Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer.

PURPOSE: Hypoxia shifts the balance of cellular energy production toward glycolysis with lactate generation as a by-product. Quantitative bioluminescence imaging allows for the quantitation of lactate concentrations in individual tumors. We assessed the relationship between pretreatment tumor lactate concentrations and subsequent development of metastatic disease in patients with newly diagnosed head-and-neck cancer. METHODS AND MATERIALS: At the time of biopsy of the primary site, a separate specimen was taken and flash-frozen for subsequent quantitation of lactate concentration using a luciferase bioluminescence technique. The two-dimensional spatial distribution of the bioluminescence intensity within the tissue section was registered directly using a microscope and an imaging photon counting system. Photon intensity was converted to distributions of volume-related tissue concentrations (micromol per gram wet weight). Treatment consisted of either surgery and postoperative radiotherapy or primary radiotherapy, based on presenting disease stage and institutional treatment policies. The subsequent development of metastatic disease constituted the primary clinical endpoint. RESULTS: Biopsies obtained from 40 patients were evaluable in 34. The larynx was the most frequent primary site (n = 25). Other sites included oropharynx (n = 5), hypopharynx (n = 3), and oral cavity (n = 1). Most patients (74%) presented with an advanced stage T3 or T4 primary tumor. Nodal involvement was present in 19 (54%) patients. The median tumor lactate concentration was 7.1 micromol/g. Tumors were classified as having either low or high lactate concentrations according to whether these values were below or above the median. The median follow-up time for surviving patients is 27 months. Two-year actuarial survival was 90% for patients with low-lactate-concentration tumor vs. 35% for patients with high-lactate-concentration primaries (<0.0001). Two-year metastasis-free survival was adversely influenced by high tumor lactate concentrations (90% vs. 25%, p < 0.0001). The median lactate concentration for tumors that subsequently metastasized was 12.9 micromol/g vs. 4.8 micromol/g for patients who remained continuously free of disease (p < 0.005). Lactate concentration was not correlated with presenting T stage or N stage. DISCUSSION: Elevated tumor lactate concentrations are associated with the subsequent development of nodal or distant metastases in head-and-neck cancer patients. This more aggressive malignant phenotype is probably associated with hypoxia-mediated radioresistance and the upregulation of metastasis-associated genes.

Endoscopic staple-assisted esophagodiverticulostomy: an excellent treatment of choice for Zenker's diverticulum.

OBJECTIVES: The objectives of the present study are to review the technique of endoscopic staple-assisted esophagodiverticulostomy (ESED) for the treatment of Zenker's diverticulum and to describe our experience and modifications with ESED and the advantages of ESED over previous treatments of Zenker's diverticulum. STUDY DESIGN: Retrospective review of 74 cases of ESED performed for the treatment of Zenker's diverticulum. METHODS: Patient's records were retrospectively reviewed and tabulated for age, sex, size of diverticulum, symptoms, duration of symptoms, operative time, length of postoperative hospital stay, oral intake, complications, and relief of symptoms. RESULTS: The senior author (R.L.S) previously reported results in 36 cases of ESED performed in 34 patients with Zenker's diverticulum. We have performed an additional 38 cases of ESED in 37 patients between March 1997 and August 1999. The rate of success of ESED was similar between the two series The average perioperative time, time until oral intake, and length of postoperative hospital stay decreased in the second series. Overall, there were no mortalities and few complications with ESED. Compared with other forms of treatment of Zenker's diverticulum, such as Dohlman's procedure, diverticulectomy, and diverticulopexy, ESED has a similar rate of success, decreased perioperative time, decreased convalescence, and decreased mortality and complications. CONCLUSIONS: Cost-effectiveness, safety, and efficacy of ESED offer new advantages over previously used treatments for Zenker's diverticulum. These results continue to support the use of ESED as the initial treatment of choice for patients with Zenker's diverticulum.

Factors related to outcome of salvage therapy for isolated cervical recurrence of squamous cell carcinoma in the previously treated neck: a multi-institutional study.

OBJECTIVE: The goal was to identify factors associated with the outcome of salvage therapy for patients with isolated cervical recurrences of squamous cell carcinoma in the previously treated neck (ICR-PTN). STUDY DESIGN AND SETTINGS: A tumor registry search for ICR-PTN patients was performed at 7 participating institutions, and the charts were reviewed. Kaplan-Meier plots for survival and time until re-recurrence were used to evaluate the significance of associated variables. RESULTS: Median survival and time until re-recurrence were both 11 months. Survival was better in patients with the following characteristics: nonsurgical initial neck treatment, negative initial disease resection margins, no history of prior recurrence, ipsilateral location of the ICR-PTN relative to the primary, and use of surgical salvage. CONCLUSIONS: By pooling the experience of 7 US tertiary care medical centers, we have identified 5 factors that are associated with outcome of salvage therapy for ICR-PTN. SIGNIFICANCE: Consideration of these factors, as well as the reviewed literature, should facilitate patient selection for salvage protocols.

Laryngeal radionecrosis and hyperbaric oxygen therapy: report of 18 cases and review of the literature.

Laryngeal radionecrosis is a difficult late complication of radiotherapy. It is associated with hoarseness, edema, pain, weight loss, and upper airway obstruction. The medical treatment options are limited, and in severe cases, the patient may require tracheostomy or laryngectomy. We report clinical results in 18 patients treated with adjunctive hyperbaric oxygen (HBO) therapy for severe radionecrosis of the larynx. Of these 18 patients, 2 had grade 3 and 16 had grade 4 radionecrosis. The patients received a mean number of 41 HBO treatments (range, 6 to 80) at 2 atmospheres absolute for 2 hours, twice a day, 6 days a week. Thirteen patients (72.2%) had a major improvement after HBO therapy, and none of them required total laryngectomy. All patients preserved their voice and deglutition in good or normal condition. Five patients (27.8%) failed to have a good response to HBO and underwent total laryngectomy. One of these patients had local recurrence of his cancer 4 months later, and the other 3 had significant concurrent medical problems. The remaining patient received only 6 HBO treatments because of emergency heart surgery. These encouraging results are comparable to those of smaller previous studies suggesting that HBO has a beneficial effect in the management of advanced laryngeal radionecrosis.

Endoscopic management of lateral pharyngeal pouch.

A patient with dysphagia including symptoms of regurgitation of food and worsening pulmonary symptoms was found to have a lateral pharyngeal pouch. The diagnosis was made by barium swallow study and confirmed by endoscopy. The characteristic barium swallow findings include retention of barium in a sac or diverticulum. Endoscopy showed a pouch in the left lateral pharynx, adjacent to the vallecula. Surgical therapy consisting of endoscopic stapling of the mucosal band separating the pouch from the pharynx was performed successfully, and the patient improved dramatically.

Middle ear carcinoid: an indolent tumor with metastatic potential.

BACKGROUND: Neuroendocrine tumors of the head and neck region may present problems in diagnosis. Middle ear carcinoid is a rare, recently recognized tumor, which to date has not been reported to metastasize. METHODS: We report the case of a 64-year-old man with a 9-year history of recurrent middle ear neoplasm and ipsilateral cervical lymphadenopathy. A microscopic parathyroid tumor was also identified. The approach to the diagnosis of this unusual combination is presented. RESULTS: The patient had a neuroendocrine tumor metastatic to multiple unilateral cervical lymph nodes, which was morphologically identical to his recurrent middle ear neoplasm. The neoplasm had the morphologic, immunohistochemical, and ultrastructural features of a carcinoid tumor. CONCLUSIONS: This case illustrates that middle ear carcinoids may metastasize. We suggest that immunohistochemical studies be performed on all biopsy specimens from neoplasms of the middle ear, as distinction from the more common paraganglioma may be difficult on morphologic grounds alone.

In situ identification of normal visceral tissues using contact telescopic microscopy.

OBJECTIVES: To improve the intraoperative anatomic identification of normal tissues during surgery using histologic-like criteria STUDY DESIGN: A contact telescope was used to identify normal visceral tissues in an animal model using pigs and dogs during routine human surgical procedures. METHODS: Tissues that could be identified grossly were stained topically with methylene blue and then examined with the contact telescope. The histologic appearance of these tissues with the contact telescope was correlated with routine histologic hematoxylin and eosin stains obtained after such tissues were excised. RESULTS: Normal tissues, such as fat, blood vessels, muscle, and parathyroid tissue, can be identified reliably in animals and humans. The contact telescope appears to be able to differentiate between a variety of visceral tissues in the neck and may become useful for practical differentiation between tissues during surgery.

Identification of sialyl Lewis-x in squamous cell carcinoma of the head and neck.

BACKGROUND: Sialyl Lewis-x (sLx) is a cellular adhesion molecule (CAM) that has been implicated in the inflammatory reaction and cancer metastasis. The sLx is the carbohydrate ligand of endothelial-selectin (E-selectin), an inducible vascular endothelial CAM. The role of sLx has been investigated in several cancers, and its presence has been correlated with advanced disease stage, decreased disease-free survival, and greater metastatic potential. A recent study has found that cultured head and neck (HN) squamous cell carcinoma (SCC) cell lines express sLx and that binding of these cells to cytokine activated endothelium correlates with the endothelial expression of E-selectin. The purpose of this study was to identify sLx in the tumors of patients with HNSCC and to see if the presence of sLx correlated with disease status. METHODS: We performed immunohistochemical (IHC) staining to detect the sLx antigen using the monoclonal antibody (MAb) KM-93. Eighty-two specimens of HNSCC that were obtained at the time of resection or biopsy were analyzed for sLx staining patterns and intensities. The clinical outcomes of survival, disease-free interval, and incidence of distant metastasis were then assessed to determine whether there was a correlation with sLx tumor expression. In addition, we analyzed specimens from metastatic HNSCC sites for expression of sLx. RESULTS: The sLx expression was identified in 62% of the primary tumor specimens and 87% of the metastatic tumor specimens analyzed by IHC. The staining pattern in the HNSCC tumors differed from that seen in normal squamous epithelium but was variable in both intensity and distribution. The sLx expression in the metastatic sites was higher than in the primary sites in 67% of the specimens (10 of 15). There was no correlation between sLx staining and disease status. CONCLUSIONS: The results of this study demonstrate that sLx is present in HNSCC and supports the data that show that sLx may play a role in the metastasis of HNSCC. Future studies are warranted to evaluate the role of sLx, E-selectin, and other CAMs in HNSCC.

Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer.

BACKGROUND: Radiotherapy is often the primary treatment for advanced head and neck cancer, but the rates of locoregional recurrence are high and survival is poor. We investigated whether hyperfractionated irradiation plus concurrent chemotherapy (combined treatment) is superior to hyperfractionated irradiation alone. METHODS: Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy. RESULTS: Of 122 patients who underwent randomization, 116 were included in the analysis. Most patients in both treatment groups had unresectable disease. The median follow-up was 41 months (range, 19 to 86). At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group (P=0.07). The relapse-free survival rate was higher in the combined-treatment group (61 percent vs. 41 percent, P=0.08). The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group (P=0.01). Confluent mucositis developed in 77 percent and 75 percent of the two groups, respectively. Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group. CONCLUSIONS: Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.

Fenretinide-induced apoptosis of human head and neck squamous carcinoma cell lines.

BACKGROUND: Squamous cell carcinoma of the head and neck (HNSCC) has a high incidence of recurrence and associated second primary malignancy. The retinoid 13-cis-retinoic acid has been shown to be effective as both a chemopreventive and chemotherapeutic agent for HNSCC, but often with treatment-limiting toxicity. The synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide) (HPR) has significant antiproliferative activity against a number of animal and human malignancies and has been used in clinical trials as a chemopreventive agent in patients with breast and prostate cancer and oral leukoplakia. HPR has been shown to have a toxicity profile lower than that for other retinoids used in clinical trials. PURPOSE: The aim of this study was to investigate the effect of HPR on the growth of HNSCC cell lines in vitro. METHODS: Four HNSCC cell lines (JHU-011-SCC, JHU-020-SCC, JHU-022-SCC, and FaDu) were treated with a range of concentrations of HPR for various times. After HPR exposure, cell viability was determined by tetrazolium dye (MTT) colorimetric assay, comparing cell survival with that of untreated control cells. HPR-induced apoptosis was determined by flow-cytometric deoxyribonucleic acid cell-cycle analysis, ultrastructural analysis with electron microscopy, and deoxyribonucleic acid fragmentation detected by gel electrophoresis. RESULTS: HPR caused significant growth inhibition in three of the four HNSCC cell lines in a dose- and time-dependent fashion. In two cell lines (JHU-011-SCC, JHU-020-SCC) a significant antiproliferative effect was achieved between 1 and 2.5 micromol/L HPR after 72 hours of treatment. By deoxyribonucleic acid cell-cycle analysis, electron microscopy, and gel electrophoresis, HPR was shown to induce apoptosis in the JHU-011-SCC and JHU-020-SCC cell lines, but not in the FaDu cell line, which was insensitive to the growth inhibitory effect of HPR. CONCLUSIONS: This study has demonstrated that HPR reduces cell viability in HNSCC cells in vitro at clinically relevant doses, with the growth inhibition occurring through the induction of apoptosis.

Long-term experience with endoscopic staple-assisted esophagodiverticulostomy for Zenker's diverticulum.

The authors have previously described the endoscopic staple-assisted esophagodiverticulostomy (ESED) technique for treatment of Zenker's diverticulum. In the initial series of six patients, ESED was shown to be safe and effective in the short term, with a significant reduction in hospital stay and convalescence as compared with other surgical techniques. This report documents the authors' long-term experience with ESED (average follow-up, 9.3 months; range, 1.5 to 25 months) and discusses the long-term results of this therapy, technical issues, and variations they have utilized, as well as the advantages and limitations of this approach. Thirty-six patients with Zenker's diverticula have been treated from March 1995 to March 1997. In 34 of the patients, ESED was accomplished, resulting in successful resolution of preoperative symptoms in 32 (94%). Two patients had persistent dysphagia after initial ESED; a revision ESED was successfully performed without complication in both. Two patients were unable to be treated with ESED because of inability to expose the diverticulum with the Weerda laryngoscope. Oral liquid diet has been resumed, on average, 0.8 days after surgery (range, 0 to 4 days), with solid diet resumed by day 5 (range, 1 to 14 days). The average hospital stay has been 1.3 days (range, 1 to 4 days). There have been no postoperative deaths, infections, or airway difficulties. Perioperative morbidity to date has included one case of iatrogenic pharyngeal perforation, one postoperative fever, one transient true vocal fold paralysis, and two dental injuries, with no long-term sequelae. The results support the use of ESED as the initial treatment of choice for patients with Zenker's diverticula.

Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck.

PURPOSE: Tumor hypoxia adversely affects short term clinical radiation response of head and neck cancer lymph node metastases and long term disease-free survival (DFS) in cervix carcinoma. This study was performed to evaluate the relationship between tumor hypoxia and DFS in patients with squamous carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Pretreatment tumor pO2 was assessed polarographically in SCCHN patients. All patients were AJCC Stage IV and had pretreatment oxygen measurements taken from locally advanced primaries (T3 or T4) or neck nodes > or = 1.5 cm diameter. Treatment consisted of once daily (2 Gy/day to 66-70 Gy) or twice daily irradiation (1.25 Gy B.I.D. to 70-75 Gy) +/- planned neck dissection (for > or = N2A disease) according to institutional treatment protocols. RESULTS: Twenty-eight patients underwent tumor pO2 measurement. The average pre-treatment median pO2 was 11.2 mm Hg (range 0.4-60 mm Hg). The DFS at 12 months was 42%. The DFS was 78% for patients with median tumor pO2 > 10 mm Hg but only 22% for median pO2 < 10 mm Hg (p = 0.009). The average tumor median pO2 for relapsing patients was 4.1 mm Hg and 17.1 mm Hg in non-relapsing (NED) patients (p = 0.007). CONCLUSION: Tumor hypoxia adversely affected the prognosis of patients in this study. Understanding of the mechanistic relationship between hypoxia and treatment outcome will allow for the development of new and rational treatment programs in the future.

Telescopic laryngeal and pharyngeal surgery.

Surgery of the hypopharynx and larynx has traditionally been performed with either direct, unaided vision or the operating microscope. We proposed to extend the surgical capability provided by angled Hopkins telescopes to the larynx and hypopharynx. Forty-eight cases in which rigid telescopes were employed primarily for intervention were reviewed. We found significant advantages of the telescopic system when performing procedures on surfaces that were not 90 degrees from the observer, such as the walls of the hypopharynx, the petiole of the epiglottis, the ventricle, and the posterior commissure. Both 30 degree and 70 degree telescopes were found useful, but required complementary instruments. The potassium titanyl phosphate laser's flexible fiber provided a distinct advantage in resecting lesions that presented on vertical surfaces. Telescopes also permitted the use of large instruments designed for intraperitoneal and intrathoracic surgery that blocked the view of the operating microscope. Telescopic pharyngeal and laryngeal visualization allowed surgical procedures complementary to more traditional forms of endoscopic surgery.

Endoscopic staple-assisted esophagodiverticulostomy for Zenker's diverticulum.

We have used a new technique, endoscopic staple-assisted esophagodiverticulostomy (ESED), for the treatment of Zenker's diverticulum. This technique is a modification of the endoscopic approach first described by Mosher in 1917 and popularized by Dohlman and Mattsson in which the common wall between the esophagus and diverticulum was divided without mucosal closure. ESED differs in that an endosurgical stapler is used to create an esophagodiverticulostomy by dividing the common wall between the esophagus and diverticulum, with the mucosal and muscular edges sealed by the staples. We have performed this procedure in six patients, with no perioperative morbidity in any patient. All patients resumed oral intake on either the first or second postoperative day, with no evidence of fistula formation or mediastinitis. Hospital stay has averaged 2 days (range, 1 to 3 days). Patient follow-up after ESED averages 6 months and is available for five of the six patients treated. There has been complete resolution of pretreatment symptoms in these five patients, with resumption of regular diet between postoperative day 3 and day 14 (average, day 9). Our results demonstrate that ESED is a safe and effective treatment for Zenker's diverticulum. This endoscopic approach offers a number of advantages over previously used treatments for Zenker's diverticulum, including reduced morbidity, rapid convalescence, short hospitalization, brief operative time, and predictable resolution of symptoms.

Adhesion of head and neck squamous cell carcinoma to endothelial cells. The missing links.

OBJECTIVES: To examine the direct adhesion of head and neck squamous cell carcinoma (HNSCC) cells to basal and cytokine-activated human endothelial cells and to determine the cell adhesion molecules (CAMs) that mediate binding under these two conditions. DESIGN: Using an established model of tumor metastasis, the adhesion of four HNSCC cell lines to human umbilical vein endothelial cell (HUVEC) monolayers was examined, with and without pretreatment of HUVEC with tumor necrosis factor alpha (TNF-alpha). Surface CAM expression of HNSCC and HUVEC was determined by flow cytometry, and the results were used to direct studies of adhesion blocking using monoclonal antibodies. The contribution of various CAM to HNSCC binding of basal and cytokine-activated human endothelial cells in vitro was established. MAIN OUTCOME MEASURES: Adhesion of HNSCC to HUVEC monolayers was determined by a sodium chromate Cr 51-labeling assay in the presence or absence of monoclonal antibodies directed against specific CAMs. RESULTS: Four HNSCC cell lines were shown by flow cytometry to constitutively express the following CAMs: intercellular CAM-1, CD44, lymphocyte function-associated antigen-3, integrin chains alpha 6 and beta 1, and sialyl Lewis(x). No cell lines expressed lymphocyte function-associated antigen-1 or the integrin subunit alpha 4. Adhesion of JHU-011-SCC to TNF-alpha-activated HUVEC was enhanced above the untreated level in a time-dependent manner, with maximal adhesion at 12 hours. This increase correlated with endothelial-selectin expression by HUVEC and HNSCC expression of its ligand sialyl Lewis(x). Monoclonal antibody to sialyl Lewis(x) blocked the increased adhesion to TNF-alpha-activated HUVEC in two of four HNSCC cell lines. Monoclonal antibody to the alpha 6 integrin reduced binding to TNF-alpha-activated and non-activated HUVEC and to subendothelial matrix, but not to fibronectin. CONCLUSIONS: Studies of four HNSCC cell lines disclosed a consistent and distinctive pattern of adhesion molecule expression. The alpha 6 integrin subunit may be involved in direct adhesion to nonactivate and cytokine-activated endothelial cells or to laminin present on the endothelial surface. Sialyl Lewis(x) was more specifically involved in the increased adhesion to cytokine-activated HUVEC. This suggests that the sialyl Lewis(x)-endothelial-selectin ligand interaction may be important in facilitating HNSCC adhesion during metastasis to sites of active or chronic inflammation in vivo.

Interferon gamma enhances lymphokine-activated killer cell adhesion but not lysis of head and neck squamous cell carcinoma.

OBJECTIVES: To determine if treatment with recombinant human interferon gamma (rHuIFN-gamma) increases the adhesion to, and lysis of, head and neck squamous cell carcinoma (SCC) cells by lymphokine-activated killer (LAK) and peripheral blood mononuclear (PBM) effector cells in vitro and to evaluate the role of cell surface adhesion molecules in these processes. DESIGN: Two human SCC cell lines, JHU-020-SCC and JHU-022-SCC, were used. Lymphokine-activated killer cells were generated by interleukin-2 stimulation of PBM cells obtained from the hemapheresis blood donor packs of healthy individuals. Adhesion assays were performed to assess the level of binding of both effector populations to SCC cells, which were treated with either fresh media or rHuIFN-gamma (100 U/mL). Binding was measured by flow cytometric detection of effector cells labeled with fluorescein-conjugated anti-CD45 monoclonal antibody. Monoclonal antibodies to the cell adhesion molecules HLA-DR, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1 were used in blocking experiments to determine their contribution to the process of effector-SCC cell adhesion. Cytotoxicity experiments were performed using a colorimetric assay to determine the cytotoxic response generated by LAK and PBM cells against SCC cells, with and without prior rHuIFN-gamma treatment of the tumor cells. MAIN OUTCOME MEASURES: Effector cell binding level and percent cytotoxicity of SCC cells. RESULTS: Recombinant human interferon gamma treatment of JHU-020-SCC cells resulted in increased adhesion to both LAK cells and PBM cells (P < .001). The presence of anti-lymphocyte function-associated antigen 1 antibody resulted in elimination of the enhanced adhesion seen with rHuIFN-gamma pretreatment of SCC cells (P =.03), but antibody to intercellular adhesion molecule 1 and HLA-DR did not reduce the level of effector binding. The greatest cytotoxic response against both JHU-020-SCC and JHU-022-SCC was seen with LAK cells (P < or = .001). Pretreatment of tumor targets by rHuIFN-gamma (100 U/mL) resulted in no enhancement of cytotoxic response by either LAK or PBM cells; at the effector-target ratio of 30:1, there was a significant decrease in LAK cell-mediated cytotoxic response against rHuIFN-gamma-treated SCC cells (P < or = .02). CONCLUSIONS: Recombinant human interferon gamma treatment of head and neck SCC cells does increase binding of both LAK cells and PBM cells to tumor cells, in part via the lymphocyte function-associated antigen 1 ligand mechanism. The cytotoxic effect mediated by LAK cells against head and neck SCC cells is reduced after rHuIFN-gamma treatment, suggesting that the activity of this cytokine may be more important in regulating antigen-specific cytotoxic response mediated by cytotoxic T-lymphocytes.