Predicting Postsurgical Complications of Peripheral Nerve Decompression: NSQIP Analysis of Frailty Measures Versus Historic Proxies.

Background: Peripheral nerve decompression (PND) is generally safe, and newer techniques allow frail patients to undergo PND at less common sites. Current literature suggests patient frailty measures may more accurately predict postsurgical complications versus other proxies, but no current literature examines frailty in PND. Methods: The authors reviewed data from the National Surgical Quality Improvement Program for patients who underwent PND outside the most common sites from 2013 to 2019. The modified 5-Item Frailty Index (mFI-5) and modified Charlson Comorbidity Index (mCCI) scores were calculated, and complications data were gathered. Age, body mass index (BMI), major comorbidities, American Society of Anesthesiologists class, and frailty were compared as predictors of all-cause 30-day complications, 30-day surgical site complications, length of stay, and complication severity, using univariate and multivariate logistic regression. Results: Of 1120 patients, the mean age was 51.3 (15.4) years and mean BMI was 30.6 (7.0) kg/m2. Patients were predominantly white and healthy. The complication rate was 3.4%. All-cause complications were predicted by ≥3 major comorbidities (odds ratio [OR], 95% confidence interval [CI]: 6.26, 1.36-21.32; P = .007), followed by mFI-5 score and mCCI score. Complication severity was associated with major comorbidities and mFI-5 score, while length of stay was most strongly predicted by age ≥ 65 years (OR, 95% CI: 2.17, 1.37-3.42; P = .0008) and mCCI score of 3 (OR, 95% CI: 1.77, 1.01-3.05; P = 0.041). The only risk factor for readmission was mFI-5 score of 1 (OR, 95% CI: 7.00, 1.68-47.16; P = .016). Conclusions: Frailty and risk proxies may predict postoperative complications in PND at uncommon sites. Use of frailty indices may expand the age range of patients offered PND. Further research is necessary to delineate contributing risk factors and to clarify 24-hour observation and admissions.

Frailty Indices Outperform Historic Risk Proxies as Predictors of Postabdominoplasty Complications: An Analysis of a National Database.

BACKGROUND: Although age, body mass index (BMI), and major comorbidities were historically used as predictors of surgical risk, recent literature supports patient frailty as a more accurate predictor. Database studies and chart reviews support the modified Charlson Comorbidity Index (mCCI) and the Modified Five-Item Frailty Index (mFI-5) as predictors of postsurgical complications in plastic surgery. The authors hypothesized that the mFI-5 and mCCI are more predictive of abdominoplasty complications than historic risk proxies. METHODS: A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program database was performed for abdominoplasty patients from 2013 to 2019. Demographics, comorbidities, and complications were gathered. The mFI-5 and mCCI scores were calculated per patient. Age, BMI, major comorbidities, American Society of Anesthesiologists class, mFI-5 score, and mCCI score were compared as predictors of all-cause 30-day complications, 30-day surgical-site complications, length of stay, and aggregate Clavien-Dindo complication severity score. RESULTS: Of 421 patients, the strongest predictors for all-cause complications and complication severity were mCCI score greater than or equal to 3 and mFI-5 score greater than or equal to 2. The mFI-5 score was the strongest predictor of unplanned reoperation. Length of stay was best predicted by age greater than or equal to 65. The only predictor of surgical-site complications was BMI greater than or equal to 30.0 kg/m 2 . Smoking was predictive of complication severity, but not any other outcome. CONCLUSIONS: The mFI-5 and mCCI are stronger outcome predictors than historically used factors, which showed little predictive value in this cohort. Although the mCCI is a stronger predictor than the mFI-5, the mFI-5 is easily calculated during an initial consultation. Surgeons can apply these tools to aid in risk stratification for abdominoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Communication network within the essential AAA-ATPase Rix7 drives ribosome assembly.

Rix7 is an essential AAA+ ATPase that functions during the early stages of ribosome biogenesis. Rix7 is composed of three domains including an N-terminal domain (NTD) and two AAA+ domains (D1 and D2) that assemble into an asymmetric stacked hexamer. It was recently established that Rix7 is a presumed protein translocase that removes substrates from preribosomes by translocating them through its central pore. However, how the different domains of Rix7 coordinate their activities within the overall hexameric structure was unknown. We captured cryo-electron microscopy (EM) structures of single and double Walker B variants of full length Rix7. The disordered NTD was not visible in the cryo-EM reconstructions, but cross-linking mass spectrometry revealed that the NTD can associate with the central channel in vitro. Deletion of the disordered NTD enabled us to obtain a structure of the Rix7 hexamer to 2.9 Å resolution, providing high resolution details of critical motifs involved in substrate translocation and interdomain communication. This structure coupled with cell-based assays established that the linker connecting the D1 and D2 domains as well as the pore loops lining the central channel are essential for formation of the large ribosomal subunit. Together, our work shows that Rix7 utilizes a complex communication network to drive ribosome biogenesis.

ß-Hydroxy-ß-Methylbutyrate Supplementation Promotes Antitumor Immunity in an Obesity Responsive Mouse Model of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States, and effective therapies for PDAC are currently lacking. Moreover, PDAC is promoted and exacerbated by obesity, while cachexia and sarcopenia are exceptionally common comorbidities that predict both poor survival and treatment response. Managing PDAC with immunotherapies has thus far proven ineffective, partly due to the metabolically hostile tumor microenvironment. ß-hydroxy-ß-methylbutyrate (HMB), a metabolite of leucine commonly used as a dietary supplement to boost muscle growth and immune function, may be an attractive candidate to augment PDAC therapy. We therefore sought to test the hypothesis that HMB would enhance antitumor immunity while protecting mouse muscle mass. Control and diet-induced obese C57BL/6 male mice bearing subcutaneously injected Panc02 tumors were supplemented with 1% HMB and treated with or without 50 mg/kg gemcitabine (n = 15/group). HMB was associated with reduced muscle inflammation and increased muscle fiber size. HMB also reduced tumor growth and promoted antitumor immunity in obese, but not lean, mice, independent of the gemcitabine treatment. Separately, in lean tumor-bearing mice, HMB supplementation promoted an anti-PD1 immunotherapy response (n = 15/group). Digital cytometry implicated the decreased abundance of M2-like macrophages in PDAC tumors, an effect that was enhanced by anti-PD1 immunotherapy. We confirmed that HMB augments M1-like macrophage (antitumor) polarization. These preclinical findings suggest that HMB has muscle-sparing and antitumor activities against PDAC in the context of obesity, and that it may sensitize otherwise nonresponsive PDAC to immunotherapy.

Dietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer.

Cancer cells experience unique and dynamic shifts in their metabolic function in order to survive, proliferate, and evade growth inhibition in the resource-scarce tumor microenvironment. Therefore, identification of pharmacological agents with potential to reprogram cancer cell metabolism may improve clinical outcomes in cancer therapy. Cancer cells also often exhibit an increased dependence on the process known as autophagy, both for baseline survival and as a response to stressors such as chemotherapy or a decline in nutrient availability. There is evidence to suggest that this increased dependence on autophagy in cancer cells may be exploitable clinically by combining autophagy modulators with existing chemotherapies. In light of the increased metabolic rate in cancer cells, interest is growing in approaches aimed at "starving" cancer through dietary and pharmacologic interventions that reduce availability of nutrients and pro-growth hormonal signals known to promote cancer progression. Several dietary approaches, including chronic calorie restriction and multiple forms of fasting, have been investigated for their potential anti-cancer benefits, yielding promising results in animal models. Induction of autophagy in response to dietary energy restriction may underlie some of the observed benefit. However, while interventions based on dietary energy restriction have demonstrated safety in clinical trials, uncertainty remains regarding translation to humans as well as feasibility of achieving compliance due to the potential discomfort and weight loss that accompanies dietary restriction. Further induction of autophagy through dietary or pharmacologic metabolic reprogramming interventions may enhance the efficacy of autophagy inhibition in the context of adjuvant or neo-adjuvant chemotherapy. Nonetheless, it remains unclear whether therapeutic agents aimed at autophagy induction, autophagy inhibition, or both are a viable therapeutic strategy for improving cancer outcomes. This review discusses the literature available for the therapeutic potential of these approaches.

Cell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy.

Immune checkpoint inhibitor (ICI) therapy has shown extraordinary promise at treating cancers otherwise resistant to treatment. However, for ICI therapy to be effective, it must overcome the metabolic limitations of the tumor microenvironment. Tumor metabolism has long been understood to be highly dysregulated, with potent immunosuppressive effects. Moreover, T cell activation and longevity within the tumor microenvironment are intimately tied to T cell metabolism and are required for the long-term efficacy of ICI therapy. We discuss in this review the intersection of metabolic competition in the tumor microenvironment, T cell activation and metabolism, the roles of tumor cell metabolism in immune evasion, and the impact of host metabolism in determining immune surveillance and ICI therapy outcomes. We also discussed the effects of obesity and calorie restriction-two important systemic metabolic perturbations that impact intrinsic metabolic pathways in T cells as well as cancer cells.