Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients.

This study investigated the impact of ABCB5, ABCC5 and RLIP76 polymorphisms on doxorubicin pharmacokinetics in Asian breast cancer patients (N=62). Direct sequencing was performed to screen for previously identified ABCC5 polymorphisms as well as polymorphisms in the exons and exon-intron boundaries of ABCB5 and RLIP76 genes. Genotype-phenotype correlations were analyzed using Mann-Whitney U-test. The homozygous variant allele at the ABCC5 g.+7161G>A (rs1533682) locus was significantly associated with higher doxorubicin clearance (g.+7161AA vs g.+7161GG, CL/BSA (Lh-1m-2): 30.34 (25.41-33.60) vs 22.46 (15.04-49.4), P=0.04). Homozygosity for the reference allele at the ABCC5 g.-1679T>A locus was associated with significantly higher doxorubicinol exposure (g.-1679TT vs g.-1679TA, AUC0-∞/dose/BSA (hm-5): 15.48 (6.18-67.17) vs 8.88 (3.68-21.71), P=0.0001). No significant influence of the three newly identified ABCB5 polymorphisms (c.2T>C, c.343A>G and c.1573G>A) on doxorubicin pharmacokinetics was observed. No polymorphisms were identified in the RLIP76 gene. These findings suggest that ABCC5 polymorphisms may explain partially the interpatient variability in doxorubicin disposition.

Predictive Risk Factors in the Development of Intraoperative Hyperkalemia in Adult Living Donor Liver Transplantation.

BACKGROUND: Hyperkalemia, defined as a serum potassium level higher than 5 mEq/L, is common in the liver transplantation setting. Severe hyperkalemia may induce fatal cardiac arrhythmias; therefore, it should be monitored and treated accordingly. The aim of the current retrospective study is to evaluate and indentify the predictive risk factors of hyperkalemia during living-donor liver transplantation (LDLT). METHODS AND PATIENTS: Four hundred eighty-seven adult LDLT patients were included in the study. Intraoperative serum potassium levels were monitored at least five times during LDLT; patients with a potassium level higher than 5 mEq/L were included in group 1, and the others with normokalemia in group 2. Patients' categorical characteristics and intraoperative numeric variables with a P value <.1 were selected into a multiple binary logistic regression model. In multivariate analysis, a P value of <.05 is regarded as a risk factor in the development of hyperkalemia. RESULTS: Fifty-one of 487 (10.4%) patients had hyperkalemia with a serum potassium level higher than 5.0 mEq/L during LDLT. Predictive factors with P < .1 in univariate analysis (Table 1), such as anesthesia time, preoperative albumin level, Model for End-stage Liver Disease score, preoperative bilirubin level, amount of blood loss, red blood cell (RBC) and fresh frozen plasma transfused, 5% albumin administered, hemoglobin at the end of surgery, and the amount of furosemide used, were further analyzed by multivariate binary regression. Results show that the anesthesia time, preoperative serum albumin level, and RBC count are determinant risk factors in the development of the hyperkalemia in our LDLT serials. CONCLUSION: Prolonged anesthesia time, preoperative serum albumin level, and intraoperative RBC transfusion are three determinant factors in the development of intraoperative hyperkalemia, and close monitoring of serum potassium levels in patients with abovementioned risk factors are recommended.

Review of critical incidents in a university department of anaesthesia.

In 2011, our hospital started a new system of 100% procedural audit of anaesthesia work, in which we incorporated the reporting of critical incidents. This monitoring of critical incidents has enabled identification of the spectrum of incidents and risk factors and helped in the education of trainees and specialists. In this review, we analyse 379 incidents that had been reported among 44,915 anaesthetics administered in a two-year period. The risk of incidents was higher in patients of lower American Society of Anesthesiologists physical status, anaesthesia of long duration and anaesthesia carried out after-hours. The most common incidents were airway problems and drug administration problems. Fifty-nine percent of incidents were evaluated to be preventable and adverse outcomes occurred in 48% of cases. Human factors were the major contributors to incidents. We suggest that incorporating critical incident reporting as part of a 100% procedural audit facilitated, rather than discouraged, the reporting of critical incidents, even though reporting was not anonymous. The rate of incident reporting increased from 0.37% to 0.84%.

A case of metastatic squamous cell carcinoma of the hypopharynx manifesting as acute abdomen.

INTRODUCTION: Squamous cell head and neck cancers are usually confined to local and regional sites but occasionally, patients may present with rare manifestations of distant metastases. CLINICAL PICTURE: A 23-year-old female was treated with concurrent chemo-radiotherapy for stage IVA post-cricoid squamous cell carcinoma. A month later, she presented with acute abdomen and was found to have extensive peritoneal nodules at laparotomy. Intestinal obstruction soon followed. TREATMENT: She was managed conservatively for the intestinal obstruction and given weekly paclitaxel. OUTCOME: She continued to deteriorate and succumbed shortly after the diagnosis of carcinomatosis peritoneii. CONCLUSION: This rare and aggressive presentation reminds us to be cognizant of relapsed head and neck cancers manifesting atypically, and the need for more aggressive search of distant disease in at least some subgroups of head and neck cancer.

First-line endocrine treatment of breast cancer: aromatase inhibitor or antioestrogen?

Until recently, endocrine therapy for breast cancer was relatively simple. If the tumour expressed hormone receptors, regardless of stage and age, tamoxifen was indicated. While this largely remains the case for premenopausal women, clinical trials in postmenopausal women have broadened our choice to include one of three selective aromatase inhibitors (AIs), the nonsteroidal agents anastrozole or letrozole and the steroidal agent exemestane. Comparative data concerning the efficacy, toxicity, tolerability and cost of AI vs tamoxifen continues to evolve with over 40 000 women slated to be involved in clinical trials. Currently, tamoxifen remains an appropriate choice for adjuvant treatment, and will remain so unless a clear survival advantage emerges for adjuvant AI therapy. However, anastrozole is widely seen as a useful alternative, with particular merit for patients prone to the development of serious tamoxifen side effects. For endocrine therapy naïve advanced disease, several trials have provided evidence that a nonsteroidal AI has replaced tamoxifen as optimal treatment. In the neoadjuvant setting, letrozole was also more effective than tamoxifen, both in terms of response rates and the incidence of breast-conserving surgery, and so AI therefore also dominates this evolving indication. The ongoing adjuvant clinical trials ask all the relevant questions regarding tamoxifen and AI in combination, sequence and duration, except for 5 years of an AI vs a longer period. For both the advanced and early-stage disease, resistance remains the key obstacle to overcome, and trials that combine endocrine agents with signal transduction inhibitors such as HER1 and HER2 kinase inhibitors, farnesyl transferase inhibitors, mTOR inhibitors as well as COX2 inhibitors are being developed in a concerted attempt to address this problem.

A case report of a patient with bronchial carcinoid tumour and late presentation of Cushing's syndrome.

Bronchial carcinoid tumour with ectopic adrenocorticotrophin (ACTH) production is an uncommon cause of Cushing's syndrome. In most instances, the patient presents with clinical hyperglucocorticolism and a search for its underlying pathology leads to the discovery of an inconspicuous bronchial carcinoid tumour, if at all. Often the tumour is not immediately detectable. We report a patient who presented in the reverse order--she initially had a large asymptomatic bronchial carcinoid tumour that subsequently manifested as clinical Cushing's syndrome after remaining quiescent for four years.