Browsing by Author "Novinger, Leah J."
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Item ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia(Wiley, 2020-12) Huot, Joshua R.; Pin, Fabrizio; Narasimhan, Ashok; Novinger, Leah J.; Keith, Austin S.; Zimmers, Teresa A.; Willis, Monte S.; Bonetto, Andrea; Surgery, School of MedicineBackground: Advanced colorectal cancer (CRC) is often accompanied by the development of liver metastases, as well as cachexia, a multi-organ co-morbidity primarily affecting skeletal (SKM) and cardiac muscles. Activin receptor type 2B (ACVR2B) signalling is known to cause SKM wasting, and its inhibition restores SKM mass and prolongs survival in cancer. Using a recently generated mouse model, here we tested whether ACVR2B blockade could preserve multiple organs, including skeletal and cardiac muscle, in the presence of metastatic CRC. Methods: NSG male mice (8 weeks old) were injected intrasplenically with HCT116 human CRC cells (mHCT116), while sham-operated animals received saline (n = 5-10 per group). Sham and tumour-bearing mice received weekly injections of ACVR2B/Fc, a synthetic peptide inhibitor of ACVR2B. Results: mHCT116 hosts displayed losses in fat mass ( - 79%, P < 0.0001), bone mass ( - 39%, P < 0.05), and SKM mass (quadriceps: - 22%, P < 0.001), in line with reduced muscle cross-sectional area ( - 24%, P < 0.01) and plantarflexion force ( - 28%, P < 0.05). Further, despite only moderately affected heart size, cardiac function was significantly impaired (ejection fraction %: - 16%, P < 0.0001; fractional shortening %: - 25%, P < 0.0001) in the mHCT116 hosts. Conversely, ACVR2B/Fc preserved fat mass ( + 238%, P < 0.001), bone mass ( + 124%, P < 0.0001), SKM mass (quadriceps: + 31%, P < 0.0001), size (cross-sectional area: + 43%, P < 0.0001) and plantarflexion force ( + 28%, P < 0.05) in tumour hosts. Cardiac function was also completely preserved in tumour hosts receiving ACVR2B/Fc (ejection fraction %: + 19%, P < 0.0001), despite no effect on heart size. RNA sequencing analysis of heart muscle revealed rescue of genes related to cardiac development and contraction in tumour hosts treated with ACVR2B/Fc. Conclusions: Our metastatic CRC model recapitulates the multi-systemic derangements of cachexia by displaying loss of fat, bone, and SKM along with decreased muscle strength in mHCT116 hosts. Additionally, with evidence of severe cardiac dysfunction, our data support the development of cardiac cachexia in the occurrence of metastatic CRC. Notably, ACVR2B antagonism preserved adipose tissue, bone, and SKM, whereas muscle and cardiac functions were completely maintained upon treatment. Altogether, our observations implicate ACVR2B signalling in the development of multi-organ perturbations in metastatic CRC and further dictate that ACVR2B represents a promising therapeutic target to preserve body composition and functionality in cancer cachexia.Item Anterolateral thigh osteomyocutaneous femur (ALTO) flap reconstruction for composite mandible and near total tongue defect utilizing a retrograde intramedullary femoral nail stabilization technique: Report of a first case(Elsevier, 2020-06-01) Novinger, Leah J.; Cannady, Steven B.; Wurtz, Lawrence D.; Sim, Michael W.; Moore, Michael G.; Mantravadi, Avinash V.; Shipchandler, Taha Z.; Otolaryngology – Head and Neck Surgery, School of MedicineThe anterior lateral thigh osteomyocutaneous free flap (ALTO) offers the advantage of reconstructing large bony and soft tissue defects. We report a novel approach for femur stabilization via retrograde intramedullary nail placement in a patient with a near total tongue and large mandibular defect who underwent ALTO reconstruction that saves operating room time and decreases risk of post-operative fracture.Item Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia(American Society for Clinical Investigation, 2020-04-16) Huot, Joshua R.; Novinger, Leah J.; Pin, Fabrizio; Narasimhan, Ashok; Zimmers, Teresa A.; O’Connell, Thomas M.; Bonetto, Andrea; Surgery, School of MedicineAdvanced colorectal cancer (CRC) is often accompanied by development of liver metastases (LMs) and skeletal muscle wasting (i.e., cachexia). Despite plaguing the majority of CRC patients, cachexia remains unresolved. By using mice injected with Colon-26 mouse tumors, either subcutaneously (s.c.; C26) or intrasplenically to mimic hepatic dissemination of cancer cells (mC26), here we aimed to further characterize functional, molecular, and metabolic effects on skeletal muscle and examine whether LMs exacerbate CRC-induced cachexia. C26-derived LMs were associated with progressive loss of body weight, as well as with significant reductions in skeletal muscle size and strength, in line with reduced phosphorylation of markers of protein anabolism and enhanced protein catabolism. mC26 hosts showed prevalence of fibers with glycolytic metabolism and enhanced lipid accumulation, consistent with abnormalities of mitochondrial homeostasis and energy metabolism. In a comparison with mice bearing s.c. C26, cachexia appeared exacerbated in the mC26 hosts, as also supported by differentially expressed pathways within skeletal muscle. Overall, our model recapitulates the cachectic phenotype of metastatic CRC and reveals that formation of LMs resulting from CRC exacerbate cancer-induced skeletal muscle wasting by promoting differential gene expression signatures.Item Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia(Wiley, 2018-07-17) Pin, Fabrizio; Barreto, Rafael; Kitase, Yukiko; Mitra, Sumegha; Erne, Carlie E.; Novinger, Leah J.; Zimmers, Teresa A.; Couch, Marion E.; Bonewald, Lynda F.; Bonetto, Andrea; Surgery, School of MedicineBackground Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under-studied in OC due to a limited number of pre-clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. Methods Nod SCID gamma mice (n = 6–10) were injected intraperitoneally with 1 × 107 ES-2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour-derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL-6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. Results In about 2 weeks, ES-2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES-2 tumours caused severe cachexia with marked loss of body weight (–12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour-bearing mice (approximately –35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross-sectional area (–34%, P < 0.01) and muscle weakness (–50%, P < 0.001). Body composition assessment by dual-energy X-ray absorptiometry revealed decreased bone mineral density (–8%, P < 0.01) and bone mineral content (–19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro-CT imaging of bone morphometry. In the ES-2 mouse model, cachexia was also associated with high tumour-derived IL-6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho-STAT3 (+274%, P < 0.001), reduced phospho-AKT (–44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES-2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (–16%, P < 0.001), consistent with elevated phospho-STAT3 (+1.4-fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL-6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. Conclusions Our results suggest that the development of ES-2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL-6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC.Item HCT116 colorectal liver metastases exacerbate muscle wasting in a mouse model for the study of colorectal cancer cachexia(Company of Biologists, 2020-01-24) Huot, Joshua R.; Novinger, Leah J.; Pin, Fabrizio; Bonetto, Andrea; Surgery, School of MedicineColorectal cancer (CRC) is often accompanied by formation of liver metastases (LM) and skeletal muscle wasting, i.e. cachexia. Despite affecting the majority of CRC patients, cachexia remains underserved, understudied and uncured. Animal models for the study of CRC-induced cachexia, in particular models containing LM, are sparse; therefore, we aimed to characterize two new models of CRC cachexia. Male NSG mice were injected subcutaneously (HCT116) or intrasplenically (mHCT116) with human HCT116 CRC tumor cells to disseminate LM, whereas experimental controls received saline (n=5-8/group). Tumor growth was accompanied by loss of skeletal muscle mass (HCT116: -20%; mHCT116: -31%; quadriceps muscle) and strength (HCT116: -20%; mHCT116: -27%), with worsened loss of skeletal muscle mass in mHCT116 compared with HCT116 (gastrocnemius: -19%; tibialis anterior: -22%; quadriceps: -21%). Molecular analyses revealed elevated protein ubiquitination in HCT116, whereas mHCT116 also displayed elevated Murf1 and atrogin-1 expression, along with reduced mitochondrial proteins PGC1α, OPA1, mitofusin 2 and cytochrome C. Further, elevated IL6 levels were found in the blood of mHCT116 hosts, which was associated with higher phosphorylation of STAT3 in skeletal muscle. To clarify whether STAT3 was a main player in muscle wasting in this model, HCT116 cells were co-cultured with C2C12 myotubes. Marked myotube atrophy (-53%) was observed, along with elevated phospho-STAT3 levels (+149%). Conversely, inhibition of STAT3 signaling by means of a JAK/STAT3 inhibitor was sufficient to rescue myotube atrophy induced by HCT116 cells (+55%). Overall, our results indicate that the formation of LM exacerbates cachectic phenotype and associated skeletal muscle molecular alterations in HCT116 tumor hosts.Item Histopathologic Features of Mucosal Head and Neck Cancer Cachexia(Hindawi, 2024-06-27) Jones, Alexander J.; Novinger, Leah J.; Bonetto, Andrea; Davis, Kyle P.; Giuliano, Marelle M.; Mantravadi, Avinash V.; Sim, Michael W.; Moore, Michael G.; Yesensky, Jessica A.; Otolaryngology -- Head and Neck Surgery, School of MedicineObjective: Determine the histopathologic features that correlate with head and neck cancer (HNC) cachexia. Methods: A single-institution, retrospective study was performed on adults with HPV-negative, mucosal squamous cell carcinoma of the aerodigestive tract undergoing resection and free flap reconstruction from 2014 to 2019. Patients with distant metastases were excluded. Demographics, comorbidities, preoperative nutrition, and surgical pathology reports were collected. Comparisons of histopathologic features and cachexia severity were made. Results: The study included 222 predominantly male (64.9%) patients aged 61.3 ± 11.8 years. Cachexia was identified in 57.2% patients, and 18.5% were severe (≥15% weight loss). No differences in demographics were identified between the groups. Compared to control, patients with severe cachexia had lower serum hemoglobin (p=0.048) and albumin (p < 0.001), larger tumor diameter (p < 0.001), greater depth of invasion (p < 0.001), and elevated proportions of pT4 disease (p < 0.001), pN2-N3 disease (p=0.001), lymphovascular invasion (p=0.009), and extranodal extension (p=0.014). Multivariate logistic regression identified tumor size (OR [95% CI] = 1.36 [1.08-1.73]), oral cavity tumor (OR [95% CI] = 0.30 [0.11-0.84]), and nodal burden (OR [95% CI] = 1.16 [0.98-1.38]) as significant histopathologic contributors of cancer cachexia. Conclusions: Larger, more invasive tumors with nodal metastases and aggressive histologic features are associated with greater cachexia severity in mucosal HNC.Item PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia(Wiley, 2019-06) Pin, Fabrizio; Novinger, Leah J.; Huot, Joshua R.; Harris, Robert A.; Couch, Marion E.; O'Connell, Thomas M.; Bonetto, Andrea; Anatomy and Cell Biology, School of MedicineCachexia 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.Item Sarcopenia is associated with blood transfusions in head and neck cancer free flap surgery(Wiley, 2021-04) Jones, Alexander Joseph; Campiti, Vincent J.; Alwani, Mohamedkazim; Novinger, Leah J.; Tucker, Brady Jay; Bonetto, Andrea; Yesensky, Jessica A.; Sim, Michael W.; Moore, Michael G.; Mantravadi, Avinash V.; Otolaryngology -- Head and Neck Surgery, School of MedicineObjective: 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.Item An Unusual Retropharyngeal Lesion(AMA, 2021) Yang, Christine J.; Novinger, Leah J.; Sim, Michael W.; Otolaryngology -- Head and Neck Surgery, School of MedicineA female smoker in her 50s was referred for hyperparathyroidism and a multinodular goiter. The patient reported symptoms of joint and musculoskeletal pain and fatigue but denied fever, sore throat, abdominal pain, and kidney stones. Her medical history was remarkable for congestive heart failure and schizophrenia. Neck examination revealed no meaningful findings except right thyroid enlargement. Results of laboratory evaluation demonstrated normal white blood cell count, borderline hypercalcemia (10.6 mg/dL), and elevated parathyroid hormone level (208 pg/mL). She underwent ultrasonography at an outside facility, and results demonstrated a 2.2-cm dominant right thyroid nodule with additional smaller thyroid nodules. Findings of preoperative technetium-99m (Tc-99m) sestamibi planar and single-photon emission computed tomographic/computed tomographic (SPECT/CT) imaging (Figure, A) were nonlocalizing for a parathyroid adenoma and showed increased uptake in the dominant right thyroid nodule (Figure, B). Results of an ultrasound-guided biopsy of the thyroid nodule demonstrated a benign colloid nodule with cystic changes. Computed tomography with intravenous contrast was obtained, and findings were initially reported as negative except for right multinodular goiter. However, on additional review, a well-circumscribed fat density mass measuring 3.0 × 2.3 × 1.1-cm was identified in the right retropharyngeal space posterior to the hypopharynx (Figure, C).