Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.

The 2022 WHO classification of urinary and male genital tumors introduced several novel kidney entities exhibiting eosinophilic/oncocytic features with specific mutational backgrounds. Thus, molecular techniques, such as next-generation sequencing (NGS), became more commonly used for their evaluation. We studied 12 low-grade oncocytic tumors (LOT) of the kidney (from 11 patients), identified in a cohort of 210 eosinophilic/oncocytic renal tumors, diagnosed in our institution between October 2019 and May 2023, which represented 5.7% (12/210) of all eosinophilic/oncocytic renal tumors during this period. We reviewed their clinicopathologic, histologic, and immunohistochemical features, as well as their mutational profiles. We also reviewed the literature on NGS-derived data of LOT, by selecting papers in which LOT diagnosis was rendered according to the criteria proposed initially. Median age was 65 years (mean: 63.5; range 43-79) and median tumor size was 2.0 cm (mean: 2.2; range: 0.9-3.1). All tumors were positive for PAX8, CK7, and GATA3, and negative or focally positive for CD117/KIT. We found the following gene mutations: MTOR ((6/11), 54.5%)), TSC1 ((2/11), 18.2%)), and 1 had both NOTCH1 and NOTCH4 ((1/11), 9.1%)). Wild-type status was found in 2/11 (18.2%) patients and one tumor was not analyzable. A review of 8 previous studies that included 79 LOTs revealed frequent mutations in the genes that regulate the mammalian target of rapamycin (mTOR) pathway: MTOR (32/79 (40.5%)), TSC1 (21/79 (26.6%)), and TSC2 (9/79 (11.4%)). Other mutated genes included PIK3CA, NF2, and PTEN, not typically known to affect the mTOR pathway, but potentially acting as upstream and downstream effectors. Our study shows that LOT is increasingly diagnosed in routine practice when applying the appropriate diagnostic criteria. We also confirm that the mTOR pathway is strongly implicated in the pathogenesis of this tumor mainly through MTOR, TCS1, and TSC2 mutations, but other genes could also be involved in the pathway activation, especially in LOTs without \"canonical\" mutations.

BACKGROUND: Tumors are rare in neonatal age. Congenital mesoblastic nephroma (CMN) is a usually benign renal tumor observed at birth, or in the first months of life. It may also be identified prenatally and associated with polyhydramnios leading to preterm delivery. Effective treatment is surgical in most cases, consisting in total nephrectomy. In literature, very few studies report on the neonatal management of such a rare disease, and even less are those describing its uncommon complications.
METHODS: We report on two single-center newborns affected with CMN. The first patient is a preterm female baby, born at 30+ 1 weeks of gestation (WG) due to premature labor, with prenatal (25 WG) identification of an intra-abdominal fetal mass associated with polyhydramnios. Once obtained the clinical stability, weight gain, instrumental (computed tomography, CT, showing a 4.8 × 3.3 cm left renal neoformation) and histological/molecular characterization of the lesion (renal needle biopsy picture of classic CMN with ETV6-NTRK3 translocation), a left nephrectomy was performed at 5 weeks of chronological age. The following clinical course was complicated by intestinal obstruction due to bowel adherences formation, then by an enterocutaneous fistula, requiring multiple surgical approaches including transitory ileo- and colostomy, before the conclusive anastomoses intervention. The second patient is a 17-day-old male term baby, coming to our observation due to postnatal evidence of palpable left abdominal mass (soon defined through CT, showing a 7.5 × 6.5 cm neoformation in the left renal lodge), feeding difficulties and poor weight gain. An intravenous diuretic treatment was needed due to the developed hypertension and hypercalcemia, which regressed after the nephrectomy (histological diagnosis of cellular CMN with ETV6-NTRK3 fusion) performed at day 26. In neither case was chemotherapy added. Both patients have been included in multidisciplinary follow-up, they presently show regular growth and neuromotor development, normal renal function and no local/systemic recurrences or other gastrointestinal/urinary disorders.
CONCLUSIONS: The finding of a fetal abdominal mass should prompt suspicion of CMN, especially if it is associated with polyhydramnios; it should also alert obstetricians and neonatologists to the risk of preterm delivery. Although being a usually benign condition, CMN may be associated with neonatal systemic-metabolic or postoperative complications. High-level surgical expertise, careful neonatological intensive care and histopathological/cytogenetic-molecular definition are the cornerstones for the optimal management of patients. This should also include an individualized follow-up, oriented to the early detection of any possible recurrences or associated anomalies and to a better quality of life of children and their families.

Wunderlich syndrome (WS) is a rare, potentially life-threatening medical condition characterized by spontaneous renal or perinephric hemorrhage occurring in the absence of known trauma. WS usually presents as Lenk\'s triad: acute flank pain, flank mass sensation, and hypovolemic shock; however, the presentation of this condition can vary in terms of symptom type and duration. We present the case of a 23-year-old previously healthy woman who consulted our emergency department with an unusual subacute form of presentation of WS (eight days of pain) due to an angiomyolipoma. Considering that the patient was clinically stable, a conservative approach with strict follow-up with serial computed tomography scans was taken.

Genomic alterations (GA) in NF2 tumor-suppressor gene have been associated with aggressive behavior in kidney tumors. We used comprehensive genomic profiling (CGP) to evaluate the frequencies of NF2 GA in histologic subtypes of kidney tumors and co-occurring GA in other genes and biomarkers. Advanced kidney tumors included 1875 clear cell (ccRCC), 405 papillary (pRCC), 108 chromophobe (chRCC), 171 sarcomatoid (sRCC), 61 collecting duct (cdRCC), 49 medullary (mRCC), 134 unclassified (uRCC), 906 urothelial carcinoma of renal pelvis (UC), and 147 Wilms tumors underwent hybrid-capture based CGP to evaluate all classes of GA. 192 (4.9%) of kidney tumors featured NF2 GA which were predominantly structural variant mutations (89%), followed by copy number alterations (9%). Gender and age were similar between NF2-mutant (NF2mut) and NF2-wild type (NF2wt) cohorts with male preponderance. NF2 GA frequency was highest in cdRCC (30%), sRCC (21%), uRCC (15%), and pRCC (12%) while lowest in ccRCC (3%), UC (3%) Wilms tumor (1%), and chRCC (0%). NF2 mutational status was associated with loss of Ch 22 (P < .001). NF2mut RCC harbored co-occurring GA including CDKN2A, CDKN2B, SETD2, and BAP1. VHL, PBRM1, PTEN, and FGFR3 GA were significantly more frequent in NF2wt than in NF2mut tumors. MTOR pathway GAs were uncommon in NF2mut tumors. No NF2 mutated RCC featured MSI-high or high TMB. sRCC was associated with high PD-L1 expression. PD-L1 SP142 tumoral (P = .04) and immune cells (P = .013) were more frequent in NF2mut as compared to NF2wt group. Among histologic subtypes of RCC, cdRCC, sRCC, pRCC, and uRCC are enriched in NF2 GA. Co-occurrent GA in CDKN2A/B, SETD2, and BAP1 may represent potential therapeutic targets. Higher level of PD-L1 expression in NF2mut cohort suggests that these tumors might be sensitive to immune checkpoint inhibitor therapies.

Peritoneal carcinomatosis associated with renal cell carcinoma is an infrequent entity, usually associated with large renal masses, and with a very rare presentation after surgery of localized renal tumors. Our objective is to review the literature and analyze the factors involved in the development of peritoneal carcinomatosis after laparoscopic partial nephrectomy in localized tumors.
We present our experience with two cases of peritoneal carcinomatosis after laparoscopic partial nephrectomy. We reviewed the literature and analyzed the factors associated with the development of peritoneal carcinomatosis after laparoscopic partial surgery in renal cell carcinoma.
Between 2005-2018, 225 patients underwent laparoscopic partial nephrectomy for localized renal neoplasia in our service. Two patients developed peritoneal carcinomatosis during follow-up, at 1.5 and 7 years after surgery. Few cases of postoperative peritoneal carcinomatosis for renal neoplasia have been described in the literature, being more frequently associated with large renal masses, with multiple metastases at diagnosis, with a poor prognosis. The dissemination of tumor cells during surgery, direct tumor extension or metastasis by hematogenous route, are among the factors involved in the development of this condition.
Peritoneal carcinomatosis after laparoscopic partial nephrectomy constitutes a very rare event. However, it should be taken into consideration, and, since it is the only factor we can influence, we must maximize precautions during the surgical act, following oncological principles.

The vascular disrupting activity of a promising tubulin-binding agent (OXi6196) was demonstrated in mice in MDA-MB-231 human breast tumor xenografts growing orthotopically in mammary fat pad and syngeneic RENCA kidney tumors growing orthotopically in the kidney. To enhance water solubility, OXi6196, was derivatized as its corresponding phosphate prodrug salt OXi6197, facilitating effective delivery. OXi6197 is stable in water, but rapidly releases OXi6196 in the presence of alkaline phosphatase. At low nanomolar concentrations OXi6196 caused G2/M cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells and monolayers of rapidly growing HUVECs underwent concentration-dependent changes in their morphology. Loss of the microtubule structure and increased bundling of filamentous actin into stress fibers followed by cell collapse, rounding and blebbing was observed. OXi6196 (100 nM) disrupted capillary-like endothelial networks pre-established with HUVECs on Matrigel®. When prodrug OXi6197 was administered to mice bearing orthotopic MDA-MB-231-luc tumors, dynamic bioluminescence imaging (BLI) revealed dose-dependent vascular shutdown with >80% signal loss within 2 h at doses ≥30 mg/kg and >90% shutdown after 6 h for doses ≥35 mg/kg, which remained depressed by at least 70% after 24 h. Twice weekly treatment with prodrug OXi6197 (20 mg/kg) caused a significant tumor growth delay, but no overall survival benefit. Similar efficacy was observed for the first time in orthotopic RENCA-luc tumors, which showed massive hemorrhage and necrosis after 24 h. Twice weekly dosing with prodrug OXi6197 (35 mg/kg) caused tumor growth delay in most orthotopic RENCA tumors. Immunohistochemistry revealed extensive necrosis, though with surviving peripheral tissues. These results demonstrate effective vascular disruption at doses comparable to the most effective vascular-disrupting agents (VDAs) suggesting opportunities for further development.

The literature review provides an analysis of a rare malignant tumor of the kidney: thyroid-like follicular carcinoma of the kidney (TLFCK). In morphology, this tumor is extremely similar to thyroid follicular carcinoma, but the immunophenotype of tumor cells is different. TLFCK has an indolent clinical course, rarely metastasizes, and even the development of metastases does not mean an unfavorable prognosis for the patient. The literature review presents the features of the clinical course of the disease, macroscopic, microscopic, immunohistochemical characteristics of the tumor and typical cytogenetic breakdowns. Particular attention is paid to the issues of differential diagnosis of the tumor with other pathological processes that may microscopically resemble TLFCK.
В представленном обзоре литературы приводится анализ редкой злокачественной опухоли почки: тиреоидоподобной фолликулярной карциномы почки (ТПФКП). По морфологии эта опухоль чрезвычайно напоминает фолликулярную карциному щитовидной железы, но при этом иммунофенотип опухолевых клеток отличается. ТПФКП имеет индолентное клиническое течение, редко метастазирует, однако даже развитие метастазов не означает неблагоприятный прогноз для пациента. В обзоре литературы приводятся особенности клинического течения заболевания, макроскопические, микроскопические, иммуногистохимические характеристики опухоли и типичные цитогенетические поломки. Особое внимание уделено вопросам дифференциальной диагностики опухоли с другими патологическими процессами, которые микроскопически могут напоминать ТПФКП.

Purpose: Clinicians rely on imaging features to calculate complexity of renal masses based on validated scoring systems. These scoring methods are labor-intensive and are subjected to interobserver variability. Artificial intelligence has been increasingly utilized by the medical community to solve such issues. However, developing reliable algorithms is usually time-consuming and costly. We created an international community-driven competition (KiTS19) to develop and identify the best system for automatic segmentation of kidneys and kidney tumors in contrast CT and report the results. Methods: A training and test set of CT scans that was manually annotated by trained individuals were generated from consecutive patients undergoing renal surgery for whom demographic, clinical and outcome data were available. The KiTS19 Challenge was a machine learning competition hosted on grand-challenge.org in conjunction with an international conference. Teams were given 3 months to develop their algorithm using a full-annotated training set of images and an unannotated test set was released for 2 weeks from which average Sørensen-Dice coefficient between kidney and tumor regions were calculated across all 90 test cases. Results: There were 100 valid submissions that were based on deep neural networks but there were differences in pre-processing strategies, architectural details, and training procedures. The winning team scored a 0.974 kidney Dice and a 0.851 tumor Dice resulting in 0.912 composite score. Automatic segmentation of the kidney by the participating teams performed comparably to expert manual segmentation but was less reliable when segmenting the tumor. Conclusion: Rapid advancement in automated semantic segmentation of kidney lesions is possible with relatively high accuracy when the data is released publicly, and participation is incentivized. We hope that our findings will encourage further research that would enable the potential of adopting AI into the medical field.

The selective disruption of tumor-associated vasculature represents an attractive therapeutic approach. We have undertaken the first in vivo evaluation of KGP265, a water-soluble prodrug of a benzosuberene-based tubulin-binding agent, and found promising vascular-disrupting activity in three distinct tumor types. Dose escalation in orthotopic MDA-MB-231-luc breast tumor xenografts in mice indicated that higher doses produced more effective vascular shutdown, as revealed by dynamic bioluminescence imaging (BLI). In syngeneic orthotopic 4T1-luc breast and RENCA-luc kidney tumors, dynamic BLI and oxygen enhanced multispectral optoacoustic tomography (OE-MSOT) were used to compare vascular shutdown following the administration of KGP265 (7.5 mg/kg). The BLI signal and vascular oxygenation response (ΔsO2) to a gas breathing challenge were both significantly reduced within 2 h, indicating vascular disruption, which continued over 24 h. A correlative histology confirmed increased necrosis and hemorrhage. Twice-weekly doses of KGP265 caused significant growth delay in both MDA-MB-231 and 4T1 breast tumors, with no obvious systemic toxicity. A combination with carboplatin produced significantly greater tumor growth delay than carboplatin alone, though significant carboplatin-associated toxicity was observed (whole-body weight loss). KGP265 was found to be effective at low concentrations, generating long-term vascular shutdown and tumor growth delay, thus providing strong rationale for further development, particularly in combination therapies.