Radu Caprariu

Immune checkpoint inhibitors (ICIs) are established across the treatment continuum of urothelial carcinoma of the bladder, yet most patients derive no durable benefit. This narrative review appraises candidate predictors of ICI benefit in bladder urothelial carcinoma, distinguishing prognostic from predictive biomarkers, applying the same three evidentiary standards to every biomarker, classifying the supporting studies by design and separating evidence from regulatory status. Programmed death-ligand 1 (PD-L1) immunohistochemistry meets the enrichment standard in three co-primary PD-L1-positive populations, in trials also positive overall, but not the predictive standard: its four registrational assays are not interchangeable; randomized comparisons show inconsistent subgroup effects, failed prespecified tests in IMvigor211 and DANUBE and no significant treatment-by-PD-L1 interaction; and the benefit of first-line enfortumab vedotin plus pembrolizumab is independent of combined positive score. Its remaining role is confined to label restrictions, chiefly European. Tumor mutational burden, molecular subtypes, expression signatures, DNA damage response and FGFR3 alterations remain investigational. Tumor-informed circulating tumor DNA (ctDNA) answers a different question: whether residual disease persists after cystectomy. After an exploratory signal in IMvigor010, the prospective enrichment trial IMvigor011 showed that ctDNA-positive patients derive disease-free and overall survival benefit from adjuvant atezolizumab; persistently ctDNA-negative patients were observed without randomization, so their 88% two-year disease-free survival does not exclude a benefit of treatment. This underpins US companion-diagnostic approval and a Category 1 guideline recommendation, not yet European authorization. Post-cystectomy ctDNA thus meets the same enrichment standard as PD-L1 and, like PD-L1, neither the predictive nor the strategy standard; what sets it apart is that the marker was necessary for the result, adjuvant atezolizumab having failed unselected, and that it directs whether to treat rather than which regimen; its role after perioperative immunotherapy is unresolved.

Renal cell carcinoma (RCC) predominantly affects older men, and the phenotype of RCC arising in women younger than 45 years has not, to our knowledge, been characterized in a defined population. We conducted a narrative review of registry analyses, multi-institutional pathology series, germline-testing cohorts, consensus classifications and guidelines, and graded every finding by how directly it applies to young women. Registry data show that the male-to-female ratio narrows with decreasing age, from approximately 1.7:1 across all ages to near parity in pediatric and adolescent cohorts. In the only registry analysis with a sex-by-age subtype breakdown (Surveillance, Epidemiology, and End Results [SEER]-18, 2001–2008), chromophobe RCC accounted for 215 of 330 non-clear cell RCC cases (65.2%; 95% confidence interval 59.9–70.1%) in surgically treated women younger than 40 years, whereas papillary RCC led in every other sex-by-age group and among young Black women. In an exploratory reanalysis of the published counts, this pattern was explained by independent, multiplicative effects of female sex and young age on chromophobe histology, without evidence of a sex-by-age interaction among non-clear cell tumors; it rests on a single registry period with registry-coded histology and awaits validation. Clear cell RCC nevertheless remains the most common subtype in all strata. Entities with documented female predominance (chromophobe RCC, eosinophilic solid and cystic RCC, tuberous sclerosis-associated RCC, mucinous tubular and spindle cell carcinoma) and entities concentrated in the young (microphthalmia-associated transcription factor [MiT] family translocation RCC, succinate dehydrogenase [SDH]-deficient RCC, fumarate hydratase-deficient RCC, renal medullary carcinoma) together define a phenotype landscape that differs from that of older men. Most of this landscape, however, is inferred from mixed-sex young-onset cohorts, all-age sex-difference analyses, and entity-defining pathology series rather than from studies of women younger than 45 years. Early-onset RCC is enriched for hereditary syndromes, some of which present in women through uterine leiomyomas or lymphangioleiomyomatosis, and current American and European guidelines recommend genetic evaluation for patients diagnosed at 46 years or younger. Syndrome-directed therapies now exist for von Hippel–Lindau disease, hereditary leiomyomatosis and renal cell cancer, and tuberous sclerosis complex, but sex- and age-stratified treatment data are sparse. Evidence on hormonal and reproductive determinants is inconsistent, and sex-stratified data on early-onset germline burden and outcomes are lacking. We distinguish verified findings from hypotheses, flag common but unsupported claims, and outline the contemporary, population-based and molecularly classified cohorts needed to validate the proposed phenotype landscape.

Pyonephrosis—pus within an obstructed, infected renal collecting system, with suppurative parenchymal destruction—is a urological emergency and a potentially reversible cause of acute kidney injury (AKI); a contribution to chronic kidney disease (CKD) is biologically plausible but has not been demonstrated in pyonephrosis-specific longitudinal studies. This narrative review, reported with reference to the SANRA criteria and based on structured searches of PubMed/MEDLINE, Scopus, and Web of Science, synthesizes the epidemiology, pathophysiology, microbiology, morphological diagnosis, and contemporary management of pyonephrosis, distinguishing evidence generated in confirmed pyonephrosis from that in infected hydronephrosis, obstructive pyelonephritis, and stone-associated sepsis. Sonographic, computed tomographic, and magnetic resonance features are illustrated with original schematics and a case of perforated calculous pyonephrosis; reported Hounsfield-unit thresholds and apparent diffusion coefficients derive from small, single-center cohorts and are protocol- and population-dependent rather than universal cut-offs. Urgent decompression is strongly recommended by guidelines, but the supporting data are observational, so associations between drainage, its timing, and mortality remain vulnerable to confounding. Randomized comparisons of percutaneous nephrostomy and retrograde stenting are few, small, and inconsistent, and establish neither superiority nor equivalence in infected systems. We rate the certainty of each principal conclusion and identify research priorities.

Background/Objectives: International Society of Urological Pathology (ISUP) Grade Group discordance between prostate biopsy and radical prostatectomy (RP) affects 25–50% of men with localized prostate cancer and has direct implications for active surveillance, nerve-sparing, and adjuvant-treatment decisions. We synthesized contemporary evidence on the frequency of biopsy-to-RP grade migration and on emerging imaging, molecular/genomic, and artificial-intelligence (AI)-based predictors of migration. Methods: MEDLINE (PubMed) was searched from 1 January 2010 to 5 May 2026, supplemented by citation searching of recent systematic reviews. Eligible studies reported paired biopsy–RP pathology under the modified 2005 Gleason or the 2014/2019 ISUP Grade Group system, with ≥50 paired cases. Risk of bias was assessed with QUIPS, PROBAST, and QUADAS-2; certainty of evidence was rated with a GRADE framework adapted for prognostic research. Synthesis followed the SWiM reporting guidance. Results: Thirty-seven primary studies and eight prior systematic reviews were included. Concordance ranged from 44% to ~70%, upgrading from 14% to 67%, and downgrading from 5% to 26%. Biopsy GG1 disease showed the highest absolute upgrading risk (55–67%). Four predictors reached moderate GRADE certainty: PI-RADS category, biopsy approach (combined vs. systematic), PSMA-PET maximum standardized uptake value, and PSA density (PSAD). Cribriform/intraductal carcinoma at biopsy, the Decipher genomic classifier, the Prostate Health Index, and machine-learning and radiomics models reached very low certainty; clinical nomograms reached low certainty; germline alterations as direct predictors reached very low certainty. PROBAST flagged the analysis domain as high risk in five of eight prediction-model studies, and only one of eight models was externally validated. Conclusions: Despite a decade of refinements in grading, imaging, biopsy technique, and molecular profiling, biopsy-to-RP grade discordance remains substantial. Contemporary evidence supports incorporating PI-RADS, biopsy approach, and PSAD into shared decision-making; emerging molecular and AI-based predictors require prospective external validation in adequately powered, geographically representative cohorts before routine clinical adoption.

Prostate biopsy is among the most frequently performed diagnostic procedures in men, and two shifts have reshaped it over the past decade: the incorporation of multiparametric MRI (mpMRI) with targeted sampling, and migration from the transrectal to the transperineal route. Because these changes are usually adopted together, the practical choice facing many units is between a contemporary transperineal MRI-targeted pathway and the historical transrectal systematic one. This narrative review weights cancer detection, procedure-related harms, and implementation approximately equally, drawing on evidence that isolates route from targeting wherever possible. Across randomized trials and meta-analyses, the two pathways achieve broadly comparable detection of clinically significant cancer (ISUP grade group ≥ 2), although the transperineal route samples anterior and apical tumors more effectively and the largest randomized comparison reported a modest transperineal advantage. The principal transperineal benefit is a marked reduction in infectious complications, enabling reduced antibiotic prophylaxis and improved stewardship; its main cost is greater procedural discomfort. We review mpMRI and PI-RADS with illustrative examples, fusion technique, cost-effectiveness, special populations, emerging adjuncts, and divergent guidelines, concluding that route and targeting decisions are best individualized, with infection risk and lesion location dominant.

Background/Objectives: CT-guided transthoracic core needle biopsy (CT-TTNB) is the standard technique for histological characterization of pulmonary lesions, yet it carries a 15–42% rate of pneumothorax and a 5–27% rate of alveolar hemorrhage. Accurate identification of modifiable and non-modifiable procedural determinants is essential for pre-procedural risk stratification, technique optimization, and post-procedural care. Methods: We conducted a single-centre retrospective cohort study of 240 consecutive CT-TTNB procedures performed between November 2023 and January 2025. The variables were extracted from medical records and PACS and entered into univariate and multivariate analysis models. Model performance was assessed by AUC-ROC, Nagelkerke R², and the Hosmer–Lemeshow test. Results: Pneumothorax occurred in 79 patients (32.9%), with chest tube drainage required in 14 (5.8%). Alveolar hemorrhage was identified in 49 patients (20.4%). Four independent predictors for pneumothorax were identified: needle–pleural angle (OR 0.837/1°; p < 0.001), pleura-to-lesion distance (OR 1.675/10 mm; p < 0.001), fissure traversal (OR 26.718; p = 0.003), and patient age (OR 1.076/year; p = 0.002); AUC-ROC 0.927. The alveolar hemorrhage model identified pleura-to-lesion distance (OR 1.768/10 mm; p < 0.001), RUL apical segment (OR 4.281; p < 0.001), and carcinomatous lymphangitis as protective factors (OR 0.359; p = 0.030); AUC-ROC 0.822. The needle–pleural angle was not independently associated with alveolar hemorrhage, confirming mechanistically distinct complication pathways. Conclusions: Needle–pleural angle is the dominant modifiable determinant of pneumothorax and pneumothorax-related complications. Optimizing the trajectory towards perpendicularity does not increase hemorrhage risk. These findings support the implementation of angle-based trajectory planning protocols and risk-stratified post-procedural monitoring.

Background/Objectives: Hungry bone syndrome (HBS) is a frequent and potentially life-threatening complication following parathyroidectomy (PTX) for secondary hyperparathyroidism (SHPT) in dialysis patients, yet existing prediction tools offer limited discriminative accuracy. This study aimed to develop and internally validate an interpretable machine learning (ML) framework for preoperative HBS prediction and to derive a pragmatic bedside risk score from ML-derived feature importance. Methods: Ninety end-stage renal disease patients who underwent PTX for drug-refractory SHPT at a single center (2019–2023) were analyzed. Eight supervised ML classifiers were trained on 24 preoperative features (19 raw variables plus 5 engineered features) and evaluated under 5-fold stratified cross-validation repeated 10 times. SHapley Additive exPlanations (SHAP) analysis was applied for model interpretability, and a composite bedside risk score was constructed from SHAP-derived feature rankings. Results: HBS occurred in 41 patients (45.6%). Random forest achieved the numerically highest discrimination among multi-feature models (AUC = 0.933 ± 0.065), outperforming previously published models, though univariate alkaline phosphatase (ALP) alone achieved a comparable cross-validated AUC of 0.958. ALP overwhelmingly dominated all predictors (mean |SHAP| = 3.37, exceeding the next-ranked feature by approximately 6.5-fold). Partial dependence analysis revealed a sigmoid-shaped ALP–HBS relationship with a critical inflection zone between 250–350 U/L, and SHAP dependence plots demonstrated that total parathyroidectomy amplifies ALP-mediated risk. A SHAP-guided composite bedside risk score (range 0–9) achieved an AUC of 0.883, with observed HBS rates rising monotonically from 0% (score 0) to 100% (score ≥ 6). Decision-curve analysis showed that univariate ALP and the multi-feature pipeline yielded comparable net benefit, with ALP preferable in the high-sensitivity regime and the multi-feature model preferable at high-specificity thresholds; net reclassification improvement was negative for the multi-feature model vs. univariate ALP, supporting the framework’s role as an interpretive rather than discriminative advance. Conclusions: An interpretable ML framework substantially improves HBS prediction over conventional models, confirms ALP as the overwhelmingly dominant predictor through a nonlinear dose–response relationship, and yields a clinically interpretable bedside risk score that, pending external validation, may support preoperative risk stratification.

Background/Objectives: Renal cell carcinoma (RCC) with venous tumor thrombus (VTT) extending into the inferior vena cava (IVC) occurs in 4–10% of patients and represents one of the most technically demanding scenarios in urologic surgery. Open radical nephrectomy with en bloc thrombectomy remains the gold standard for infradiaphragmatic disease (Mayo Levels 0–III), offering the only realistic prospect for long-term cure. This narrative review provides a technically oriented, evidence-based guide for surgical urologists managing these complex cases. Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched (1970–March 2025) using terms related to RCC, venous tumor thrombus, IVC thrombectomy, and perioperative management. Priority was given to prospective studies, systematic reviews, large retrospective cohorts, and current guidelines (EAU 2025, NCCN v2.2024). Original intraoperative photographs supplement procedural descriptions. Results: We detail the complete perioperative pathway: VTT classification (Mayo/AJCC), multimodal imaging, patient optimization, and level-specific open surgical techniques—ranging from Satinsky clamping for Level 0–I thrombi to full piggyback liver mobilization with hepatic vascular exclusion for Level III disease. Contemporary perioperative mortality is <2% at high-volume centers (reported in single and multicenter retrospective series from high-volume institutions), with 5-year cancer-specific survival of approximately 50–60% in non-metastatic cases. Adjuvant pembrolizumab is now a standard of care following the KEYNOTE-564 trial. Neoadjuvant immune checkpoint inhibitor plus tyrosine kinase inhibitor combinations show promising VTT downstaging rates (44–100%), though their role remains investigational. Robotic-assisted thrombectomy demonstrates favorable perioperative outcomes for Level I–II thrombi at experienced centers. Conclusions: Open surgery remains the cornerstone of curative treatment for RCC with infradiaphragmatic VTT, requiring meticulous preoperative planning and multidisciplinary collaboration at high-volume centers. Integration of perioperative systemic therapies and robotic-assisted approaches holds promise for further improving outcomes in this challenging patient population.

Background/Objectives: Despite multiparametric MRI (mpMRI)-guided biopsy, clinically significant upgrading (CSU) of ISUP Grade Group (GG) at radical prostatectomy (RP) remains common in prostate cancer (PCa). We aimed to identify predictors of CSU (biopsy GG ≤ 2 to RP GG ≥ 3) using routine preoperative variables, and to benchmark a parsimonious logistic model against multiple machine learning (ML) classifiers. Methods: In this single-center exploratory analysis, 96 consecutive PCa patients underwent pre-biopsy mpMRI, systematic ± MRI-targeted biopsy, and RP. Predictive modeling was restricted to biopsy GG 1–2 patients (n = 64). LASSO-guided feature selection and Firth-penalized logistic regression were used to build a locked reference model, evaluated against ML classifiers using cross-validated discrimination, calibration, and decision curve analysis. Results: CSU occurred in 10/64 patients (15.6%). Positive core ratio was the dominant independent predictor (adjusted OR 1.54 per 10% increase, 95% CI 1.10–2.17). PSA density (PSAD) showed a consistent positive association but did not retain independent significance. The locked two-variable model (AUC ≈ 0.75–0.79) outperformed all ML classifiers in discrimination, calibration, and net clinical benefit; however, the limited event count (n = 10) constrains model stability, and these findings require external validation. Conclusions: In a PCa mpMRI-informed diagnostic pathway, CSU is primarily driven by biopsy tumor burden. A simple logistic model based on positive core ratio and PSAD outperformed more complex ML approaches in this exploratory cohort, supporting integration of biopsy tumor burden metrics into preoperative risk stratification pending external validation.

Introduction: The 9th edition of the TNM classification for lung cancer implemented significant revisions, notably the subdivision of the N2 and M1c categories, to enhance anatomical precision and prognostic accuracy. Nonetheless, the actual effects of these modifications on stage distribution, histology-specific patterns, and clinical interpretation remain to be fully evaluated. Objectives: To compare lung cancer staging distributions between the 8th and 9th TNM editions, analyze patterns of stage migration, and evaluate histology-specific reclassification trends. Although TNM 9 applies the same descriptors across all histological subtypes, the magnitude of stage migration varies. In our cohort and in international datasets, adenocarcinoma demonstrated a higher likelihood of reclassification into advanced stages compared to other subtypes. Methods: A retrospective analysis was performed on a cohort of lung cancer patients staged according to the 8th and 9th editions of the TNM classification. Stage distribution alterations were analyzed by chi-squared tests, whereas McNemar’s test examined the directional shifts in upstaging and downstaging. Further investigations evaluated the correlation between histological subtype and stage reclassification. Results: A statistically significant redistribution of stages was noted (χ² = 1013.03, df = 64, p < 0.0001), with a notable prevalence of upstaging (p = 0.0019). The most significant proportional increase was observed in stage IIIA, mostly attributable to the N2 subdivision (N2a vs. N2b). Adenocarcinoma was the predominant histological subtype at all stages and showed a greater tendency for reclassification into advanced stages, specifically IIIA and IIIB. Squamous cell carcinoma was predominantly observed in stages IIB and IIIA, whereas small cell and large cell carcinomas were concentrated in advanced stages. These histology-specific patterns correspond with international findings, including research confirming the prognostic relevance of N2 subdivision. Conclusions: The 9th edition of the TNM classification results in significant stage migration, particularly in adenocarcinoma cases, indicating the improved sensitivity of the updated criteria in identifying advanced nodal disease. These modifications significantly impact prognostic evaluation and global comparability of clinical cohorts, supporting the implementation of TNM 9 as a more anatomically and biologically relevant staging system.