[A case of locally advanced breast cancer treated with hyperthermia in combination with radiotherapy].

A 59-year-old woman was admitted to our hospital because of massive bleeding from a right breast tumor. The breast tumor had existed for ten years occupied the entire right breast (23 x 20 cm), its central part forming an ulcer 17 x 15 cm in size. Radiotherapy to the right breast and medication with tamoxifen were started, after which five courses of CMF chemotherapy were given. The tumor decreased to 16 x 14 cm, and hyperthermia to the right breast was performed for a total of 87 sessions from January 1999. The irregular protruding portion of the ulcer caused the necrosis, and was sloughed off about one month after hyperthermia. No viable tumor cells were observed in a biopsy taken at 5 months after the start of treatment (40 sessions). A total of 87 hyperthermia sessions were performed, and the ulcer disappeared. For 15 months after the end of hyperthermia, the patient showed a continuous CR. Hyperthermia in combination with radiotherapy or chemotherapy for breast cancer may produce a remarkable effect as in the present case, and may become one choice for medical treatment of locally advanced or recurrent breast cancer.

A case of leiomyoma of the breast.

Leiomyomas are common in the genitourinary and gastrointestinal tracts and less frequent in skin and soft tissue. It is quite uncommon for them to develop in the breast, especially in the breast parenchyma. Only 12 cases of leiomyoma in the breast parenchyma proper apart from the areola have been reported. We present a thirteenth case, the first to be reported in Japan. Its clinical features, mammographic and ultrasonographic findings, histological and immunohistochemical characteristics are quite consistent with previous reports.

[A case of intra-arterial infusion chemotherapy for liver metastases of breast cancer].

A 55-year-old woman was seen in our clinic for liver metastases of breast cancer. She underwent a standard radical mastectomy in June, 1987. Five years and 3 months after the operation, multiple bone metastases were found on bone scintigram and 10 years after the operation multiple liver metastases on CT. She was treated with a combination of intra-arterial chemotherapy using 20-30 mg/body epirubicin every 2 weeks and chemo-endocrine therapy using medroxyprogesterone acetrate (MPA) 600 mg/day + 5'-DFUR 600 mg/day. The treatment seemed to be very useful. The liver metastases regressed by 99% in size, and the duration of response was 9 months. Bone metastases did not progress from the treatment.

Nucleotides and intestine.

BACKGROUND: Dietary nucleotides play an important role in the growth and development of the intestine. Parenteral supplementation of nucleic acids may be necessary to maintain the mucosal proliferation and barrier functions during parenteral nutrition (PN). METHODS: Male Wistar rats were divided into 3 groups: FED (food ad libitum with saline infusion); PN (a standard PN solution); and OG (OG-6, a mixture of nucleotide and nucleosides, in addition to the PN solution). The mucosal wet weight, protein, and DNA contents, villous height and crypt depth, electronmicroscopic examination of the intercellular junctions, proliferating activity of the mucosal cells, mucosal permeability, bacterial translocation, and mucosal cathepsin activities were examined. RESULTS: The wet weight, protein, and DNA contents of the jejunal mucosa were significantly increased in the OG group, compared with those in the PN group. The morphometric examination revealed a significant increase in the villous height but not in the crypt depth in the OG group. The widths of both the tight and intermediate junctions were narrower in the OG group than those in the PN group. The activity of diamine oxidase was increased in the OG group, compared with that in the PN group. The ratio of proliferating cell nuclear antigen positive cells and the index of bromodeoxy uridine labeling index in the OG group were as high as in the FED group, and significantly higher than those in the PN group. The portal concentration of fluorescein isothiocyanate-dextran 70,000 after intragastric loading was significantly higher in the PN group than that in OG group. Likewise, the rate of urinary lactulose excretion after intragastric loading was higher in the PN group. The positive rate of bacteria cultured in mesenteric lymph nodes was higher in the PN group than in the OG group although the difference was not significant. The activities of mucosal cathepsins (B, H, and L), markers for phagocytic degradation of extrinsic substances and organisms, were higher in the PN group than those in the OG and FED groups. CONCLUSIONS: Parenteral supplementation of nucleic acids supports the mucosal cell proliferation and functions.

Effect of parenteral and enteral nutrition on hepatic albumin synthesis in rats.

The route of nutrient delivery may alter the production of albumin and induce changes at the molecular level. Donryu rats (n = 75) were divided into the following three groups. The oral feeding (OR) group received a non-purified solid diet ad libitum, the parenteral nutrition (PN) group received a total parenteral nutrition (TPN) solution intravenously, and the enteral nutrition (EN) group received intragastric infusions of the TPN solution for 7 d. Serum albumin and glucocorticoid levels were measured and messenger RNA (mRNA) levels of albumin and hepatic specific transcription factors in the liver were analyzed. Serum albumin and albumin mRNA levels in the PN group became significantly decreased compared to those in the OR group, whereas the EN group did not show a significant difference compared to the OR group. mRNA levels of DBP, D-site binding transcription factor for the albumin gene, showed a circadian rhythm in the OR and EN groups, but not in the PN group, as indicated by a DBP mRNA level at 2200 h in the PN group that was significantly lower than that in the OR group. mRNA levels of C/EBP alpha, CCAAT-enhancer binding protein alpha, were highest in the OR group and lowest in the PN group. In contrast, mRNA levels of C/EBP beta were highest in the PN group and lowest in the OR group. Serum glucocorticoid level showed a circadian rhythm in the OR group, highest at 2200 h and lowest at 1000 h, whereas such a rhythm was not found in either the PN or the EN group. Albumin synthesis was down-regulated in PN in association with changes in transcription factors. A loss of circadian rhythm reflected in changes of DBP mRNA and serum glucocorticoid level may play a role. Down-regulation of albumin was improved by enteral feeding, indicating that EN is more advantageous for albumin synthesis than PN.

Regulation of albumin mRNA and its promoter-binding nuclear factors under different perioperative nutritional methods in hepatectomized rats.

BACKGROUND: Regulation of perioperative albumin synthesis under parenteral (PN) and enteral (EN) nutrition was investigated. METHODS: Rats were divided into PN and EN groups. Both groups received the same regimen of artificial nutrition for 7 days and then underwent 70% hepatectomy. Serum albumin and mRNA levels of albumin and its promoter-binding nuclear factors (C/EBPalpha, beta, and DBP) were measured. RESULTS: Serum albumin and albumin mRNA in the PN group were significantly lower than those in the EN group at 72 hours after hepatectomy. Preoperative and postoperative DBP and C/EBPalpha mRNA levels in the EN group were significantly higher than those in the PN group. CONCLUSION: Serum albumin was well maintained by EN after hepatectomy owing to an early recovery of albumin mRNA level and its nuclear factor mRNA levels (C/EBPalpha and DBP). Compared with PN, EN is a more advantageous from of perioperative nutrition as pertains to albumin synthesis.

Involvement of interleukin-6 in activation of lysosomal cathepsin and atrophy of muscle fibers induced by intramuscular injection of turpentine oil in mice.

Serum IL-6 level increased after the injection of turpentine oil into the right gastrocnemius muscle in mice. The mRNA level of IL-6 was highest in the injected muscle at 12 h after injection, but was not identified in the opposite muscle. The activities of cathepsins B and B+L started to elevate after 12 h in the injected muscle and markedly increased after day 3. Likewise, the mRNA levels of cathepsins B and L markedly increased from day 1 to day 5 in the injected muscle. However, a very mild increase was also observed in the opposite muscle. Immunohistochemical staining of cathepsins B and L exhibited positive reactions as fine granules in myofibers at 12 h and strong positive reactions in the infiltrating macrophages at 3 days. Atrophy of myofibers type 1 and 2 was evident in a time-dependent manner in the injected muscle. Treatment with rat anti-mouse IL-6 receptor monoclonal antibody inhibited the increase in cathepsin activities in the injected muscle. We conclude that IL-6 produced in the inflamed muscle is involved in the process of muscle degeneration, especially through the activation of lysosomal cathepsins.

Gene expression of albumin and liver-specific nuclear transcription factors in liver of protein-deprived rats.

Protein-energy malnutrition causes hypoalbuminemia. Recent work has suggested that this may be partly due to decreased transcription of the albumin gene. This study examined the role of cis-acting and transacting elements of the albumin gene during protein deprivation. Male 7-wk-old Donryu rats were fed a protein-free diet (0% casein diet) for 10 d or given restricted (pair-fed control) or free access (freely fed control) to a 25% casein diet. Serum albumin concentrations were significantly lower in the protein-deprived rats (29 +/- 1 g/L) than in the pair-fed controls (42 +/- 3 g/L) or the freely fed controls (45 +/- 3 g/L). The albumin mRNA level was also significantly lower in livers of protein-deprived rats (36% of pair-fed control). However, gel mobility shift analysis using liver nuclear extracts did not show any significant difference between the protein-deprived rats and the pair-fed controls in the binding activity to the B and D sites of the albumin promoter. Furthermore, gel mobility shift-Western blot analysis showed no significant difference between the two groups in the protein levels of nuclear transcription factors binding to the D sites. The amounts of mRNA of hepatocyte nuclear factor-1 binding to the B site were not significantly different between these two groups. These results suggest that the proximal promoter region may not play a major role in the down-regulation of the albumin gene during protein deprivation.

Role of supplementation of a nucleic acid solution on the intestinal mucosa under total parenteral nutrition.

Since dietary nucleotides play an important role in the growth and development of the intestine, supplementation of a nucleic acid solution (OG-VI) may support the optimal growth and integrity of the intestine under total parenteral nutrition (TPN). Supplementation of OG-VI to a TPN solution improved mucosal morphologic and functional changes, increased mucosal proliferation, and decreased mucosal permeability of the intestine. After 80% small bowel resection, OG-VI supplementation to a TPN solution attenuated the initial mucosal atrophy and improved intestinal cell turnover. Nucleic acid supplementation may be clinically beneficial in certain situations.

Effects of cyclic and continuous parenteral nutrition on albumin gene transcription in rat liver.

To evaluate schedule-dependent effects of parenteral nutrition on albumin gene expression and regulation, mRNA levels for albumin and its promoter-binding nuclear factors in the liver were measured in rats receiving cyclic or continuous parenteral nutrition. Rats were divided into three groups: the control group (n = 5) received a nonpurified diet, the continuous parenteral nutrition group (n = 5) received a continuous infusion of a defined parenteral nutrition formula, and the cyclic parenteral nutrition group (n = 5) received a cyclic (between 2000 and 0800) infusion of the same formula. After 7 d, rats were killed to obtain serum and liver. The serum albumin concentrations were 44 +/- 3 g/L in the controls, 31 +/- 2 g/L in the continuous parenteral nutrition group, and 33 +/- 3 g/L in the cyclic parenteral nutrition group. The mRNA for albumin and D site binding protein (DBP) was more abundant and mRNA for CCAAT/enhancer binding protein beta (C/EBP beta) was less abundant in the cyclic parenteral nutrition group than in the continuous parenteral nutrition group. Gel-shift assay for D site and gel-shift Western blotting of DBP carried out using another three rats in each group revealed an increase of DBP in rats receiving cyclic parenteral nutrition compared with continuous parenteral nutrition. In conclusion, although parenteral nutrition decreases serum albumin concentrations, cyclic parenteral nutrition maintains transcription of the albumin gene to a greater extent than does continuous parenteral nutrition. Cyclic parenteral nutrition, in contrast with continuous parenteral nutrition, sustains the mRNA and concentrations of DBP.

Effects of nucleosides and a nucleotide mixture on gut mucosal barrier function on parenteral nutrition in rats.

BACKGROUND: We have previously reported that the addition of nucleosides and a nucleotide mixture (OG-VI) to total parenteral nutrition (TPN) prevents TPN-induced intestinal mucosal atrophy and results in increased intestinal cathepsin activities under TPN. The aims of the present study are to examine the effects of OG-VI on mucosal barrier functions and to clarify whether the intestinal cathepsins can be used as a new marker of mucosal barrier function. METHODS: Male Wistar rats were divided into three groups: FED (food ad libitum), TPN (a standard TPN solution), and OG (OG-VI in addition to the TPN solution). Mucosal barrier functions were analyzed by the lactulose/mannitol (L/M) test, mucosal ZO-1 messenger RNA level, and electron micrographs in the gut. Intestinal cathepsin B, H, and L activities were also measured. RESULTS: The L/M ratio for TPN was much higher than that for FED. Only lactulose excretion was significantly reduced by OG-VI. The intercellular spaces of the mucosal cells for TPN were significantly wider than those for FED, but were reduced in size by the addition of OG-VI. All cathepsin activities of the ileum were higher for TPN than for FED, whereas OG showed no increase. CONCLUSION: OG-VI contributes to the improvement of gut mucosal barrier function. Intestinal cathepsin activities can be used as a new marker of mucosal barrier function.

A total parenteral nutrition solution supplemented with a nucleoside and nucleotide mixture sustains intestinal integrity, but does not stimulate intestinal function after massive bowel resection in rats.

The effects of supplementing a total parenteral nutrition solution with a nucleoside and nucleotide mixture on mucosal adaptive processes after massive bowel resection were studied. Male Wistar rats (n=30) underwent 80% small intestine resection, were randomized into two groups and received either standard total parenteral nutrition (TPN) or TPN supplemented with a nucleoside and nucleotide mixture (2.5 mL.kg-1.d-1). An additional five rats, fed a nonpurified diet and not resected, were used as controls. After 4 or 7 d, rats were killed and samples were collected for mucosal indices and intestinal enzymatic activities (disaccharidases and diamine oxidase). After massive small bowel resection and TPN, residual jejunal mucosal wet weights, villus heights, protein and RNA contents on d 4 and 7, and total wet weights and DNA contents on d 7 were significantly lower than in the control group. Administration of the nucleoside and nucleotide mixture resulted in significantly higher residual jejunal total and mucosal weights, proteins, DNA, RNA contents, and the ratio of proliferating cell nuclear antigen positive cells per crypt than did the standard TPN solution on d 7. However, disaccharidase and diamine oxidase activities were not affected by supplementation with the nucleoside and nucleotide mixture. Our data suggest the supplementation of a nucleoside and nucleotide mixture to a TPN solution can attenuate the initial mucosal atrophy and improve intestinal cell turnover after massive bowel resection, but the supplementation has little effect on enterocyte enzymatic activities.

Modulation of thermogenic response to parenteral amino acid infusion in surgical stress.

Thermogenic response to parenteral infusion of amino acid mixtures in rats undergoing surgical stress was investigated with the aid of a small animal indirect calorimeter. Male Wistar rats (n = 12) were laparotomized and received intestinal abrasion along with construction of a parenteral route. After 48 h, nutrient-induced thermogenesis (NIT) produced by amino acid mixtures was examined and compared with that of control rats (n = 12) without surgical stress. The NIT values of the leucine-enriched solution were greater than those of the control solution in both rats with and without surgical stress. The NIT generated by the leucine-enriched solution in rats with surgical stress was significantly higher than that in rats without. NIT values for 10 different kinds of single amino acid solutions with identical concentrations was then examined in 60 rats. The NIT values of the leucine and the glycine solutions were relatively higher than those of other solutions. However, when puromycin was injected intraperitoneally into 12 rats just before measurement of the NIT in response to amino acid mixtures, no significant differences were found in NIT values between the mixtures. In summary, surgical stress increased the thermogenic response to the leucine-enriched solution, indicating that utilization of leucine may be augmented under surgical stress. In fact, leucine itself may be a thermogenic amino acid. Inhibition of protein synthesis prevented the increase in thermogenic response induced by the leucine-enriched solution. We conclude that thermogenic responses to parenteral amino acid mixtures may differ depending not only upon the compositions of amino acids but also upon the host conditions.

Interrelation of intracellular proteases with total parenteral nutrition-induced gut mucosal atrophy and increase of mucosal macromolecular transmission in rats.

Total parenteral nutrition (TPN) is known to induce mucosal atrophy and to increase macromolecular transmission of the small intestine. The potential participation of various proteases in that process was investigated. Male Wistar rats were randomly divided into two groups: the TPN group (n = 11) received a standard TPN (250 kcal/kg per day, 1.78 g nitrogen/kg per day) and the FED group (n = 10) received a standard rat food for 1 week. This was followed by an examination of gut macromolecular transmission of fluorescein isothiocyanate dextran 70,000 (FITC-dextran) after intragastric injection and of the activities of gut mucosal cathepsins B, H, and L and of proteasome. Mucosal wet weight and protein content decreased significantly by TPN for 1 week. In both groups, the activities of all proteases in the ileum were significantly greater than in the jejunum. In the TPN group, cathepsin L and H activities in the ileum, and cathepsin B activity in both the jejunum and the ileum, were greater than those in the FED group. The portal concentration of FITC-dextran was higher than arterial and venous concentrations in the both groups. In the TPN group, the portal FITC-dextran concentration increased significantly compared with the FED group. In conclusion, active proteolysis is not associated with TPN-induced mucosal atrophy. Cathepsins activities in the ileum increase as a result of TPN. Interrelationship is implicated between increase of lysosomal protease activity and the deterioration of the intestinal barrier function, which permits macromolecular transmission.

Muscle undergoes atrophy in association with increase of lysosomal cathepsin activity in interleukin-6 transgenic mouse.

Interleukin(IL)-6 transgenic mice were produced by microinjection of human IL-6 cDNA fused with H-2Ld promoter into the pronucleus of fertilized eggs from C57BL/6J mice. At 16 weeks old, the gastrocnemius muscles of the IL-6 transgenic mice became atrophic as compared to those of the normal mice, while the body weights increased significantly. The activities and mRNA levels of lysosomal cathepsins B and L were increased in the muscles of the transgenic mice. Immunohistochemical study on the muscles showed increased staining of both cathepsins B and L in the transgenic mice. IL-6 is responsible for enhanced muscle catabolism by activating the lysosomal cathepsin (B and L) system.

[Hepatic metastases from jejunal leiomyosarcoma treated effectively by repeated transarterial embolization with carboplatin].

A 67-year-old man complained of abdominal mass, abdominal pain and tarry stool. He was diagnosed as having jejunal leiomyosarcoma and multiple liver metastases after examination. The jejunal leiomyosarcoma was resected by operation. Unrectable liver metastases were repeatedly treated by transarterial embolization with carboplatin and Lipiodol, and a significant reduction was achieved. TAE with carboplatin and Lipiodol was considered evaluating efficiency therapy without side effect. He has remained well presently for 1 years 10 months after operation.