Michael E. Kupferman

Endoscopic Resection of Sinonasal Cancers With and Without Craniotomy: Oncologic Results

OBJECTIVE To evaluate the oncologic outcomes of patients with sinonasal cancer treated with endoscopic resection. DESIGN Retrospective review. SETTING Tertiary care academic cancer center. PATIENTS All patients with biopsy-proved malignant neoplasm of the sinonasal region who were treated with endoscopic resection between 1992 and 2007 were included in the study, and their charts were reviewed for demographics, histopathologic findings, treatment details, and outcome. MAIN OUTCOME MEASURES Oncologic outcomes, including disease recurrence and survival. RESULTS Of a total of 120 patients, 93 (77.5%) underwent an exclusively endoscopic approach (EEA) and 27 (22.5%) underwent a cranioendoscopic approach (CEA) in which the surgical resection involved the addition of a frontal or subfrontal craniotomy to the transnasal endoscopic approach. Of the 120 patients, 41% presented with previously untreated disease, 46% presented with persistent disease that had been partially resected, and 13% presented with recurrent disease after prior treatment. The most common site of tumor origin was the nasal cavity (52%), followed by the ethmoid sinuses (28%). Approximately 10% of the tumors had an intracranial epicenter, most commonly around the olfactory groove. Tumors extended to or invaded the skull base in 20% and 11% of the patients, respectively. An intracranial epicenter (P < .001) and extension to (P = .001) or invasion of (P < .001) the skull base were significantly more common in patients treated with CEA than in those treated with EEA. The primary T stage was evenly distributed across all patients as follows: T1, 25%; T2, 25%; T3, 22%; and T4, 28%. However, the T-stage distribution was significantly different between the EEA group and the CEA group. Approximately two-thirds (63%) of the patients treated with EEA had a lower (T1-2) disease stage, while 95% of patients treated with CEA had a higher (T3-4) disease stage (P < .001). The most common tumor types were esthesioneuroblastoma (17%), sarcoma (15%), adenocarcinoma (14%), melanoma (14%), and squamous cell carcinoma (13%). Other, less common tumors included adenoid cystic carcinoma (7%), neuroendocrine carcinoma (4%), and sinonasal undifferentiated carcinoma (2%). Microscopically positive margins were reported in 15% of patients. Of the 120 patients, 50% were treated with surgery alone, 37% received postoperative radiation therapy, and 13% were treated with surgery, radiation therapy, and chemotherapy. The overall surgical complication rate was 11% for the whole group. Postoperative cerebrospinal fluid leakage occurred in 4 of 120 patients (3%) and was not significantly different between the CEA group (1 of 27 patients) and the EEA group (3 of 93 patients) (P > .99). The cerebrospinal fluid leak resolved spontaneously in 3 patients, and the fourth patient underwent successful endoscopic repair. With a mean follow-up of 37 months, 18 patients (15%) experienced local recurrence, with a local disease control of 85%. Regional and distant failure occurred as the first sign of disease recurrence in 6% and 5% of patients, respectively. The 5- and 10-year disease-specific survival rates were 87% and 80%, respectively. Disease recurrence and survival did not differ significantly between the EEA group and the CEA group. CONCLUSIONS To the best of our knowledge, this is the largest US series to date of patients with malignant tumors of the sinonasal tract treated with endoscopic resection. Our results suggest that, in well-selected patients and with appropriate use of adjuvant therapy, endoscopic resection of sinonasal cancer results in acceptable oncologic outcomes.

Gene expression signature predicts lymphatic metastasis in squamous cell carcinoma of the oral cavity

Metastasis via the lymphatics is a major risk factor in squamous cell carcinoma of the oral cavity (OSCC). We sought to determine whether the presence of metastasis in the regional lymph node could be predicted by a gene expression signature of the primary tumor. A total of 18 OSCCs were characterized for gene expression by hybridizing RNA to Affymetrix U133A gene chips. Genes with differential expression were identified using a permutation technique and verified by quantitative RT–PCR and immunohistochemistry. A predictive rule was built using a support vector machine, and the accuracy of the rule was evaluated using crossvalidation on the original data set and prediction of an independent set of four patients. Metastatic primary tumors could be differentiated from nonmetastatic primary tumors by a signature gene set of 116 genes. This signature gene set correctly predicted the four independent patients as well as associating five lymph node metastases from the original patient set with the metastatic primary tumor group. We concluded that lymph node metastasis could be predicted by gene expression profiles of primary oral cavity squamous cell carcinomas. The presence of a gene expression signature for lymph node metastasis indicates that clinical testing to assess risk for lymph node metastasis should be possible.

Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson cancer center

Sinonasal mucosal melanoma is a rare disease associated with a very poor prognosis. Because most of the series extend retrospectively several decades, we sought to determine prognostic factors and outcomes with recent treatment modalities.

Matrix Metalloproteinase 9 Promoter Activity Is Induced Coincident with Invasion during Tumor Progression

Matrix metalloproteinase 9 (MMP-9, also known as gelatinase B or 92-kd Type IV collagenase) is overexpressed in many human and murine cancers. We induced carcinomas in mice carrying a transgene that links the MMP-9 promoter to the reporter ss-galactosidase so that activation of the MMP-9 promoter would be indicated by ss-galactosidase. Mammary carcinomas were induced by mating the MMP-9 promoter reporter transgenic mice with mice carrying a transgene for murine mammary tumor virus promoter linked to polyoma middle T antigen, a transgene that leads to rapid development of mammary tumors in female mice. None of the hyperplastic mammary glands and none of the carcinomas in situ expressed ss-galactosidase. However, all invasive tumors had evidence of ss-galactosidase expression. In addition to the breast carcinomas, a malignant teratoma in a female and a papillary adenocarcinoma in the pelvic region of a male arose and were also ss-galactosidase positive. We also induced skin tumors in the mice with the MMP-9 reporter transgene with 7, 12-dimethylbenz[a]anthracene (DMBA) treatment followed by phorbol 12 myristate 13-acetate (TPA). None of the papillomas or in situ carcinomas showed any ss-galactosidase expression, but expression was seen in invasive carcinoma. Although normal skin epithelial cells did not express ss-galactosidase, we did find staining in a few cells at the duct of the sebaceous gland at the base of the hair follicles. The MMP-9 reporter transgene did not lead to expression in the alveolar macrophages, confirming that additional upstream sequences are required for expression in macrophages. These experiments have revealed that MMP-9 promoter activity is induced coincident with invasion during tumor progression. Furthermore, this indicates that the more proximal upstream elements of the promoter are sufficient for MMP-9 transcription during tumor progression.

TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) remains a significant public health problem, accounting for over 5% of all cancer-related deaths, and these deaths primarily result from metastatic disease. The molecular processes involved in HNSCC pathogenesis and progression are poorly understood, and here we present experimental evidence for a direct role of the cell surface receptor tyrosine kinase, TrkB, in HNSCC tumor progression. Using immunohistochemical analysis and transcriptional profiling of archival HNSCC tumor specimens, we found that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are expresses in greater than 50% of human HNSCC tumors, but not in normal upper aerodigestive tract (UADT) epithelia. Studies with HNSCC cell lines reveal that in vitro stimulation with BDNF, the ligand for TrkB, upregulates the migration and invasion of HNSCC cells, and both transient and stable suppressions of TrkB result in significant abrogation of constitutive and ligand-mediated migration and invasion. Furthermore, enforced overexpression of TrkB results in altered expression of molecular mediators of epithelial-to-mesenchymal transition (EMT), including downregulation of E-cadherin and upregulation of Twist. Using an in vivo mouse model of HNSCC, we were able to show that downregulation of TrkB suppresses tumor growth. These results directly implicate TrkB in EMT and the invasive behavior of HNSCC, and correlate with the in vivo overexpression of TrkB in human HNSCC. Taken together, these data suggest that the TrkB receptor may be a critical component in the multi-step tumor progression of HNSCC, and may be an attractive target for much needed new therapies for this disease.

Coronary Microvascular Pericytes Are the Cellular Target of Sunitinib Malate–Induced Cardiotoxicity

Sunitinib-induced cardiotoxicity is caused by depletion of coronary pericytes due to loss of PDGFR signaling; this side effect can be prevented by thalidomide. Saving Pericytes to Prevent a Broken Heart In the world of targeted cancer therapies, sunitinib is a versatile one, targeting a variety of tyrosine kinase receptors. The breadth of its activity allows it to be effective in multiple different types of cancer but also increases the chances of unintended adverse effects. One such side effect is cardiotoxicity, with frequent reports of left ventricular dysfunction and heart failure in patients treated with sunitinib. Chintalgattu and co-workers have now uncovered the mechanism for this toxicity and demonstrated a way to protect the heart from treatment-induced damage in a mouse model. Pericytes are contractile cells that wrap around small blood vessels and are essential to their function. After sunitinib treatment, pericytes were no longer coating the coronary microvasculature in a mouse model. The blood vessels depleted of pericytes were unusually leaky, and the hearts of treated animals showed clear evidence of cardiac dysfunction. The depletion of pericytes was caused by the inhibition of signaling through platelet-derived growth factor receptor (PDGFR), a known target of sunitinib. The authors also discovered that thalidomide, a small-molecule drug that is already used in humans for the treatment of some cancers, could protect pericytes and prevent sunitinib-induced cardiotoxicity without affecting the antitumor effects of sunitinib. Future studies will be needed to uncover additional mechanism explaining why coronary pericytes in particular are so sensitive to inhibition of PDGFR and how thalidomide can protect these cells from toxicity. Eventually, this research could enable the creation of more specific targeted drugs that inhibit the kinases driving cancer cell proliferation without injuring pericytes and other healthy cells. In the meantime, the current findings of Chintalgattu et al. provide a rationale for testing the combination of thalidomide and sunitinib in human cancer patients to protect the patients’ hearts from injury while continuing to effectively target cancer cells. Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor used in the treatment of human malignancies. A substantial number of sunitinib-treated patients develop cardiac dysfunction, but the mechanism of sunitinib-induced cardiotoxicity is poorly understood. We show that mice treated with sunitinib develop cardiac and coronary microvascular dysfunction and exhibit an impaired cardiac response to stress. The physiological changes caused by treatment with sunitinib are accompanied by a substantial depletion of coronary microvascular pericytes. Pericytes are a cell type that is dependent on intact platelet-derived growth factor receptor (PDGFR) signaling but whose role in the heart is poorly defined. Sunitinib-induced pericyte depletion and coronary microvascular dysfunction are recapitulated by CP-673451, a structurally distinct PDGFR inhibitor, confirming the role of PDGFR in pericyte survival. Thalidomide, an anticancer agent that is known to exert beneficial effects on pericyte survival and function, prevents sunitinib-induced pericyte cell death in vitro and prevents sunitinib-induced cardiotoxicity in vivo in a mouse model. Our findings suggest that pericytes are the primary cellular target of sunitinib-induced cardiotoxicity and reveal the pericyte as a cell type of concern in the regulation of coronary microvascular function. Furthermore, our data provide preliminary evidence that thalidomide may prevent cardiotoxicity in sunitinib-treated cancer patients.

Sinonasal adenoid cystic carcinoma: the M. D. Anderson Cancer Center experience.

Adenoid cystic carcinoma of the sinonasal tract is a rare cancer that accounts for 10% of all malignancies at this site. The objective of the current study was to evaluate prognostic factors, treatment outcomes, recurrence patterns, and survival rates for sinonasal adenoid cystic carcinoma.

Oncologic Outcomes After Transoral Robotic Surgery : A Multi-institutional Study

IMPORTANCE Large patient cohorts are necessary to validate the efficacy of transoral robotic surgery (TORS) in the management of head and neck cancer. OBJECTIVES To review oncologic outcomes of TORS from a large multi-institutional collaboration and to identify predictors of disease recurrence and disease-specific mortality. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of records from 410 patients undergoing TORS for laryngeal and pharyngeal cancers from January 1, 2007, through December 31, 2012, was performed. Pertinent data were obtained from 11 participating medical institutions. INTERVENTIONS Select patients received radiation therapy and/or chemotherapy before or after TORS. MAIN OUTCOMES AND MEASURES Locoregional control, disease-specific survival, and overall survival were calculated. We used Kaplan-Meier survival analysis with log-rank testing to evaluate individual variable association with these outcomes, followed by multivariate analysis with Cox proportional hazards regression modeling to identify independent predictors. RESULTS Of the 410 patients treated with TORS in this study, 364 (88.8%) had oropharyngeal cancer. Of these 364 patients, information about post-operative adjuvant therapy was known about 338: 106 (31.3) received radiation therapy alone, and 72 (21.3%) received radiation therapy with concurrent chemotherapy. Neck dissection was performed in 323 patients (78.8%). Mean follow-up time was 20 months. Local, regional, and distant recurrence occurred in 18 (4.4%), 15 (3.7%), and 10 (2.4%) of 410 patients, respectively. Seventeen (4.1%) died of disease, and 13 (3.2%) died of other causes. The 2-year locoregional control rate was 91.8% (95% CI, 87.6%-94.7%), disease-specific survival 94.5% (95% CI, 90.6%-96.8%), and overall survival 91% (95% CI, 86.5%-94.0%). Multivariate analysis identified improved survival among women (P = .05) and for patients with tumors arising in tonsil (P = .01). Smoking was associated with worse overall all-cause mortality (P = .01). Although advanced age and tobacco use were associated with locoregional recurrence and disease-specific survival, they, as well as tumor stage and other adverse histopathologic features, did not remain significant on multivariate analysis. CONCLUSIONS AND RELEVANCE This large, multi-institutional study supports the role of TORS within the multidisciplinary treatment paradigm for the treatment of head and neck cancer, especially for patients with oropharyngeal cancer. Favorable oncologic outcomes have been found across institutions. Ongoing comparative clinical trials funded by the National Cancer Institute will further evaluate the role of robotic surgery for patients with head and neck cancers.

Prognostic factors in mucoepidermoid carcinoma of the salivary glands

Mucoepidermoid carcinoma (MEC) is the most common malignancy of the major salivary glands. Prior reports noted histological grade and tumor stage as consistently important prognostic factors. This study reviewed the experience of patients with MEC at the University of Texas MD Anderson Cancer Center to determine the impact of clinical and pathologic findings on disease outcomes.

Prognosis and risk factors for early-stage adenoid cystic carcinoma of the major salivary glands

Adenoid cystic carcinoma (ACC) is characterized by slow growth, frequent local recurrences, and distant metastasis (DM). However, these findings frequently are reported in patients with advanced‐stage tumors, but the outcomes of early‐stage tumors are poorly defined. We sought to evaluate the risk factors for the development of DM in early‐stage ACC.