A close association between alteration in growth kinetics by neoadjuvant chemotherapy and survival outcome in primary breast cancer

Few surrogate markers are available for predicting the survival benefit from chemotherapy in primary breast cancer. We examined tumor growth kinetics by assessing cytokeratin 18 neo-epitope (CK18NE), an apoptosis marker detected by M30 antibody and Ki-67 antigen, a proliferation marker detected by MIB-1 antibody in 72 primary breast cancer patients who underwent pre-operative anthracycline-based chemotherapy. Increase in M30 index and decrease in MIB-1 index after the exposure of 2 to 4 cycles of chemotherapy correlated significantly with pathological tumor response. Univariate survival analysis, conducted in the subgroup of 42 patients who underwent CAF (cyclophosphamide, adriamycin and 5-FU) therapy alone, showed that the patients with the high levels of M30 index (>35 counts/1000 tumor cells) and the low levels of MIB-1 index (<140 counts/1000 tumor cells) after chemotherapy had a remarkably favorable prognosis as compared with patients in other categories. In addition, the alteration in growth kinetics by the treatment showed a significant prognostic value. Multivariate analysis also confirmed that the post-treatment growth kinetics was an independent prognostic indicator. These findings suggest that the alteration in growth kinetics revealed by CK18NE and MIB-1 might be a surrogate marker for predicting the survival benefit from chemotherapy in primary breast cancer.     

Successful treatment of ruptured hepatocellular carcinoma with intraperitoneal injection of OK-432

We report a 51-year-old man with a ruptured hepatocellular carcinoma (HCC). He was admitted to the hospital with abdominal pain and distension. Imaging studies revealed massive ascites, liver cirrhosis, and a 3-cm tumor at the inferior edge of the medial segment of the liver, with adhesions to the greater omentum. Abdominal paracentesis showed bloody ascites, and the patient was diagnosed with a ruptured HCC. OK-432, an immunomodulatory agent prepared from an attenuated strain of Streptococcus pyogenes, was injected (10KE) into the peritoneal cavity four times within 1 week; the massive ascites disappeared, and the serum alpha-fetoprotein (AFP) level decreased to within the normal limits. Afterwards, he underwent a curative operation for HCC. His postoperative course was uneventful and he was discharged from the hospital on the twenty-second postoperative day. He had shown no evidence of recurrence or metastases at the time he died of hepatic failure related to alcohol abuse 9 months after the operation.     

Transepithelial transport of telmisartan in caco-2 monolayers

Telmisartan is the most recently marketed angiotensin II type 1 receptor antagonist. Drug-drug interactions involving transporters can directly affect the therapeutic safety and efficacy of many important drugs. In clinical practice, telmisartan is coadministered with many kinds of drugs. However, little is known about the contribution of transporters to the intestinal transport of telmisartan. The aim of this study was to determine the transport mechanism of telmisartan across intestinal epithelial cells. In the presence of an inwardly directed proton gradient, the apical-to-basal transport of telmisartan was greater than basal-to-apical transport. Thus, we focused on the uptake mechanism of telmisartan across brush-border membranes. The uptake of telmisartan by Caco-2 cells was shown to be energy- and proton-dependent. Although some monocarboxylates inhibited the uptake of telmisartan, L-lactic acid, which is a typical substrate of the monocarboxylate transporter (MCT) 1-MCT4, did not affect the uptake of telmisartan. Preloading of acetic acid enhanced the uptake of telmisartan, showing a trans-stimulation effect. These results suggest that the carrier-mediated transport system is involved in the uptake of telmisartan by Caco-2 cells and that the apical-localized transport system is similar to MCTs, but not MCT1-MCT4. It is possible that telmisartan reduce the absorption of coadministered drugs by sharing the MCTs. Since MCTs have an important role in the intestinal absorption of pharmacologically active compounds, it is important to be aware of the potential of telmisartan-drug interactions involving MCTs and to act in order to prevent undesirable and harmful consequences.     

Examination of Purification Methods and Development of Intravitreal Injection of Triamcinolone Acetonide

Purpose

Intravitreal injection of triamcinolone acetonide (TA) is used in ophthalmic treatment, but the reliability of commercially available TA preparations has still not been established. We evaluated two previously reported purification methods, and developed a more reliable TA injection which can be prepared in a hospital pharmacy.

Methods

We tested the two methods previously reported for purifying commercial TA preparations, the sedimentation and the filtration and backflushing methods. We developed a new TA injection made of pure TA suspended in 0.5% sodium hyaluronate. We measured the TA content in each preparation by high-performance liquid chromatography to evaluate the three methods.

Results

In the sedimentation purification method, the TA content of a nominal 4-mg preparation varied from 1.43 to 7.37?mg, and the average recovery rate was 91.6%. In the filtration and backflushing method, TA content was 0.10–10.33?mg and recovery was 59.5%. In the TA injection we developed, the mean TA content was 102.5% (SD, 0.24; CV, 2.9%). The stability of this preparation was 99% after sterilization, and 97% after 3 months of storage.

Conclusions

The results of our investigation showed that the purification methods used for commercial preparations are simple and easy but not precise enough for an intravitreal injection. In contrast, the TA injection prepared by our method is reliable, stable, and safe enough for clinical use. Jpn J Ophthalmol 2005;49:384–387 © Japanese Ophthalmological Society 2005     

Neuroprotective Effect of the Novel Na+/Ca2+ Channel Blocker NS-7 on Rat Retinal Ganglion Cells

Purpose

To investigate whether NS-7, 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride, a novel Na⁺/Ca²⁺ channel blocker, can protect the rat retina subjected to ischemia–reperfusion insult.

Methods

To evaluate the protective effect of NS-7 against retinal damage, the drug was administered before and after ischemia–reperfusion. Damage to the retina was assessed by measuring the thickness of the inner plexiform layer (IPL) and the outer nuclear layer (ONL) of each eye. In a subsequent experiment, electroretinographic (ERG) evaluation was also used.

Results

In histopathologic evaluation, ischemia–reperfusion injury caused a significant reduction of IPL thickness (measured as the IPL/ONL ratio). In the NS-7-treated group, retinal damage was partially prevented by a concentration of 0.25?mg/kg per day. In the ERG evaluation, ischemia–reperfusion injury caused a reduction of A- and B-wave amplitudes. NS-7 treatment significantly prevented the reduction of the B wave at a concentration of 0.1 or 0.3?mg/kg, while the reduction of the A wave was not significantly affected.

Conclusions

NS-7 has neuroprotective effects against retinal damage resulting from subjection to ischemia. In addition, NS-7 can be used as an agent for treating acute ischemic retinopathy, including diseases associated with very high intraocular pressure, such as acute angle-closure glaucoma. Jpn J Ophthalmol 2005;49:371–376 © Japanese Ophthalmological Society 2005     

MRI-diffusion weighted images of encephalopathy associated with human herpesvirus 6 infection

Encephalopathy associated with human herpes virus 6 infection (HHV-6 encephalopathy) is not rare. The pathophysiology of HHV-6 encephalopathy has not been clearly established and diagnosis in the early stages is difficult. To elucidate the diagnostic value of MRI in the early stages of HHV-6 encephalopathy, we performed MRI including diffusion weighted imaging (DWI) on 6 patients. No abnormalities were found in the T1, T2 weighted images and fluid attenuated inversion recovery (FLAIR) images of any of the patients. DWI revealed an increase of signal in the subcortical white matter of the frontal lobes during the acute phase in all 6 patients. Follow-up MRI in two patients showed lesions expanded to the cortical regions, and disappearance of high signal-lesions followed by atrophy of the corresponding areas in 2 patients. To our knowledge, these findings have not previously been reported in acute encephalopathy and encephalitis and may be characteristic of HHV-6 encephalopathy. DWI may be a useful diagnostic procedure in the early stages of HHV-6 encephalopathy.     

Effect of remnant-like particle on shear-induced platelet activation and its inhibition by antiplatelet agents

Remnant-like particles (RLPs) have been reported to promote atherosclerosis and to have effects on platelet function. We studied the effects of RLP on shear-induced platelet activation and their inhibition by antiplatelet agents in vitro. RLP were separated using two monoclonal antibodies, anti apo B-100 and anti apo A-I. These RLP fractions were added to whole blood (WB) or platelet-rich plasma (PRP) in serial dilution of 1, 10 or 100 microg RLP triglyceride (TG) per ml of total sample volume. These samples were incubated, and then stimulated with a high shear stress of 108 dyn/cm(2). Shear-induced platelet aggregation (SIPA) was calculated from the percentage of single platelet loss. P-selectin expression on platelet surface and platelet-derived microparticle (PMP) generation were measured before and after stimulation with shear stress using flow cytometer. SIPA was significantly enhanced by RLP in WB but not in PRP. This enhancing effect was not dose-dependent and was greatest at 10 microg TG/ml. P-selectin expression induced by shear stress was only enhanced by RLP at a concentration of 100 microg TG/ml in both WB and PRP, while generation of PMP induced by shear stress was only enhanced by RLP at a concentration of 100 microg TG/ml in WB. Aspirin inhibited only the enhancement of SIPA by RLPs, while cilostazol inhibited the enhancement of not only SIPA but also p-selectin expression and PMP generation by RLPs.