Feasibility and safety of extended adjuvant temozolomide beyond six cycles for patients with glioblastoma.

INTRODUCTION: Temozolomide is the first chemotherapeutic agent proven effective for patients with newly diagnosed glioblastoma. The drug is well tolerated for its low toxicity. The current standard practice is concomitant chemoradiotherapy for 6 weeks followed by 6 cycles of adjuvant temozolomide. Some Caucasian studies have suggested that patients might benefit from extended adjuvant cycles of temozolomide (>6 cycles) to lengthen both progression-free survival and overall survival. In the present study, we compared differences in survival and toxicity profile between patients who received conventional 6-cycle temozolomide and those who received more than 6 cycles of temozolomide. METHODS: Patients with newly diagnosed glioblastoma without progressive disease and completed concomitant chemoradiotherapy during a 4-year period were studied. Progression-free survival was compared using Kaplan-Meier survival curves. t Test, U test, and correlation were chosen accordingly to examine the impact of age, extent of resection, MGMT promoter methylation status and adjuvant cycles on progression-free survival. For factors with a P value of <0.05 in univariate analyses, Cox regression hazard model was adopted to determine the strongest factors related to progression-free survival. RESULTS: The median progression-free survival was 17.0 months for patients who received 6 cycles of temozolomide (n=7) and 43.4 months for those who received more than 6 cycles (n=7) [P=0.007, log-rank test]. Two patients in the former group and one in the latter group encountered grade 1 toxicity and recovered following dose adjustment. Cycles of adjuvant temozolomide were correlated with progression-free survival (P=0.016, hazard ratio=0.68). CONCLUSION: Extended cycles of temozolomide are safe and feasible for Chinese patients with disease responsive to temozolomide.

Frameless stereotactic radiosurgery for brain metastases: a review of outcomes and prognostic scores evaluation.

INTRODUCTION: Stereotactic brain radiosurgery provides good local control in patients with limited brain metastases. A newly developed frameless system allows pain-free treatment. We reviewed the effectiveness of this frameless stereotactic brain radiosurgery and identified prognostic factors that may aid better patient selection. METHODS: Medical records of patients with brain metastases treated with linear accelerator-based frameless stereotactic brain radiosurgery between January 2010 and July 2015 in a university affiliated hospital in Hong Kong were reviewed. Outcomes including local and distant brain control rate, progression-free survival, and overall survival were analysed. Prognostic factors were identified by univariable and multivariable analyses. Association of outcomes with four common prognostic scores was performed. RESULTS: In this study, 64 patients with 94 lesions were treated with a median dose of 18 Gy (range, 12-22 Gy) in a single fraction. The median follow-up was 11.5 months. One-year actuarial local and distant brain control rates were 72% and 71%, respectively. The median overall survival was 13.0 months. On multivariable analysis, Karnofsky performance status score (>50 vs ≤50) and number of lesions (1-2 vs ≥3) were found to associate significantly with distinct brain progression-free survival (P=0.022, hazard ratio=0.20, 95% confidence interval 0.05-0.80 and P=0.003, hazard ratio=0.31, 95% confidence interval 0.14-0.68, respectively). Overall survival was associated significantly with Basic Score for Brain Metastases (P=0.031), Score Index for Radiosurgery in Brain Metastases (P=0.007), and Graded Prognostic Assessment (P=0.003). Improvement in overall survival was observed in all groups of different prognostic scores. CONCLUSION: Frameless stereotactic brain radiosurgery is effective in patients with oligo-metastases of brain and should be increasingly considered in patients with favourable prognostic scoring.

Ten-year review of survival and management of malignant glioma in Hong Kong.

INTRODUCTION: Surgical resection used to be the mainstay of treatment for glioma. In the last decade, however, opinion has changed about the goal of surgical resection in treating glioma. Ample evidence shows that maximum safe resection in glioblastoma improves survival. Neurosurgeons have therefore revised their objective of surgery from diagnostic biopsy or limited debulking to maximum safe resection. Given these changes in the management of glioma, we compared the survival of local Chinese patients with glioblastoma multiforme over a period of 10 years. METHODS: We retrospectively reviewed the data of the brain tumour registry of the CUHK Otto Wong Brain Tumour Centre in Hong Kong. Data of patients with glioblastoma multiforme were reviewed for two periods, during 1 January 2003 to 31 December 2005 and 1 January 2010 to 31 December 2012. Overall survival during these two periods of time was assessed by Kaplan-Meier survival estimates. Risk factors including age, type and extent of resection, use of chemotherapy, and methylation status of O6-methylguanine-DNA methyltransferase were also assessed. RESULTS: There were 26 patients with glioblastoma multiforme with a mean age of 52.2 years during 2003 to 2005, and 42 patients with a mean age of 55.1 years during 2010 to 2012. The mean overall survival during these two periods was 7.4 months and 12.7 months, respectively (P<0.001). The proportion of patients who underwent surgical resection was similar: 69.2% in 2003 to 2005 versus 78.6% in 2010 to 2012 (P=0.404). There was a higher proportion of patients in whom surgery achieved total removal in 2010 to 2012 than in 2003 to 2005 (35.7% and 7.7%, respectively; P=0.015). During 2010 to 2012, patients who were given concomitant chemoradiotherapy showed definitively longer survival than those who were not (17.9 months vs 4.5 months; P=0.001). The proportion of patients who survived 2 years after surgery increased from 11.5% in 2003 to 2005 to 21.4% in 2010 to 2012. CONCLUSIONS: Hong Kong has made substantial improvements in the management of glioblastoma multiforme over the last decade with corresponding improved survival outcomes. The combination of an aggressive surgical strategy and concomitant chemoradiotherapy are probably the driving force for the improvement.

Ultrasound-guided plugged percutaneous biopsy of solid organs in patients with bleeding tendencies.

OBJECTIVE: To establish and verify the utility of plugging biopsy tracts, using a combination of Gelfoam slurry and torpedo in the prevention of post-biopsy bleeding in patients at high risk of post-procedure haemorrhage following ultrasound-guided percutaneous biopsy of solid organs. DESIGN: Case series. SETTING: Radiology Department of a regional hospital in Hong Kong. PATIENTS: In our unit, all patients considered to be at high risk of post-biopsy haemorrhage of a solid organ underwent ultrasound-guided plugged percutaneous biopsy from year 2005 to 2012. INTERVENTIONS: All the included patients had undergone real-time ultrasound-guided biopsy of solid organs (liver in 10 and spleen in one patient). In all cases, a combination of a coaxial introducer needle and Temno needle were used. After adequate specimens were obtained, Gelfoam slurry (for distal embolisation) followed by Gelfoam torpedo (for proximal embolisation) were used to plug the biopsy tract. MAIN OUTCOME MEASURES: Technical success, any post-biopsy haemorrhage treated by transfusion or other intervention, and plugging-related complications were reviewed for each patient. RESULTS: Technical success was achieved in all patients and none experienced post-biopsy haemorrhage treated by blood transfusion or any other intervention. CONCLUSION: Plugging of the biopsy tract with Gelfoam slurry followed by Gelfoam torpedo is a direct and simple procedure that can safely and effectively prevent haemorrhage in patients at high risk of post-biopsy haemorrhage.

Acute appendicitis complicating Amyand's hernia: imaging features and literature review.

Acute appendicitis complicating Amyand's hernia is an extremely rare condition, in which the appendix herniates into the inguinal sac and, subsequently, gets inflamed. The condition is difficult to diagnose clinically. Imaging is valuable for its diagnosis and detection of the associated complications. In this article, we will discuss the imaging features of acute appendicitis complicating Amyand's hernia and the results of a literature review on the condition.

Adjuvant chemoradiation for gastric cancer: experience in the Chinese population.

AIMS: The role of adjuvant chemoradiation for gastric cancer after curative R0 gastrectomy was first established by the US Intergroup 0116 study. Although confirmatory studies are in progress, few data are available regarding its application to the Chinese population. We describe our radiotherapy technique and report the treatment results in Hong Kong. MATERIALS AND METHODS: This was a single centre retrospective study on 63 Chinese patients who underwent adjuvant chemoradiation for gastric adenocarcinoma between June 2000 and December 2004. The treatment protocol was based on that of the Intergroup study. Computed tomography planned anteroposterior opposing field arrangement and treatment under breath hold at deep inspiration position were adopted. RESULTS: In total, 63 patients, mean age 50 years, with gastric cancer stage IB to limited metastatic IV disease were analysed. The median follow-up time was 27.2 months. The relapse-free survival and overall survival at 3 years were 50 and 54%, respectively. The recurrence pattern was dominated by distant failure and only one patient developed isolated locoregional recurrence. Of the 10 patients who had positive microscopic surgical margins after surgery, seven had recurred and died. On multivariate analysis, margin status was the only significant prognosticator for survival. Thirty per cent of patients experienced grade 3 or above acute toxicity (24% haematological, 14% gastrointestinal) and one patient died of neutropenic sepsis. There was one case of grade 3 late toxicity. CONCLUSIONS: The outcome after adjuvant chemoradiation for gastric cancer seemed to be favourable, with manageable toxicities, in the Chinese population. Locoregional failure was uncommon. Patients with microscopic surgical margin involvement had a very high failure rate despite adjuvant chemoradiation.

Sodium ramping reduces hypotension and symptoms during haemodialysis.

OBJECTIVES: To evaluate the effectiveness of sodium ramping (profiling) in reducing hypotensive episodes and symptoms during haemodialysis. DESIGN: Prospective study. SETTING: Regional hospital, Hong Kong. PATIENTS: Thirteen patients who experienced frequent episodes of hypotension and/or symptoms such as cramps, dizziness, chest pain, nausea, vomiting, and headache during haemodialysis in the preceding 4 weeks. INTERVENTIONS: Each patient was switched from standard haemodialysis with a constant dialysate sodium concentration of 135 to 140 mmol/L to a ramped sodium haemodialysis for a period of 4 weeks. During this time the dialysate sodium concentration was ramped linearly downwards from 150 mmol/L at the beginning of dialysis to 140 mmol/L at the end of dialysis. MAIN OUTCOME MEASURES: Intradialytic hypotensive episodes, intradialytic symptoms, nursing interventions, systolic and diastolic blood pressures, and interdialytic weight gain. RESULTS: A total of 248 haemodialysis sessions undertaken by 13 patients were analysed. Switching from constant sodium haemodialysis to ramped sodium haemodialysis resulted in a significant reduction in the number of intradialytic hypotensive episodes from 5.8 (standard deviation, 6.4) to 2.2 (3.3) [P<0.05], the total number of intradialytic symptoms from 7.1 (3.4) to 0.9 (1.3) [P<0.01], and nursing interventions from 11.3 (6.3) to 1.7 (3.9) [P<0.01]. Post-dialysis systolic and diastolic blood pressures were higher during ramped sodium haemodialysis compared with constant sodium haemodialysis (systolic blood pressure, 139 [standard deviation, 23] vs 133 [22] mm Hg, P<0.001; diastolic blood pressure, 77 [11] vs 74 [13] mm Hg, P<0.01), and there was a trend towards a smaller drop in blood pressure after dialysis. The interdialytic weight gain with sodium ramping haemodialysis was greater compared with constant sodium haemodialysis (3.1 [standard deviation, 1.0] vs 2.7 [1.1] kg, P<0.001). CONCLUSION: Sodium ramping during haemodialysis effectively reduces hypotensive episodes and intradialytic symptoms. Post-dialysis blood pressure is better maintained. A side-effect of sodium ramping is a greater interdialytic weight gain.

Renal tubular acidosis and severe hypophosphataemia due to toluene inhalation.

A 21-year-old woman developed severe muscle paralysis after sniffing toluene-containing thinner solution for 2 weeks. Her serum chemistries revealed severe hypokalaemia and a normal anion gap hyperchloraemic metabolic acidosis secondary to renal tubular acidosis. Her initial presentation mimicked hypokalaemic periodic paralysis, but toxicology screening of her blood and urine revealed the correct diagnosis of toluene poisoning. Her electrolyte and acid-base status returned to normal 4 days after cessation of toluene sniffing. On another occasion, apart from renal tubular acidosis, the patient also developed severe hypophosphataemia with the phosphate level decreasing to 0.15 mmol/L. Hypophosphataemia with such a low phosphate level after toluene poisoning has been rarely reported in the literature. Toluene inhalation can result in multiple electrolyte and acid-base abnormalities, and should be considered in the diagnosis of any young patient who presents with unexplained hypokalaemia and normal anion gap metabolic acidosis.

'Genotypic shuffling' of sequential clones of Candida albicans in HIV-infected individuals with and without symptomatic oral candidiasis.

Although HIV-infected individuals harbour multiple strains of oral Candida albicans, little is known of their micro-evolution over time. Therefore, a prospective study was conducted with 16 HIV-infected ethnic Chinese individuals with and without symptoms of oropharyngeal candidiasis to evaluate the genotype distribution of oral C. albicans isolates during HIV disease progression. Oral-rinse samples were obtained from all individuals and up to five C. albicans colonies were selected for each visit, over a 12 month period of multiple visits. After identification of isolates using standard mycological criteria, the genetic similarities of yeast isolates within and between sequential clones of C. albicans were assessed by DNA fingerprinting through random amplification of polymorphic DNA (RAPD). The results of RAPD gel profiles and the lineage of each isolate were further analysed using commercially available software. RAPD studies revealed the prevalence of up to 14 different genotypes per individual during the study period, with multiple genotypes isolated simultaneously from a single oral rinse. Computer analysis of RAPD profiles revealed that yeasts isolated over sequential visits from symptomatic individuals demonstrated a striking level of relatedness compared with isolates from asymptomatic individuals. Genetically identical C. albicans strains also formed 'loosely' connected subclusters that overlapped multiple visits, implying genetic 'shuffling' in these isolates during disease progression. These data point to varying evolutionary genetic trends in C. albicans associated with symptomatic oral candidiasis and asymptomatic carriage in HIV disease.

Subject control as a determinant of the reinforcing properties of intracranial stimulation.

There has been some controversy whether experimenter-administered electrical stimulation of the brain is aversive or simply less reinforcing than that delivered via self-stimulation. Rats with MFB-LH electrodes self-stimulated with high, medium, and low currents and the self-produced rates were tape recorded. In Experiment 1, the rats were allowed to choose between self-administered versus replayed ESB. When both types of stimulation were available at medium intensities, the rats preferred to self-administer the ESB. This preference was increased when the re-played stimulation was presented at a lower intensity than the self-administered ESB. However, the preference for contingent ESB decreased when the intensity of the experimenter administered ESB was increased suggesting that experimenter-administered ESB is not aversive. In Experiment 2, the rats chose between experimenter administered ESB delivered at the played-back self-generated rate versus a regular averaged rate. All Ss preferred the previously self-generated mode. In Experiment 3, the rats were deprived of water and given four daily competition tests between experimenter administered ESB versus water. All rats "self-dehydrated" again demonstrating that experimenter-administered ESB is not aversive. It is concluded that rats prefer to control the rate at which ESB is presented, but that non-contingent stimulation is clearly not aversive.

Morphine and self-stimulation: evidence for action on a common neural substrate.

Recent studies have demonstrated that the self-stimulation phenomenon may provide a useful technique for investigating the rewarding properties of potentially addictive drugs such as morphine. The present study attempted to examine the nature of morphine's effects on self-stimulation by observing changes in rate-intensity functions following morphine administration. The results indicate that morphine markedly enhanced bar pressing for low intensity stimulation when the intensities were presented in an ascending sequence but morphine produced only slight changes in self-stimulation rates when a descending series was used. The failure of morphine to facilitate responding in the descending series suggests that adaptation of the self-stimulation system can block morphine's effects on this system. These findings appear to support the hypothesis that morphine affects the excitability of the neural system which mediates self-stimulation.

Facilitation of self-stimulation in rats by methadone.

The effects of morphine and its derivatives on self-stimulation behavior have been widely studied. In those experiments which have used multiple injections (over days) and multiple post-injection tests (within days), the typical findings includes a depression of responding after the initial injections followed by a facilitation of responding on subsequent days. There have been only a few reports which have tested the effects of methadone in this paradigm. Some investigators have observed only depression of self-stimulation while others have reported both the transient depression and the subsequent facilitation generally obtained with morphine. In the present experiment we administered either 5 mg/kg or 10 mg/kg methadone IP over a five day period and tested MFB-LH self-stimulation at 2, 4, 6, 8, 10 and 23 hours post-injection. Compared to saline controls, the 10 mg/kg dose produced the typical opiate-induced changes in self-stimulation, i.e., an initial depression which lasted for two hours on the first two days but was replaced by significant facilitation by hour 4 of day 3. This facilitation persisted for at least 10 hours on all 5 days of the experiment. Except for a transient (days 2-3) depression of self-stimulation, 5 mg/kg was without effects. The present experiment demonstrates that methadone does facilitate self-stimulation but that its ability to do so is highly dose-dependent.

Intraperitoneal pulse calcitriol in the treatment of secondary hyperparathyroidism in patients on continuous ambulatory peritoneal dialysis.

OBJECTIVE: To determine whether it is practicable to use intraperitoneal calcitriol to treat continuous ambulatory peritoneal dialysis (CAPD) patients with secondary hyperparathyroidism and whether this form of therapy is effective and safe. DESIGN: A prospective, nonrandomized study. SETTING: Division of Nephrology, Tertiary Hospital. METHOD: Eight patients from our CAPD population were recruited (5 F, 3 M), aged 24 to 63 years (mean 38.9 +/- 7.6 yr). They had been on CAPD for 8 to 84 months (mean 47.6 +/- 24.6 months). All the patients had bone biopsy-proven secondary hyperparathyroidism with 2 patients showing mixed lesions. The CAPD system was changed to the twin-bag system (Ultrabag, Baxter Healthcare, McGaw Park, IL, U.S.A.) in all 8 patients, who were taught to inject the calcitriol directly through the short transfer set and the Tenckhoff catheter into the peritoneal cavity, twice per week before bedtime. Calcium carbonate or calcium acetate was used as the main phosphate binder. Intact parathyroid hormone level (iPTH), serum ionized calcium (iCa), serum phosphate, and serum total alkaline phosphatase (alk. phos.) levels were measured at baseline and then every 4 weeks. The mean duration of follow-up was 10.5 months +/- 1.9 months. RESULTS: There was a significant drop of iPTH level from the pretreatment level of 100.6 +/- 35.8 pmol/L to a level of 63.8 +/- 48.7 pmol/L at 24 weeks (p = 0.036). The lowest level of iPTH attained was 43.4 +/- 27.0 pmol/L at 48 weeks. Serum total alk. phos. also dropped from 232.4 +/- 83.3 IU/L pretreatment to 147.9 +/- 52.0 IU/L at 24 weeks (p = 0.017). The decrease in alk. phos. level paralleled the decrease in iPTH level. The mean serum iCa level did not show any significant rise throughout the study period. The maximum dose of calcitriol used was 6.6 +/- 1.5 microg/week and the average dose of calcitriol was 5.4 +/- 1.2 microg/week. One patient did not respond satisfactorily and she subsequently had a parathyroidectomy. Two episodes of peritonitis occurred during the study period, giving a peritonitis rate of one episode per 42 patient-months. There was no significant change in the urea clearance tests or the peritoneal equilibration tests before and after the study. CONCLUSION: Intraperitoneal calcitriol is practicable, effective, and safe in the treatment of secondary hyperparathyroidism in CAPD patients.

Primary immunosuppression with tacrolimus and low-dose mycophenolate mofetil in renal transplant recipients.

Both tacrolimus and mycophenolate mofetil (MMF) are potent immunosuppressive agents used in combination for prevention of acute rejection in renal transplantation. We studied the efficacy and safety of tacrolimus/MMF-based primary immunosuppression as well as their pharmacokinetics (PK) in Chinese renal transplant recipients. Oral tacrolimus was initiated at about 0.2 mg/kg/d, dose which was adjusted to achieve target trough levels of 10 to 20 ng/mL at 3 months and 5 to 10 ng/mL thereafter. The patients also received MMF (0.5 g bid) and prednisolone. PK profiles were studied at 1 week, and 1, 3, and 6 months posttransplant. Blood samples were taken at 0 (predose), 20, 40, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, and 12 hours postdose for each profile. Plasma MPA and whole blood tacrolimus levels were determined by HPLC and EMIT methods respectively. Eight patients were studied with mean follow-up of 16.1 +/- 2.4 months. One patient (12.5%) experienced a borderline acute rejection episode. Both 1-year graft and patient survival rates were 100%. Posttransplant diabetes, diarrhea, and hand tremor occurred in 12.5%, 12.5%, and 37.5%, respectively. No patient had an opportunistic infection. Tacrolimus trough concentrations showed a fair correlation with AUC(0-12h) (R(2) = 0.587). Mean MPA AUC values at 1, 3, and 6 months were 40.5 +/- 9.4, 44.4 +/- 17.3, and 57.2 +/- 20.7 mug*h/mL, respectively (P = .0486, n = 7). In conclusion, primary immunosuppression with tacrolimus, low-dose MMF (0.5 g bid), and prednisolone is effective and safe with adequate systemic MPA exposure in renal transplant recipients.