Search Results (4,928)

Although the parental recombinant protein rLj-RGD3 exhibits antitumor activity, it carries immunogenicity risks owing to its large molecular size (13.5 kDa). We generated a genetically truncated mutant, rLj-RGD4 (6.27 kDa, four RGD motifs), which inhibited B16 melanoma cell proliferation, migration, and invasion in vitro. However, the in vivo efficacy and mechanisms of action remain unclear. Here, B16 xenograft mice were treated with rLj-RGD4 (5, 10, and 20 μg/kg i.p. daily for 14 days). Tumor growth was measured, and histopathology/apoptosis was evaluated using hematoxylin and eosin (HE), Masson’s dye, Hoechst, and TUNEL staining. Apoptotic pathways (mitochondrial, death receptor, and MAPK) were analyzed via Western blotting, whereas endocytosis mechanisms were explored using inhibitors (filipin III, NaN₃, cytochalasin D), and EGFR (epidermal growth factor receptor) interactions via fluorescence co-localization and phosphoprotein assays. The results demonstrated dose-dependent tumor growth inhibition (21.60–89.26% volume reduction, 41.03–86.51% weight reduction), with histological evidence of tissue loosening, fibrosis, and apoptosis. rLj-RGD4 induced apoptosis by activating the mitochondrial (Bax/Bcl-2 upregulation), death receptor (caspase-8 activation), and MAPK (JNK/p38 phosphorylation) pathways. Internalization was blocked by NaN₃ and cytochalasin D, indicating actin-dependent macropinocytosis. Direct EGFR binding was confirmed, accompanied by reduced EGFR expression and the inhibition of FAK/AKT/Src signaling. In conclusion, rLj-RGD4 exerts potent in vivo antitumor activity via two mechanisms: induction of multi-pathway apoptosis and EGFR-targeted suppression of pro-survival signaling. RGD4 exerts its antitumor function in vivo by targeting and co-internalizing with EGFR. Full article

Background: Cardiovascular risk in chronic kidney disease (CKD) remains high despite frequently normal conventional lipid parameters. The extent to which lipid patterns vary across CKD severity and metabolic complications remains incompletely characterized. Therefore, this study evaluated lipid patterns and their associations with renal function and CKD-related metabolic complications. Methods: This retrospective cross-sectional study included 229 CKD patients from the nephrology clinic at King Saud Medical City. Single-time-point laboratory data and clinical variables were extracted from medical records. Patients were stratified by KDIGO eGFR stage, uremia, and phosphate status. Lipid parameters were analyzed using nonparametric tests, multivariable regression, and ROC analysis. Results: Among 229 CKD patients, the most prevalent lipid abnormalities were low HDL-C (49.8%) and elevated remnant cholesterol (RC) (31.4%). HDL-C was reduced and RC increased with declining eGFR, while TC, LDL-C, and TG remained unchanged. In uremia, HDL-C remained reduced and RC increased, with additional reductions in TC and LDL-C, whereas TG did not differ. No significant lipid changes were observed with hyperphosphatemia. In multivariable analyses, HDL-C was positively associated with eGFR (β = 48.8, q = 0.003) and inversely associated with BUN (β = −14.3, q = 0.0014), while RC showed an inverse association with eGFR (β = −19.9, q = 0.0005) and a positive association with BUN (β = 3.37, q = 0.0315). These relationships remained independent of age, sex, BMI, smoking status, hypertension, and type 2 diabetes. ROC analysis further demonstrated the moderate discriminatory ability of HDL-C and RC for identifying CKD stages and uremia. Conclusions: Alterations in HDL-C and RC were independently associated with renal function and uremic status. These findings suggest that lipoprotein composition may reflect metabolic disturbances accompanying CKD progression. Full article

Background: Cardiovascular disease remains a leading cause of morbidity and mortality after kidney transplantation. The relative contribution of metabolic abnormalities and inflammatory burden to cardiac remodeling and subsequent clinical outcomes in kidney transplant recipients (KTRs) remains incompletely understood. Methods: In this retrospective cohort study, 152 KTRs underwent comprehensive cardiovascular evaluation at a stable post-transplant time point (12 ± 4 months after transplantation). Metabolic phenotype was assessed using metabolic syndrome and indices of insulin resistance and atherogenic dyslipidemia (TyG index, TG/HDL ratio, and atherogenic index of plasma [AIP]). Inflammatory status was evaluated using hs-CRP and complete blood count-derived indices. Echocardiographic damage composite (EDC) was defined as the presence of left ventricular hypertrophy, diastolic dysfunction, or left atrial enlargement. Patients were followed for major adverse clinical outcome (MACO), defined as cardiovascular event, graft failure, or death, and major adverse cardiovascular and cerebrovascular events (MACCE). Results: At baseline, 78 patients (51.3%) met criteria for EDC. EDC was strongly associated with higher TyG, AIP, TG/HDL, LDL/HDL ratio, and metabolic syndrome, whereas inflammatory markers showed no association. In multivariable logistic regression adjusted for age, sex, eGFR, and proteinuria, TyG remained independently associated with EDC (OR 1.13 per 0.1 increase, 95% CI 1.05–1.21; p = 0.001), independent of hs-CRP. Similar results were observed when AIP was evaluated in place of TyG (OR 10.39, 95% CI 2.22–48.71; p = 0.003). During follow-up, 78 patients developed MACO and 49 developed MACCE. In Cox regression analysis, graft dysfunction and inflammatory markers independently predicted MACO, whereas TyG was no longer significant. In contrast, TyG remained an independent predictor of MACCE after adjustment for confounders and inflammatory markers (HR 1.10 per 0.1 increase, 95% CI 1.04–1.16; p < 0.001). Similar results were observed when AIP was tested in place of TyG (HR 10.8, 95% CI 3.06–38.11; p < 0.001). Echocardiographic damage did not independently predict outcomes after adjustment. Conclusions: In KTRs, metabolic abnormalities reflecting insulin resistance and atherogenic dyslipidemia are closely associated with cardiac remodeling one year after transplantation and remain specifically linked to subsequent cardiovascular events. In contrast, systemic inflammation and graft dysfunction are the primary determinants of overall adverse clinical outcomes. Simple metabolic indices such as TyG and AIP may provide practical tools for cardiovascular risk stratification in this population. In Cox proportional hazards models, TyG (HR 1.102, 95% CI 1.043–1.164, p = 0.001) and AIP (HR 10.8, 95% CI 3.06–38.11, p < 0.001) were independently associated with cardiovascular events during follow-up, underscoring the role of atherogenic dyslipidemia in cardiovascular risk. Full article

Background: Renal dysfunction is common in patients hospitalized with acute decompensated heart failure (ADHF) and represents a key component of cardiorenal syndrome. However, the relationships between renal impairment, cardiorenal biomarkers, and echocardiographic markers of myocardial function remain incompletely characterized in ADHF populations. Methods: We conducted a cross-sectional analysis of 144 consecutive patients hospitalized with ADHF. Renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m². Clinical, laboratory, and echocardiographic parameters were compared according to renal function. Correlation analyses, multivariable logistic regression, and receiver operating characteristic (ROC) curve analyses were performed to evaluate associations between renal dysfunction, cardiorenal biomarkers, and myocardial functional indices. Results: Patients with renal dysfunction were older (p = 0.002) and more frequently had diabetes mellitus (p = 0.006). Echocardiographic evaluation demonstrated significantly lower systolic mitral annular velocity (S′) (p < 0.001) and higher E/e′ ratios (p < 0.001) in patients with renal dysfunction, whereas left ventricular ejection fraction (p = 0.133) and global longitudinal strain (GLS) (p = 0.121) were similar between groups. Log-transformed NT-proBNP and albuminuria were significantly correlated with S′, GLS, and E/e′ (all p < 0.001). In multivariable analysis adjusted for clinically relevant confounders, chronic kidney disease (OR 8.16, 95% CI 2.13–31.34; p = 0.002) and the E/e′ ratio (OR 2.01, 95% CI 1.52–2.66; p < 0.001) remained independently associated with renal dysfunction. ROC analysis showed that E/e′ had the strongest ability to distinguish between patients with and without renal dysfunction (AUC 0.887, 95% CI 0.834–0.941; p < 0.001). Conclusions: Renal dysfunction in ADHF is associated with echocardiographic markers reflecting impaired longitudinal myocardial function and elevated filling pressure, with E/e′ emerging as the strongest echocardiographic correlate. The integration of echocardiographic parameters with cardiorenal biomarkers may improve the characterization of the cardiorenal profile in patients hospitalized with ADHF. Full article

Pyrazole derivatives have emerged as an important class of heterocyclic compounds in anticancer research due to their structural versatility and broad spectrum of biological activities. This review provides a concise overview of recent advances in the development of pyrazole-based anticancer agents, with emphasis on synthetic strategies, structure–activity relationships, and molecular mechanisms of action. Common synthetic approaches, particularly condensation and cyclization reactions, have enabled the preparation of structurally diverse pyrazole derivatives for biological evaluation. Available evidence indicates that the type and position of substituents within the pyrazole scaffold markedly influence anticancer potency, selectivity, and target affinity. Reported compounds act through multiple mechanisms, including inhibition of cancer-related targets such as tubulin, epidermal growth factor receptor (EGFR), cyclin-dependent kinases (CDKs), Bruton tyrosine kinase (BTK), and deoxyribonucleic acid (DNA)-associated pathways, as well as induction of apoptosis and disruption of cell-cycle progression. Several pyrazole derivatives have shown promising activity in in vitro and in vivo models. Overall, the findings summarized in this review identify the pyrazole scaffold as a valuable platform for the design and optimization of novel anticancer agents and support its continued exploration in medicinal chemistry. Full article

Background: Patients with type 2 diabetes mellitus (T2DM) undergoing cardiac surgery represent a high-risk population characterized by substantial cardiometabolic stress and increased susceptibility to postoperative heart failure, renal dysfunction, and unplanned rehospitalization. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors provide established cardiorenal protection in ambulatory populations, their perioperative impact in cardiac surgery cohorts remains insufficiently defined. Methods: In a single-center retrospective cohort of 620 T2DM patients, inverse probability of treatment weighting and time-dependent Cox regression were applied to account for perioperative treatment interruption and delayed postoperative reinitiation when evaluating the association between chronic SGLT2 inhibitor therapy and 12-month rehospitalization risk. To provide biological context for the observed clinical associations, target-driven systems pharmacology, molecular docking against SGLT2, NHE1, AMPK, and NLRP3, and protein–protein interaction (PPI) network analysis were performed. Hub proteins were identified using Maximal Clique Centrality, followed by functional enrichment (GO/KEGG) analysis. Results: Chronic SGLT2 inhibitor therapy was associated with reduced first rehospitalization (HR 0.64; 95% CI 0.48–0.85; p = 0.002) and a lower cumulative rehospitalization burden (IRR 0.61; 95% CI 0.46–0.82; p = 0.001), primarily driven by heart failure-related and metabolic phenotypes. Molecular docking analyses identified favorable binding with SGLT2 and additional cardiometabolic and inflammatory targets, including NHE1, AMPK, NLRP3, IKKβ, IL-6Rα, and PPAR isoforms, suggesting modulation of myocardial ion homeostasis, metabolic resilience, and inflammatory signaling. PPI analysis identified eight hub proteins (AKT1, MTOR, STAT3, EGFR, PIK3CA, SRC, MAPK1, and MAPK3) significantly enriched in PI3K/AKT, MAPK/ERK, and ErbB signaling pathways. Conclusions: Chronic SGLT2 inhibitor therapy was independently associated with reduced postoperative rehospitalization and cumulative event burden in T2DM patients undergoing cardiac surgery. Integrated in silico analyses offer mechanistic hypotheses consistent with the observed clinical associations. These findings suggest that structured perioperative SGLT2 inhibitor management may contribute to improved postoperative outcomes, while prospective validation in future studies would strengthen these findings. However, given the retrospective observational design, these findings should be interpreted as associative rather than causal. Full article

Background and Objectives: Serum carcinoembryonic antigen (CEA) is a widely used biomarker in non-small cell lung cancer (NSCLC). However, its association with oncogenic driver alterations and prognostic significance across molecular subtypes in metastatic disease remains insufficiently defined. Materials and Methods: This retrospective multicenter study included 332 patients with metastatic NSCLC harboring oncogenic alterations (EGFR, ALK, ROS1, KRAS, and others) from eight oncology centers in Türkiye. Baseline serum CEA levels measured at metastatic diagnosis were analyzed on the natural logarithmic scale. Associations between CEA levels, molecular subtypes, clinical features, and overall survival (OS) were evaluated using generalized linear models and Cox proportional hazards regression. Results: Baseline CEA levels differed significantly across molecular subtypes (p = 0.001), with EGFR-mutant tumors showing the highest median levels. Multivariable analysis identified driver alteration, histology, and metastatic burden as independent determinants of baseline CEA. Higher baseline CEA and metastatic site count were independently associated with increased mortality risk (HR 1.151 and 1.279 per unit increase, respectively; p < 0.001), while female sex was protective (HR 0.626; p = 0.004). KRAS mutations were associated with poorer survival compared with EGFR (HR 2.370; p < 0.001). Kaplan–Meier analyses showed a consistent trend toward longer OS in patients with CEA < 5 ng/mL, with significance only in the rare alteration subgroup. Conclusions: Baseline CEA may reflect underlying tumor biology across molecular subtypes and are associated with survival outcomes in metastatic NSCLC. However, given the variability across subgroups and modest effect sizes, these findings should be interpreted with caution. Prospective studies evaluating longitudinal CEA dynamics are warranted. Full article

Background: Obesity, type 2 diabetes mellitus, and hypertension are increasingly prevalent components of metabolic syndrome and major contributors to cardiovascular disease and chronic kidney disease progression; however, in end-stage kidney disease an “obesity paradox” has been described, with higher body mass index (BMI) sometimes associated with improved survival on hemodialysis. Material and methods: This retrospective, single-center Eastern European cohort study aimed to characterize mortality and its causes around hemodialysis initiation in the contemporary era of cardiometabolic prevention and to test whether the obesity paradox persists at this high-risk transition. Adult patients initiating dialysis at the “Pius Brânzeu” Emergency Clinical Hospital (Timișoara, Romania) between January 2022 and December 2025 (n = 268; median age 66 years; 61% male; median eGFR 6.4 mL/min/1.73 m²) were analyzed using Kaplan–Meier methods and Cox regression, with comprehensive baseline clinical, laboratory, echocardiographic, medication, infection, and vascular access data; follow-up was obtained at 3, 6, 12, 24, and 36 months. Results: Late referral was common (61% < 3 months of nephrology follow-up), dialysis initiation was predominantly urgent (only 16% scheduled), and central venous catheters were the main access (81%), with substantial comorbidity burden (cardiovascular disease 71%, hypertension 90%) and frequent infections at initiation. BMI categories were non-obese (<25 kg/m², 30%), overweight (25–29.9 kg/m², 48%), and obese (≥30 kg/m², 22%); diabetes prevalence rose with BMI (32% to 58%). Unadjusted mortality did not differ by BMI (19.8%, 18.8%, 15.3%; log-rank p = 0.622), yet multivariable Cox models showed overweight status independently reduced mortality (HR 0.22 at 3 months, 0.29 at 1 year, 0.31 at 3 years vs. non-obese), whereas obesity was not protective. Early mortality was driven mainly by age ≥ 65 years, while diabetes and chronic obstructive pulmonary disease predicted later mortality; longer pre-dialysis follow-up time was strongly protective (HR per year 0.70 at 3 years), and higher intact parathyroid hormone showed an inverse association with 1-year mortality. Conclusions: These findings show a modified obesity paradox at dialysis initiation in which moderate excess weight, but not obesity, is associated with improved adjusted survival, underscoring the clinical importance of earlier nephrology engagement and individualized nutritional and risk-factor management during the pre-dialysis and early dialysis periods. Full article

Background: Cardiovascular disease (CVD) represents the second leading cause of death among kidney transplant recipients (KTRs). CVD risks post-transplantation increase with aging, obesity, dyslipidemia, diabetes, hypertension, inactivity, sleep disturbances, immunosuppressant medications use, and graft dysfunction. This study assessed CVD prevalence and risk factors among KTRs. Methods: A cross-sectional study was conducted at National Guard Hospital, Jeddah between 2012–2022. Information was collected from the patients’ medical records. Physical activity, sleep, and adherence to immunosuppressant therapy were evaluated via interviews with adult KTRs using the International Physical Activity Scale, Jenkins Sleep Scale, and Immunosuppressant Therapy Barrier Adherence Scale, respectively. Results: Sixty-four KTRs were included: 67% were males, and the median age was 44.7 years. Eighteen patients (28.1%) had CVD, and 61.1% of them developed ischemic heart disease. KTRs with CVD were older, had lower estimated glomerular filtration rate (eGFR), and higher Hemoglobin A1c (HbA1c), but these differences were not statistically significant (p > 0.05). Patients with CVD had significantly lower LDL (p = 0.02) and more aspirin and statin use (p < 0.05). Forty-five patients (70.3%) completed the interview; most of them had few sleep disturbances and good adherence to immunosuppressant therapy. Low physical activity was reported by KTRs with CVD. Conclusions: CVD was present in over one-quarter of KTRs. Patients with CVD were older, less active, had lower GFR, higher HbA1c, and significantly lower LDL. More use of aspirin and statin improved the glycemic control, physical activity, and medication adherence, and may help in reducing CVD burden among KTRs. Full article

Diagnosis and monitoring of type 2 diabetes mellitus (T2DM) typically rely on invasive blood-based biomarkers. To explore non-invasive alternatives, this study examined tongue coating metabolites to identify metabolic signatures linked to diabetes progression. A case-control observational study categorized participants into control, prediabetes, and diabetes groups. Tongue coating samples were analyzed using liquid chromatography-mass spectrometry (LC-MS). Differential metabolites were correlated with clinical parameters, including HbA1c, BMI, and eGFR. Distinct metabolic profiles emerged across groups, with significant differences in five endogenous metabolites (phenylpyruvic acid, propionylcarnitine, pyridoxal 5′-phosphate, phenethylamine, phenethylamine glucuronide) and four amino acids (isoleucine, lysine, phenylalanine, tyrosine). Diabetic subjects showed elevated phenylpyruvic acid and phenethylamine, while propionylcarnitine, pyridoxal 5′-phosphate, and phenethylamine glucuronide were reduced. Phenethylamine was positively correlated with HbA1c; propionylcarnitine and phenethylamine glucuronide showed negative correlations with HbA1c and BMI. Detected total amino acids were inversely correlated with eGFR. Additionally, a diabetes index derived from these metabolic features also holds potential for discriminating disease states. These findings underscore the potential of tongue coating metabolites as a relatively non-invasive approach for evaluating T2DM states. The observed metabolic alterations provide valuable insights into diabetes-associated dysregulation, including protein glycation, obesity-related metabolic shifts, and renal impairment. Full article

Background: Multimorbidity frequently involves overlapping neuro-psychic, cardiometabolic, and renal disturbances, yet clinical assessment often relies on diagnosis-based comorbidity counts that may not fully capture cumulative physiological stress. We developed the Neuro–Cardio–Renal Stress Index (NCR-SI) as a pragmatic composite framework to describe multisystem burden using routinely available clinical data. Methods: This cross-sectional study analyzed electronic medical record data from adult patients with chronic conditions. NCR-SI integrates three domains: neuro-psychic burden (text-derived indicators and psychotropic medication use), cardiometabolic stress (triglyceride–glucose index and cardiometabolic diagnoses), and renal function (MDRD-estimated eGFR staging). Importantly, this study is not intended to demonstrate incremental predictive value over individual components or established comorbidity indices. Rather, it presents NCR-SI as a transparent, domain-based descriptive framework and reports its internal coherence and distribution across clinically recognizable multimorbidity contexts. Results: A total of 148 patient records were screened; 143 patients met complete-case criteria and were included in the main NCR-SI analyses. NCR-SI ranged from 0 to 10 (median 5). Higher scores were observed in renometabolic profiles. NCR-SI showed expected structural associations with declining renal function (eGFR; ρ ≈ −0.71), moderately with the TyG index (ρ ≈ 0.42), and weakly with medication burden. Correlation with age-adjusted CCI was minimal (ρ ≈ 0.09), indicating limited overlap with diagnosis-based comorbidity counts. Domain-specific correlations were consistent with predefined score construction rules, particularly between the renal domain and eGFR, and between the cardiometabolic domain and TyG. Conclusions: NCR-SI provides a pragmatic, integrative descriptor of neuro-cardio-renal stress using routinely collected clinical data. Rather than replacing established comorbidity indices, NCR-SI may complement them by summarizing multidimensional physiological burden patterns. NCR-SI is proposed as a research-oriented, hypothesis-generating descriptive framework. External validation in independent cohorts and longitudinal evaluation against clinically meaningful outcomes (e.g., hospitalization, mortality, functional status, healthcare utilization) are required before any claims of clinical performance can be made. Full article

Background: Diabetic nephropathy (DN), also referred to as diabetic kidney disease, represents one of the most common microvascular complications of type 2 diabetes mellitus (T2DM) and remains a leading cause of end-stage renal disease worldwide. Conventional clinical markers, including albuminuria and estimated glomerular filtration rate (eGFR), are widely used for diagnosis and staging but may have limited sensitivity for detecting early renal injury and predicting disease progression. In recent years, circulating microRNAs (miRNAs) have emerged as promising non-invasive biomarkers that reflect underlying molecular mechanisms of diabetic nephropathy and may complement traditional clinical indicators. Objective: The present study aimed to evaluate serum and urinary levels of hsa-miRNA-770-5p across different stages of diabetic nephropathy and to assess its potential diagnostic value in relation to established indicators of renal function. Methods: A total of 257 participants were included and divided into four groups: healthy controls, patients with T2DM without nephropathy, patients with T2DM and DN in CKD stages I–II, and patients with DN undergoing maintenance hemodialysis (MHD). Serum and urinary levels of miRNA-770-5p were measured using quantitative real-time polymerase chain reaction (qPCR) and analyzed using the 2^−ΔΔCt method. Statistical analyses included comparisons between groups using ANOVA, correlation analyses with renal function parameters such as eGFR and proteinuria/albuminuria, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic performance. Results: Serum levels of miRNA-770-5p were significantly elevated in patients with DN and in patients undergoing maintenance hemodialysis compared with healthy controls and patients with T2DM without nephropathy. In contrast, urinary levels of miRNA-770-5p were markedly reduced in patients with DN. Serum levels in patients with T2DM without nephropathy were slightly lower than those observed in healthy controls. Significant correlations were identified between miRNA-770-5p levels and renal function parameters, including eGFR and proteinuria/albuminuria, supporting the biological relevance of this microRNA in renal injury. ROC curve analysis demonstrated good discriminatory ability for differentiating DN from T2DM without nephropathy (serum AUC = 0.82; urine AUC = 0.79). Conclusions: hsa-miRNA-770-5p demonstrates distinct and opposite patterns in serum and urine that correlate with the severity of diabetic nephropathy. The complementary changes observed in circulating and urinary levels support the potential of miRNA-770-5p as a non-invasive biomarker that may complement conventional clinical markers and provide additional insight into the molecular mechanisms involved in the development and progression of diabetic nephropathy. Full article

A new series of eight novel etodolac-based 1,3,4-oxadiazoles was synthesized, characterized, and tested in silico in multidimensional routes, starting with etodolac, a well-known nonsteroidal anti-inflammatory medication (NSAID). In silico studies were performed prior to synthesis using the molecular docking technique in CCDC GOLD suite software (2025.3) to assess the interactions with two key targets involved in cancer pathogenesis: the crystal structure of the epidermal growth factor receptor EGFR tyrosine kinase domain (PDB ID: 4HJO) and the matrix metalloproteinase (MMP-9) complex (PDB ID: 5CUH). ADME studies were performed to assess the physicochemical properties of the synthesized molecules. Importantly, biotransformation prediction also indicated that the derivatives possess high metabolic stability, with hydroxylation of the thio-ether group as the primary predicted biotransformation route. All compounds were characterized using melting point, FT-IR, ¹H-NMR, and ¹³C-NMR spectroscopy. In vitro and/or in vivo experiments are needed to confirm this preliminary anticancer study. Full article

Objectives: The impact of renal ischemia during partial nephrectomy (PN) on postoperative renal function remains controversial. On-clamp PN provides improved surgical exposure and haemostasis but induces warm ischemia, which may impair renal function. Off-clamp PN avoids ischemia-related injury and may better preserve renal function, although concerns persist regarding blood loss and oncological safety. We systematically compared perioperative and functional outcomes, as well as surgical margin status between on-clamp and off-clamp PN. Methods: We performed a systematic search of PubMed, Embase, Cochrane, Web of Science, and Scopus to identify randomized controlled trials (RCTs) and observational studies comparing on-clamp versus off-clamp PN with no publication time limitations. Outcomes included estimated glomerular filtration rate (eGFR), percentage eGFR change, estimated blood loss (EBL), transfusion rates, positive surgical margins (PSMs), operative time, and complications. Results: Thirty-nine studies (four RCTs) including 10,154 patients were analysed. Off-clamp PN was associated with a smaller decline in eGFR (mean difference [MD] −4 mL/min/1.73 m², 95% CI −5.7 to −2.8) and lower percentage eGFR loss (MD −1.7%, 95% CI −2.8 to −0.7). On-clamp PN was associated with lower EBL (MD −48 mL, 95% CI −72 to −25). Transfusion rates favored on-clamp PN but were not statistically significant (OR 0.7, 95% CI 0.5–1.0). On-clamp PN was associated with a higher risk of PSM (OR 1.3, 95% CI 1.0–1.7) and postoperative complications (OR 1.3, 95% CI 1.1–1.6). Between-study heterogeneity and predominance of observational data were key limitations. Conclusions: Off-clamp PN provides superior renal functional preservation and lower risks of PSMs and complications, at the cost of increased blood loss. These findings support individualized surgical decision-making based on patient and tumor characteristics. What does the study add?: This study provides an extensive and detailed comparison of off-clamp versus on-clamp partial nephrectomy, encompassing more than 10,000 patients from 39 studies. By integrating the available evidence up to late 2024, it delivers comprehensive estimates of the renal functional benefits associated with ischemia-free surgery. Our findings delineate the trade-offs between renal preservation, blood loss, and surgical margin status, thereby informing individualised decision-making in nephron-sparing surgery and refining current understanding of when ischemia avoidance is most clinically advantageous. Patient summary: Our study suggests that performing partial nephrectomy without temporarily clamping the kidney blood vessels may better preserve kidney function and reduce cancer-related surgical risks, but can lead to increased blood loss during surgery. These findings indicate that the choice of surgical technique should be individualised, taking into account tumour features and patient-specific factors. Full article

The emergence of novel cytotoxic agents, multikinase inhibitors, and various antibody-based therapies has significantly expanded salvage therapy options for metastatic colorectal cancer (mCRC). Consequently, establishing the optimal treatment sequence for patients has become a formidable clinical challenge. Emerging evidence highlights the value of comprehensive biomarker assessment, particularly longitudinal monitoring of circulating tumor DNA (ctDNA), to capture dynamic molecular changes during treatment. Liquid biopsy-based technologies now enable real-time tracking of molecular alterations, supporting truly personalized therapeutic decision-making. Furthermore, prior treatment exposure and residual toxicities must be carefully considered to balance efficacy, safety, and quality of life. This review provides a comprehensive overview of the current salvage-line landscape for mCRC, discusses the clinical utility of ctDNA as a predictive and prognostic tool, and proposes integrated strategies to optimize therapeutic outcomes in the evolving era of precision medicine. Full article