Clinical significance of dihydropyrimidine dehydrogenase and thymidylate synthase expression in patients with pancreatic cancer

Background

Little is known about the clinical significance of TS and DPD in pancreatic cancer. We aimed to evaluate TS and DPD expression levels in not only pancreatic cancer but also surrounding normal pancreatic tissues to assess the clinical implications of the expression of TS and DPD in this study.

Patients and methods

Pancreatic cancer and normal pancreatic tissues were obtained from 18 patients with pancreatic cancer who underwent pancreatic resection to measure TS and DPD activities. The TS and DPD activities were determined by enzyme-linked immunosorbent assay using non-fixed fresh-frozen specimens.

Results

Pancreatic cancer tissues had significantly higher DPD and TS enzyme activities than surrounding normal tissue. Anaplastic ductal carcinoma had higher DPD and TS activities than the other histological types. Patients with high DPD in this study demonstrated poorer prognosis than those with low DPD. On the other hand, there was no statistically significant difference in survival between the high and the low TS groups.

Conclusions

The efficacy of 5-FU may be lower in pancreatic cancer tissue than in normal tissue because DPD activity is upregulated in pancreatic cancer tissue compared to normal pancreatic tissue. It is necessary to develop an effective 5-FU delivery system and/or 5-FU combined with an inhibitor for DPD that can be used when 5-FU must be administered to patients with pancreatic cancer. High DPD activity may be a prognostic factor in patients with pancreatic cancer.     

Long-term effects of filmed social contact or internet-based self-study on mental health-related stigma: a 2-year follow-up of a randomised controlled trial

Purpose

There is a critical need to clarify the long-term effects of anti-stigma interventions. The study aimed to assess the long-term effects of repeated filmed social contact or internet-based self-study on mental health-related stigma through a randomised controlled trial with 2-year follow-up.

Methods

We randomly allocated 259 university or college students to a filmed social contact group, an internet-based self-study group, or a control group. The filmed social contact and internet-based self-study groups each received a 30-min initial intervention followed by emailed interventions every 2 months over a 12-month period. The Japanese version of the Reported and Intended Behaviour Scale (RIBS-J) and the Mental Illness and Disorder Understanding Scale (MIDUS) were used to assess behaviour, behavioural intentions (attitudes), and knowledge regarding mental health.

Results

Of the 259 original participants, 187 completed the 24-month follow-up assessment. Mean scores for the RIBS-J future domain and MIDUS peaked at 1 month after initial intervention. Compared with baseline, at 24-month follow-up, we found a significant difference in RIBS-J future domain scores between the filmed social contact and control groups at 24-month follow-up (B = 0.95, 95% CI = 0.01,1.90, p = 0.049), while MIDUS scores in the filmed social contact group (B = − 4.59, 95%CI = − 6.85, − 2.33, p < 0.001) and the internet-based self-study group (B = − 4.51, 95%CI = − 6.86, − 2.15, p < 0.001) significantly decreased compared with the control group.

Conclusion

While outcome scores peaked at 1 month after initial intervention, results suggest that filmed social contact might have a long-term effect on behavioural intentions, and both filmed social contact and internet-based self-study may contribute to improved knowledge of mental health.

     

Dual topology of functional Toll-like receptor 3 expression in human hepatocellular carcinoma: differential signaling mechanisms of TLR3-induced NF-kappaB activation and apoptosis

Toll-like receptor 3 (TLR3) is a pattern-recognizing receptor that is involved in immune signaling and plays a crucial role in survival by being able to recognize various viral components including double-stranded RNA (dsRNA). TLR3 expression and function in cancer cells are not well understood. We investigated the expression of TLR3 in hepatocellular carcinoma (HCC) cells and the function of TLR3 signaling by stimulation and transfection with polyinosinic-polycytidylic acid (Poly I:C), a synthetic form of dsRNA. TLR3 mRNA was expressed in HCC tissues as well as in non-tumor tissues. Positive immunohistochemical staining for TLR3 was observed in 52.7% of HCC tissues, and in HCC cells we found both membranous and cytoplasmic expression of TLR3. While cell surface stimulation of TLR3 with Poly I:C did not affect cell viability, it did activate NF-kappaB levels. In contrast, cytoplasmic stimulation with transfected Poly I:C significantly induced apoptosis accompanied by the down-regulation of anti-apoptotic protein. Transfected Poly I:C also synergistically augmented TRAIL-induced apoptosis, but only with low levels of transfected Poly I:C was IFN-beta production not observed. In conclusion, our results indicate that TLR3 expression in HCC plays an important role with regard to cell survival and proapoptotic activity. Endogenously expressed TLR3 may provide new clinical prospects for TLR3 agonists as cytotoxic agents in HCC.     

Association of a missense single nucleotide polymorphism, Cys1367Arg of the WRN gene, with the risk of bone and soft tissue sarcomas in Japan

Bone and soft tissue sarcomas (BSTSs) are rare malignant tumors of mesenchymal origin. Although BSTSs frequently occur in some hereditary cancer syndromes with germline mutations of DNA repair genes, genetic factors responsible for sporadic cases have not been determined. In the present study we undertook a case-control study and analyzed possible associations between the susceptibility to BSTS and the single nucleotide polymorphisms (SNPs) in DNA repair genes. Genomic DNAs extracted from case and control peripheral blood leukocytes were genotyped by pyrosequencing. For candidate polymorphisms, we chose 50 non-synonymous missense SNPs, which we have previously been identified by resequencing 36 DNA repair genes among the Japanese population. In the first screening, we analyzed 240 cases and 685 controls and selected six SNPs at the significance level of P  < 0.1 (Fisher's exact test). The six SNPs were further analyzed in the second genotyping on an additional set of 304 cases and 834 controls. In the joint analysis (the first and second genotyping combined) of 544 cases and 1378 controls, Cys1367Arg of the WRN gene was found to be a protective factor of BSTS (odds ratio = 0.66, 95% confidence interval = 0.49–0.88, P  = 0.005). An exploratory subgroup analysis without multiple comparison adjustment suggested that the WRN-Cys1367Arg SNP is associated with soft tissue sarcomas, sarcomas with reciprocal chromosomal translocations and malignant fibrous histiocytoma. ( Cancer Sci 2008; 99: 333–339)     

Fractional anisotropy value by diffusion tensor magnetic resonance imaging as a predictor of cell density and proliferation activity of glioblastomas

BACKGROUND: In vivo, water diffusion displays directionality due to presence of complex microstructural barriers in tissue. The extent of directionality of water diffusion can be expressed as a fractional anisotropy (FA) value using diffusion tensor magnetic resonance imaging (DTI). The FA value has been suggested as an indicator of the cell density of astrocytic tumors. The aim of the present study was to confirm beyond doubt that FA values indicate cell density even when limited in glioblastomas and to determine whether the FA value of a given patient predicts proliferation activity in the individual glioblastoma. METHODS: We performed DTI in 19 patients with glioblastoma and measured the FA values of tumor and normal brain regions prior to computed tomography-guided stereotactic biopsy. Differences in mean FA value between normal brain regions and glioblastoma lesion were compared. Cell density and MIB-1 indices were examined using tumor specimens obtained from biopsies. Correlation among FA values, cell density, and MIB-1 indices was also evaluated. RESULTS: The mean FA value significantly differed between normal brain regions and glioblastoma lesions. Positive correlation was observed between FA value and cell density (r = 0.73, P < 0.05) and between FA value and MIB-1 index (r = 0.80, P < 0.05). CONCLUSIONS: Our results suggest that the FA value of glioblastoma as determined by DTI prior to surgery is a good predictor of cell density and, consequently, proliferation activity.     

Use of fractional anisotropy value by diffusion tensor MRI for preoperative diagnosis of astrocytic tumors: case report

The fractional anisotropy (FA) value calculated by diffusion tensor MRI can indicate the degree of directionality of water diffusion in astrocytic tumors. Here, we report a case of anaplastic astrocytoma in which FA proved invaluable for the preoperative differential diagnosis. A 60-year-old man complained of headache, and underwent routine neuroimaging and DTI. The routine images suggested a low-grade glioma in the left temporal lobe, based on lack of enhancement on MRI with contrast medium and lack of tumor staining on angiograms, whereas FA value was very high. Based on these findings, a preoperative diagnosis of high-grade glioma was suspected. The surgical specimen exhibited the histological features of anaplastic astrocytoma with a high density of spindle shaped cells and low vascularity. In this report, we discuss the relationship between FA and other characteristics of the present tumor, and discuss the utility of FA measurement in astrocytic tumors.     

A successfully resected case of colorectal cancer with multiple liver metastases treated with systemic chemotherapy

The patient was a-54-year-old man. Sigmoidectomy was performed for sigmoid colon cancer in 1991. Partial liver resection in 1992 and microwave coagulation therapy (MCT) in 1994 were carried out for liver metastasis. Complete remission of the metastasis was achieved. In June 2002, multiple liver and lung metastases were identified. 5-FU, CDDP therapy was applied as systemic chemotherapy. The liver metastasis was improved and the level of CEA was reduced. However, a new lesion appeared in the right lobe of the liver, followed by an increase of the CEA level. Although CPT-11, 5-FU, CDDP therapy was applied, it was not effective. The reason was considered to be from the decrease of drug delivery resulting from an unbalanced blood supply in the right lobe of the liver. Right lobectomy and radio-frequency ablation was performed on June 17, 2003. The level of CEA was dramatically decreased. Additionally, CPT-11, 5-FU, CDDP therapy was applied. The patient has survived for 11 years after liver metastasis was first detected.     

High incidence of left ventricular thrombosis and systemic embolism in patients with left ventricular assist system]

The purpose of this study was to determine the incidence of left ventricular (LV) thrombosis and systemic embolism in 14 patients with LV assist systems. Echocardiography was used to detect LV wall motion abnormalities, intracavitary smoke-like echoes and thrombosis, and the effect of anticoagulant therapy was serially examined. During full assist of the circulation, the aortic valve did not open in any patient. Smoke-like echoes were observed in 9 patients (64%) and thrombi in 8 (57%). The thrombus developed within the first 3 assist days. Systemic anticoagulant therapy decreased the thrombus size in only 3 patients, but there was a possibility of intracranial or mediastinal bleeding in other 3 patients. Systemic embolism was noted in 7 of 11 autopsy patients (64%). The characteristic finding was that there were multiple embolized organs, such as the brain, kidneys, spleen and liver, in all patients. Development of a thrombus is a serious complication in all patients with LV assist systems. However, the problem does not lie in the assist system but in the left ventricle of the patient's own heart. It is also noteworthy that systemic anticoagulation is not effective for an LV thrombus. A new method of assisting the failing heart, or a new anticoagulant delivery technique for the LV cavity to prevent LV thrombus development is needed.