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Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon-26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral-mediated PDK4 overexpression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer-associated muscle metabolic alterations and skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Background  Sarcopenia has been implicated as a positive predictor of postsurgical complications. Its role in head and neck (H&N) free flap reconstruction has yet to be examined. Our study aimed to determine the clinical impact of sarcopenia on postoperative outcomes in patients receiving autologous free tissue reconstruction for H&N cancer (HNC). Methods  A retrospective case–control study was conducted at our tertiary referral center. Patients with HNC who received oncologic resection followed by autologous free tissue reconstruction were included. Preoperative abdominal computed tomography (CT) imaging was analyzed at the third lumbar vertebra (L3) to calculate skeletal muscle cross-sectional area (CSA, cm 2). Skeletal muscle index (SMI, cm 2 /m 2) was calculated by normalizing CSA to patient height. Sarcopenia at L3 was defined as SMI ≤ 41.6 cm 2 /m 2 for males and ≤ 32.0 cm 2 /m 2 for females. Data analyses were performed to compare postoperative outcomes. Results  Of the 168 patients who met inclusion criteria, 47 patients (28.0%) were determined to have preoperative sarcopenia. The sarcopenic group was older (63 vs. 58 years, p  = 0.017), had lower body mass index (BMI; 21.2 vs. 27.2, p  < 0.001), had greater incidence of alcohol abuse (55.3 vs. 23.1%, OR = 4.11, p  < 0.001). Intraoperatively, sarcopenic patients were found to have greater rates of blood transfusions (63.8 vs. 29.8%, p  < 0.001). Postoperatively, sarcopenic patients had higher rates of pneumonia (p  < 0.01), venous thromboembolism (p  < 0.01), prolonged ventilation (p  < 0.01), delirium (p  < 0.01), fistula (p  < 0.05), wound disruption (p  < 0.05), and longer intensive care unit stays (p  < 0.05). Sarcopenic patients were ultimately found to have higher overall rates of general postoperative complications (p  < 0.001) and flap-specific complications (p  < 0.01). Conclusion  Sarcopenia was found to be a predictor of postoperative complications in H&N free flap reconstruction, signifying its value as a negative prognostic factor in surgical outcomes. This study reflects level of evidence IV. [ABSTRACT FROM AUTHOR]

Objective: To determine if sarcopenia is a predictor of blood transfusion requirements in head and neck cancer free flap reconstruction (HNCFFR). Methods: A single‐institution, retrospective review was performed of HNCFFR patients with preoperative abdominal imaging from 2014 to 2019. Demographics, comorbidities (modified Charlson Comorbidity Index [mCCI]), skeletal muscle index (cm2/m2), oncologic history, intraoperative data, and 30‐day postoperative complications (Clavien‐Dindo score [CD]) were collected. Binary logistic regression was performed to determine predictors of transfusion. Results: Eighty (33.5%), 66 (27.6%), and 110 (46.0%) of n = 239 total patients received an intraoperative, postoperative, or any perioperative blood transfusion, respectively. Sixty‐two (25.9%) patients had sarcopenia. Patients receiving intraoperative transfusions had older age (P =.035), more frequent alcoholism (P =.028) and sarcopenia (P <.001), greater mCCI (P <.001), lower preoperative hemoglobin (P <.001), reconstruction with flaps other than forearm (P =.003), and greater operative times (P =.001), intravenous fluids (P <.001), and estimated blood loss (EBL, P <.001). Postoperative transfusions were associated with major complications (CD ≥ 3; P <.001). Multivariate regression determined sarcopenia (P =.023), mCCI (P =.013), preoperative hemoglobin (P =.002), operative time (P =.036), and EBL (P <.001) as independent predictors of intraoperative transfusion requirements. Postoperative transfusions were predicted by preoperative hemoglobin (P =.007), osseous flap (P =.036), and CD ≥ 3 (P <.001). A perioperative transfusion was predicted by sarcopenia (P =.021), preoperative hemoglobin (P <.001), operative time (P =.008), and CD ≥ 3 (P =.018). Conclusion: Sarcopenia is associated with increased blood transfusions in HNCFFR. Patients should be counseled preoperatively on the associated risks, and the increased blood product requirement should be accounted in resource‐limited scenarios. Level of Evidence: 4. [ABSTRACT FROM AUTHOR]

Breast cancer frequently metastasizes to the skeleton resulting in bone degradation due to osteoclast activation. Metastases also downregulate differentiation and the bone-rebuilding function of osteoblasts. Moreover, cancer cells trigger osteoblast inflammatory stress responses. Pro-inflammatory mediators such as interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), expressed by osteoblasts (MC3T3-E1) stimulated with human breast cancer cell (MDA-MB-231) conditioned medium, are pivotal to osteoclast activation and metastasis. Given that these genes are regulated by nuclear factor-κB (NF-κB), a redox-sensitive transcription factor, we hypothesized that selenium (Se) could abrogate the inflammatory response to metastatic breast cancer cells by modulating NF-κB. Caffeic acid phenethyl ester and parthenolide inhibited NF-κB activation, as seen by gel shift assays and immunoblotting for p65 in nuclear fractions, as well as decreased production of IL-6 and MCP-1. Supplementation of MC3T3-E1 with methylseleninic acid (MSA) (0.5 μM to 4 μM) reduced the activation of NF-κB leading to a decrease in IL-6, MCP-1, COX-2 and iNOS in response to MDA-MB-231 conditioned medium. Addition of MSA to osteoblasts for as little as 15 min suppressed activation of NF-κB suggesting that short-lived active metabolites might be involved. However, brief exposure to MSA also brought about an increase in selenoprotein glutathione peroxidase 1. In summary, our data indicate that the osteoblast response to metastatic breast cancer cells is regulated by NF-κB activation, which can be effectively suppressed by MSA either through short-lived active metabolites and/or selenoproteins. Thus, Se supplementation may prevent the osteoblast inflammatory response or dampen the vicious cycle established when breast cancer cells, osteoblasts and osteoclasts interact. [ABSTRACT FROM PUBLISHER]