CYP2E1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan.

BACKGROUND: Nasopharyngeal carcinoma occurs disproportionately among individuals of Chinese descent. The cytochrome P450 2E1 enzyme (CYP2E1) is known to activate nitrosamines and other carcinogens that are possibly involved in the development of this disease. Certain alleles of the CYP2E1 gene are thought to be more highly expressed than others, and their distribution varies between Asian and Caucasian populations. We conducted a case-control study to investigate whether such variations affect the risk of developing nasopharyngeal cancer. METHODS: Three hundred sixty-four patients with nasopharyngeal carcinoma (96% of 378 eligible patients) and 320 control subjects (86% of 374 eligible subjects) were studied. A risk factor questionnaire was administered to participants to assess factors postulated to be linked to nasopharyngeal carcinoma. Peripheral blood was obtained from all subjects and DNA was purified from nucleated cells. A polymerase chain reaction-based restriction fragment length polymorphism assay that used the restriction enzymes Rsa I and Dra I was used to detect wild-type and variant forms of the CYP2E1 gene. RESULTS: Individuals homozygous for an allele of the CYP2E1 gene that is detected by Rsa I digestion (c2 allele) were found to have an increased risk of nasopharyngeal carcinoma (relative risk [RR] = 2.6; 95% confidence interval [CI] = 1.2-5.7); this effect was limited to nonsmokers (RR = 9.3; 95% CI = 2.7-32) and was not affected by alcohol consumption. CONCLUSIONS: Our findings suggest that the CYP2E1 genotype is a determinant of nasopharyngeal carcinoma risk.

Induction chemotherapy with mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: Survival in advanced nasopharyngeal carcinoma (NPC) is compromised by distant metastasis. Because mitomycin is active against hypoxic and G0 cells, which may help to eradicate micrometastasis, we investigated the effect of mitomycin-containing cisplatin-based induction chemotherapy. PATIENTS AND METHODS: Recruited for this study were American Joint Committee on Cancer (AJCC) 1992 staging system stage IV NPC patients with the following adverse features: obvious intracranial invasion, supraclavicular or bilateral neck lymph node metastasis, large neck node (> 6 cm), or elevated serum lactate dehydrogenase (LDH) level. Patients were given three cycles of chemotherapy before radiotherapy. The chemotherapy comprised a 3-week cycle of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL). RESULTS: From January 1994 to December 1997, 111 patients were recruited. The median follow-up period was 43 months. The actuarial 5-year overall survival rate was 70% (95% confidence interval [CI], 60% to 80%; n = 111). For patients having completed radiotherapy (n = 100), the 5-year locoregional control rate was 70% (95% CI, 55% to 84%) and the distant metastasis-free rate was 81% (95% CI, 73% to 89%). The 5-year distant metastasis-free rate of N3a and N3b disease of AJCC 1997 staging system were 79% (95% CI, 62% to 95%) and 74% (95% CI, 60% to 89%), respectively. By Cox multivariate analysis, high pretreatment serum LDH level (P = .04) and neck nodal enlargement before radiotherapy (P = .001) were adverse prognostic factors of survival. CONCLUSION: The good 5-year survival of N3 disease supports the effectiveness of induction MEPFL in the primary treatment of advanced NPC. Further investigation to incorporate concurrent chemoradiotherapy is warranted.

Cytochrome P4502E1 genetic polymorphisms and risk of nasopharyngeal carcinoma: results from a case-control study conducted in Taiwan.

CYP2E1 is responsible for the metabolic activation of nitrosamines believed to be involved in the pathogenesis of various tumors. Nasopharyngeal carcinoma (NPC) is a tumor thought to be linked to nitrosamine exposure. To investigate the possible role of CYP2E1 genetic polymorphisms in the etiology of this tumor, we investigated 50 histologically confirmed NPC cases from Taiwan and 50 controls matched to cases on age, sex, and residence. Samples were examined for RFLPs in the CYP2E1 gene by PCR amplification followed by digestion with DraI and RsaI. Among healthy controls, the allelic frequency of wild-type and variant forms of CYP2E1 were 79 and 21%, respectively, using DraI enzyme digestion and 82 and 18%, respectively, using RsaI enzyme digestion. As compared with individuals who were homozygous for the wild-type CYP2E1 gene, those found to be homozygous for the variant form of the gene by DraI digestion were at a 5-fold excess risk of disease (95% confidence interval = 0.95-16). Similarly, subjects homozygous for the variant form of the CYP2E1 gene by RsaI digestion were at 7.7-fold excess risk of developing NPC (95% confidence interval = 0.87-68). Individuals found to be heterozygous for the gene were at similar risk of disease compared to those homozygous for the wild-type gene. A strong association was observed between the RFLPs detected by DraI and RsaI digestion of CYP2E1; a correlation coefficient of 0.86 for controls and 0.91 for cases was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma.

Our objective was to evaluate the link between occupational exposures to wood dust, formaldehyde, and solvents and the development of nasopharyngeal carcinoma (NPC). A case-control study was conducted among 375 newly diagnosed cases of NPC in Taipei, Taiwan, and 325 community controls matched to cases on sex, age, and geographical residence (99 and 87% response rates, respectively). Most cases (>90%) were diagnosed with WHO Types 2 or 3 (nonkeratinizing and undifferentiated carcinomas), whereas the remaining cases were diagnosed with WHO Type 1 (squamous cell carcinomas). A complete occupational history was obtained via a personal interview and blindly assessed by an industrial hygienist for intensity and probability of exposure to wood dust, formaldehyde, and solvents. Information on socio-demographic characteristics, cigarette smoking, dietary consumption of nitrosamines, and other potential confounding factors was obtained via a personal interview. Blood specimens were tested for human leukocyte antigen class I/II genotypes, polymorphisms in cytochrome P450 2E1 genotype, and various anti-EBV antibodies known to be associated with NPC. Analysis was performed using logistic regression; relative risk (RR) estimates and 95% confidence intervals (CI) were calculated. Individuals exposed to wood dust had an adjusted RR of 1.7 (95% CI = 1.0-3.0). Those exposed to wood dust for >10 years had an adjusted RR of 2.4 (95% CI = 1.1-5.0; p(trend) = 0.02). Risk was strongest for those first exposed before the age of 25 years and those seropositive to EBV. Individuals exposed to formaldehyde were at a more modest and nonsignificant increased risk of NPC (RR = 1.4; 95% CI = 0.93-2.2). Those exposed to formaldehyde for >10 years had an adjusted RR of 1.6 (95% CI = 0.91-2.9). The association between formaldehyde and NPC was stronger in analyses restricted to EBV seropositive individuals (RR = 2.7; 95% CI = 1.2-5.9). However, no dose response was observed with increasing duration or cumulative use. No association was observed between solvent exposure and NPC (RR = 1.2; 95% CI = 0.86-1.7). Occupational exposure to wood dust is likely to be involved in the development of NPC, a finding that is consistent with the known link between wood exposure and nasal adenocarcinomas. Formaldehyde exposure is less clearly linked to NPC, whereas exposure to solvents is unlikely to be involved in NPC pathogenesis.

Second primary epithelial malignancy of nasopharynx and nasal cavity after successful curative radiation therapy of nasopharyngeal carcinoma.

Patients with head and neck cancer are at high risk of developing additional second primary tumors in the aerodigestive tract as a result of the field cancerization phenomenon. In this context, the appearance of a new neoplasm often poses a problem in differential diagnosis between recurrence and new primary tumor. Twelve patients with nasopharyngeal carcinoma (NPC) who received radiation therapy for the primary tumor and developed a second epithelial malignancy in the nasal cavity or nasopharynx during the follow-up period are presented in this report. The differentiation between the 2 entities based on the spatiotemporal relations, histological features, and the status of Epstein-Barr virus in tumor lesions are also presented. Our study showed that the epithelial malignancy after NPC having late-onset or prolonged interval (range, 5 to 18 years), different histological patterns (keratinizing squamous cell carcinoma, neuroendocrine carcinoma, or small cell carcinoma) distinct from the primary NPC (differentiated or undifferentiated nonkeratinizing carcinoma), and absence of Epstein-Barr virus, indicate a newly developed tumor rather than recurrent NPC. Our observations showed for the first time that second primary epithelial malignancy developed in the nasal cavity or nasopharynx years after curative therapy for NPC with a prevalence of 0.4% (12/2,794). Wild-type p53 protein was expressed more often in the original NPC (9 of 12) than in the second tumors (4 of 10), but the significance was not statistically significant (P = .2048). Genomic analysis for p53 mutation and in situ hybridization for human papillomavirus showed negative results, indicating that both important molecular events in NPC or head and neck cancer play a small role in this particular type of newly developed second malignant tumor. More studies are warranted for further clarification for the development of second epithelial malignancies in treated NPC patients.

Electrophysiological study of the connection between medial thalamus and anterior cingulate cortex in the rat.

We characterized the neuronal properties of the anterior cingulate cortex (ACC) evoked by electrical stimulation of the medial thalamus (MT). MT stimulation sites were found by their neuronal responses to noxious stimuli. Of 487 units identified histologically in the rat ACC, 94% were activated trans-synaptically at different areas of the ACC. Six percent of MT-evoked ACC units were activated antidromically and all of these units projected to a specific nucleus of MT. We suggest that MT nuclei mediate different aspects of nociceptive information to specific ACC areas, and that nociceptive information in the MT is modulated reciprocally by activities from the ACC.

[3H]ouabain binding to cultured endothelial cells: effect of cholesterol enrichment.

Binding experiments were performed with [3H]ouabain on cultured human umbilical vein endothelial cells (huvEC). Saturation studies yielded a binding capacity (Bmax) of 820 +/- 81 fmole/mg pr.(n = 4) and dissociation constant (KD) of 11.7 +/- 2.1nM (n = 4) in K(+)-free buffer for specific [3H] ouabain binding on these cells. External K+ inhibited this binding in a dose-dependent manner. The mean value of Bmax is equivalent to about 4 x 10(5) sites per cell, comparable with that of smooth muscle cell. These data demonstrated the presence of specific [3H]ouabain binding linked to Na+/K+ pump, consistent with the observations of ouabain-sensitive 86Rb uptake in huvEC. Effect of cholesterol enrichment was also studied. Incubation in media supplemented with cholesterol-phospholipid liposomes of molar ratio of 2:1 for 18 hours reduced the Bmax by 31% (P < 0.05) without significantly changed the value of KD. This reduction of [3H]ouabain binding appeared to be specific for cholesterol since liposome made with pure phospholipid did not alter binding. Recent findings indicate that cholesterol-enrichment and plasma lipoproteins enhance vascular contractile response, our results suggest that the cholesterol-enrichment of endothelial cells may also indirectly affect the vascular response via disturbing the function of Na+/K+ pump.

Increased sister chromatid exchange frequency in peripheral lymphocytes of nasopharyngeal carcinoma and cervical cancer patients.

The specific aim of this study was to compare the frequency of sister chromatid exchange (SCE) in peripheral lymphocytes using it as a biomarker of integral exposures to carcinogens in 14 untreated newly-diagnosed nasopharyngeal carcinoma (NPC) patients, 16 untreated newly-diagnosed cervical cancer patients, and 30 healthy controls matched with patients on age, sex, cigarette smoking and alcohol drinking. Peripheral lymphocytes were cultured in RPMI 1640 medium containing 20% fetal calf serum and 6 microM phytohemagglutinin. After culture for 24 hours, 20 microM 5-bromo-2-deoxyuridine was added into the medium. Colcemid solution was further added after 70 hours. Harvested cells were stained with Hoesch 33258, illuminated, and restained with Giemsa. The SCE frequency was scored by two readers independently and blindly. The results showed a significantly increased SCE frequency in lymphocytes for NPC patients (mean +/- standard error = 14.7 +/- 1.7 SCEs/cell) compared with their matched controls (10.1 +/- 0.7 SCEs/cell) and for cervical cancer patients (12.0 +/- 0.9 SCEs/cell) compared with their matched controls (9.2 +/- 0.7 SCEs/cell). These results suggest that NPC and cervical cancer patients have a higher integral exposures to both viral and chemical carcinogens than matched controls.

Human leukocyte antigen (HLA) frequency among patients with nasopharyngeal carcinoma in Taiwan.

In order to assess the association between human leukocyte antigens (HLA) and nasopharyngeal carcinoma (NPC), a total of 10 familial and 10 sporadic NPC patients and 171 unrelated healthy controls were studied. HLA typing was performed using commercial trays which defined 30 specificities of HLA-A, B and C loci and 10 specificities of HLA-D locus according to the method of Tiwari and Terasaki. HLA-A2, B16 and DR1 were found to be higher among patients with NPC than unrelated healthy controls with an odds ratio (OR) and a 95% confidence interval of 5.91 (2.1-16.6), 6.00 (2.0-18.0) and 6.89 (1.3-37.5), respectively. Further analysis showed that A2(+) B16(+) haplotype was significantly associated with a much higher risk of NPC (OR = 15.5) as compared with A2(-) B16(-) haplotype. No difference in frequency distributions of HLA-A, B, C and D antigens was observed between familial and sporadic NPC patients.

Multiple risk factors of nasopharyngeal carcinoma: Epstein-Barr virus, malarial infection, cigarette smoking and familial tendency.

A community-based case-control study was carried out to assess multiple risk factors and familial aggregation of nasopharyngeal carcinoma (NPC). All of the 347 pathologically-confirmed NPC new cases were serially recruited from the National Taiwan University Hospital, and healthy community controls one-to-one matched with cases on age, sex and residence were selected from household registration offices. NPC risk factors were obtained from the study subjects through standardized interviews according to a structured questionnaire. Levels of antibody to EBV-specific DNase (anti-EBV DNase) and IgA antibody to EBV viral capsid antigen (anti-EBV VCA) were determined by standard methods blindly. Multiple logistic regression analysis for matched data showed significant associations of NPC with high levels of anti-EBV DNase and anti-EBV VCA independently. The effect of cigarette smoking on NPC was modified by age. The older the age, the more striking the dose-response relation between cigarette smoking and NPC. There was no significant association between alcohol consumption and NPC. Malarial infection history was associated with NPC with an odds ratio of 2.2, but the association was significant in males only. First-degree relatives of NPC cases had a greater NPC-affected rate than those of matched healthy controls with a relative risk of 19.2, and the heritability of NPC was estimated as 0.60 (95% confidence interval = 0.55-0.64) based on the multifactorial inheritance model. Familial NPC cases were younger than sporadic cases, but environmental risk factors were similar in the two groups.

Familial and sporadic cases of nasopharyngeal carcinoma in Taiwan.

BACKGROUND: Nasopharyngeal carcinoma (NPC) has a striking geographic/ethnic distribution, with especially high rates among southern Chinese. Previous studies have indicated that a family history of NPC is associated with increased risk and noted familial clustering in low-risk populations. MATERIALS AND METHODS: We investigated differences between sporadic and familial cases of NPC in a case-control study of 375 histologically confirmed NPC cases (99% response rate) and 328 age-, sex-, and geographically-matched controls (88% response rate). All participants answered a detailed risk factor interview and donated blood for EBV and CYP 2E1 testing. RESULTS: Subjects with a first degree relative with NPC had on odds ratio (OR) of 7.6 (95% confidence interval (CI) = 2.3-25), while those with a family history of any other cancer had only a slightly elevated risk of disease (OR = 1.4; 95% CI = .93-2.2). Of the cases, 25 (6.7%) were familial--having at least one first degree relative with NPC. No significant difference was seen between familial and sporadic cases with respect to sex, age, ethnicity, histology or stage. There was a nonsignificant (p = 0.16) increase in T1N2 tumors among familial cases, suggesting a more aggressive tumor. Family history of other cancers, EBV serologies, or the distribution of the RsaI c2 form of the allele of cytochrome P450 2E1 were also not significantly different between the two groups. CONCLUSIONS: In conclusion, while genetic factors are likely to play an important role in NPC pathogenesis, our results provide little evidence that a familial form of NPC exists with characteristics notably distinct from sporadic cases.

Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.

Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.

Stretch-activated nonselective cation, Cl- and K+ channels in apical membrane of epithelial cells of Reissner's membrane.

Ion channels on the apical membrane of epithelial cells (the surface facing the endolymph) of acutely isolated Reissner's membrane from guinea-pig cochlea were investigated by using patch-clamp technique in cell-attached and inside-out configurations. Three types of ion channel were identified: namely, a stretch-activated nonselective cation, a chloride and a potassium channel. When the pipette was filled with high-K+ endolymph-like solution, the most significant channel activity was nonselective cation channels (85/110, 77% patches). The current versus voltage relationship was linear with a unitary conductance of 22.1 +/- 0.4 pS and reversal potential (Vr) of 2.3 +/- 0.8 mV (n = 18). The channel exhibited a lower conductance (14.0 +/- 0.6 pS, n = 8) to Ca2+. The open probability was low (NPo approximately 0.1) in cell-attached configuration under +60 mV pipette potential and increased when the membrane was stretched with negative pressure. The channel was blocked by 10 microM extracellular Gd3+. The two other types of channels were a small voltage-sensitive Cl- channel (6.0 +/- 0.3 pS; 91/99, 92% patches) and a K+ channel (approximately 30 pS; 29/191, 15% patches). These channels might play roles in the regulation of cell volume, in balancing the hydrostatic pressure across Reissner's membrane and in maintaining the electrochemical composition of endolymph.

Nasopharyngeal carcinoma with dermatomyositis. Analysis of 12 cases.

OBJECTIVES: To evaluate the incidence rate of nasopharyngeal carcinoma with dermatomyositis, the influence of dermatomyositis on clinical course, and complications and survival of patients with nasopharyngeal carcinoma after radiotherapy. DESIGN: A retrospective study of 12 patients with nasopharyngeal carcinoma associated with dermatomyositis, with a maximum follow-up of 228 months. SETTING: Academic tertiary referral center. PATIENTS: There were 6441 new patients with nasopharyngeal carcinoma who were seen at the National Taiwan University Hospital, Taipei, during the period from 1970 through 1993. Twelve patients were found to have dermatomyositis. MAIN OUTCOME MEASURE: Clinical manifestations of nasopharyngeal carcinoma with dermatomyositis. RESULTS: Twenty-seven (26%) of 104 patients with dermatomyositis had an associated malignancy. Twelve of these patients were diagnosed as having nasopharyngeal carcinoma. The typical skin manifestation of dermatomyositis was found in all 12 patients. Myopathy occurred in 10 patients. Three patients died of recurrence of nasopharyngeal carcinoma, one died of a second malignancy, one died of upper gastrointestinal bleeding, and one became unavailable for follow-up. The other six patients have had disease-free survival, with a mean follow-up period of 100.5 months (range, 5 to 228 months). The 1-year survival rate was 83.8%, and the 5-year survival rate was 69.4%. CONCLUSIONS: In Taiwan, dermatomyositis is associated with an increased incidence rate of nasopharyngeal carcinoma. A search for nasopharyngeal carcinoma in patients with dermatomyositis should be performed in areas prevalent for nasopharyngeal carcinoma. If present, nasopharyngeal carcinoma can precede, occur concurrently with, or follow the diagnosis of dermatomyositis. Treatment of nasopharyngeal carcinoma may affect myositic or cutaneous disease. The prognosis and survival rates of nasopharyngeal carcinoma remained unaffected by dermatomyositis. No complications were noted owing to the radiotherapy used to treat dermatomyositis.

Elevated levels of soluble interleukin 2 receptor and tumor necrosis factor in nasopharyngeal carcinoma.

Depressed cell-mediated immunity as a measure of the mitogenic response of mononuclear cells in patients with nasopharyngeal carcinoma is well documented, but the mechanism is still unclear. The enzyme-linked immunosorbent assay was used to measure soluble interleukin 2 receptor and tumor necrosis factor levels in 295 patients with nasopharyngeal carcinoma and 97 age-matched control subjects. Soluble interleukin 2 receptor levels in patients with nasopharyngeal carcinoma were elevated and correlated with clinical staging. Higher soluble interleukin 2 receptor levels were found in patients with bone metastasis but not in patients with intracranial involvement. The levels of tumor necrosis factor in nasopharyngeal carcinoma were higher than in control subjects but did not correlate with clinical staging. These data suggest that soluble interleukin 2 receptor levels might be more useful than soluble tumor necrosis factor levels that indicate tumor bulk. Soluble interleukin 2 receptor serves as a blocking factor that competes with interleukin 2 function, resulting in a decreased mitogenic response in patients with nasopharyngeal carcinoma. The usefulness of the levels of soluble interleukin 2 receptor to monitor the efficacy of treatment in patients with nasopharyngeal carcinoma with bone metastasis requires further study.

Radiation-induced malignant fibrous histiocytoma in patients with nasopharyngeal carcinoma.

OBJECTIVE: To evaluate the prevalence, 15-year cumulative incidence, time interval, and prognosis of radiation-induced malignant fibrous histiocytoma of the head and neck in long-term survivors of nasopharyngeal carcinoma. DESIGN: Cohort. SETTING: Tertiary care hospital. PATIENTS: Eight long-term survivors of nasopharyngeal carcinoma with malignant fibrous histiocytoma in the maxillary sinus or nasal cavity. MAIN OUTCOME MEASUREMENT: Survival of postirradiation malignant fibrous histiocytoma in patients with nasopharyngeal carcinoma. RESULTS: The prevalence of radiation-induced malignant fibrous histiocytoma in long-term survivors of nasopharyngeal carcinoma was 0.38%. The 15-year cumulative incidence was 2.2%. Most tumors occurred in the maxillary sinus and were characterized by spindle-shaped tumor cells with plump nuclei arranged in a whorl or storiform pattern in a fibrous stroma. The mean interval between malignant fibrous histiocytoma and nasopharyngeal carcinoma was 121 months. Local recurrence developed in all cases within 9 months after surgery. Six patients died of disease without distant metastasis within 30 months. Two patients were alive with disease for 20 and 32 months, respectively. CONCLUSIONS: Radiation-induced malignant fibrous histiocytoma in the head and neck region in long-term survivors of nasopharyngeal carcinoma is rare. It takes a long time to occur after irradiation and is locally invasive with poor prognosis.

Increased mutagen sensitivity in patients with head and neck cancer is less pronounced in patients with nasopharyngeal carcinoma.

BACKGROUND: Mutagen sensitivity tested with bleomycin sulfate can determine a susceptible phenotype, which is relevant only in organs and tissues that have direct contact with the external environment. Patients with head and neck cancers have more mutagen sensitivity than control subjects without cancer, and the hypersensitive phenotype has a risk for the development of a second primary cancer. Head and neck cancers, however, represent a heterogeneous group of neoplasm. The biological behavior of nasopharyngeal carcinoma (NPC) and other head and neck cancers differs. OBJECTIVE: To evaluate the difference in mutagen sensitivity among patients without cancer, patients with NPC, patients with oral or oropharyngeal cancer (ORC), and patients with laryngeal or hypopharyngeal cancer (LHC). DESIGN: Peripheral blood was cultured at 37 degrees C, using 5% carbon dioxide, for 72 hours. After 67 hours of incubation, bleomycin in a concentration of 30 IU/L was added to induce chromatid breaks. The number of chromatid breaks per cell was scored in 50 metaphases of cultured lymphocytes and compared in the 4 groups. SUBJECTS: Patients with histologically proven squamous cell carcinoma of the mucosa of the upper digestive tract, which included 3 groups: patients with NPC, patients with ORC, and those with LHC. Control subjects were hospital inpatients with no tumor history. There were 35 patients in each group. RESULTS: The mean (+/-SD) number of breaks per cell in the control group and in the groups with NPC, ORC, and LHC were 0.80 (+/-0.32), 1.03 (+/-0.45), 1.30 (+/-0.44), and 1.35 (+/-0.46), respectively. All the cancer groups had significantly higher mean breaks per cell and a higher prevalence of hypersensitivity than the control group. Patients with NPC had a significantly lower mean number of breaks per cell than the group with ORC or that with LHC. CONCLUSIONS: Patients with NPC had less mutagen sensitivity than those with ORC or LHC. Our results support the clinical and epidemiological findings of a difference between NPC and other head and neck cancers. Environmental factors might play a less pronounced role in the carcinogenesis of NPC.

Salvage surgery for recurrent nasopharyngeal carcinoma.

OBJECTIVE: To assess the efficacy of salvage surgery for patients with recurrent nasopharyngeal carcinoma (NPC) at the primary site after radiotherapy. DESIGN: Retrospective analysis of 24 patients treated by transpalatal, transmaxillary, or transmandibular approach to resect the recurrent tumor, with maximum follow-up of 50 months. SETTING: Academic tertiary referral center. RESULTS: Radiotherapy before salvage surgery included 1 to 3 courses of radiation to the nasopharynx, with doses ranging from 60 to 190 Gy. Eighteen (75%) of the patients relapsed within 2 years, and 6 (25%) relapsed more than 6 years after the last irradiation. In 4 of 6 late-relapsing cases, the histopathological type changed to keratinizing squamous cell carcinoma, which is rare in cases of NPC in Taiwan. Fourteen patients (58%) survived for 8 to 50 months after surgery (median, 18 months). The surgical complications were tolerable. CONCLUSIONS: Salvage surgery is feasible in selected patients with recurrent disease at the primary site. Thus, we can offer alternative retreatment in addition to external irradiation for patients with recurrent NPC.

Factors affecting the overall survival after salvage surgery in patients with recurrent nasopharyngeal carcinoma at the primary site: experience with 60 cases.

OBJECTIVE: To analyze the factors affecting overall survival after salvage surgery in patients with recurrent nasopharyngeal carcinoma at the primary site after a full course of radiotherapy. DESIGN: Retrospective analysis of 60 consecutive patients treated by surgical resection of the recurrent tumors, with a mean follow-up of 43.1 months (range, 19-96 months). SETTING: Academic tertiary referral center. RESULTS: The overall survival and locoregional relapse-free survival were 56% and 60% at 2 years, respectively, and 30% and 40% at 5 years. Twenty-nine (81%) of 36 patients died with uncontrolled local disease. The T stage of the recurrent tumors appeared to be an important prognostic factor. Age, sex, pathologic findings, and disease-free interval (time between previous radiotherapy and local recurrence) were not significant prognosis-affecting factors by the log-rank test. Multivariate analysis showed that patients with recurrent tumors of undifferentiated carcinoma, sarcoma, or small cell carcinoma had unfavorable prognoses. Uncontrolled local disease and the emergence of distant metastasis predicted grave results as well. Postoperative irradiation showed some benefit to patients, but the difference was not statistically significant. CONCLUSIONS: The T stage of the recurrence was the prominent prognosis-affecting factor in patients with recurrent nasopharyngeal carcinoma who received salvage surgery. Patients with local recurrence should be carefully selected for the salvage surgery. We recommend this surgery for patients with rT1, rT2, or limited rT3 lesions. The results of surgical resection in terms of local control and overall survival were slightly better than those of high-dose reirradiation, with fewer late complications.

Intracranial relapse of nasopharyngeal carcinoma manifested as sudden deafness.

OBJECTIVE: To differentiate tumor relapse from postirradiation sudden deafness (PISD) in patients with nasopharyngeal carcinoma (NPC). STUDY DESIGN: A retrospective study from December 1991 to November 1999. SETTING: University hospital. PATIENTS: Twenty-five irradiated NPC patients with sudden deafness were investigated. All patients received local examination of ears, nose, nasopharynx, and throat fields, as well as a battery of audiologic and neurotologic tests. RESULTS: Three patients with sudden deafness within 3 years after irradiation received a diagnosis of tumor relapse. Magnetic resonance imaging revealed cerebellopontine angle metastasis in one and intracranial invasion in two. Comparison of the remaining 22 NPC patients who had PISD showed that the mean interval between the completion of irradiation to the onset of sudden deafness was 10+/-5 years. CONCLUSION: Magnetic resonance imaging should be performed to exclude intracranial relapse if sudden deafness develops in a patient with NPC within 5 years after irradiation.