Comprehensive analysis of HER2 expression and gene amplification in gastric cancers using immunohistochemistry and in situ hybridization: which scoring system should we use?

It has been reported that HER2 expression is different in gastric and breast cancers, and a gastric cancer scoring system (GCSS) has recently been suggested. We investigated HER2 protein expression using GCSS and a breast cancer scoring system (BCSS) and correlated it with HER2 gene amplification. HER2 status was evaluated in 1091 cases by analyzing tissue microarrays constructed using 2 different cores from each case. Polyclonal (HercepTest) and monoclonal (Pathway) antibodies were used for immunohistochemistry (IHC), and results were scored by BCSS and GCSS. Gene amplification was evaluated by automated dual-color silver-enhanced in situ hybridization (SISH) in all cases and correlated with the results from fluorescence in situ hybridization (FISH) in 590 cases. The concordance between the IHC results using polyclonal and monoclonal antibodies was high (κ = 0.785). The results of dual-color SISH and FISH showed very high concordance as well (κ = 0.918). GCSS was significantly more sensitive for detecting SISH positivity than was BCSS in both antibodies (polyclonal, P = .003; monoclonal, P < .001), but specificity was higher in BCSS than GCSS (polyclonal, P = .004; monoclonal, P < .001). It has been recently shown that HER2-overexpressing patients with unresectable gastric cancer benefited from trastuzumab therapy. Because IHC is recommended before gene amplification studies in HER2 testing, GCSS should be used for evaluating HER2 expression in gastric cancers.     

Suppression of seizure by cathodal transcranial direct current stimulation in an epileptic patient - a case report -

Epilepsy is an intractable disease, though many treatment modalities have been developed. Recently, noninvasive transcranial direct current stimulation (tDCS), which can change brain excitability, was introduced and has been applied for therapeutic purposes regarding epilepsy. A suppression of seizures was experienced by cathodal tDCS in a medication refractory pediatric epileptic patient. The patient was an 11-year-old female who had focal cortical dysplasia of the cerebral hemisphere. The patient was treated with antiepileptic drugs but the mean seizure frequency was still eight episodes per month. The tDCS cathode was placed at the midpoint of P4 and T4 in the 10-20 EEG system where the abnormal wave was observed on a sleep EEG. Two mA of tDCS was applied 20 minutes a day, five days a week for two weeks. During a two-month period after treatment termination, only six seizure attacks occurred, and the duration of each seizure episode also decreased. tDCS was applied under the same conditions for another two weeks. For two months after the second treatment session, only one seizure attack occurred, and it showed great improvement compared to the eight seizure attacks per month before the tDCS treatment. The medications were not changed, and there were no notable side effects that were caused by tDCS.     

Ten Years Experience of In-Center Thrice Weekly Long Overnight Hemodialysis

Background and objectives: Published studies suggest that longer hemodialysis (HD) sessions are associated with improved morbidity and mortality, but few centers offer long sessions. The Western Infirmary renal unit has offered long overnight hemodialysis (LOH) (6 to 7 h) thrice weekly since 1998. The aim of this study was to describe patients who chose LOH and compare outcomes with patients on conventional hours (4 to 5 h) HD.Design, settings, participants, & measurements: Patients who ever had LOH for three or more consecutive sessions were identified (n = 146). Indices of urea reduction ratio (URR), anemia, hyperphosphatemia, and predialysis BP (BP) control in a subgroup of all patients on LOH for at least 1 yr since 2004 were compared with age, sex, and diabetes-matched controls undergoing conventional duration HD.Results: The mean age at the time of starting LOH was 51.8 yr and 74.7% started with a functioning arteriovenous fistula. Median duration of continuous LOH was 1.6 yr. Of those no longer on LOH, only 33.3% reverted to conventional hours HD (mean duration LOH 2.2 yr). When comparing LOH and conventional HD cohorts, there was increased URR and mean hemoglobin with a trend toward lower mean erythropoietin index. There was a trend toward fewer phosphate binder tablets but no difference in mean serum phosphate, BP, or number of prescribed antihypertensive medicines.Conclusions: LOH is a well tolerated hemodialysis option, associated with improved URR and better control of anemia.There is no consensus on the optimal duration or frequency of hemodialysis sessions for patients with established renal failure, but constraints on time and resources mean that 3 to 5 hr, three times a week hemodialysis is routine practice for most hemodialysis units.Most of the evidence relating to dialysis session duration comes from small observational, single-center studies, but one randomized control trial has been performed in the United States (1). Several of these centers have reported data suggesting more frequent or longer hemodialysis sessions may be associated with improvements in all or some of the following: small solute clearance, BP control, left ventricular hypertrophy, anemia, hyperphosphatemia, nutritional parameters, and mortality (2–9).The Western Infirmary renal unit has offered long overnight hemodialysis (LOH) since 1998. This consists of 6 to 7 h sessions three times per week at the main unit and one of our satellite units. The unit decided to provide thrice weekly in-center LOH in the belief that improved solute clearance and more prolonged ultrafiltration might be associated with improved outcomes and that the option of overnight hemodialysis might be socially attractive to some patients, as well as to increase dialysis capacity. We place few restrictions on the type of patients who can receive LOH. Patients are offered LOH if they do not need a two-person ambulance to take them to and from their dialysis sessions and are prepared to travel home from dialysis sessions at 2 to 4 a.m.The aim of this study was to describe all of the patients who chose LOH over the 10-yr period. In a subset of these patients, a case-controlled analysis was also performed of the impact of LOH on small solute clearance, hyperphosphatemia, anemia, and BP compared with age, sex, and diabetes-matched controls undergoing conventional duration hemodialysis (HD). The study hoped to demonstrate that LOH was a suitable modality for the majority of dialysis patients and would be associated with clinically meaningful benefits.     

Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt

Background and purpose:

Lipid rafts and caveolae are membrane microdomains with important roles in cell survival signalling involving the Akt pathway. Cholesterol is important for the structure and function of these microdomains. The ginsenoside Rh2 exhibits anti-tumour activity. Because Rh2 is structurally similar to cholesterol, we investigated the possibility that Rh2 exerted its anti-tumour effect by modulating rafts and caveolae.

Experimental approach:

A431 cells (human epidermoid carcinoma cell line) were treated with Rh2 and the effects on cell apoptosis, raft localization and Akt activation measured. We also examined the effects of over-expression of Akt and active-Akt on Rh2-induced cell death.

Key results:

Rh2 induced apoptosis concentration- and time-dependently. Rh2 reduced the levels of rafts and caveolae in the plasma membrane and increased their internalization. Furthermore, Akt activity was decreased and consequently, Akt-dependent phosphorylation of Bad, a pro-survival protein, was decreased whereas the pro-apoptotic proteins, Bim and Bax, were increased upon Rh2 treatment. Unlike microdomain internalization induce by cholesterol depletion, Rh2-mediated internalization of rafts and caveolae was not reversed by cholesterol addition. Also, cholesterol addition did not restore Akt activation or rescue cells from Rh2-induced cell death. Rh2-induced cell death was attenuated in MDA-MB-231 cells over-expressing either wild-type or dominant-active Akt.

Conclusions and implications:

Rh2 induced internalization of rafts and caveolae, leading to Akt inactivation, and ultimately apoptosis. Because elevated levels of membrane rafts and caveolae, and Akt activation have been correlated with cancer development, internalization of these microdomains by Rh2 could potentially be used as an anti-cancer therapy.