In vivo interaction of cis-platinum and fosfomycin on squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Cis-platinum is the most frequently used chemotherapeutic agent for the treatment of head and neck squamous cell carcinoma (SCCA). Ototoxicity and nephrotoxicity continue to be the primary dose-limiting toxicities encountered. Fosfomycin, a broad-spectrum antibiotic, has been previously shown to be both otoprotective and nephroprotective against cis-platinum toxicity. Previous in vitro work demonstrated that fosfomycin does not inhibit the tumoricidal actions of cis-platinum. This study tests whether fosfomycin inhibits cisplatinum in vivo. METHODS: An SCCA cell line was grown in vivo in four groups of nude mice, which then received no treatment, standard-dose cis-platinum, high-dose cis-platinum, or high-dose cis-platinum with fosfomycin. RESULTS: Fosfomycin did not inhibit the tumoricidal activity of cis-platinum. Mice treated with fosfomycin also had longer survival, which is probably due to lessening of immediate cis-platinum systemic toxicity. CONCLUSION: This study shows that fosfomycin in combination with cis-platinum may be useful in treating advanced, and possibly relatively chemoresistant, SCCA of the head and neck.

Predictive markers for response to chemotherapy, organ preservation, and survival in patients with advanced laryngeal carcinoma.

OBJECTIVE: A systematic retrospective study of the largest randomized trial of induction chemotherapy and radiation for advanced laryngeal cancer was undertaken to determine whether specific tumor or biologic factors were predictive of chemotherapy response, organ preservation, or survival. METHODS: The variables analyzed included clinical and histologic factors, immunohistochemical expression of proliferating cell nuclear antigen and p53, and adjusted DNA index measurements. Variables were evaluated for correlation with outcomes of tumor response, organ preservation, and survival. RESULTS: Multivariate analysis revealed that the best predictor of complete response to induction chemotherapy was low T class. The full multivariate model for predicting larynx preservation in patients treated with induction chemotherapy plus radiation shows that T class, p53 overexpression, and elevated proliferating cell nuclear antigen index were independent predictors of successful organ preservation. CONCLUSIONS: These predictive markers should be included in future clinical trials of advanced laryngeal cancer to determine their usefulness prospectively.

Fosfomycin does not inhibit the tumoricidal efficacy of cisplatinum.

OBJECTIVES: This study investigates the effect of fosfomycin on the tumoricidal efficacy of cisplatinum. STUDY DESIGN: Prospective study utilizing the FaDu squamous cell carcinoma cell line and a nude mouse tumor xenograft model. METHODS: Tumor cell growth was assessed in vitro in the presence of cisplatinum and/or fosfomycin utilizing the MTT assay. An optimal cisplatinum dose and dosing schedule was established in a nude mouse tumor xenograft model of squamous cell carcinoma. Using this model, fosfomycin was tested at three dosages and tumor growth monitored over 4 weeks. RESULTS: Mice treated with cisplatinum and fosfomycin had smaller tumors than those treated with cisplatinum alone (P<.01). CONCLUSIONS: This study is the first demonstration that fosfomycin does not inhibit the tumoricidal efficacy of cisplatinum in vivo. This suggests that fosfomycin may be useful in preventing cisplatinum-induced ototoxicity and nephrotoxicity in humans without altering the tumor response rate.

Lateral thigh flap reconstruction in the head and neck.

The lateral thigh free flap is a fasciocutaneous flap based on the cutaneous perforators of the deep femoral vessels. Although originally described in 1983, it has had very few reports in the literature. This article describes the flap and reports our findings and outcomes in nine cadavers (18 thighs) and 33 clinical cases. The position of the vascular pedicle may vary in each case but has always been found to be present. Successful transfer occurred in 30 of 33 cases. Flap loss was attributable to infection, fistula, and hematoma in three of four cases. The flap was especially useful in large defects, most commonly total and base-of-tongue defects. We have found this flap to be reliable and to result in minimal morbidity.

Tongue reconstruction procedures for treatment of cancer.

Cancer of the tongue is the second most common oral cavity malignancy seen in the general population. When otolaryngologists decide to treat patients surgically, perioperative nurses must institute special nursing interventions directed toward patients' tongue reconstruction procedures and rehabilitation. Surgical management of patients undergoing tongue reconstruction procedures requires extensive knowledge of the tongue's anatomy and both current and new physiology created by surgical reconstructive procedures. Equally important is the multidisciplinary care provided to patients during rehabilitation.

Intensive radiation therapy concurrent with up to 7-week continuous-infusion paclitaxel for locally advanced solid tumors: phase I studies.

Patients with locally advanced solid tumors of the lung, head and neck, and malignant astrocytomas usually succumb to their disease despite aggressive standard therapy. Laboratory data suggest that the addition of 1.0 to 10 nmol/L paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a microtubule stabilizing drug, to radiation therapy may result in significant radiation sensitization, perhaps due to accumulation of cells at G2/M. Relatively low concentrations (1.0 to 10 nmol/L) appear to be optimal for direct cytotoxicity and radiosensitization in vitro. Within this dose range, more prolonged exposure seems to result in higher response rates. The phase I trials reported here are designed to test the combination of paclitaxel, administered by continuous intravenous infusion (24 hours a day, 7 days a week), and standard, curative-intent radiation therapy. The ultimate goal of this study is to improve local and systemic control and survival for patients with these three tumor types. To date, 39 evaluable patients are enrolled in this study; there has been no dose-limiting toxicity up to 6.5 mg/m2/d. Observed toxicities include anemia, lymphopenia, mucositis, and cutaneous toxicities.

Increased immunogenicity of tumors bearing mutant p53 and P1A epitopes after transduction of B7-1 via recombinant adenovirus.

The majority of human solid tumors are likely to express protein epitopes which can act as targets for cytotoxic T cells, but these are frequently not effectively recognized. We tested whether the introduction of the costimulatory molecule B7-1 using a recombinant adenovirus (Ad-B7) can result in effective induction of epitope-specific immunity in two tumor models that express defined endogenous protein epitopes: D459, a fibroblast-derived cell line transfected with a human missense mutant p53 (C to Y at position 135), and P815, a mastocytoma expressing the endogenous tumor epitope P1A. Under the conditions studied, both of these tumors grow and kill their hosts without evidence of significant immune rejection. However, after transduction with the adenovirus containing B7-1, both of these tumors lose tumorigenicity and elicit specific cellular immunity to the mutant p53 epitope in D459 and P1A in P815. In addition, animals exposed to B7-transduced tumor cells were protected from subsequent challenge with nontransduced tumor. Adenovirus has distinct advantages for this approach, as it has high infectivity not requiring in vitro culture, low lytic potential, and transient expression of sufficient duration for immunologic effectiveness but without significant concern over permanent genetic modification. We conclude that transduction of tumor cells with Ad-B7 can increase the immunogenicity of endogenous protein epitopes and may represent a practical therapeutic approach to system human cancers.

Sensory recovery in noninnervated flaps used for oral cavity and oropharyngeal reconstruction.

OBJECTIVES: To assess the clinical recovery of sensation in noninnervated flaps used for oral cavity and oropharyngeal reconstruction. To correlate the return of flap sensation to articulation and swallowing. DESIGN: Prospective nonrandomized study. Six months minimum follow-up. SETTING: Tertiary care center. PATIENTS: From April 1, 1991, to May 31, 1993, 12 patients underwent resection of stage III or greater squamous cell carcinoma of the oral cavity or oropharynx. Ten patients were previously untreated; two had failed previous full-course radiation therapy. Reconstruction was performed with either a pedicled musculocutaneous flap (four patients) or a fasciocutaneous free flap (eight patients). Flap sensation to touch, sharp vs dull, two-point discrimination, and warm vs cold was evaluated in each of these patients at monthly intervals by two independent observers. In addition, an extensive evaluation of articulation and swallowing was performed on all 12 patients a minimum of 6 months after surgery. 10 patients (83%) (eight of eight with fasciocutaneous free flaps and two of four with musculocutaneous flaps), with a strong trend for sensory recovery with the fasciocutaneous free flaps over the musculocutaneous flaps (P = .09). Sensory recovery correlated statistically with articulation (P = .045) and oral intake (P = .045). Patients who underwent reconstruction of base of tongue defects had significantly worse articulation and swallowing than those who underwent reconstruction of other sites (P = .04). No statistically significant correlation was found between patient age, flap size, history of irradiation, or length of follow-up (> 6 months) and flap sensation, articulation, or swallowing. CONCLUSIONS: Spontaneous return of flap sensation was documented by clinical testing in the majority (83%) of patients who underwent reconstruction of oral cavity or oropharyngeal defects with noninnervated flaps. Sensory recovery occurred more often in patients with fasciocutaneous free flaps (100%) than in those with musculocutaneous flaps (50%). Articulation and swallowing correlated statistically with the return of flap sensation.

Reliability of microvascular free flaps in head and neck reconstruction.

Reliable reconstructive techniques are essential in the surgical treatment of head and neck cancer patients. Free flaps have often been used as reconstructive options of last resort in the head and neck because of the need for added technical skill, a longer operating time, and a perception of poor reliability. This study reviews our experience with 39 free flaps performed by the Otolaryngology-Head and Neck Surgery Service. For the first 17 cases, an interrupted anastomotic technique was used; a running technique was performed in the remaining 22 cases. The average total ischemic time (3.7 vs. 2.7 hours; p < 0.001) was significantly less with a running technique. There were 10 complications: 7 minor would problems, 1 death from aspiration without surgical wound/flap problem, and 2 cases requiring second flaps (1 flap necrosis, 1 fistula with healthy free flap). No statistical correlation was found between complications and ischemic time, suture technique, age, or hospital (five hospitals). Free flaps are reliable and may obviate the need for sacrifice of trunk muscles for wound closure (e.g., fascicocutaneous free flaps instead of myocutaneous flaps); therefore we recommend revascularized free flaps as the primary mode of reconstruction for head and neck defects.

In vitro interaction of cisplatin and fosfomycin on squamous cell carcinoma cultures.

OBJECTIVE: Fosfomycin has been shown to be otoprotective and nephroprotective against cisplatin-induced toxic reactions. This study tests whether fosfomycin inhibits the anticancer effect of cisplatin. METHODS: Three squamous cell carcinoma cell lines were used to determine the effect of fosfomycin on cisplatin-induced tumoricidal activity. Cells were grown in 96 well plates with fosfomycin alone, cisplatin alone, or fosfomycin and cisplatin together. Cell survival was then measured by a colorimetric technique using 3-4,5-dimethylthiazol-2-yl 2,5 diphenyltetrazolium bromide (MTT). RESULTS: There was no decrease in the effectiveness of cisplatin in killing human squamous cell carcinoma in vitro when fosfomycin was present in concentrations of up to 400 mg/L. One cell line also showed killing at high concentrations of cisplatin, but not at low concentrations. CONCLUSIONS: Fosfomycin protects against cisplatin-induced toxic reactions and does not inhibit tumoricidal activity in vitro. In addition, one cell line showed relative resistance to cisplatin at low doses, but was effectively killed with high doses of cisplatin. This is the ideal situation for use of fosfomycin so that higher doses of cisplatin may be given with renal and otologic protection.

DNA content and regional metastases in patients with advanced laryngeal squamous carcinoma. Department of Veterans Affairs Laryngeal Study Group.

Abnormal DNA content of cancer cells in a primary tumor is thought to reflect the altered proliferative capacity of that cancer and overall patient prognosis. Recently, increased DNA content has been associated with early tumor recurrence in patients with advanced laryngeal cancer. To determine if DNA content correlates with a tumor's metastatic behavior, 94 previously untreated patients with stage III (n = 54) or stage IV (n = 40) squamous carcinoma of the larynx were prospectively studied. The adjusted DNA index (aDI) of the primary tumor was measured by computerized cytomorphometry, and correlations with regional metastases, number of positive nodes, extracapsular spread, and pattern of relapse were determined. Median follow-up was 35 months. Of 94 patients, 73 underwent neck dissection. Positive nodes were found in 51 patients (70%) and three or more positive nodes were found in 31 patients (42%). High aDI (> .024) was significantly associated with the presence and number of histologically positive nodes (P = .016). Among patients with high aDI, 19 (50%) of 38 had three or more nodes positive compared to 12 (21%) of 56 of those with low aDI. Median aDI levels in patients with three or more nodes were significantly higher than in patients with 1 or 2 nodes (P = .003). Time to recurrence was shorter in patients with high aDI (P = .0078). These findings provide further evidence that increased DNA content is associated with more aggressive laryngeal cancers having high rates of multiple lymph node metastases and worse overall prognosis.

DNA content and histologic growth pattern correlate with prognosis in patients with advanced squamous cell carcinoma of the larynx. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group.

BACKGROUND: Alterations in DNA content, nuclear morphologic characteristics, and histologic grading have been associated with prognosis in several types of solid malignant neoplasms. METHODS: To determine the potential usefulness of these factors in predicting tumor behavior in patients with laryngeal squamous cell carcinoma, tumor specimens from 88 previously untreated patients with Stage III or IV cancers were studied. The DNA content and nuclear area (NA) were measured for individual nuclei of each tumor with the use of Azure A-stained frozen sections. An adjusted DNA index (aDI) for each patient was calculated from the slope of the linear regression analysis of nuclear DNA index on NA. Hematoxylin and eosinstained sections were examined and graded systematically for histologic growth pattern. All patients were enrolled in a prospective clinical trial and had laryngectomy and postoperative radiation therapy. RESULTS: The disease-free survival length was longer and the relapse rates were lower in patients with a low aDI (P less than 0.005) and with tumors exhibiting low-grade growth patterns (P less than 0.001). CONCLUSIONS: These parameters were independent of staging variables and were better predictors of tumor relapse than traditional clinical staging classifications.

Predictive value of objective esophageal insufflation testing for acquisition of tracheoesophageal speech.

This prospective study was undertaken to assess the predictive value of esophageal insufflation on the acquisition of tracheoesophageal (TE) speech. Fourteen total laryngectomy patients were evaluated prior to tracheoesophageal puncture (TEP) using objective esophageal pressure measurements. These patients then were followed prospectively for 6 to 13 months. Speech was assessed at the time of prosthesis fitting, at 1 month, at less than 6 months, and at greater than 6 months post-TEP. No patient underwent pharyngeal myotomy. Pre-TEP esophageal insufflation pressure was associated (P = .065) with successful TE speech at the time of prosthesis fitting, but was not associated with successful TE speech acquisition after 6 months. This study's results suggest that patients with poor pre-TEP esophageal insufflation test results will usually obtain successful TE speech given adequate time and training, even without pharyngeal myotomy.