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BACKGROUND: Although most transplant centers preferentially offer minimally invasive approaches to donor nephrectomies, there remains less standardization specific to the kidney extraction site. This study aimed to evaluate incisional hernia occurrence in living kidney donors based on kidney extraction site location. STUDY DESIGN: This was a retrospective study of all donors who underwent minimally invasive living donor nephrectomies at the Mayo Clinic Arizona between 2011 and 2023 with a 2-year external validation cohort from Mayo Clinic Florida and Mayo Clinic Minnesota. The cohort was divided into 2 groups based on the kidney extraction site type: midline infraumbilical and Pfannenstiel. RESULTS: In the primary cohort, incisional hernia occurrence was observed in 1.2% of donors with an infraumbilical midline kidney extraction site compared with 0.1% with a Pfannenstiel extraction site (p = 0.04). Donors with an infraumbilical midline kidney extraction site were more likely to be men (50.8% vs 23.3%, p < 0.0001), have a higher BMI (mean 27.2 vs 26 kg/m2, p < 0.0001), and have current or former tobacco use (p = 0.002). There were no differences in incisional hernia occurrence when comparing minimally invasive surgical techniques (p = 0.52). In the external validation cohort, hernia occurrence was observed in 4.5% of donors with a midline incision compared with 0.0% with a Pfannenstiel incision (p = 0.09). Using combined data from the 3 sites, the use of a Pfannenstiel incision as the extraction site was associated with significantly lower odds of developing a hernia compared with the infraumbilical midline incision (odds ratio 0.06, 95% CI 0.008 to 0.456). CONCLUSIONS: Although the risk of hernia in living kidney donors is generally low, the use of a Pfannenstiel incision for kidney extraction appears to offer an additional incremental reduction in risk.

Hemorrhagic complications associated with regional anesthesia are extremely rare. The fifth edition of the American Society of Regional Anesthesia and Pain Medicine’s Evidence-Based Guidelines on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy reviews the published evidence since 2018 and provides guidance to help avoid this potentially catastrophic complication. The fifth edition of the American Society of Regional Anesthesia and Pain Medicine’s Evidence-Based Guidelines on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy uses similar methodology as previous editions but is reorganized and significantly condensed. Therefore, the clinicians are encouraged to review the earlier texts for more detailed descriptions of methods, clinical trials, case series and pharmacology. It is impossible to perform large, randomized controlled trials evaluating a complication this rare; therefore, where the evidence is limited, the authors continue to maintain an ‘antihemorrhagic’ approach focused on patient safety and have proposed conservative times for the interruption of therapy prior to neural blockade. In previous versions, the anticoagulant doses were described as prophylactic and therapeutic. In this version, we will be using ‘low dose’ and ‘high dose,’ which will allow us to be consistent with other published guidelines and more accurately describe the dose in the setting of specific patient characteristics and indications. For example, the same ‘high’ dose may be used in one patient as a treatment for deep venous thrombosis (DVT) and in another patient as prophylaxis for recurrent DVT. Due to the increasing ability to obtain drug-specific assays, we have included suggestions for when ordering these tests may be helpful and guide practice. Like previous editions, at the end of each recommendation the authors have clearly noted how the recommendation has changed from previous editions.

Key Points Studies on GFR assessment in people with cancer are needed. In this study, the creatinine–cystatin C equations performed better than other equations, and this was observed in solid and hematological cancers. Our findings give support to the preferential use of creatinine and cystatin C–based equations in people with cancer. Background GFR assessment is important in clinical practice with implications for diagnosis, prognostication, and drug dosing. People with cancer are at risk of imprecision in GFR estimation. This cross-sectional study evaluated the performance of various creatinine and cystatin C–based equations in comparison with measured GFR (mGFR) in people with cancer. Methods We retrieved data for all adult patients who had mGFR by urinary iothalamate clearance between 2011 and 2023 at Mayo Clinic and use of an electronic health record diagnosis code for cancer within 2 years before mGFR. The CKD Epidemiology Collaboration (CKD-EPI), European Kidney Function Consortium, and Cockcroft–Gault equations were computed, along with performance metrics (bias, precision, and root mean square error [RMSE]. Confidence intervals were generated by bootstrapping, and analysis were stratified by solid and hematological cancers. Results From all adults with cancer and mGFR, 1145 had both creatinine and cystatin C available within 7 days of mGFR. Among all equations, the creatinine–cystatin C CKD-EPI equation provided the best performance, with small bias (median, 3.0; 95% confidence interval, 2.3 to 3.8) and higher precision (RMSE, 14.5) compared with creatinine-only or cystatin C–only equations (RMSE varying from 16.6 to 20), and this was also true in solid and hematological cancers. The creatinine–cystatin European Kidney Function Consortium equation had a similar performance to CKD-EPI, Cockcroft–Gault showed worst precision (30% of people with errors above 30%), and cystatin C CKD-EPI equation was the most biased, prone to underestimation of mGFR. Conclusions In our cohort of patients with mGFR and cancer, the CKD-EPI creatinine–cystatin C equation performed best for GFR assessment, and this was true for both solid and hematological cancers. Our findings give support for the preferential use of creatinine and cystatin C–based equations instead of creatinine-only or cystatin C–only equations in people with cancer. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2025_03_25_CJASNMar20.3.3252025.mp3

224 Background: Metabolic pathways are reprogrammed during CRC development, leading to increased glycolysis, glutaminolysis, and fatty acid synthesis. Understanding the impact of metabolic reprogramming on treatment outcomes is paramount. Hence, we investigated whether the tumor gene expression of 4 selected major metabolic genes ( PKM, SLC2A1 , SLC16A1 , and CAV1 ) could affect treatment response in pts enrolled in the CALGB/SWOG 80405 trial. Methods: 433 mCRC pts treated with either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were analyzed. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of gene expression (high [H], medium [M] and low [L]). Logrank P -values provide a non-parametric unadjusted assessment of differences. Likelihood ratio tests (LRT) were computed from multivariate Cox proportional hazards models, adjusting for age, sex, ECOG, tumor side, number of metastatic sites, KRAS , CMS, and treatment. Results: PKM gene expression was associated with cet treatment outcomes with PKM- low tumors showing significantly longer PFS and OS (median PFS: 14.3 vs 9.8 vs 8.1 months, L vs M vs H, P < 0.0001, LRT P = 0.011; median OS: 45.9 vs 31.2 vs 20.9 months, P < 0.0001, LRT P = 0.12). Low SLC2A1 was also associated with longer OS in cet-treated pts (32.4 vs 35.8 vs 25.2 months, P = 0.02, LRT P < 0.0001). Similar results were observed in bev-treated pts where low SLC2A1 expressing tumors had longer OS (37.4 vs 26.1 vs 29 months, P = 0.037, LRT P = 0.069) and a non-significant trend for longer PFS (13.1 vs 11 vs 9.5 months, P = 0.076). CAV1 low gene expression was associated with longer OS in cet-treated pts (37.4 vs 34 vs 21.5 months, P = 0.0048, LRT P = 0.013), while no significant associations were found in bev-treated (interaction LRT P = 0.0009). No significant results were observed for SLC16A1 . Conclusions: The intratumoral expression of metabolic genes was prognostic and predictive in mCRC pts treated with first-line therapy. GLUT1 (encoded by SLC2A1 ) and PKM2 (encoded by PKM ) promote aerobic glycolysis of cancer cells, known as Warburg effect, supporting rapid cell proliferation and survival. CAV1 has been shown to be involved in mitochondrial bioenergetics and fatty acid metabolism and to play either a tumor suppressor or oncogenic role depending on the cancer type and stage. Lower expression of SLC2A1 and PKM was associated with improved survival and increased benefit from cet treatment in our cohort. Low CAV1 expression was also associated with increase survival suggesting a cancer-promoting role in mCRC. Our results suggest that targeting cancer cell metabolism through novel inhibitors of the aforementioned pathways may be a promising therapeutic strategy.

269 Background: Sirtuins (SIRT1-7) are class III histone deacetylases with different roles in CRC as tumor suppressive and oncogenic, mainly influencing proliferation, migration, invasion, DNA damage and chemoresistance. In the present study, we explored the association between tumor gene expression of sirtuins and first-line treatment outcomes in mCRC pts. Methods: We evaluated the impact of the tumor gene expression of sirtuin genes ( SIRT1 -7) on treatment outcomes (overall survival: OS; progression free survival: PFS) in 433 pts enrolled in the randomized, phase III CALGB/SWOG 80405 (NCT00265850) trial. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) vs. cetuximab [cet] (N = 207)). For each gene, expression was divided into tertiles of high, medium and low. The associations between tumor gene expression and outcomes (PFS and OS) were assessed using log-rank test in univariate analysis. Multivariable Cox proportional hazards regression model was used to compute hazard ratios (HR) and 95% confidence intervals while adjusting for baseline characteristics. Treatment-gene interactions were analyzed using the likelihood ratio test. Results: Of the seven genes analyzed, SIRT3 high was associated with both longer PFS (HR: 0.59 [95% CI: 0.46-0.74], P < 0.001) and OS (HR:0.64 [95% CI: 0.50-0.83], P = 0.002) overall. Treatment-gene interaction testing found significant interactions for SIRT1 and SIRT5 with PFS ( P values: 0.021 and 0.016, respectively) and OS ( P values: 0.038 and 0.014, respectively) with targeted therapies (bev vs. cet). Multivariate analysis showed SIRT1 high associated with longer PFS (HR: 0.62 [95% CI: 0.42-0.89], P = 0.014) and OS (HR: 0.59 [95% CI: 0.40-0.89], P = 0.036) in cet-treated pts; in contrast with shorter observed PFS (HR: 1.38 [95% CI: 0.96-1.99], P = 0.22) and OS (HR: 1.31 [95% CI: 0.90-1.93], P = 0.23) in bev-treated pts. SIRT5 high showed similar results and associated with longer PFS (HR: 0.64 [95% CI: 0.45-0.91], P = 0.039) and OS (HR: 0.57 [95% CI: 0.39-0.83], P = 0.013) in cet-treated pts, with no similar associations in bev-treated pts. Conclusions: Our results highlight a potential role for SIRT3 as prognostic and, SIRT1 and SIRT5 as predictive biomarkers for first-line treatment in mCRC, with differential effects based on targeted agents. Significant interaction favored cet treatment in SIRT1 high and SIRT5 high tumors. However, previous reports suggest an opposite role of SIRT5 that has been linked to chemotherapy and/or cet resistance in CRC via the inactivation of succinate dehydrogenase complex subunit A. Therefore, further studies are warranted to dissect the mechanism behind the interaction of SIRT5 with cetuximab activity and establish the potential of targeting SIRT1/5 in CRC.

254 Background: SLFN11 was recently identified as a dominant determinant of response to DNA-damaging anticancer agents. Several studies showed SLFN11 expression led to better sensitivity to topoisomerase inhibitors and PARP inhibitors. However, clinical evidence in mCRC has been lacking. Methods: Two independent cohorts (CALGB/SWOG 80405 trial and a real-world patient [Caris CODEai] cohort) were included in this study. Patients were stratified into SLFN11 -high and -low groups based on the median SLFN11 gene expression levels. Survival outcomes were compared between SLFN11 -high and SLFN11 -low in irinotecan-treated and oxaliplatin-treated patients. Median time was estimated using Kaplan-Meier method and Cox models were used for covariate adjustment. Endpoints of interest were progression-free survival (PFS) and overall survival (OS). Results: In the CALGB/SWOG 80405 trial cohort, 433 patients were included (110 treated with FOLFIRI-based chemotherapy and 323 treated with FOLFOX-based chemotherapy). In patients treated with FOLFIRI-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS, 13.4 vs 11.2 months, log-rank p = 0.03, adjusted hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.55-1.39, p = 0.50) and OS (median OS, 39.6 vs 30.3 months, log-rank p = 0.02, adjusted HR = 0.73, 95% CI 0.46-1.16, p = 0.19) compared to SLFN11 -high patients. In patients treated with FOLFOX-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS 11.2 vs 9.8 months, log-rank p = 0.03, adjusted HR = 0.83, 95% CI 0.65-1.05, p = 0.12) and OS (31.1 vs 26.1 months, log-rank p = 0.07, adjusted HR = 0.84, 95% CI 0.65-1.08, p = 0.16) compared to SLFN11 -high patients. No significant interaction was observed between treatment and SLFN11 expression in terms of PFS ( p = 0.69) and OS ( p = 0.44). In the Caris CODEai cohort, a better OS in SLFN11 -low patients than in SLFN11 -high patients was observed in irinotecan-treated patients ( N = 2906) (median OS, 25.5 vs 21.7 months, HR = 0.90, 95% CI 0.82-1.00, p = 0.048). However, no significant difference in OS between SLFN11 -low and SLFN11-high was observed in oxaliplatin-treated patients ( N = 4428) (median OS, 39.5 vs 35.8 months, HR = 0.98, 95% CI 0.90-1.06, p = 0.56). Conclusions: Low SLFN11 expression showed a potential for better prognosis in mCRC patients receiving irinotecan- and oxaliplatin-containing chemotherapies. These findings are not consistently aligned with preclinical data and clinical evidence in other cancer types previously reported. Further investigation is warranted to better understand the biological role and clinical implication of SLFN11 in mCRC.

285 Background: Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC) outside of mismatch repair (MMR) deficient/microsatellite instability-high (MSI-H) tumors. Most CRC cases are MMR proficient /microsatellite stable and demonstrate resistance to ICIs, attributed to the tumor microenvironment. Colony Stimulating Factor 1 Receptor (CSF1R), a regulator of tumor-associated macrophages, has emerged as a potential target due to its association with poor prognosis in CRC. Methods: Data from 433 metastatic CRC (mCRC) patients in the CALGB/SWOG 80405 trial were analyzed. CSF1R RNA was extracted from formalin-fixed, paraffin-embedded tumor samples and sequenced. Patients were divided into tertiles of CSF1R expression (high, medium, low). Progression-free survival (PFS) and overall survival (OS) were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Subgroup analyses were conducted based on liver metastases, treatment type (Bevacizumab, Cetuximab, FOLFOX, FOLFIRI), and MSI status. Results: Low CSF1R expression (CSF1R-L) was associated with significantly better survival outcomes. Median PFS was 12.9 months for CSF1R-L, compared to 11.2 and 9.2 months for CSF1R-M and CSF1R-H (p = 0.003). Median OS was 35.8 months for CSF1R-L versus 32.5 and 24.4 months for CSF1R-M and CSF1R-H (p = 0.00086). Stratification by liver metastases showed that CSF1R-L remained a strong prognostic factor only in patients with liver metastases. There were no significant survival differences based on CSF1R expression in bevacizumab-treated patients. However, in cetuximab-treated patients, CSF1R-L tumors had significantly longer PFS (12.9 vs 8.8 months, p = 0.037) and OS (35.8 vs 21.4 months, p = 0.002) than CSF1R-H tumors. Similarly, in FOLFOX-treated patients, CSF1R-L tumors showed longer PFS and OS (p = 0.018 and p = 0.013, respectively), and in FOLFIRI-treated patients, OS was significantly longer for CSF1R-L tumors (42.2 vs 24.7 months, p = 0.022) than CSF1R-H tumors. Conclusions: Our data suggests that CSF1R expression may serve as a prognostic biomarker in CRC, with lower expression potentially linked to improved survival, particularly in patients with liver metastases. These findings warrant further investigation of CSF1R as a possible prognostic and predictive biomarker, as well as a potential therapeutic target in CRC. Clinical trial information: NCT00265850 .

ABSTRACT Background Existing risk scores assessing geriatric vulnerability in the emergency department (ED) have shown limited predictive power, especially in diverse populations. We investigated the relationship of a quick and easy‐to‐administer geriatric vulnerability scoring system with functional decline and mortality in older patients admitted to multiple hospitals through the ED in the United States (US) and Brazil (BR). Method Federated, international, multicenter observational study of hospitalized ED patients aged ≥ 65 from US and BR. The six criteria from the PRO‐AGE score (Physical impairment, Recent hospitalization, Older age [≥ 90], Acute mental alteration, Getting thinner, and Exhaustion; 0–8; higher scores = greater vulnerability) were assessed on admission. We used proportional hazards models to investigate the relationships between PRO‐AGE score groups and 90‐day mortality and functional decline, defined as new dependence in activities of daily living (ADL) and instrumental ADL (IADL), after adjusting for age, sex, race and ethnicity, education, Charlson comorbidity score, and study site. Death was considered a competing event for the functional decline outcome. Results A total of 1390 patients were included (US = 560; Brazil = 830). The 90‐day risk of death was higher for the upper compared with the lower (reference) PRO‐AGE group in both cohorts (US: HR = 11.76; 95% confidence interval [CI] = 2.56–54.04; BR: HR = 12.29; 95% CI = 3.54–42.59), whereas the risk of new 90‐day ADL disability was higher for upper (HR = 2.08; 95% CI = 1.21–3.56) and middle groups (HR = 2.10; 95% CI = 1.35–3.27) in the US but only the upper group in BR (HR = 1.70; 95% CI = 1.02–2.85). Conclusion A higher PRO‐AGE score was associated with mortality and functional decline in older ED patients admitted to hospitals in the US and BR, demonstrating its generalizability as a geriatric vulnerability risk score.

Background To provide recommendations on risk mitigation, diagnosis and treatment of infectious complications associated with the practice of regional anesthesia, acute and chronic pain management. Methods Following board approval, in 2020 the American Society of Regional Anesthesia and Pain Medicine (ASRA Pain Medicine) commissioned evidence-based guidelines for best practices for infection control. More than 80 research questions were developed and literature searches undertaken by assigned working groups comprising four to five members. Modified US Preventive Services Task Force criteria were used to determine levels of evidence and certainty. Using a modified Delphi method, >50% agreement was needed to accept a recommendation for author review, and >75% agreement for a recommendation to be accepted. The ASRA Pain Medicine Board of Directors reviewed and approved the final guidelines. Results After documenting the incidence and infectious complications associated with regional anesthesia and interventional pain procedures including implanted devices, we made recommendations regarding the role of the anesthesiologist and pain physician in infection control, preoperative patient risk factors and management, sterile technique, equipment use and maintenance, healthcare setting (office, hospital, operating room), surgical technique, postoperative risk reduction, and infection symptoms, diagnosis, and treatment. Consensus recommendations were based on risks associated with different settings and procedures, and keeping in mind each patient’s unique characteristics. Conclusions The recommendations are intended to be multidisciplinary guidelines for clinical care and clinical decision-making in the regional anesthesia and chronic interventional pain practice. The issues addressed are constantly evolving, therefore, consistent updating will be required.