Chuan-Jen Hsu

Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma

Background:Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.Methods:Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg–1 on day 1 and capecitabine 800 mg m–2 twice daily on days 1–14 every 3 weeks as first-line therapy.Results:A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.Conclusion:The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.

Deep neck infection in diabetic patients : Comparison of clinical picture and outcomes with nondiabetic patients

OBJECTIVE: To compare the difference in the clinical picture and outcomes between diabetic and nondiabetic patients with deep neck infections. STUDY DESIGN AND SETTING: We retrospectively reviewed the records of patients who were diagnosed with deep neck infections and who received treatment at the Department of Otolaryngology of National Taiwan University Hospital between 1997 and 2002. One hundred eighty-five patients were included in our study. Fifty-six patients with diabetes mellitus were enrolled for further analysis (diabetic group) and compared with the other 129 patients without diabetes mellitus (nondiabetic group) in demography, etiology, bacteriology, treatment, duration of hospital stay, complications, and outcome. RESULTS: The parapharyngeal space was the space most commonly involved in both the diabetic (33.9%) and nondiabetic groups (40.3%). Odontogenic infections and upper airway infections were the 2 leading causes of deep neck infection in diabetic and nondiabetic groups. Streptococcus viridans is the most commonly isolated organism in the nondiabetic group (43.7%). However, the most common organism in the diabetic group was Klebsiella pneumoniae (56.1%). There were 89.3% of diabetic patients, versus 71.3% of nondiabetic patients, with abscess formation (P = 0.0136). Surgical drainage was performed more frequently in the diabetic group than in the nondiabetic group (86.0% versus 65.2%, P = 0.0142). In comparison with the nondiabetic group, the diabetic group tended to have older mean age (57.2 y versus 46.2 y, P = 0.0007), longer duration of hospital stay (19.7 days versus 10.2 days, P >0.0001), more frequent complications (33.9% versus 8.5%, P >0.0001), and more frequent tracheostomy or intubation (19.6% versus 6.2%, P = 0.0123). CONCLUSIONS: Patients with diabetes mellitus are susceptible to deep neck infection. We should pay more attention when dealing with deep neck infections in patients with diabetes mellitus because those patients tend to have complications more frequently and a longer duration of hospital stay. Empirical antibiotics should cover K. pneumoniae in patients with deep neck infection who have diabetes mellitus.

Factors affecting the bacteriology of deep neck infection: a retrospective study of 128 patients

Conclusions. Broad-spectrum antibiotics are advocated for treating deep neck infection. Anaerobic coverage is necessary, especially in odontogenic cases. The presence of diabetes, infection of the parotid space and an obvious odontogenic source of infection can aid in determining the causative organisms. Objectives: This study aimed to analyze the bacteriology in deep neck infections and identify the factors that influenced the causative pathogens. Materials and methods. The records of 212 patients who were diagnosed as having deep neck infections at the National Taiwan University Hospital between 1997 and 2003 were reviewed; 128 patients with bacterial isolation from their pus cultures were enrolled. Results. The cultures of 46 patients (35.9%) were polymicrobial. Viridans Streptococcus was the most commonly isolated organism (38.3%), followed by Klebsiella pneumoniae (32.0%) and Peptostreptococcus (17.2%). The most common organism in 44 diabetic patients was K. pneumoniae (54.5%), versus viridans streptococcus (48.8%) in 84 nondiabetic patients. In patients with dental sources of infections, the culture rate of anaerobes was 59.3%; in upper airway infections and other sources of infections they were 22.7% and 21.5%, respectively (χ2 test, p = 0.0008). The differences in age, sex, and climate did not show any significant changes in the common causative pathogens. Common pathogens in the infection of parapharyngeal, submandibular, and extended spaces were the same as viridans streptococcus, but in the parotid space K. pneumoniae was the most common pathogen.

Prevalent SLC26A4 Mutations in Patients with Enlarged Vestibular Aqueduct and/or Mondini Dysplasia: A Unique Spectrum of Mutations in Taiwan, Including a Frequent Founder Mutation†

Objectives/Hypothesis: The purpose of the study is to elucidate the mutation spectrum of SLC26A4 among patients with enlarged vestibular aqueduct and/or Mondini dysplasia in Taiwan and to explore the origin of the most common mutation, IVS7‐2A>G. The correlation between the genotypes and the phenotypes is also investigated, with special emphasis placed on comparison between the genotypes and hearing levels.

Neurotoxicological mechanism of methylmercury induced by low-dose and long-term exposure in mice : Oxidative stress and down-regulated Na+/K+-ATPase involved

Methylmercury (MeHg), a potent neurotoxicant, easily passes through the blood-brain barrier (BBB), accumulates in the brain regions and causes severe irreversible damage. However, the neurotoxic effects and action mechanisms of MeHg are still unclear, especially in low-dose and long-term exposure. In this study, we attempted to explore the toxic effects of low-dose MeHg (0.05 mg/kg/day), which was the possible exposed dose by ingestion in MeHg-contaminated areas, on the time course of changes in locomotor activities and auditory brainstem response (ABR) system after administration for 7 consecutive weeks in mice. The results showed that the retention time on the rotating rod (60 rpm) was preferentially decreased after 1-week oral administration with MeHg. The locomotor activities parameters of ambulatory distances and stereotype-1 episodes were significantly increased and vertical-plane entries were progressively decreased after MeHg exposure in 3 consecutive weeks. Gradually progressive abnormality of ABR (increase in hearing thresholds, prolonged absolute and interwave latencies) was found during 4-6 weeks administration of MeHg. These impairments correlated with significant Hg accumulation and biochemical alterations in brain regions and/or other tissues, including the increase of lipid peroxidation (LPO) production, influence of Na+/K(+)-ATPase activities and nitric oxide (NO) levels were found. These findings provide evidence that the signaling of oxidative stress/Na+/K(+)-ATPase/NO plays a role in the underlying mechanisms of the neurotoxic effects induced by low-dose and long-term exposure of MeHg.

Effects of speech processing strategy on Chinese tone recognition by nucleus-24 cochlear implant users.

Objective: To evaluate the effects of speech processing strategy on Chinese tone recognition by Nucleus-24 cochlear implant users. Methods: Recognition of Chinese tones was measured with the spectral peak (SPEAK), advanced combination encoders (ACE), and continuous interleaved sampling (CIS) strategies in nine Nucleus-24 cochlear implant users. Recognition of Chinese sentences was also measured with the ACE strategy (1200 pulse-per-sec on each electrode). As the stimulation rate in the SPEAK processor is fixed at 250 pulses per sec per electrode (ppspe), only one stimulation rate was tested with the SPEAK processor. Three stimulation rates (900, 1200, and 1800 ppspe) were tested in the ACE processing conditions. Four stimulation rates (1200, 1800, 2400, and 3600 ppspe) were tested in the CIS processing conditions. Because the number of stimulating electrodes determines the stimulation rate in CIS processors, the number of electrodes was reduced from 12 to 8 to 6 to 4 to achieve stimulation rates of 1200, 1800, 2400, to 3600 pps. Results: Results showed that mean Chinese tone recognition scores with the ACE and CIS strategies were significantly higher than those with the SPEAK strategy. For the ACE strategy, there was no significant difference in performance among the various stimulation rates (for the ACE processing conditions, the stimulation rate was varied while keeping the number of stimulating electrodes constant). For the CIS strategy, there was no significant difference among the various stimulation rates and electrode configurations (for the CIS processing conditions, the stimulation rate was varied by changing the number of stimulating electrodes). There was also a significant correlation between Chinese tone recognition and the recognition of everyday sentences. Conclusions: The latest-generation speech processing strategies were able to provide cochlear implant users with considerable amounts of tonal information. However, Chinese tone recognition was significantly affected by the choice in speech processing strategy. Relatively higher stimulation rates (>900 ppspe) may improve Chinese tone recognition. Furthermore, it may be necessary to develop speech processing strategies to specifically improve tone recognition, which is critical for understanding tonal languages.

Association of central obesity with the severity and audiometric configurations of age-related hearing impairment.

To investigate the effect of central obesity on the severity and characteristics of age‐related hearing impairment (ARHI), we recruited 690 adult subjects with normal or symmetrical sensorineural hearing loss (SNHL). The effects of age, gender, morphometry, habits, systemic diseases, and environmental noise exposure on average pure tone hearing level at low frequencies (pure tone audiometry (PTA)‐low) and high frequencies (PTA‐high) were analyzed. After adjusting for age, gender, systemic disease, and other variables, waist circumference (WC) showed a significant positive association with PTA‐low and PTA‐high. In females, PTA‐low and PTA‐high only showed significant positive association with age, but not with WC or other variables. However, PTA‐high showed a positive association with borderline significance with WC in female subjects older than 55. In males, WC as well as age and noise exposure showed significant positive associations with both PTA‐low and PTA‐high, primarily in subjects younger than 55. When both WC and BMI were taken into account in a backward stepwise multivariate linear regression analysis, WC, but not BMI, showed a significant positive association with PTA‐low and PTA‐high in males younger than 55, and with PTA‐high with borderline significance in females older than 55. However, the audiogram patterns were not significantly affected by central obesity in either age or gender. Our results suggest that WC was, even after adjustment for BMI, an independent risk factor of ARHI, particularly for low and high frequencies in males younger than 55 and for high frequencies in female subjects older than 55.

Common clinical features of children with enlarged vestibular aqueduct and Mondini dysplasia.

Objectives/Hypothesis: The purpose of the study was to investigate the etiological factors and the audiological data of different types of inner ear malformations, which the authors thought might be helpful in elucidating the inter‐relation among malformations and shedding light on pathogenesis.

A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer

BACKGROUND Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. PATIENTS AND METHODS ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m(2) gemcitabine and 85 mg/m(2) oxaliplatin) or C-GEMOX (500 mg/m(2) cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). RESULTS The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. CONCLUSIONS Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status. CLINICAL TRIALS NUMBER This study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.

Correlation of increased activities of Na+, K+-ATPase and Ca2+-Atpase with the reversal of cisplatin ototoxicity induced by D-methionine in guinea pigs

Na(+), K(+)-ATPase and Ca(2+)-ATPase in the cochlear lateral wall play an important role in maintaining ionic homeostasis and physiologic function of the cochlea. The present study was designed to test whether the changes of Na(+), K(+)-ATPase and Ca(2+)-ATPase activities of the cochlear lateral wall and the brainstem of guinea pigs after receiving cisplatin for seven consecutive days were correlated with the altered auditory brainstem responses (ABR). Furthermore, whether a chemoprotective agent, D-methionine reversed the increased ABR threshold induced by cisplatin accompanied with the increased ATPase activities was also evaluated. The results obtained showed that cisplatin exposure caused not only a significant increase of threshold but also altered various absolute wave and interwave latencies of ABR. In addition, cisplatin significantly decreased the Na(+), K(+)-ATPase and Ca(2+)-ATPase activities in the cochlear lateral wall with a good dose-response relationship. Regression analysis indicated that an increase of ABR threshold was well correlated with a decrease of both Na(+), K(+)-ATPase and Ca(2+)-ATPase activities in the cochlear lateral wall. A chemoprotectant, D-methionine indeed reversed both abnormalities of ABR and ATPase activities in a well correlation function. The selectivity of these observed changes induced by cisplatin and D-methionine was revealed by the findings that cisplatin-treated guinea pigs had normal III-V interwave latency of ABR and no reduction of Na(+), K(+)-ATPase and Ca(2+)-ATPase specific activities in the brainstem, which is in accordance with the nonpenetrable cisplatin across the blood brain barrier. Taken all together, the present findings suggest that biochemical damage and ionic disturbance may contribute to cisplatin-induced ototoxicity to some extent, which can be reversed by d-methionine.