Final results of a randomized phase III trial of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with stage IVA and IVB nasopharyngeal carcinoma-Taiwan Cooperative Oncology Group (TCOG) 1303 Study.

Background: Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation. Patients and methods: This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received three cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30 mg/m2 cisplatin weekly during radiotherapy, which was delivered as 1.8-2.2 Gy per fraction with five daily fractions per week, to a total dose of 70 Gy or greater to the primary tumor and 66-70 Gy to the involved neck. The primary end point was disease-free survival (DFS). Results: In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side-effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0 months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm [5-year rate 61% versus 50%; hazard ratio=0.739, 95% confidence interval (CI)=0.565-0.965; P = 0.0264], after stratified for N3b and LDH, and adjusted for T stage. Conclusion: Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved. Clinical trial information: NCT00201396.

Trismus, xerostomia and nutrition status in nasopharyngeal carcinoma survivors treated with radiation.

The aims of the study were to: (1) examine levels of trismus, xerostomia and nutritional status; (2) compare levels of trismus, xerostomia and nutritional status in patients with nasopharyngeal carcinoma (NPC) receiving different types of radiation modalities; and (3) identify factors related to NPC survivors' risk status for malnutrition and existing malnutrition. A cross-sectional study with consecutive sampling was conducted. NPC survivors were recruited from otolaryngology/oncology outpatient clinics in a medical centre in Northern Taiwan. Study measures included (1) Mandibular Function Impairment Questionnaire, (2) Xerostomia Questionnaire, (3) Mini Nutrition Assessment, (4) Hospital Anxiety and Depression Scale - Depression subscale, and (5) Symptom Severity Scale. A total of 110 subjects were recruited. Those receiving intensity-modulated radiation therapy had less trismus and xerostomia than patients receiving two-dimensional radiation therapy. Patients with female gender, advanced stage, completion of treatments within 1 year, higher levels of depression, more severe trismus and higher symptom severity tended to have malnutrition or were at risk of malnutrition. Trismus and xerostomia are long-term problems in some NPC survivors and may contribute to malnutrition. To better manage a patient's trismus and xerostomia and to enhance nutritional status, clinicians should develop a patient-specific care programme based on careful assessment and targeted measures to improve oral function and insure adequate nutritional intake.

Intensity-modulated radiation therapy for T4 nasopharyngeal carcinoma. Treatment results and locoregional recurrence.

PURPOSE: The purpose of this work was to examine outcomes in patients with T4 nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Between 2007 and 2010, 154 patients with nonmetastatic T4 NPC were treated with IMRT to a total dose of 70 Gy in 33-35 fractions. In addition, 97% of patients received concurrent platinum-based chemotherapy. The median follow-up time was 52.8 months. RESULTS: The rates of 5-year actuarial locoregional control, distant metastasis-free survival, progression free-survival, and overall survival (OS) were 81.2, 72.2, 61.9, and 78.1%, respectively. A total of 27 patients had locoregional recurrence: 85.2% in-field failures, 11.1% marginal failures, and 3.7% out-of-field failures. Fourteen patients with locoregional recurrence received aggressive treatments, including nasopharyngectomy, neck dissection, or re-irradiation, and the 5-year OS rate tended to be better (61.9%) compared to those receiving conservative treatment (32.0%, p=0.051). In patients treated with 1 course of radiotherapy, grade ≥3 toxicities of ototoxicity, neck fibrosis, xerostomia, epistaxis, and radiographic temporal lobe necrosis occurred in 18.2, 9.8, 6.3, 2.1, and 5.6% of patients, respectively. Increased ototoxicity, osteonecrosis, severe nasal bleeding, and temporal necrosis were observed in patients treated by re-irradiation. CONCLUSION: IMRT offers good locoregional control in patients with T4 NPC. For patients with locoregional recurrence after definitive radiotherapy, aggressive local treatment may be considered for a better outcome.

Correlates of anti-EBV EBNA1 IgA positivity among unaffected relatives from nasopharyngeal carcinoma multiplex families.

BACKGROUND: To determine whether non-viral nasopharyngeal carcinoma (NPC) risk factors might be associated with (and mediated through) Epstein-Barr virus (EBV) serological responses linked to NPC risk, we evaluated predictors of risk of anti-EBNA1 IgA seropositivity and other markers among unaffected relatives from a large NPC family study in Taiwan. METHODS: Multivariate logistic regression conditioned on family was used to examine the associations between sociodemographic, dietary, lifestyle, and occupational variables and risk of anti-EBV EBNA1 IgA positivity, anti-VCA IgA, and anti-DNase positivity. RESULTS: Among 2393 unaffected relatives from 319 multiplex families, 1180 (49.3%) were anti-EBV EBNA1 IgA seropositive. None of the associations with anti-EBNA1 IgA were statistically significant, except for being 31-50 years of age (vs <30, adjusted ORs 0.51-0.57). For one or more EBV serological markers, there were suggestive associations for older age, GuangDong firm salted fish, betel use, current alcohol use, and male gender. CONCLUSION: Overall, we found little evidence to suggest that non-viral NPC risk factors significantly alter EBV serological patterns, suggesting that non-viral NPC risk factors act through pathways independent of EBV serological responses.

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness.

This corrects the article DOI: 10.1038/onc.2017.8.

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness.

GATA binding protein 3 (GATA3) is indispensable in development of human organs. However, the role of GATA3 in cancers remains elusive. Hypoxia inducible factor (HIF)-1 plays an important role in pathogenesis of human cancers. Regulation of HIF-1α degradation is orchestrated through collaboration of its interacting proteins. In this study, we discover that GATA3 is upregulated in head and neck squamous cell carcinoma (HNSCC) and is an independent predictor for poor disease-free survival. GATA3 promotes invasive behaviours of HNSCC and melanoma cells in vitro and in immunodeficient mice. Mechanistically, GATA3 physically associates with HIF-1α under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1α, which is independent of HIF-1α prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1α complex binds to and regulates HIF-1 target genes, which is also supported by the microarray analysis. Notably, the GATA3-mediated invasiveness can be significantly reversed by HIF-1α knockdown, suggesting a critical role of HIF-1α in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1α to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1α axis as a potential therapeutic target for cancer treatment.

High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability.

BACKGROUND AND PURPOSE: Elevated von Willebrand factor (vWF) concentrations are associated with an increased risk of ischemic heart disease. Several factors influence vWF antigen levels and activity, including blood group, genetic variability, acute-phase response, and proteolysis by A Disintegrin and Metalloprotease with ThromboSpondin motif (ADAMTS13), a determinant of proteolytic cleavage of vWF. We assessed how these factors affect the relation between vWF and the occurrence of stroke to understand the underlying mechanism. METHODS: In a case-control study of 124 first-ever ischemic stroke patients and 125 age- and sex-matched controls, we studied vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), ADAMTS13 activity, the -1793C/G polymorphism in the vWF gene, and C-reactive protein. RESULTS: vWF antigen and activity levels were significantly higher in cases than in controls. The relative risk of ischemic stroke was highest in individuals in the upper quartile of vWF:Ag (odds ratio, 3.2; 95% CI, 1.4 to 7.5) and vWF:RCo (odds ratio, 2.1; 95% CI, 0.9 to 4.8) compared with individuals in the lowest quartiles. In individuals with ADAMTS13 in the lowest quartile, the relative risk of stroke was 1.7 (95% CI, 0.7 to 3.9) compared with the highest quartile. C-reactive protein, ADAMTS13, and genetic variation did not affect the association between vWF and the relative risk of stroke, whereas blood group did affect the association. CONCLUSIONS: vWF antigen and activity are associated with the occurrence of acute ischemic stroke. This relation is unaffected by the severity of the acute-phase response or by genetic variation or degradation.

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.

Plasma homocysteine is a risk factor for recurrent vascular events in young patients with an ischaemic stroke or TIA.

OBJECTIVES: Young patients with an ischaemic stroke or transient ischaemic attack (TIA) often have no vascular risk factors. Hyper-homocysteinaemia is an established risk factor for stroke in elderly patients but it is uncertain whether it is also important for the prognosis of young ischaemic stroke and TIA patients. We examined the possible effect of the plasma homocysteine level on the risk of recurrent vascular events in patients between 18 and 45 years of age. METHODS: The study population consisted of 161 consecutive patients with a recent cerebral infarction or TIA. Data on the primary event and the homocysteine level were collected retrospectively from hospital records. General practitioners and patients were contacted by telephone to record vascular events and the type of medication used during the follow-up period. Vascular events included cerebral infarction, TIA, pulmonary embolism, venous thrombosis, myocardial infarction and peripheral arterial disease. RESULTS: A Kaplan- Meier curve showed a dose effect relationship between event-free survival time and tertiles of the homocysteine level (Log rank statistic 5.91; p=0.05). The Cox hazard ratio, after adjustment for homocysteine lowering treatment, was 1.7 (95 % CI, 1.1 to 2.8) for any vascular outcome event, 1.9 (95% CI, 1.1 to 3.0) for arterial outcome events and 1.8 (95 % CI, 1.1 to 2.9) for cerebral outcome events. CONCLUSIONS: In spite of our small number of outcome events we found a significant association at the 95% confidence level between homocysteine level and the risk of recurrent vascular events in young patients with an ischaemic stroke or TIA. The association is of the same magnitude as in elderly people.

PLA1/A2 polymorphism of the platelet glycoprotein receptor IIb/IIIa in young patients with cryptogenic TIA or ischemic stroke.

BACKGROUND: The relationship between the PIA2 allele of the Leu(33)Pro polymorphism of glycoprotein IIb/IIIa receptor (GPIIb/IIIa) and ischemic stroke is uncertain. The purpose of this study was to investigate a possible association between the GPIIb/IIIa PIA1/A2 polymorphism and the occurrence of cryptogenic stroke in young patients. METHODS: From a consecutive series of 80 patients aged 45 or less with a recent ischemic stroke or TIA, we selected 45 patients with stroke due to small vessel occlusion or stroke of undetermined etiology (according to the TOAST criteria). Controls were 60 healthy blood donors with a similar age distribution. All patients underwent CT of the brain and were screened for cardiovascular risk factors, cardiac disorders and large vessel disease. The frequency of the PIA2 allele was determined by PCR and Msp1 restriction analysis. RESULTS: Eight patients (16%) and 16 controls (27%) were heterozygous for PIA2 allele. Two patients (4%) were homozygous for PIA2. The relative risk of ischemic stroke associated with PIA2 allele was estimated at 0.8 (95% CI: 0.3-1.9). CONCLUSION: This study does not support the association between the PIA1/A2 polymorphism and cryptogenic stroke or TIA in patients aged 45 or less.

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.

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.

Multicentricity of intraparotid facial nerve schwannomas.

Facial nerve schwannomas are uncommon neoplasms. Multiple schwannomas of the facial nerve in the parotid region are rare. Research regarding the pathogenesis of multiple facial nerve schwannomas is incomplete. Both the neoplastic bridging of tumor cells and tumor multicentricity have been hypothesized. We present a case of multiple intraparotid facial nerve schwannomas. In this case, the histologic features of the tumors support the multicentric hypothesis.

Actinomycosis imitating nasopharyngeal carcinoma.

The incidence of nasopharyngeal actinomycosis is exceedingly rare. To our knowledge, only 1 case has been reported previously. This article presents 4 cases of actinomycosis involving the nasopharynx that imitated nasopharyngeal carcinoma. Acidic gas exposure and farming of aquatic products are possibly involved in the pathogenesis of nasopharyngeal actinomycosis. Patients in the case studies completely recovered after 4 weeks of oral antibiotic treatment. We recommend including actinomycosis in the differential diagnosis of nasopharyngeal neoplasms.

Patulous eustachian tube in long-term survivors of nasopharyngeal carcinoma.

This article reports on 21 long-term (10 years) survivors of nasopharyngeal carcinoma, divided into 2 groups: those subjected to an inflation-deflation test and a clearance function test in a longitudinal study, and those receiving sonotubometry in a cross-sectional study. On the inflation-deflation test, 12 (55%) out of 22 ears had a patulous eustachian tube, and on sonotubometry, 10 (50%) out of 20 ears also revealed a patulous eustachian tube. Except for 4 ears with chronic otitis media, the ears had resolved to a normal eardrum appearance at 10 years postirradiation. The phenomenon might be attributed to both restoration of the impaired tubal function and the development of a patulous tube.

Delayed irradiation effects on nasal epithelium in patients with nasopharyngeal carcinoma. An ultrastructural study.

The ostiomeatal complex is responsible for the clearance of most sinus secretions. To evaluate the delayed effects of irradiation. this study examined the infundibulum mucosa of 10 patients who developed sinusitis after receiving radiotherapy for nasopharyngeal carcinoma (NPC). Pathologic findings under the light microscope revealed an increased deposition of dense collagenous fibers in the lamina propria. The epithelial cells also transformed into a stratified arrangement and showed gradual reduction of cytoplasmic volume. Ultrastructural observations detected areas of ciliary loss, intercellular and intracellular vacuolation, and ciliary dysmorphism. Most of these pathologic findings were observed even in a patient 23 years after irradiation. The results presented herein suggest that radiotherapy may cause long-term damage to the nasal epithelium that may be responsible for the prolonged sinusitis of irradiated NPC patients.

Mucociliary transport pathway on laryngotracheal tract and stented glottis in guinea pigs.

We investigated the laryngotracheal mucociliary transport pathway of guinea pigs in vivo and immediately postmortem. Only intraperitoneal anesthesia was used during the procedure to avoid the disturbance of mucociliary function. Resin particles were used as the marking substance. A microcolpohysteroscope was placed at different levels in the laryngotracheal region for observing the marking particles and recording the transport pattern. The tracheal mucociliary transport flow primarily moved along the posterior wall and both lateral walls in a zigzag trace. Upon reaching the subglottis, the resin particles stayed underneath the vocal cords, and a whirlpool phenomenon developed. The majority of the particles were shifted and directed onto the posterior glottic area. With a short delay, some resin particles crossed over the free edge of the vocal cords and turned posteriorly along the medial upper cordal margin. No mucociliary transport could be observed on the entire upper surface of the true vocal cords, which is covered by squamous epithelium. Occasionally, a few resin particles in the vicinity of the epiglottic root traveled along the aryepiglottic folds toward the posterior commissure. All streams of mucociliary transport finally joined together in the interarytenoid area. After leaving the glottis, the resin particles traveled to the hypopharynx and entered the esophagus through the motion of deglutition. The pattern of mucociliary clearance in the laryngotracheal region was not delayed by stenting.