Multivariate analysis of the parameters affecting the choice of surgical treatment for patients with localized renal cell carcinoma (RCC).

OBJECTIVE: to determine the key factors affecting the surgical treatment selection for patients with localized Renal-Cell Carcinoma (RCC) based on clinical and nephrometry data. MATERIALS AND METHODS: A retrospective cohort study to determine the key factors affecting the surgical treatment on a subset of patients with localized RCC (T1-T2) that underwent surgical treatment at primary investigational center from 2010 to 2017. Primary results were validated on the retrospective dataset of patients treated at high-volume referent center. Validation aimed to test applicability of the predictive model designed during primary analysis. To determine the relationship between the risks of radical or partial nephrectomy, the multivariate predictive modeling method was used. RESULTS: Based on the analysis, for polary and laterally located tumors, the risk of RN was conditioned only by remaining functioning parenchyma volume (RFPV). The average critical value of RFPV for polar lesions was = 58%; for lateral tumors = 67%. For medial location, the risk of RN only depended on the tumor size. Average critical value of the tumor size in the medial location was = 38mm. Based on the ROC curve comparison, there were no statistically significant differences between the predictive models containing 12 and 3 factors (AUCLin_12 and AUCMLP_3; P = 0.12); thus, the reduced amount of the factor indicators from 12 to 3 did not worsen the model predictive qualities. Designed during primary analysis hypothesis was successfully validated in a referent center on the cohort of 300 patients. Predictive model is characterized by high sensitivity (95.2%) and specificity (95.4%) in selecting patients for partial nephrectomy. CONCLUSIONS: For the polar and lateral tumor locations, the functioning parenchymal volumes of over 58 and 67% respectively serve as PN indications. However, for the medial lesions, the primary PN indication is a tumor size less than 38 mm.

Frequency of benign tumors after partial nephrectomy and the association between malignant tumor findings and preoperative clinical parameters.

BACKGROUND: Partial nephrectomy (PN) has become the dominant treatment modality for cT1 renal tumor lesions. Tumors suspected of malignant potential are indicated for surgery, but some are histologically classified as benign lesions after surgery. This study aims to analyze the number of benign findings after PN according to definitive histology and to evaluate whether there is an association between malignant tumor findings and individual factors. METHODS: The retrospective study included 555 patients who underwent open or robotic-assisted PN for a tumor in our clinic from January 2013 to December 2020. The cohort was divided into groups according to definitive tumor histology (malignant tumors vs. benign lesions). The association of factors (age, sex, tumor size, R.E.N.A.L.) with the malignant potential of the tumor was further evaluated. RESULTS: In total, 462 tumors were malignant (83%) and 93 benign (17%). Of the malignant tumors, 66% were clear-cell RCC (renal cell carcinoma), 12% papillary RCC, and 6% chromophobe RCC. The most common benign tumor was oncocytoma in 10% of patients, angiomyolipoma in 2%, and papillary adenoma in 1%. In univariate analysis, there was a higher risk of malignant tumor in males (OR 2.13, 95% CI 1.36-3.36, p = 0.001), a higher risk of malignancy in tumors larger than 20 mm (OR 2.32, 95% CI 1.43-3.74, p < 0.001), and a higher risk of malignancy in tumors evaluated by R.E.N.A.L. as tumors of intermediate or high complexity (OR 2.8, 95% CI 1.76-4.47, p < 0.001). In contrast, there was no association between older age and the risk of malignant renal tumor (p = 0.878). CONCLUSIONS: In this group, 17% of tumors had benign histology. Male sex, tumor size greater than 20 mm, and intermediate or high R.E.N.A.L. complexity were statistically significant predictors of malignant tumor findings.

Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

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.

Comparison of aggressiveness in central versus peripheral T1a clear-cell renal cell carcinoma.

PURPOSE: This study aimed to estimate the difference between peripheral and central small renal lesions in terms of their oncologic potential. METHODS: Cross-sectional retrospective analysis of patients with small renal masses (T1a) who underwent surgical treatment between January 2008 and July 2019 at the affiliated hospital. Only patients with ccRCC pathology were included. Cases were divided into 2 groups depending on tumor location (central or peripheral) based on the R.E.N.A.L and local nephrometry scoring. Presence of nodal involvement, distant metastases, ISUP grade and endophytic growth were defined as aggressiveness predictors. Statistical analyses was performed using a standard statistical software (IBM SPPS Statistics Ver. 22), with P < 0.05 considered statistically significant. Associations between tumor location and Fuhrman grade, exo-/endophytic growth, TNM classification, and type of operation were tested using the Pearson χ² test and 1-way ANOVA test. RESULTS: Patients with centrally located tumors had a higher incidence of clinical and pathological lymph node involvement (P = 0.02, χ2 = 5.1). Patients in both groups had an equal number of distant metastases at the time of diagnosis (P = 0.3, χ2 = 0.8). The operation time was significantly longer in patients with central lesions, which obviously showed higher tumor complexity in this group (P < 0.005). Pathological evaluation revealed differences between ISUP grades in both groups (P < 0.005, χ2 = 29.9). Central masses were characterized by higher aggressiveness, indicating a worse prognosis. Furthermore, the cases in the first group were more often endophytic (P = 0.03, χ2 = 0.9). Nevertheless, this did not affect the surgical strategy in most cases with a tendency toward partial nephrectomy. Eventually, organ-sparing treatment was preferable in both groups (P = 0.13, χ2 = 2.29). CONCLUSION: Centrally located kidney cancer has showed in present study a higher incidence of high ISUP grade, regional nodal involvement and endophytic growth type. Endophytic growth type was associated with worse ISUP grading. Distribution of ISUP grade was not age depended, thus showing no difference by this criterion, when comparing different age groups. Higher ISUP grade was strongly associated with presence of distant metastases in T1a kidney tumors. Further analysis is needed to investigate aggressiveness of centrally located T1a RCC, as it may influence current conservative management options.

Evaluation of an institutional series of low-grade oncocytic tumor (LOT) of the kidney and review of the mutational landscape of LOT.

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.

Report and follow-up on two new patients with congenital mesoblastic nephroma.

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. CASES PRESENTATION: 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.

Decoding the Possible Molecular Mechanisms in Pediatric Wilms Tumor and Rhabdoid Tumor of the Kidney through Machine Learning Approaches.

Objective: Wilms tumor (WT) and Rhabdoid tumor (RT) are pediatric renal tumors and their differentiation is based on histopathological and molecular analysis. The present study aimed to introduce the panels of mRNAs and microRNAs involved in the pathogenesis of these cancers using deep learning algorithms. Methods: Filter, graph, and association rule mining algorithms were applied to the mRNAs/microRNAs data. Results: Candidate miRNAs and mRNAs with high accuracy (AUC: 97%/93% and 94%/97%, respectively) could differentiate the WT and RT classes in training and test data. Let-7a-2 and C19orf24 were identified in the WT, while miR-199b and RP1-3E10.2 were detected in the RT by analysis of Association Rule Mining. Conclusion: The application of the machine learning methods could identify mRNA/miRNA patterns to discriminate WT from RT. The identified miRNAs/mRNAs panels could offer novel insights into the underlying molecular mechanisms that are responsible for the initiation and development of these cancers. They may provide further insight into the pathogenesis, prognosis, diagnosis, and molecular-targeted therapy in pediatric renal tumors.

A Subacute Presentation of Wunderlich Syndrome in a Young Woman: A Case Report.

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.

A Multi-Institutional Matched-Pair Analysis of Robotic Partial Nephrectomy for Single vs Multiple Ipsilateral Renal Masses.

Introduction: Nephron-sparing surgery is important in patients with multiple renal tumors, especially if associated with a solitary kidney or hereditary syndrome. Prior studies have shown partial nephrectomy (PN) of multiple ipsilateral renal masses to have good oncologic and renal function outcomes. We aim to compare renal function changes, complications, and warm ischemia time (WIT) of partial nephrectomy of a single renal mass (sPN) vs those of partial nephrectomy of multiple ipsilateral renal masses (mPN). Materials and Methods: We retrospectively reviewed our multi-institutional PN database. We matched robotic sPN and mPN patients ∼3:1 using "nearest neighbor" propensity score matching based on age, Charlson comorbidity index (CCI), total tumor size, and nephrometry score. Univariate analysis was performed, and multivariable models were fit controlling for age, gender, CCI, and tumor size. Results: Fifty mPN and 146 sPN patients were matched. The mean total tumor size was 3.3 and 3.2 cm, respectively (p = 0.363). The mean nephrometry score in both groups was 7.3 and 7.2, respectively (p = 0.772). Estimated blood loss (EBL) was 137.6 and 117.8 mL, respectively (p = 0.184). The mPN group had higher operative time (174.6 vs 156.4 minutes, p = 0.008) and WIT (17.0 vs 15.3 minutes, p = 0.032). There was no significant difference in the change in glomerular filtration rate (mPN -6.4% vs sPN -8.7%, p = 0.712). Complications (Clavien 2+) occurred in 10.2% of mPN and 11.3% of sPN patients (p = 0.837). A multivariable linear model predicts a nonstatistically significant difference of 1.4 minutes of additional WIT in the mPN group (p = 0.242). There was no statistical difference in complication rates between groups in a multivariable model (odds ratio 1.00, p = 0.991). Conclusions: Robotic PN in our multi-institutional matched comparison of mPN and sPN showed no difference in complications, renal functional outcomes, or EBL. mPN was associated with increased operative time and WIT, though the WIT difference was not significant on multivariable analysis.

Comprehensive Genomic Profiling of NF2-Mutated Kidney Tumors Reveals Potential Targets for Therapy.

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.

Carcinomatosis peritoneal tras nefrectomía parcial laparoscópica en carcinoma de células renales: nuestra experiencia y revisión de la literatura / Peritoneal carcinomatosis after partial nephrectomy for renal cell carcinoma: Our experience and literature review

Objetivo: La carcinomatosis peritoneal asociada al carcinoma de células renales es una entidad infrecuente, normalmente asociada a grandes masas renales, siendo muy rara su presentación tras la cirugía de tumores renales localizados. Nuestro objetivo es revisar la literatura y analizar los factores implicados en el desarrollo de carcinomatosis peritoneal tras nefrectomía parcial laparoscópica en tumores localizados.Material y métodos: Presentamos nuestra experiencia con 2 casos de carcinomatosis peritoneal tras cirugía parcial laparoscópica. Realizamos revisión de la literatura y analizamos los factores asociados al desarrollo de carcinomatosis peritoneal tras cirugía parcial laparoscópica en carcinoma de células renales.Resultados: Entre 2005-2018 en nuestro servicio fueron sometidos a nefrectomía parcial laparoscópica 225 pacientes por neoplasia renal localizada. Dos pacientes desarrollaron carcinomatosis peritoneal en el seguimiento, uno al año y medio de la cirugía y un segundo caso a los 7 años. Pocos casos de carcinomatosis peritoneal tras cirugías de neoplasia renal han sido descritos en la literatura, estando más frecuentemente asociados a grandes masas renales, con múltiples metástasis al diagnóstico, siendo el pronóstico infausto. Entre los factores implicados en su desarrollo pueden estar la diseminación de células tumorales durante la cirugía, la extensión tumoral directa o la metástasis por vía hematógena.Conclusiones: La carcinomatosis peritoneal tras nefrectomía parcial laparoscópica constituye un evento muy raro, pero que debe ser tenido en cuenta y, dado que es el único factor en el que podemos influir, extremar al máximo las precauciones durante el acto quirúrgico, siguiendo los principios oncológicos. (AU)

Objective: 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.Material and methods: 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.Results: 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.Conclusions: 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. (AU)

Demonstrating Tumor Vascular Disrupting Activity of the Small-Molecule Dihydronaphthalene Tubulin-Binding Agent OXi6196 as a Potential Therapeutic for Cancer Treatment.

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.

Peritoneal carcinomatosis after partial nephrectomy for renal cell carcinoma: Our experience and literature review.

OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Rare kidney tumor - thyroid-like follicular carcinoma]. / Redkaya opukhol' pochki ­ tireoidopodobnaya follikulyarnaya kartsinoma.

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.

[CME-Sonography 104: Angiomyolipomas]. / CME-Sonografie 104: Angiomyolipome.

CME-Sonography 104: Angiomyolipomas Abstract. Angiomyolipomas are the most common benign kidney tumors. Approximately 80 % are spontaneously occurring tumors, the majority <1.0 cm (approximately 54 %). These tumors do not grow and are harmless. Tumors between 1.0 and 2.5 cm (approx. 44 %) also very rarely grow and remain harmless. Larger tumors are rarely found (about 2 %). These must be carefully monitored, as tumors >4.0 cm can spontaneously manifest dangerous bleeding. Apart from spontaneous occurrence, there are also angiomyolipomas in the context of the tuberous sclerosis complex (TCS). Such tumors are often larger and combined with renal cysts and renal cell carcinomas. Measuring the of echo intensity is important for diagnosis.

Anaplastic Sarcoma of the Kidney With Heterologous Ganglioneuroblastic Differentiation: Another DICER1-Associated Tumor.

Anaplastic sarcoma of the kidney (ASK) is a rare renal tumor for which less than thirty cases have been described in the literature to date. Diagnosis of ASK is primarily based on histology, which features solid spindle cell neoplastic islands arranged in a fascicular pattern, prominent anaplastic nuclear morphology, brisk mitoses, and multiple multiloculated cysts lined by hobnail epithelium reminiscent of cystic nephroma. Chondroid or rhabdomyocytic differentiation is often present within the sarcoma. It has been recently suggested that this tumor entity belongs to the DICER1 syndrome tumors based on identification of DICER1 mutations. We report on a case of this rare tumor found in a twenty-month-old female. In addition to the typical histologic findings of ASK, this case also displayed heterologous neuroblastic-gangliocytic differentiation, which has not been previously described in the literature. TP53 and BRAF v600E had aberrant immunostaining. Chromosomal microarray and genomic sequencing revealed loss of chromosome 10 p15.3-p11.2 and both somatic and germline DICER1 mutations, consistent with recent research and further supporting the classification of this tumor within the DICER1 syndrome associated tumors.

Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment.

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.

[Are multiple trichodiscomas/fibrofolliculomas the Birt-Hogg-Dubé syndrome?] / Mnozhestvennye trikhodiskomy/fibrofollikulomy ­ sindrom Berta­Khogg­D'yuba?

Birt-Hogg-Dubé syndrome is a rare autosomal dominant disease caused by a mutation in the FLCN gene and presents with a triad of multiple fibrofolliculomas, trichodiscomas, and masses that clinically resemble fibroepithelial polyps (acrochordones), accompanied by an increased risk of kidney tumors and lung cysts. The paper provides a literature review supplemented by clinical cases and the morphological pattern of skin lesions. It presents the clinical and morphological features of cutaneous manifestations of the syndrome and gives diagnostic criteria.

Low-Grade Oncocytic Tumor of Kidney (CK7-Positive, CD117-Negative): Incidence in a single institutional experience with clinicopathological and molecular characteristics.

Low-grade oncocytic tumor of the kidney (LOT) is characterized by cytoplasmic eosinophilia and a CK7-positive/CD117-negative immunophenotype. Morphologically, they exhibit overlapping features with oncocytoma and chromophobe renal cell carcinoma. Our aim was to obtain long-term clinical follow-up data, clinicopathological and molecular characteristics, and incidence of LOT. Tissue microarrays were constructed from 574 tumors historically diagnosed as oncocytoma and surgically treated at Mayo Clinic between 1970 and 2012, and immunostained for CK7 and CD117. An extended immunophenotype was obtained on whole slide sections, along with FISH for CCND1 rearrangement status and chromosomal microarray for copy number status. In addition, two cases were retrospectively identified in a set of tuberous sclerosis complex (TSC)-associated neoplasms and three more cases diagnosed on needle core biopsies were obtained during routine clinical practice. Twenty-four cases of LOT were identified among 574 consecutive tumors diagnosed as oncocytoma and treated with partial or radical nephrectomy, corresponding to an incidence of 4.18% of tumors historically diagnosed as oncocytomas, and 0.35% of 6944 nephrectomies performed between 1970 and 2012. Overall, 29 cases of LOT were identified in three clinical settings: sporadic, TSC-associated, and end-stage renal disease (ESRD). Multifocality was seen only in the setting of TSC and ESRD. No metastases attributable to LOT were identified (median follow-up 9.6 years). There were no recurrent arm level copy number changes detected by chromosomal microarray and all tested cases were negative for CCND1 rearrangement by FISH. LOT is an uncommon eosinophilic renal neoplasm with an indolent prognosis that constitutes ∼4% of tumors historically diagnosed as oncocytoma. The morphologic, immunophenotypic, and molecular features of this neoplasm suggest it is a distinct entity of renal neoplasia.

Inhibitors of TGFßR1/ALK4/JNK3/Flt1 Kinases in Cynomolgus Macaques Lead to the Rapid Induction of Renal Epithelial Tumors.

Two young cynomolgus macaques (Macaca fascicularis) given a small molecule kinase inhibitor ((S)-4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)-N-(2-hydroxypropyl)nicotinamide [SCIO-120]) via nasogastric intubation gavage, once-daily for 21 days at 400 mg/kg/day, developed an unusual epithelial proliferative process in the renal parenchyma. Morphological and immunohistochemical characterization of the lesions confirmed an invasive malignant epithelial neoplasm (carcinoma). A similar renal neoplasm was seen in a third macaque after a 14-day exposure to a second kinase inhibitor in the same chemical series ((S) 4-((2-(5-chloro-2-fluorophenyl)-5-methoxypyrimidin-4-yl)amino)-N-cyclopropylnicotinamide [SCIO-974]). Despite remarkably short latency periods, exposure to these kinase inhibitors was likely causally associated with the induction of the renal tumors, as renal carcinomas are exceedingly rare spontaneously in macaques. Both SCIO-120 and SCIO-974 were designed as potent TGFßR1 inhibitors (IC50s 37 and 39 nM, respectively). SCIO-120 and SCIO-974 inhibited additional kinases, most notably closely related ALK4 (IC50 = 34 and 20 nM, respectively), c-Jun n-Terminal kinase 3 (JNK3, IC50 = 10 and 20 nM, respectively), and Fms-related tyrosine kinase 1 (29 and 76 nM, respectively). TGFßR1 has been specifically implicated in epithelial proliferative disorders, including neoplasia. Neither SCIO-120 nor SCIO-974 was genotoxic based on bacterial reverse mutation and/or clastogenicity screening assays. The rapid appearance of renal carcinomas in primates following short-term treatment with nongenotoxic kinase inhibitors is remarkable and suggests that the compounds had noteworthy tumor-enhancing effects, hypothetically linked to their TGFßR1 inhibition activity. These observations have implications for mechanisms of carcinogenesis and TGFßR1 biology.