Ziv Gil

Current concepts in management of oral cancer--surgery.

Oral cancer is the sixth most common cancer worldwide, with a high prevalence in South Asia. Tobacco and alcohol consumption remain the most dominant etiologic factors, however HPV has been recently implicated in oral cancer. Surgery is the most well established mode of initial definitive treatment for a majority of oral cancers. The factors that affect choice of treatment are related to the tumor and the patient. Primary site, location, size, proximity to bone, and depth of infiltration are factors which influence a particular surgical approach. Tumors that approach or involve the mandible require specific understanding of the mechanism of bone involvement. This facilitates the employment of mandible sparing approaches such as marginal mandibulectomy and mandibulotomy. Reconstruction of major surgical defects in the oral cavity requires use of a free flap. The radial forearm free flap provides excellent soft tissue and lining for soft tissue defects in the oral cavity. The fibula free flap remains the choice for mandibular reconstruction. Over the course of the past thirty years there has been improvement in the overall survival of patients with oral carcinoma largely due to the improved understanding of the biology of local progression, early identification and treatment of metastatic lymph nodes in the neck, and employment of adjuvant post-operative radiotherapy or chemoradiotherapy. The role of surgery in primary squamous cell carcinomas in other sites in the head and neck has evolved with integration of multidisciplinary treatment approaches employing chemotherapy and radiotherapy either sequentially or concurrently. Thus, larynx preservation with concurrent chemoradiotherapy has become the standard of care for locally advanced carcinomas of the larynx or pharynx requiring total laryngectomy. On the other hand, for early staged tumors of the larynx and pharynx, transoral laser microsurgery has become an effective means of local control of these lesions. Advances in skull base surgery have significantly improved the survivorship of patients with malignant tumors of the paranasal sinuses approaching or involving the skull base. Surgery thus remains the mainstay of management of a majority of neoplasms arising in the head and neck area. Similarly, the role of the surgeon is essential throughout the life history of a patient with a malignant neoplasm in the head and neck area, from initial diagnosis through definitive treatment, post-treatment surveillance, management of complications, rehabilitation of the sequelae of treatment, and finally for palliation of symptoms.

Lymph node density is a significant predictor of outcome in patients with oral cancer

The impact of lymph node metastases on prognosis in patients with oral cavity squamous cell carcinoma (OSCC) has been well recognized. However, accurate stratification of risk for recurrence among patients with lymph node metastases is difficult based on the existing staging systems. In the current study, the utility of lymph node density (LND) was evaluated as an alternative method for predicting survival.

Surgical management of parapharyngeal space tumors: a 10-year review.

OBJECTIVE: The purpose of this article is to describe the diagnostic evaluation and surgical approaches to parapharyngeal space tumors in a tertiary referral center. STUDY DESIGN AND SETTING: The study is a retrospective review of 47 patients diagnosed with tumors of the parapharyngeal space (12 with malignant diseases and 35 with benign lesions) and surgically treated during a 10-year period. The transcervical (40%) and the transcervical-transparotid approaches (46%) were the most commonly performed surgical procedures followed by the orbitozygomatic-middle fossa approach (12%) and the transmandibular approach (2%). RESULTS: The surgical procedures were uneventful and there were no postoperative mortalities. Complications were rare; the most common was transient facial nerve paralysis (5 patients). After an average follow-up of 35 months, only 1 of 35 patients with benign diseases had a recurrence 5 years following transcervical resection of a pleomorphic adenoma. Of 12 patients with malignant tumors, 5 (42%) are alive with no evidence of disease. The sensitivity of preoperative fine needle aspiration biopsy (n = 23 patients) was 87% for detection of malignant disease and specificity was 100%. CONCLUSIONS: Most benign parapharyngeal space tumors can be removed surgically with a low rate of complications and recurrence. Malignant neoplasms, however, carry an ominous prognosis and a low rate of disease-free survival. Fine needle aspiration may be helpful in preoperative diagnostic evaluation of patients with parapharyngeal space tumors.

Paracrine Regulation of Pancreatic Cancer Cell Invasion by Peripheral Nerves

BACKGROUND The ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown. METHODS We used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function. RESULTS Nerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean = 187.1 microm, 95% confidence interval [CI] = 148 to 226 microm vs 14.4 microm, 95% CI = 9.58 to 19.22 microm, difference = 143 microm; P < .001; n = 20). PNMC was induced by secretion of GDNF, via phosphorylation of the RET-Ras-mitogen-activated protein kinase pathway. Nerves from mice deficient in GDNF had reduced ability to attract cancer cells (nerve invasion index: wild type vs gdnf+/-, mean = 0.76, 95% CI = 0.75 to 0.77 vs 0.43, 95% CI = 0.42 to 0.44; P < .001; n = 60-66). Tumor specimens excised from patients with neuroinvasive pancreatic carcinoma had higher expression of the GDNF receptors RET and GRFalpha1 as compared with normal tissue. Finally, systemic therapy with pyrazolopyrimidine-1, a tyrosine kinase inhibitor targeting the RET pathway, suppressed nerve invasion toward the spinal cord and prevented paralysis in mice. CONCLUSION These data provide evidence for paracrine regulation of pancreatic cancer invasion by nerves, which may have important implications for potential therapy directed against nerve invasion by cancer.

Olfactory Groove Meningiomas from Neurosurgical and Ear, Nose, and Throat Perspectives: Approaches, Techniques, and Outcomes

OBJECTIVE: To review the surgical approaches, techniques, outcomes, and recurrence rates in a series of 80 olfactory groove meningioma (OGM) patients operated on between 1990 and 2003. METHODS: Eighty patients underwent 81 OGM surgeries. Tumor diameter varied from 2 to 9 cm (average, 4.6 cm). In 35 surgeries (43.2%), the tumor was removed through bifrontal craniotomy; nine operations (11.1%) were performed through a unilateral subfrontal approach; 18 surgeries (22.2%) were performed through a pterional approach; seven surgeries (8.6%) were carried out using a fronto-orbital craniotomy; and 12 procedures (14.8%) were accomplished via a subcranial approach. Nine patients (11.3%) had undergone surgery previously and had recurrent tumor. RESULTS: Total removal was obtained in 72 patients (90.0%); subtotal removal was achieved in 8 patients (10.0%). Two patients, one with total and one with subtotal removal, had atypical (World Health Organization Grade II) meningiomas, whereas 78 patients had World Health Organization Grade I tumors. There was no operative mortality and no new permanent focal neurological deficit besides anosmia. Twenty-five patients (31.3%) experienced surgery-related complications. There were no recurrences in 75 patients (93.8%) 6 to 164 months (mean, 70.8 mo) after surgery. Three patients (3.8%) were lost to follow-up. In two patients (2.5%) with subtotal removal, the residual evidenced growth on computed tomography and/or magnetic resonance imaging 1 year after surgery. One of them had an atypical meningioma. The second, a multiple meningiomata patient, was operated on twice in this series. CONCLUSION: A variety of surgical approaches are used for OGM resection. An approach tailored to the tumor’s size, location, and extension, combined with modern microsurgical cranial base techniques, allows full OGM removal with minimal permanent morbidity, excellent neurological outcome, and very low recurrence rates.

Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase

Resistance to pharmacologic agents used in chemotherapy is common in most human carcinomas, including pancreatic ductal adenocarcinoma (PDA), which is resistant to almost all drugs, including gemcitabine, a nucleoside analog used as a first-line treatment. Poor survival rates of PDA patients have, therefore, not changed much over 4 decades. Recent data indicated that tumor-associated macrophages (TAMs), which are abundant in the microenvironment of several tumors, including PDA, secrete pro-tumorigenic factors that contribute to cancer progression and dissemination. In this study, we show for the first time that TAMs can also induce chemoresistance of PDA by reducing gemcitabine-induced apoptosis. Macrophages co-cultured with cancer cells or TAM-conditioned medium significantly reduced apoptosis and activation of the caspase-3 pathway during gemcitabine treatment. In vivo PDA models of mice, which have reduced macrophage recruitment and activation, demonstrated improved response to gemcitabine compared with controls. Similarly, inhibition of monocytes/macrophages trafficking by a CSF1-receptor antagonist GW2580 augmented the effect of gemcitabine in a transgenic mouse PDA model that was resistant to gemcitabine alone. Analysis of multiple proteins involved in gemcitabine delivery and metabolism revealed that TAMs induced upregulation of cytidine deaminase (CDA), the enzyme that metabolizes the drug following its transport into the cell. Decreasing CDA expression by PDA cells blocked the protective effect of TAMs against gemcitabine. These results provide the first evidence of a paracrine effect of TAMs, which mediates acquired resistance of cancer cells to chemotherapy. Modulation of macrophage trafficking or inhibition of CDA may offer a new strategy for augmenting the response of PDA to chemotherapy.

Lymphoscintigraphy for sentinel node mapping using a hybrid single photon emission CT (SPECT)/CT system in oral cavity squamous cell carcinoma.

We assessed the added clinical value of fused single photon emission computed tomography (SPECT) and low‐dose CT images compared with planar images for sentinel node (SN) mapping in patients with oral cavity squamous cell carcinoma (SCC).

The Role of Pectoralis Major Muscle Flap in Salvage Total Laryngectomy

OBJECTIVE To assess the utility of the pectoralis major muscle flap (PMMF) in patients undergoing salvage total laryngectomy. DESIGN Retrospective cohort analysis. SETTING Tertiary care cancer center. PATIENTS The study included 461 patients who underwent laryngectomy. Eighty of them underwent salvage surgery with primary pharyngeal closure. INTERVENTIONS Of the 80 patients, 69 (86%) underwent primary pharyngeal closure alone and 11 (14%) underwent a PMMF, which was used to buttress the pharyngeal suture line. MAIN OUTCOME MEASURE Two hundred thirty-six variables were recorded for each patient. Complications related to pharyngeal closure were measured. RESULTS Sixty-four percent of the patients who underwent PMMF also underwent chemoradiation therapy as the initial definitive treatment compared with 25% in the non-PMMF group (P = .03). On multivariate analysis, chemoradiation therapy was the only independent predictor of pharyngocutaneous fistula formation (relative risk, 1.82; P = .02). Nevertheless, the pharyngocutaneous fistula rate was similar in the PMMF (27%) and the non-PMMF (24%) groups. Furthermore, similar durations of tube feeding, days to oral feeding, and hospitalization period were recorded in both groups. CONCLUSION The PMMF should be used judiciously as a surgical adjunct in high-risk patients, with the goal of minimizing the risk for the development of a pharyngocutaneous fistula.

Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research

Background:Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed to validate the concept of LND in OSCC.Methods:The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan–Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis.Results:The OS was 49% for patients with LND⩽0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND⩽0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures.Conclusion:This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed.

Curcumin: A new radio-sensitizer of squamous cell carcinoma cells

PURPOSE: Curcumin, a potential chemopreventive agent, was found to inhibit cancer cells in S/G2M phases of the cell cycle, when radiation is more effective. The purpose of the current study was to investigate whether curcumin can sensitize squamous cell carcinoma (SCC) cells to the ionizing effects of irradiation. METHODS: Curcumin (3.5 μM) was added for 48 hours to an SCC cell line prior to irradiation. Cell growth (counts) and colony-formation (colonogenic assay) were examined after radiation. RESULTS: Incubation with curcumin only (3.75 μM) for 48 hours did not decrease the number of cells or the ability to form colonies in the absence of radiation. However, in plates that were exposed to 1–5 Gy of radiation, cell counts dropped significantly if pretreated with curcumin with a maximal effect at 2.5 Gy (where the cell counts dropped from 1240 to 1017, P < 0.001). The colonogenic assay revealed a significant decrease in the ability to form colonies following pretreatment with curcumin in all radiation doses (P < 0.05). CONCLUSIONS: Given the appropriate doses, curcumin exhibits radio-sensitizing effects on SCC cells in vitro.