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.

Tobacco smoke exposure and multiplexed immunoglobulin E sensitization in children: a population-based study.

BACKGROUND: Although there is evidence that exposure to tobacco smoke is harmful to children's respiratory health, the effects of tobacco smoke exposure on the regulation of immunoglobulin E (IgE)-mediated immune responses to specific allergens remain unclear. This study aimed to investigate the relationship between objectively assessed tobacco smoke exposure and specific IgE profiles for a broad spectrum of allergens in a population setting. METHODS: Children aged 5-18 years (N = 1315) were assessed using serum cotinine measurement and microarray-based multiplexed detection of specific IgE against 40 allergens. RESULTS: Serum cotinine levels were positively associated with sensitization to foods (adjusted odds ratio [AOR] = 4.95; 95% CI: 1.59-15.34), cockroaches (AOR = 3.77; 95% CI: 1.49-9.51), and pollen (AOR = 2.84; 95% CI: 1.20-6.73) while the association was borderline significant for animals (AOR = 2.53; 95% CI: 0.92-6.93). No associations were found for sensitization against mites, mold, and latex. When considering the degree of allergic sensitization, serum cotinine levels were positively correlated to the number of sensitization to cockroaches (P = 0.004), pollen (P = 0.006), and foods (P < 0.001), with statistically significant positive dose-response relationships (all P < 0.01). Similar results were observed when summing up specific IgE concentrations for the aforementioned allergen categories. CONCLUSIONS: The association between tobacco smoke exposure and IgE sensitization to environmental allergens varies for different allergens among children. This study demonstrates that elevated serum cotinine levels are significantly associated with IgE sensitization to cockroaches, grass pollen, and certain foods, with potential dose-dependent relationships.

Prognostic significance of NPM1 mutation-modulated microRNA-mRNA regulation in acute myeloid leukemia.

Distinct microRNA (miRNA) and mRNA signatures were reported in nucleophosmin (NPM1)-mutated acute myeloid leukemia (AML). However, it remains unknown whether the mutation participates in the dynamic interaction between miRNA and mRNA. In this study, we aimed to investigate the role of NPM1 mutation in modulating miRNA-mRNA regulation (MMR). From the sample-paired miRNA/mRNA microarrays of 181 de novo AML patients, we found that MMR was dynamic and could be affected by NPM1 mutation. By a systematic framework, we identified 493 NPM1 mutation-modulated MMR pairs, where the strength of MMR was significantly attenuated in patients carrying NPM1 mutations, compared to those with wild-type NPM1. These miRNAs/mRNAs were associated with pathways implicated in cancer and known functions of NPM1 mutation. Such modulation of MMR was validated in two independent cohorts as well as in cells with different NPM1 mutant burdens. Furthermore, we showed that the regulatory strength of nine MMR pairs could predict patients' outcomes. Combining these pairs, a scoring system was proposed and shown to predict survival in discovery and validation data sets, independent of other known prognostic factors. Our study provides novel biological insights into the role of NPM1 mutation as a modulator of MMR, based on which a novel prognostic marker is proposed in AML.

Optimal ileocolic flap length for a reconstructed voice tube after laryngopharyngectomy.

BACKGROUND: Voice restoration after laryngopharyngectomy can be achieved with an autologous ileocolic flap. We have observed that the length of the flap influences vocal outcome. This investigation aimed to evaluate the association between ileocolic flap length and vocal quality after laryngopharyngectomy. METHODS: The charts of patients who underwent voice rehabilitation with an ileocolic flap after laryngopharyngectomy between 1 January 2011 and 30 December 2012 were abstracted. The length of ileum segment in the ileocolic flap was stratified, and voice outcome was evaluated three months post-operatively, while adjusting for confounding variables. RESULTS: There was a significant association between flap length and loudness, maximum phonation time and sound pressure level (p < 0.05). All three parameters were best in the 10 cm length group. CONCLUSION: Voice rehabilitation after laryngopharyngectomy is possible with an ileocolic flap. The optimal ileocolic flap contains a 10 cm ileum segment. Complications are frequent but amenable to revision surgery.

Detection and identification of occult HBV in blood donors in Taiwan using a commercial, multiplex, multi-dye nucleic acid amplification technology screening test.

BACKGROUND: The ability of a new generation commercial, multiplex, multi-dye test from Roche, the cobas TaqScreen MPX test, version 2.0, to detect and identify occult HBV infections was evaluated using routine donor samples from Kaohsiung Blood Bank, Taiwan. STUDY DESIGN AND METHODS: A total of 5973 samples were tested by nucleic acid amplification technology (NAT); 5898 in pools of six, 66 in pools of less than six and nine samples individually. NAT-reactive samples were retested with alternative NAT tests, and follow-up samples from the donors were tested individually by NAT and for all the HBV serological markers. RESULTS: Eight NAT-only-reactive donors were identified, and follow-up samples were obtained from six of the donors. The results indicated that all eight donors had an occult HBV infection with viral loads <12 IU/ml. CONCLUSION: The cobas(®) TaqScreen MPX test, version 2.0, has an advantage over the current Roche blood screening test, the cobas TaqScreen MPX test, for screening donations in countries with a high prevalence of occult HBV infections since the uncertainty associated with identifying samples with very low viremia is removed by the ability of the test to identify the viral target in samples that are reactive with the cobas TaqScreen MPX test, version 2.0.

Endoscopic management of pediatric sinonasal schwannoma: case report.

OBJECTIVES: To describe an extremely rare pediatric sinonasal schwannoma, and to reviewmanagement strategies and relevant literature. METHODS: Case report of pediatric sinonasal schwannoma, that was imaged with computed tomography and magnetic resonance imaging and managed endoscopically. Immunohistochemical analysis was performed to determine pathology. RESULTS: A 12-year-old girl presented with a 2-month history of progressive left exophthalmos. Imaging studies showed a large heterogeneous tumour arising from the ethmoid sinus and extending to the base of the skull and to the orbital cavity. The lesion was removed with an endonasal radical excision. The final pathological diagnosis was schwannoma. There was no tumour recurrence or any major complication during the 2-year follow up. CONCLUSION: Schwannoma should be considered in the differential diagnosis for pediatric patients with intranasal masses. Depending on the location and extent of the tumour, endonasal endoscopic excision could be a suitable management strategy.

Micronucleus scoring in liver fine needle aspiration cytology.

OBJECTIVE: This study evaluated the role of the micronucleus (MN) in liver fine needle aspiration (FNA) cytology. METHODS: Histological features of 75 cases of hepatocellular carcinoma (HCC), of which 25 were well differentiated, 37 moderately differentiated and 13 poorly differentiated, and 58 benign hepatic lesions (total, 133 cases) were correlated with MN expression observed in FNA smears reported as benign (n =40), atypical (n = 14), suspicious (n = 30) and malignant (n =49). RESULTS: Stepwise increases in the MN score (0.4 ± 0.6, 1.2 ± 1.3, 6.3 ± 4.2 and 14.8 ± 8.8) correlated with the degree of cytological abnormality: benign, atypia, suspicious and malignant, respectively. The mean MN scores for well-, moderately and poorly differentiated HCC were 5.4 ± 2.2, 11.5 ± 4.5 and 24.9 ± 9.1, respectively, which was significantly different between malignant and suspicious (P < 0.0001), between suspicious and atypical (P= 0.008) but not between atypical and benign. The MN scores differed significantly between all degrees of differentiation of HCC and between the HCC and benign hepatic lesions (P < 0.0001). High sensitivity, specificity and accuracy of liver FNA for diagnosing HCC (96%, 98%, and 96%, respectively) were obtained at a cutoff of three for the MN score. CONCLUSIONS: The MN score is an effective HCC biomarker and has a good potential use as an ancillary tool for diagnosing HCC using FNA cytology.

Differential effects of arsenic on calcium signaling in primary keratinocytes and malignant (HSC-1) cells.

Arsenic is highly toxic to living cells, especially skin, and skin cancer is induced by drinking water containing arsenic. The molecular mechanisms of arsenic-induced cancer, however, are not well understood. To examine the initial processes in the development of arsenic-induced cancer, we analyzed calcium signaling at an early stage of arsenic treatment of human primary cells and compared the effects with those observed with arsenic treatment in carcinoma-derived cells. We found that arsenic inhibited inositol trisphosphate receptor (IP3R) function in the endoplasmic reticulum by inducing phosphorylation, which led to decreased intracellular calcium levels. Blockade of IP3R phosphorylation by the serine/threonine protein kinase Akt inhibitor wortmannin rescued calcium signaling. In contrast, arsenic treatment of cells derived from a carcinoma (human squamous carcinoma; HSC-1) for 1h had no obvious effect. Taken together, these results suggest that arsenic-induced reduction in calcium signaling is one of the initial mechanisms underlying the malignant transformation in the development of skin cancer.

Gustatory changes in patients with chronic otitis media, before and after middle-ear surgery.

OBJECTIVE: We investigated gustatory changes in patients with chronic otitis media, before and after middle-ear surgery. METHODS: This prospective study included 38 patients with unilateral chronic otitis media. We used taste testing solutions to evaluate each patient's taste function. Intra-operative assessments of the chorda tympani nerve were also compared and analysed. RESULTS: Patients with chronic otitis media had significantly worse ipsilateral perception of sour, bitter and salty tastes. In patients with good intra-operative preservation of the chorda tympani nerve, there was significant improvement in gustatory function one month post-operatively, compared with the pre-operative baseline. In patients who sustained intra-operative chorda tympani nerve injury, one month post-operative gustatory function was the same as the pre-operative baseline. CONCLUSION: Middle-ear surgery for chronic otitis media not only treats the ear but also improves gustatory function in the majority of patients. In patients with intra-operative injury to the chorda tympani nerve, post-operative taste decline is only temporary.

Impact of neck dissection in early tongue and buccal cancer without neck extension.

PROBLEM: The role of elective neck dissection in early stage tongue and buccal squamous cell carcinoma with negative neck lymph nodes is still controversial. METHODS: We retrospectively reviewed patients with T1-2N0M0 buccal and tongue cancer who underwent primary tumour excision with or without elective neck dissection between January 1997 and December 2006. RESULTS: Elective neck dissection specifically improved disease-free survival of T2N0M0 buccal cancer and overall survival of T2N0M0 tongue cancer. CONCLUSION: Elective neck dissection seems to improve the disease-free survival rate of T2N0M0 buccal cancer and the overall survival rate of T2N0M0 tongue cancer but has no beneficial effect on the survival rate of T1N0M0 buccal and tongue cancer.

Pleomorphic adenoma of nasal septum: a case report.

Pleomorphic adenoma of the nasal septum presents a clinical diagnostic challenge. We report a rare case of pleomorphic adenoma of the nasal septum in a 39-year-old woman with a 1-month history of nasal obstruction. Wide surgical excision is the recommended treatment for this tumour.

Pulmonary changes induced by trans,trans-2,4-decadienal, a component of cooking oil fumes.

Cooking oil fumes (COF) are known to be associated with respiratory diseases and risk of lung cancer. Involvement of trans,trans-2,4-decadienal (tt-DDE), a major component in COF, is suspected. Male CD-1(R) (ICR) mice were intratracheally instilled with either 8 or 24 mg.kg(-1) tt-DDE weekly for 8 weeks. Total numbers and types of cells in bronchoalveolar lavage fluid (BALF), as well as pathological changes, and inflammatory gene modulations in the lung tissues were assessed. We demonstrated that the number of alveolar macrophages in the BALF was significantly increased in tt-DDE-exposed animals. Histologically, there was a dose-correlated increase in epithelial hyperplasia and granulomatous nodules at the bronchioloalveolar junctions (BAJ). Although both Clara and alveolar type II cells were present in the BAJ lesion, only Clara cells were actively proliferative. However, only alveolar type II cells were found in the BAJ granulomatous nodules. Enhanced accumulation of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a known pro-carcinogenic factor, was also detected in many alveolar type II cells at the BAJ lesions. As both BAJ hyperplasia and enhanced pSTAT3 accumulation are known risk factors associated with increased lung adenocarcinoma development, these findings suggest that tt-DDE may pose a risk in lung carcinogenesis.

Three-dimensional image analysis of the temporal bone in patients with unilateral attic cholesteatoma.

We determined temporal bone anatomy in patients with unilateral attic cholesteatoma. We compared the affected and normal ears of ten patients with unilateral attic cholesteatoma using three-dimensionally reconstructed high-resolution computed tomography images of the temporal bone. We determined the eustachian tube angle, eustachian tube length, sizes of the tympanic orifice of the eustachian tube, the pars flaccida, and the mastoid cavity, and distances of the pars flaccida and the tympanic orifice of the eustachian tube from the epitympanic roof. No significant differences were found between the normal and affected ears with regard to the size of the eustachian tube orifice, eustachian tube length or distances of the pars flaccida and the tympanic orifice of the eustachian tube from the epitympanic roof. By contrast, the mastoid cavity and the eustachian tube angle were significantly larger in the normal ears than in the affected ears [mean, 6.99 cm(3) (S.D.,4.9 cm(3)) vs. 1.28 cm(3) (0.81 cm(3)) and 16.7° (4.12°) vs. 13.89° (5.30°), respectively]. The pars flaccida was significantly smaller in the normal ears [1.07 cm (0.31 cm)] than in the affected ears [2.19 cm (0.77 cm)]. The inherent anatomy of the eustachian tube may be particularly important in the formation of attic cholesteatomas.

Expression profile of metastasis-related genes in invasive oral cancers.

We used suppression subtractive hybridization (SSH) and oligonucleotide microarray to differentiate expression profiles of metastasis-related genes and to evaluate their clinical significance in patients with invasive oral cancer (OCa). Overexpression of the specific genes was confirmed by reverse transcription-PCR (RT-PCR). Cells expressing the gene were identified by immunohistochemistry in pathology specimens. Clinical correlation and significance were analyzed statistically. Using these methods, we detected increased expressions of MMP-1, -3, -7, -9, -10 and interleukin (IL)-8 in invasive OCa. Moreover, our data showed that overexpressions of MMP-1, -3, -7, -10 and IL-8 were associated with reduced survival.

Hypopharyngeal cancer treatment based on definitive radiotherapy: who is suitable for laryngeal preservation?

AIMS: To investigate prognostic factors for survival and locoregional control in patients with stage I-IVA hypopharyngeal cancer treated with laryngeal preservation radiotherapy. METHODS: This study was a retrospective analysis of 108 patients with stage I-IVA squamous cell carcinoma of the hypopharynx, treated with laryngeal preservation radiotherapy. Actuarial survival, disease-specific survival and local relapse-free survival were calculated, and multivariate analyses were performed using Cox's proportional hazards model. RESULTS: After a median follow-up duration of 39 months, the five-year local relapse-free survival rate was 35 per cent for all patients, 66 per cent for those with stage I-II disease, 46 per cent for those with stage III disease and 20 per cent for those with stage IVA disease (p = 0.004). Multivariate analyses showed that tumour and node stages were independent prognostic factors. CONCLUSIONS: Patients with stage I-II disease were suitable for laryngeal preservation radiotherapy. For most patients with stage III-IVA disease, other than those who were T1 N1 or T2 N1, the treatment results were poor.

Oxidative stress in nonallergic nasal polyps associated with bronchial hyperresponsiveness.

BACKGROUND: Nasal polyposis (NP) is a chronic inflammatory disease of upper airway with unknown etiology. NP is frequently associated with asthma; the interaction between these comorbidities remains interesting. Oxidative stress has been implicated in the pathophysiology of NP and asthma. The aim of this study is to investigate the significance of oxidative stress in sinonasal microenvironments by evaluating its association with clinopathological parameters and its impacts on the pathogenesis of bronchial hyperresponsiveness (BHR) in NP. METHODS: Polyp biopsy specimens were obtained from 20 nonallergic patients; control mucosas were obtained from 20 volunteers. The levels of free radicals in the tissues and in blood were determined by a sensitive chemiluminescence (CL) method. NP patients were substratified into three subgroups, NP without BHR, NP with asymptomatic BHR, and NP with BHR and asthma by the results of provocative testing. Four histological characteristics of NP, inflammatory cells, eosinophil infiltration, edema and fibrosis were estimated and applied to correlate with the tissue-CL. RESULTS: The mean CL level in polyp-tissues, but not in blood, was higher than in the control specimens. In NP patients, tissue-CL was associated with endoscopy score; high tissue-CL levels were positively correlated with the abundance of inflammatory cells and eosinophils. Tissue-CL and endoscopy score were associated with BHR/asthma phenotype. CONCLUSION: These results suggest an important role for oxidative stress in the pathophysiology of NP and a causal relation between oxidative stress and inflammatory cells, especially the eosinophils. Free radical levels in polyp-tissues associated with NP severity and with BHR/asthma phenotype in nonallergic NP patients.

Transcriptional responses to ionizing radiation reveal that p53R2 protects against radiation-induced mutagenesis in human lymphoblastoid cells.

The p53 protein has been implicated in multiple cellular responses related to DNA damage. Alterations in any of these cellular responses could be related to increased genomic instability. Our previous study has shown that mutations in p53 lead to hypermutability to ionizing radiation. To investigate further how p53 is involved in regulating mutational processes, we used 8K cDNA microarrays to compare the patterns of gene expression among three closely related human cell lines with different p53 status including TK6 (wild-type p53), NH32 (p53-null), and WTK1 (mutant p53). Total RNA samples were collected at 1, 3, 6, 9, and 24 h after 10 Gy gamma-irradiation. Template-based clustering analysis of the gene expression over the time course showed that 464 genes are either up or downregulated by at least twofold following radiation treatment. In addition, cluster analyses of gene expression profiles among these three cell lines revealed distinct patterns. In TK6, 165 genes were upregulated, while 36 genes were downregulated. In contrast, in WTK1 75 genes were upregulated and 12 genes were downregulated. In NH32, only 54 genes were upregulated. Furthermore, we found several genes associated with DNA repair namely p53R2, DDB2, XPC, PCNA, BTG2, and MSH2 that were highly induced in TK6 compared to WTK1 and NH32. p53R2, which is regulated by the tumor suppressor p53, is a small subunit of ribonucleotide reductase. To determine whether it is involved in radiation-induced mutagenesis, p53R2 protein was inhibited by siRNA in TK6 cells and followed by 2 Gy radiation. The background mutation frequencies at the TK locus of siRNA-transfected TK6 cells were about three times higher than those seen in TK6 cells. The mutation frequencies of siRNA-transfected TK6 cells after 2 Gy radiation were significantly higher than the irradiated TK6 cells without p53R2 knock down. These results indicate that p53R2 was induced by p53 protein and is involved in protecting against radiation-induced mutagenesis.

Detection of cervical lymph node metastases in nasopharyngeal carcinomas: comparison between technetium-99m methoxyisobutylisonitrile single photon emission computed tomography and magnetic resonance imaging.

We compared the effectiveness technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI) single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) of head and neck in evaluating cervical lymph node (LN) metastasis in nasopharyngeal carcinomas (NPC). Forty NPC patients with cervical LN metastases confirmed histopathologically underwent Te-99m MIBI SPECT and MRI of the head and neck to evaluate cervical LN metastases. For 16 LN lesions with discordant results between Tc-99m MIBI SPECT and MRI, Tc-99m MIBI SPECT could correctly detect 1 metastatic and 10 benign LN lesions as well as MRI could correctly detect 3 metastatic and 2 benign LN lesions. Agreement positive results of Tc-99m MIBI SPECT and MRI could correctly detect all of the remaining 24 metastatic LN lesions. Tc-99m MIBI SPECT has a better specificity but a lower sensitivity for detecting cervical LN metastases in NPC when compared with MRI. The combined use of Tc-99m MIBI SPECT and MRI could increase the accuracy compared with the single use of either Te-99m MIBI SPECT or MRI to detect cervical LN metastases in NPC.

Detection of recurrent nasopharyngeal carcinomas with positron emission tomography using 18-fluoro-2-deoxyglucose in patients with indeterminate magnetic resonance imaging findings after radiotherapy.

PURPOSE: The aim of this study was to evaluate the effectiveness of positron emission tomography (PET) using 18-fluoro-2-deoxyglucose (FDG) to detect recurrent nasopharyngeal carcinomas (NPC) when magnetic resonance imaging (MRI) findings are indeterminate. PATIENTS AND METHODS: After radiotherapy, 28 NPC patients with indeterminate MRI findings were included. MRI, FDG-PET, and biopsy were performed at least 4 months after radiotherapy and within 1 week. The final results were based on histopathologic findings and a clinical follow-up of at least 6 months. RESULTS: For detecting recurrent NPC in indeterminate MRI findings, the sensitivity, specificity and accuracy of FDG-PET were 100.0%, 92.9% and 96.4%, respectively. CONCLUSIONS: Based on these results, we can recommend FDG-PET for detecting recurrent NPC when MRI findings are indeterminate.