The novel CaMKII inhibitor GS-680 reduces diastolic SR Ca leak and prevents CaMKII-dependent pro-arrhythmic activity.

RATIONALE: Ca/calmodulin-dependent protein kinase II (CaMKII) was shown to increase diastolic sarcoplasmic reticulum (SR) Ca leak, which can result in delayed afterdepolarizations and triggered arrhythmias. Since increased CaMKII expression and activity has been mechanistically linked to arrhythmias in human heart failure (HF) and atrial fibrillation (AF), specific strategies aimed at CaMKII inhibition may have therapeutic potential. OBJECTIVE: We tested the antiarrhythmic and inotropic effects of a novel selective and ATP-competitive CaMKII inhibitor (GS-680). METHODS AND RESULTS: Trabeculae were isolated from right atrial appendage biopsies of patients undergoing cardiac surgery. Premature atrial contractions (PACs) were induced by stimulation with isoproterenol (ISO, 100 nM) at increased [Ca]o (3.5 mM). Interestingly, compared to vehicle, PACs were significantly inhibited by exposure to GS-680 (at 100 and 300 nM). GS-680 also significantly decreased early and delayed afterdepolarizations in isolated human atrial myocytes. Moreover, GS-680 (at 100 or 300 nM) significantly inhibited diastolic SR Ca leak, measured as frequency of spontaneous SR Ca release events (Ca sparks) in isolated human atrial myocytes (Fluo-4 loaded) similar to the well-established peptide CaMKII inhibitor AIP. In accordance, GS-680 significantly reduced CaMKII autophosphorylation (Western blot) but enhanced developed tension after 10 or 30 s pause of electrical stimulation (post-rest behavior). Surprisingly, we found a strong negative inotropic effect of GS-680 in atrial trabeculae at 1 Hz stimulation rate, which was not observed at 4 Hz and abolished by beta-adrenergic stimulation. In contrast, GS-680 did not impair systolic force of isolated ventricular trabeculae from explanted hearts of heart transplant recipients at 1 Hz, blunted the negative force-frequency relationship (1-3 Hz) and significantly increased the Ca transient amplitude. CONCLUSION: The novel ATP-competitive and selective CaMKII inhibitor GS-680 inhibits pro-arrhythmic activity in human atrium and improves contractility in failing human ventricle, which may have therapeutic implications.

Early data from the first population-wide breast cancer-specific registry in Hong Kong.

BACKGROUND: Current measures for breast cancer prevention and options for treatment adopted in Hong Kong are mainly based on research data and clinical evidence from overseas. It is essential to establish a cancer-specific registry to monitor the status of breast cancer in Hong Kong. OBJECTIVES: We summarized the current status of breast cancer in Hong Kong based on the data collected from Hong Kong Breast Cancer Registry (HKBCR). METHODS: Prevalent and newly diagnosed breast cancers (including in situ and invasive breast cancers) were registered in the HKBCR. Information on patient demographics, risk factors, medical information, and survival were analyzed and reported in this study. RESULTS: Data of 2,330 breast cancer patients were analyzed. We observed an earlier median age at diagnosis in Hong Kong than those reported in other countries. Distribution of cancer stage was: stage 0 (11.4%), stage I (31.4%), stage II (41%), stage III (12.5%), stage IV (0.8%), and unclassified (2.9%). The percentages of patients who received surgery, chemotherapy, radiation therapy, and endocrine therapy were 98.7, 67.9, 64.8, and 64.1%, respectively. At a median follow-up of 1.2 years, locoregional recurrence was recorded at 2%, distant recurrence at 2.8%, and breast-cancer-related mortality at 0.3%. CONCLUSIONS: The HKBCR serves as a surveillance program to monitor disease and treatment patterns. It is pivotal to support research for more effective breast cancer prevention and treatment strategies in Hong Kong.

Localisation of occult breast lesion: a comparative analysis of hookwire and radioguided procedures.

OBJECTIVES: For occult breast lesions, to retrospectively compare the performance of radioguided and hookwire methods in terms of ease of localisation and surgical procedures, and the ability to obtain a specimen with a clear margin. DESIGN: Retrospective study. SETTING: Regional hospital, Hong Kong. PATIENTS: All patients who underwent occult breast lesion localisation by either ultrasonography- or stereotactic-guided radioguided occult lesion localisation or hookwire localisation from August 2003 to December 2007 were included. MAIN OUTCOME MEASURES: Demographic data, localisation and operation procedure time, size of specimens and margin clearance. RESULTS: In all, 165 patients (mean age, 52 years) having these procedures were assessed. In 98 instances, the procedure (hookwire=53, radioguided=45) was for diagnostic purposes and in 67 (hookwire=23, radioguided=44) for therapy. Both techniques attained a very high success rate (>95%). For radioguided occult lesion localisation, there was a significantly shorter mean localisation time than for hookwire localisation (18 min versus 31 min; P<0.001), while the mean operating time was similar. Radioguided occult lesion localisation entailed larger specimens and fewer cases with close or involved margins, or recourse to intra-operative re-excision or a second operation, but these differences were not statistically significant. Within the radioguided occult lesion localisation group, there were 42 patients who had a simultaneous sentinel lymph node biopsy (sentinel node and occult lesion localisation), with a 98% success rate although no lymph node metastasis was revealed. CONCLUSION: Radioguided occult lesion localisation excels in yielding a much shorter localisation time and is as good as hookwire localisation in terms of specimen margin clearance and need for re-excision. It also offers the advantage of enabling simultaneous sentinel lymph node biopsy for invasive cancers. Therefore it is a recommended procedure that should be used more widely.

Minimally invasive technology in the management of breast disease.

Minimally invasive surgery is gaining popularity around the world because it achieves the same or even superior results when compared to standard surgery but with less morbidity. Minimally invasive breast surgery is a broad concept encompassing new developments in the field of breast surgery that work on this minimally invasive principle. In this regard, breast-conserving surgery and sentinel lymph node biopsy are good illustrations of this concept. There are three major areas of progress in the minimally invasive management of breast disease. First, percutaneous excisional devices are now available that can replace the surgical excision of breast mass lesions. Second, various ablative treatments are capable of destroying breast cancers in situ instead of surgical excision. Third, mammary ductoscopy provides a new approach to the investigation of mammary duct pathology. Clinical experience and potential applications of these new technologies are reviewed.

Esophageal hematoma.

Hematoma of the esophagus is an uncommon condition. Patients often present with acute odynophagia or retrosternal pain, which may be confused with other diagnoses. We report herein two patients with esophageal hematoma caused by foreign body ingestion. Conservative treatment resulted in complete resolution. The literature is reviewed for the etiology, clinical features and management of this condition.

Identification of RASSF1A modulated genes in nasopharyngeal carcinoma.

RASSF1A is a tumor suppressor gene on 3p21.3 frequently inactivated by promoter hypermethylation in nasopharyngeal carcinoma (NPC). To identify RASSF1A target genes in NPC, we have investigated the expression profile of the stable RASSF1A transfectants and controls by high-density oligonucleotide array. A total of 57 genes showed differential expression in the RASSF1A-expressing cells. These RASSF1A target genes were involved in multiple cellular regulatory processes such as transcription, signal transduction, cell adhesion and RNA processing. The RASSF1A-modulated expression of eight selected genes with the highest fold changes (ATF5, TCRB, RGS1, activin betaE, HNRPH1, HNRPD, Id2 and CKS2) by RASSF1A was confirmed in both stable and transient transfectants. Compared with the RASSF1A transfectants, an inverse expression pattern of activin betaE, Id2 and ATF5 was shown in the immortalized nasopharyngeal epithelial cells treated with siRNA against RASSF1A. The findings imply that the expression of activin betaE, Id2 and ATF5 was tightly regulated by RASSF1A and may associate with its tumor suppressor function. Strikingly, overexpression of Id2 is common in NPC and RASSF1A-induced repression of Id2 was mediated by the overexpression of activin betaE. The results suggest a novel RASSF1A pathway in which both activin betaE and Id2 are involved.

Randomized clinical trial comparing blue dye with combined dye and isotope for sentinel lymph node biopsy in breast cancer.

BACKGROUND: Use of blue dye alone as a marker for sentinel lymph node (SLN) biopsy is effective, but combining it with isotope marking can improve the success rate. Use of the isotope adds extra cost and there are potential radiation hazards. The two techniques were compared in a randomized trial. METHODS: Women with early breast cancer (less than 3 cm) and no palpable axillary nodes were recruited. Women older than 70 years with multicentric cancers or previous surgery to the breast or axilla were excluded. Patients were randomized to either blue dye alone or combined mapping for SLN biopsy. All women had a level I and II axillary dissection after the SLN biopsy. RESULTS: A total of 123 patients were recruited, of whom five were excluded from analysis. Blue dye alone was used in 57 women and 61 had combined mapping. Baseline demographic data were similar in the two cohorts. The success rate of SLN biopsy was higher with combined mapping than with blue dye alone (100 versus 86 per cent; P = 0.002). The accuracy and false-negative rate were similar (accuracy 100 per cent for combined mapping versus 98 per cent for blue dye; false-negative rate 0 versus 5 per cent). CONCLUSION: Combined mapping was superior to blue dye alone in identification of the SLN, but accuracy and false-negative rates were similar.

Wire-guided excision of mammographic abnormalities.

OBJECTIVE: A review of wire-guided excision of abnormal lesions viewed on screening mammography. DESIGN. Retrospective review. SETTING: Regional hospital, Hong Kong. PATIENTS: Patients who underwent wire-guided excision of abnormalities visualised on screening mammography between 1999 and 2002. INTERVENTION: Wire-guided excision. MAIN OUTCOME MEASURES: Biopsy rate and positive biopsy rate. RESULTS: A total of 65 patients underwent wire-guided excision of an abnormal lesion previously identified by screening mammography. Twenty-one were benign, two were lobular carcinoma in situ, and 42 were malignant. Of the latter, 30 were identified as ductal carcinoma in situ, and 12 as invasive breast cancer. Thirty-eight of the 42 malignant cases required further treatment, and 24 of them underwent further operation. Radiological assessment of the 65 patients suggested that nine lesions were probably benign, 31 indeterminate, 20 suspicious, and five malignant. Malignancy was subsequently confirmed by histological examination in 6, 20, 13, and 3 cases of the respective group of radiological assessment. CONCLUSION: The biopsy rate was approximately 3.7 per 1000 screened women, with results benign in 1.19 per 1000. The positive biopsy rate was 64.6%, and invasion was evident in 28.6%.

One-week ranitidine bismuth citrate, amoxicillin and metronidazole triple therapy for the treatment of Helicobacter pylori infection in Chinese.

BACKGROUND: We have previously shown that ranitidine bismuth citrate-based, clarithromycin-containing triple therapy achieves a higher eradication rate than proton pump inhibitor-based regimens in areas with a high prevalence of metronidazole resistance. AIM: To evaluate whether this higher efficacy of ranitidine bismuth citrate over proton pump inhibitor can be extended to non-clarithromycin-containing regimens. METHODS: Helicobacter pylori-positive dyspeptic patients were randomized to receive either ranitidine bismuth citrate, 400 mg, amoxicillin, 1000 mg, and metronidazole, 400 mg, or omeprazole, 20 mg, amoxicillin, 1000 mg, and metronidazole, 400 mg, each given twice daily for 1 week. H. pylori eradication was confirmed by 13C-urea breath test 5 weeks later. The side-effects of the treatments were documented. RESULTS: Two hundred and twenty-nine patients were eligible for analysis. By intention-to-treat and per protocol analysis, the eradication rates were 77% and 79%, respectively, in the ranitidine bismuth citrate-amoxicillin-metronidazole group and 77% and 82%, respectively, in the omeprazole-amoxicillin-metronidazole group (P = 0.58 and P = 0.65). However, patients in the omeprazole-amoxicillin-metronidazole group reported a significantly higher incidence of minor side-effects when compared to those in the ranitidine bismuth citrate-amoxicillin-metronidazole group (P = 0.001). CONCLUSIONS: Ranitidine bismuth citrate-amoxicillin-metronidazole was equally as effective as omeprazole-amoxicillin-metronidazole triple therapy, and may be considered as an alternative non-clarithromycin-based regimen in the Chinese population.

Double blind, randomised, placebo controlled study of four weeks of lansoprazole for the treatment of functional dyspepsia in Chinese patients.

BACKGROUND: The use of proton pump inhibitors for the treatment of functional dyspepsia is controversial and the role of Helicobacter pylori infection in functional dyspepsia is uncertain. AIM: To evaluate the efficacy of different doses of lansoprazole for the treatment of functional dyspepsia in Chinese patients. METHOD: Patients with a clinical diagnosis of functional dyspepsia according to the Rome II criteria and normal upper gastrointestinal endoscopy were recruited and randomised to receive: (1) lansoprazole 30 mg, (2) lansoprazole 15 mg, or (3) placebo, all given daily for four weeks. Dyspepsia symptom scores and quality of life (SF-36 score) were evaluated before and four weeks after treatment. RESULTS: A total of 453 patients were randomised. There was no difference in the proportion of patients with complete symptom relief in the lansoprazole 30 mg (23%) and lansoprazole 15 mg (23%) groups compared with the placebo group (30%). The proportion of H pylori positive patients with a complete response was similar with lansoprazole 30 mg (34%) and lansoprazole 15 mg (20%) versus placebo (22%). All symptom subgroups (ulcer-like, dysmotility-like, reflux-like, and unspecified dyspepsia) had similar proportions of patients with complete symptom relief after treatment. CONCLUSION: Proton pump inhibitor treatment is not superior to placebo for the management of functional dyspepsia in Chinese patients.

Rabeprazole-based 3-day and 7-day triple therapy vs. omeprazole-based 7-day triple therapy for the treatment of Helicobacter pylori infection.

BACKGROUND: Rabeprazole is a new proton pump inhibitor with more potent acid suppressive and anti-Helicobacter effects. AIM: To compare two different regimens of rabeprazole-based triple therapy vs. 7-day omeprazole-based triple therapy for the eradication of Helicobacter pylori infection. METHOD: Patients with proven H. pylori infection were randomized to receive: (i) 7-day rabeprazole, 10 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, all twice daily; (ii) 3-day rabeprazole, 20 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, all twice daily; or (iii) 7-day omeprazole, 20 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, all twice daily. Endoscopy (CLO test, histology) was performed before randomization and 6 weeks after drug treatment. RESULTS: One hundred and seventy-three patients were randomized. H. pylori eradication rates (intention-to-treat, n=173/per protocol, n=167) were 88%/91% for 7-day rabeprazole-based therapy, 72%/72% for 3-day rabeprazole-based therapy and 82%/89% for 7-day omeprazole-based therapy, respectively. The per protocol eradication rate was significantly better in the 7-day rabeprazole-based therapy and 7-day omeprazole-based therapy groups when compared to the 3-day rabeprazole-based therapy group (P=0.01 and P=0.04, respectively). Compliance was excellent and all three regimens were well tolerated. CONCLUSIONS: The efficacy of seven-day rabeprazole-based triple therapy is similar to 7-day omeprazole-based triple therapy for the eradication of H. pylori infection.

Diagnostic accuracy of vacuum-assisted biopsy device for image-detected breast lesions.

BACKGROUND: Non-palpable breast lesions present diagnostic difficulties. Ultrasound-guided fine-needle aspiration cytology (FNAC) is a common method used to obtain a diagnosis, but FNAC is frequently inconclusive or insufficiently accurate. Recently a vacuum-assisted biopsy device (Mammotome, Ethicon, Endo-surgery, USA) has been introduced. The diagnostic accuracy of this biopsy device was assessed for lesions that were visible on ultrasound. METHODS: Fifty ultrasound-guided mammotome biopsies were performed. All were small breast lesions primarily detected by ultrasound. All received FNAC as initial assessment. Mammotome biopsy was performed whenever the breast lesion was considered indeterminate or if it was considered benign and there were associated risk factors such as a family history of breast cancer. RESULTS: Of 50 mammotome biopsies 45 had benign histology. Three of 45 lesions were excised at the patients' request and were confirmed to be benign. The remaining 42 patients received an ultrasound follow up at 6 months. The lesion size remained static in 39 patients. In three patients the lesion size increased and they were excised and histology was benign. For the four malignancies diagnosed with mammotome biopsy, three patients received definitive treatment and one patient defaulted. There was one failed mammotome biopsy in the present series. CONCLUSIONS: Mammotome biopsy is an acceptable diagnostic method for small breast lesions seen on ultrasound. It reduces the need for open biopsy without compromising diagnostic accuracy.

Experience of neoadjuvant chemotherapy for breast cancer at a public hospital: retrospective study.

OBJECTIVE: To review local experience of neoadjuvant chemotherapy in breast cancer. DESIGN: Retrospective study. SETTING: Public hospital, Hong Kong. PATIENTS: Seventeen patients who presented from August 1988 through April 1997 with locally advanced breast cancer, which was treated with neoadjuvant chemotherapy. RESULTS: The clinical response rate was 71% and two of the 12 patients who responded to chemotherapy achieved complete remission. Three patients had their tumours downstaged sufficiently to allow them to undergo breast conservation surgery after neoadjuvant chemotherapy. None of these three patients has so far had a local recurrence of disease. CONCLUSION: Neoadjuvant chemotherapy can achieve a high objective response rate in patients with locally advanced breast cancer and thus enables breast conservation surgery to be performed on patients who are initially not suitable for this procedure.