LINC00365 as a potential biomarker for total nephrectomy in advanced-stage renal cell carcinoma patients.

BACKGROUND: Renal cell carcinoma (RCC) is one of the most frequent urological cancers globally that has a good prognosis in the early tumor stages. However, there is a poor prognosis in metastatic RCC patients. Therefore, it is needed to evaluate the molecular biology of RCC progression to introduce the efficient diagnostic and therapeutic markers in these patients. Long non-coding RNAs (lncRNAs) have key roles in regulation of molecular mechanisms during RCC progression. In the present study, we assessed the levels of LINC00365 expressions in RCC patients to suggest that as a tumor marker in these patients. METHODS: Fifty fresh RCC tumor tissues and their normal margins were collected to assess the levels of LINC00365 expressions and probable correlations with clinicopathological features of RCC patients. RESULTS: There was significant LINC00365 up regulation in females compared with males (p=0.050). Among the RCC patients with total nephrectomy, there was a significant LINC00365 up regulation in advanced stage compared with primary stage tumors (p=0.035). RCC patients older than 60 years old who were undergone the total nephrectomy had also significant LINC00365 up regulation compared with RCC patients younger than 60 years old (p=0.039). CONCLUSIONS: given the significant increase in LINC00365 expression in advanced stage RCC tumors and patients over 60 years old who had total nephrectomy; it could serve as a useful diagnostic marker in screening programs for old high-risk individuals. It was also noticed that female RCC patients had elevated levels of LINC00365 expressions in their tumor samples, suggesting its potential use as a gender-specific diagnostic marker for high-risk females. Nevertheless, evaluating the levels of LINC00365 in serum samples of RCC patients is necessary to suggest that as a reliable diagnostic marker in clinical settings.

Retrospective study assessing the role of the androgen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy.

BACKGROUND AND PURPOSE: Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions. PATIENTS AND METHODS: We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis. RESULTS: Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC. CONCLUSIONS: AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Health-related Quality of Life Assessment in Renal Cell Cancer: A Scoping Review.

BACKGROUND AND OBJECTIVE: In oncology, patient-reported outcome measures (PROMs) capturing health-related quality of life (HRQOL) play an increasing role in clinical trials, drug approval, and policy making. This scoping review aimed to identify and elaborate on HRQOL-focussed PROMs used in renal cell cancer (RCC) clinical trials. METHODS: MEDLINE, Web of Science, PsychINFO, Academic Search Elite, CINAHL, Embase, and the Cochrane Library were searched systematically for original peer-reviewed articles on clinical trials including RCC patients and using PROMs, published between 1950 and 2023. Prespecified trial characteristics and information on the PROMs used were extracted. Frequencies and proportions of categorical data, and ranges and medians of continuous variables were calculated. KEY FINDINGS AND LIMITATIONS: Of the 48 unique studies included, the majority followed a randomised controlled design (34, 71%) and evaluated systemic treatments (38, 79%). The trials used 27 different PROMs (max = 6, median = 2), of which only 4 (15%) were developed specifically for kidney cancer patients. Of the trials, 46% did not use any RCC-specific PROM. European Quality of Life-5 Dimensions (EQ-5D), European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30), Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI) -15/19-item version, FKSI-Disease Related Symptoms, and Functional Assessment of Cancer Therapy-General (FACT-G) were the most frequently used questionnaires, with pain, ability to work, fatigue, worry, and sleep quality being the most commonly assessed issues. CONCLUSIONS AND CLINICAL IMPLICATIONS: A variety of PROMs are used in RCC patients, hindering interpretability across trials. The PROMs used differ in terms of both the domains assessed and how the issues are translated into questionnaire items. Though RCC-specific PROMs exist, these have flaws in terms of relevance to patients. To answer predefined relevant HRQOL research questions, revised RCC-specific PROMs and standardisation of their integration into clinical trials are warranted. PATIENT SUMMARY: Researchers are more and more interested in the health-related quality of life of kidney cancer patients and use questionnaires to measure it. This review shows that there are many different health-related quality of life questionnaires that are used in different combinations in clinical trials for kidney cancer patients. This makes it very difficult to compare these study results and draw reliable conclusions for the actual clinical treatment. It was even found that some of the questionnaires used do not capture things that patients actually consider important (eg, emotional issues such as dealing with thoughts about cancer and depression). Therefore, more work needs to be done to develop questionnaires that ask what is really important to kidney cancer patients' health-related quality of life. If these questionnaires are used in a consistent way in clinical trials, the results can be better compared. This will help treat kidney cancer patients in the best possible way.

Real-World Survival Outcomes of First-Line Therapies in Patients with Metastatic Clear Cell Renal Cell Carcinoma: A Retrospective Analysis from Two Centres in Saudi Arabia.

Background: Metastatic renal cell carcinoma (mRCC) represents a challenging condition characterised by poor prognosis and limited response to chemoradiotherapy. In this retrospective study, we compared the survival outcomes of first-line ICI regimens versus single-agent TKIs in patients with mRCC from two centres in Saudi Arabia. Methods: This study included 84 patients diagnosed with clear cell mRCC between January 2016 and December 2023. Patients were grouped based on treatment regimens. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and Cox proportional hazards regression. Results: The median first-line PFS was 9.7 months (95% CI: 5.3-14.1) for the overall cohort, with no significant difference between the single-agent tyrosine kinase inhibitor (TKI) group (9.4 months; 95% CI: 6.4-12.4), combination ICI group (9.0 months; 95% CI: 0.0-24.9), and single-agent ICI group (21.2 months; 95% CI: 2.6-39.8; p = 0.591). The median OS for the overall cohort was 42.0 months (95% CI: 14.9-69.2), with the single-agent TKI group having a median OS of 33.3 months (95% CI: 0.0-71.7), the combination ICI group, 42.0 months (95% CI: 0.06-84.0), and the single-agent ICI group, 23.0 months (95% CI: 19.2-26.7; p = 0.73). In comparison, the ICI-based combination therapy group exhibited a higher ORR of 41.0% (95% CI: 26.3-57.8%), while the single-agent ICI group had an ORR of 20.0% (95% CI: 3.5-55.8%). Cox regression identified liver metastasis as a significant independent predictor of PFS (HR = 1.8, p = 0.043), while a lower Karnofsky Performance Status was a significant independent predictor of OS (HR = 3.5, p < 0.001). Conclusions: In real-world practice from Saudi Arabia, first-line, single-agent ICI therapy offers promising anti-tumour activity and non-inferior survival outcomes compared to standard ICI-based combinations and single-agent TKIs.

Impact of No-Clamping Partial Nephrectomy on Early Estimated Glomerular Filtration Rate Preservation.

Incidences of kidney cancers are steadily increasing. The surgical resection of renal tumors remains the treatment of choice, and different techniques provide similar oncological outcomes. Minimally invasive methods, especially partial nephrectomy (PN), have emerged as the preferred method of tumor resection, both in traditional and robot-assisted laparoscopy. PN may be performed as an open or laparoscopic operation. On-clamp PN is a variant of PN that includes the clamping of renal vessels; off-clamp PN is performed without any ischemia. Objectives: To assess the short-term loss of eGFR after on-clamp and off-clamp PN. Methods: Data from 2021 to 2024 were retrospectively collected from a hospital database. The patients included in the study had a diagnosed kidney tumor that was confirmed by MRI or CT imaging. The patients were divided into two groups depending on the type of treatment they received: on-clamp PN or off-clamp PN. Hematocrit (HCT), hemoglobin (Hb) and eGFR were measured and compared. Results: Both groups had comparable preoperative HTC, Hb, and eGFR. eGFR loss 24 h after the procedure was 35.4% lower in the off-clamp group compared to the on-clamp group (p = 0.027). Conclusions: Off-clamp PN is a safe and viable method for kidney tumor resection, both in traditional and robot-assisted laparoscopy. This technique results in a smaller perioperative loss of eGFR, which relates to better short-term functional outcomes than on-clamp PN.

Is fat quantification based on proton density fat fraction useful for differentiating renal tumor types?

PURPOSE: This study retrospectively assessed the diagnostic accuracy of fat quantification based on proton density fat fraction (PDFF) for differentiating renal tumors. METHODS: In this retrospective study, 98 histologically confirmed clear cell renal cell carcinomas (ccRCCs), 35 papillary renal cell carcinomas (pRCCs), 14 renal oncocytomas, 16 chromophobe renal cell carcinomas (chRCCs), 10 lymphomas, 19 uroepithelial tumors, 10 lipid-poor angiomyolipomas (AMLs), and 25 lipid-rich AMLs were identified in 226 patients (127 males and 99 females) over 5 years. All patients underwent multiparametric kidney MRI. The MRI protocol included an axial plane and a volumetric 3D fat fraction sequence known as mDIXON-Quant for PDFF measurement. Demographic data were recorded, and PDFF values were independently reviewed by two radiologists blinded to pathologic results. MRI examinations were performed using a 1.5 T system. MRI-PDFF measurements were obtained from the solid parts of all renal tumors. Fat quantification was performed using a standard region of interest for each tumor, compared to histopathological diagnoses. Sensitivity and specificity analyses were performed to calculate the diagnostic accuracy for each histopathological tumor type. Nonparametric variables were compared among the subgroups using the Kruskal-Wallis H test and Mann Whitney U test. P-values < 0.05 were considered statistically significant. RESULTS: In all, 102 patients underwent partial nephrectomy, 70 patients underwent radical nephrectomy, and the remaining 54 had biopsies. Patient age (mean: 58.11 years; range: 18-87 years) and tumor size (mean: 29.5 mm; range: 14-147 mm) did not significantly differ across groups. All measurements exhibited good interobserver agreement. The mean ccRCC MRI-PDFF was 12.6 ± 5.06% (range: 11.58-13.61%), the mean pRCC MRI-PDFF was 2.72 ± 2.42% (range: 2.12-3.32%), and the mean chRCC MRI-PDFF was 1.8 ± 1.4% (range: 1.09-2.5%). Clear cell RCCs presented a significantly higher fat ratio than other RCC types, uroepithelial tumors, lymphomas, and lipid-poor AMLs (p < 0.05). Lipid-rich AMLs demonstrated a very high fat ratio. CONCLUSION: MRI-PDFF facilitated accurate differentiation of ccRCCs from other renal tumors with high sensitivity and specificity.

The efficacy and safety of cabozantinib in patients with metastatic or advanced renal cell carcinoma: a systematic review and meta-analysis.

Background: Cabozantinib, a new first-line treatment for advanced renal cell carcinoma (aRCC), targets essential tyrosine kinases and outperforms the established comparator (sunitinib) in various efficacy outcomes. This systematic review and meta-analysis aimed to assess the efficacy and safety of cabozantinib compared to other aRCC treatments. Methods: Following PRISMA and Cochrane guidelines, our protocol was registered in PROSPERO. A systematic search, without date limits, was conducted on PubMed, Cochrane, Web of Science, and EMBASE until October 8, 2023. Data extraction encompassed study details, baseline information, and outcomes. Hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals were employed for each outcome, and a random-effects model was applied to account for expected heterogeneity. Results: Three studies, encompassing 967 patients, were included in our analysis. In terms of efficacy, the pooled rate for overall survival significantly favored cabozantinib. However, in subgroup analyses, cabozantinib was only statistically superior to everolimus. For progression-free survival and tumor objective response rate, cabozantinib outperformed both everolimus and sunitinib. In adverse events, compared to sunitinib, cabozantinib exhibited inferiority in nearly all evaluated aspects, except for nausea and stomatitis, which showed no difference between the two groups. Conversely, it demonstrated a comparable risk profile with everolimus across various side effects. Conclusion: Cabozantinib shows significant efficacy in extending overall survival, progression-free survival, and tumor objective response rate despite a potentially higher risk of adverse events compared to sunitinib. These findings support cabozantinib as a first-line therapy for aRCC, either as an initial treatment or after prior VEGFR-targeted therapies.

Single nucleotide polymorphism rs4961 in the adducin 1 gene is not associated with gastric cancer or preneoplastic cancer lesions.

Gastric cancer (GC) is the fourth most deadly cancer globally. The adducin 1 (ADD1) protein is involved in oncogenic signal transduction pathways in several types of cancer, and the rs4961 variant (c.1378 G>T, p.Gly460Trp) of the ADD1 gene is associated with salt-sensitive hypertension, renal cell cancer and breast cancer susceptibility; however, it has not been investigated in GC. The aim of the present study was to evaluate the association between the rs4961 variant and the development of GC and preneoplastic gastric lesions (PGLs) in a population from western Mexico. A total of 225 individuals who underwent an endoscopy were evaluated, of which 71 patients had histopathologically diagnosed GC and 53 patients had PGLs, with 101 patients used as controls. The rs4961 variant was genotyped by using PCR and DNA sequencing. The frequency of the mutated homozygous genotype (TT) of the rs4961 variant was <10% in the three evaluated groups, and the frequency of the minor allele (T) was <21% in the GC, PGL and control groups. Genotypic and allelic frequencies were similarly distributed in all of the studied groups (P>0.05). In summary, in the study population, the rs4961 variant was not associated with GC risk; however, its role in other populations and in other types of cancer is worthy of future research.

Sequential therapy for hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma: a case report and report of a new family pedigree.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal-dominant disorder caused by a heterozygous germline mutation in the fumarate hydratase (FH) gene. HLRCC is clinically characterized by the development of three tumors: uterine leiomyomata, cutaneous leiomyomata, and renal cell carcinoma (RCC). HLRCC-associated RCC is aggressive and diagnosed at a much earlier age than sporadic RCC. It is essential for carriers of HLRCC to undergo annual renal screening by magnetic resonance imaging to detect early stage RCCs. Metastatic HLRCC-associated RCC must be treated by systemic therapy; however, it is unclear which medicines are most effective in treating this cancer owing to its low incidence rate. Immune checkpoint inhibitor (ICI) combinations or ICIs plus tyrosine kinase inhibitors are administered as systemic therapy for clear cell RCC. Here, we report a patient with HLRCC-associated RCC treated with sequential therapy, including ipilimumab plus nivolumab combination and cabozantinib, after diagnosis of HLRCC-associated RCC using FoundationOne Liquid CDx and single-site analysis. We also investigated familial FH mutations and describe a new family pedigree for HLRCC.

The Landscape of Stereotactic Ablative Radiotherapy (SABR) for Renal Cell Cancer (RCC).

Renal cell cancer (RCC) has traditionally been considered radioresistant. Because of this, conventional radiotherapy (RT) has been predominantly relegated to the palliation of symptomatic metastatic disease. The implementation of stereotactic ablative radiotherapy (SABR) has made it possible to deliver higher ablative doses safely, shifting the renal radioresistance paradigm. SABR has increasingly been adopted into the multidisciplinary framework for the treatment of locally recurrent, oligoprogressive, and oligometastatic disease. Furthermore, there is growing evidence of SABR as a non-invasive definitive therapy in patients with primary RCC who are medically inoperable or who decline surgery, unsuited to invasive ablation (surgery or percutaneous techniques), or at high-risk of requiring post-operative dialysis. Encouraging outcomes have even been reported in cases of solitary kidney or pre-existing chronic disease (poor eGFR), with a high likelihood of preserving renal function. A review of clinical evidence supporting the use of ablative radiotherapy (SABR) in primary, recurrent, and metastatic RCC has been conducted. Given the potential immunogenic effect of the high RT doses, we also explore emerging opportunities to combine SABR with systemic treatments. In addition, we explore future directions and ongoing clinical trials in the evolving landscape of this disease.

External validation of the ability of the mRENAL nephrometry score to identify patients at risk for major adverse events or local tumor recurrence after percutaneous renal cryoablation.

PURPOSE: The purpose of this study was to evaluate the ability of the mRENAL score to identify patients at risk of either major adverse events (AEs) and/or local tumor recurrence (LR) after percutaneous cryoablation (PCA) in an external patient population. METHODS: Patient demographic data were recorded. The RENAL and mRENAL nephrometry scores were calculated. Clinical outcomes such as AEs, LR, cancer-specific survival (CSS), and overall survival (OS) were collected. AEs were classified according to SIR criteria. Continuous variables and categorical variables were analyzed using the Wilcoxon rank sum test and chi-square test, respectively. Logistic regression analysis was performed to identify variables associated with major AEs or LR. RESULTS: The study included 207 patients (Males: n = 117 (56.5%)) with a mean age of 65.8 (± 11.2) years (range:27-90). Overall, the mean tumor diameter, RENAL score, and mean mRENAL score were 30.1 mm (± 11.4), 6.3 (± 1.7), and 6.8 (± 1.9), respectively. 14 patients (6.8%) and 13 patients (6.3%) experienced a major AE or LR after PCA, respectively. CSS and OS were 98.6% and 90.3%, respectively. For patients with major AEs after PCA, the mean tumor diameter (p < 0.0001), mean RENAL score (p = 0.03), and mean mRENAL score (p = 0.009) were all higher than those for patients without a major AE. Multi-variate regression analysis showed that only mean tumor diameter (p = 0.005) was predictive of a major AE. There were no statistically significant differences between patients with LR and patients without LR after PCA with regards to tumor size (p = 0.07), mean RENAL score (p = 0.32), or mean mRENAL score (p = 0.07). Multi-variate regression analysis showed that only mean tumor diameter (p = 0.01) was predictive of LR. CONCLUSION: The mRENAL score did not accurately identify patients at risk for either major AEs or LR. Maximum tumor diameter alone was predictive of both major AEs and LR, and should be the primary focus during patient selection.

Prognostic assessment of patients with bone metastatic renal cell cancer treated with palliative radiotherapy.

The present study investigated the prognosis of patients who received palliative radiotherapy (RT) for bone metastases (BMs) from renal cell cancer (RCC), and assessed the prognostic factors specific to BMs from RCC. A total of 109 patients with RCC and BMs who underwent RT for the first time were included in the study. Prognostic factors were evaluated using multivariate analysis and a scoring system based on regression coefficients was devised. The median follow-up time was 9 months, and the 0.5-year overall survival (OS) rate was 73.0%. In the multivariate analysis, the significant prognostic factors were higher performance status (≥2), no control of the primary site, disseminated metastasis, lymph node metastasis and multiple BMs. A score of 1 point was assigned to each risk factor. The median OS times were 19.0 and 5.0 months in patients with a total score of ≤1 (n=49) and >1 (n=60), respectively (P<0.01). In conclusion, a comprehensive prognostic assessment using these factors may be useful for predicting the prognoses of patients with BMs from RCC. In addition, this scoring system may be useful in selecting the optimal RT dose.

Renal Cell Carcinoma Metastasizing to Oral Soft Tissues: Systematic Review.

Background Renal cancer metastasis to oral region is very rare. Studies have been published analyzing the cases of metastatic tumors to the oral cavity by many researchers. Very few research studies have been conducted till date to analyze the renal cancer metastasis as the sole primary source to the oral soft tissues. The goal of this study was to examine the published cases of oral soft tissue metastasis from renal cell carcinoma as the only primary source from 1911 to 2022. Materials and Methods An electronic search of the published literature was performed without publication year limitation in PubMed/Medline, Scopus, Google Scholar, Web of Science, Science Direct, Embase, and Research Gate databases, using mesh keywords like ("Renal cancer," or "Renal carcinoma" or "Renal cell cancer" or "Renal cell carcinoma"), and ("Metastasis" or "Metastases"), and ("Oral soft tissues" or "Tongue" or "Palate" or "Tonsil" or "Buccal mucosa" or "Salivary glands"). We also searched related journals manually and the reference lists. Results Our research revealed a total of 226 relevant articles with 250 patients. Parotid glands and tongue were the most common sites of metastasis. 23% patients died with a survival time of 10 days to 4 years. Conclusions Oral soft tissue metastasis from renal cell carcinoma has a bad prognosis. More cases need to be published in order to raise awareness of these lesions.

Prevalence of diabetes and hospitalization due to poor glycemic control in people with bladder cancer or renal cell carcinoma in Sweden.

BACKGROUND: Bladder cancer (BC) and Renal cell carcinoma (RCC) are the most common urogenital cancers among both sexes, with a yearly global incidence of around 500 000 each. Both BC and RCC have been linked to diabetes. Poor glycemic control (malglycemia) is a serious consequence of diabetes and a possible consequence of systemic treatments used in BC and RCC. The objective of this study was to investigate the prevalence of diabetes and use of hospital-based care for malglycemia in people with BC or RCC. METHODS: This Swedish retrospective population-based register study used national health-data registers for longitudinal data on cancer incidence covering 15 years, use of hospital-based health care, and filled prescriptions of outpatient medications. Study endpoints included co-prevalence of diabetes in individuals with BC/RCC, healthcare resource utilization due to malglycemia, use of systemic corticosteroids, and changes in diabetes management for people with concomitant type 2 diabetes. RESULTS: We identified 36,620 and 15,581 individuals diagnosed with BC and RCC, respectively, between 2006 and 2019. The proportion of individuals registered with diabetes was 24% in BC and 23% in RCC. An association between BC/RCC and poor glycemic control was found, although the number of malglycemic events in hospital-based care were few (65/59 per 1000 individuals with diabetes and BC/RCC respectively with at least one event). An earlier switch to insulin-based diabetes management was observed in BC/RCC compared to matched individuals with type 2 diabetes but no cancer. The results also indicated an association between steroid treatment and poor glycemic control, and that systemic corticosteroids were more common among people with BC/RCC compared to diabetes controls. CONCLUSION: The high prevalence of diabetes and increased use of systemic corticosteroid treatment observed in this large national study highlights the need for specific clinical management, risk-assessment, and monitoring of individuals with BC/RCC and diabetes.

DNA Methylation as Drug Sensitivity Marker in RCC: A Systematic Review.

Patient response after treatment of renal cell cancer (RCC) with systemic agents, which include various drug categories, is generally poor and unpredictable. In this context, the ideal drug administration includes tools to predict the sensitivity of the disease to therapy. The aim of this study was to systematically summarize the reports on the predictive value of the methylation status in the systemic therapy of RCC. Only original articles reporting on the association of promoter methylation with the response of patients or cell lines to systemic agents were included in this review. We applied PRISMA recommendations to the structure and methodology of this systematic review. Our literature search concluded with 31 articles conducted on RCC cell lines and patient tissues. The majority of the studies demonstrated a methylation-dependent response to systemic agents. This correlation suggests that the methylation pattern can be used as a predictive tool in the management of RCC with various classes of systemic agents. However, although methylation biomarkers show promise for predicting response, the evidence of such correlation is still weak. More studies on the gene methylation pattern in patients under systemic therapy and its correlation with different degrees of response are needed.

Whole-Exome Sequencing Revealed a Pathogenic Germline Variant in the Fumarate Hydratase Gene, Leading to the Diagnosis of Hereditary Leiomyomatosis and Renal Cell Cancer.

The diagnosis of hereditary skin tumors is difficult for "old" diagnostic tools such as immunohistochemistry. Whole-exome sequencing analysis as a "new" diagnostic tool enables us to make a final diagnosis in spite of unknown hereditary diseases in the past. Hereditary leiomyomatosis and renal cell cancer are autosomal dominant hereditary cancer syndromes characterized by uterine myomas, cutaneous leiomyomas, and aggressive renal cell cancer. The syndrome is associated with pathogenic germline variants in the fumarate hydratase gene. Herein, we demonstrate a pathogenic germline variant of the fumarate hydratase gene in a 60-year-old woman with multiple cutaneous leiomyomas, leading to the diagnosis of hereditary leiomyomatosis and renal cell cancer. Whole-exome sequencing analysis using genomic DNA extracted from peripheral blood leukocytes revealed one germline variant in the FH gene on chromosome 1 (c.290G>A, p.Gly97Asp). She received total hysterectomy due to uterine myoma, which strongly supported the diagnosis. No tumor was detected in her kidney by computed tomography and ultrasound examination. Genetic examination for the mutation of the fumarate hydratase gene is important in order to reach the correct diagnosis and to detect renal cancer at its early stage.

Case report: A healthy baby achieved after preimplantation genetic testing from an infertile woman with hereditary leiomyomatosis and renal cell cancer syndrome.

Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant inheritable disease caused by Fumarate hydratase (FH) gene germline mutation. It is speculated that for HRLCC infertility women with multiple uterine leiomyomas, preimplantation genetic testing may help block transmission of mutated FH gene during pregnancy. Case presentation: We present the case of a 26-year-old nulligravida with a history of early-onset uterine leiomyomatosis had a heterozygous nonsense mutation [NM_000143.4 (FH): c.1027C > T(p.Arg343Ter)] in the HRLLC gene. After ovulation induction and in vitro fertilization, preimplantation genetic testing for monogenic disorders (PGT-M) on embryos revealed the absence of the pathogenic allele in two blastomeres. Uterine fibroids were identified before embryo transfer, leading to a submucosal myomectomy and long period of pituitary suppression by Gonadotropin-releasing hormone analog (GnRHa). The patient achieved a healthy live birth after the second cycle of frozen-thawed embryo transfer. Conclusion: This case details the successful treatment of an infertile patient with an HRLLC family history, resulting in a healthy birth through myomectomy and PGT-M selected embryo transplantation. Our literature search indicates the first reported live birth after HRLLC-PGT-M.

First-Line Immune Combination Therapies for Nonclear Cell Versus Clear Cell Metastatic Renal Cell Carcinoma: Real-World Multicenter Data From Germany.

INTRODUCTION: The aim was to compare treatment outcomes of clear cell metastatic renal cell carcinoma (ccmRCC) versus non-ccmRCC (nccmRCC) patients who received first-line immune combination therapies. MATERIALS AND METHODS: Within our retrospective multi-institutional consecutive database of eight tertiary-care centers, we identified mRCC patients treated with first-line immune combination therapies between 11/2017 and 12/2022. Using log-rank analysis and multivariable Cox regression, we tested for differences in overall survival (OS) and progression-free survival (PFS) of nccmRCC versus ccmRCC patients. Covariables consisted of age at diagnosis, sex, International Metastatic Renal Cell Carcinoma Database Consortium risk groups, Eastern Cooperative Oncology Group status, and sarcomatoid feature. RESULTS: Of 289 study patients, 39 (13%) patients harbored nccmRCC. Median OS was 37 months versus not reached for ccmRCC versus nccmRCC patients (P = .6). Median PFS was 13 versus 15 months (P = .9). Multivariable Cox regression models did not identify nccmRCC as an independent predictor of higher overall mortality in mRCC patients (hazard ratio [HR]: 1.23; P = .6) or a higher progression rate (HR: 1.0; P = 1.0). CONCLUSION: In our real-world multi-institutional study, no differences in OS and PFS between ccmRCC and nccmRCC patients receiving first-line immune combination treatment were observed, even after adjustment for important patient and tumor characteristics. More prospective trials in nccmRCC patients are needed.

Fumarate Hydratase-Deficient Renal Cell Carcinoma with Nucleolar Pattern of GATA3 Immunoexpression: Report of 2 Cases.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare aggressive type of renal cell carcinoma. The significant morphologic overlap with other types of renal neoplasia and the limited availability of FH and 2-succinylcholine immunostains for diagnostic use outside large referral centers have created numerous diagnostic pitfalls. As FH-deficient RCC can be associated with hereditary leiomyomatosis and renal cell cancer syndrome, the importance of an accurate diagnosis goes beyond the prognosis and treatment of an individual patient. We present 2 patients with FH-deficient RCC showing a peculiar pattern of GATA3 immunoexpression restricted to tumor nucleoli. If confirmed in further larger studies, this could provide an additional diagnostic clue for considering the FH-deficient RCC diagnosis, and given the frequent papillary morphology and possible hilar location can lead to the misdiagnosis as high-grade urothelial carcinoma, and is an important diagnostic pitfall to be aware of.