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BACKGROUND: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. METHODS: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. RESULTS: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. CONCLUSIONS: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03260894 .

Background: Synchronous occurrence of prostate cancer (PCa) and renal cell carcinoma (RCC) is uncommon. RCC has a higher tendency to metastasize to the adrenal glands, renal hilar, and retroperitoneal lymph nodes compared to PCa. To date, there are no documented cases existing where metastatic tumors in these regions, observed in patients concurrently with PCa and RCC, have originated from the PCa rather than the RCC. Case presentation: In this case report, we described a 67-year-old male presented with dysuria for two months and left lower extremity edema for three days. Percutaneous biopsies revealed synchronous primary RCC and PCa. However, the origin of the metastatic tumors, especially those involving the adrenal glands, renal hilum, and retroperitoneal regions, remained undetermined. Subsequent surgical procedures identified that the metastatic lesions originated from the PCa, while the RCC was localized. Ultimately, the patient with metastatic hormone-sensitive prostate cancer (mHSPC) received combination therapy with rezvilutamide and goserelin, which resulted in a satisfactory treatment response. Conclusion: In patients with concurrent PCa and RCC, metastatic lesions in the adrenal glands, renal hilar, and retroperitoneal lymph nodes may also originate from the PCa. Accurate identification of the primary tumor and proper staging are critical for the appropriate management of patients with multiple primary malignancies with concurrent metastases. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is the most common primary renal malignancy. Prevalence of RCC in developed countries has slowly increased. Although partial or total nephrectomy has been the first-line treatment for early-stage RCC, improved or similar safety and treatment outcomes with locoregional therapies have challenged this paradigm. In this review, we explore locoregional techniques for early-stage RCC, including radiofrequency ablation, cryoablation, and microwave ablation with a focus on procedural technique, patient selection, and safety/treatment outcomes. Furthermore, we discuss future advances and novel techniques, including radiomics, combination therapy, high-intensity focused ultrasound, and catheter-directed techniques. [ABSTRACT FROM AUTHOR]

The mTOR inhibitor everolimus has been approved as a sequential or second‐line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI‐1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI‐1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME‐dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti‐tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI‐1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus‐resistance overcoming. [ABSTRACT FROM AUTHOR]

Background: The main objective is to discuss why treatment of non-prostate cancers with [177Lu]Lu-PSMA-radioligand achieved only low tumor dose in most published cases, despite high uptake on PSMA PET. We use a patient with renal cell carcinoma as an illustrative example. Furthermore, we discuss how the problem with early washout and low tumor dose might be overcome by using a radionuclide with shorter half-life, matching the target binding residence time. Case presentation: [68Ga]Ga-PSMA-11 PET/CT of a 56-year old man with metastatic renal cell carcinoma showed high lesion uptake. One dose of 6.9 GBq [177Lu]Lu-PSMA-I&T was administrated. Post-therapy dosimetry was performed with SPECT/CT and whole-body planar imaging after 5, 24 and 48 h. Doses to target lesions were only 0.2–0.5 Gy. No treatment effect was achieved. Conclusion: Rapid tumor washout of [177Lu]Lu-PSMA-I&T and low tumor dose despite high uptake of [68Ga]Ga-PSMA-11 are most likely caused by localization of PSMA-receptors on neovasculature rather than on the tumor cells, and unlike in prostate cancer cells, the PSMA-RL / PSMA-receptor complex is not internalized. To overcome the problem with early washout, the use of a radionuclide with shorter half-life matching the target binding residence time will be needed. [ABSTRACT FROM AUTHOR]

Background: Malignant cells exhibit reduced period circadian regulator 3 (PER3) expression. However, the underlying mechanisms of variations in PER3 expression in cancers and the specific function of PER3 in tumor progression remain poorly understood. Results: We explored multiple public databases, conducted bioinformatics analyses, and performed in vitro and in vivo experiments for validation. We found PER3 expression was decreased in most types of cancers, and PER3 downregulation was associated with a poor prognosis in 8 types of cancer. PER3 promoter methylation levels were increased in 11 types of cancer. Promoter hypermethylation (CpG islands [CGIs] cg12258811 and cg14204433) correlated with decreased PER3 expression in six cancers (breast invasive carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma [KIRP], lung adenocarcinoma [LUAD], and uterine corpus endometrial carcinoma). CGI cg12258811 hypermethylation was associated with reduced survival time and advanced cancer stages. Moreover, the bisulfite pyrosequencing assay confirmed CGI cg12258811 hypermethylation and its negative correlation with PER3 expression. In vitro and in vivo experiments demonstrated that PER3 inhibited KIRP and LUAD progression. Decitabine enhanced PER3 expression and inhibited KIRP cell functions by reducing promoter (cg12258811) methylation level. Conclusions: Our findings advanced the mechanistic understanding of variations in PER3 expression in cancers and confirmed the tumor-associated function of PER3 hypermethylation and downregulation. [ABSTRACT FROM AUTHOR]

Background: Growing evidence shows that ultra-processed food consumption is associated with the risk of cancer. However, prospective evidence is limited on renal cell carcinoma (RCC) incidence and mortality. In this study, we aimed to examine the association of ultra-processed food consumption and RCC incidence and mortality in a large cohort of US adults. Methods: A population-based cohort of 101,688 participants were included from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Ultra-processed food items were confirmed by using the NOVA food classification system. The consumption of ultra-processed food was expressed as a percentage of total food intake (g/day). Prospective associations were calculated using Cox regression. Restricted cubic spline regression was used to assess nonlinearity. Subgroup analyses were performed to investigate the potential effect modifiers on the incidence and mortality of RCC. Results: A total of 410 participants developed RCC during a total of 899,731 person-years of follow-up (median 9.41 years) and 230 RCC deaths during 1,533,930 person-years of follow-up (median 16.85 years). In the fully adjusted model, participants in the highest compared with the lowest quintiles of ultra-processed food consumption had a higher risk of RCC (HR quartile 4 vs 1:1.42; 95% CI: 1.06–1.91; Ptrend = 0.004) and mortality (HR quartile 4 vs. quartile 1: 1.64; 95% CI: 1.10–2.43; Ptrend = 0.027). Linear dose–response associations with RCC incidence and mortality were observed for ultra-processed food consumption (all Pnonlinearity > 0.05). The reliability of these results was supported by sensitivity and subgroup analyses. Conclusion: In conclusion, higher consumption of ultra-processed food is associated with an increased risk of RCC incidence and mortality. Limiting ultra-processed food consumption might be a primary prevention method of RCC. [ABSTRACT FROM AUTHOR]

Aims: Decreased oestrogen receptor (ER) expression is a marker of poor prognosis in endometrial carcinomas (EC) of no specific molecular profile (NSMP), but the optimal cut‐off to separate high‐risk 'low ER' versus low‐risk 'high ER' expression has not been defined. Here we characterised the distribution of ER staining in a cohort of ECs. Methods and results: Biopsy specimens from 120 cases of NSMP EC were stained for ER and assigned an Allred score. In 66 additional cases ER staining of matched biopsy and hysterectomy were compared. Twelve of 120 tumours had an Allred score of 0–3, including three endometrioid carcinomas (EEA) (one G1, two G3), four clear cell carcinomas (CCC), two mesonephric‐like adenocarcinoma (MLA) and one each of: gastric‐type adenocarcinoma, carcinosarcoma and endometrial carcinoma NOS. Three had Allred scores of 4–5: two MLA and one high‐grade carcinoma with yolk sac differentiation. Five had Allred scores of 6: four EEA (one G1, one G2, two G3) and one mixed clear cell and endometrioid carcinoma. The remaining 100 tumours with Allred scores ≥ 7 were all EEA (66 G1, 28 G2, five G3 and one grade unknown). Comparing the biopsy versus hysterectomy ER staining (n = 66), the results were within a single Allred score point, except two cases with strong diffuse expression in the biopsy (Allred 8) and moderate expression in the hysterectomy (Allred 5). Conclusions: Most NSMP ECs (> 80%) show high ER expression (Allred score ≥ 7). All non‐endometrioid carcinomas and a few endometrioid carcinomas had lower ER expression (Allred score ≤ 6) or were completely negative. [ABSTRACT FROM AUTHOR]

Aims: Traditionally, mismatch repair (MMR) status is determined by a panel of four antibodies (MLH1, PMS2, MSH2, MSH6). If all proteins are retained, cases are MMR proficient (pMMR), while loss of one or more proteins is indicative of MMR deficiency (dMMR). This approach has been challenged in favour of a two‐antibody approach, using PMS2 and MSH6 as a first screening. Their retainment is deemed sufficient to declare cases pMMR. In this study we aim to verify the validity of the two‐antibody approach. Methods and Results: We performed a nationwide study in colorectal cancer (CRC) and endometrial cancer (EC) diagnosed between 2016 and 2023, including 47,657 patients to evaluate the two‐antibody approach. In 0.17% and 0.4% of cases of CRC and EC, respectively, dMMR cases would be missed with the two‐antibody approach. Subgroup analyses pointed towards slightly increased miss rates in younger patients (under the age of 50 years) in both groups and identified special subtypes (signet ring cell carcinoma, medullary carcinoma, and mucinous carcinoma in CRC and clear cell carcinoma in EC) with increased miss rates. For these specific subgroups, a low threshold should be used for further testing. In case of ambiguous or heterogeneous staining patterns, four antibodies should be used. Conclusion: In general, the application of a two‐antibody MMR testing strategy does not lead to considerable failure of dMMR identification and saves costs. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion The evolution of combination therapies integrating immune checkpoint inhibitors has revolutionized the first‐line treatment of metastatic renal cell carcinoma (mRCC). Although these therapies are clinically approved, direct comparisons between dual immune checkpoint inhibitors (IOIO) and immune checkpoint inhibitors combined with tyrosine kinase inhibitors (IOTKI) in clinical trials are lacking. This gap creates uncertainties in selecting the most appropriate treatment based on patient‐specific factors.This study employed the inverse probability of treatment weighting (IPTW) method to analyze progression‐free survival (PFS) and overall survival (OS) for patients with mRCC receiving IOIO or IOTKI treatment regimens.A total of 171 patients were analyzed after applying inclusion criteria and propensity scoring. The study found no significant differences in PFS and OS between the two treatment modalities in the IPTW cohort. However, subgroup analyses revealed that IOTKI therapy was associated with better PFS and OS for patients without bone metastases and better OS for patients with a body mass index (BMI) over 25. IOIO therapy showed better OS for patients with a BMI below 18.5.Both IOIO and IOTKI therapies were effective. Therapy selection could be better tailored to patient characteristics by including factors such as the presence of bone metastases and BMI. This study enhances understanding of how patient‐specific factors interact with different treatment modalities, potentially guiding more personalized treatment decisions in clinical practice for mRCC. [ABSTRACT FROM AUTHOR]

Giant cell glioblastoma often exhibits genome instability and is frequently associated with mutations in genes involved in DNA repair pathways including TP53 and DNA mismatch repair genes. Several germline mutations have been identified in giant cell glioblastoma, including mutations of MSH1 and MSH2, TP53, and POLE. We have documented a case of a germline mutation in CHEK2, another gene crucial to DNA repair, in a patient with giant cell glioblastoma. The CHEK2 mutation was inherited from the patient's father, who had a history of gastric cancer and renal cell carcinoma. In addition to the germline CHEK2 mutation, the giant cell glioblastoma exhibited a genome-wide loss of heterozygosity, a characteristic observed in a subset of giant cell glioblastomas. Additional mutations detected in the tumor included TP53, PTEN, and a PTPRZ1-MET fusion. This represents the first reported case of a CHEK2 germline mutation in giant cell glioblastoma, further supporting the significance of impaired DNA repair mechanisms in the development of this disease. [ABSTRACT FROM AUTHOR]

As the main type of renal cell carcinoma (RCC), clear cell RCC (ccRCC) is often associated with the deletion or mutation of the von Hippel Lindau (VHL) gene, enhancement of glucose and lipid metabolism, and heterogeneity of the tumor microenvironment. VHL alterations in RCC cells lead to the activation of hypoxiainducible factors and their downstream target vascular endothelial growth factor, and to the reprogramming of multiple cell death pathways and metabolic weakness, including ferroptosis, which are associated with targeted therapy or immunotherapy. The changes in biological metabolites (e.g., iron and lipids) support ferroptosis as a potential therapeutic strategy for RCC, while iron metabolism and ferroptosis regulation have been examined as anti-RCC agents in numerous studies, and various ferroptosis-related molecules have been shown to be related to the metastasis and prognosis of ccRCC. For example, glutathione peroxidase 4 and glutaminase inhibitors can inhibit pyrimidine synthesis and increase reactive oxygen species levels in VHLdeficient RCC cells. In addition, the release of damage-associated molecular patterns by tumor cells undergoing ferroptosis also mediates antitumor immunity, and immune therapy can synergize with targeted therapy or radiotherapy through ferroptosis. However, Inducing ferroptosis not only suppresses cancer, but also promotes cancer development due to its potential negative effects on anti-cancer immunity. Therefore, ferroptosis and various tumor microenviroment-related molecules may co-occur during the development and treatment of RCC, and further understanding of the interactions, core targets, and related drugs of ferroptosis may provide new combination drug strategies for RCC treatment. Here we summarize the key genes and compounds on ferroptosis and RCC in order to envision future treatment strategies and to provide sufficient information for overcoming RCC resistance through ferroptosis. [ABSTRACT FROM AUTHOR]

Background: One key focus of partial nephrectomy is preserving renal function. Segmental renal artery occlusion with microdissection at the renal hilum confines ischemia, effectively reducing warm ischemic injury. Ultrasound-Guided Renal Artery Balloon Catheter Occluded Hybrid Partial Nephrectomy (UBo-HPN) can achieve branch occlusion without the need for dissecting the renal hilum. Objective: To investigate the feasibility and safety of UBo-HPN of branch renal artery occlusion in the treatment of localized renal tumors. Subject and methods: A prospective single-arm analysis involving 20 patients with renal localized tumors underwent robot assisted UBo-HPN with branch renal artery occlusion from August 2021 to July 2023, with an average follow-up of 12 months. Results: All patient was successfully operated on without conversion to conventional arterial clamping or radical nephrectomy. One case (5%) of minor complication occurred in the whole cohort, which was bruising around the puncture site. The mean total operative time was 95.8 min, with a mean operative time of 21.25 min for vascular intervention. The mean warm ischemia time was 20.35 min, and the median estimated blood loss was 50 ml. The median eGFR preservation percentage at postoperative 48 h, 30 days, and the latest follow-up were 87.52%, 91.47%, and 92.2%, respectively. After a median follow-up of 10.2 (2.3–19.2) months, no patients had radiological tumor recurrence or died from tumor-related causes. Conclusions: UBo-HPN with renal artery branch occlusion emerges as an efficient alternative to partial nephrectomy (PN), which achieved branch artery occlusion without dissecting the renal hilum. Long-term follow-up is expected for functional outcomes. [ABSTRACT FROM AUTHOR]

This study aims to broaden the morphological scope of SDH-deficient renal cell carcinoma and to assist clinicians and pathologists in better understanding this entity to prevent misdiagnosis. This study used immunohistochemistry staining and the first-generation sequencing Sanger method for gene detection. It retrospectively analysed the clinical pathology, molecular characteristics, biological behaviour, and treatment information of one case of SDH-deficient renal cell carcinoma. The patient was a 57-year-old female with right back pain for more than 20 days and had no personal or family history of kidney tumours. In addition, the tumour cells had clear boundaries in morphology, and residual normal renal tubules could be seen around them. There were also ossification and adipose tissue around the tumour centre. The tumour cells were arranged in a glandular tubular and cord-like manner. Vacuolar and eosinophilic inclusion bodies could be observed in the cytoplasm. The nucleus was regular, the chromatin distribution was fine, and there were no obvious nucleoli. They were low-grade nuclei. In addition, no atypical mitosis or necrosis could been found. Furthermore, immunohistochemistry staining showed SDHB-negative and keratin 20 -positive tumour. Meanwhile, the first-generation sequencing also pointed out the presence of SDHB gene mutations in the tumour. After 12 months of follow-up, there was no evidence of disease recurrence in the patient. SDH-deficient renal cell carcinoma is a rare tumour associated with SDH gene germline mutations, and suspected cases should undergo SDHB immunohistochemistry staining. Most SDH-deficient renal cell carcinomas have a good prognosis, but undifferentiated cases require long-term follow-up. [ABSTRACT FROM AUTHOR]

Introduction: Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer in adults, presents significant challenges owing to its resistance to conventional therapies. Standard treatment primarily revolves around surgical methods, particularly nephrectomy, which is critical for managing localized diseases. Despite recent advancements, the metastatic potential of ccRCC necessitates ongoing vigilance in postoperative monitoring to manage and detect disease recurrence. Recent shifts in treatment paradigms, especially with the integration of molecular patterns in ccRCC, have enabled the development of targeted therapies. Immune checkpoint and tyrosine kinase inhibitors (TKIs) have become central to managing metastatic ccRCC, offering new hope through improved survival outcomes. Recent studies have corroborated this by demonstrating the benefits of combining these therapies. Case Presentation: This report discusses a case study of a patient with high-grade ccRCC and thyroid metastases initially deemed non-resectable. The combination of immunotherapy and TKIs reduced tumor size, transforming the thyroid metastasis to a resectable state. Conclusion: This case highlights significant advancements in treatment approaches and the critical in the management of ccRCC, underscoring the necessity for continuous adaptation of clinical practices to incorporate new therapeutic developments. [ABSTRACT FROM AUTHOR]

Background: Lipid droplets (LD) in renal clear cell carcinoma (ccRCC)play a crucial role in lipid metabolism and immune response modulation. The purpose of this study was to create a LD-related signature to predict prognosis and guide the immunotherapy and targeted therapy in ccRCC patients. Methods: We conducted a comprehensive analysis using transcriptional profiles and clinical data obtained from The Cancer Genome Atlas (TCGA). LD-related genes were identified from existing literature and the GeneCards database, and differentially expressed genes were determined. Sequentially, we conducted Cox regression analysis and Lasso regression analysis, to establish a prognostic risk model. The performance of the risk model was evaluated using Kaplan–Meier (KM) analysis and time-dependent receiver operating characteristic (ROC) analysis. Additionally, gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, and immunophenoscore (IPS) algorithm were used to assess the tumor microenvironment (TME) and treatment response. Results: We constructed a risk signature with four LD-related genes in the TCGA dataset, which could be an independent prognostic factor in ccRCC patients. Then, patients were classified into two risk groups and exhibited notable differences in overall survival (OS), progression-free survival (PFS), and TME characteristics. Furthermore, we developed a comprehensive nomogram based on clinical features, which demonstrated good prognostic predictive value. According to the results of GSEA analysis, immune-related pathways were found to be significantly enriched in the high-risk group. Additionally, the high-risk group displayed high levels of immune cell infiltration, TMB and IPS scores, indicating better efficacy of immune checkpoint inhibitors (ICIs). Finally, high-risk demonstrated reduced IC50 values compared to the low-risk counterpart for specific targeted and chemotherapeutic drugs, suggesting that the patients receiving these targeted drugs in high-risk group had better treatment outcomes. Conclusions: Our findings suggested that the LD-related gene signature could potentially predict the prognosis of ccRCC patients. Additionally, it showed promise for predicting responses to immunotherapy and targeted therapy in ccRCC patients. These insights might potentially have guided the clinical management of these patients, but further validation and broader data analysis are needed to confirm these preliminary observations. [ABSTRACT FROM AUTHOR]

CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1, and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard-of-care agent, axitinib. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2 independent. [ABSTRACT FROM AUTHOR]

Objectives: Under the classification of multicategory survival outcomes of cancer patients, it is crucial to identify biomarkers that affect specific outcome categories. The classification of multicategory survival outcomes from transcriptomic data has been thoroughly investigated in computational biology. Nevertheless, several challenges must be addressed, including the ultra-high-dimensional feature space, feature contamination, and data imbalance, all of which contribute to the instability of the diagnostic model. Furthermore, although most methods achieve accurate predicted performance for binary classification with high-dimensional transcriptomic data, their extension to multi-class classification is not straightforward. Methods: We employ the One-versus-One strategy to transform multi-class classification into multiple binary classification, and utilize the overlapping group screening procedure with binary logistic regression to include pathway information for identifying important genes and gene-gene interactions for multicategory survival outcomes. Results: A series of simulation studies are conducted to compare the classification accuracy of our proposed approach with some existing machine learning methods. In practical data applications, we utilize the random oversampling procedure to tackle class imbalance issues. We then apply the proposed method to analyze transcriptomic data from various cancers in The Cancer Genome Atlas, such as kidney renal papillary cell carcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma. Our aim is to establish an accurate microarray-based multicategory cancer diagnosis model. The numerical results illustrate that the new proposal effectively enhances cancer diagnosis compared to approaches that neglect pathway information. Conclusions: We showcase the effectiveness of the proposed method in terms of class prediction accuracy through evaluations on simulated synthetic datasets as well as real dataset applications. We also identified the cancer-related gene-gene interaction biomarkers and reported the corresponding network structure. According to the identified major genes and gene-gene interactions, we can predict for each patient the probabilities that he/she belongs to each of the survival outcome classes. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib–nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting. TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting. From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib–nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0–7·4) with tivozanib–nivolumab and 7·4 months (5·6–9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84–1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6–9·6) with tivozanib–nivolumab and 9·2 months (7·4–10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib–nivolumab 3·7 months [95% CI 2·7–5·4] and with tivozanib monotherapy 3·7 months [1·9–7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib–nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group). These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting. Aveo Pharmaceuticals. [ABSTRACT FROM AUTHOR]

While renal cell carcinoma (RCC) is often linked to smoking, obesity, and hypertension, hereditary forms also account for about 3% of RCC cases. Notably, NCCN guidelines identify 7 major hereditary syndromes associated with an increased RCC risk. Inherited mutations in DNA repair genes, such as ATM, BRCA, and TP53, significantly increase the risk of various cancers. Biallelic pathogenic mutations in ATM cause Ataxia-Telangiectasia (A-T) syndrome, while heterozygous germline pathogenic ATM mutations, present in about 1% of the population, also elevate cancer risk. RCC has not traditionally been associated with germline pathogenic ATM mutations, only limited retrospective analyses have identified such mutations. This case report presents a 68-year-old woman with a germline pathogenic ATM mutation (c.8786+1 G>A) who developed high-risk clear cell RCC followed by an acquired somatic VHL mutation in RCC and a 3-cm serous cystadenoma, illustrating the double-hit phenomenon. Her brother, who shares the same germline pathogenic mutation, was diagnosed with pancreatic cancer and prostate cancer. This case highlights the potential use for enhanced screening protocols for RCC in patients who have germline pathogenic ATM mutations and the importance of research in targeted treatments for tumors driven by dual genetic mechanisms. Increased awareness and vigilant screening for RCC are crucial in managing hereditary cancer syndromes effectively. [ABSTRACT FROM AUTHOR]

Background: The presence of collateral vessels (CVs) on contrast-enhanced computed tomography is a poor prognostic factor in renal cell carcinoma (RCC), but its value in small RCC (sRCC; < 4 cm) remains unknown. In this study, we investigated whether presence of CVs is a predictor of high potential for metastasis in sRCC. Methods: We retrospectively reviewed clinical and imaging data of patients with pathologically confirmed sRCC evaluated at our institution between 2011 and 2021. All sRCCs were pathologically diagnosed by biopsy, metastasectomy, partial nephrectomy, or radical nephrectomy. CVs were defined as blood vessels of any diameter connecting the tumor with the surrounding perirenal tissues on contrast-enhanced computed tomography. The rate of metastasis-free survival (MFS), defined as the time from pathological diagnosis to confirmed metastasis, was compared among patients without CVs, those with one CV, and those with two or more CVs. Results: Of 141 patients, 4 (2.8%) had metastatic sRCC at initial diagnosis. In the 137 patients with nonmetastatic sRCC, the diagnosis was pathologically confirmed following radical surgery. The median follow-up period from pathological diagnosis was 73.9 months, and the overall 5-year MFS was 93.5%. The 5-year MFS was significantly poorer in patients with two or more CVs than in those with one CV (63.8% vs. 96.3%; p = 0.0003) and those without CVs (63.8% vs. 100%; p < 0.0001). Conclusions: sRCCs with two or more CVs might have high potential for metastasis. Conversely, sRCCs without CVs might not be aggressive and be suitable for active surveillance. [ABSTRACT FROM AUTHOR]

Objective: Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH‐wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo‐angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib‐dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells. Methods: We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N‐Acetyl‐L‐Cysteine (NAC) might be used to reduce senescence‐associated adverse effects of axitinib treatment without altering its anti‐tumor activity. Results: We demonstrate that the use of the antioxidant molecule N‐Acetyl‐Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib‐dependent toxicity. Conclusion: Overall, we found that NAC co‐treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib‐dependent toxicity. [ABSTRACT FROM AUTHOR]

Axitinib (AXTN) is an oral tyrosine kinase inhibitor for the treatment of early to advanced renal cell carcinoma. In this work, solvates of AXTN were prepared in five solvents and subjected to desolvation treatment. The crystal form A of AXTN can form solvates in acetonitrile, DMF, acetic acid, acetic acid + water, and methanol. Different ratios of AXTN and acetic acid will form different products (solvate or directly crystallized into another crystal form (form IV)). The characterization results of thermal analyses confirmed the types of the five solvates. The obtained solvates were desolvated using methods of solid-phase desolvation (heating, exposure to solvent steam, microwave) and solvent-mediated phase transformation (SMPT). The desolvated solids were characterized by PXRD, TGA, DSC, FT-IR, and SEM, and it was ultimately inferred that a new crystal form (form Z) of AXTN could be formed after desolvation. In addition, the solvates obtained in this work experienced mutual transformation via SMPT, which depends on the type of solvents or mixed solvents. The phase transformations of different solid forms were summarized. This study is instructive for exploring solvates and polymorphs of AXTN and understanding phase transitions under different environments. [ABSTRACT FROM AUTHOR]

Laminin, fibronectin, and collagen IV are pivotal extracellular matrix (ECM) components. The ECM environment governs the fundamental properties of tumors, including proliferation, vascularization, and invasion. Given the critical role of cell-matrix adhesion in malignant tumor progression, we hypothesize that the concentrations of these proteins may be altered in the plasma of patients with clear cell renal cell carcinoma (ccRCC). This study aimed to evaluate the serum, urine, and tissue levels of laminin-5, collagen IV, and fibronectin among a control group and ccRCC patients, with the latter divided into stages T1–T2 and T3–T4 according to the TNM classification. We included 60 patients with histopathologically confirmed ccRCC and 26 patients diagnosed with chronic cystitis or benign prostatic hyperplasia (BPH). Collagen IV, laminin-5, and fibronectin were detected using Surface Plasmon Resonance Imaging biosensors. Significant differences were observed between the control group and ccRCC patients, as well as between the T1–T2 and T3–T4 subgroups. Levels were generally higher in plasma and tissue for fibronectin and collagen IV in ccRCC patients and lower for laminin. The ROC (Receiver operating characteristic) analysis yielded satisfactory results for differentiating between ccRCC patients and controls (AUC 0.84–0.93), with statistical significance for both fibronectin and laminin in plasma and urine. Analysis between the T1–T2 and T3–T4 groups revealed interesting findings for all examined substances in plasma (AUC 0.8–0.95). The results suggest a positive correlation between fibronectin and collagen levels and ccRCC staging, while laminin shows a negative correlation, implying a potential protective role. The relationship between plasma and urine concentrations of these biomarkers may be instrumental for tumor detection and staging, thereby streamlining therapeutic decision-making. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is characterized by a loss of muscle mass and function and is often associated with frailty, a syndrome linked to physical disability and shortened survival in various patient populations, including cancer patients. Low serum alanine aminotransferase (ALT) values, serving as a biomarker for sarcopenia, were previously associated with frailty and shortened survival in several cancers. In the current study, we aimed to test the association between low ALT and shorter survival in renal cell carcinoma (RCC) patients and survivors. Methods: This was a retrospective analysis of RCC patients and survivors, both in- and outpatients. We defined patients with sarcopenia as those presenting with ALT < 17 IU/L. Results: We identified records of 3012 RCC patients. The cohort included 1830 patients (mean age 65.6 ± 13.3 years, 68% were men) of whom only 179 underwent surgical treatment. Out of the eligible cohort, 811 patients (44.3%) had ALT < 17 IU/L, with a mean ALT value of patients within the low-ALT group of 11.79 IU/L, while the mean value in the higher ALT level group was 24.44 IU/L (p < 0.001). Patients in the low-ALT group were older (67.9 vs. 63.7 years; p < 0.001) and had lower BMIs (26.6 vs. 28; p < 0.001). In addition, patients with low ALT had lower hemoglobin values (12.14 vs. 12.91 g/dL; p < 0.001), higher serum creatinine (1.49 vs. 1.14; p < 0.001) and higher platelet to lymphocyte ratios (178 vs. 156; p < 0.001). In a univariate analysis, low ALT levels were associated with a 72% increase in mortality (95% CI 1.46–2.02, p < 0.001). In a multivariate model controlled for age, gender, hemoglobin, platelets, LDH, neutrophil to lymphocyte ratios and platelet to lymphocyte ratios, low ALT levels were still associated with a 27% increase in mortality (HR = 1.27, 95% CI 1.08–1.51; p = 0.005). Conclusion. Low ALT values, associated with sarcopenia and frailty, are also associated with shortened survival in RCC patients, and survivors and could potentially be applied for optimizing individual treatment decisions. [ABSTRACT FROM AUTHOR]

Objectives: Cytoreductive nephrectomy for metastatic renal cell carcinoma (mRCC) is a standard of care. Partial nephrectomy (PN) in the setting of metastatic disease is an uncommon occurrence, and we aimed to characterize its utilization in a modern cohort. Methods: The National Cancer Database was reviewed for patients with mRCC from 2010 to 2017. Patients with cTanyNanyM1 who underwent cytoreductive surgery in the form of PN or radical nephrectomy (RN) were compiled. Our primary outcome was survival outcome for patients who underwent PN compared to RN. Secondary outcomes included 30-day readmission, length of stay, and survival outcomes. Results obtained: A total of 13,896 patients with mRCC who underwent cytoreductive surgery were identified. In total, 13,242 underwent RN and 654 underwent PN. The RN population was more likely to have cN positive disease, while the PN population was more likely to have cT1 disease. Length of stay, readmission and 30-day mortality were not significantly different between PN and RN, but overall mortality and 90-day mortality favored PN (p < 0.001). Cox regression for death showed PN with improved overall survival (HR 0.782, p < 0.001). Logistic regression for predictors of cytoreductive PN revealed cT1 and cN0 as significant factors. Overall survival, as seen on KM analysis, identified that PN exhibited improved 2-year (67.1% vs. 52.0%) and 5-year (40.7% vs. 29.2%) overall survival relative to RN (p < 0.001). Conclusions: PN is an infrequent treatment with mRCC and its utilization is stable from 2010 to 2017. Overall survival is significantly better for those undergoing PN, likely due to their favorable oncologic disease characteristics. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have become the cornerstone of treatment in renal cell carcinoma (RCC), for both metastatic disease and in an adjuvant setting. However, an adaptive resistance from cancer cells may arise during ICI treatment, therefore many studies are focusing on additional immune checkpoint inhibitor pathways. Promising targets of immunotherapeutic agents under investigation include T cell immunoglobulin and ITIM domain (TIGIT), immunoglobulin-like transcript 4 (ILT4), lymphocyte activation gene-3 (LAG-3), vaccines, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and chimeric antigen receptor (CAR) T cells. In this review of the literature, we recollect the current knowledge of the novel treatment strategies in the field of immunotherapy that are being investigated in RCC and analyze their mechanism of action, their activity and the clinical studies that are currently underway. [ABSTRACT FROM AUTHOR]

Simple Summary: The characterization of molecular alterations is continuously gaining relevance in pathology as it can contribute to explaining tumors' pathogenesis and address specific targeted therapies. As for the kidney, in recent years, much scientific research has been focused on the MiTF family genes, particularly on the TFE3 gene. In this setting, while initially just accustomed to a subtype of renal cell carcinoma, currently classified as TFE3-rearranged renal cell carcinoma, TFE3 fusions have been identified in a few mesenchymal neoplasms of the kidney viewed as PEComas. In this work, we gather the available data regarding the key clinical and pathological features of these TFE3-rearranged renal epithelial and mesenchymal neoplasms. We seek to propose a comprehensive solution regarding their pathogenesis and sort out their classification conundrum. Background: Identical translocations involving the TFE3 gene and various partners have been found in both renal and soft tissue tumors, like alveolar soft part sarcoma (ASPSCR1), ossifying fibromyxoid tumor (PHF1), epithelioid hemangioendothelioma, and the clear cell stromal tumor of the lung (YAP1). Methods: Herein, we review in detail the clinicopathologic and molecular data of TFE3-rearranged renal tumors and propose our perspective, which may shed light on this emerging conundrum. Results: Among the kidney tumors carrying TFE3 translocations, most are morphologically heterogeneous carcinomas labeling for the tubular marker PAX8. The others are mesenchymal neoplasms known as PEComas, characterized by epithelioid cells co-expressing smooth muscle actin, cathepsin-K, melanogenesis markers, and sometimes melanin pigment deposition. Over the past 30 years, numerous TFE3 fusion partners have been identified, with ASPL/ASPSCR1, PRCC, SFPQ/PSF, and NONO being the most frequent. Conclusions: It is not well understood why similar gene fusions can give rise to renal tumors with different morpho-immunophenotypes, which may contribute to the recent disagreement regarding their classification. However, as these two entities, respectively, epithelial and mesenchymal in nature, are widely recognized by the pathology community and their clinicopathologic features well established, we overall believe it is still better to retain the names TFE3-rearranged renal cell carcinoma and TFE3-rearranged PEComa. [ABSTRACT FROM AUTHOR]

Simple Summary: Stereotactic body radiotherapy (SBRT) is a treatment technique that delivers higher doses of conformal radiation precisely to specific targets. SBRT is utilized for the treatment of the more common cancers such as lung, liver and prostate malignancies, both in the early stage and the oligometastatic setting. The aim of this review is to highlight the current role of SBRT for renal cell carcinoma (RCC), a disease which was previously thought to be radioresistant, particularly to conventionally fractionated radiotherapy. There is now an increasing body of literature encompassing published phase II trials, reviews and meta-analyses demonstrating the effectiveness of SBRT in both early-stage RCC (as an alternative to patients who are not surgical candidates) and within the context of metastasis-directed therapy (MDT) for patients with oligometastatic and oligoprogressive RCC. Ongoing randomized trials are also exploring the role of SBRT as a cytoreductive treatment in metastatic RCC. Renal cell carcinoma (RCC) has been increasing in incidence by around 1.5% per year for several years. However, the mortality rate has been decreasing by 1.6% per year, and this can be attributed to stage migration and improvements in treatment. One treatment modality that has emerged in recent years is stereotactic body radiotherapy (SBRT), which is an advanced radiotherapy technique that allows the delivery of high-dose radiation to the tumor while minimizing doses to the organs at risk. SBRT has developed a role in the treatment of early-stage, oligometastatic and oligoprogressive RCC. In localized disease, phase II trials and meta-analyses have shown that SBRT provides a very high probability of long-term local control with a low risk of severe late toxicity. In oligometastatic (OMD) RCC, the same level of evidence has similarly shown good local control and minimal toxicity. SBRT could also delay the necessity to start or switch systemic treatments. Medical societies have started to incorporate SBRT in their guidelines in the treatment of localized disease and OMD. A possible future role of SBRT involves cytoreduction. It is theorized that SBRT can lower tumor burden and enhance immune-related response, but it cannot be recommended until the results of the phase II trials are published. [ABSTRACT FROM AUTHOR]

Simple Summary: 3-Monochloropropanediol esters (3-MCPDEs) are process contaminants generated during food processing. Although there is no clinical evidence directly linking them to adverse health effects, concerns have been raised regarding their potential to cause renal damage and cancer. To investigate this, we analyzed the concentrations of 3-MCPDEs in kidney tissues from 68 individuals, categorized into two groups: those with kidney cancer and those without. The levels of 3-MCPDEs were quantified using a validated analytical method, with the analyst blinded to the sample origins to ensure objectivity. The results indicated that 3-MCPDE concentrations were significantly higher in the kidneys of patients with kidney cancer compared to those without cancer. However, no significant correlation was found between 3-MCPDE levels and tumor size or stage. These findings suggest that 3-MCPDEs can accumulate in human kidneys and that their levels are elevated in cancerous tissues. Background: 3-Monochloro-propanediol esters (3-MCPDEs), commonly found in refined edible oils and related products, have generated concerns due to their nephrotoxicity and carcinogenicity, yet clinical evidence remains limited. Objectives: In this study, we aimed to assess, for the first time, the accumulation of 3-MCPDEs in human kidney tissues, focusing on 68 participants, some with and others without renal cell carcinoma (RCC). Methods: An analytical method for 3-MCPDE determination in kidney tissues underwent partial validation to ensure its suitability for sample analysis. The analyst was blind to the sample groups. Results: Results revealed significantly higher 3-MCPDE levels in RCC patients compared to non-RCC counterparts (0.22 vs. 0.01 µg/g) (p < 0.01). Moreover, no significant correlation was found between 3-MCPDE levels and tumor stage or size in the RCC group. Conclusions: Accumulation of 3-MCPDEs in humans, with significantly higher levels was observed in kidney tumor specimens compared to non-patients. These findings suggest minimizing the intake of 3-MCPD and its esters in diets in order to reduce potential negative health impacts. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cancer is the eighth most frequent cancer in Europe, and its prevalence is increasing. Surgery is the treatment of choice for localised renal cell carcinoma requiring interventional management, but less invasive treatment methods are emerging. Stereotactic body radiotherapy (SBRT) utilises precise delivery of high doses of radiation to ablate the primary cancer. In our systematic review and meta-analysis, we pooled data from available prospective trials, including 13 studies involving 308 patients. The results of the meta-analysis show that SBRT for localised renal cell carcinoma is highly effective in controlling local diseases and has low complication rates. In the second year, 97% of patients were free from local recurrence. Only 3% experienced severe adverse events, which included abdominal pain and fatigue. SBRT presents a valuable treatment for patients who require treatment but cannot undergo surgery; however, it has not been yet confirmed to be equieffective to surgery as trials directly comparing these methods are missing. Context: Surgery is the gold standard for the local treatment of primary renal cell carcinoma (RCC), but alternatives are emerging. We conducted a systematic review and meta-analysis to assess the results of prospective studies using definitive stereotactic body radiotherapy (SBRT) to treat primary localised RCC. Evidence acquisition: This review was prospectively registered in PROSPERO (CRD42023447274). We searched PubMed, Embase, Scopus, and Google Scholar for reports of prospective studies published since 2003, describing the outcomes of SBRT for localised RCC. Meta-analyses were performed for local control (LC), overall survival (OS), and rates of adverse events (AEs) using generalised linear mixed models (GLMMs). Outcomes were presented as rates with corresponding 95% confidence intervals (95% CIs). Risk-of-bias was assessed using the ROBINS-I tool. Evidence synthesis: Of the 2983 records, 13 prospective studies (n = 308) were included in the meta-analysis. The median diameter of the irradiated tumours ranged between 1.9 and 5.5 cm in individual studies. Grade ≥ 3 AEs were reported in 15 patients, and their estimated rate was 0.03 (95%CI: 0.01–0.11; n = 291). One- and two-year LC rates were 0.98 (95%CI: 0.95–0.99; n = 293) and 0.97 (95%CI: 0.93–0.99; n = 253), while one- and two-year OS rates were 0.95 (95%CI: 0.88–0.98; n = 294) and 0.86 (95%CI: 0.77–0.91; n = 224). There was no statistically significant heterogeneity, and the estimations were consistent after excluding studies at a high risk of bias in a sensitivity analysis. Major limitations include a relatively short follow-up, inhomogeneous reporting of renal function deterioration, and a lack of prospective comparative evidence. Conclusions: The short-term results suggest that SBRT is a valuable treatment method for selected inoperable patients (or those who refuse surgery) with localised RCC associated with low rates of high-grade AEs and excellent LC. However, until the long-term data from randomised controlled trials are available, surgical management remains a standard of care in operable patients. [ABSTRACT FROM AUTHOR]

To our knowledge, this is the first report of percutaneous endoscopic intragastric surgery (PEIGS) for gastric metastases from other organs. A 70‐year‐old male with a history of renal cell carcinoma (RCC) was referred to our department for the treatment of gastric metastasis of RCC. Partial gastrectomy was performed using single‐incision PEIGS. Two years after the surgery, a follow‐up esophagogastroduodenoscopy revealed a tumor located on the middle greater curvature of the stomach. The diagnosis was metastatic renal cell carcinoma, prompting a similar surgery. No recurrence was observed after the second surgery. PEIGS is a minimally invasive option for the treatment of metastatic gastric tumors. [ABSTRACT FROM AUTHOR]

Background: Integrated immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) are now the recommended first-line therapy to manage renal cell carcinoma (mRCC). Proteasome 26S subunit non-ATPase 2 (PSMD2) overexpression in tumors has been correlated with tumor progression. Currently, mRCC lacks an established biomarker for the combination of ICI+TKI. Methods: This study involved RNA sequencing of RCC patients from two cohorts treated with ICI+TKI (ZS-MRCC and JAVELIN-Renal-101). We utilized immunohistochemistry alongside flow cytometry, aiming at assessing immune cell infiltration and functionality in high-risk localized RCC samples. Response and progression-free survival (PFS) were evaluated relying upon RECIST criteria. Results: PSMD2 was significantly overexpressed in advanced RCC and among non-responders to ICI+TKI therapy. Overexpressed PSMD2 was correlated with poor PFS in the ZS-MRCC and JAVELIN-101 cohorts. Multivariate Cox analysis validated PSMD2 as an independent PFS predictor. PSMD2 overexpression was related to a reduction in CD8+ T cells, especially GZMB+ CD8+ T cells, besides an increase in PD1+ CD4+ T cells. Additionally, tumors with high PSMD2 levels showed enhanced T cell exhaustion levels and a higher regulatory T cell presence. A Machine Learning (ML) model based on PSMD2 expression and other screened factors was subsequently developed to predict the effectiveness of ICI+TKI. Conclusions: Elevated PSMD2 expression is linked to resistance and decreased PFS in mRCC patients undergoing ICI+TKI therapy. High PSMD2 levels are also associated with impaired function and increased exhaustion of tumor-infiltrating lymphocytes. An ML model incorporating PSMD2 expression could potentially identify patients who may have a higher likelihood of benefiting from ICI+TKI. [ABSTRACT FROM AUTHOR]

Background: To define the incidence and independent predictive factors of intraoperative adverse events (IOAEs) after minimally invasive radical nephrectomy and thrombectomy (RNAT) and to determine the impact of intraoperative adverse events on oncological outcomes. Patients and methods: A total of 294 patients underwent minimally invasive RNAT from January 2010 to December 2023 in our center were included. IOAEs are defined as any deviation from the normal surgical procedure during the operation course. Multivariate logistic regression analysis was performed to identify the independent predictive factors of IOAEs. The Kaplan–Meier curves was used to compare overall survival and cancer-specific survival between patients with IOAEs or not. Results: Seventy-four IOAEs occurred in 57 of 294 patients (19.4%) and the most frequent IOAEs were conversion to open surgery (42/74, 56.7%), followed by excessive hemorrhage (20/74, 27.0%). In multivariate logistic analysis, side (OR 0.0929; 95%Cl 0.0367–0.2160; p < 0.001), operation approach (OR 0.1762; 95%Cl 0.06828–0.4109; p < 0.001), and Mayo grade (OR 6.321; 95%Cl 3.846–11.13; p < 0.001) were independent predictive predictors of IOAEs during minimally invasive RNAT. IOAEs (OR 2.713; 95%Cl 1.242–5.897; p = 0.012) was an independent risk factor of the occurrence of postoperative complications. Between the patients with IOAEs or not, neither overall survival (OS) nor cancer-specific survival (CSS) showed statistical differences. Patients with postoperative complications show shorter OS and CSS. Conclusion: We found that the independent predictive factors of minimally invasive RNAT were side, operation approach and Mayo grade, and it is a risk factor of the occurrence of postoperative complications. In addition, the occurrence of IOAEs had no effect on long-term oncological outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Nuclear envelope spectrin repeat protein (Nesprin) 1 encoded by SYNE1, crucially regulates the morphology and functions of the cell. Mutations in the SYNE1 gene are associated with various diseases; however, their significance in renal cell carcinoma (RCC) remains unknown. In this study, we have investigated the association of SYNE1/Nesprin1 with the progression and prognosis of clear cell RCC (ccRCC). Methods: In silico analyses of publicly available datasets of patients with RCC were performed. Based on the cohort data, Nesprin1 expression in nephrectomized tissue samples acquired from patients with ccRCC was analyzed using immunohistochemical staining. The invasion, migration, and proliferation of the SYNE1-knockdown human RCC cell lines were analyzed in vitro; moreover, RNA sequencing and gene set enrichment analysis were conducted to study the molecular mechanism underlying the association of SYNE1/Nesprin1 with prognosis of RCC. Results: Patients with RCC-associated SYNE1 gene mutations exhibited significantly worse overall and progression-free survivals. Patients with Nesprin1-negative ccRCC tumors exhibit significantly poorer overall, cancer-specific, and recurrence-free survival rates than those recorded in the Nesprin1-positive group. SYNE1 knockdown enhanced the invasion and migration of RCC cells; however, it did not influence the proliferation of cells. RNA sequencing and gene set enrichment analysis revealed that SYNE1 knockdown significantly altered the expression of genes associated with oxidative phosphorylation. Consistently, patients with RCC exhibiting low SYNE1 expression, who were treated with the vascular endothelial growth factor receptor inhibitor sunitinib, had worse progression-free survival. Conclusions: The results indicate that the expression of SYNE1/Nesprin1 and SYNE1 mutations in patients with RCC are closely linked to their prognosis and responsiveness to sunitinib treatment. [ABSTRACT FROM AUTHOR]

Elucidating the molecular dependencies behind the cancer-type specificity of driver mutations may reveal new therapeutic opportunities. We hypothesized that developmental programs would impact the transduction of oncogenic signaling activated by a driver mutation and shape its cancer-type specificity. Therefore, we designed a computational analysis framework by combining single-cell gene expression profiles during fetal organ development, latent factor discovery, and information theory-based differential network analysis to systematically identify transcription factors that selectively respond to driver mutations under the influence of organ-specific developmental programs. After applying this approach to VHL mutations, which are highly specific to clear cell renal cell carcinoma (ccRCC), we revealed important regulators downstream of VHL mutations in ccRCC and used their activities to cluster patients with ccRCC into three subtypes. This classification revealed a more significant difference in prognosis than the previous mRNA profile-based method and was validated in an independent cohort. Moreover, we found that EP300, a key epigenetic factor maintaining the regulatory network of the subtype with the worst prognosis, can be targeted by a small inhibitor, suggesting a potential treatment option for a subset of patients with ccRCC. This work demonstrated an intimate relationship between organ development and oncogenesis from the perspective of systems biology, and the method can be generalized to study the influence of other biological processes on cancer driver mutations. [ABSTRACT FROM AUTHOR]

This article discusses Grover's disease (GD) in oncologic patients and provides a systematic review of relevant literature. GD is a skin condition whose pathogenesis is not fully understood, but recent evidence suggests it may involve an overexpression of interleukin 4 (IL-4). The association between GD and malignancies, as well as between GD and systemic oncologic treatments, has been sporadically reported. The review includes 31 patients with GD, with the most strongly associated malignancies being metastatic melanoma and hematologic malignancies. Immunotherapy was the most common observed oncologic treatment. The article also discusses the histological features, comorbidities, and treatment options for GD. [Extracted from the article]

With limitations of conventional imaging and biopsy, accurate, non-invasive techniques to detect clear-cell renal cell carcinoma in patients with renal masses remain an unmet need. 89Zr-labelled monoclonal antibody ([89Zr]Zr-girentuximab) has high affinity for carbonic anhydrase 9, a tumour antigen highly expressed in clear-cell renal cell carcinoma. We aimed to evaluate [89Zr]Zr-girentuximab PET–CT imaging for detection and characterisation of clear-cell renal cell carcinoma. ZIRCON was a prospective, open-label, multicentre, phase 3 trial conducted at 36 research hospitals and practices across nine countries (the USA, Australia, Canada, the UK, Türkiye, Belgium, the Netherlands, Spain, and France). Patients aged 18 years or older with an indeterminate renal mass 7 cm or smaller (cT1) suspicious for clear-cell renal cell carcinoma and scheduled for nephrectomy received a single dose of [89Zr]Zr-girentuximab (37 MBq ±10%; 10 mg girentuximab) intravenously followed by abdominal PET–CT imaging 5 days (±2 days) later. Surgery was performed no later than 90 days after administration of [89Zr]Zr-girentuximab. Blinded central review, conducted by three independent readers, determined the histology from surgical samples. The coprimary endpoints, determined for each individual reader, were the sensitivity and specificity of [89Zr]Zr-girentuximab PET–CT imaging to detect clear-cell renal cell carcinoma, with histopathological confirmation as standard of truth. Analyses were on the full analysis set of patients, defined as patients who had evaluable PET–CT imaging and a confirmed histopathological diagnosis. The trial is registered with ClinicalTrials.gov, NCT03849118, and EUDRA Clinical Trials Register, 2018-002773-21, and is closed to enrolment. Between Aug 14, 2019, and July 8, 2022, 371 patients were screened for eligibility, 332 of whom were enrolled. 300 patients received [89Zr]Zr-girentuximab (214 [71%] male and 86 [29%] female). 284 (95%) evaluable patients were included in the primary analysis. The mean sensitivity was 85·5% (95% CI 81·5–89·6) and mean specificity was 87·0% (81·0–93·1). No safety signals were observed. Most adverse events were not or were unlikely to be related to [89Zr]Zr-girentuximab, with most (193 [74%] of 261 events) occurring during or after surgery. The most common grade 3 or worse adverse events were post-procedural haemorrhage (in six [2%] of 261 patients), urinary retention (three [1%]), and hypertension (three [1%]). In 25 (8%) of 300 patients, 52 serious adverse events were reported, of which 51 (98%) occurred after surgery. There were no treatment-related deaths. Our results suggest that [89Zr]Zr-girentuximab PET–CT has a favourable safety profile and is a highly accurate, non-invasive imaging modality for the detection and characterisation of clear-cell renal cell carcinoma, which has the potential to be practice changing. Telix Pharmaceuticals. [ABSTRACT FROM AUTHOR]

The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, showed clinically meaningful antitumour activity in von Hippel-Lindau (VHL) disease-associated neoplasms in the ongoing, single-arm, phase 2 LITESPARK-004 study. We aimed to investigate antitumour activity with an additional 16 months of follow-up and present updated results for the subgroup of patients with CNS haemangioblastomas. In the multicentre, single-arm, phase 2 LITESPARK-004 study, adults (aged ≥18 years) from 11 cancer centres or hospitals in the USA, Denmark, France, and the UK, with germline VHL alterations, at least one measurable renal cell carcinoma tumour, no renal cell carcinoma tumour greater than 3 cm requiring immediate surgical intervention, an Eastern Cooperative Oncology Group performance status 0 or 1, and no previous systemic therapy received oral belzutifan 120 mg once daily until unacceptable toxicity, disease progression, or patient decision to withdraw. The primary endpoint, evaluated in patients with CNS haemangioblastomas, was the proportion of patients with an objective response per RECIST version 1.1 by an independent review committee. We assessed response using two approaches. In approach 1, we evaluated all measurable (≥1 cm maximum diameter) or non-measurable lesions at baseline, including both the solid lesion and the associated cystic component if present. In approach 2, we evaluated only baseline lesions with a measurable (≥1 cm maximum diameter) solid lesion. Antitumour activity was assessed in all patients who received at least one dose of belzutifan. This study is no longer recruiting but is ongoing, and is registered with Clinicaltrials.gov, NCT03401788. Between May 31, 2018, and March 29, 2019, of 67 patients screened, 61 (32 [52%] male and 29 [48%] female) were enrolled; 50 (82%) had at least one CNS haemangioblastoma evaluable at baseline (184 total lesions). Median follow-up for the 50 patients with CNS haemangioblastomas was 38·0 months (IQR 36·7–40·1). In approach 1, 22 of 50 patients (44% [95% CI 30–59]) had an objective response. In approach 2, 19 of 25 patients (76% [55–91] had an objective response. 23 (46%) of 50 patients had a grade 3–5 all-cause adverse event. 19 (38%) patients reported grade 3 adverse events, the most common of which was anaemia (in 6 [12%] patients). Two of 50 patients (4%) reported grade 4 events (retinal vein occlusion and embolism). Two patients died owing to adverse events not considered treatment-related (suicide and toxicity to various agents). Belzutifan showed meaningful antitumour activity in VHL disease-associated CNS haemangioblastomas that was sustained for more than 3 years of treatment. These results continue to support belzutifan as a systemic treatment option for patients with VHL disease-related CNS haemangioblastomas. Merck Sharp & Dohme, National Institutes of Health, and National Cancer Institute. [ABSTRACT FROM AUTHOR]

Background: Non-invasive detection of renal cell carcinoma (RCC) recurrence is a major challenge that could radically affect patient survival. To date, there are no approved biomarkers for inclusion in the monitoring and follow-up of RCC; therefore, assessment of treatment response is lacking. Materials and Methods: A Cross-sectional study was carried out on biopsy-proven renal cell carcinoma patients scheduled for nephrectomy at Hayatabad Medical Complex (HMC) Hospital, Peshawar, Pakistan, between September 2022 and January 2024. Results: A total of 160 samples were included in the study. Eighty samples were obtained from biopsy-proven non-metastatic renal cell carcinoma patients, of which 40 were collected pre-nephrectomy, 40 were collected post-nephrectomy from the same patients, and 80 samples were collected from age and gender-matched healthy individuals. Total plasma glycosaminoglycans (GAGs) levels were analyzed through a manual enzyme-linked immunosorbent assay using a non-competitive sandwich technique. Quantitative variables were summarized as means and standard deviation, while qualitative variables were summarized as frequency and percentage. A paired t-test was performed to check whether the difference between the mean plasma GAG levels in prenephrectomy and post-nephrectomy groups was significant. Conclusion: The results revealed that post-nephrectomy GAG levels have significantly decreased compared to pre-nephrectomy levels (P<0.001). Plasma glycosaminoglycan levels could be promising markers for monitoring renal cell carcinoma patients post-nephrectomy. [ABSTRACT FROM AUTHOR]

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia‐inducible factor‐2α inhibitor, recently approved in the United States for the treatment of von Hippel–Lindau (VHL) disease‐associated renal cell carcinoma (RCC) and other VHL disease‐associated neoplasms. Safety and efficacy were investigated in two clinical studies: a Phase 1 dose escalation/expansion study in solid tumors and RCC and a Phase 2 study in VHL‐RCC. A population pharmacokinetic model was used to estimate belzutifan exposures to facilitate exposure–response (E‐R) analyses for efficacy and safety endpoints. Relationships between exposure and efficacy (overall response rate, disease control rate, progression‐free survival, best overall tumor size response, and other endpoints), safety outcomes (Grade ≥3 anemia, Grade ≥3 hypoxia, and time to first dose reduction/dose interruption), and pharmacodynamic biomarkers (erythropoietin [EPO] and hemoglobin [Hgb]) were evaluated using various regression techniques and time‐to‐event analyses. Efficacy E‐R was generally flat with non‐significant positive trends with exposure. The safety E‐R analyses demonstrated a lack of relationship for Grade ≥3 hypoxia and a positive relationship for Grade ≥3 anemia, with incidences also significantly dependent on baseline Hgb. Exposure‐dependent reductions in EPO and Hgb were observed. Based on the cumulative benefit–risk assessment in VHL disease‐associated neoplasms using E‐R, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit–risk profile of belzutifan 120 mg once daily dosing in patients with VHL‐RCC for labeling and the overall development program. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma with fibromyomatous stroma, recognized as a provisional entity in the current 2022 World Health Organization classification of renal neoplasms, is rare. Recent evidence suggests recurrent alterations in the mTOR pathway, supporting its recognition as a distinct entity. Herein, we report 2 renal cell carcinomas with fibromyomatous stroma with MTOR mutations occurring in 62- and 72-year-old women and review the literature to support its recognition as a distinct entity, focusing on the characteristic morphology, immunohistochemical staining patterns as well as genetic alterations. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) was diagnosed in over 400 000 individuals globally in 2020, making it a significant global health concern. The incidence of RCC varies by region and overall mortality rates have been declining. This decline is attributed in part to advancements in early cancer detection through imaging and the development of more effective systemic therapies. Cytoreductive nephrectomy (CN) was adopted as a standard treatment for metastatic RCC (mRCC) based on clinical experience and early clinical trials. However, the treatment landscape has shifted with the introduction of tyrosine kinase inhibitors (TKI) in 2007 and, more recently, immune checkpoint inhibitors (ICIs). Dual ICI therapy and combinations of ICIs with TKIs are collectively referred to as immuno‐combination therapies and have become standard first‐line treatments. This review examines the evolving role of CN in the era of immuno‐combination therapies, with a focus on patient selection and the timing of surgery. The immunogenic nature of RCC, characterized by spontaneous tumor regression and immune cell infiltration, suggests a potential benefit from combining CN with ICI therapy to enhance treatment outcomes. This is supported by several clinical studies that reported improved outcomes; however, these were limited by their retrospective nature. Ongoing clinical trials, such as NORDIC‐SUN, PROBE, and SEVURO‐CN, are expected to provide critical insights into the role of CN in the ICI era. Their findings will ultimately guide future clinical decision‐making and further refine treatment strategies for mRCC. [ABSTRACT FROM AUTHOR]

Purpose: Indeterminate renal masses are increasingly incidentally found on cross-sectional imaging. 99mTc-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) scans can be used to identify oncocytomas and oncocytic renal neoplasms, including a subset of chromophobe renal cell carcinomas (chRCCs), which are viewed as false-positive. Procedure: Patients imaged with renal sestamibi scans between 2014 and 2023 were reviewed. Those patients with solitary tumors that were originally classified as chRCC were included in the analysis. Imaging with SPECT/CT from the liver dome down had been carried out 75 min after the administration of 925 MBq of 99mTc-sestamibi. All available H&E and immunostained slides were re-reviewed and classified according to WHO 2022 criteria. Confirmatory immunohistochemical stains were performed in tumors considered morphologically suspicious for non-chRCC entities. Result: A total of 18 patients with solitary tumors were included in the final analysis. 13/18 (72.2%) tumors in this cohort remained classified as chRCC, with 4/18 (22.2%) being eosinophilic-variant chRCC. The reclassified tumors (5/18 [27.8%]) included 2/18 (11.1%) low-grade oncocytic tumor (LOT), 1/18 (5.5%) eosinophilic vacuolated tumor (EVT), and 2/18 (11.1%) unclassified low-grade oncocytic neoplasms. As such, only 2/9 (22.2%) qualitatively "hot" tumors were chRCC other than eosinophilic-variant and only 1/9 (11.1%) "cold" tumors was a histology other than chRCC. Conclusion: Based on current histopathologic classification methods, it is likely that the "false-positive" rate of uptake on renal sestamibi scans with chRCC has been over-stated. Further study is warranted to better refine the optimal utility of renal sestamibi scans for non-invasive risk stratification of indeterminate renal masses. [ABSTRACT FROM AUTHOR]

Context.--Eosinophilic solid and cystic renal cell carcinoma is now defined in the 5th edition of the 2022 World Health Organization classification of urogenital tumors. Objective.--To perform morphologic, immunohistochemical, and preliminary genetic studies about this new entity in China for the purpose of understanding it better. Design.--The study includes 18 patients from a regional tertiary oncology center in northern China (Tianjin, China). We investigated the clinical and immunohistochemical features of these cases. Results.--The mean age of patients was 49.6 years, and the male to female ratio was 11:7. Macroscopically, 1 case had the classic cystic and solid appearance, whereas the others appeared purely solid. Microscopically, all 18 tumors shared a similar solid and focal macrocystic or microcystic growth pattern, and the cells were characterized by voluminous and eosinophilic cytoplasm, along with coarse ampho-philic stippling. Immunohistochemically, most of the tumors had a predominant cytokeratin (CK) 20-positive feature, ranging from focal cytoplasmic staining to diffuse membranous accentuation. Initially, we separated these cases into different immunohistochemical phenotypes. Group 1 (7 of 18; 38.5%) was characterized by positive phospho-4EBP1 and phospho-S6, which can imply hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling. Group 2 (4 of 18; 23%) was negative for NF2, probably implying a germ-line mutation of NF2. Group 3 (7 of 18; 38.5%) consisted of the remaining cases. One case had metastatic spread and exhibited an aggressive clinical course, and we detected cyclin-dependent kinase inhibitor 2A (CDKN2A) mutation in this case; other patients were alive and without disease progression. Conclusions.--Our research proposes that eosinophilic solid and cystic renal cell carcinoma exhibits prototypical pathologic features with CK20 positivity and has aggressive potential. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare the efficacy of robot-assisted partial nephrectomy for completely endophytic renal tumors with the reported outcomes of conventional laparoscopic partial nephrectomy and investigate the transition of renal function after robot-assisted partial nephrectomy. Methods: We conducted a prospective, multicenter, single-arm, open-label trial across 17 academic centers in Japan. Patients with endophytic renal tumors classified as cT1, cN0, cM0 were included and underwent robot-assisted partial nephrectomy. We defined two primary outcomes to assess functional and oncological aspects of the procedure, which were represented by the warm ischemic time and positive surgical margin, respectively. Comparisons were made using control values previously reported in laparoscopic partial nephrectomy studies. In the historical control group, the warm ischemia time was 25.2, and the positive surgical margin was 13%. Results: Our per-protocol analysis included 98 participants. The mean warm ischemic time was 20.3 min (99% confidence interval 18.3–22.3; p < 0.0001 vs. 25.2). None of the 98 participants had a positive surgical margin (99% confidence interval 0–5.3%; p < 0.0001 vs. 13.0%). The renal function ratio of eGFR before and after protocol treatment multiplied by splits was 0.70 (95% confidence interval: 0.66–0.75). Factors such as preoperative eGFR, resected weight, and warm ischemic time influenced the functional loss of the partially nephrectomized kidney after robot-assisted partial nephrectomy. Conclusions: Robot-assisted partial nephrectomy for completely endophytic renal tumors offers a shorter warm ischemia time and comparable positive surgical margin rate compared with conventional laparoscopic partial nephrectomy. [ABSTRACT FROM AUTHOR]

Background: Whether immune checkpoint inhibitor (ICI) plus ICI combination therapy or ICI plus tyrosine kinase inhibitor (TKI) combination therapy is useful for renal cell carcinoma (RCC) with inferior vena cava tumor thrombosis (IVCTT) remains unclear. Methods: We retrospectively evaluated the therapeutic effects and incidence of treatment-related adverse events (TRAEs) associated with ICI-based combination therapy in 36 patients with advanced RCC with IVCTT. Results: The median age at initiation of treatment was 71 years; the IVCTT stages were cT3b in 22 patients and cT3c in 14. The ICI–ICI and ICI–TKI groups comprised 15 and 21 patients, respectively. Median tumor shrinkage at the best response showed that the primary tumor diameter decreased by 1.8 cm (22%), and the IVCTT height decreased by 1.5 cm (26%). A higher proportion of patients in the ICI–TKI group experienced tumor shrinkage than those in the ICI–ICI group (primary tumor, p = 0.0325; IVCTT, p = 0.0112). Approximately 27% of patients experienced an increase in the IVCTT height with ICI–ICI combination therapy. No significant difference was observed in the relative tumor shrinkage of IVCTT, primary or level-down staging of IVCTT, other treatment effects, incidence of TRAEs, surgical outcomes, or prognosis between the groups. Conclusion: ICI-based combination therapy is effective against IVCTT and primary RCC. Although ICI–ICI is associated with a higher probability of tumor growth compared with ICI–TKI in the frequency of tumor regression, both therapies may be almost equally effective against primary RCC with IVCTT. [ABSTRACT FROM AUTHOR]

Background: A useful biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in advanced renal cell carcinoma (RCC) has not yet been established. This study aims to investigate whether inflammatory markers are associated with the efficacy of nivolumab plus ipilimumab therapy before and during treatment. Methods: Data from patients with advanced clear cell RCC who received a combination treatment of nivolumab plus ipilimumab were retrospectively analyzed. The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) levels were assessed at baseline and 3, 6, and 9 weeks after treatment initiation. The correlation between these inflammatory markers and the patient's prognosis was investigated. Results: Eighty-four patients were identified. The multivariate analysis identified NLR at week 3, CRP at week 6, and NLR and CRP at week 9 as the consistent predictor associated with poor overall survival (OS) at each time point. The survival analysis and receiver operating characteristic (ROC) curve analysis revealed that an NLR of ≥ 2.4 at week 3, CRP of ≥ 1.4 mg/dL at week 6, and NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 were associated with worse OS (hazard ratios (HR) = 5.70, P = 0.008, HR = 3.23, P = 0.004, HR = 7.38, P < 0.001 and HR = 3.55, P = 0.002). Conclusions: Both NLR and CRP were considered useful biomarkers for understanding the prognosis during nivolumab plus ipilimumab therapy. Furthermore, an NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 are helpful in reconsidering treatment continuation. [ABSTRACT FROM AUTHOR]