Search Results (1,640)

Liquid biopsy enables minimally invasive detection and longitudinal monitoring of tumor-derived material in blood and urine. In genitourinary cancers, most applications have focused on genomic alterations in circulating tumor DNA (ctDNA), together with circulating tumor cells (CTCs), extracellular vesicles (EVs), and cell-free RNAs. These measurements are clinically informative but are often interpreted as isolated, predominantly descriptive biomarkers and therefore incompletely represent the adaptive processes that determine progression and treatment response. We propose circulating tumor function (CTF) as a systems biology framework for integrating tumor-derived and host-derived genomic, regulatory, metabolic, redox, and immune signals obtained through serial liquid biopsy. CTF is not a single analyte or assay; rather, it is an inference model intended to generate interpretable functional states, including proliferative activity, immune evasion, metastatic potential, metabolic stress, and therapeutic adaptation. We review the contributions and limitations of ctDNA, ncRNA networks, EV-mediated signaling, redox biomarkers, and tumor–host crosstalk in prostate, bladder, renal, and testicular cancers. We also outline the analytical and clinical validation required to determine whether integrated CTF models provide incremental value over established single-analyte approaches. This framework may help reposition liquid biopsy from molecular detection toward functional precision oncology. Full article

Background: Cytochrome P450 2J2 (CYP2J2) has been implicated in tumor biology, but its expression pattern and clinical significance in prostate and renal cancers remain poorly characterized. Methods: Commercially available tissue microarrays containing 208 renal and 121 prostate tissue specimens were used for immunohistochemical (IHC) characterization of CYP2J2 protein expression. We performed transcriptomic analysis and examined correlations with clinicopathological features and survival using the OncoDB 2.0 platform. Results: CYP2J2 immunoreactivity was mainly cytoplasmic, with minimal protein expression in both cancers. We identified positive staining in 7/100 (7.0%) prostate adenocarcinomas and 2/192 (1.0%) clear cell renal cell carcinoma (ccRCC) specimens, with negative expression in corresponding normal tissues. We detected no significant associations between protein expression and clinicopathological features in either cohort (all p > 0.05). In contrast, transcriptomic analysis revealed elevated CYP2J2 mRNA expression in both malignancies, with a slight increase in prostate adenocarcinoma (log₂ fold change = 1.10) and marked overexpression in ccRCC (log₂ fold change = 5.24) compared with normal tissues. We observed significant associations between CYP2J2 mRNA expression and pathological T stage in prostate adenocarcinoma (p = 0.0019) and pathological M stage in ccRCC (p = 0.0079). Moreover, higher CYP2J2 mRNA expression was associated with longer overall survival in ccRCC (HR = 0.64, 95% CI: 0.47–0.86; log-rank p = 0.0029) but not in prostate adenocarcinoma; however, these findings remain exploratory and do not establish independent prognostic value. Conclusions: Despite elevated transcript expression, CYP2J2 protein expression was infrequent in prostate adenocarcinoma and ccRCC, suggesting limited clinicopathological relevance and warranting further investigation using functional techniques. Full article

Background/Objectives: Breast cancer exhibits substantial molecular heterogeneity, resulting in diverse therapeutic vulnerabilities and limiting the efficacy of single-agent therapies. Although multi-target strategies may offer improved therapeutic benefit, the systematic identification of synergistic higher-order target combinations remains challenging. This study aimed to identify and validate effective higher-order target combinations for heterogeneous breast cancer. Methods: DeepMDS, a previously developed deep learning-based multi-compound synergy prediction model, was used to prioritize candidate target combinations for breast cancer. Exhaustive two-target and three-target combinations were ranked in the gene-expression contexts of ER-positive luminal-like MCF-7 and triple-negative MDA-MB-231 breast cancer cells. The top-ranked target combinations were evaluated using single, pairwise, and triple small interfering RNA (siRNA) perturbations. Representative inhibitors were subsequently assessed in fixed-ratio combinations in MCF-7, MDA-MB-231, and 4T1 cells and in a 4T1 syngeneic mouse experiment. Results: BIRC5-NAMPT-TOP1 ranked first in both cell lines. Triple siRNA co-transfection targeting BIRC5, NAMPT, and TOP1 produced the strongest antiproliferative effects, with inhibition rates of 62.94% in MCF-7 cells and 55.62% in MDA-MB-231 cells. The corresponding inhibitors, LQZ-7I, FK866, and topotecan, exhibited synergistic antiproliferative activity at multiple molar ratios, with combination index values below 1. The optimized 2.5:10:1 molar ratio showed strong synergy in MCF-7, MDA-MB-231, and 4T1 cells, with combination index values of 0.26, 0.19, and 0.15, respectively. In tumor-bearing mice model, the triple-inhibitor regimen achieved a tumor inhibition rate of 62.05%. Topotecan-containing groups showed hematological alterations, whereas no statistically detectable elevations were observed in the measured terminal serum hepatic or renal biomarkers. Conclusions: The BIRC5-NAMPT-TOP1 combination showed reproducible phenotypic activity in the tested genetic and pharmacological models. These findings support the use of DeepMDS as a hypothesis-generation tool for higher-order target prioritization. Full article

Adjuvant and perioperative immune checkpoint inhibitors (ICIs) have created a growing population of patients who relapse after prior programmed death-1 or programmed death-ligand 1 blockade, yet these patients were underrepresented in many trials that established metastatic standards. We performed a structured narrative review of PubMed/MEDLINE, ClinicalTrials.gov, reference lists, and international oncology guideline repositories through 15 August 2026. Eligible reports addressed recurrence patterns or treatment after curative-intent ICI in melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple-negative breast cancer (TNBC); landmark metastatic studies were included only when direct evidence was unavailable and are labeled as extrapolation. Timing was standardized as on-treatment recurrence, early off-treatment recurrence (after the last ICI dose through 12 months), and late recurrence (>12 months). Shorter disease-free interval is consistently prognostic, but treatment-by-timing interactions are rarely available; timing should not be described as a validated pan-tumor predictive biomarker. Direct post-adjuvant evidence supports switching away from anti-PD-1 monotherapy for melanoma recurring on treatment, while selected late relapses may retain sensitivity. In RCC, retrospective post-adjuvant data support VEGF-targeted options, whereas CONTACT-03 and TiNivo-2 discourage routine ICI-TKI rechallenge specifically after prior ICI-treated metastatic RCC. Evidence in NSCLC, urothelial carcinoma, and TNBC is largely indirect. IMpassion132 was not an ICI-rechallenge trial, and only a small minority of ASCENT-04 participants had prior perioperative ICI. Treatment should integrate tumor-specific biology, actionable alterations, recurrence distribution, prior toxicity, comorbidity, access, and patient preference. Prospective trials dedicated to post-adjuvant ICI recurrence are needed. Full article

Background: Tumor hypoxia is a major determinant of radioresistance, limiting oxygen-mediated fixation of radiation-induced DNA damage and promoting metabolic adaptation, tumor aggressiveness, and treatment failure. Nitroimidazole derivatives and related hypoxia-targeting compounds have been investigated as radiosensitizers because of their oxygen-mimetic properties and selective activation under low-oxygen conditions. Methods: A structured narrative review was conducted to evaluate recent evidence on hypoxia-targeting strategies and nitroimidazole-based radiosensitizers combined with radiotherapy. PubMed and Scopus were searched in March 2026 using terms related to radiotherapy and nitroimidazoles. Studies published within the last five years were included if they investigated hypoxia-targeting compounds, radiosensitization strategies, or dose–response relationships relevant to radiotherapy. Preclinical, computational, and clinical studies were considered. Results: Sixteen studies were included, comprising preclinical, computational, and clinical investigations. Most studies were preclinical and evaluated in vitro cell lines, murine tumor models, or xenografts across multiple tumor types, including head and neck cancer, glioblastoma, breast cancer, colorectal cancer, cervical cancer, renal carcinoma, pancreatic cancer, and ovarian-related models. Nitroimidazole-based and related hypoxia-targeting strategies generally enhanced radiation response under hypoxic conditions, with sensitizer enhancement ratio values ranging from approximately 1.09 to 1.65. In vivo studies reported reductions in tumor growth or tumor volume when radiosensitizers were combined with radiotherapy. Clinical evidence, mainly in head and neck squamous cell carcinoma, showed variable effects on locoregional outcomes. Conclusions: Current evidence supports the biological relevance of hypoxia-targeting strategies for improving radiotherapy response. Nitroimidazole-based compounds show consistent radiosensitizing effects in preclinical models, but clinical translation remains heterogeneous. Future studies should integrate hypoxia imaging, standardized endpoints, advanced drug delivery systems, and clinically relevant radiotherapy models to better define their role in modern radiation oncology. Full article

Background: Sarcopenia, systemic inflammation, and malnutrition are established poor prognostic factors in renal cell carcinoma (RCC). This study investigated the utility of a novel preoperative score combining psoas muscle density (PMD)—an imaging-based indicator of muscle quality—and the albumin–bilirubin (ALBI) grade—a blood-based biomarker of liver reserve and systemic nutritional status—for predicting disease-free survival (DFS) and overall survival (OS) in patients undergoing curative surgery for RCC. Methods: This retrospective observational study included 274 patients with non-metastatic RCC treated with radical or partial nephrectomy. Preoperative computed tomography was utilized to measure PMD, defining “low PMD” as a value below the sex-specific median (males: 47.75 Hounsfield Units [HU]; females: 46.25 HU). “Worsened ALBI” was defined as an ALBI grade ≥ 2. Patients were stratified into three risk categories: Score 0 (both normal, n = 122), Score 1 (either abnormal, n = 114), and Score 2 (both abnormal, n = 38). Results: Kaplan–Meier analysis revealed a highly significant, stepwise decline in both DFS and OS as the risk score increased (log–rank p < 0.001 and p = 0.004, respectively). Multivariate Cox regression identified the combined risk score as a robust, independent prognostic factor for DFS (Score 1: HR 1.93, 95% CI 1.11–3.37, p = 0.020; Score 2: HR 3.58, 95% CI 1.82–7.02, p < 0.001). Furthermore, after adjusting for age and comorbidities, the score remained an independent predictor of poor OS (Score 1: HR 2.35, 95% CI 1.08–5.13, p = 0.032; Score 2: HR 3.01, 95% CI 1.16–7.82, p = 0.024). The combined model synergistically enhanced risk stratification accuracy compared to evaluating either factor independently. Conclusions: The concurrent presence of preoperative low PMD and a worsened ALBI grade is a powerful, independent predictor of poor prognosis in localized RCC. Derived solely from routine preoperative imaging and laboratory tests, this straightforward scoring system effectively captures the structural and immunometabolic dimensions of cancer cachexia and host vulnerability. This tool can significantly aid in personalizing postoperative surveillance strategies and identifying high-risk patients who may warrant closer postoperative surveillance or who might be considered as high-risk candidates for adjuvant therapy discussions. Full article

Background/Objectives: Drug resistance is a major challenge in cancer therapy, and mitochondria contribute to this process by controlling both metabolic adaptability and cell survival signaling. Mitophagy, the selective lysosomal removal of dysfunctional mitochondria, has been implicated in therapy resistance, yet its role in sunitinib-resistant renal cancer remains poorly defined. Methods: In this study, acquired sunitinib resistance was established in ACHN renal cancer cells through eight months of stepwise dose escalation. Initial selection conditions were determined using CCK-8 viability and crystal violet colony assays in parental ACHN cells, whereas sustained proliferation under continuous sunitinib exposure was used as the operational criterion for the resistant phenotype. Resistant and parental sensitive cells were treated with 25 µM and 50 µM succinic acid, alone or in combination with sunitinib. Gene expression of BNIP3, NIX, FUNDC1, LC3, PINK1, Parkin, PGAM5, SRC, LONP1, and ATP5F1A was measured by RT-qPCR, and BNIP3 and NIX protein levels were assessed by ELISA. Results: Resistant cells showed significant upregulation of receptor-mediated mitophagy components BNIP3, NIX and FUNDC1 (p < 0.05), with no significant change in LC3, alongside suppression of PINK1, Parkin, and mitochondrial homeostasis-associated genes LONP1, PGAM5, and ATP5F1A (p < 0.05). Succinic acid predominantly reduced BNIP3 and NIX protein levels in both cell lines and suppressed BNIP3, NIX, and LC3 mRNA expression in resistant cells. In contrast, the sunitinib + 50 µM succinic acid combination selectively increased PARKIN, PGAM5, LONP1, and ATP5F1A expression in resistant cells (2.49- to 5.98-fold; p < 0.005), a pattern not observed in parental cells. Conclusions: These findings indicate that sunitinib resistance in ACHN cells is associated with upregulated transcription of receptor-mediated mitophagy components and downregulated transcription of PINK1/Parkin pathway genes, and that exogenous succinic acid selectively upregulates PARKIN and other mitochondrial homeostasis-related gene expression in resistant, but not parental, cells. Full article

Background: Renal cell carcinomas (RCCs) represent neoplasms with variable biological behaviour, some of which remain difficult to classify within the current diagnostic framework. Clear cell papillary renal cell tumor (CCPRCT) is now recognised as an indolent entity, whereas RCC with fibromyomatous stroma (RCCFMS) remains a provisional subtype with partially overlapping morphological features. Methods: We analysed a multifocal RCC with clear cell morphology and prominent fibromyomatous stroma via whole-genome and RNA sequencing. The obtained molecular profile was compared with The Cancer Genome Atlas (TCGA) pan-cancer dataset, which includes 885 RCC cases, and histological re-evaluation of 10 identified similar cases was performed. Transcriptional data were mined for potential markers, which were validated in an independent cohort. Results: The 10 TCGA cases with similar transcriptomic features were characterised by diploid genomes, absence of recurrent chromosomal alterations, and lack of VHL mutations. Reduced VHL mRNA expression was observed, with increased methylation at selected CpG sites consistent with possible epigenetic down-regulation. Diagnostic variability was identified during histological re-evaluation of the 10 similar cases by three urological pathologists. Differential expression analysis highlighted cytokeratin 17 (CK17) and collagen 17A1 (COL17A1) as candidate markers. Immunohistochemical evaluation in a small (n = 6) independent CCPRCT cohort demonstrated expression of both markers, whereas tissue microarrays from 257 clear cell and 68 papillary RCC cases were found to be negative. Conclusions: These findings suggest that a subset of renal tumors with overlapping morphological features of CCPRCT and RCCFMS may share common molecular characteristics. CK17 and COL17A1 emerged as candidate markers for recognising these tumors, although their diagnostic sensitivity and specificity require validation across a broader spectrum of renal neoplasms. These observations are exploratory and hypothesis-generating, and further studies in large, well-characterised cohorts are required to clarify the biological and diagnostic significance of this subgroup. Full article

Background/Objectives: Accurate prognostic stratification after nephrectomy for clear cell renal carcinoma (ccRCC) remains challenging. Traditional models often lack the intuitive clinical application or the ability to handle non-linear interactions between variables. We aimed to develop and internally validate a decision tree-based model to predict cancer-specific survival in patients with ccRCC following nephrectomy. Methods: We analyzed 79,526 patients with ccRCC who underwent nephrectomy from the SEER database (2012–2018). Patients were randomized into development (2/3) and validation (1/3) cohorts. A conditional inference tree was constructed to predict cancer-specific survival. Multiple imputation by chained equations was used to handle missing data. Discriminatory ability was assessed using the C-index. Net clinical benefit was evaluated with decision curve analysis. The model was evaluated using CHARMS and PROBAST. Results: A decision tree with 15 risk groups is presented, further classified into high-, intermediate-, and low-risk categories according to observed median survival. The final predictors were tumor localization, tumor grade, TNM stage, age, and sarcomatoid differentiation. The model demonstrated excellent discriminatory performance, with a C-index of 0.846 (95% CI: 0.834–0.847). PROBAST assessment showed low risk of bias and low concern regarding applicability. Conclusions: The use of decision trees provides an interpretable alternative to conventional regression-based models. Three main risk categories and 15 subgroups are proposed based on tumor localization, tumor grade, TNM stage, age, and sarcomatoid differentiation. Our model demonstrates good applicability and a low risk of bias according to PROBAST guidelines; however, external validation in independent cohorts is required prior to clinical implementation. Full article

Background/Objectives: To compare perioperative, pathological, functional, and oncological outcomes of robot-assisted radical nephrectomy with inferior vena cava tumor thrombectomy (RARN-TT) versus open (ORN-TT) and laparoscopic (LRN-TT) approaches. Methods: PubMed, Scopus, and Web of Science were searched for studies of adults with renal cell carcinoma and Mayo/Neves level I–IV inferior vena cava tumor thrombus undergoing RARN-TT versus ORN-TT and/or LRN-TT. Risk ratios and mean differences with 95% confidence intervals were calculated using random effects models with restricted maximum-likelihood estimation. Results: Eight retrospective studies including 1781 patients were included: 221 underwent robotic surgery, 1411 open surgery, and 149 laparoscopic surgery. Compared with ORN-TT, RARN-TT was associated with lower estimated blood loss (mean difference −900.5 mL, 95% confidence interval −1234.0 to −566.9; p = 0.001), lower transfusion probability (risk ratio 0.395, 95% confidence interval 0.159–0.979; p = 0.046), and shorter hospital stay (mean difference −3.79 days, 95% confidence interval −4.83 to −2.76; p < 0.001). No significant differences were observed in operative time, intensive care unit stay, postoperative complications, perioperative mortality, pathological outcomes, or overall survival. Evidence for cancer-specific and progression-free survival was limited. Comparisons with LRN-TT were exploratory. Conclusions: RARN-TT may reduce blood loss, transfusion requirements, and hospital stay compared with ORN-TT, without evidence of worse perioperative, pathological, or survival outcomes. However, all studies were retrospective and affected by selection bias and heterogeneity. RARN-TT may be considered for selected patients at experienced centers, particularly for lower-level thrombi. Prospective multicenter studies stratified by thrombus level are needed. Full article

Sorafenib is widely used to treat metastatic renal cell carcinoma (RCC); however, the acquired drug resistance limits its efficacy and application in clinical practice. The receptor tyrosine kinases c-Met and AXL play important roles in cancer progression and are involved in tyrosine kinase inhibitor-induced drug resistance in cancers, but whether these two receptors also contribute to sorafenib-induced drug resistance in RCC is unclear. In this study, we evaluated our synthesized compound 1D228, a TKI derived from Tepotinib, in sorafenib-resistant RCC models, which demonstrated further inhibition in sorafenib-resistant RCC cells, and induced 25% more reduction in resistant RCC tumor size by 1D228 combined with sorafenib compared with sorafenib monotherapy in animal models. Mechanistically, resistant RCC exhibited elevated phosphorylation of c-Met and AXL, which was effectively suppressed by 1D228. These findings indicated that compound 1D228 sensitized the sorafenib resistance of RCC by dual targeting the c-Met and AXL signaling pathways. This study suggests that 1D228 may represent a promising preclinical therapeutic strategy for RCC patients with sorafenib resistance mediated by c-Met and AXL activation. Full article

Background: Robot-assisted partial nephrectomy (RAPN) has become the preferred surgical approach for localized renal tumours, yet the optimal surgical technique remains uncertain. Ongoing refinements aim to reduce morbidity while maximizing renal function preservation. In this study, we compared perioperative outcomes, postoperative complications, and early renal function between the no-touch adaptive RAPN technique, designed to minimize vascular and parenchymal trauma, and the conventional approach. Methods: We retrospectively analyzed 387 consecutive patients undergoing RAPN for localized renal tumours between June 2017 and February 2026 at a single tertiary referral centre. Patients were treated with either the no-touch adaptive (n = 178) or conventional (n = 209) technique. The no-touch approach consisted of sutureless off-clamp simple tumour enucleation with incremental haemostasis and on-demand conversion to arterial clamping, tumour enucleoresection, or renorrhaphy when required. The conventional technique consisted of an on-clamp minimal enucleoresection with double-layer renorrhaphy. Completion rate of a fully no-touch procedure was assessed in the study group, and perioperative outcomes, 90-day complications, and renal function at 3 months were compared between the groups. Exploratory multivariable logistic regression identified predictors of postoperative complications. Absolute and relative changes in estimated glomerular filtration rate (eGFR) from baseline were analyzed, and a linear regression model adjusted for baseline eGFR was used to compare postoperative renal function between the groups. Results: Among the 175 evaluable patients after excluding three immediate conversions to radical nephrectomy before tumour excision, a fully no-touch procedure was completed in 153 (87.4%). Compared with conventional RAPN, the no-touch group had a significantly shorter hospital stay (3 vs. 5 days, p < 0.01), lower 90-day readmission rate (0% vs. 4.3%, p = 0.01), fewer overall complications (16.3% vs. 40.7%, p < 0.01), and fewer major complications (3.9% vs. 11%, p = 0.02), with no cases of delayed vascular bleeding. Low tumour complexity and the no-touch technique independently predicted a lower risk of postoperative complications. The median decline in eGFR from baseline to 3 months was significantly smaller in the no-touch group, which also showed a lower rate of clinically meaningful renal function deterioration (eGFR decline ≥ 30%; 1.1% vs. 5.7%, p = 0.03). After adjustment for baseline eGFR, the no-touch adaptive technique was associated with a 5.4 mL/min/1.73 m² higher 3-month eGFR than the conventional technique (95% CI 3.6–7.2; p < 0.001). Conclusions: Within the limitations of this retrospective comparative study, the no-touch adaptive technique for RAPN was associated with lower perioperative morbidity and better preservation of early renal function than the conventional approach. These findings support further prospective multicentre studies to determine the reproducibility, durability, and clinical relevance of this surgical strategy. Full article

Background: Balkan nephropathy (BEN), caused by chronic dietary exposure to aristolochic acid (AA), is a tubulointerstitial kidney disease strongly associated with upper-tract urothelial carcinoma (UTUC). Patient and graft survival, the cumulative incidence and timing of post-transplant UTUC, and the burden of non-urothelial malignancy after kidney transplantation remain poorly defined. Methods: We retrospectively analyzed all patients with BEN as the primary cause of end-stage kidney disease transplanted at University Hospital Center Zagreb between October 1973 and December 2023. Outcomes included patient and graft survival, the incidence and timing of post-transplant UTUC, and burden of non-urothelial malignancies. Results: Of 2282 kidney transplants performed in the study period, 44 (2%) were in patients with BEN. The median age at transplantation was 56 years, and the median dialysis vintage was 3.7 years. After 10 years (median) of follow up, among 34 patients with adequate follow-up, 16 (47%) developed a de novo malignancy: eight (24%) UTUC, one renal cell carcinoma, four other solid tumors, and three hematological. UTUC was diagnosed between 6 months and 15 years post-transplant (median 7 years); five of eight patients died within one year of diagnosis. Five- and ten-year patient survival rates were 82% and 54.5%. Conclusions: Kidney transplantation in patients with BEN carries a lifelong cancer risk dominated by UTUC. Prophylactic bilateral nephroureterectomy should be the default management strategy when feasible, with lifelong surveillance extending beyond the urothelium. Full article

Research Background: Breast cancer is a malignant tumor that threatens women’s health. Among breast cancer patients, about 4.2% to 17% may suffer from multiple primary malignant neoplasms. Cases of patients suffering from both breast cancer and multiple myeloma are relatively rare in clinical practice. This paper reports one case of a patient who developed multiple myeloma during the treatment of breast cancer. Clinical Data: The patient was a 56-year-old female, admitted to hospital due to “fever for 4 days, one year after the treatment of left breast cancer”. The patient was diagnosed with left breast cancer (ypT1N1M0, HER2-overexpressing subtype) approximately one year prior to presentation. Following diagnosis, the patient was treated sequentially with TcbHP and THP chemotherapy regimens, and subsequently received local radiotherapy. The patient developed fever four days prior to admission. Further laboratory examinations revealed pancytopenia, positive IgA-λ-type monoclonal immunoglobulin by immunofixation electrophoresis, and myeloma cells accounting for 11% in bone marrow smears. Bone marrow immunophenotyping indicated abnormal plasma cells, and pathological results of bone marrow biopsy were consistent with multiple myeloma. The final diagnosis was breast cancer complicated with multiple myeloma. After confirmed diagnosis, the patient was transferred to another hospital for targeted treatment of multiple myeloma and has been receiving continuous treatment there up to the time of follow-up. Conclusions: For patients with breast cancer, if they develop bone pain, anemia, hypercalcemia or renal dysfunction that cannot be explained by tumor metastasis or conventional complications after surgery or during follow-up, clinicians should be alert to the possibility of second primary tumors. Full article

Background/Objectives: Evaluation of renal tumour masses relies on conventional imaging, which cannot reliably characterise the histopathological type, and no validated blood-based diagnostic marker is available for renal cell carcinoma. The cfDNA integrity index, the ratio of long to short circulating cell-free DNA (cfDNA) fragments, may reflect the necrotic origin of tumour-derived DNA and is a candidate qualitative marker of malignancy. This exploratory, single-centre case–control study assessed the preoperative plasma cfDNA integrity index in patients with clear cell renal cell carcinoma (ccRCC). Methods: Plasma concentrations of 90 bp and 222 bp cfDNA fragments were measured by quantitative real-time PCR (qPCR) in 46 patients with histopathologically confirmed ccRCC (before surgery) and 17 healthy volunteers; the two groups were a convenience sample, were not matched, and differed in age and body-mass index. The cfDNA integrity index was defined as the ratio of the 222 bp to the 90 bp fragment concentration. Results: The cfDNA integrity index was higher in patients with ccRCC than in controls (median 0.28 vs. 0.15; p < 0.001, Mann–Whitney test) and rose progressively across healthy, non-metastatic (M0) and metastatic (M1) groups (p < 0.001, Kruskal–Wallis test; M0 vs. M1 p = 0.004). In unadjusted ROC analysis, both the integrity index (AUC 0.83, 95% CI 0.72–0.94) and its long 222 bp fragment component (AUC 0.93) discriminated patients with ccRCC from healthy volunteers, and the index separated metastatic from non-metastatic disease with an AUC of 0.79 (95% CI 0.64–0.88). The index was higher in high-grade (Fuhrman G3 + G4) tumours (p = 0.04) and in tumours with lymphovascular invasion (p < 0.001), and correlated with primary-tumour diameter. Conclusions: In this exploratory cohort, the preoperative plasma cfDNA integrity index was higher in patients with ccRCC than in healthy volunteers and was associated with several adverse pathological features; these findings require confirmation in larger, matched studies that include benign renal masses before any diagnostic role can be claimed. Full article