Salvage surgery for recurrent carcinoma of the hypopharynx and reconstruction using jejunal free tissue transfer and pectoralis major muscle pedicled flap.

OBJECTIVE: To evaluate patients undergoing salvage surgery after recurrent squamous cell carcinoma of the hypopharynx. DESIGN: Retrospective analysis. SETTING: All patients underwent surgery and follow-up evaluations at the Medical University of Vienna. The departments of Surgery and Otorhinolaryngology carried out patient care and analysis of data. PATIENTS: A total of 8 consecutive patients with recurrent hypopharyngeal squamous cell carcinoma. INTERVENTIONS: An interdisciplinary team of surgeons, including a head and neck surgeon, a reconstructive surgeon, and an abdominal surgeon, performed salvage surgery. After pharyngolaryngectomy and neck dissection, reconstruction using free, autotransplanted jejunum covered by a pectoralis major muscle flap was achieved. MAIN OUTCOME MEASURES: All data concerning the surgical procedure, perioperative morbidity, and functional and oncologic outcome were reviewed. RESULTS: The cohort of patients was heavily pretreated owing to late stages of disease at diagnosis. Mean time to recurrence before salvage surgery was 7.5 months. Mean time after surgery until ability to swallow was regained was 17.2 days, including 1 patient who ultimately underwent interventional dilation owing to stenosis. There were no complications requiring further surgical therapy, and all patients were transferred to outpatient care within 2 months. Three patients, all with advanced nodal involvement, died within months after surgery. Five patients are alive, 4 of whom have shown no evidence of disease 4 years or more after salvage surgery. CONCLUSIONS: Jejunal transfer and pectoralis major muscle flap were carried out in a single, reconstructive procedure after salvage resection in hypopharyngeal carcinoma. Potential long-term survival and minor perioperative and postoperative morbidity can be achieved using an interdisciplinary approach.

1,25(OH)2Vitamin D3 induces elevated expression of the cell cycle inhibitor p18 in a squamous cell carcinoma cell line of the head and neck.

BACKGROUND: 1Alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2) Vitamin D(3)] induces growth inhibition in squamous cell carcinoma (SCC) cell lines of the head and neck by arresting the cells in the G0/G1 phase of the cell cycle, probably due to an enhanced expression of p21, which could be demonstrated in other cell lines (JPPA, SCC9) before. In SCC25, a SCC cell line isolated from tongue, growth inhibition but no overexpression of p21 was detected. The retinoblastoma gene, as a direct target of G1 cyclin-CDK complexes, showed an obvious shift from the hyperphosphorylated to the hypophosphorylated form under 1,25(OH)(2)Vitamin D(3), which indicates that the growth inhibition takes place in the G0/G1 phase. To explore the possible pathway of growth inhibition in SCC25 we investigated other cell cycle inhibitors (p18, p19, p27). METHODS: Synchronized cells were treated with 1,25(OH)(2)Vitamin D(3) over 96 h. The cell cycle status and expression of cell cycle-regulating proteins was determined by fluorescence-activated cell sorting (FACS) and Western blotting. An overexpression of p18 in 1,25(OH)(2)Vitamin D(3) vs. ethanol-treated cells was determined until 30 h in SCC25. No influence was detectable on the expression of p27 and p19. CONCLUSION: One mechanism by which 1,25(OH)(2)Vitamin D(3) controls cell growth might be the upregulation of p21. As p21 was unsusceptible to 1,25(OH)(2)Vitamin D(3) in SCC25, other inhibiting proteins were necessary to be tested. The proven upregulation of p18 seems to be the responsible step for growth inhibition of 1,25(OH)(2)Vitamin D(3) in SCC25.

Molecular analysis of p21 promoter activity isolated from squamous carcinoma cell lines of the head and neck under the influence of 1,25(OH)2 vitamin D3 and its analogs.

OBJECTIVE: The biologically active 1,25(OH)2 vitamin D3 and its analogs have been shown to have antiproliferative and differentiating effects in a variety of malignant and non-malignant cells. For squamous carcinoma cell lines of the head and neck (SCCHN) we could show that this antiproliferative activity of 1,25(OH)2 vitamin D3 is due to induced expression of the cell-cycle inhibitory proteins p21 and p27, causing an arrest in the G0/G1 cell-cycle phase. MATERIAL AND METHODS: In this work we investigated the effects of three vitamin D3 analogs, EB1089, MC1288 and CB1093, on proliferation behavior and cell-cycle status in a laryngeal carcinoma cell line (JPPA) as well as in control human immortalized keratinocytes (HaCaT). To study the molecular mechanism the functional activity of the promoter region of p21, a potential target gene of vitamin D3 transcriptional regulation, was investigated. For this reason a 2.7-kb fragment of the p21 promoter was isolated by polymerase chain reaction from HaCaT, JPPA and SCC9 (tongue carcinoma) cells and directionally cloned into an enhanced green fluorescence protein (EGFP) reporter gene vector system. A construct was used to stably transfect HaCaT cells and to monitor the expression of the EGFP gene by confocal microscopy. RESULTS: Analysis of proliferation and cell-cycle status revealed decreased growth rates and G0/G1I cell-cycle arrest in cells treated with 1,25(OH)2 vitamin D3 and its analogs The EGFP reporter gene-transfected cells showed distinct fluorescence under the influence of 1,25(OH)2 vitamin D3 and its analogs compared to control cells. CONCLUSION: These results demonstrate that the cell-cycle inhibitor protein p21 is a direct target gene of biologically active 1,25(OH)2 vitamin D3, inducing G0/G1 cell-cycle arrest. The ability of vitamin D analogs to act via the same molecular mechanism as the natural hormone but with less hypercalcemic activity may have therapeutic implications for patients with SCCHN malignancy.

Mitoxantrone and cisplatin in recurrent and/or metastatic salivary gland malignancies.

A phase II study was performed to assess the safety and efficacy of mitoxantrone and cisplatin in locally recurrent and/or metastatic carcinomas of the salivary glands. Between May 1997 and March 2001, a total of 14 patients were entered on this trial. All of them had previously undergone radical resection and 10 were subsequently treated with adjuvant radiation therapy with (n=3) or without (n=7) concomitant chemotherapy. Therapy according to the study protocol consisted of mitoxantrone given as i.v. bolus on day 1 at a dose of 12 mg/m2 and cisplatin given as 90-min infusion at a dose of 30 mg/m2 on days 1-3. We observed two partial responses (14.3%) and stabilization of disease in nine patients (64.3%); progression during therapy was noted in only three cases (21.4%). The median time to progression was 15 months (range 2-36) and the median survival time was 27 months (range 4-54). Myelosuppression was commonly observed. Leukocytopenia occurred in all patients, and was grade 3 or 4 in three (21%) and four (29%) patients. WHO grade 3 thrombocytopenia and anemia was seen in three (21%) and four (29%) patients, respectively. Non-hematologic toxicity was in general mild to moderate except for two cases (14%) of grade 3 nausea and vomiting; overall incidence rates were nausea and vomiting (n=14), stomatitis (n=6), diarrhea (n=3), alopecia (n=11), infection (n=7), increase of serum creatinine (n=3), and peripheral neuropathy (n=3). The combination of mitoxantrone and cisplatin seems to be an active and fairly well-tolerated regimen for the treatment of advanced salivary gland cancers. According to the observed high rate of abrogating progressive disease for a long duration, and the resulting promising progression-free and overall survival time, further investigation seems warranted.

Ethanol decreases negative cell-cycle-regulating proteins in a head and neck squamous cell carcinoma cell line.

Epidemiologic studies have provided evidence of an alcohol-associated increased risk of upper aerodigestive tract cancers. Recently we reported ethanol-induced proliferation in a squamous cell carcinoma of the head and neck (SCCHN) cell line, but the underlying mechanisms are unknown. In order to further clarify these findings, major G0/G1-regulating proteins were investigated in the present study. Synchronized cells of a SCCHN line (JP-PA) and a human immortalized keratinocyte line (HaCaT)-used as a control-were cultured with or without 10(-3) M ethanol for up to 96 h. At distinct time intervals the expression of cyclin D1 and the inhibitors p16, p18, p19 and p21 were determined by Western blot analyses. In both lines ethanol had no influence on the protein expression of cyclin D1. In contrast, distinct downregulations of p21, p18 and p19 were detectable at the protein level. The p16 protein was not expressed in the SCCHN line and was unchanged in the control line after the addition of ethanol. In these in vitro experiments the marked downregulation of important cell-cycle inhibitors may accelerate progression from the G1 to the S phase of the cell cycle. The relevance of our findings to in vivo conditions remains speculative, but the observed mechanisms of significantly reduced expression of cell-cycle inhibitor proteins may be involved in the carcinogenesis of head and neck malignancies.

Tumor staging of laryngeal and hypopharyngeal carcinomas with functional spiral CT: comparison with nonfunctional CT, histopathology, and microlaryngoscopy.

PURPOSE: The purpose of this work was to compare nonfunctional and functional spiral CT in the tumor (T) staging of laryngeal and hypopharyngeal tumors and to correlate the CT results with microlaryngoscopy and postoperative pathology. METHOD: Twenty-six patients (3 women, 23 men) with clinically suspected laryngeal and hypopharyngeal tumors underwent both nonfunctional CT during quiet breathing and functional spiral CT during either a modified Valsalva (n = 19) or E phonation (n = 7) maneuver. CT slice thickness was 3 mm, table feed was 3 mm, and 40-80 ml of intravenous contrast material was administered at a flow of 1.5 ml/s. T stages as determined by nonfunctional and functional CT were compared and correlated with postoperative pathology or microlaryngoscopy. RESULTS: The T stages determined with functional CT were better correlated with postoperative pathology (rS = 0.88, p = 0.001) and microlaryngoscopy (rS = 0.77, p = 0.008) than T stages determined with nonfunctional CT (rS = 0.80, p = 0.001; and rS = 0.51, p = 0.13, respectively). Twelve of 26 patients (46%) had a lower T stage on functional than on nonfunctional CT. In 14 of 26 patients (54%), the T stage was identical with both modalities. In no patients was the T stage increased by functional CT. CONCLUSION: Functional CT appears to be more accurate than nonfunctional CT in the T staging of laryngeal and hypopharyngeal carcinomas. Functional CT also results in lower T stages than nonfunctional CT in a substantial number of patients.