Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS-ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of hepatocellular carcinoma (HCC) was published in 2018, and covered the diagnosis, management, treatment and follow-up of early, intermediate and advanced disease. At the ESMO Asia Meeting in November 2018 it was decided by both the ESMO and the Taiwan Oncology Society (TOS) to convene a special guidelines meeting immediately after the Taiwan Joint Cancer Conference (TJCC) in May 2019 in Taipei. The aim was to adapt the ESMO 2018 guidelines to take into account both the ethnic and the geographic differences in practice associated with the treatment of HCC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with intermediate and advanced/relapsed HCC representing the oncology societies of Taiwan (TOS), China (CSCO), India (ISMPO) Japan (JSMO), Korea (KSMO), Malaysia (MOS) and Singapore (SSO). The voting was based on scientific evidence, and was independent of the current treatment practices, the drug availability and reimbursement situations in the individual participating Asian countries.

Short communication: The antilipogenic effect of trans-10,cis-12 conjugated linoleic acid in bovine mammary epithelial cells is associated with proteasome activity and ATP production.

Proteasomes play a widespread role in the control of protein abundance via degrading ubiquitinated proteins. Activity of proteasomes is regulated by constitutive ATPases that respond to intracellular concentrations of ATP. Although recent data suggest a role of proteasomes in fatty acid metabolism, whether lipogenic activity in mammary cells is responsive to ATP concentrations and proteasome activity is unknown. To investigate whether proteasomes play a role in milk fat depression induced by trans-10,cis-12 conjugated linoleic acid (t10,c12 CLA), a bovine mammary epithelial cell line was treated with t10,c12 CLA for 24 h before analysis of lipogenic protein abundance. Western blot analysis of inactive sterol response element-binding protein-1 (pSREBP1) and active (nSREBP1) fragments indicated a decrease in abundance induced by exogenous t10,c12 CLA. At 150 nM t10,c12 CLA, abundance of both pSREBP1 and nSREBP1 was lowest, and decreased from basal levels by 16 and 64%, respectively. Exogenous t10,c12 CLA had no effect on abundance of peroxisome proliferator-activated receptor-gamma (PPARγ), but at 150 and 300 nM it decreased abundance of SREBF chaperone (SCAP). Inhibition of proteasome activity via incubation with MG-132 (a proteasome inhibitor) alone had no effect on pSREBP1, nSREBP1, PPARγ, or SCAP abundance. However, when cells were pre-incubated with MG-132, treatment with t10,c12 CLA reduced pSREBP1 (∼27%) and nSREBP1 (∼41%) abundance without affecting PPARγ or SCAP. Compared with the control, exogenous t10,c12 CLA increased ATP concentrations, and MG-132 alone had no effect. However, ATP concentration decreased markedly in cells incubated with both MG-132 and t10,c12 CLA. Combined with the alteration of SCAP and nSREBP1, the increase of ATP concentrations with t10,c12 CLA suggested that this fatty acid influenced the function of the SREBP1-SCAP complex through altering proteasome activity. Collectively, the current data highlight a role of proteasomes and intracellular ATP concentrations in the antilipogenic effect induced by t10,c12 CLA that leads to milk fat depression.

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer.

BACKGROUND: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

The Royal Free Hospital 'hub-and-spoke network model' delivers effective care and increased access to liver transplantation.

OBJECTIVES: 'Hub-and-spoke' networks may be one solution to reduce the geographical inequality in access to liver transplantation (LT) and the growing demands on, and saturation of, LT centres. It is not clear if such networks improve equity of access, deliver comparable patient outcomes or effect patient satisfaction. STUDY DESIGN: Retrospective evaluation of outcomes and patient satisfaction within the Royal Free liver transplant 'hub-and-spoke' network. METHODS: Patient outcomes in those assessed for LT between September 2011 and 2014 at spoke centres (n = 4) were compared retrospectively with those assessed at the LT hub centre. Patient satisfaction questionnaires were completed and changes in LT referral patterns were explored with data obtained directly from NHS Blood and Transplant (NHSBT). RESULTS: A total of 655 patients (180 spoke; 475 hub) were assessed for LT. Patients referred from spoke centres were more likely to have viral hepatitis as an underlying aetiology (72/180 vs 110/475; P < 0.001), or hepatocellular carcinoma (48/180 vs 60/475; P < 0.001) as an indication for LT and were more likely to be listed for LT when compared with hub patients (139/180 vs 312/475, P = 0.005). Mortality on the waiting list (9/123 vs 25/269, P = 0.57), waiting time to LT (64-days vs 78-days, P = 0.91) and Model for End-Stage liver disease (MELD)/United Kingdom End-Stage Liver Disease (UKELD) score (P = 0.24/0.26) in listed patients were equivalent as were 1- and 3-year patient and graft survival rates. Patient satisfaction rates were high at both types of centre, with significantly more patients preferring 'locally delivered care' at spoke vs hub (11/50 vs 70/73, P≤0.0001). Since the development of formal hub-and-spoke networks data from NHSBT based on postcode confirmed a significant increase in patients undergoing LT (153%) from spoke centres, whereas numbers assessed and transplanted from the hub centre have remained static. CONCLUSION: Hub-and-spoke LT networks are effective in offering equivalent clinical outcomes, high patient satisfaction and alleviate clinical pressure on the hub centre. They have to potential to help eliminate the geographical disparity in mortality rates from chronic liver disease.

Histone H3K9 acetylation influences growth characteristics of goat adipose-derived stem cells in vitro.

Adipose-derived stem cells (ADSCs) show nearly unlimited potential in medical and animal science. Currently, understanding of the biological mechanisms regulating ADSC growth in vitro remains very limited. Histone acetylation, an epigenetic modification, plays a key role in maintaining stem cell properties. To further study its effect on ADSC growth characteristics in vitro, we treated goat ADSCs with the histone deacetylase inhibitors trichostatin A (TSA) and vorinostat (SAHA). This inhibited SIRT1 expression and increased histone H3K9 acetylation, leading to decreased cell viability, cell cycle arrest, and apoptosis. Quantitative real-time polymerase chain reaction revealed that H3K9 hyperacetylation stimulated transcription of NANOG, OCT4, SOX2, and TERT, but inhibited that of PCNA, P53, and BAX. Western blotting indicated that TSA and SAHA increased protein expression of NANOG, reduced that of SOX2, TERT, PCNA, P53, and BAX, and did not change that of OCT4. These findings provide new experimental evidence contributing to our understanding of the mechanisms underlying ADSC growth characteristics in vitro.

Development of operational immunologic tolerance with neonatal gene transfer in nonhuman primates: preliminary studies.

Achieving persistent expression is a prerequisite for effective genetic therapies for inherited disorders. These proof-of-concept studies focused on adeno-associated virus (AAV) administration to newborn monkeys. Serotype rh10 AAV expressing ovalbumin and green fluorescent protein (GFP) was administered intravenously at birth and compared with vehicle controls. At 4 months postnatal age, a second injection was administered intramuscularly, followed by vaccination at 1 year of age with ovalbumin and GFP. Ovalbumin was highest 2 weeks post administration in the treated monkey, which declined but remained detectable thereafter; controls demonstrated no expression. Long-term AAV genome copies were present in myocytes. At 4 weeks, neutralizing antibodies to rh10 were present in the experimental animal only. With AAV9 administration at 4 months, controls showed transient ovalbumin expression that disappeared with the development of strong anti-ovalbumin and anti-GFP antibodies. In contrast, increased and maintained ovalbumin expression was noted in the monkey administered AAV at birth, without antibody development. After vaccination, the experimental monkey maintained levels of ovalbumin without antibodies, whereas controls demonstrated high levels of antibodies. These preliminary studies suggest that newborn AAV administration expressing secreted and intracellular xenogenic proteins may result in persistent expression in muscle, and subsequent vector administration can result in augmented expression without humoral immune responses.

Minimal ureagenesis is necessary for survival in the murine model of hyperargininemia treated by AAV-based gene therapy.

Hyperammonemia is less severe in arginase 1 deficiency compared with other urea cycle defects. Affected patients manifest hyperargininemia and infrequent episodes of hyperammonemia. Patients typically suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation, seizures and intellectual disability; death is less common than with other urea cycle disorders. In a mouse model of arginase I deficiency, the onset of symptoms begins with weight loss and gait instability, which progresses toward development of tail tremor with seizure-like activity; death typically occurs at about 2 weeks of life. Adeno-associated viral vector gene replacement strategies result in long-term survival of mice with this disorder. With neonatal administration of vector, the viral copy number in the liver greatly declines with hepatocyte proliferation in the first 5 weeks of life. Although the animals do survive, it is not known from a functional standpoint how well the urea cycle is functioning in the adult animals that receive adeno-associated virus. In these studies, we administered [1-13C] acetate to both littermate controls and adeno-associated virus-treated arginase 1 knockout animals and examined flux through the urea cycle. Circulating ammonia levels were mildly elevated in treated animals. Arginine and glutamine also had perturbations. Assessment 30 min after acetate administration demonstrated that ureagenesis was present in the treated knockout liver at levels as low at 3.3% of control animals. These studies demonstrate that only minimal levels of hepatic arginase activity are necessary for survival and ureagenesis in arginase-deficient mice and that this level of activity results in control of circulating ammonia. These results may have implications for potential therapy in humans with arginase deficiency.

An innovative, multi-arm, complete phase 1b study of the novel anti-cancer agent tasisulam in patients with advanced solid tumors.

BACKGROUND: This phase Ib study used a parallel, multi-arm design to examine tasisulam-sodium (hereafter tasisulam), a drug with complex pharmacology, combined with standard chemotherapies in patients with advanced solid tumors, with the ultimate goal of accelerating drug development. METHODS: Patients received escalating doses of tasisulam (3 + 3 schema; target Cmax 300-400 µg/mL) every 28 days plus 1,000 mg/m(2) gemcitabine HCl (days 1 and 15), 60 mg/m(2) docetaxel, 200 mg/m(2)/day temozolomide, 75 mg/m(2) cisplatin, or 150 mg/day erlotinib. Following dose-escalation, patients were enrolled into specific tumor subtype arms, chosen based on the established activity of the standard agent. Because tasisulam is highly albumin-bound, patients in the tumor-specific confirmation arms were dosed targeting specific albumin-corrected exposure ranges (AUCalb) identified during dose-escalation (3,500 h*µg/mL [75th percentile] for docetaxel, temozolomide, and cisplatin; 4,000 h*µg/mL for gemcitabine and erlotinib). RESULTS: A total of 234 patients were enrolled. The safety profile of tasisulam with standard chemotherapies was sufficient to allow enrollment into the dose-confirmation phase in all arms. The primary dose-limiting toxicities were hematologic (thrombocytopenia and neutropenia). The most common grade ≥3 drug-related treatment-emergent adverse event was neutropenia, with the highest incidence in the docetaxel arm. CONCLUSIONS: The multi-arm design allowed the efficient determination of the maximum tolerated dose of tasisulam across multiple combinations, and a preliminary characterization of pharmacokinetics, safety, and potential efficacy. Although enrollment into all planned groups was not completed due to termination of compound development, these data support the feasibility of this approach for accelerated cancer drug development, even for drugs with complex pharmacology.

Phase III trial of gemcitabine plus docetaxel versus capecitabine plus docetaxel with planned crossover to the alternate single agent in metastatic breast cancer.

BACKGROUND: Safety and efficacy of gemcitabine plus docetaxel (GD) and capecitabine plus docetaxel (CD) were compared in patients with metastatic breast cancer, where the alternate crossover monotherapy (GD→C or CD→G) was predetermined. PATIENTS AND METHODS: Patients were randomly assigned to 3-week cycles of either gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 75 mg/m(2) on day 1 or capecitabine 1000 mg/m(2) twice daily on days 1-14 plus docetaxel 75 mg/m(2) day 1. Upon progression, patients received crossover monotherapy. Primary end point was time to progression (TtP). Secondary end points evaluated overall response rate (ORR), overall survival (OS), and adverse events (AEs). RESULTS: Despite over-accrual of 475 patients, the trial matured with only 324 of 385 planned TtP events due to patient discontinuations. Human epidermal growth factor receptor 2 status was not captured in this study. More CD patients (28%) discontinued due to AEs than GD patients (18.0%, P = 0.009). TtP [hazard ratio (HR) = 1.101, 95% confidence interval (CI) 0.885-1.370, P = 0.387] and OS (HR = 1.031, 95% CI 0.830-1.280, P = 0.785) were not significantly different comparing GD and CD. ORR was not statistically different (P = 0.239) comparing GD (72 of 207, 34.8%) and CD (78 of 191, 40.8%). TtP, OS, and ORR were not significantly different comparing crossover groups. GD caused greater fatigue, hepatotoxicity, neutropenia, and thrombocytopenia but not febrile neutropenia; CD caused more hand-foot syndrome, gastrointestinal toxicity, and mucositis. CONCLUSIONS: GD and CD produced similar efficacy and toxicity profiles consistent with prior clinical experience.

Locoregional therapy in hepatocellular carcinoma: when to start and when to stop and when to revisit.

With increasing therapeutic options available for advanced hepatocellular carcinoma (HCC), the timing and sequencing of locoregional and systemic therapy need to be re-examined. This is especially so for patients with intermediate HCC, so as to optimize responses while preserving liver reserves, and in so allowing our patients to achieve the best survival outcomes possible.

Risk factors for recurrent falls in older adults: A systematic review with meta-analysis.

Older adults who fall recurrently (i.e., 2 or more falls/year) are at risk of functional decline and mortality. Understanding which risk factors for recurrent falls are most important will inform secondary fall prevention strategies that can reduce recurrent falls risk. Thus, we conducted a systematic review with meta-analysis to determine the relative risk of recurrent falls for different types of falls risk factors. MEDLINE, EMBASE, PsycINFO, and CINAHL databases were searched on April 25, 2019 (Prospero Registration: CRD42019118888). We included peer-reviewed prospective studies which examined risk factors that contributed to recurrent falls in adults aged ≥ 60 years. Using the falls risk classification system of Lord and colleagues, we classified each risk factor into one of the following domains: 1) balance and mobility; 2) environmental; 3) psychological; 4) medical; 5) medication; 6) sensory and neuromuscular; or 7) sociodemographic. We calculated the summary relative risk (RR) for each domain and evaluated the risk of bias and quality of reporting. Twenty-two studies were included in this systematic review and meta-analysis. Four domains predicted recurrent falls: balance and mobility (RR:1.32;95 % CI:[1.10, 1.59]), medication (RR:1.53;95 % CI:[1.11, 2.10]), psychological (RR:1.35;95 % CI:[1.03, 1.78]), and sensory and neuromuscular (RR:1.51;95 % CI:[1.18, 1.92]). Each of these four domains can be viewed as a marker of frailty. The risk of bias was low, and the study quality was high (minimum:19/22). Older adults with markers of frailty are up to 53 % more likely to experience recurrent falls. Strategies that identify and resolve frailty markers should be a frontline approach to preventing recurrent falls.

A phase I trial of pemetrexed plus gemcitabine given biweekly with B-vitamin support in solid tumor malignancies or advanced epithelial ovarian cancer.

PURPOSE: To determine the maximally tolerated dose (MTD) of biweekly pemetrexed with gemcitabine plus B(12) and folate supplementation in patients with advanced solid tumors and ovarian cancer. EXPERIMENTAL DESIGN: Patients with no prior pemetrexed or gemcitabine therapy enrolled in cohorts of three, expanding to six if dose-limiting toxicity (DLT) was observed. Pemetrexed, escalated from to 700 mg/m(2), was given before gemcitabine 1,500 mg/m(2) every 14 days. DLTs were grade 4 neutropenia lasting >7 days or febrile neutropenia, grade 4 or 3 thrombocytopenia (with bleeding), grade > or =3 nonhematologic toxicity, or treatment delay of > or =1 week due to unresolved toxicity. RESULTS: The ovarian cancer cohort enrolled 24 patients with unlimited prior cytotoxic chemotherapies. MTD was observed at pemetrexed 600 mg/m(2), with 2 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (83%), leukopenia (67%), lymphopenia (73%), and febrile neutropenia (12%). Median cycle per patient was 8 (range, 1-16). Six of 21 (28%) patients had confirmed partial responses. Study protocol was modified for the solid tumor cohort (n = 30) to enroll patients with two or more prior cytotoxic regimens. MTD was observed at pemetrexed 500 mg/m(2), with 1 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (63%), lymphopenia (43%), leukopenia (70%) and febrile neutropenia (6.6%). Median cycle per patient was 4 (range, 1-20). Three of 29 (10.3%) response-evaluable patients had confirmed partial responses: 2 squamous cell carcinomas of head and neck and 1 nasopharyngeal cancer. CONCLUSION: MTDs for the solid tumor and ovarian cancer cohorts were reached at pemetrexed 500 and 600 mg/m(2), respectively, given biweekly with gemcitabine 1,500 mg/m(2).

Phase II trial of subcutaneous interferon followed by intravenous hybrid bolus/continuous infusion interleukin-2 in the treatment of renal cell carcinoma: final results of Cancer Biotherapy Research Group 95-09.

OBJECTIVE: We conducted a phase II trial in metastatic renal cell cancer of outpatient subcutaneous (s.c.) interferon-alpha2b (IFN), followed by an inpatient hybrid schedule of bolus and continuous interleukin-2 (IL- 2). METHODS: Treatment consisted of monthly IFN 10 MU/m(2) s.c. for 4 consecutive days, followed by 36 MIU/m(2) bolus IL-2, then 72-hour continuous intravenous (i.v.) infusion of 18 MIU/m(2) IL-2 per day. Between May 1997 and June 2000, 25 men and 11 women enrolled, with a median age of 57 years (range, 42-77), including 9 patients over 65. Prior treatment included nephrectomy (31), radiation (8), biotherapy (7), and chemotherapy (4). Sites of disease included 26 lung, 13 lymph node, 9 bone, 8 liver, 4 kidney, and 4 adrenal locations. Patients received an average of 3.1 treatment cycles (range, 1-6). RESULTS: There was 1 complete and 3 partial responses, for a response rate of 11% (3% to 27%; 95% confidence interval [CI]); 40% had stable disease. Median failure-free survival was 2.5 months; median overall survival was 15.0 months. The 1-, 2-, and 5-year survival rates were 53%, 30%, and 12%, respectively. Only 8 patients required a reduction in IL-2 dose. The most frequent grade 3 or 4 toxicities were 11% fatigue, 9% renal insufficiency, and 7% hypotension. CONCLUSIONS: Response and survival rates were similar to those seen in other multicenter trials using inpatient high-dose IL-2.

Identification and characterization of a prevalent hepatitis B virus X protein mutant in Taiwanese patients with hepatocellular carcinoma.

The aim of this study was to investigate whether there was a particular hepatitis B virus (HBV) X protein (HBx) mutant associated with Taiwanese patients with hepatocellular carcinoma (HCC). Initially, the entire coding region of HBx gene from the serum samples of 14 Taiwanese patients were sequenced. A novel mutant, HBx-A31, was preferentially found in patients with HCC. Sera from 67 patients with HCC and 100 patients with chronic hepatitis B were thus subjected for codon 31 analysis using a dual amplification created restriction site method. HBx-A31 was detected more frequently in patients with HCC (52% versus 12%; P<0.001) and in patients with liver cirrhosis (44% versus 6%; P<0.001). Site directed mutagenesis experiment revealed that HBx-A31 was less effective in transactivating HBV enhancer I-X promoter complex, less efficient in supporting HBV replication, and less potent in enhancing TNF-alpha induced increment of CPP32/caspase 3 activities in HepG2 cells. In conclusion, a prevalent HBx mutant was identified in Taiwanese patients with hepatocellular carcinoma. Development of this mutant might represent a strategy of the virus to escape immune surveillance and thus contribute to the process of multiple-step hepatocarcinogenesis.

Mechanisms of verapamil-induced conduction block in anomalous atrioventricular bypass tracts.

Verapamil, a calcium channel blocking agent, has been demonstrated to have depressive effects on the atrioventricular (AV) node but not anomalous AV bypass tracts. Of 39 patients with AV reciprocating tachycardia utilizing left-sided bypass tracts for retrograde conduction, intravenous infusion of verapamil (0.15 mg/kg) terminated the tachycardia in 31 patients. Verapamil interrupted the tachycardia circuit by inducing retrograde conduction block in the bypass tract rather than the AV node in 5 of these 31 patients. Electrophysiologic studies in these five patients revealed that verapamil-induced conduction block in the bypass tract could be accounted for by two distinctly different mechanisms. In three patients, verapamil induced alternating slow and fast AV nodal conduction resulting in alternating long and short cycle lengths during the tachycardia; consequently, development of the Ashman phenomenon in the bypass tract terminated the tachycardia. In the remaining two patients, the bypass tract exhibited properties similar to those of the AV node; verapamil prolonged the effective refractory period of the bypass tract, thereby terminating the tachycardia. Thus, depending on the functional properties of the bypass tract, verapamil may interrupt an AV reciprocating tachycardia circuit by exerting either a direct or indirect depressive action on the bypass tract.

Electrophysiologic demonstration of concealed conduction in anomalous atrioventricular bypass tracts.

To demonstrate the occurrence of concealed conduction in anomalous atrioventricular (AV) bypass tracts, 11 patients were selected for study. Two had a right-sided and nine had a left-sided bypass tract. Electrode catheters were placed in the right atrium, coronary sinus, AV junction and right ventricle. After every eighth atrial or ventricular driving beat (A1 or V1) at a constant cycle length, two successive atrial or ventricular premature beats (A2 and A3 or V2 and V3) were delivered. The A1A2 or V1V2 interval was fixed at 30 ms greater than the effective refractory period of the atrium or right ventricle, but less than the effective refractory period of the bypass tract in the anterograde or retrograde direction. This allows A2 or V2 to capture the atrium or ventricle, but not conduct in the bypass tract. The A3 or V3 was delivered from late diastole with a progressively shorter A2A3 or V2V3 interval until atrial or ventricular refractoriness was encountered. In the anterograde direction, the presence of A2 prevented A3 conduction in the bypass tract despite A1A3 intervals being longer than the anterograde effective refractory period of the bypass tract in 8 of the 11 patients. In the retrograde direction, the presence of V2 prevented V3 conduction in the bypass tract despite V1V3 intervals being longer than the retrograde effective refractory period of the bypass tract in 3 of the 11 patients. Thus, using the technique of programmed electrical stimulation, concealed conduction in anomalous AV bypass tracts can be demonstrated in both anterograde and retrograde directions.

Carbon monoxide poisoning: a five year review at Tan Tock Seng Hospital, Singapore.

INTRODUCTION: Carbon monoxide poisoning (COP) is one of the leading causes of death from poisoning worldwide. There is no published study of COP in Singapore so far. MATERIALS AND METHODS: All patients admitted with the diagnosis of COP to Tan Tock Seng Hospital (TTSH) over 5 years from 1999 to 2003 were retrospectively reviewed. The diagnosis was based on a history of potential exposure to carbon monoxide (CO) and elevated levels of carboxyhaemoglobin (COHb). The causes, demographic data, clinical presentations, management and complications were analysed. RESULTS: There were 12 patients with COP. Their average age was 38.9 (+/-11.8) years, with a male-to-female ratio of 3:1. Accidental COP (58.3%) was more common than intentional COP (41.7%). The most common cause of accidental COP was smoke inhalation from a faulty vehicle. Gas stove was the most preferred source for intentional poisoning. Presenting features were headache (83.3%), confusion (83.3%), coma (12.7%) and agitation (8.3%). The mean COHb level on admission was 35.9% (+/-13.6). All were treated with 100% oxygen. All the patients achieved normal levels of COHb within 24 hours of admission. Two (16.7%) required intubation for airway protection as they were comatose on arrival, of which 1 presented with very high level of COHb (48.1%) and was the only patient to be treated with hyperbaric oxygen. Acute complications were globus pallidus infarction (16.6%), acute respiratory distress syndrome (8.3%) and myocardial ischaemia (8.3%). Most of the patients (91.7%) were discharged well from the hospital. One patient developed parkinsonism after a follow-up of 2 years. There were no deaths. CONCLUSION: COP is relatively uncommon in Singapore. It has a low rate of short- and long-term complications.