compare residual urine presence and prostatic urethra measurements between patients with and without midline radiotracer activity. The influence of anatomical factors including prostate volume and urethral curvature on urinary stagnation was also explored. RESULTS: Midline activity on PSMA PET imaging was seen in 14 patients included in the case group, whereas the remaining 71 with no midline activity constituted the control group. A total of 71.4% (10/14) and 29.6% (21/71) of patients in the case and control groups had urethral hyperintensity on T2W MRI, respectively ( P < 0.01). Patients in the case group had significantly larger mean urethral dimensions, larger prostate volumes, and higher incidence of severe urethral curvature compared with the controls. CONCLUSIONS: Stagnated urine within the prostatic urethra is a potential confounding factor on PSMA PET scans. Integrating PET imaging with T2W MRI can mitigate false-positive calls, especially as PSMA PET/CT continues to gain traction in diagnosing localized prostate cancer.

Functional recovery after partial nephrectomy in a solitary kidney.

OBJECTIVES: Partial nephrectomy (PN) is the reference standard for renal mass in a solitary kidney (RMSK), although factors determining functional recovery in this setting remain poorly defined. PATIENTS/METHODS: Single center, retrospective analysis of 841 RMSK patients (1975-2022) managed with PN with functional data, including 361/435/45 with cold/warm/zero ischemia, respectively. A total of 155 of these patients also had necessary studies for detailed analysis of parenchymal volume preserved. Acute kidney injury (AKI) was classified by RIFLE (Risk/Injury/Failure/Loss/Endstage). Recovery-from-ischemia (Rec-Ischemia) was defined as glomerular filtration rate (GFR) saved normalized by parenchymal volume saved. Logistic regression identified predictive factors for AKI and predictors of Rec-Ischemia were analyzed by multivariable linear regression. RESULTS: Overall, median preoperative GFR was 56.7 ml/min/1.73m2 and new-baseline and 5-year GFRs were 43.1 and 44.5 ml/min/1.73m2, respectively. Median follow-up was 55 months; 5-year dialysis-free survival was 97%. In the detailed analysis cohort, a primary focus of this study, median warm (n = 70)/cold (n = 85) ischemia times were 25/34 minutes, respectively; and median preoperative, new-baseline and 5-year GFRs were 57.8, 45.0, and 41.7 ml/min/1.73m2, respectively. Functional recovery correlated strongly with parenchymal volume preserved (r = 0.84, p < 0.001). Parenchymal volume loss accounted for 69% of the total median GFR decline associated with PN, leaving only 3 to 4 ml/min/1.73m2 attributed to ischemia and other factors. AKI occurred in 52% of patients and the only independent predictor of AKI was ischemia time. Independent predictors of reduced Rec-Ischemia were increased age, warm ischemia, and AKI. CONCLUSION: The main determinant of functional recovery after PN in RMSK is parenchymal volume preservation. Type/duration of ischemia, AKI, and age also correlated, although altogether their contributions were less impactful. Our findings suggest multiple opportunities for optimizing functional outcomes although preservation of parenchymal volume remains predominant. Long-term function generally remains stable with dialysis only occasionally required.

Parenchymal obliteration by renal masses: Functional and oncologic implications.

OBJECTIVES: Most renal tumors merely displace nephrons while others can obliterate parenchyma in an invasive manner. Substantial parenchymal volume replacement (PVR) by renal cell carcinoma (RCC) may have oncologic implications; however, studies regarding PVR remain limited. Our objective was to evaluate the oncologic implications associated with PVR using improved methodology including more accurate and objective tools. PATIENTS/METHODS: A total of 1,222 patients with non-metastatic renal tumors managed with partial nephrectomy (PN) or radical nephrectomy (RN) at Cleveland Clinic (2011-2014) with necessary studies were retrospectively evaluated. Parenchymal volume analysis via semiautomated software was used to estimate split renal function and preoperative parenchymal volumes. Using the contralateral kidney as a control, %PVR was defined: (parenchymal volumecontralateral-parenchymal volumeipsilateral) normalized by parenchymal volumecontralateral x100%. PVR was determined preoperatively and not altered by management. Patients were grouped by degree of PVR: minimal (<5%, N = 566), modest (5%-25%, N = 414), and prominent (≥25%, N = 142). Kaplan-Meier was used to evaluate survival outcomes relative to degree of PVR. Multivariable Cox-regression models evaluated predictors of recurrence-free survival (RFS). RESULTS: Of 1,122 patients, 801 (71%) were selected for PN and 321 (29%) for RN. Overall, median tumor size was 3.1 cm and 6.8 cm for PN and RN, respectively, and median follow-up was 8.6 years. Median %PVR was 15% (IQR = 6%-29%) for patients selected for RN and negligible for those selected for PN. %PVR correlated inversely with preoperative ipsilateral GFR (r = -0.49, P < 0.01) and directly with advanced pathologic stage, high tumor grade, clear cell histology, and sarcomatoid features (all P < 0.01). PVR≥25% associated with shortened recurrence-free, cancer-specific, and overall survival (all P < 0.01). Male sex, ≥pT3a, tumor grade 4, positive surgical margins, and PVR≥25% independently associated with reduced RFS (all P < 0.02). CONCLUSIONS: Obliteration of normal parenchyma by RCC substantially impacts preoperative renal function and patient selection. Our data suggests that increased PVR is primarily driven by aggressive tumor characteristics and independently associates with reduced RFS, although further studies will be needed to substantiate our findings.

Long-Term Renal Function Following Renal Cancer Surgery: Historical Perspectives, Current Status, and Future Considerations.

Knowledge of functional recovery after partial (PN) and radical nephrectomy for renal cancer has advanced considerably, with PN now established as the reference standard for most localized renal masses. However, it is still unclear whether PN provides an overall survival benefit in patients with a normal contralateral kidney. While early studies seemingly demonstrated the importance of minimizing warm-ischemia time during PN, multiple new investigations over the last 10 years have proven that parenchymal mass lost is the most important predictor of new baseline renal function. Minimizing loss of parenchymal mass during resection and reconstruction is the most important controllable aspect of long-term post-operative renal function preservation.