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A significantly increased level of the reactive oxygen species (ROS) scavenger glutathione (GSH) has been identified as a hallmark of renal cell carcinoma (RCC). The proposed mechanism for increased GSH levels is to counteract damaging ROS to sustain the viability and growth of the malignancy. Here, we review the current knowledge about the three main RCC subtypes, namely clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC), at the genetic, transcript, protein, and metabolite level and highlight their mutual influence on GSH metabolism. A further discussion addresses the question of how the manipulation of GSH levels can be exploited as a potential treatment strategy for RCC.

Cell lines are still a tool of choice for many fields of biomedical research, including oncology. Although cancer is a very complex disease, many discoveries have been made using monocultures of established cell lines. Therefore, the proper use of in vitro models is crucial to enhance our understanding of cancer. Therapeutics against renal cell cancer (RCC) are also screened with the use of cell lines. Multiple RCC in vitro cultures are available, allowing in vivo heterogeneity in the laboratory, but at the same time, these can be a source of errors. In this review, we tried to sum up the data on the RCC cell lines used currently. An increasing amount of data on RCC shed new light on the molecular background of the disease; however, it revealed how much still needs to be done. As new types of RCC are being distinguished, novel cell lines and the re-exploration of old ones seems to be indispensable to create effective in vitro tools for drug screening and more.

This study compares recurrence-free survival (RFS) and overall survival (OS) in patients with non-clear cell (nccRCC) and clear cell renal cell carcinoma (ccRCC) undergoing surgical nephrectomy with thrombectomy (SNTx) for RCC with venous thrombus. Data from patients who underwent SNTx at two tertiary centers (June 1990–December 2022) were retrospectively reviewed. Patients were grouped as ccRCC or nccRCC and stratified by metastasis status at surgery. Primary endpoints were RFS and OS for metastasis-naive RCC and OS for the entire cohort, including both metastasis-naive and metastatic RCC. Kaplan–Meier analysis with log-rank tests and adjusted multivariable Cox proportional hazards models were performed, with TN adjustments for the metastasis-naive group and TNM adjustments for the entire population. Among 604 patients, 504 (83.5%) were ccRCC. In nccRCC, 44 (44.0%) were papillary, 17 (17.0%) were chromophobe, and 39 (39.0%) were rare subtypes, most commonly TFE3 rearranged RCC, followed by the RCC not otherwise specified subtype (according to the 2022 World Health Organization Classification of RCC). Median OS was 85.8 months for ccRCC, 37.7 for papillary, 90.2 for chromophobe, and 16.9 for rare subtypes. Rare RCC histology was significantly associated with worse RFS (HR 1.63, p  = 0.038) and OS (HR 1.82, p  = 0.039) in metastasis-naive RCC. For the entire cohort including metastatic diseases, rare subtypes had worse OS (HR 2.20, p  < 0.001), while other nccRCC subtypes did not differ significantly from ccRCC in OS. In patients with RCC with venous thrombosis, rare nccRCC subtypes exhibited poorer survival outcomes, even after adjustment for TN(M) stage.

Objectives: The aim of the study was to assess the utility of contrast-enhanced ultrasound (CEUS), using both qualitative and quantitative perfusion analysis, in differentiating subtypes of renal cell carcinoma (RCC). Methods: This prospective, single-center study includes 91 patients with histologically confirmed RCC. We performed a CEUS within one week prior to nephrectomy. Qualitative parameters (enhancement pattern, heterogeneity, pseudocapsule) and quantitative perfusion metrics were assessed. Logistic regression models were developed to evaluate the diagnostic performance of CEUS in differentiating high-grade (clear cell RCC) from low-grade RCC (papillary and chromophobe). Results: Qualitative CEUS findings showed that hyperenhancement and isoenhancement were significantly associated with high-grade RCC (OR = 38.3 and OR = 7.8, respectively; p < 0.001 and p = 0.014). Hypoenhancement was predominant in low-grade RCC (80.0%). Quantitative parameters, including peak enhancement and wash-in/wash-out area under the curve, significantly differed between tumor grades (p < 0.001). A model using qualitative parameters alone achieved an AUC of 0.847 and 81.9% accuracy. Adding quantitative metrics marginally improved performance (AUC 0.912, accuracy 86.2%), though not significantly. Conclusions: CEUS provides valuable diagnostic information in differentiating RCC subtypes, with qualitative parameters alone demonstrating strong predictive power. While quantitative analysis slightly enhances diagnostic accuracy, its added value may be limited by technical challenges.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which renal manifestations are prominent. There are three major renal lesions in TSC: angiomyolipomas, cysts, and renal cell carcinoma (RCC). Major recent advances have revolutionized our understanding of TSC-associated RCC, including two series that together include more than 100 TSC-RCC cases, demonstrating a mean age at onset of about 36 years, tumors in children as young as 7, and a striking 2:1 female predominance. These series also provide the first detailed understanding of the pathologic features of these distinctive tumors, which include chromophobe-like features and eosinophilia, with some of the tumors unclassified. This pathologic heterogeneity is distinctive and reminiscent of the pathologic heterogeneity in Birt–Hogg–Dube-associated RCC, which also includes chromophobe-like tumors. Additional advances include the identification of sporadic counterpart tumors that carry somatic TSC1/TSC2/mTOR mutations. These include unclassified eosinophilic tumors, eosinophilic solid cystic RCC (ESC-RCC), and RCC with leiomyomatous stroma (RCCLMS). A variety of epithelial renal neoplasms have been identified both in patients with tuberous sclerosis complex (TSC) and in the nonsyndromic setting associated with somatic mutations in the TSC1 and TSC2 genes. Interestingly, whether tumors are related to a germline or somatic TSC1/2 mutation, these tumors often display similar morphologic and immunophenotypic features. Finally, recent work has identified molecular links between TSC and BHD-associated tumors, involving the TFEB/TFE3 transcription factors.

This retrospective study aims to describe the characteristics of renal cell carcinoma (RCC) in Saudi Arabia, in terms of epidemiology, clinical presentation, tumor subtype, Fuhrman grade, tumor size and stage, and overall survival. A total of 431 adult patients with a histopathological diagnosis of RCC between 2015 and 2023 were included in the analysis. Most patients (72.4%) had clear cell tumors, followed by chromophobe (15.1%) and papillary (12.5%) subtypes. In males, papillary RCC (85.2%) was more common compared to clear cell (59.8%) and chromophobe (67.7%) subtypes. Significant differences were observed in median body mass index (BMI) across tumor subtypes, and papillary tumor patients exhibited the highest incidence of hematuria (33.3%) compared to other subtypes. The Fuhrman grade also varied significantly among RCC types. Survival times were found to be lower for patients with papillary tumors. No significant difference was observed based on patients' nationality. This study can inform clinical decision-making on patient prognosis and management as well as public health efforts aimed at reducing the alarming rise of RCC incidence.

Background Prostate-specific membrane antigen (PSMA) has been shown to be overexpressed in the neo-vasculature of renal cancers. However, studies investigating the pattern of PSMA expression in primary RCC and RCC metastases according to metastatic sites are rare. 44 frozen samples of RCC, 19 primaries (9 clear cell (cc) RCC, 7 papillary (pap) RCC, and 3 chromophobe (ch) RCC) and 25 (24 samples have ccRCC histology and one is unclassified) unpaired metastases (8 from adrenals, 8 from bones, 2 from lungs, 2 from liver and 5 others (1 lymph node, 1 pancreas, 1 brain, 1 gallbladder and 1 muscle)), were available from the UroCCR project (NCT03293563). PSMA expression was assessed by autoradiography using [ 177 Lu]Lu-PSMA-617 as binding agent and the specific binding (total binding—non-specific binding) was calculated and expressed as a percentage of total binding. A patient suffering from metastatic ccRCC was also administered [ 68 Ga]Ga-PSMA-11 to evaluate PSMA expression. Results The mean specific binding was 28.9 ± 40.4% for primary renal cancer and 65.0 ± 38.9% for metastasis. Regarding histology, high PSMA expression was depicted in 33.3% of ccRCC, 33.3% of chRCC and 57.1% of papRCC. PSMA was more frequently expressed in primary samples of papRCC histology with renal capsule invasion ( p  = 0.0286). A higher PSMA-specific binding and a higher number of samples with high PSMA-expression were depicted in metastatic samples. Bone metastasis showed lower binding than other metastatic sites combined ( p  = 0.0005). The patient suffering from metastatic ccRCC showed high [ 68 Ga]Ga-PSMA-11 uptake on known distant metastases and additional site uncovered. Conclusion PSMA showed high expression in metastases of ccRCC. Clinical trial registration NCT, NCT03293563, prospectively registered September 20, 2017, http://www.clinicaltrials.gov .

While the clear-cell renal cell carcinoma (ccRCC) treatment has undergone several paradigm shifts in recent years, the non-clear cell renal cell carcinoma (nccRCC) therapeutic approach has yet to be extensively investigated and improved. The WHO 2022 classification of renal neoplasms redefined the most common nccRCC subtypes (papillary and chromophobe RCC) and introduced the molecularly defined RCC class, which is a first step in the direction of better molecular profiling of nccRCC. We reviewed the literature data on known genomic alterations of clinical interest in nccRCC and discussed their potential role in guiding therapeutic choices in each nccRCC entity. Among the alterations discussed, we focused on the ones that could be treated with already available drugs, such as MET-driven papillary RCC, mechanistic target of rapamycin altered chromophobe RCC, anaplastic lymphoma kinase-rearranged RCC, and fumarate-hydratase deficient RCC. Furthermore, we focused on the currently ongoing clinical trials and further evidence for all the other entities, such as SMARCB1-deficient RCC, TFE3 and transcription factorEB (TFEB)-altered RCC, and Elongin C (ELOC)-mutated RCC. The vast heterogeneity of nccRCC does not allow a one-size-fits-all solution; therefore, molecular characterization is the path toward effective therapies and fully personalized medicine for these entities.

Renal cell carcinoma (RCC) represents a heterogeneous disease, encompassing an increasing number of tumor subtypes. Post-2016, the World Health Organization (WHO) classification recognized that the spectrum of papillary renal cell carcinoma is evolving and has long surpassed the dichotomic simplistic “type 1 versus type 2” classification. The differential diagnosis of pRCC includes several new provisional/emerging entities with papillary growth. Type 2 tumors have been cleared out of several confounding entities, now regarded as independent tumors with specific clinical and molecular backgrounds. In this work we describe the prevalence and characteristics of emerging papillary tumor entities in two renal tumor cohorts (one consisting of consecutive papillary tumors from a single institute, the other consisting of consultation cases from several centers). After a review of 154 consecutive pRCC cases, 58% remained type 1 pRCC, and 34% type 2 pRCC. Papillary renal neoplasm with reversed polarity (1.3%), biphasic hyalinizing psammomatous RCC (1.3%), and biphasic squamoid/alveolar RCC (4.5%) were rare. Among 281 consultation cases, 121 (43%) tumors had a dominant papillary growth (most frequently MiT family translocation RCCs, mucinous tubular and spindle cell carcinoma and clear cell papillary RCC). Our data confirm that the spectrum of RCCs with papillary growth represents a major diagnostical challenge, frequently requiring a second expert opinion. Papillary renal neoplasm with reversed polarity, biphasic hyalinizing psammomatous RCC, and biphasic squamoid/alveolar RCC are rarely sent out for a second opinion, but correct classification and knowledge of these variants will improve our understanding of the clinical behavior of renal tumors with papillary growth.

To compare the oncological outcomes of clear cell RCC (ccRCC), which is common in renal cell carcinomas (RCC), and chromophobic RCC (chRCC), which is less common, and to define the factors affecting survival in the Turkish patient population for both RCC subclassifications. Patients with a pathologically confirmed RCC diagnosis after radical or partial nephrectomy in the Turkish Urooncology Association (TUOA), Urological Cancers Database-Kidney (UroCaD-K), were retrospectively reviewed. Patients with ccRCC and chRCC were included in the study. Primary outcomes of this study are recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) for each histological subtype. Data from 5300 patients in the TUOA UroCaD-K are reviewed and a total of 2560 patients (2225 in the ccRCC group and 335 in the chRCC group) are included in the final analysis. In the comparison of the groups, tumor size was greater both radiologically and pathologically in chRCC (p=0.019 vs 0.002 respectively). Recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) rates are worse in ccRCC subgroup. In the evaluation of risk factors; pathological stage, local invasion and Fuhrmann grade were found to be significant for recurrence in ccRCC. Age, body mass index and pathological stage were the risk factors affecting overall mortality (OM). Pathological tumor size was an independent risk factor for recurrence in chRCC, while age was analyzed as the only parameter affecting OM. chRCC oncological data and OS, CSS and RFS rates were found to be better than ccRCC in the Turkish patient population.