Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma.

Cancer-related fatigue (CRF) is one of the most common complications in patients with multiple cancer types and severely affects patients' quality of life. However, there have only been single symptom-relieving adjuvant therapies but no effective pharmaceutical treatment for the CRF syndrome. Dichloroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase kinase, has been tested as a potential therapy to slow tumor growth, based largely on its effects in vitro to halt cell division. We found that although DCA did not affect rates of tumor growth or the efficacy of standard cancer treatment (immunotherapy and chemotherapy) in two murine cancer models, DCA preserved physical function in mice with late-stage tumors by reducing circulating lactate concentrations. In vivo liquid chromatography-mass spectrometry/mass spectrometry studies suggest that DCA treatment may preserve membrane potential, postpone proteolysis, and relieve oxidative stress in muscles of tumor-bearing mice. In all, this study provides evidence for DCA as a novel pharmaceutical treatment to maintain physical function and motivation in murine models of CRF.NEW & NOTEWORTHY We identify a new metabolic target for cancer-related fatigue, dichloroacetate (DCA). They demonstrate that in mice, DCA preserves physical function and protects against the detrimental effects of cancer treatment by reducing cancer-induced increases in circulating lactate. As DCA is already FDA approved for another indication, these results could be rapidly translated to clinical trials for this condition for which no pharmaceutical therapies exist beyond symptom management.

Lipoprotein Insulin Resistance Index: A Simple, Accurate Method for Assessing Insulin Resistance in South Asians.

Context: Identification of insulin resistance (IR) in South Asians, who are at a higher risk for type 2 diabetes, is important. Lack of standardization of insulin assays limits the clinical use of insulin-based surrogate indices. The lipoprotein insulin resistance index (LP-IR), a metabolomic marker, reflects the lipoprotein abnormalities observed in IR. The reliability of the LP-IR index in South Asians is unknown. Objective: We evaluated the predictive accuracy of LP-IR compared with other IR surrogate indices in South Asians. Methods: In a cross-sectional study (n = 55), we used calibration model analysis to assess the ability of the LP-IR score and other simple surrogate indices (Homeostatic Model Assessment of Insulin Resistance, Quantitative insulin sensitivity check index, Adipose insulin resistance index, and Matsuda Index) to predict insulin sensitivity (SI) derived from the reference frequently sampled intravenous glucose tolerance test. LP-IR index was derived from lipoprotein particle concentrations and sizes measured by nuclear magnetic resonance spectroscopy. Predictive accuracy was determined by root mean squared error (RMSE) of prediction and leave-one-out cross-validation type RMSE of prediction (CVPE). The optimal cut-off of the LP-IR index was determined by the area under the receiver operating characteristic curve (AUROC) and the Youden index. Results: The simple surrogate indices showed moderate correlations with SI (r = 0.53-0.69, P < .0001). CVPE and RMSE were not different in any of the surrogate indices when compared with LP-IR. The AUROC was 0.77 (95% CI 0.64-0.89). The optimal cut-off for IR in South Asians was LP-IR >48 (sensitivity: 75%, specificity: 70%). Conclusion: The LP-IR index is a simple, accurate, and clinically useful test to assess IR in South Asians.

Incidence, Timing, and Risk Factors for 5-Year Revision Surgery After Autologous Chondrocyte Implantation in 533 Patients.

BACKGROUND: Autologous chondrocyte implantation (ACI) can be used to treat focal, full-thickness chondral defects of the knee. However, there is limited large-sample evidence available regarding the incidence, timing, and risk factors for revision surgery after ACI. PURPOSE: To assess the 5-year incidence, timing, and risk factors for revision surgery after ACI in a large national cohort. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The 2010-2020 PearlDiver database was queried for patients aged 20 to 59 years who underwent primary ACI of the knee without previous chondral procedures or knee arthroplasty. Revision surgery was defined as subsequent revision ACI, osteochondral allograft transplantation, osteochondral autograft transfer, unicompartmental knee arthroplasty, or total knee arthroplasty within 5 years. Kaplan-Meier analysis was used to assess both incidence and timing of revision surgery. Risk factors evaluated for revision surgery included patient age, sex, body mass index (BMI), Elixhauser Comorbidity Index (ECI) score, and previous or concomitant bony realignment procedures. RESULTS: In total, 533 patients underwent primary ACI and met inclusion criteria. The 5-year incidence of revision surgery was 10.3%, with 63% of revisions occurring in the first 2 years after surgery. Risk factors associated with revision surgery included female sex (odds ratio, 2.58; 95% CI, 1.22-5.45; P = .013) and BMI ≥35 (odds ratio, 2.24; 95% CI, 1.01-4.94; P = .047). There was no relationship between age, ECI score, or previous or concomitant bony realignment procedures and revision surgery at 5 years (P > .05). CONCLUSION: In an analysis of 533 patients who underwent ACI, 10.3% required a subsequent articular cartilage procedure or conversion to knee arthroplasty in the first 5 postoperative years. Revision surgery was greatest in the first 2 postoperative years. Female sex and severe obesity (BMI, ≥35) were associated with increased risk of revision surgery, while age, ECI score, and previous or concomitant bony realignment procedures were not. These findings suggest that treatment of chondral defects of the knee with ACI is associated with durable outcomes at the 5-year follow-up.

A Novel MRI Mapping Technique for Evaluating Bone Bruising Patterns Associated With Noncontact ACL Ruptures.

Background: Bone bruise patterns in the knee can aid in understanding the mechanism of injury in anterior cruciate ligament (ACL) ruptures. There is no universally accepted magnetic resonance imaging (MRI) mapping technique to describe the specific locations of bone bruises. Hypothesis: The authors hypothesized that (1) our novel mapping technique would show high interrater and intrarater reliability for the location of bone bruises in noncontact ACL-injured knees and (2) the bone bruise patterns reported from this technique would support the most common mechanisms of noncontact ACL injury, including valgus stress, anterior tibial translation, and internal tibial rotation. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Included were 43 patients who underwent ACL reconstruction between 2018 and 2020, with MRI within 30 days of the injury on a 3.0-T scanner, documentation of a noncontact mechanism of injury, and no concomitant or previous knee injuries. Images were retrospectively reviewed by 2 radiologists blinded to all clinical data. The locations of bone bruises were mapped on fat-suppressed T2-weighted coronal and sagittal images using a novel technique that combined the International Cartilage Repair Society (ICRS) tibiofemoral articular cartilage surgical lesions diagram and the Whole-Organ Magnetic Resonance Imaging Scoring (WORMS) mapping system. Reliability between the reviewers was assessed using the intraclass correlation coefficient (ICC), where ICC >0.90 indicated excellent agreement. Results: The interrater and intrarater ICCs were 0.918 and 0.974, respectively, for femoral edema mapping and 0.979 and 0.978, respectively, for tibial edema mapping. Significantly more bone bruises were seen within the lateral femoral condyle compared with the medial femoral condyle (67% vs 33%; P < .0001), and more bruises were seen within the lateral tibial plateau compared with the medial tibial plateau (65% vs 35%; P < .0001). Femoral bruises were almost exclusively located in the anterior/central regions (98%) of the condyles as opposed to the posterior region (2%; P < .0001). Tibial bruises were localized to the posterior region (78%) of both plateaus as opposed to the anterior/central regions (22%; P < .0001). Conclusion: The combined mapping technique offered a standardized and reliable method for reporting bone bruises in noncontact ACL injuries. The contusion patterns identified using this technique were indicative of the most commonly reported mechanisms for noncontact ACL injuries.

Examining the Bone Bruise Patterns in Multiligament Knee Injuries With Peroneal Nerve Injury.

BACKGROUND: Tibiofemoral bone bruise patterns seen on magnetic resonance imaging (MRI) are associated with ligamentous injuries in the acutely injured knee. Bone bruise patterns in multiligament knee injuries (MLKIs) and particularly their association with common peroneal nerve (CPN) injuries are not well described. PURPOSE: To analyze the tibiofemoral bone bruise patterns in MLKIs with and without peroneal nerve injury. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We retrospectively identified 123 patients treated for an acute MLKI at a level 1 trauma center between January 2001 and March 2021. Patients were grouped into injury subtypes using the Schenck classification. Within this cohort, patients with clinically documented complete (motor and sensory loss) and/or partial CPN palsies on physical examination were identified. Imaging criteria required an MRI scan on a 1.5 or 3 Tesla scanner within 30 days of the initial MLKI. Images were retrospectively interpreted for bone bruising patterns by 2 board-certified musculoskeletal radiologists. The location of the bone bruises was mapped on fat-suppressed T2-weighted coronal and sagittal images. Bruise patterns were compared among patients with and without CPN injury. RESULTS: Of the 108 patients with a MLKI who met the a priori inclusion criteria, 26 (24.1%) were found to have a CPN injury (N = 20 complete; N = 6 partial) on physical examination. For CPN-injured patients, the most common mechanism of injury was high-energy trauma (N = 19 [73%]). The presence of a grade 3 posterolateral corner (PLC) injury (N = 25; odds ratio [OR], 23.81 [95% CI, 3.08-184.1]; P = .0024), anteromedial femoral condyle bone bruising (N = 24; OR, 21.9 [95% CI, 3.40-202.9]; P < .001), or a documented knee dislocation (N = 16; OR, 3.45 [95% CI, 1.38-8.62]; P = .007) was significantly associated with the presence of a CPN injury. Of the 26 patients with CPN injury, 24 (92.3%) had at least 1 anteromedial femoral condyle bone bruise. All 20 (100%) patients with complete CPN injury also had at least 1 anteromedial femoral condyle bone bruise on MRI. In our MLKI cohort, the presence of anteromedial femoral condyle bone bruising had a sensitivity of 92.3% and a specificity of 64.6% for the presence of CPN injury on physical examination. CONCLUSION: In our MLKI cohort, the presence of a grade 3 PLC injury had the greatest association with CPN injury. Additionally, anteromedial femoral condyle bone bruising on MRI was a highly sensitive finding that was significantly correlated with CPN injury on physical examination. The high prevalence of grade 3 PLC injuries and anteromedial tibiofemoral bone bruising suggests that these MLKIs with CPN injuries most commonly occurred from a hyperextension-varus mechanism caused by a high-energy blow to the anteromedial knee.

Minimal Model-Derived Insulin Sensitivity Index Underestimates Insulin Sensitivity in Black Americans.

OBJECTIVE: To examine the ethnic differences in insulin sensitivity (SI) as measured by the minimal model approach (SI-MM) and the reference method, the euglycemic-hyperinsulinemic clamp (EHC). RESEARCH DESIGN AND METHODS: In a prospective study design, thirty Black Americans (BA) were age, sex, and BMI matched with non-Hispanic Whites (NHW). Participants underwent frequently sampled intravenous tolerance test (FSIVGTT) and EHC on 2 separate days during a single visit. RESULTS: SI-MM values were significantly lower in BA when compared with NHW (0.035 ± 0.025 vs. 0.058 ± 0.036 [dL/min]/[µU/mL]; P = 0.003). However, there were no ethnic differences in SI measured by EHC (0.028 ± 0.012 vs. 0.035 ± 0.019 [dL/min]/[µU/mL]; P = 0.18). CONCLUSIONS: SI-MM systematically underestimates SI in BA when compared with NHW. These findings suggest that studies inferring lower SI in BA based on FSIVGTT and SI-MM should be interpreted cautiously.

Insulin sensitivity and pancreatic ß-cell function in patients with primary aldosteronism.

BACKGROUND: Primary aldosteronism (PA) is associated with an increased risk for dysglycemia. However, the effects of hyperaldosteronism on insulin sensitivity and ß-cell function are unclear. METHODS: Using a cross-sectional study design, we assessed insulin sensitivity and pancreatic ß-cell function from an oral glucose tolerance test (OGTT) in patients from two cohorts: subjects with PA (n = 21) and essential hypertension control (EHC) subjects (n = 22). Age, sex, BMI, and mean arterial pressure adjusted measures of insulin sensitivity and ß-cell function were compared between the groups. RESULTS: PA individuals were less insulin sensitive compared to EHC subjects (Quantitative insulin sensitivity check index [QUICKI]: 0.340 ± 0.006 vs. 0.374 ± 0.013, p < 0.001; Matsuda index: 4.14 ± 0.49 vs. 7.87 ± 1.42, p < 0.001; SI: 11.45 ± 4.85 vs. 21.23 ± 6.11 dL/kg/min per µU/mL, p = 0.02). The hepatic insulin resistance index (HIRI) was higher in PA subjects (PA: 5.61 ± 1.01 vs. EHC: 4.13 ± 0.61, p = 0.002). The insulinogenic index (IGI), an index of ß-cell function was higher in the PA cohort (PA: 1.49 ± 0.27 vs. 1.11 ± 0.21 µU/mL/mg/dL, p = 0.03). However, the oral disposition index (DI) was similar between the groups (PA: 4.77 ± 0.73 vs. EHC: 5.46 ± 0.85, p = 0.42), which likely accounts for the similar glucose tolerance between the two cohorts, despite lower sensitivity. CONCLUSIONS: In summary, insulin sensitivity is significantly lower in PA with an appropriately compensated ß-cell function. These results suggest that excess aldosterone and/or other steroids in the context of PA may negatively affect insulin action without adversely impacting ß-cell function.

Current mechanisms in obesity and tumor progression.

PURPOSE OF REVIEW: Hyperadiposity, as present in obesity, is a substantial threat to cancer risk and prognosis. Studies that have investigated the link between obesity and tumor progression have proposed several mechanistic frameworks, yet, these mechanisms are not fully defined. Further, a comprehensive understanding of how these various mechanisms may interact to create a dynamic disease state is lacking in the current literature. RECENT FINDINGS: Recent work has begun to explore not only discrete mechanisms by which obesity may promote tumor growth (for instance, metabolic and growth factor functions of insulin; inflammatory cytokines; adipokines; and others), but also how these putative tumor-promoting factors may interact. SUMMARY: This review will highlight the present understanding of obesity, as it relates to tumor development and progression. First, we will introduce the impact of obesity in cancer within the dynamic tumor microenvironment, which will serve as a theme to frame this review. The core of this review will discuss recently proposed mechanisms that implicate obesity in tumor progression, including chronic inflammation and the role of pro-inflammatory cytokines, adipokines, hormones, and genetic approaches. Furthermore, we intend to offer current insight in targeting adipose tissue during the development of cancer prevention and treatment strategies.

Increased ß-Cell Responsivity Independent of Insulin Sensitivity in Healthy African American Adults.

BACKGROUND: Primary insulin hypersecretion predicts type 2 diabetes (T2DM) independent of insulin resistance. Enhanced ß-cell glucose responsivity contributes to insulin hypersecretion. African Americans (AAs) are at a higher risk for T2DM than non-Hispanic Whites (NHWs). Whether AAs manifest primary insulin hypersecretion is an important topic that has not been examined systematically. OBJECTIVE: To examine if nondiabetic AA adults have a higher ß-cell glucose responsivity compared with NHWs. METHODS: Healthy nondiabetic AA (n = 18) and NHW (n=18) subjects were prospectively recruited. Indices of ß-cell function, acute C-peptide secretion (X0); basal (Φ B), first-phase (Φ 1), second-phase (Φ 2), and total ß-cell responsivity to glucose (Φ TOT), were derived from modeling of insulin, C-peptide, and glucose concentrations during an intravenous glucose tolerance test. Insulin sensitivity was assessed by the hyperinsulinemic-euglycemic glucose clamp technique. RESULTS: Glucose disposal rate (GDR) during clamp was similar in AAs and NHWs (GDR: [AA] 12.6 ± 3.2 vs [NHW] 12.6 ± 4.2 mg/kg fat free mass +17.7/min, P = .49). Basal insulin secretion rates were similar between the groups. AA had significantly higher X0 (4423 ± 593 vs 1807 ± 176 pmol/L, P = .007), Φ 1 [377.5 ± 59.0 vs 194.5 ± 26.6 (109) P = 0.03], and Φ TOT [76.7 ± 18.3 vs 29.6 ± 4.7 (109/min), P = 0.03], with no significant ethnic differences in Φ B and Φ 2. CONCLUSIONS: Independent of insulin sensitivity, AAs showed significantly higher first-phase and total ß-cell responsivity than NHWs. We propose that this difference reflects increased ß-cell responsivity specifically to first-phase readily releasable insulin secretion. Future studies are warranted to identify mechanisms leading to primary ß-cell hypersensitivity in AAs.

Reduced Insulin Clearance and Insulin-Degrading Enzyme Activity Contribute to Hyperinsulinemia in African Americans.

BACKGROUND: African Americans (AAs) are at a higher risk for developing type 2 diabetes compared with non-Hispanic whites (NHWs). The causal role of ß-cell glucose sensitivity (ß-GS) and insulin clearance in hyperinsulinemia in AA adults is unclear. OBJECTIVE: Using a cross-sectional study design, we compared ß-cell function and insulin clearance in nondiabetic AAs (n = 36) and NHWs (n = 47) after a mixed meal test (MMT). METHODS: Insulin secretion rate, glucose sensitivity, rate sensitivity, and insulin sensitivity during MMT were derived from a mathematical model. Levels of insulin-degrading enzyme (IDE) and carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), key players in insulin clearance, were measured (by enzyme-linked immunosorbent assay) in hepatic cytosolic fractions from age-, sex-, and body mass index-matched AA and NHW cadaveric donors (n = 10). RESULTS: Fasting and mean postprandial plasma glucose levels were similar in both ethnic groups. AAs had significantly higher fasting and mean postprandial plasma insulin levels. However, fasting ISR, total insulin output, and insulin sensitivity during MMT were not different between the groups. ß-GS and rate sensitivity were higher in AAs. Fasting and meal plasma insulin clearance were lower in AAs. Hepatic levels of IDE and CEACAM-1 were similar in AAs and NHWs. Hepatic IDE activity was significantly lower in AAs. CONCLUSIONS: In this study, lower insulin clearance contributes to higher plasma insulin levels in AAs. Reduced insulin clearance may be explained by lower IDE activity levels in AAs. Further confirmatory studies are needed to investigate diminished insulin clearance in AAs as a result of lower IDE activity levels.

Metabolomic Analysis of the Effects of Leptin Replacement Therapy in Patients with Lipodystrophy.

CONTEXT AND OBJECTIVE: Leptin treatment has dramatic clinical effects on glucose and lipid metabolism in leptin-deficient patients with lipodystrophy. Further elucidation of metabolic effects of exogenous leptin therapy will shed light on understanding leptin physiology in humans. Our objective was to utilize metabolomic profiling to examine the changes associated with administration of short-term metreleptin therapy in patients with lipodystrophy. STUDY DESIGN: We conducted a pre-post-treatment study in 19 patients (75% female) with varying forms of lipodystrophy (congenital generalized lipodystrophy, n = 10; acquired generalized lipodystrophy, n = 1; familial partial lipodystrophy, n = 8) who received daily subcutaneous metreleptin injections for a period of 16 to 23 weeks. A 3-hour oral glucose tolerance test and body composition measurements were conducted before and after the treatment period, and fasting blood samples were used for metabolomic profiling. The study outcome aimed at measuring changes in physiologically relevant metabolites before and after leptin therapy. RESULTS: Metabolomic analysis revealed changes in pathways involving branched-chain amino acid metabolism, fatty acid oxidation, protein degradation, urea cycle, tryptophan metabolism, nucleotide catabolism, vitamin E, and steroid metabolism. Fold changes in pre- to post-treatment metabolite levels indicated increased breakdown of fatty acids, branched chain amino acids proteins, and nucleic acids. CONCLUSIONS: Leptin replacement therapy has significant effects on important metabolic pathways implicated in patients with lipodystrophy. Continued metabolomic studies may provide further insight into the mechanisms of action of leptin replacement therapy and provide novel biomarkers of lipodystrophy.Abbreviations: 1,5-AG, 1,5-anhydroglucitol; 11ßHSD1, 11-ß hydroxysteroid dehydrogenase 1; BCAA, branched-chain amino acid; FFA, free fatty acid; GC-MS, gas chromatography mass spectrometry; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-γ; m/z, mass to charge ratio; OGTT, oral glucose tolerance test; TDO, tryptophan 2,3-dioxygenase; TNF-α, tumor necrosis factor-α; UPLC-MS/MS, ultra-performance liquid chromatography-tandem mass spectrometry.