Patrick Tassone

Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis

Background. Metabolism in the tumor microenvironment can play a critical role in tumorigenesis and tumor aggression. Metabolic coupling may occur between tumor compartments; this phenomenon can be prognostically significant and may be conserved across tumor types. Monocarboxylate transporters (MCTs) play an integral role in cellular metabolism via lactate transport and have been implicated in metabolic synergy in tumors. The transporters MCT1 and MCT4 are regulated via expression of their chaperone, CD147. Methods. We conducted a meta-analysis of existing publications on the relationship between MCT1, MCT4, and CD147 expression and overall survival and disease-free survival in cancer, using hazard ratios derived via multivariate Cox regression analyses. Results. Increased MCT4 expressions in the tumor microenvironment, cancer cells, or stromal cells were all associated with decreased overall survival and decreased disease-free survival (p < 0.001 for all analyses). Increased CD147 expression in cancer cells was associated with decreased overall survival and disease-free survival (p < 0.0001 for both analyses). Few studies were available on MCT1 expression; MCT1 expression was not clearly associated with overall or disease-free survival. Conclusion. MCT4 and CD147 expression correlate with worse prognosis across many cancer types. These results warrant further investigation of these associations.

TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer.

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer.

Metformin effects on head and neck squamous carcinoma microenvironment: window of opportunity trial

The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in head and neck squamous cell carcinoma (HNSCC). We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors.

Multicompartment metabolism in papillary thyroid cancer

In many cancers, varying regions within the tumor are often phenotypically heterogeneous, including their metabolic phenotype. Further, tumor regions can be metabolically compartmentalized, with metabolites transferred between compartments. When present, this metabolic coupling can promote aggressive behavior. Tumor metabolism in papillary thyroid cancer (PTC) is poorly characterized.

Thyroid Cancer Metabolism: A Review

Metabolic dysregulation within the tumor microenvironment (TME) is critical to the process of tumorigenesis in various cancer types. Thyrocyte metabolism in papillary and anaplastic thyroid cancer, however, remains poorly characterized, and studies analyzing the role of multicompartment metabolism in thyrocyte oncogenesis are sparse. We present a review of the current knowledge on cellular metabolism in non-cancerous and cancerous thyroid tissues, focusing on the monocarboxylate transporters MCT1 and MCT4, and on a transporter of the outer mitochondrial membrane TOMM20. Understanding the metabolic phenotype of tumor cells and associated stromal cells in thyroid cancer can have profound implications on the use of biomarker staining in detecting subclinical cancer, imaging as it relates to expression of various transport proteins, and therapeutic interventions that manipulate this dysregulated tumor metabolism to halt tumorigenesis and eradicate the cancer. Future studies are required to confirm the prognostic significance of these biomarkers and their correlation with existing staging schemas such as the AGES, AMES, ATA and MACIS scoring systems.

Pathologic Markers in Surgically Treated HPV-Associated Oropharyngeal Cancer: Retrospective Study, Systematic Review, and Meta-analysis

Objective: Human papillomavirus–associated (HPV) oropharyngeal cancer is a unique clinical entity whose incidence is increasing. It is controversial whether traditional pathologic markers of aggressive head and neck cancer also apply in surgically treated HPV-associated disease. Study Design: Retrospective study, systematic review, and meta-analysis Data Sources: PubMed and Cochrane review. Review Methods: PubMed and Cochrane review were searched for published articles on surgically treated HPV-associated oropharyngeal cancer. Eligible studies were included in a meta-analysis of survival using several clinicopathologic markers as predictors. Surgically treated HPV-positive oropharyngeal cancer patients at our institution were studied retrospectively and added to the meta-analysis. Results: Eight published reports, plus our retrospective series, were included in the meta-analysis. This showed significant impact on event-free survival for T stage, nodal number, perineural invasion, and lymphovascular invasion (all P < .05) but not for N stage extracapsular extension (P = ns). Conclusions: While many traditional clinico-pathologic markers of aggressive disease in head and neck cancer also impact survival in surgically treated HPV-associated oropharyngeal cancer, extracapsular extension may be less important.

Water Clear Cell Parathyroid Adenoma: Case Report and Literature Review

Water clear cell parathyroid adenoma is a rare cause of primary hyperparathyroidism. In this rare disease entity, normal parathyroid tissue is replaced with growth of water-clear cells, instead of the chief cell hyperplasia associated with the majority of parathyroid adenomas. We present the case of a water clear cell parathyroid adenoma in a 54 year old woman with symptomatic hypercalcemia, as well as a review of the literature on this rare disease. This constitutes the 17th reported case of water clear cell parathyroid adenoma.

Metformin Effects on Metabolic Coupling and Tumor Growth in Oral Cavity Squamous Cell Carcinoma Coinjection Xenografts

Objective Many aggressive head and neck cancers contain 2 metabolically coupled tumor compartments: a glycolytic stromal compartment with low caveolin-1 (CAV1) and high monocarboxylate transporter 4 (MCT4) expression and a highly proliferative carcinoma cell compartment with high MCT1. Metabolites are shuttled by MCTs from stroma to carcinoma to fuel tumor growth. We studied the effect of carcinoma-fibroblast coinjection and metformin administration on a mouse model of head and neck squamous cell carcinoma. Study Design Xenograft head and neck squamous cell carcinoma model. Setting Basic science laboratory. Subjects and Methods Oral cavity carcinoma cells were injected alone or as coinjection with human fibroblasts into nude mice to generate xenograft tumors. Tumors were excised and stained with immunohistochemistry for markers of metabolic coupling and apoptosis, including MCT1, MCT4, CAV1, and TUNEL assay (terminal deoxynucleotidyl transferase nick end labeling). Strength of staining was assessed by a pathologist or computer-assisted pathology software. Metformin was administered orally to mice to test effects on immunohistochemical markers in xenografts. Results Coinjection tumors were 2.8-fold larger (P = .048) and had 1.4-fold stronger MCT1 staining (P = .016) than tumors from homotypic carcinoma cell injection. Metformin decreased the size of coinjection xenograft tumors by 45% (P = .025). Metformin reduced MCT1 staining by 28% (P = .05) and increased carcinoma cell apoptosis 1.8-fold as marked by TUNEL assay (P = .005). Metformin did not have a significant effect on tumor size when CAV1 knockdown fibroblasts were used in coinjection. Conclusion Coinjection with fibroblasts increases tumor growth and metabolic coupling in oral cavity cancer xenografts. Fibroblast CAV1 expression is required for metformin to disrupt metabolic coupling and decrease xenograft size.

Tumor Metabolism in the Microenvironment of Nodal Metastasis in Oral Squamous Cell Carcinoma

Objective In many cancers, including head and neck squamous cell carcinoma (HNSCC), different regions within a tumor have different metabolic phenotypes. Transfer of metabolites between compartments promotes tumor growth and aggressive behavior. Metabolic compartmentalization in HNSCC nodal metastases has not been studied, nor has its impact on extracapsular extension or clinical outcomes been determined. Study Design Retrospective analysis based on immunohistochemistry staining. Setting Tertiary care center. Subjects and Methods Primary tumors and nodal metastases from 34 surgically treated oral cavity HNSCC patients with extracapsular extension (ECE) were stained for monocarboyxlate transporter (MCT) 4, MCT1, translocase of outer mitochondrial membrane 20, and Ki-67. Strength of staining was assessed using a computer-assisted pathology algorithm. Immunohistochemistry (IHC) scores along with clinical factors were used to predict disease-free survival (DFS). Results Patterns of IHC staining showed metabolic compartmentalization both at the primary tumor sites and in nodal metastases. MCT4 staining in the perinodal stroma was significantly higher in specimens with ECE greater than 1 mm (macro-ECE, P = .01). Patients with high perinodal MCT4 staining were compared with those with low perinodal MCT4 staining. On multivariate analysis, only high perinodal MCT4 staining had a significant impact on DFS (P = .02); patients with high perinodal MCT4 had worse survival. DFS was not significantly worsened by advancing T stage, N stage, ECE extent, or perineural invasion. Conclusion Oral HNSCC displays compartmentalized tumor metabolism at both primary and metastases. Greater cancer-associated stromal conversion around ECE, denoted by high stromal MCT4, may be a biomarker for aggressive disease and worsened DFS.

Unplanned readmission following transoral robotic surgery

OBJECTIVES To determine the rate of unplanned readmission after transoral robotic surgery (TORS), and to determine which patient or surgical factors increase the likelihood of readmission. MATERIALS AND METHODS Retrospective chart review of all patients who underwent TORS for squamous cell carcinoma at our institution from March 2010 through July 2016. Primary outcome was unplanned readmission to the hospital within 30 days of discharge. Univariable and multivariable logistic regression were performed to identify risk factors for unplanned readmission. RESULTS 297 patients met eligibility criteria. 23 patients (7.7%) had unplanned readmissions within 30 days. Most common reasons for readmission were oropharyngeal bleed (n = 13) and pain/dehydration (n = 10). Average time to unplanned readmission was 6.52 days (range 0-25 days). Discharge on clopidogrel was the only variable independently associated with an increased risk of 30-day unplanned readmission on multivariable analysis with an OR = 6.85 (95% CI 1.59-26.36). Unplanned return to the operating room during initial hospitalization (OR = 7.55, 95% CI 1.26-38.50) and discharge on clopidogrel (OR = 10.45, 95% CI 1.06-82.69) were associated with increased risk of postoperative bleeding. Bilateral neck dissection (OR = 5.17, 95% CI 1.15-23.08) was associated with significantly increased odds of unplanned readmission secondary to pain and dehydration. CONCLUSION Unplanned readmission following TORS occurs in a small but significant number of patients. Oropharyngeal bleeding and dehydration were the most common reasons for unplanned readmission following TORS.