David Cognetti

Quality of Life, Functional Outcome, and Costs of Early Glottic Cancer†

Objective To analyze quality of life, functional outcome, and hidden costs by primary treatment with surgery or radiation therapy in patients with early glottic cancer.

Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer

Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (OXPHOS) and the uptake of mitochondrial fuels, as detected via MCT1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/TOMM20+/COX+/MCT1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67−/TOMM20−/COX−/MCT1−); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67−/TOMM20−/COX−/MCT1−). In addition, high oxidative stress (MCT4+) was very specific for cancer tissues. Thus, we next evaluated the prognostic value of MCT4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCT4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-PET avidity (p < 0.04). Similarly, oxidative stress (MCT4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCT4 inhibitors should be developed to metabolically target “three-compartment tumor metabolism” in head and neck cancers. It is remarkable that two “non-proliferating” populations of cells (Ki-67−/MCT4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial “fuels” for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial “stem cell” layer is hyper-proliferative (Ki-67+), mitochondrial-rich (TOMM20+/COX+) and is metabolically programmed to use mitochondrial fuels (MCT1+), such as ketone bodies and L-lactate. Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target “metabolic symbiosis.”

Head and Neck Cancer: An Evolving Treatment Paradigm

Since the inception of this journal in 1948, the understanding of etiologic factors that contribute to and the treatment of head and neck cancer has evolved dramatically. Advances in surgery, radiation therapy, and chemotherapy have improved locoregional control, survival, and quality of life. The outcomes of these treatment modalities have shifted the focus of curative efforts from radical ablation to preservation and restoration of function. This evolution has been documented in the pages of Cancer for the past 6 decades. This review focuses on the evolution of treatment approaches for head and neck cancer and future directions while recognizing the historic contributions recorded within this journal. Cancer 2008;113(7 suppl):1911–32.

The Candida albicans 14-3-3 gene, BMH1, is essential for growth

The 14‐3‐3 proteins are a family of conserved small acidic proteins that have been implicated in playing major roles in a wide variety of signalling cascades. In Saccharomyces cerevisiae, the 14‐3‐3 genes (BMH1 and BMH2) are essential for normal pseudohyphal induction and normal bud cell development. The Bmh proteins function in the cAMP‐dependent RAS/MAPK and rapamycin‐sensitive signalling cascades. Deletion of only one BMH gene demonstrates no phenotypic differences under normal growth conditions. Strains deleted of both BMH1 and BMH2 are either non‐viable or demonstrate sensitivity to environmental stresses. In Schizosaccharomyces pombe, the BMH homologues (RAD24 and RAD25) are essential for cell cycle control after DNA damage and deletion of both genes renders the cell inviable. The 14‐3‐3 gene in Candida albicans (BMH1) was identified using a novel adherence assay and differential display RT–PCR. Unlike other yeasts, C. albicans has only one 14‐3‐3 gene (BMH1). It was not possible to construct double knockouts by routine methods. These results suggested that the C. albicans BMH1 gene is essential. The essentiality of C. albicans BMH1 was confirmed by a PCR disruption technique. The C. albicans bmh1Δ/BMH1 heterozygotes exhibit growth and morphogenetic defects. Therefore, the BMH1 gene in C. albicans (Accession No. AF038154) isan excellent candidate to improve our understanding of the coordinate regulation of cell cycle and morphogenesis. Copyright

Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4

Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of “normal” and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the “bystander” effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for “metabolic symbiosis” between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial “lactate-shuttle”, to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as “partners” for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an “MCT4 inhibitor”. Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish “metabolic parasites”, like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted “antibiotics” to selectively starve cancer cells. Our results provide new support for the “seed and soil” hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget.

Detection of evolving injury to the brachial plexus during transaxillary robotic thyroidectomy.

Continuous intraoperative neuromonitoring (IONM) of transcranial electric motor evoked potentials (tceMEPs) and somatosensory evoked potentials (SSEPs) has gained universal acceptance as an efficacious method for detecting emerging positional brachial plexopathy or peripheral nerve compression during spinal and shoulder surgery. This has implications for transaxillary thyroid surgery.

Early Adoption of Transoral Robotic Surgical Program Preliminary Outcomes

Objective The objective of this study is to demonstrate the feasibility and safety of establishing a transoral robotic surgical (TORS) program in the post–Food and Drug Administration (FDA) approval setting. Early outcomes are compared with the previously reported results of pioneering centers. Study Design Clinical data from a prospective TORS study. Setting Academic university institution. Subjects and Methods Sixty-one patients treated with 63 TORS procedures. Main outcome measures: intraoperative times, margin status, complications, time to diet, and percutaneous endoscopic gastrostomy (PEG) tube retention rate. The authors also report oncologic outcomes on their first 30 patients. Results The spectrum of subsites included tongue base, tonsil, parapharyngeal space, retromolar trigone, supraglottis, and posterior pharyngeal wall. Surgical console time averaged 79 ± 53 minutes. After re-resection of 4 patients, final negative margin status was 94% (50/53). A subset of 30 patients with squamous cell carcinoma reaching an average of 18 months of follow-up had a local regional control rate of 97% with a disease-free survival rate of 90%. The PEG tube retention rate was 7%. Complications included 2 readmissions with dehydration, 1 aspiration pneumonia, and 2 with minor oropharyngeal bleeding. Ninety-one percent of patients resumed an oral diet by the first postoperative visit. Conclusion The initiation of a TORS program in the post-FDA setting can be achieved in a safe and efficient manner. Early results of pioneering TORS centers are reproducible. Continued investigation of TORS as a treatment option for oropharygneal carcinoma is warranted.

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.

Ultrasound-guided contrast-enhanced sentinel node biopsy of the head and neck in a porcine model

Objective To test the feasibility of contrast-enhanced ultrasound (CEUS)–guided sentinel lymph node biopsy (SNB) of the head and neck in a porcine model. Study Design and Setting In this prospective, non-randomized study, methylene blue and Sonazoid were injected into the lateral tongue or floor of mouth (FOM) of four swine. Real-time CEUS was used to identify contrast in the lymphatic channels flowing to the sentinel lymph node (SLN). Endoscopic or open SNB was performed. Neck dissection was then performed, and the residual nodal packet was examined for remaining contrast-enhancing or blue dye–stained nodes. Results In all eight procedures, the SLN was visualized with ultrasound and blue dye. Seven procedures identified a single SLN, and one identified two SLNs. Subsequent neck dissections revealed no other nodes containing methylene blue or contrast in the nodal specimen or operative bed. Conclusion/Significance CEUS-guided SNB of the head and neck in swine is feasible, with success comparable to blue dye–guided SNB. This technique may offer several advantages over traditional techniques, and warrants further study.

Management of aerodigestive tract foreign bodies: innovative teaching concepts.

Objectives: We discuss a method to provide medical education in bronchoesophagology by using high-fidelity patient simulation manikins. Methods: A sophisticated, life-sized infant manikin with realistic anatomic, physiologic, and hemodynamic responses to interventions was programmed to simulate endobronchial foreign body lodgment by blocking ventilation of one lung and manifesting audible stridor, asymmetric chest wall motion, and decreased oxygen saturation. Results: Otolaryngology residents participated in simulation exercises incorporating the cognitive and technical skills necessary for successful airway endoscopy, including technical proficiency and teamwork, to learn to coordinate endoscopy and ventilation and manage laryngospasm. Rather than relying on instructor description, the participants responded directly to the manikin. This sense of realism stimulated participants to rehearse to improve provider performance and patient safety. Simulation provided an agenda determined by the needs of the learners, exploration without direct risk to patients, immediate feedback, and objective documentation. Conclusions: Rapidly evolving medical simulation technologies support activated, effective adult learning; they will play an increasing role in medical education.