Maria J. Merino

Background/Objectives: Prostate cancer is the second most frequent cancer among men and the 5th leading cause of cancer death among men worldwide. Identification of urine-derived biomarkers, such as exosomal miRNAs, in liquid biopsies for prostate cancer could be very beneficial for screening and active surveillance. Methods: Urine was collected from 42 patients with biopsy-proven evidence of prostate cancer and exosomes were extracted. Transcriptomic analysis was performed on the urine-derived exosomal miRNA and compared to the urine-derived exosomal miRNA profiles from 10 normal control donors and 15 von Hippel-Lindau (VHL) syndrome patients with clear cell renal cell carcinoma (ccRCC). Results: Urine-derived exosomal miRNA profiles of prostate patients were significantly different from normal control individuals. Significantly increased expression of miR-122-5p and decreased expression of miR-125-5p and miR-16-5p were observed in the urine-derived exosomes from prostate cancer patients. Significant upregulation of miR-30a-5p and downregulation of miR-320-5p, miR-320b, and miR-320c were observed in the urine-derived exosomes from both prostate cancer patients and VHL patients with ccRCC, indicating these miRNAs could be non-specific markers of urological cancer. Increased expression of miR-10a-5p and miR-30e-5p or miR-532-5p and miR-206 correlated with the presence of either extracapsular or perineural invasion, respectively. Conclusions: This study highlights the potential for urine-derived exosomal miRNA profiles to identify the presence of prostate cancer and predict clinical features, additionally showing that miRNA signals could be non-specific markers of urologic cancer types. Further validation studies are necessary to demonstrate the utility of urine-derived exosomal miRNA profiles as biomarkers for diagnosis or prognosis in prostate cancer.

Purpose Birt-Hogg-Dubé (BHD) syndrome is a rare genetic condition characterized by pathogenic variation in the folliculin (FLCN) gene on chromosome 17p11.2. Individuals affected with BHD are at risk to develop renal cysts and masses (13–34% of cases); renal masses are mostly hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, or oncocytomas. This study aims to investigate the computed tomography (CT) manifestations of renal masses associated with BHD syndrome. Methods Multiphase CT imaging of patients with BHD syndrome who underwent renal surgery between March 2000 and December 2020 was evaluated. Imaging characteristics of the masses, including laterality, diameter, margin, tumor configuration, homogeneity, longitudinal location, percentage of tumor deepening into the kidney, location relative to the rim, presence of central scar, fat, calcification, pre-contrast density, and enhancing pattern, were recorded. Results This investigation included 169 renal masses from 30 adult patients with BHD syndrome (mean age 53 ± 12 years, 15 males). Surgical laterality was 36.7% left, 40.0% right, and 23.3% bilateral. The mean diameter of the examined masses was 2.71 ± 1.62 cm. Growth rate analysis of 132 masses showed a growth rate of 0.04 cm per year (95% CI: 0.01– 0.07). The majority of masses selected for analysis (94.1%) were hybrid tumors. In the hybrid masses, 98.8% were predominantly solid, 68.0% were homogeneous, and 73.4% had well-defined margins. Exophytic masses were predominant (79.9%), primarily located on the lateral rim (45.6%). Longitudinally, 32.6% were in the upper pole, 36.0% interpolar, and 30.5 in % lower pole. Central scar was present in 9.5%, calcification in 4.1%, and none contained fat. In the pre-contrast phase, the mean density of masses was 36.1 HU ± 8.9. Normalized enhancement based on the renal cortex was lower in the venous than the arterial phase (0.73 vs. 0.88). Conclusions Our analysis confirmed that while BHD-associated renal masses demonstrate diversity in CT presentations, most are solid, homogeneous, exophytic, exhibit a pre-contrast density of 36.1 HU ± 8.9, and have well-defined margins in the lateral rim.

Detailed evaluation of prostate cancer glands is an essential yet labor-intensive step in grading prostate cancer. Gland segmentation can serve as a valuable preliminary step for machine-learning-based downstream tasks, such as Gleason grading, patient classification, cancer biomarker building, and survival analysis. Despite its importance, there is currently a lack of a reliable gland segmentation model for prostate cancer. Without accurate gland segmentation, researchers rely on cell-level or human-annotated regions of interest for pathomic and deep feature extraction. This approach is sub-optimal, as the extracted features are not explicitly tailored to gland information. Although foundational segmentation models have gained a lot of interest, we demonstrated the limitations of this approach. This work proposes a prostate gland segmentation framework that utilizes a dual-path Swin Transformer UNet structure and leverages Masked Image Modeling for large-scale self-supervised pretaining. A tumor-guided self-distillation step further fused the binary tumor labels of each patch to the encoder to ensure the encoders are suitable for the gland segmentation step. We united heterogeneous data sources for self-supervised training, including biopsy and surgical specimens, to reflect the diversity of benign and cancerous pathology features. We evaluated the segmentation performance on two publicly available prostate cancer datasets. We achieved state-of-the-art segmentation performance with a test mDice of 0.947 on the PANDA dataset and a test mDice of 0.664 on the SICAPv2 dataset.

Von Hippel-Lindau (VHL) is an autosomal-dominant hereditary tumour susceptibility disease associated with pathogenic germline variants in the VHL tumour suppressor gene. VHL patients are at increased risk of developing multiple benign and malignant tumours. Current CLIA-based genetic tests demonstrate a very high detection rate of germline VHL variants in patients with clinical manifestations of VHL. In this report, we describe a large family with canonical VHL manifestations, for which no germline alteration had been detected by conventional germline testing. We identified a novel 291 kb chromosomal inversion involving chromosome 3p in affected family members. This inversion disrupts the VHL gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family.

Introduction: Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information. Methods: Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs. Results: MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney. Conclusions: This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer.

Intratumoral heterogeneity (IH) has been recently described as an important contributor to tumor growth through a branched rather than a linear pattern of tumor evolution for renal cell carcinoma. As to whether the miRNA profiling of the different and heterogeneous areas is the same or not, it is not known. This study analyzed the differences and similarities of the miRNA profiles in histologically distinct regions within several RCC tumors. The observed differences may have great implications for the development of predictive biomarkers and the identification of druggable targets with improvement of combinatorial therapeutic approaches for the effective treatment of kidney cancer, as well as for the identification of circulating malignant cells that can be useful to detect tumor recurrences.

Renal cell carcinoma (RCC) is a heterogenous disease composed of several different cancer types characterized by distinct histologies and genetic alterations, including mutation of the Krebs cycle enzyme genes for fumarate hydratase and succinate dehydrogenase (SDH). This report describes a patient with multifocal renal tumors that presented with a novel, biphasic histologic morphology with one component consisting of small cells growing in a diffuse pattern occasionally forming glandular and cystic structures, reminiscent of type 1 papillary RCC, and the other component having larger cells with abundant eosinophilic and clear cytoplasm and appearing in a solid pattern of growth. Genetic analysis of multiple tumors showed that all had a somatic mutation of the IDH2 gene that created the known pathogenic, gain-of-function p.R172M alteration that results in abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Analysis of multiple tumors demonstrated highly elevated levels of 2-HG and a CpG island methylator phenotype that is characteristic of 2-HG-related inhibition of the Ten-eleven translocation (TET) family of DNA demethylases. In combination with fumarate hydratase–deficient and succinate dehydrogenase–deficient RCCs that have increased levels of the fumarate and succinate oncometabolites, respectively, the mutation of isocitrate dehydrogenase 2 represents the third Krebs cycle enzyme alteration to be associated with oncometabolite-induced RCC tumorigenesis. This study associates the discovery of a new histologic presentation of RCC with the first report of an IDH2 gain-of-function mutation in RCC.

Immunotherapy is reportedly an effective form of therapy for some advanced cancers such as lung adenocarcinoma, malignant melanoma and colorectal adenocarcinoma. In renal cell carcinoma (RCC), the role of immunotherapy is under investigation. Programmed Death-Ligand 1 (PD-L1) is a molecule expressed on the surface of certain tumor cells and binds to the Programmed cell death protein 1 (PD-1) on cytotoxic T-cells, an interaction that inhibits the antitumor immune response. The aim of this study is to evaluate PD-L1 expression in the morphologic spectrum of RCC. A total of 172 cases of RCC comprising all types were studied and the PD-L1 was correlated with immune response for CD4 and CD8. Positive membranous staining for PD-L1 was seen in 59 (34%) of the 172 samples. The positive cases were HLRCC (31/53), Type 1 Papillary RCC (10/31), Chromophobe (7/20), Hybrid (3/9), TFE-3 related cancer (3/8), Undifferentiated (3/5), and TFEB tumors (2/2).

MicroRNAs (miRNAs) are small, non-coding RNA molecules with multiple roles in many biological processes. Few studies have shown the molecular characteristics in younger prostate cancer (PCa) patients. In this study, we performed miRNA profiling in young PCa (EO-PCa) cases compared with PCa arising in older men (LO-PCa).