Surgical outcomes of totally extraperitoneal repair for inguinal hernia: A retrospective multicenter propensity score-matched study.

BACKGROUND: Laparoscopic surgical approaches, including total extraperitoneal repair (TEP), have been widely accepted for inguinal hernia repair in Japan. However, there are limited data regarding recurrence after TEP in Japan, given the limited versatility of this procedure. This study retrospectively evaluated the rates of hernia recurrence after TEP and open mesh repair at multiple Japanese centers. METHODS: This retrospective study evaluated 1917 patients who underwent inguinal hernia repair at 32 institutions in the Oita prefecture between January 2014 and December 2015. Eligible patients were grouped according to whether they underwent TEP (1011 patients) or open mesh repair (636 patients). Propensity score matching was performed 1:1 (total: 1076 patients, 538 patients from each group). The outcomes of interest were recurrence, morbidity, and postoperative recovery. RESULTS: The TEP and open mesh repair groups had similar baseline characteristics. After propensity score matching, there was no significant difference between the two groups in terms of recurrence rate (TEP: 0.5% vs open mesh repair: 1.0%, P = .375). However, the TEP group had significantly longer operating times (median: 70.2 min vs 65.0 min, P < .001), significantly less blood loss (0-5.1 mL vs 0-20.4 mL, P < .001), and significantly shorter postoperative hospital stays (median: 5.0 days vs 6.4 days, P < .001). The overall incidences of morbidity were 6.2% in the TEP group and 7.2% in the open mesh repair group (P = .535). CONCLUSION: This multicenter retrospective study with propensity score matching revealed that the recurrence rates were similarly low for TEP and open mesh repair of inguinal hernia. Thus, a well-trained surgical team could use TEP as a standard procedure.

Serum matrix-metalloproteinase-1 is a bona fide prognostic marker for colorectal cancer.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the degradation of extracellular matrix components and are associated with invasion and metastasis. MMP proteins could be serum tumor markers or molecular targets in the treatment of malignancy. The purpose of the current study was to identify a prognostic serum marker in cases of colorectal cancer (CRC) prior to surgical intervention. MATERIALS AND METHODS: Laser microdissection and microarray analysis were used to characterize gene expression in 73 cases of CRC. We then focused on expression of MMP-1. We examined serum MMP-1 activity before resection in another subset of 75 cases of CRC to validate the clinical significance of MMP-1 as a prognostic marker in CRC after surgically curative operation. RESULTS: Disease-free survival was 51% in the MMP-1 high expression group and 81% in the low-expression group (P < .05). Survival was 52% in the MMP-1 high expression group and 90% in the low group (P < .05). In multivariate analysis for disease-free survival, MMP-1 and lymph node metastasis were significant independent prognostic indicators. In multivariate analysis of overall survival, serum MMP-1 level was the only significant independent indicator among factors. CONCLUSIONS: Within the MMP family of proteins, MMP-1 is not a cancer-specific protease. However, MMP-1 activity does predict the future course of progression of malignant cells. Thus, MMP-1, which is activated at the primary lesion and is found in serum, assists in the clinical diagnosis of CRC. It is also an important molecule for understanding the underlying mechanism of invasion and metastasis of CRC.

Saline replacement after local resection of the breast: a simple technique with good control and improved patient satisfaction.

BACKGROUND: Here we report a study on the use of saline replacement after local resection of the breast. Local resection of breast tissue is widely used in the treatment of breast cancer due to the development of imaging analysis technology such as mammography, ultrasound sonography, computed tomography, and magnetic resonance. Preserving the size and shape of the breast after treatment is beneficial for the patient, and deformity of the residual breast can be a serious problem. METHODS: Following resection, the subcutaneous tissue was sutured with 4-0 polydioaxanone, and a 20-G syringe was inserted through the skin into the hole. After suturing the skin with 4-0 nylon, an adequate volume of saline was injected. A conservative treatment group did not receive saline injections and was used as controls. We sent self-administered questionnaires to 60 patients who had undergone local resection of the breast and received 55 responses (92%). RESULTS: Saline replacement was performed in 28 of the 55 patients, and conservative treatment (no saline replacement) was performed in 27 patients. The average volume of injected saline was 46 ml (range, 5-150 ml). There were no statistically significant differences in skin irritation, pain, fatigue, or daily activity between the two groups, but the saline replacement group was more satisfied with the surgical scar (p < 0.05) and shape of the breast (p = 0.05) after surgery. CONCLUSIONS: Saline replacement after local resection of the breast is a simple technique that provides benefits for patients undergoing conservative surgery of the breast.

Clinicopathologic significance of KIAA1199 overexpression in human gastric cancer.

BACKGROUND: KIAA1199 is an inner-ear-specific gene which encodes KIAA1199 protein, the function of which is unknown. KIAA1199 might be a novel, positively regulated target of Wnt signaling. The aim of this study was to examine the expression of KIAA1199 in surgical specimens of gastric cancer to evaluate the clinical outcome. METHODS: The expression of KIAA1199 mRNA was studied by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), and the expression status was analyzed from the viewpoint of clinical and pathological factors. Univariate and multivariate analyses were performed. In addition, an immunohistochemical study was performed in the selected samples. RESULTS: A significantly higher expression of KIAA1199 messenger RNA (mRNA) was recognized in tumor tissue compared with that of paired normal tissues (P < 0.01). The cases were divided into high- (n = 39) and low-expression (n = 71) groups according to KIAA1199 expression status in the tumor. The overall 5-year survival rate was significantly better in the KIAA1199 low-expression group (61.2%) than in the high-expression group (29.6%) (P < 0.05). Clinicopathological factors such as well and moderately tumor differentiation, positive lymph node metastasis, positive distant metastases, and positive peritoneal dissemination were more frequently observed in the high-expression group than in the low-expression group (P = 0.02, 0.08, 0.01, and 0.03, respectively). KIAA1199 expression was an independent prognostic factor (P = 0.03). CONCLUSIONS: KIAA1199 was highly expressed in gastric cancer, and was associated with prognosis and lymph node metastasis in multivariate analyses. Taken together, KIAA1199 may be a novel gene that plays an important role in progression of gastric cancer.

Subcutaneous gluteal metastasis from gastric cancer: case report and clinicopathologic analysis of 50 Japanese patients.

Skin metastasis from gastric cancer is rare. We report a case of gluteal skin metastasis from gastric cancer. A 74-year-old woman underwent curative gastrectomy for advanced gastric cancer. Thirty-six months after surgery, follow-up abdominal computed tomography showed a subcutaneous gluteal tumor, and surgical extirpation was performed. Histopathologic examination of the resected tumor revealed poorly differentiated adenocarcinoma, coinciding with the histopathologic diagnosis of the resected gastric cancer. Further systemic evaluation revealed a lung metastasis and left supraclavicular lymph node metastasis. The patient was treated with chemotherapeutic reagents. However, she died of the disease 9 months after the diagnosis of skin metastasis. We reviewed the cases of 50 Japanese patients with skin metastasis from gastric cancer and analyzed the clinicopathologic features.

Clinical significance of low expression of Prostasin mRNA in human gastric cancer.

BACKGROUND: Prostasin is considered to have suppressive activities against tumor progression. The aim of this study was to clarify its clinical significance in gastric cancer. METHODS: Tumor and the corresponding normal samples were prepared from a total of 108 gastric cancer patients. Prostasin expression was assayed by real time reverse transcription (RT)-polymerase chain reaction (PCR) and by immunohistochemistry. Epigenetic silencing of the expression was examined by demethylation treatment. Survival was examined in Kaplan-Meier plots, and the relationship between its expression and clinicopathologic factors was statistically analyzed. RESULTS: Prostasin mRNA expression was significantly down-regulated in tumor tissues. Immunohistochemistry confirmed loss of Prostasin expression in gastric cancer. Gastric cancer cell lines that did not express Prostasin mRNA retrieved its expression following demethylation treatment. In those patients whose tumor expressed Prostasin mRNA at reduced levels, we observed shorter survival (P = 0.0110), due to a higher incidence of lymph node metastasis (P = 0.0087), lymphatic permeation (P = 0.0542) and venous permeation (P = 0.0492). CONCLUSIONS: Prostasin mRNA expression was frequently down-regulated in gastric cancer. Loss of expression might be regulated by epigenetic factors, contributing to the shorter survival. Reduced Prostasin mRNA expression might be a novel indicator for biological aggressiveness in gastric cancer.

Risk factors for morbidity and mortality following abdominal surgery in patients on maintenance hemodialysis.

BACKGROUND/AIMS: Major surgery in patients on maintenance hemodialysis is associated with an increased incidence of postoperative complications. We conducted the retrospective study to identify risk factors for morbidity and mortality after abdominal surgery in hemodialysis patients. METHODOLOGY: Subjects were 28 consecutive patients on maintenance hemodialysis who underwent abdominal surgery for gastrointestinal disease. They were classified into two groups according to the presence (n = 11) or absence (n = 17) of postoperative complications. Clinical, laboratory, and operative data were obtained from medical records and compared between the two groups. RESULTS: Overall morbidity and mortality rates were 39% (11/28) and 14% (4/28), respectively. The most frequent morbidity was wound complication (6/28). There were statistically significant differences between the patients with and without postoperative complications in the blood urea nitrogen concentration (41.6 vs. 27.5 mg/dL, P < 0.05), total protein level (5.8 vs. 6.9 g/dL, P < 0.01), and hematocrit level (25.7 us. 31.1%, P < 0.05). There were four hospital deaths. All four patients underwent emergency surgery for perforation of the gastrointestinal tract. CONCLUSIONS: A poor surgical outcome after abdominal surgery in patients on maintenance hemodialysis was associated with a high concentration of blood urea nitrogen, hypoproteinemia, severe anemia, and emergency surgery. These factors should be considered in the perioperative management of chronic hemodialysis patients undergoing abdominal surgery.

Inactivation of PTEN is associated with a low p27Kip1 protein expression in breast carcinoma.

BACKGROUND: It was previously demonstrated that PTEN protein expression is reduced in 67 of 236 (28%) breast carcinomas. Recent experimental studies suggested that the cell cycle inhibitor p27Kip1 (p27) is a downstream mediator through which PTEN negatively regulates cell cycle progression. METHODS: The immunohistochemic expression of p27 and PTEN protein expression was evaluated in a series of 228 invasive ductal carcinomas of the breast. RESULTS: PTEN protein expression was found to have decreased in 65 of 228 (29%) cases, while the nuclear accumulation of p27 protein was low in 99 of 228 (43%) cases. A reduced PTEN protein expression correlated significantly (P = 0.0214) with a low p27 protein expression. Univariate analysis indicated that the patients demonstrating a combined decrease in PTEN and p27 protein expression have a significantly (P = 0.0044) worse disease-free survival (DFS) than those with other combinations of these two protein expression patterns, while multivariate analysis indicated that the lymph node status, MIB-1 counts, and the combination of PTEN/p27 protein expression (P = 0.0452) are independently significant prognostic factors for DFS. CONCLUSIONS: A reduced PTEN protein expression correlated significantly with a low p27 protein expression in breast carcinoma. The finding that the patients with a combined decrease in both protein expressions had a poor prognosis thus suggests that a combined loss of PTEN and p27 function is associated with an aggressive phenotype in breast carcinoma.

Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density.

Stromal cells, within and around the tumor, as well as tumor cells are both involved in angiogenesis which is an important step in tumor growth and metastasis. Among such stromal cells, macrophages are known to play various roles in tumor angiogenesis and have thus been called tumor-associated macrophages (TAMs). The TAM density, vascular endothelial growth factor (VEGF) expression and the microvessel density (MVD) were immunohistochemically evaluated in 249 paraffin-embedded sections of invasive ductal carcinoma of the breast. The TAM density and MVD were assessed as the average density of three hot spots at a magnification of x400 and x200, respectively. The TAM density showed a significant correlation with both the VEGF expression and MVD, while a significant correlation was also found between the VEGF expression and MVD. The TAM density was also associated with the nuclear grade, estrogen receptor status and MIB-1 count. Patients with a high TAM density had a significantly (p=0.0025) worse disease-free survival (DFS) prognosis than those with a low TAM density, while univariate analyses also indicated both the MVD (p<0.0001) and VEGF expression (p=0.0152) to be prognostic factors for DFS. A multivariate analysis indicated MVD (p=0.0057), as well as lymph node metastasis and the MIB-1 count, to be independently significant prognostic factors for DFS. In conclusion, the present study demonstrated a close association between TAM infiltration and both the VEGF expression and MVD. The prognostic significance of MVD was the strongest among these three factors in breast cancer. These findings suggested that the prognostic implications of TAM infiltration are due to the involvement of TAMs in tumor angiogenesis.

Prognostic implication of p53 protein expression in relation to nuclear pleomorphism and the MIB-1 counts in breast cancer.

BACKGROUND: A close correlation of the p53 protein expression to nuclear pleomorphism and proliferative activity in breast cancer has been reported. The prognostic implications of p53 protein expression, however, in relation to nuclear pleomorphism and proliferative activity in breast cancer remain controversial. PATIENTS AND METHODS: Nuclear pleomorphism and immunohistochemical reactivity for p53 protein and MIB-1 were evaluated on formalin-fixed paraffin-stored sections from 250 patients with breast cancer for whom the median follow-up duration was 6.4 years. RESULTS: p53 protein expression was positive in 66 (26.4%) of 250 cases. Nuclear pleomorphism was grade I or II in 169 (67.6%) cases and grade III in 81(32.4%)cases. The MIB-1 counts were more than 10% in 102 (40.8%) cases and less than 10% in 148 (59.2%) cases. There was a close correlation between p53 protein expression and nuclear pleomorphism (p<0.0001) and between p53 protein expression and MIB-1 counts (p<0.0001). Univariate analyses showed the 66 cases with positive p53 protein expression to have a significantly (p=0.0284) worse disease free survival (DFS) than the 184 cases with negative p53 protein expression. A multivariate analysis, however, on the variables including all of p53 protein expression, nuclear pleomorphism and MIB-1 counts indicated the MIB-1 counts (p=0.0041) as well as the lymph node status to be independently significant factors for DFS, while neither p53 protein expression nor nuclear pleomorphism were independently significant factors for DFS. CONCLUSION: The present study demonstrated that the p53 protein expression, nuclear pleomorphism and MIB-1 counts all demonstrated prognostic significance for breast cancer, while the most significant prognostic indicator among these three biological parameters was the MIB-1 counts.

Immunoactivative role of indoleamine 2,3-dioxygenase in human hepatocellular carcinoma.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catabolic enzyme. Recent studies have focused on the immunoregulatory role of IDO in mononuclear cells. The role of IDO in hepatocellular carcinoma (HCC) cell lines and HCC patients was examined. METHODS: The expression of IDO mRNA in peripheral blood mononuclear cells (PBMC) cocultured with HCC cell lines was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The cytotoxicity of PBMC against HCC cell lines cultured with and without IDO inhibitor was examined by sodium 51chromate release assay. In the tumor portion of 21 HCC patients, the expression of mRNA of IDO, tryptophan 2,3-dioxygenase and some cytokines was detected by RT-PCR. The expression and distribution of IDO protein in HCC specimens was analyzed by immunohistochemistry. RESULTS: The IDO mRNA was strongly induced in PBMC cocultured with HepG2 and PLC/PRF/5 and faintly induced in PBMC cocultured with Hep3B and HuH7. The cytotoxicity of PBMC against HCC cell lines was directly proportional to the level of expression of IDO mRNA and reduced by IDO inhibitor. The expression of IDO mRNA in the tumor portion was detected in 12 out of 21 HCC patients. Immunohistochemistry revealed that the IDO-positive cells were identified to be tumor-infiltrating cells, not tumor cells. The IDO mRNA correlated significantly with gene expression of interferon-gamma, tumor necrosis factor-alpha and interleukin-1beta. The recurrence-free survival rate of IDO-positive HCC patients was significantly higher than that of IDO-negative HCC patients (P<0.05). CONCLUSIONS: These results suggest that IDO is a necessary enzyme for anticancer immune reactions of tumor-infiltrating cells.

Inhibition of indoleamine 2,3-dioxygenase suppresses NK cell activity and accelerates tumor growth.

Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, is induced under various pathological conditions, including viral and bacterial infection, allograft rejection, cerebral ischemia, and tumor growth. We have previously reported that the expression of IDO mRNA was increased in some clinical cases of hepatocellular carcinoma in which the recurrence-free survival rate in these IDO-positive patients was significantly higher than that in patients without IDO mRNA induction in tumors. Additionally, IDO expressed in tumors was localized not to the tumor cells but instead to tumor-infiltrating cells by immunohistochemistry. In this study, in order to elucidate the mechanisms underlying anti-tumor effect of IDO, we investigated whether IDO inhibitor (1-methyl-dl-tryptophan, 1MT) affects the growth of subcutaneous B16 tumors in mice. Subsequently, the activity of natural killer (NK) cells was investigated under the conditions of inhibited IDO activity in vivo and in vitro. IDO mRNA expression of B16 cells, B16 subcutaneous tumor, sprenocytes of mice, and human NK cells were studied by reverse transcription-polymerase chain reaction. B16 subcutaneous tumor growth with or without IDO inhibition was observed and cytotoxic activity of NK cells were investigated under the conditions of inhibited IDO activity in vivo and in vitro. IDO mRNA was expressed in B16 subcutaneous tumor, splenocytes of tumor bearing mice, co-cultured splenocytes with B16, and human NK cells. On day 14, after injection of B16 melanoma cells, the sizes of tumors in IDO-inhibited mice were significantly larger than those in control mice. The cytotoxic activity of mice NK cells was reduced by IDO inhibition in vivo. In vitro inhibition of IDO, NK activity was reduced in dose-dependent manner of 1MT. In conclusion, these results indicated that IDO plays an important role in anti-tumor immunity by regulating cytotoxic activity of NK cells.

Potent stimuli combined with lipopolysaccaride and IFNgamma may improve immunotherapy against HCC by increasing the maturation and subsequent immune response of the dendritic cells.

Dendritic cells (DCs)-based immunotherapy is a new strategy for cancer treatment and has been used in some clinical trials against cancer, including melanoma, and has shown promising results. However, the conventional protocol of DC immunotherapy may not be effective for hepatocellular carcinoma (HCC) because of impaired DC maturation in HCC patients. In order to induce sufficient maturation on HCC derived DCs, we tested various stimuli such as tumor necrosis factor (TNF) alpha, lipopolysaccharide (LPS), interferon (IFN)gamma and CD40-ligand. In stimulating with LPS + IFNgamma, DCs of HCC patients expressed significantly high levels of CD86 (p < 0.05) and produced high levels of IL-12 as compared to DCs stimulated with TNFalpha alone. Moreover, it showed better ability to stimulate allogeneic mixed lymphocyte reaction. It concluded that LPS and IFNgamma was the best combination of stimuli for induction of sufficient maturation on DCs derived from HCC.

A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer.

BACKGROUND/AIMS: To evaluate the safety and feasibility of immunotherapy based on autologous dendritic cells (DC) for patients with unresectable primary liver cancer (PLC). METHODS: A total of ten patients were enrolled and immunized with DCs. Autologous DCs were generated ex vivo in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Cells were then pulsed with tumor lysate (TL), tumor necrosis factor-alpha (TNF-alpha) and keyhole limpet hemocyanin (KLH). Non-adherent cells were collected on day 9 and cells were administered into the inguinal lymph node. Each patient received 1-10 x 10(6) cells four times at weekly intervals. RESULTS: Immunization was well tolerated in all patients without significant toxicity. DC vaccination induced delayed-type hypersensitivity (DTH) against KLH in seven out of ten patients. In one patient, one of the two liver tumors (tumor in segment 7, 13 mm in diameter) decreased in size to 7 mm and showed necrotic change on computed tomography examination after eight immunizations. In two patients, serum levels of tumor markers decreased after vaccination. CONCLUSION: The present clinical trial suggested that immunization by TL-pulsed DCs is feasible in patients with unresectable PLC without any toxicity. Further improvement in the clinical results of immunotherapy might be expected by modifying the therapeutic protocol.

Antitumor and antivascular effects of AC-7700, a combretastatin A-4 derivative, against rat liver cancer.

BACKGROUND: Unlike the many chemotherapeutic agents that do not effectively stop blood flow or induce necrosis in hepatocellular carcinoma, AC-7700 has been shown to inhibit tubulin polymerization and selectively stop tumor blood flow. The aim of this study was to elucidate the antivascular and antitumor effects of AC-7700 on rat hepatoma. METHODS: AH-130 cells, a rat hepatoma cell line, were solidified and implanted into the liver of Donryu rats. Vascularity of the liver tumor was directly identified by in-vivo fluorescence microscopy from 0 to 60 min after the injection of 10 mg/kg AC-7700. To observe the antivascular effect of AC-7700, the vascular density of the tumor was measured and assessed as the ratio of preinjection to postinjection values. The antitumor effects were evaluated with histopathologic findings and analysis of animal survival. RESULTS: In-vivo microscopic observation showed that tumor perfusion diminished within 30 min after AC-7700 administration. Vascular density in the AC-7700 group was significantly less than that in the control group at 60 min (AC-7700, 26.3 +/- 16.4%; control, 88.5 +/- 9.2%; P < 0.001). After AC-7700 injection, marked necrosis of tumor cells was observed histologically, and tumor area was decreased significantly (AC-7700, 11.5 +/- 15.4 mm2; control, 43.5 +/- 18.3 mm2; P < 0.05). The survival rate (50%) of the AC-7700 group animals was better than that of the control group (0%; P < 0.01). CONCLUSION: Markedly decreased tumor perfusion was induced by AC-7700 within 30 min, and this decrease may have contributed to the tumor necrosis and favorable outcome in the treatment group. AC-7700 appears to be a promising agent for the treatment of hepatocellular carcinoma.

Microwave coagulation therapy accelerates growth of cancer in rat liver.

BACKGROUND/AIMS: Although microwave coagulation therapy (MCT) has been performed for liver cancer, there has been no report examining the influence of this therapy on the growth of possible remnant cancer. METHODS: A solid cube of AH-130 cells (ascites hepatoma cell line) was implanted into the left lateral lobe of the rat liver. Five days later, MCT was applied to the middle liver lobe of these rats. Tumor growth and cytokine levels in plasma and the liver were compared between rats that underwent MCT and rats that did not. RESULTS: The mean tumor weight in the MCT group (222.6+/-51.5 mg, mean+/-SD) was significantly greater than that in the control group (126.7+/-19.7 mg, P<0.01) at postoperative day (POD) 5. Immunohistochemistry for anti-proliferating cell nuclear antigen showed the labeling index in the MCT group (90.4%) to be higher than that in the control group (76.7%, P<0.01). Liver basic fibroblast growth factor and transforming growth factor-beta 1 levels in the MCT group on POD 3 were significantly higher than levels in the control group. CONCLUSIONS: The present study suggests the clinically important finding that MCT accelerates the growth of small residual tumors in the liver.