Evaluation of preoperative portal embolization for safe hepatectomy,with special reference to assessment of nonembolized lobe function with 99mTc-GSA SPECT scintigraphy

BACKGROUND: Preoperative portal embolization (PE) is used to stimulate liver hypertrophy in the nonembolized lobe. We studied liver volume and function with computed tomography and technetium-99m-galactosyl human serum albumin ((99m)Tc-GSA) scintigraphy before PE and at 1 or 2 weeks after PE. METHODS: Right PE was performed in 30 patients. Morphologic and functional hypertrophy in the left lobe after PE was determined and related to the presence or absence of cholestasis, biliary drainage of the embolized lobe, and postoperative liver failure. RESULTS: The volume of the left lobe and (99m)Tc-GSA uptake increased rapidly for the first week after PE, but no significant increase was seen during the second week. Morphologic hypertrophy was less pronounced in patients with jaundice (P =.03). When PE was performed at a total bilirubin level above 2 mg/dL, the interval between PE and surgery was prolonged because of cholangitis and liver abscess formation. The net morphologic hypertrophy ratio was significantly higher in livers that had undergone left lobe drainage only (9.1% +/- 0.9%) compared with those in which there was drainage of the embolized lobes (5.7% +/- 0.9%; P =.03). The volume and (99m)Tc-GSA uptake of the left lobe in the second week after PE was significantly smaller in patients with postoperative liver failure (33.7% +/- 2.4% and 18.0% +/- 2.1%, respectively) than in patients without liver failure (46.2% +/- 1.4% and 38.4% +/- 2.3%; P =.003 and P =.01, respectively). CONCLUSION: In the nonembolized lobe, the functional increase in (99m)Tc-GSA uptake is more pronounced than suggested by the degree of morphologic hypertrophy. Whenever possible, biliary drainage should not be performed in the lobe undergoing hepatectomy. (99m)Tc-GSA SPECT scintigraphy is useful for the evaluation of postoperative liver failure.     

A case responding to weekly paclitaxel (TXL) therapy as third line chemotherapy for scirrhous type gastric cancer

A 67-year-old female was admitted to our hospital in May, 2001 for examination. She was diagnosed with advanced gastric cancer that was inoperable due to peritoneal dissemination. Seventeen courses of sequential MTX and 5-FU therapy, and 2 courses of TS-1 plus CDDP were carried out. A partial response (PR) and prolonged NC were obtained after these chemotherapies. However, pleural effusion and ascites appeared again, and we diagnosed progressive disease. As a third line chemotherapy for this patient, paclitaxel (TXL) was administered. Treatment consisted of two 3-week courses of paclitaxel 70 mg per m2 on day 1 of each week, with a 1-week break between the courses. Two weeks after the start of this therapy, pleural effusion and ascites had completely disappeared. Paclitaxel is considered to be promising for advanced gastric cancers, as second or third line chemotherapy with paclitaxel for patients with inoperable gastric cancer seems to be effective in improving QOL.     

Injectable drug carriers with sustained release of cis-platinum

The authors devised injectable drug carriers with sustained release of cis-platinum (CDDP). We formed the carriers using biodegradable medical materials applied clinically: namely, fibrin hydrogel clot (FC) made from tissue adhesive, and gelatin powder (Gp) for hemostasis. Two different types of carriers were prepared: plain fibrin hydrogel clots (FCs) and Gp-containing FCs. Each carrier was dehydrated and crushed into granules, then irradiated with ultraviolet (UV) rays. These modified materials were saturated with a CDDP solution to prepare CDDP-loaded injectable sol, which were incubated at 37 degrees C in our experimental fibrinolytic systems. We examined the in vitro release profile of the CDDP and antineoplastic activities with the drug delivered from the sol. The UV-treated materials gradually released the CDDP over more than 20-30 days. Non-UV-treated carriers released the drug within 3-5 days. More than 90% of the released CDDP was revealed to be a protein-binding type, which favorably inhibited the growth of cultured cancer cells. Conversely, the CDDP incubated with human plasma showed no inhibiting functions against the growth of cancer cells. Our newly devised material appears to have great potential for loco-regional cancer chemotherapy based on the principle of local drug delivery.     

Differential gene expression screening between parental and highly metastatic pancreatic cancer variants using a DNA microarray

To clarify the difference in genes expressed in hematogenous metastasis and peritoneal dissemination, a broad analysis of differential gene expression analysis between parental cell lines and established metastatic sublines was performed. Using an oligonucleotide array (Gene Chip, Affymetrix), approximately 2,000 genes involved in cancer were analyzed for each of the cell lines. HPC-4H4 (highly metastatic lines to the liver) compared with HPC-4 (low metastatic parental lines), in which 20 overexpressed genes and 5 underexpressed genes were recognized. HPC-4P4a (highly metastatic to the peritoneum) compared with HPC-4, in which 12 overexpressed genes and 15 underexpressed genes were also recognized. Analysis of HPC-4H4 and HPC-4P4a showed comparative up-regulation of 20 genes and down-regulation of 13 in the former, HPC-4H4. Further studies are needed to validate our hypothesis that some of the resulting differentially expressed genes might be implicated in the development of metastasis in pancreatic cancer. In conclusion, this genome-wide expression analysis will help to clarify the molecular mechanisms of cancer metastasis and of the different levels of gene expression in a variety of metastatic potentials in pancreatic cancer.     

Loss of von Hippel-Lindau protein causes cell density dependent deregulation of CyclinD1 expression through hypoxia-inducible factor

Loss of the von Hippel-Lindau gene (VHL) expression ca-uses deregulation of contact inhibition of cell growth, which might be one of the bases of the tumor suppressor function of VHL. Here we show that this function of the VHL gene product (pVHL) depends on cell autonomous events. To identify the target gene of pVHL, which is directly involved in the contact inhibition, we compared the gene expression profile between VHL-deficient renal carcinoma 786-O cells and those infected with an adenovirus vector encoding VHL. In addition to known pVHL-regulated genes, such as vascular endothelial growth factor and carbonic anhydrase, we found cyclinD1 as a new target of pVHL at a high cell density. In VHL-expressing cells (VHL (+) cells), the cyclinD1 mRNA expression level diminishes at a high cell density, while it remains at a relatively high level in VHL-deficient cells (VHL (-) cells). The cyclinD1 expression level was also abnormally high in VHL (-) cells at a high cell density. Consequently, the phosporylation level of the retinoblastoma (Rb) protein remained high in these cells, whereas there was no phosporylated Rb in VHL (+) cells under the contact inhibition. The abnormal expression of cyclinD1 at a high cell density was observed even in VHL (+) cells under the hypoxic state. Moreover, ectopic expression of a HIF mutant resistant to pVHL-mediated proteolysis causes the abnormal cyclinD1 expression in VHL (+) cells. Taken together, these observations indicate that VHL is required for the downregulation of cyclinD1 at a high cell density through HIF.     

Antitumor effect by interleukin-11 receptor alpha-locus chemokine/CCL27, introduced into tumor cells through a recombinant adenovirus vector

In this study, we examined antitumor activity of a mouse CC chemokine ILC/CCL27 and a mouse CX(3)C chemokine fractalkine/CX(3)CL1 in vivo. We generated recombinant adenovirus vectors with a fiber mutation, encoding mILC (Ad-RGD-mILC) and mFKN (Ad-RGD-mFKN). We confirmed tumor cells infected with Ad-RGD-mILC and Ad-RGD-mFKN to express and release these chemokines. Tumor rejection experiments in vivo were carried out by inoculating OV-HM cells infected with Ad-RGD-mILC or Ad-RGD-mFKN into immunocompetent mice. mILC significantly suppressed the tumor growth, whereas no such significant effect was observed by mFKN. The antitumor activity induced by mILC was T cell dependent, involving both CD4(+) and CD8(+) T cells. Immunohistochemical analysis revealed accumulation of both CD3(+) lymphocytes and NK cells in the tumor tissue transduced with mILC and mFKN. However, there was a significant difference in the distribution of infiltrating cells. Furthermore, mFKN appeared to have an angiogenic activity, which might have masked its tumor suppressive activity. Collectively, ILC/CCL27 may be a good candidate molecule for cancer gene therapy.     

Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancer

Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 +/- 17% (p = 0.33) and 21 +/- 11% (p = 0.060), respectively. Multivariate analysis using Cox's proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 +/- 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 +/- 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I - IIIA breast cancer for the prolongation of the recurrence-free survival period.     

Effects of hot deep seawater bathing on the immune cell distribution in peripheral blood from healthy young men

Objectives Deep seawater (DSW) utilization technology has been developed for the fields of medicine and health, among others. To clarify the health effects of DSW as compared with surface seawater (SSW) or tap water (TW), we investigated the changes of immune cell distribution of the peripheral blood, or subjective judgment scores, after hot water bathing. Methods Ten healthy young men were immersed for 10 min in DSW, SSW and TW heated to 42°C. Blood samples were collected before bathing, immediately after bathing and 60 min after bathing. Total and differential numbers of leucocytes and lymphocyte subsets (CD3, CD4, CD8, CD19, CD16, and CD56) were examined using an automated hematology analyzer and a flow cytometer, respectively. The subjective judgment scores were obtained by an oral comprehension test. Results Since the pre-bathing leukocyte count in the TW group was significantly different from those in the DSW and SSW groups, we excluded the findings of TW bathing from consideration. In hot DSW bathing, CD8-lymphocytes increased significantly immediately after bathing (p<0.05), in contrast to hot SSW bathing, in which no significant changes were detected in the lymphocyte subsets. Additionally, there were no significant changes between repeated measurements in the subjective judgment scores, though the score of thermal sensation in SSW bathing showed a significantly higher value immediately after bathing than before bathing (p<0.01). Conclusions Our findings suggest that increased CD8-lymphocytes in hot DSW bathing may improve human immune function as well as hot springs do, as compared with SSW bathing. Although hot DSW bathing may have the ability to change human immune cell distribution, well-designed studies are needed to clarify the health effects including not only DSW and SSW but also TW.