A case of 6-pyruvoyl-tetrahydropterin synthase deficiency demonstrates a more significant correlation of L-Dopa dosage with serum prolactin levels than CSF homovanillic acid levels

6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a tetrahydrobiopterin (BH4) deficiency that presents as hyperphenylalaninemia. Administration of the neurotransmitter precursors L-Dopa/carbidopa and 5-hydroxytryptophan (5HTP), as well as BH4, is necessary for treatment. It has been reported that serum prolactin levels are elevated in patients with PTPS deficiency indicating that inhibition of prolactin secretion by dopamine is insufficient and is negatively correlated with the CSF level of HVA. Here, we present a case of PTPS deficiency which showed a more significant correlation of dosage of L-Dopa/carbidopa with serum prolactin levels than with CSF HVA levels. Combined treatment of BH4, L-Dopa/carbidopa, and 5HTP was started as the CSF neopterin/biopterin ratio (N/B ratio 7.54, control 0.46-1.59) and serum prolactin level (36.79 ng/ml, control <15) were elevated. The dosage of L-Dopa/carbidopa was adjusted in the range of 9.08-10.5mg/kg/day. The CSF level of HVA stayed within normal limits using these dosages of L-Dopa/carbidopa, and there was no correlation between dose given and HVA level (R=0.230, p=0.71). On the other hand, even in this relatively small dosing range, the serum prolactin level showed significant negative correlation with the dosage of L-Dopa/carbidopa (R=0.645, p=0.023). The patient did not show any neurological symptoms even when the serum prolactin level was elevated. From these results, we suggest that the serum prolactin level may be a more sensitive marker than the CSF HVA level to guide the dose adjustment of L-Dopa/carbidopa in the management of patients with PTPS deficiency.     

Effect of mivazerol, a alpha-agonist, on striatal norepinephrine concentration during transient forebrain ischemia in rats

Background: We have previously reported that mivazerol, a α₂‐agonist, possibly provides neuroprotection against transient forebrain ischemia in rats. This study was designed to investigate the ability of mivazerol to attenuate ischemia‐induced increase in striatal norepinephrine concentration after transient forebrain ischemia in rats. Methods: Male Sprague–Dawley rats, anesthetized with halothane, were assigned to one of three groups (n=10 each); control (C, normal saline 1 ml/kg), mivazerol 20 μg/kg (M20), and 40 μg/kg (M40) groups. Monitored variables included temporal muscle temperature (maintained at 37.5±0.1 °C), electroencephalogram, systolic/diastolic blood pressure, heart rate, arterial blood gases, and blood glucose concentrations. Thirty minutes after subcutaneous drug administration, forebrain ischemia was induced with hemorrhagic hypotension (systolic arterial pressure: 40–50 mmHg) and bilateral carotid artery occlusion for 10 min, and then the brain was reperfused. Norepinephrine concentration in the interstitial fluids in the striatum was analyzed using in vivo microdialysis in combination with high‐performance liquid chromatography. Results: Ischemia resulted in a prompt increase in norepinephrine concentrations in the striatum in all groups. However, there were no significant differences in norepinephrine concentrations in the striatum between the three groups at any period. Conclusions: Our results indicate that mivazerol did not attenuate ischemia‐induced increase in striatal norepinephrine concentration. This suggests that the possible neuroprotective property of mivazerol is not related to inhibition of norepinephrine release in the brain.     

Follicular dendritic cell tumor as an unknown primary tumor

A 70-year-old Japanese man presented to our hospital with a 1-month history of progressive general fatigue and anorexia. A physical examination revealed severe anemic condition, mild persistent splenomegaly, and no palpable surface lymph nodes. He had pleural effusion and ascites, though no malignant cells were detected in the effusion. He eventually died without any diagnosis of his disease. Immunohistochemical staining of his tumor after autopsy showed atypical cells that were negative for epithelial membrane antigen (EMA), keratin (AE1/3), keratin-20, vimentin, factor VIII, leukocyte common antigen (LCA/T200; CD45), myeloperoxidase (MPO), terminal deoxynucleotidyl tranferase (TdT), lysozyme, CD1a, CD3, CD4, CD10, CD15, CD20 (L26), CD21, CD23, CD34, CD43, CD56, CD68, CD79a, CD138, and EBER-1 in situ. Only a few scattered cells expressed CD30, but they showed no staining for anaplastic large-cell lymphoma kinase (ALK). A few scattered cells expressed S-100 antigen and the majority of cells dominantly expressed dendritic cell-associated antigens (CD35, FDC, Ki-M1p). In conclusion, we found this unknown primary tumor to be consistent with a follicular dendritic cell tumor with anaplastic features.     

Concomitant activation of AKT with extracellular-regulated kinase 1/2 occurs independently of PTEN or PIK3CA mutations in endometrial cancer and may be associated with favorable prognosiss

Deregulated signaling via the phosphatidylinositol 3-kinase (PI3K) pathway is common in many types of cancer, but its clinicopathological significance in endometrial cancer remains unclear. In the present study, we examined the status of the PI3K signaling pathway, especially in relation to PTEN and PIK3CA status, in endometrioid-type endometrial cancer. The immunohistochemical analysis revealed a high level of phosphorylated (p)-AKT expression, which is a hallmark of activated PI3K signaling, in approximately 60% of endometrial cancers. There was no correlation between p-AKT expression and clinicopathological characteristics, such as International Federation of Gynecology and Obstetrics stage, tumor grade, and myometrial invasion. Unexpectedly, a high level of p-AKT expression occurred independently of the presence of PTEN or PIK3CA mutations. Furthermore, p-AKT expression did not correlate with the expression of potential downstream targets, including p-mTOR and p-FOXO1/3a. In turn, p-AKT expression was strongly associated with extracellular-regulated kinase 1/2 expression ( P =  0.0031), which is representative of the activated RAS–MAP kinase pathway. Kaplan–Meier analysis suggested that low p-AKT expression was associated with low rates of relapse-free survival, although the difference was not statistically significant, indicating that AKT activation does not confer worse prognosis. The present study demonstrates the presence of complex signaling pathways that might mask the conventional tumorigenic PTEN–PI3K–AKT–mTOR pathway, and strongly suggests a close association between the extracellular-regulated kinase and PI3K pathways in this tumor type. ( Cancer Sci 2007; 98: 1881–1888)     

Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs

Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nucleotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response.     

Glucose transporter type 1 expression are associated with poor prognosis in patients with salivary gland tumors

The objective of this study was to investigate the expression of Glucose transporter type 1 (GLUT1) and its relation to clinicopathologic parameters in patients with salivary gland tumors. Tissue samples were 49 cases of malignant tumors, 38 cases of benign tumors, mainly pleomorphic adenoma and 10 cases of normal salivary glands. Immunohistochemically, GLUT1 Labeling Index of malignant tumor was significantly higher than benign tumor. In RT-PCR assay, GLUT1 mRNA level in malignant tumor were higher than that of normal tissue. In malignant tumors, expression of GLUT1 correlated significantly with tumor size (p=0.002) and distant metastasis (p=0.007). Cumulative survival rate of high expression group was significantly lower than that of low (p<0.001). In multivariable analysis, overall survival significantly correlated with lymph node metastasis (p=0.042) and GLUT1 expression (p=0.022). These results suggest that GLUT1 expression may provide useful prognostic information in patients with salivary gland carcinoma.     

Breast cancer in first-degree relatives and risk of lung cancer: assessment of the existence of gene sex interactions

BACKGROUND: Previous studies have shown the sex differences in lung cancer and the associations between estrogen-related genes and non-small cell lung cancer. In the present study, we assumed the existence of shared candidate genes that are common in lung and breast cancers, and examined whether women with a family history of breast cancer are at increased risk of lung cancer compared with men, especially adenocarcinoma, in a case-only study. METHODS: This case-only study was conducted based on the Lung Cancer Database Project at the National Cancer Center Hospital East. A total of 1566 patients with newly diagnosed primary lung cancer were consecutively recruited between 1999 and 2003. Information on their family history of cancer and smoking habit was obtained from a self-administered questionnaire. To assess an interactions between two factors, odds ratios for interaction (ORis) and 95% confidence intervals (CIs) were calculated by case-only contingency table. RESULTS: A statistically significant ORi was observed between a family history of breast cancer in first-degree relatives (parent and siblings, not including children) and the sex of a patient (ORi: 2.22, 95% CI: 1.02-4.81). A stratified analysis by histologic subtypes showed a statistically significant ORi only for adenocarcinoma (ORi: 3.27, 95% CI: 1.19-8.98). No other family history of cancer, such as stomach, colon and lung cancer, showed a statistically significant ORi. CONCLUSION: This study suggests the possibility of gene-sex interaction in lung cancer.     

A case with a single liver metastasis from pancreatic cancer surviving for 29 months

We report a 62-year-old man with advanced pancreatic cancer who underwent pancreatoduodenectomy and was then found to have a single hepatic metastasis. Hepatic resection was performed after 19 months of systemic chemotherapy. The patient survived for 29 months after diagnosis of the hepatic metastasis without occurrence of further metastatic lesions. The patient was given a diagnosis of pancreatic head cancer and underwent pancreatoduodenectomy in September 2001. A single hepatic metastasis was found in July 2002. No local recurrence, lymph node metastasis, distant metastasis or peritoneal metastasis were noted on imaging studies. Chemotherapy with S-1 was performed. The hepatic metastasis remained single and there were no other metastatic lesions for 19 months. A metastasis was found in the right lung in May 2004. The patient died in December 2004 without local recurrence, lymph node metastasis or new hepatic metastasis.     

Cancer stem cell

Recently it is considered that there is a small population of cells with stem cell property not only in leukemia but also in solid cancer.These cells show the ability of self-renewal and multi-potential differentiation, and can initiate and maintain a tumor. The origin of cancer stem cells might be their normal stem cells, progenitor cells, or bone marrow-derived cells. It is still difficult to isolate cancer stem cells in solid cancer. There are three possible methodologies to isolate or identify cancer stem cells; the use of a surface marker, use of cells cultured in a specific condition (sphere), or the use of side population cells identified by FACS. The gold standard assay that fulfills the definition of cancer stem cell may be serial transplantation in animal models. Cancer stem cells are likely to be responsible for disease relapse or metastasis, and also for resistance to radiation or conventional chemotherapy. The stem cell niche plays an important role on maintaining cancer stem cells. The novel promising therapies against cancer stem cells are considered, including antibody-based therapy, signal inhibitors, overcoming radiation and drug resistance, or differentiation therapy. Another interesting therapy targeting the niche may also be considered.     

Transradial approach for transcatheter arterial chemoembolization in patients with unresectable and recurrent hepatocellular carcinoma--a comparison with a conventional transfemoral approach

We evaluated a clinical usefulness and safety of transradial approach for transcatheter arterial chemoembolization (TAE) in patients with unresectable and recurrent hepatocellular carcinoma (HCC) compared with that of conventional transfemoral approach. The two groups (radial group; n=385, 1999.7-2007.3, femoral group; n=150, 1997.4-1999.6) of cases were retrospectively compared with regard to the successful rate of angiography, TAE, interventional time, Lipiodol retention pattern and complications. Hepatic angiography and TAE were completed in 379 (98.4%) of 385 cases in the radial group. There was no inter-group difference of interventional time. Minor complications (dull pain or numbness of puncture site) occurred in 29 (7.6%) patients in the radial group. Transradial approach has some advantages as follows: (1) No time will be required to stop breeding after removal of sheath. (2) The patient may freely walk after the examination. TAE by our new transradial approach for HCC was found to have a therapeutic efficacy with lower complications comparable to that of conventional transfemoral approach.