Usefulness of transanal tube placement for prevention of anastomotic leakage following laparoscopic low anterior resection.

INTRODUCTION: Anastomotic leakage (AL) is a major complication of laparoscopic low anterior resection (LLAR) for rectal cancer. Although several recent reports have suggested that transanal tube placement can prevent AL, this practice is still controversial. Additionally, the mechanism by which a transanal tube prevents AL is unknown. The aim of this study was to evaluate the efficacy of transanal tube placement for prevention of AL following LLAR. METHODS: This was a retrospective study that included 69 patients who underwent LLAR between February 2012 and January 2016. After an anastomosis using a double stapling technique, a transanal tube was placed in 28 patients. A diverting stoma was created in 26 patients. Univariate and multivariate analyses of clinicopathological characteristics were performed. RESULTS: The overall incidence of AL was 15.9% (11/69). Univariate analysis showed that transanal tube placement (P = 0.022) and early postoperative diarrhea (P < 0.001) were associated with AL. The duration of the postoperative hospital stay for patients with transanal tube placement (13.1 ± 4.1 days) was significantly shorter than for patients without a transanal tube (22.7 ± 12.3 days; P < 0.001). However, transanal tube placement did not reduce postoperative diarrhea. Creation of a diverting stoma did not affect the incidence of AL. Multivariate analysis revealed that the absence of a transanal tube (odds ratio = 33.5, P = 0.018) and the occurrence of postoperative diarrhea (odds ratio = 86.3, P = 0.001) were independent risk factors for AL. CONCLUSION: Transanal tube placement prevents AL after LLAR. Furthermore, this protective effect may be due to a reduction in the unfavorable incidence of early postoperative diarrhea.

Suppression of MicroRNA-7 (miR-7) Biogenesis by Nuclear Factor 90-Nuclear Factor 45 Complex (NF90-NF45) Controls Cell Proliferation in Hepatocellular Carcinoma.

MicroRNA-7 (miR-7)has been characterized as an anti-oncogenic microRNA (miRNA) in several cancers, including hepatocellular carcinoma (HCC). However, the mechanism for the regulation of miR-7 production in tumors remains unclear. Here, we identified nuclear factor 90 (NF90) and NF45 complex (NF90-NF45) as negative regulators of miR-7 processing in HCC. Expression of NF90 and NF45 was significantly elevated in primary HCC tissues compared with adjacent non-tumor tissues. To examine which miRNAs are controlled by NF90-NF45, we performed an miRNA microarray and quantitative RT-PCR analyses of HCC cell lines. Depletion of NF90 resulted in elevated levels of mature miR-7, whereas the expression of primary miR-7-1 (pri-miR-7-1) was decreased in cells following knockdown of NF90. Conversely, the levels of mature miR-7 were reduced in cells overexpressing NF90 and NF45, although pri-miR-7-1 was accumulated in the same cells. Furthermore, NF90-NF45 was found to bind pri-miR-7-1 in vitro These results suggest that NF90-NF45 inhibits the pri-miR-7-1 processing step through the binding of NF90-NF45 to pri-miR-7-1. We also found that levels of the EGF receptor, an oncogenic factor that is a direct target of miR-7, and phosphorylation of AKT were significantly decreased in HCC cell lines depleted of NF90 or NF45. Of note, knockdown of NF90 or NF45 caused a reduction in the proliferation rate of HCC cells. Taken together, NF90-NF45 stimulates an elevation of EGF receptor levels via the suppression of miR-7 biogenesis, resulting in the promotion of cell proliferation in HCC.

A case of primary adenocarcinoma of the third portion of the duodenum resected by laparoscopic and endoscopic cooperating surgery.

INTRODUCTION: We report a case of primary adenocarcinoma in the third portion of the duodenum (D3) curatively resected by laparoscopic and endoscopic cooperating surgery (LECS). PRESENTATION OF CASE: A 65-year-old woman had a routine visit to our hospital for a follow-up of rectal cancer resected curatively 2 years ago. A routine screening gastroduodenal endoscopy revealed an elevated lesion of 20mm in diameter in the D3. The preoperative diagnosis was adenoma with high-grade dysplasia; however, suspicion about potential adenocarcinoma was undeniable. Curative resection was performed by LECS. Pathological examination revealed intramucosal adenocarcinoma arising from normal duodenal mucosa. The tumor was stage I (T1/N0/M0) in terms of the tumor, nodes, metastasis (TNM) classification. LECS for duodenal tumor has seldom been reported previously, and this is the first report of LECS for primary adenocarcinoma in the D3. The transverse mesocolon was removed from the head of pancreas to expose the duodenum, and the accessory right colic vein was cut; this was followed by the Kocher maneuver for mobilization of the lesion site. DISCUSSION: LECS enabled en bloc resection with adequate surgical margins and secure intra-abdominal suturing. Thorough mobilization of the mesocolon and pancreas head is essential for this procedure because it facilitates correct resection and suturing. CONCLUSION: LECS is a feasible treatment option for duodenal neoplasms, including intramucosal adenocarcinoma, even though it exists in the D3.

Adult with primary hyperoxaluria type 1 regrets not receiving preemptive liver transplantation during childhood: report of a case.

A 32-year-old male was suspected to have primary hyperoxaluria type 1 (PH1) and eventually underwent liver transplantation (LT). He was diagnosed with nephrolithiasis at 9 years of age. Right heminephrectomy was performed for a staghorn calculus. He underwent urethrotomy for urinary retention at 12 years of age. Percutaneous nephrolithotomy was performed for nephrolithiasis when he was 16 years of age. He underwent frequent extracorporeal shock wave lithotripsy for recurrent nephrolithiasis from 18 to 24 years of age. PH1 was suspected at 32 years of age, and pharmacological therapy was also initiated. He developed renal failure at 36 years of age, which was treated with intensive hemodialysis. A definitive diagnosis of PH1 was made based on a liver needle biopsy 1 month later. He received a living-donor LT at 38 years of age, and a living-donor kidney transplant from the same donor 8 months later. Though he made a good recovery, an early diagnosis and preemptive LT are important for PH1 patients.

E2A and CBP/p300 act in synergy to promote chromatin accessibility of the immunoglobulin κ locus.

V(D)J recombination of Ig and TCR genes is strictly regulated in a lineage- and stage-specific manner by the accessibility of target gene chromatin to the recombinases RAG1 and RAG2. It has been shown that enforced expression of the basic helix-loop-helix protein, E2A, together with RAG1/2 in a nonlymphoid cell line BOSC23 can induce V(D)J recombination in endogenous Igκ and TCR loci by increasing chromatin accessibility of target gene segments. In this study, we demonstrate that ectopically expressed E2A proteins in BOSC23 cells have the ability to bind directly to the promoter and recombination signal sequence of Vκ genes and to recruit histone acetyltransferase CBP/p300. Overexpression of CBP/p300 in conjunction with E2A results in enhancement of E2A-induced histone acetylation, germline transcription, and Igκ rearrangement. Conversely, knockdown of endogenous CBP/p300 expression by small interfering RNA leads to a decrease in histone acetylation, germline transcription and Igκ rearrangement. Furthermore, analyses using a mouse pre-B cell line revealed that endogenous E2A proteins also bind to a distinct set of Vκ genes and regulatory regions in the mouse Igκ locus and act to increase histone acetylation by recruiting p300, confirming the similar findings observed with BOSC23 cells. These observations indicate that E2A plays critical roles in inducing Igκ rearrangement by directly binding to and increasing chromatin accessibility at target gene segments.

Regulation of TCR Vγ2 gene rearrangement by the helix-loop-helix protein, E2A.

V(D)J recombination of Ig and TCR genes is strictly regulated by the accessibility of target gene chromatin in a lineage- and stage-specific manner. In the mouse TCRγ locus, rearrangement of the Vγ2 gene predominates over Vγ3 rearrangement in the adult thymus. This preferential rearrangement is likely due to the differential accessibility of the individual Vγ genes, because the levels of germ line transcription and histone acetylation of the Vγ genes are well correlated with the rearrangement frequency in adult thymocytes. However, factors responsible for the differential regulation of the Vγ gene rearrangement have been largely unknown. In this study, we demonstrated that Vγ2 rearrangement in the adult thymus was substantially reduced in mice deficient for the basic helix-loop-helix protein, E2A. The decreased rearrangement is likely caused by the reduced accessibility of Vγ2 chromatin, since germ line transcription and histone acetylation of the Vγ2 gene were reduced in an E2A dosage-dependent manner. We further showed that E2A bound around the Vγ2 gene in vivo and we identified two canonical E-box sites downstream of Vγ2, to which E2A can bind in vitro. Furthermore, these two E-box sites had the ability to activate transcription upon E2A over-expression. These data suggest that E2A directly binds to and increases accessibility of Vγ2 chromatin, thereby facilitating Vγ2 rearrangement in the adult thymus.

Resistance to cisplatin-induced apoptosis via PI3K-dependent survivin expression in a rat hepatoma cell line.

Hepatocellular carcinoma (HCC) is known to be resistant to chemotherapy. Survivin, a member of the inhibitor of apoptosis proteins, is overexpressed in most cancers but is absent in most normal adult tissue. The aim of this study was to investigate whether expression of survivin contributes to resistance to cisplatin-induced apoptosis. We confirmed induction of survivin expression in hepatoma in the N-diethylnitrosamine (DEN) induced rat and in the rat hepatoma cell line (K-251). We examined cell proliferation after treatment with cisplatin (CDDP) in the presence and absence of siRNA or the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 to suppress survivin or PI3K/Akt, respectively. Survivin was expressed in DEN-induced rat HCC with RT-PCR and Western blotting. Expression of survivin was observed primary in the nuclei and in the cytoplasm with immunohistochemistry. However, survivin was not detected in non-tumor tissues. Expression of survivin was also observed primarily in the nuclei and in the cytoplasm of the K-251 rat hepatoma cell line. CDDP induced survivin expression, which was blocked by siRNA. LY294002 also attenuated survivin expression induced by CDDP. Our results indicate that survivin expression via PI3K contributes to resistance to CDDP-induced apoptosis in a rat hepatoma cell line.

Dai-kenchu-to attenuates rat sinusoidal obstruction syndrome by inhibiting the accumulation of neutrophils in the liver.

BACKGROUND AND AIM: Sinusoidal obstruction syndrome (SOS) is drug-induced liver injury that occurs in patients who receive hematopoietic cell transplantation and oxaliplatin-contained chemotherapy. The aim of study was to investigate the pharmacological treatment of SOS using a traditional Japanese medicine, Dai-kenchu-to (DKT). METHODS: Male Sprague-Dawley rats were treated with monocrotaline (MCT) to induce SOS. The rats were divided into three groups: control, MCT and MCT+DKT groups. In the MCT+DKT group, DKT was gavaged at 12 h after MCT treatment and given every 12 h until the end of the protocol. The rats of MCT group were treated with water instead of DKT. At 48 h after MCT treatment, blood and liver samples were collected. RESULTS: In the MCT+DKT group, the macroscopic and histological findings revealed liver congestion, sinusoidal alteration and the destruction of sinusoidal lining, which were comparable with those of the MCT group. However, the area of hepatic necrosis and serum AST levels significantly decreased in the MCT+DKT group compared with those of the MCT group. Treatment with DKT resulted in the reduction of neutrophil accumulation, myeloperoxidase activity and the expression of cytokine-induced neutrophil chemoattractant (CINC) and intracellular adhesion molecule-1 (ICAM-1) mRNA in the liver compared with those of the MCT group. Treatment with processed ginger, one of the ingredients in DKT, resulted in similar effects to those shown by DKT. CONCLUSIONS: Dai-kenchu-to attenuates MCT-induced liver injury by preventing neutrophil-induced liver injury through blockage of upregulation of CINC and ICAM-1 mRNA level.

Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma.

UNLABELLED: Transforming growth factor beta (TGF-beta) signaling involves both tumor-suppression and oncogenesis. TGF-beta activates the TGF-beta type I receptor (TbetaRI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TbetaRI-dependent pSmad3C transmits a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promotes carcinogenesis in human chronic liver disorders. The aim of this study is to elucidate how SP600125, a JNK inhibitor, affected rat hepatocellular carcinoma (HCC) development, while focusing on the domain-specific phosphorylation of Smad3. The rats received subcutaneous injections of either SP600125 or vehicle 11 times weekly together with 100 ppm N-diethylnitrosamine (DEN) administration for 56 days and were sacrificed in order to evaluate HCC development 28 days after the last DEN administration. The number of tumor nodules greater than 3 mm in diameter and the liver weight/body weight ratio were significantly lower in the SP600125-treated rats than those in the vehicle-treated rats (7.9 +/- 0.8 versus 17.7 +/- 0.9: P < 0.001; 6.3 +/- 1.2 versus 7.1 +/- 0.2%: P < 0.05). SP600125 significantly prolonged the median survival time in rats with DEN-induced HCC (113 versus 97 days: log-rank P = 0.0018). JNK/pSmad3L/c-Myc was enhanced in the rat hepatocytes exposed to DEN. However, TbetaRI/pSmad3C/p21(WAF1) was impaired as DEN-induced HCC developed and progressed. The specific inhibition of JNK activity by SP600125 suppressed pSmad3L/c-Myc in the damaged hepatocytes and enhanced pSmad3C/p21(WAF1), acting as a tumor suppressor in normal hepatocytes. CONCLUSION: Administration of SP600125 to DEN-treated rats shifted hepatocytic Smad3-mediated signal from oncogenesis to tumor suppression, thus suggesting that JNK could be a therapeutic target of human HCC development and progression.

P-glycoprotein expression affects 18F-fluorodeoxyglucose accumulation in hepatocellular carcinoma in vivo and in vitro.

18F-fluorodeoxyglucose (FDG) uptake in hepatocellular carcinoma (HCC) is associated with tumor differentiation and expression of P-glycoprotein (P-gp), a drug efflux pump that plays an important role in chemoresistance. The aim of the study was to clarify the factors that affects FDG uptake in HCC in vivo and in vitro. The standardized uptake value (SUV) and the tumor to non-tumor SUV ratio (TNR) for FDG uptake in HCC in vivo was determined by FDG-PET in 28 patients. Expression levels of glucose transporter-1 (GLUT-1), GLUT-2 and type II hexokinase (HK-II) were examined immunohistochemically in resected specimens. The glucose-6-phosphatase (G-6-Pase) activity was determined in tissue homogenates. In vitro, PLC/PRF/5 cells and doxorubicin-resistant PLC/DOR cells were used to examine the effect of P-gp on FDG uptake. The effects of two P-gp inhibitors, verapamil and cepharanthine, on accumulation of FDG were also examined. in vivo, GLUT-1 expression was low in HCCs, but was significantly higher in poorly differentiated HCCs than in moderately differentiated HCCs (P=0.043) and was positively correlated with SUV (r=0.75, P<0.0001) and TNR (r=0.7, P<0.0001). GLUT-2 and HK-II expression and G-6-Pase activity were not correlated with tumor differentiation, SUV or TNR. P-gp was over-expressed in PLC/DOR cells, and accumulation of FDG was significantly higher in PLC/PRF/5 cells than in PLC/DOR cells (P=0.04). Verapamil and cepharanthine restored FDG uptake in PLC/DOR cells, but not in PLC/PRF/5 cells. Collectively, our results show that FDG uptake in HCC is weakly correlated with GLUT-1 expression, and that FDG could be a substrate of P-gp, which may act as an efflux pump to reduce FDG accumulation.

The NF90-NF45 complex functions as a negative regulator in the microRNA processing pathway.

The positive regulatory machinery in the microRNA (miRNA) processing pathway is relatively well characterized, but negative regulation of the pathway is largely unknown. Here we show that a complex of nuclear factor 90 (NF90) and NF45 proteins functions as a negative regulator in miRNA biogenesis. Primary miRNA (pri-miRNA) processing into precursor miRNA (pre-miRNA) was inhibited by overexpression of the NF90 and NF45 proteins, and considerable amounts of pri-miRNAs accumulated in cells coexpressing NF90 and NF45. Treatment of cells overexpressing NF90 and NF45 with an RNA polymerase II inhibitor, alpha-amanitin, did not reduce the amounts of pri-miRNAs, suggesting that the accumulation of pri-miRNAs is not due to transcriptional activation. In addition, the NF90 and NF45 complex was not found to interact with the Microprocessor complex, which is a processing factor of pri-miRNAs, but was found to bind endogenous pri-miRNAs. NF90-NF45 exhibited higher binding activity for pri-let-7a than pri-miR-21. Of note, depletion of NF90 caused a reduction of pri-let-7a and an increase of mature let-7a miRNA, which has a potent antiproliferative activity, and caused growth suppression of transformed cells. These findings suggest that the association of the NF90-NF45 complex with pri-miRNAs impairs access of the Microprocessor complex to the pri-miRNAs, resulting in a reduction of mature miRNA production.

Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells.

BACKGROUND/AIMS: Septins are ubiquitous and multifunctional scaffold proteins involved in cytoskeletal organization, exocytosis and other cellular processes. We disclose the quiescent hepatic stellate cells (HSCs)-specific expression of a septin subunit Sept4 in the liver, and explore the significance of the septin system in liver fibrosis. METHODS: We analyzed the expression of alpha-smooth muscle actin (alpha-SMA), collagens and other markers in primary cultured HSCs derived from wild-type and Sept4(-/-) mice. We compared susceptibility of these mice to liver fibrosis induced by either carbon tetrachloride treatment, bile duct ligation or methionine/choline-deficient diet. Collagen deposition, the principal parameter of liver fibrosis, was quantified both histochemically (Masson's trichrome stain) and biochemically (hydroxyproline content). RESULTS: In vitro, Sept4 mRNA/protein was remarkably downregulated in HSCs through myofibroblastic transformation. Sept4(-/-) HSCs showed normal morphology and proliferation, while myofibroblastic transformation as monitored by the upregulation of alpha-SMA and collagen was accelerated compared to wild-type HSCs. In vivo, liver fibrosis was consistently more severe in Sept4(-/-) mice than in wild-type littermates in all of the three paradigms of hepatitis/liver fibrosis. CONCLUSIONS: These data concordantly indicate that the HSC-specific septin subunit Sept4 and perhaps the septin system are involved in the suppressive modulation of myofibroblastic transformation and fibrogenesis associated with liver diseases.

Fluorine-18 fluorodeoxyglucose positron emission tomography predicts lymph node metastasis, P-glycoprotein expression, and recurrence after resection in mass-forming intrahepatic cholangiocarcinoma.

BACKGROUND: Patients with intrahepatic cholangiocarcinoma (ICC) have a poor prognosis, and lymph node metastasis is an important prognostic factor. In this study, we investigated the usefulness of fluorodeoxyglucose positron emission tomography (FDG-PET) as a marker for lymph node metastasis, P-glycoprotein (P-gp) expression, and recurrence in ICC. METHODS: The subjects were 35 patients who underwent FDG-PET. Detectability of lymph node metastasis using FDG-PET was compared with that using computed tomography (CT) or magnetic resonance imaging (MRI). In patients who underwent resection, expression of P-gp was examined immunohistochemically, and the relationship between P-gp expression and the standardized uptake value (SUV) in FDG-PET was investigated. Survival rates were analyzed using clinical and pathologic factors. RESULTS: Of the 35 patients, 5 did not undergo surgery based on FDG-PET findings (2 with extrahepatic metastasis, and 3 with para-aortic lymph node metastasis) and 3 underwent laparotomy only (2 with peritoneal dissemination and 1 with para-aortic lymph node metastasis). The diagnostic accuracies of FDG-PET, CT, and MRI for detection of lymph node metastasis were 86%, 68%, and 57%, the sensitivities were 43%, 43% and 43%, and the specificities were 100%, 76%, and 64%, respectively. A negative correlation was found between SUV and P-gp expression (P = .002; r = -0.62). The disease-free survival rates in the high SUV group (>or=8.5) were significantly lower than in the low SUV group (<8.5; P = .04), and a high SUV was an independent predictor of postoperative recurrence in multivariate analysis (risk ratio, 1.3; P = .03). CONCLUSIONS: FDG-PET is useful for prediction of lymph node metastasis, P-gp expression and recurrence in ICC.

CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury.

CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a key component in endoplasmic reticulum (ER) stress-mediated apoptosis. The goal of the study was to investigate the role of CHOP in cholestatic liver injury. Acute liver injury and liver fibrosis were assessed in wild-type (WT) and CHOP-deficient mice following bile duct ligation (BDL). In WT livers, BDL induced overexpression of CHOP and Bax, a downstream target in the CHOP-mediated ER stress pathway. Liver fibrosis was attenuated in CHOP-knockout mice. Expression levels of alpha-smooth muscle actin and transforming growth factor-beta1 were reduced, and apoptotic and necrotic hepatocyte death were both attenuated in CHOP-deficient mice. Hepatocytes were isolated from WT and CHOP-deficient mice and treated with 400 microM glycochenodeoxycholic acid (GCDCA) for 8 h to examine bile acid-induced apoptosis and necrosis. GCDCA induced overexpression of CHOP and Bax in isolated WT hepatocytes, whereas CHOP-deficient hepatocytes had reduced cleaved caspase-3 expression and a lower propidium iodide index after GCDCA treatment. In conclusion, cholestasis induces CHOP-mediated ER stress and triggers hepatocyte cell death, and CHOP deficiency attenuates this cell death and subsequent liver fibrosis. The results demonstrate an essential role of CHOP in development of liver fibrosis due to cholestatic liver damage.

Regulation of T cell receptor beta gene rearrangements and allelic exclusion by the helix-loop-helix protein, E47.

Allelic exclusion of antigen-receptor genes is ensured primarily by monoallelic locus activation upon rearrangement and subsequently by feedback inhibition of continued rearrangement. Here, we demonstrated that the basic helix-loop-helix protein, E47, promoted T cell receptor beta (TCRbeta) gene rearrangement by directly binding to target gene segments to increase chromatin accessibility in a dosage-sensitive manner. Feedback signaling abrogated E47 binding, leading to a decline in accessibility. Conversely, enforced expression of E47 induced TCRbeta gene rearrangement by antagonizing feedback inhibition. Thus, the abundance of E47 is rate limiting in locus activation, and feedback signaling downregulates E47 activity to ensure allelic exclusion.

Fluorine-18 fluorodeoxyglucose positron emission tomography predicts tumor differentiation, P-glycoprotein expression, and outcome after resection in hepatocellular carcinoma.

PURPOSE: To investigate the diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for prediction of tumor differentiation, P-glycoprotein (P-gp) expression, and outcome in hepatocellular carcinoma (HCC) patients. EXPERIMENTAL DESIGN: Seventy HCC patients who underwent curative resection were prospectively enrolled in the study. FDG-PET was done 2 weeks preoperatively, and the standardized uptake value (SUV) and the tumor to nontumor SUV ratio (TNR) were calculated from FDG uptake. Tumor differentiation and P-gp expression were examined with H&E and immunohistochemical staining, respectively. RESULTS: SUV and TNR were significantly higher in poorly differentiated HCCs than in well-differentiated (P = 0.001 and 0.002) and moderately differentiated HCCs (P < 0.0001 and P < 0.0001). The percentage P-gp-positive area was significantly higher in well-differentiated HCCs than in poorly differentiated (P < 0.0001) and moderately differentiated HCCs (P = 0.0001). Inverse correlations were found between SUV and P-gp expression (r = -0.44; P < 0.0001) and between TNR and P-gp expression (r = -0.47; P = 0.01). Forty-three (61.4%) patients had postoperative recurrence. The overall and disease-free survival rates in the high TNR (> or =2.0) group were significantly lower than in the low TNR (<2.0) group (P = 0.0001 and 0.0002). In multivariate analysis, a high alpha-fetoprotein level (risk ratio, 5.46; P = 0.003; risk ratio, 8.78; P = 0.006) and high TNR (risk ratio, 1.3; P = 0.03; risk ratio, 1.6; P = 0.02) were independent predictors of postoperative recurrence and overall survival. CONCLUSIONS: The results suggest that preoperative FDG-PET reflects tumor differentiation and P-gp expression and may be a good predictor of outcome in HCC.

Primary osteosarcoma of the breast.

We report a case of primary osteosarcoma of the breast, which is a rare histological type of all breast tumors. A 58-year-old woman had noticed a right breast mass long before presenting to our hospital because it had gradually increased in size. The mass was bony-hard, 90 x 70 mm in size, and was located mainly in the upper outer quadrant of the left breast. Mammography demonstrated a round radiopaque mass with a shaggy outline. There were small bone metastases to the pelvis and scapula on bone radionuclide scan, but no other metastasis was observed with subsequent investigations. Modified radical mastectomy including axillary lymph node dissection was performed. Histologically, the excised tumor was consistent with extraskeletal osteosarcoma of the breast accompanied by lymph node metastses. In spite of adjuvant chemotherapy, the patient suffered a local recurrence four months later and died of aggressive multiple metastases 7 months after surgery.

[Three cases of advanced gastric cancer treated by TS-1 in combination with low-dose cisplatinum].

TS-1, a DPD inhibitory fluoropyrimidine, is a novel oral formation of 5-fluorouracil (5-FU). In patients with advanced gastric cancer, the response rate was reportedly over 40%. We report three cases of advanced gastric cancer treated using TS-1 in combination with a low-dose of cisplatinum (CDDP) that well responded. Case 1: A 62-year-old women underwent total gastrectomy. Ten weeks later, she suffered intestinal obstruction due to peritoneal recurrence of gastric cancer. Eighty mg of TS-1 in combination with bi-weekly administration of CDDP (10 mg) improved her intestinal obstruction. Case 2: A 50-year-old man suffered peritoneal recurrence of gastric cancer. Computed tomography (CT) showed intestinal obstruction, ascites, and hydronephrosis. After 100 mg of TS-1 in combination with bi-weekly administration of CDDP (20 mg) for 1 year, CT showed almost complete improvement of peritonitis carcinomatosa. Case 3: A 58-year-old man, who suffered advanced gastric cancer with peritonitis carcinomatosa, was administrated 100 mg of TS-1 in combination with bi-weekly administration of CDDP (20 mg). After 2 months of administration, remarkable improvement was observed in the upper gastrointestinal series. Adverse reactions, which were grade 1 for stomatitis, were observed only in case 1. All three patients are alive (case 1 and 2 have survived more than one year) and therapy is continuing. In conclusion, combined chemotherapy of TS-1 and low-dose CDDP was effective and well tolerable for advanced gastric cancer patients. It was suggested that effective biochemical modulation might be achieved by these two drugs.