A case of unresectable advanced gallbladder cancer treated by systemic chemotherapy combined with hepatic arterial infusion

A 53-year-old woman was revealed to have gallbladder cancer with liver metastases (H 1). Since a curative operation is impossible in this case, we started systemic chemotherapy employing S-1 combined with hepatic arterial infusion using epirubicin hydrochloride and mitomycin C. After three months, the primary lesion was reduced in size. The patient has been receiving systemic chemotherapy using S-1 only as an outpatient for 16 months. Although there is not enough evidence to support standard treatment, systemic chemotherapy combined with hepatic arterial infusion would improve the survival time without deterioration of quality of life in patients with advanced gallbladder cancer. This combined therapy should be considered one of the promising strategies for advanced gallbladder cancer.     

Two cases treated with trastuzumab as primary chemotherapy

We report two cases treated with primary chemotherapy containing trastuzumab with a review of some important papers. The first patient was a 43-year-old female. A 33-mm left breast invasive ductal carcinoma (ER (-), PgR (-), HER2 3+(IHC) ) with several lymph node metastases in the Ax, Ic and Sc was found. After primary chemotherapy with 6 courses of EC and 4 courses of weekly paclitaxel + trastuzumab, the efficacy for the local tumor was judged as PR. However, brain metastases appeared, so the operation was canceled. Brain metastases were then treated by gamma-knife three times, but systemic chemotherapy was not administered. Eight months later, carcinomatous meningitis appeared. Intrathecal chemotherapy with MTX+Ara-C was started, but the patient died after 20 months from the beginning of the treatment. Local efficacy was judged as CR. The second patient was a 41-year-old female. A 39-mm right breast invasive ductal carcinoma (ER (-), PgR (-), HER2 3+(IHC) ) with two lymph node metastases in the Ax was found. After primary chemotherapy with 6 courses of FEC and 4 courses of weekly paclitaxel + trastuzumab, the efficacy was judged as PR. The operation was scheduled, but he patient wished to continue chemotherapy for cosmetic reasons. Later, because of mild tumor regrowth, we used 2 courses of vinorelbine in combination with trastuzumab. The tumor grew more, so Bp + Ax was done. The woman is alive at this writing with no recurrence.     

Expression and roles of keratinocyte growth factor and its receptor in esophageal cancer cells

The keratinocyte growth factor receptor (KGFR), also known as FGFR2 IIIb, is mainly localized in epithelial cells and is activated by the keratinocyte growth factor (KGF) that is predominantly synthesized by mesenchymal cells. In this study, we examined the roles of KGFR and KGF in human esophageal cancer (EC). In noncancerous esophageal tissues, KGFR was localized in epithelial cells from the basal region of the epithelium to the lower one-third of the epithelium, and KGF was weakly localized in the basal to parabasal epithelial cells. On the other hand, Ki-67 was localized in the parabasal cells. In EC tissues, KGFR and KGF were expressed in cancer cells in 22 and 37 of 54 patients, respectively. The coexpression of KGFR and KGF in cancer cells was detected in 14 of 54 (26%) patients. Clinicopathologically, KGFR expression correlated with the well-differentiated cell type of EC (p<0.001), and KGF expression correlated with lymphatic invasion and lymph node metastasis (p=0.004 and 0.021, respectively). The coexpression of KGFR and KGF in cancer cells correlated with the well-differentiated cell type of EC (p=0.001). KGFR-positive, KGF-positive and KGFR/KGF coexpression patients tended to have shorter survival rates, but the survival rates were not statistically significantly different (p=0.44, 0.059 and 0.112, respectively). In human EC cell lines (TE-1, TE-8 and TE-11), KGFR mRNA was expressed but no KGF mRNA was detected. The KGFR mRNA level was highest in TE-1 cells, derived from well-differentiated SCC and lowest in TE-8 cells. KGFR was detected in the cancer cell lines by Western blot analysis. Recombinant human KGF significantly stimulated the growth of TE-8 and -11 cells, derived from moderately differentiated SCC, but had no effect on TE-1 cell growth. These results suggest that KGFR expression correlates with the differentiation of a normal esophageal epithelium and the well-differentiated cell type of EC. On the other hand, KGF may induce the growth of some EC cells in a paracrine manner and closely correlates with lymphatic invasion and lymph node metastasis.     

Tumor suppressor Prdx1 is a prognostic factor in esophageal squamous cell carcinoma patients

Peroxiredoxins (Prdxs) are a family of antioxidant enzymes that are also known as scavengers of peroxide in mammalian cells. Some reports have shown that the overexpression of Prdx1, which is one of the peroxiredoxins that is a ubiquitously expressed protein, was related to a poor prognosis in several types of human cancers. In this study, we investigated the expression levels of Prdx1 in esophageal squamous cell carcinoma by immunohistochemistry, and the correlation between the Prdx1 expression and the clinical status was elucidated. Immunohistochemical staining was performed in 114 samples which were collected from surgical esophageal cancer specimens. Cytoplasmic staining of Prdx1 was evaluated based on the following scoring criteria: Grade I, negative or weak staining; Grade II, moderate staining; and Grade III, strong staining. The percentage of patients with a Grade I expression of Prx1 was 20% (23 of 114), 44% had Grade II (50 of 114), and 36% had Grade III (41 of 114). The Prdx1 immunoreactivity showed an inverse significant correlation with T-category (P<0.0001), lymph node metastasis (P=0.048), and stage (P=0.001). In addition, the patients with tumors exhibiting a reduced Prdx1 expression had shorter overall survival (P=0.022) in comparison to the patients with tumors which had a higher Prdx1 expression. Currently, Prdx1 has been shown to act as a tumor suppressor. Our results provide strong evidence that the reduced Prdx1 expression is an important factor in esophageal squamous cancer progression and could serve as a useful prognostic marker.     

Estimation of CYP2C19 activity by the omeprazole hydroxylation index at a single point in time after intravenous and oral administration

Objective The purpose of this study was to identify the common time point to achieve hydroxylation index (HI: omeprazole plasma concentration/5-hydroxyomeprazole plasma concentration) reflecting AUC_OPZ/AUC_5OH-OPZ after intravenous (IV) and oral (PO) administration. Methods Twenty young and 28 elderly healthy subjects, including different CYP2C19 genotypes, were enrolled in the study. The young subjects received either 40 mg PO or 20 mg IV omeprazole, whereas the elderly subjects received 10 mg IV. The relation between AUC_OPZ/AUC_5OH-OPZ and HI was determined by Spearman’s rank correlation. Multiple stepwise linear regression analysis was performed to identify the common time point to calculate HI that reflects AUC_OPZ/AUC_5OH-OPZ after IV. Results In the correlation between HI and AUC_OPZ/AUC_5OH-OPZ IV at observed time points, HI_3h showed the highest correlation coefficients (r = 0.894, p < 0.001) in all 48 subjects. The correlation of HI between IV and PO at observed time points showed that HI_3h was highest (r = 0.916, p < 0.001) in 20 young subjects. Additionally, there was no significant difference between HI_3h of IV and that of PO (12.9 ± 15.9 and 12.9 ± 15.1, p = 0.997). The regression equation of HI_3h was the best to estimate AUC_OPZ/AUC_5OH-OPZ (AUC_OPZ/AUC_5OH-OPZ = 1.37 • HI_3h + 0.18 • Age – 7.83, r ² = 0.883, p < 0.001). Conclusions This study demonstrated that HI_3h after omeprazole IV was able to estimate AUC_OPZ/AUC_5OH-OPZ, as well as HI_3h after PO. Additionally, CYP2C19 activity can be estimated more definitely by using HI after omeprazole IV without intestinal absorption.     

Terbinafine increases the plasma concentration of paroxetine after a single oral administration of paroxetine in healthy subjects

Objective Paroxetine is believed to be a substrate of CYP2D6. However, no information was available indicating drug interaction between paroxetine and inhibitors of CYP2D6. The aim of this study was to examine the effects of terbinafine, a potent inhibitor of CYP2D6, on pharmacokinetics of paroxetine. Methods Two 6-day courses of either a daily 150-mg of terbinafine or a placebo, with at least a 4-week washout period, were conducted. Twelve volunteers took a single oral 20-mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine were monitored up to 48 h after dosing. Results Compared with the placebo, terbinafine treatment significantly increased the peak plasma concentration (C_max) of paroxetine, by 1.9-fold (6.4 ± 2.4 versus 12.1 ± 2.9 ng/ml, p < 0.001), and the area under the plasma concentration-time curve from zero to 48 h [AUC (0–48)] of paroxetine by 2.5-fold (127 ± 67 vs 318 ± 102 ng/ml, p < 0.001). Elimination half-life differed significantly (15.3 ± 2.4 vs 22.7 ± 8.8 h, p < 0.05), although the magnitude of alteration (1.4-fold) was smaller than C_max or AUC. Conclusion The present study demonstrated that the metabolism of paroxetine after a single oral dose was inhibited by terbinafine, suggesting that inhibition of CYP2D6 activity may lead to a change in the pharmacokinetics of paroxetine. However, further study is required to confirm this phenomenon at steady state.     

Long-term Results after Dissection of Positive Thoracic Lymph Nodes in Patients with Esophageal Squamous Cell Carcinoma

Background Although thoracic lymph node metastasis in patients with thoracic esophageal squamous cell carcinoma (SCC) has been reported to be a negative risk factor for long-term survival, only a few studies have evaluated the clinicopathologic difference between the impact of metastasis to the paraesophageal lymph nodes and to the nonparaesophageal lymph nodes. The purpose of this study was to evaluate surgical outcome after the clearance of metastatic thoracic lymph nodes. Methods Retrospectively reviewed were 164 consecutive patients with thoracic esophageal SCC who had not had preoperative treatment and underwent surgery from 1980 to 2005 and were found to have thoracic lymph node metastases. Of these patients, 83 underwent surgery from 1980 to 1994 and 81 from 1995 to 2005. Univariate and multivariate analyses were performed to evaluate the impact of nonparaesophageal lymph node metastasis on survival. Results Univariate analysis revealed that T3/T4 tumors and the presence of nonparaesophageal node metastases were associated with only a 20% overall five-year survival rate. The overall five-year survival for the most recent period was significantly better than for the former period (42% vs. 13%, p < 0.01). Based on a multivariate analysis of prognostic impact of each nonparaesophageal node, the presence of metastatic subcarinal and/or posterior mediastinal nodes was an independent risk factor for reduced survival. Conclusion Surgical outcome for patients with thoracic esophageal cancer and metastatic thoracic lymph nodes has improved during the last 25 years. Although postoperative chemotherapy might improve survival, the presence of T3/T4 tumors and/or metastatic nonparaesophageal nodes were unfavorable factors for survival.     

Pentaketides relating to aspinonene and dihydroaspyrone from a marine-derived fungus, Aspergillus ostianus

Three new pentaketides, aspinotriols A ( 1) and B ( 3) and aspinonediol ( 5), were isolated together with two known compounds, aspinonene ( 7) and dihydroaspyrone ( 9), from the marine fungus Aspergillus ostianus strain 01F313, which was collected in Pohnpei and cultured with bromine-modified artificial seawater. The structures of the new compounds were determined by spectroscopic analyses including 1D and 2D NMR. Although 1 and 3 are diastereomers, they show nearly superimposable (1)H and (13)C NMR spectra. The absolute configurations of compounds 1, 3, 5, and 9 were elucidated by the modified Mosher's method.