Renal Cell Cancer Research Articles

Comprehensive Pan-Cancer Analysis of Connexin 43 as a Potential Biomarker and Therapeutic Target in Human Kidney Renal Clear Cell Carcinoma (KIRC).

Background and Objectives: Connexin 43 (Cx43) is involved in the transfer of small signaling molecules between neighboring cells, thereby exerting a major influence on the initiation and progression of tumorigenesis. However, there is a lack of systematic research on Cx43 expression and its predictive role in clinical diagnosis and prognosis in pan-cancer. Materials and Methods: Several biological databases were used to evaluate the expression levels of GJA1 (encoding Cx43) and its diagnostic and prognostic significance in pan-cancer. We targeted kidney renal clear cell carcinoma (KIRC) and investigated the relationship between GJA1 expression and different clinical features of KIRC patients. Then, we performed cell-based experiments to partially confirm our results and predicted several proteins that were functionally related to Cx43. Results: The expression of GJA1 has a high level of accuracy in predicting KIRC. High GJA1 expression was remarkably correlated with a favorable prognosis, and this expression was reduced in groups with poor clinical features in KIRC. Cell experiments confirmed the inhibitory effects of increased GJA1 expression on the migratory capacity of human renal cancer (RCC) cell lines, and protein-protein interaction (PPI) analysis predicted that CDH1 and CTNNB1 were closely related to Cx43. Conclusions: GJA1 could be a promising independent favorable prognostic factor for KIRC, and upregulation of GJA1 expression could inhibit the migratory capacity of renal cancer cells.

Facial Features of Hereditary Cancer Predisposition.

In the age of telehealth medicine, an individual's facial features may provide the only physical clues signaling the presence of a heritable cancer predisposition syndrome. These syndromes include APC-associated polyposis, Birt-Hogg-Dubé syndrome, CYLD cutaneous syndrome, hereditary leiomyomatosis and renal cell cancer, multiple endocrine neoplasia, neurofibromatosis type 1, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, and tuberous sclerosis complex 1 and 2, among others. Correctly identifying characteristic features is important for genetic and nongenetic specialists as early detection can enable prompt intervention, improving patient outcomes. Advancements in the availability of genetic testing allow patients and their relatives to have more information about their genetic risk profile than before. These changes in clinical pathways, combined with improvements in screening and risk-reducing treatment, highlight the need to outline the cutaneous and morphologic features of high-risk cancer syndromes for clinicians. In this review, we describe the important facial features of hereditary cancer predisposition, with emphasis on diagnosis, cutaneous and extracutaneous manifestations, and screening.

The development of brain metastases in patients with different therapeutic strategies for metastatic renal cell cancer.

A diagnosis of brain metastasis (BM) significantly affects quality of life in patients with metastatic renal cell cancer (mRCC). Although systemic treatments have shown efficacy in mRCC, active surveillance (AS) is still commonly used in clinical practice. In this single-center cohort study, we assessed the impact of different initial treatment strategies for metastatic RCC (mRCC) on the development of BM. All consecutive patients diagnosed with mRCC between 2011 and 2022 were included at the Erasmus MC Cancer Institute, the Netherlands, and a subgroup of patients with BM was selected. In total, 381 patients with mRCC (ECM, BM, or both) were identified. Forty-six patients had BM of whom 39 had metachronous BM (diagnosed ≥1 month after ECM). Twenty-five (64.1%) of these 39 patients with metachronous BM had received prior systemic treatment for ECM and 14 (35.9%) patients were treatment naive at BM diagnosis. The median BM-free survival since ECM diagnosis was significantly longer (p = .02) in previously treated patients (29.0 [IQR 12.6-57.0] months) compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). In conclusion, patients with mRCC who received systemic treatment for ECM prior to BM diagnosis had a longer BM-free survival as compared to treatment naïve patients. These results emphasize the need for careful evaluation of treatment strategies, and especially AS, for patients with mRCC.

Time-course RNAseq data of murine AB1 mesothelioma and Renca renal cancer following immune checkpoint therapy

Time-critical transcriptional events in the immune microenvironment are important for response to immune checkpoint blockade (ICB), yet these events are difficult to characterise and remain incompletely understood. Here, we present whole tumor RNA sequencing data in the context of treatment with ICB in murine models of AB1 mesothelioma and Renca renal cell cancer. We sequenced 144 bulk RNAseq samples from these two cancer types across 4 time points prior and after treatment with ICB. We also performed single-cell sequencing on 12 samples of AB1 and Renca tumors an hour before ICB administration. Our samples were equally distributed between responders and non-responders to treatment. Additionally, we sequenced AB1-HA mesothelioma tumors treated with two sample dissociation protocols to assess the impact of these protocols on the quality transcriptional information in our samples. These datasets provide time-course information to transcriptionally characterize the ICB response and provide detailed information at the single-cell level of the early tumor microenvironment prior to ICB therapy.

Factors Associated With Prescription of Systemic Therapy in Real-world Patients With Metastatic Renal Cell Cancer Managed in a Rural Region.

Numerous new treatment options have been approved for metastatic renal cell carcinoma (mRCC) in the last decade. Nevertheless, not all patients receive systemic therapy. Certain patients present with very advanced disease, poor Eastern Cooperative Oncology Group performance status (ECOG PS), or severe comorbidity, i.e. factors that lead oncologists to prefer best supportive care (BSC) instead of systemic therapy. The aim of this quality-of-care study was to identify baseline factors (disparities) associated with receipt of systemic therapy rather than BSC. This retrospective analysis included 140 consecutive patients managed in a rural region of Norway (2007-2022). Two differently managed groups were compared in univariate tests followed by multi-nominal regression. The majority of patients (n=95, 68%) had received systemic therapy. Typical patients were males in their 60s or 70s, with clear cell histology, prior nephrectomy, and intermediate prognostic features. Patients who received systemic therapy lived significantly longer than those who did not (median 30.4 versus 5.0 months, p<0.001). Survival benefit of systemic treatment was observed even in patients with ECOG PS3 or age ≥80 years. In addition to younger age (p<0.001) and better ECOG PS (p<0.001), metachronous presentation was associated with higher rates of systemic therapy utilization (p=0.03). Assignment to systemic therapy for mRCC was individualized in the present patient population. In all age and ECOG PS subgroups, systemic therapy was associated with better survival (doubling at least). Optimum utilization rates are difficult to determine. However, in light of the survival outcomes, a rate of 12% in patients aged 80 years or older appears rather low.

Abstract Wrk1-01: Agnostic trials in the field of targeted therapies

Abstract Tumor-agnostic cancer therapy represents a significant shift in the field of precision oncology. It differs from conventional cancer treatments, which typically focus on specific tumor types, such as breast cancer, lung cancer, renal cell cancer, and others. This innovative approach brings hope to cancer patients by recognizing that identical genetic abnormalities can drive cancer in various parts of the body. The approvals of these therapies have introduced alternative treatment options, particularly for patients with advanced cancers and rare malignancies. Currently, six medicines have received US FDA approval for use in patients with solid tumors harboring one of five specific biomarkers. In this presentation, I will delve into the current landscape of these tissue-agnostic cancer therapies, providing a comprehensive exploration of the relevant clinical data that can enhance our understanding of these groundbreaking treatments. Citation Format: V. Subbiah. Agnostic trials in the field of targeted therapies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr Wrk1-01.

Abstract PO3-15-05: B cell immunology predict response and survival in PD-1/PD-L1 targeting immune checkpoint inhibition of metastatic breast cancer

Abstract Critically understudied in the era of T cell immunotherapies, aggregation of B cells within tertiary lymphoid structures (TLS) has recently been linked to improved response and survival in immune checkpoint inhibition (ICI). While this has been reported for several cancers, including melanoma, lung cancer, bladder and renal cell cancer, there is an unmet need to understand molecular patterns in tumors with limited mutational burden (TMB) and low overall abundance of tumor infiltrating lymphocytes (TILs). Here, we report on the landscape of B cells in metastatic breast cancer, inferred by bulk sequencing (WGS/RNAseq) and multiplexed ion beam imaging (MIBI-TOF) in 203 patients across the breast cancer biology (ER/PR/HER2), collected from real world data (CATCH diagnostic and register study, NCT05652569). Median age was 53 years (range, 23-79), with a median of 3 systemic treatment lines for advanced or metastatic disease. The majority of biopsies were taken from the liver (49%), followed by breast (15%), lymph node (13%), skin (6%) and lung (6%). Immunohistochemistry based subtyping revealed 61% of the HR+/HER2- (or Luminal HER2-), followed by 26% of HR-/HER2- (TNBC), and 15% of HER2+ subtype. Immunological subtyping by stromal TILs and CD8+ infiltrates defined 3 subgroups with 57% being desert, 18% inflamed and 19% of no special type (6% NA). The majority (52%) was scored CD20+ with minimal colocalization in 45% of samples. MIBI-TOF demonstrated a continuum of coordinated B cell and T cell aggregation in the tumor microenvironment with lymphoid aggregates in 29% and mature TLS structures in 26% of patients. No correlation with conventional biomarkers for immunogenicity (PD-L1, TMB) has been observed. Chart review identified 21 patients treated by immune checkpoint blockade (ICI) targeting PD-1 (Pembrolizumab) or PD-L1 (Atezolizumab), either as monotherapy or in combination with chemotherapy/targeted therapy. Overall response rate (ORR) at week 12 was 57%, disease control rate (DCR) was 71%. RNA signature levels for germinal center signalling, B cell activation and antibody secretion correlated with quality of B cell aggregation and, importantly, significantly with response to ICI (Kruskal Wallis p=0,028). B cell derived prediction of response was independent of PD-L1 protein expression, breast cancer subtype, BRCA mutation status or TMB. Downstream single cell analysis, computational immunogenomics as well as spatial neighbourhoods will be reported at the meeting. These results extent B cell centered molecular insights to metastatic breast cancer and may pave the way for a composite biomarker, selecting patients for ICI who benefit meaningful and would not have been identified by the current standard of care. Citation Format: Carlo Fremd, Markus Schulze, Miray Cetin, Hannah Boehm, Bénédicte Lenoire, Oezlem Akilli-Oeztuerk, Inka Zörnig, Pornpimol Charoentong, Yanhong Lyu, Catch Collaborators, Daniel Hübschmann, Felix Kommoss, Verena Thewes, Andreas Schneeweiss, Marc Zapatka, Felix Hartmann, Peter Lichter. B cell immunology predict response and survival in PD-1/PD-L1 targeting immune checkpoint inhibition of metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-15-05.

Using three-dimensional model-based tumour volume change to predict the symptom improvement in patients with renal cell cancer

In our recent study, we explored the efficacy of three-dimensional (3D) measurement of tumor volume in predicting the improvement of quality of life (QoL) in patients suffering from renal cell cancer (RCC), who were treated with axitinib and anti-PD-L1 antibodies. This study encompassed 18 RCC patients, including 10 men and 8 women, with an average age of 56.83 ± 9.94 years. By utilizing 3D Slicer software, we analyzed pre- and post-treatment CT scans to assess changes in tumor volume. Patients' QoL was evaluated through the FKSI–DRS questionnaire. Our findings revealed that 3D models for all patients were successfully created, and there was a moderate agreement between treatment response classifications based on RECIST 1.1 criteria and volumetric analysis (kappa = 0.556, p = 0.001). Notably, nine patients reported a clinically meaningful improvement in QoL following the treatment. Interestingly, the change in tumor volume as indicated by the 3D model showed a higher area under the curve in predicting QoL improvement compared to the change in diameter measured by CT, although this difference was not statistically significant (z = 0.593, p = 0.553). Furthermore, a multivariable analysis identified the change in tumor volume based on the 3D model as an independent predictor of QoL improvement (odds ratio = 1.073, 95% CI 1.002–1.149, p = 0.045).In conclusion, our study suggests that the change in tumor volume measured by a 3D model may be a more effective predictor of symptom improvement in RCC patients than traditional CT-based diameter measurements. This offers a novel approach for assessing treatment response and patient well-being, presenting a significant advancement in the field of RCC treatment.

MIER2/PGC1A elicits sunitinib resistance via lipid metabolism in renal cell carcinoma

IntroductionRenal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system and accounts for more than 90 % of all renal tumors. Resistance to targeted therapy has emerged as a pivotal factor that contributes to the progressive deterioration of patients with advanced RCC. Metabolic reprogramming is a hallmark of tumorigenesis and progression, with an increasing body of evidence indicating that abnormal lipid metabolism plays a crucial role in the advancement of renal clear cell carcinoma. ObjectivesClarify the precise mechanisms underlying abnormal lipid metabolism and drug resistance. MethodsBioinformatics screening and analyses were performed to identify hub gene. qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assays, and other biological methods were used to explore and verify related pathways. Various cell line models and animal models were used to perform biological functional experiments. ResultsIn this study, we identified Mesoderm induction early response 2 (MIER2) as a novel biomarker for RCC, demonstrating its role in promoting malignancy and sunitinib resistance by influencing lipid metabolism in RCC. Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. Furthermore, Trichostatin A (TSA), an inhibitor of HDAC1, was found to impede the MIER2/HDAC1/P53/PGC1A pathway, offering potential benefits for patients with sunitinib-resistant renal cell cancer. ConclusionOur findings highlight MIER2 as a key player in anchoring HDAC1 and inhibiting PGC1A expression through the deacetylation of P53, thereby inducing lipid accumulation in RCC and promoting drug resistance. Lipid-rich RCC cells compensate for energy production and sustain their own growth in a glycolysis-independent manner, evading the cytotoxic effects of targeted drugs and ultimately culminating in the development of drug resistance.

Can 18 F FDG PET/CT metabolic parameters be used to noninvasively differentiate between different histopathological subtypes and Fuhrman grades of renal cell cancer?

To evaluate relationship between metabolic PET metabolic parameters and size of the primary tumor, various histopathological subtypes of renal cell carcinoma (RCC) and Fuhrman grade of the tumors. Retrospective analysis of 93 biopsy-proven RCC patients who underwent pretreatment flourine 18 flourodeoxyglucose PET/computed tomography ( 18 F FDG PET/CT) was performed. Quantitative PET parameters, size of the primary tumor, histopathological subtypes and Fuhrman grades of the tumor were extracted. We tried to assess if there was any significant difference in the metabolic patterns of various histopathological subtypes of RCCs, Fuhrman grade of the tumors and size of the primary tumor. A significant correlation was noted between the size of primary tumor and maximum standardized uptake value (SUV max ), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) ( P < 0.01, P < 0.001 and P < 0.001, respectively). SUV max values correlated significantly with the histopathological subtype ( P < 0.001). Further sub-analyses was also done by segregating the patients into Low grade (Fuhrman grade 1 and 2) vs. High grade (Fuhrman grade 3 and 4). SUV max , MTV and TLG were significantly different between high grade vs. low grade tumors. ROC analysis yielded cut off values for SUV max , MTV and TLG to differentiate between high grade from low grade tumors. FDG PET/CT with the use of metabolic PET parameters can differentiate between different histopathological subtypes of RCC. Incorporation of metabolic parameters into clinical practice can potentially noninvasively identify patients with low-grade vs. high-grade RCC.

Molecular docking approach for the design and synthesis of new pyrazolopyrimidine analogs of roscovitine as potential CDK2 inhibitors endowed with pronounced anticancer activity

Cyclin-dependent kinase 2 (CDK2) is a vital protein for controlling cell cycle progression that is critically associated with various malignancies and its inhibition could offer a convenient therapeutic approach in designing anticancer remedies. Consequently, this study aimed to design and synthesize new CDK2 inhibitors featuring roscovitine as a template model. The purine ring of roscovitine was bioisosterically replaced with the pyrazolo[3,4-d]pyrimidine scaffold, in addition to some modifications in the side chains. A preliminary molecular docking study for the target chemotypes in the CDK2 binding domain revealed their ability to accomplish similar binding patterns and interactions to that of the lead compound roscovitine. Afterwards, synthesis of the new derivatives was accomplished. Then, the initial anticancer screening at a single dose by the NCI revealed that compounds 7a, 9c, 11c, 17a and 17b achieved the highest GI% values reaching up to 150 % indicating their remarkable activity. These derivatives were subsequently selected to undertake five-dose testing, where compounds 7a, 9c, 11c and 17a unveiled the most pronounced activity against almost the full panel with GI50 ranges; 1.41–28.2, 0.116–2.39, 0.578–60.6 and 1.75–42.4 µM, respectively and full panel GI50 (MG-MID); 8.24, 0.6, 2.46 and 6.84 µM, respectively. CDK2 inhibition assay presented compounds 7a and 9c as the most potent inhibitors with IC50 values of 0.262 and 0.281 µM, respectively which are nearly 2.4 folds higher than the reference ligand roscovitine (IC50 = 0.641 µM). Besides, flow cytometric analysis on the most susceptible and safe cell lines depicted that 7a caused cell cycle arrest at G1/S phase in renal cancer cell line (RXF393) while 9c led to cell growth arrest at S phase in breast cancer cell line (T-47D) along with pronounced apoptotic induction in the mentioned cell lines. These findings afforded new anticancer pyrazolo[3,4-d]pyrimidine, roscovitine analogs, acting via CDK2 inhibition.

Open, laparoscopic, and robotic techniques for partial nephrectomy for renal cell carcinoma: a comparison of outcomes based on "trifecta" and "pentafecta" criteria

Introduction. There is a dearth of literature comparing the three modalities of partial nephrectomy – open, laparoscopic, and robotic – based on two contemporary criteria, “trifecta” and “pentafecta”. This scarcity justifies the significance of this study.Objective. To conduct a comparative evaluation of the outcomes of the three methods of partial nephrectomy, assessed against the criteria of “trifecta” and “pentafecta”.Materials &amp; Methods. The prospective study included 600 patients with renal cell cancer from 2018 to 2022. partial nephrectomy was performed using open (200 patients), laparoscopic (200 patients) and robotic (200 patients) techniques. Outcomes were assessed by “trifecta” (negative surgical margin; warm ischemia time ≤ 25 minutes or without ischemia; no ≥ Clavien-Dindo III grade postoperative complications within 3 months after surgery) and “pentafecta” (“trifecta”, ≥ 90% estimated glomerular filtration rate preservation and no chronic kidney disease stage upgrading 12 months after surgery).Results. The “trifecta” outcome was achieved in 82%, 89%, and 84% of cases, respectively, using open, laparoscopic, and robotic approaches. No significant differences in outcomes were found between these methods (p &gt; 0.05), according to this criterion. The “pentafecta” outcome was achieved in 53%, 64%, and 66% of cases using the same three approaches, respectively. Significant differences in outcomes between the open approach and the minimally invasive techniques were observed (p &lt; 0.05) based on this criterion. For tumors that were considered easier to resect (R.E.N.A.L. 4 – 6 score), the highest “pentafecta” rates were observed with laparoscopic and robotic procedures. For tumors with moderate complexity (R.E.N.A.L. 7 – 9 score), open surgery resulted in the poorest outcomes, which were significantly different from those of robotic partial nephrectomy (p &lt; 0.05). The laparoscopic approach yielded the poorest results for the most complex tumors (R.E.N.A.L. 10 – 12 score).Conclusions. In general, all three methods of partial nephrectomy produce the same outcome according to the “trifecta”, but according to the “pentafecta” better results may be achieved using minimally invasive techniques (laparoscopic and robotic procedures). Robotic partial nephrectomy should be considered as the method of choice for high-scored R.E.N.A.L. and cT1 – cT2 tumours.

Multi-omics pan-cancer study of SPTBN2 and its value as a potential therapeutic target in pancreatic cancer

SPTBN2 is a protein-coding gene that is closely related to the development of malignant tumors. However, its prognostic value and biological function in pan-cancer, especially pancreatic cancer (PAAD), have not been reported. In the present study, a novel exploration of the value and potential mechanism of SPTBN2 in PAAD was conducted using multi-omics in the background of pan-cancer. Via various database analysis, up-regulated expression of SPTBN2 was detected in most of the tumor tissues examined. Overexpression of SPTBN2 in PAAD and kidney renal clear cell cancer patients potentially affected overall survival, disease-specific survival, and progression-free interval. In PAAD, SPTBN2 can be used as an independent factor affecting prognosis. Mutations and amplification of SPTBN2 were detected, with abnormal methylation of SPTBN2 affecting its expression and the survival outcome of PAAD patients. Immunoassay results demonstrate that SPTBN2 was a potential biomarker for predicting therapeutic response in PAAD, and may influence the immunotherapy efficacy of PAAD by regulating levels of CD8 + T cells and neutrophil infiltration. Results from an enrichment analysis indicated that SPTBN2 may regulate the development of PAAD via immune pathways. Thus, SPTBN2 is a potential prognostic biomarker and immunotherapy target based on its crucial role in the development of PAAD.

An audit of adherence to National Cancer Care Programme chemotherapy regimens and prescribing standards in systemic anti-cancer therapy prescriptions in an Irish hospital

Abstract Introduction The availability and usage of systemic anticancer therapy (SACT) has increased significantly over recent years. Whilst SACT has undeniably benefited patients, it also poses a challenge to patient safety as the number of cytotoxic drugs increases. The National Cancer Care Programme (NCCP) has set out to design and implement national policies and practices for oncology medicine in Ireland in order to maintain high levels of patient safety. Aim This study aims to evaluate adherence to NCCP national SACT regimens and prescribing standards at an Irish hospital. Methods This study was a prospective analysis involving an audit of SACT prescriptions for adherence to NCCP regimens and prescribing standards. The study was conducted from June 6th to June 30th 2023; the cohort was defined as patients who were receiving cancer services’ treatment from the medical oncology and haematology department at the hospital. The data collection tool was developed using template in the NCCP Oncology Medication Safety Review Report 2014. A report was run to identify outpatient patients who received SACT on each working day. For inpatients, a daily scheduling Excel file was consulted. Prescriptions were evaluated to complete the data collection tool. Anonymised data was captured and the results were collated to show any trends in adherence to NCCP regimens and prescribing standards. Descriptive analysis of patient and clinical characteristics was performed. Results Pharmacy prescription records of all patients who received SACT during the four-week study period were analysed. A total of 410 SACT prescriptions were reviewed. The median patient age in the study cohort was 59 years (range 23-93 years). Overall, 86.3% of the audited prescriptions adhered to NCCP regimens. The oncology department exhibited a higher adherence rate of adherence to NCCP regimens compared to the haematology department (89.2% versus 82.3%). Melanoma, non-small cell lung cancer, small cell lung cancer, renal cell, prostate, sarcoma, and bladder cancer all had 100% adherence. The lowest adherence rates occurred for CNS (25%), mesothelioma (50%), leukaemia (76.5%), and metastatic colorectal cancer (77.3%). Only 7% of prescriptions were written on pre-printed forms. In this audit, over 98% compliance was observed for eleven of the twenty-four NCCP prescribing standards in the 410 prescriptions: including patient name, patient date of birth, diagnosis, name of supervising consultant, protocol/regimen name, name of drug(s), dose in mg or mg/m2, route of administration, signature of the prescriber and date prescribed. Areas for improvement identified include information about ward/clinic, renal/hepatic function, start date, cycle numbers and medical council numbers. Conclusion This is the first audit of adherence to NCCP regimens using prescription data in Ireland, and the inclusion of 410 samples is a strength; however, the data are from a single site. This study has highlighted areas for improvement in prescribing practices. It emphasises the need for further multidisciplinary team education on adherence to NCCP regimens and prescribing standards. Healthcare professionals should ensure that pre-printed SACT prescription forms are used where available. Additionally, the use of regimen-specific pre-printed forms should be expanded.

A new missense mutation c.1240A>G in fumarate hydratase gene leads to uterine leiomyoma associated hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome in Chinese

ObjectiveThis study presents a detailed analysis of the clinical and genetic characteristics of uterine leiomyoma associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), combined with exploration of family history, pathology, and management procedures, supported by thorough evidence collection. MethodsBlood samples were collected from the proband, and the pathogenic variant was verified using Sanger sequencing. A comprehensive review of family history, FH deficiency pathology, FH and 2SC immunohistochemistry staining was conducted. Functional evidence was derived from clinical and genetic information, supplemented by a literature collection and mutation was reclassified based on ACMG/AMP guidelines. ResultsThe study successfully identifies a novel missense mutation (c.1240A>G; p.Lys414Glu) in exon 9 of FH, with no prior reports in existing databases. The patient's phenotype and family history, coupled with evidence collected from the literature, contribute to the preliminary determination of the variant as likely pathogenic. We also emphasize that the importance of combining FH-deficient morphology and immunohistochemical staining with 2SC for enhanced sensitivity. ConclusionThis research adds a novel missense mutation to the repertoire of FH gene variants, emphasizing its likely pathogenic nature based on a multidimensional analysis of phenotype, family history, and literature evidence. The findings enhance our understanding of the genetic landscape associated with FH and underscore the importance of thorough characterization for accurate variant classification.

Recording and classifying MET receptor mutations in cancers.

Tyrosine kinase inhibitors (TKI) directed against MET have been recently approved to treat advanced non-small cell lung cancer (NSCLC) harbouring activating MET mutations. This success is the consequence of a long characterization of MET mutations in cancers, which we propose to outline in this review. MET, a receptor tyrosine kinase (RTK), displays in a broad panel of cancers many deregulations liable to promote tumour progression. The first MET mutation was discovered in 1997, in hereditary papillary renal cancer (HPRC), providing the first direct link between MET mutations and cancer development. As in other RTKs, these mutations are located in the kinase domain, leading in most cases to ligand-independent MET activation. In 2014, novel MET mutations were identified in several advanced cancers, including lung cancers. These mutations alter splice sites of exon 14, causing in-frame exon 14 skipping and deletion of a regulatory domain. Because these mutations are not located in the kinase domain, they are original and their mode of action has yet to be fully elucidated. Less than five years after the discovery of such mutations, the efficacy of a MET TKI was evidenced in NSCLC patients displaying MET exon 14 skipping. Yet its use led to a resistance mechanism involving acquisition of novel and already characterized MET mutations. Furthermore, novel somatic MET mutations are constantly being discovered. The challenge is no longer to identify them but to characterize them in order to predict their transforming activity and their sensitivity or resistance to MET TKIs, in order to adapt treatment.

Antibody Drug Conjugates in Urological Cancers: A Review of the Current Landscape.

Our review delves into the progress across urological malignancies and discusses ongoing challenges and future directions in antibody-drug conjugate (ADC) development, emphasising their transformative potential in cancer care. ADCs have advanced from hematologic to solid tumours, notably in breast cancer, and are now pivotal in metastatic urological cancers as both monotherapies and in combination regimens, underscored by the FDA's approval of enfortumab vedotin and sacituzumab govitecan for metastatic urothelial cancer. Progress in metastatic prostate cancer, particularly with ADCs targeting PSMA and STEAP1, is noteworthy, although renal cell cancer presents ongoing challenges. There is a continual search for agents in the metastatic, relapsed testicular cancer landscape. ADCs have emerged as a pivotal innovation in oncology, blending targeted antibody therapy with potent cytotoxic drugs, significantly advancing treatment options for urological malignancies.

An underrecognized association: immune checkpoint inhibitor-related aortitis, a case report with the review of the literature.

Immune-checkpoint inhibitors (ICIs) are considered as the novel treatment modality in certain cancers. They may soon be used widely even as the first-line option for cancer treatment due to their remarkable efficacies and impacts on survival rates, particularly in cases of advanced metastatic cancer. Of note, these agents might unveil new autoimmune diseases as well as causing flare-ups of a pre-existing autoimmune disease. Data in this field have been accumulated during recent years. Early detection and a collaborative approach are, therefore, crucial in the management of a patient who presents with any of these conditions. Herein, we report a patient with a diagnosis of metastatic renal cell cancer presented with vasculitis involvement in the aorta during nivolumab treatment. Our aim with this case is to increase the awareness of ICI-related vasculitis involvement among rheumatologists in the light of literature.

Radiomics and machine learning for renal tumor subtype assessment using multiphase computed tomography in a multicenter setting

ObjectivesTo distinguish histological subtypes of renal tumors using radiomic features and machine learning (ML) based on multiphase computed tomography (CT).Material and methodsPatients who underwent surgical treatment for renal tumors at two tertiary centers from 2012 to 2022 were included retrospectively. Preoperative arterial (corticomedullary) and venous (nephrogenic) phase CT scans from these centers, as well as from external imaging facilities, were manually segmented, and standardized radiomic features were extracted. Following preprocessing and addressing the class imbalance, a ML algorithm based on extreme gradient boosting trees (XGB) was employed to predict renal tumor subtypes using 10-fold cross-validation. The evaluation was conducted using the multiclass area under the receiver operating characteristic curve (AUC). Algorithms were trained on data from one center and independently tested on data from the other center.ResultsThe training cohort comprised n = 297 patients (64.3% clear cell renal cell cancer [RCC], 13.5% papillary renal cell carcinoma (pRCC), 7.4% chromophobe RCC, 9.4% oncocytomas, and 5.4% angiomyolipomas (AML)), and the testing cohort n = 121 patients (56.2%/16.5%/3.3%/21.5%/2.5%).The XGB algorithm demonstrated a diagnostic performance of AUC = 0.81/0.64/0.8 for venous/arterial/combined contrast phase CT in the training cohort, and AUC = 0.75/0.67/0.75 in the independent testing cohort. In pairwise comparisons, the lowest diagnostic accuracy was evident for the identification of oncocytomas (AUC = 0.57–0.69), and the highest for the identification of AMLs (AUC = 0.9–0.94)ConclusionRadiomic feature analyses can distinguish renal tumor subtypes on routinely acquired CTs, with oncocytomas being the hardest subtype to identify.Clinical relevance statementRadiomic feature analyses yield robust results for renal tumor assessment on routine CTs. Although radiologists routinely rely on arterial phase CT for renal tumor assessment and operative planning, radiomic features derived from arterial phase did not improve the accuracy of renal tumor subtype identification in our cohort.

Multi-omics and immunogenomics analysis revealed PFKFB3 as a targetable hallmark and mediates sunitinib resistance in papillary renal cell carcinoma: in silico study with laboratory verification

Glycolysis-related metabolic reprogramming is a central hallmark of human cancers, especially in renal cell carcinoma. However, the regulatory function of glycolytic signature in papillary RCC has not been well elucidated. In the present study, the glycolysis-immune predictive signature was constructed and validated using WGCNA, glycolysis-immune clustering analysis. PPI network of DEGs was constructed and visualized. Functional enrichments and patients’ overall survival were analyzed. QRT-PCR experiments were performed to detect hub genes’ expression and distribution, siRNA technology was used to silence targeted genes; cell proliferation and migration assays were applied to evaluate the biological function. Glucose concentration, lactate secretion, and ATP production were measured. Glycolysis-Immune Related Prognostic Index (GIRPI) was constructed and combined analyzed with single-cell RNA-seq. High-GIRPI signature predicted significantly poorer outcomes and relevant clinical features of pRCC patients. Moreover, GIRPI also participated in several pathways, which affected tumor immune microenvironment and provided potential therapeutic strategy. As a key glycolysis regulator, PFKFB3 could promote renal cancer cell proliferation and migration in vitro. Blocking of PFKFB3 by selective inhibitor PFK-015 or glycolytic inhibitor 2-DG significantly restrained renal cancer cells’ neoplastic potential. PFK-015 and sunitinib could synergistically inhibit pRCC cells proliferation. Glycolysis-Immune Risk Signature is closely associated with pRCC prognosis, progression, immune infiltration, and therapeutic response. PFKFB3 may serve as a pivotal glycolysis regulator and mediates Sunitinib resistance in pRCC patients.