Hisanori Shiomi

MR-guided microwave ablation for malignancies

Since we first successfully performed magnetic resonance (MR)-guided microwave coagulation therapy for liver tumors in January 2000, we have developed new MR-compatible instruments, laparoscopy and thoracoscopy, which have enabled us to approach liver tumors located just below the diaphragm and in contact with other organs. We have customized software for an MR gradient-based tracking system for the easy detection of the location and orientation of treatment area and for the real-time display of MR temperature maps with a scale bar. Navigation software was customized to enable real-time image navigation. The reformatted images in the two perpendicular planes complemented the limitations of real-time MR imaging. Evaluation software, “FootPrint,” was useful for distinguishing treated areas from untreated areas and improved the evaluation of treatment accuracy. These newly developed MR-guided systems that utilize microwave have played important roles in more accurate, safer, and easier treatment for liver tumors. We have treated 184 patients using these new techniques without major complications.

Expression of interleukin 1-like cytokine interleukin 33 and its receptor complex (ST2L and IL1RAcP) in human pancreatic myofibroblasts

Objective Interleukin 33 (IL33) is a cytokine belonging to the IL1 family and it binds to a complex of the ST2L/IL1 receptor accessory protein (IL1RAcP). To define the role of IL33 in fibrogenesis of the pancreas, the expression of IL33, ST2L and IL1RAcP was examined in chronic pancreatitis tissues. The effects of IL33 on the functions of human pancreatic myofibroblasts were also investigated. Methods Tissue samples were obtained surgically. The expression of IL33, ST2L and IL1RAcP was evaluated by standard immunohistochemical procedures. Messenger RNA expression for IL33, ST2L and IL1RAcP was analysed by northern blotting and real-time PCR analyses, and protein expression was assessed by western blotting and ELISA. Cell proliferation and migration were assessed by a 3H-thymidine incorporation assay and the modified Boyden chamber assay, respectively. Results IL33, ST2L and IL1RAcP were expressed by α-SMA-positive myofibroblasts in the fibrosis of chronic pancreatitis. In human pancreatic myofibroblasts, IL33 was weakly immunoexpressed without any stimuli, and this was markedly enhanced by IL1β, tumour necrosis factor α (TNFα) and lipopolysaccharide (LPS) via the mitogen-activated protein kinase (MAPK)-dependent AP-1 activation pathway. ST2L mRNA was weakly detected in unstimulated cells, and IL4 and interferon γ (IFNγ) strongly enhanced ST2L expression via STAT6 and STAT1 signalling, respectively. IL33 rapidly induced the phosphorylation of MAPKs and IκBα, and enhanced the expression of inflammatory mediators (IL6, IL8, IP-10, Gro-α, Gro-β and MCP-1) in IL4- or IFNγ-pretreated cells. IL33 stimulated the proliferation and migration of pancreatic myofibroblasts. Conclusions IL33 and its receptor complex (ST2L and IL1RAcP) constitute a novel signalling system which may play an important role in the pathogenesis of chronic pancreatitis.

Cellular Distribution and Clinical Value of Urokinase-Type Plasminogen Activator, Its Receptor, and Plasminogen Activator Inhibitor-2 in Esophageal Squamous Cell Carcinoma

To assess the participation of the plasminogen activation system in the invasiveness of esophageal squamous cell carcinoma, we performed immunohistochemistry and in situ hybridization to study the distribution of a urokinase-type plasminogen activator (u-PA), u-PA receptor (u-PAR), and plasminogen activator inhibitor-2 (PAI-2). u-PA and PAI-2 were expressed heterogeneously in cancer cells, and restricted expression was found in stromal cells, especially fibroblasts, that were located in the immediate proximity of the cancerous cells. u-PAR was found only in cancer cells located at the periphery of tumors. Compared with patients with u-PA-negative cancer cells, patients with u-PA-positive cancer cells more frequently showed a neoplastic invasion beyond the muscularis propria and lymph node metastases. They also showed a significantly shorter 5-year overall survival. Patients with PAI-2-positive fibroblasts showed significantly lower levels of local invasiveness, represented by a neoplastic invasion beyond the muscularis propria, than those who were PAI-2 negative. Our results suggest that the expression of u-PA in esophageal squamous cell carcinoma is predictive of poor survival, whereas the expression of PAI-2 in the fibroblasts surrounding them is protective. An analysis of u-PA and PAI-2 expression in cancer cells and their surrounding fibroblasts may be useful for predicting the prognosis of patients with esophageal squamous cell carcinoma.

Thoracoscopy-assisted magnetic resonance guided microwave coagulation therapy for hepatic tumors.

BACKGROUND Microwave coagulation therapy (MCT) has become a safe and effective modality with which to treat hepatic tumors; MCT can be applied percutaneously, laparoscopically, thoracoscopically, and during laparotomy. When combined with magnetic resonance (MR) imaging, MCT can be used to treat hepatic tumors located in the subdiaphragmatic area that are difficult to approach by ultrasound, because of the overlaying lower lung field. METHODS To determine the usefulness of thoracoscopy-assisted interventional MR-MCT (T-IVMR-MCT, n = 73), we compared patients with hepatic tumors that were treated with percutaneous IVMR-MCT (P-IVMR-MCT, n = 69) and with T-IVMR-MCT. RESULTS None of patient background, complication and recurrence rate, or length of hospital stay significantly differed between the 2 groups. CONCLUSIONS IVMR-MCT is a useful modality for treating hepatic tumors. Especially when tumors are located at the hepatic dome, T-IVMR-MCT was minimally invasive, while it appears to improve targeting of peridiagmatic hepatic lesions and has a complication profile similar to P-IVMR-MCT.

Handlebar hernia with intra-abdominal extraluminal air presenting as a novel form of traumatic abdominal wall hernia : Report of a case

An 18-year-old male was admitted to our Emergency Department with a traumatic abdominal wall hernia (TAWH) of the left lower quadrant (LLQ) after suffering hypogastric blunt injury and urogenital lacerations in a motorcycle accident. Upright chest X-ray showed a small amount of right infradiaphragmatic free air, and a computed tomographic (CT) scan demonstrated an abdominal wall hernia. At surgery, no impairment was found in the digestive tract, and an abdominal herniorrhaphy was performed. It is suggested that the free air had passed through a connection between the scrotal laceration and the contralateral abdominal defect via the subcutaneous space and was palpated as emphysema. This is a new type of TAWH, which suggests that blunt abdominal trauma may result in negative pressure in the subcutaneous and peritoneal cavity, and this could reflect the pathophysiology of TAWH.

Cytogenetic heterogeneity and progression of esophageal squamous cell carcinoma.

It is widely believed that most human tumors, including esophageal squamous cell carcinoma (ESCC), arise through multistep genetic and cytogenetic alterations. The time sequence of these alterations, however, is still unknown. The present study was designed to differentiate common early changes from uncommon later ones with combined comparative genomic hybridization (CGH) and ploidy analyses in multiple or single samples of 12 ESCCs. We first demonstrated that the mean copy numbers of chromosomes 3 and 11, determined directly by fluorescence in situ hybridization, showed linear correlation with the mean copy numbers calculated from the G/R ratio of CGH and DNA ploidy (R(2)=0.714, P<0.0001). On this basis, we estimated the absolute copy numbers of chromosomal parts by applying the ploidy-dependent threshold criteria to the G/R ratio data after the criteria were corrected by the percentage of tumor cells in each sample. One-copy changes in the DNA-diploid stage may give large shifts of the G/R ratio, even after tetraploidization, whereas those after tetraploidization undergo small shift. Using the tumors with multiple samples, it was actually demonstrated that most of the gains common to the samples in individual tumors showed the large shifts. Though early changes varied from tumor to tumor in the nine informative cases, it was found that gains of 3q (5/7: number of cases with large-shift 3q+/total number of cases with 3q+), 8q (3/4), 11q13 (4/5), and 14q (3/4) were early events, while losses of 3p (2/8), 5q (1/5), 13q (1/5), and 21q (1/5), and gains of 1p (1/4) and Xq (1/4) were later events in progression of individual tumors.

Non-Epstein-Barr virus associated lymphoepithelioma-like carcinoma of the inferior common bile duct

A carcinoma displaying undifferentiated features with dense lymphoplasmacytic infiltration is defined as a lymphoepithelioma-like carcinoma (LEC), and some of LEC is associated with Epstein-Barr virus (EBV). All of the 13 previously reported cases of LEC of the biliary system were intrahepatic in location. Herein, we describe the first case of LEC of the inferior common bile duct. A 68-year-old Japanese man, who had been previously treated for hepatocellular carcinoma using microwave coagulation therapy, was found to have tumors of the common bile duct and pancreas head. Histopathological study of the resected tumor showed solid or cohesive nests of large undifferentiated cells with irregular large vesicular nuclei and nucleoli. Around the tumor cell nests, dense lymphoplasmacytic infiltration was observed. Focal glandular differentiation (approximately 5%) was also present. These histopathological features corresponded morphologically to LEC. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) 7, CK 19 and CA19-9, but negative for CK 20 and Hep Par 1. In situ hybridization for Epstein Barr virus early small RNAs disclosed no nuclear signal in tumor cells. Therefore, a diagnosis of non-EBV-associated LEC of the inferior common bile duct was made. Although the prognosis of the biliary LEC is thought to be better than that of conventional cholangiocarcinoma, the differences in prognosis between EBV-positive and -negative cases have not yet been established. Therefore, additional case studies will be needed to clarify the clinicopathological features of LEC of the biliary tract.

Resting energy expenditure in patients undergoing pylorus preserving pancreatoduodenectomies for bile duct cancer or pancreatic tumors

We measured the energy expenditure weekly in patients undergoing a pylorus preserving pancreatoduodenectomy for bile duct cancer or pancreatic tumors. Twelve patients (5 women and 7 men; mean age 70.1 years) were enrolled in this study, and their resting energy expenditure levels were determined by indirect calorimetry. In these patients, a significant correlation was observed between the measured resting energy expenditures and the predicted resting energy expenditures calculated by the Harris-Benedict equation. The resting energy expenditures measured before surgery were almost the same as the predicted resting energy expenditures (measured resting energy expenditure: 22.4 ± 3.9 kcal/kg/day vs predicted resting energy expenditure: 21.7 ± 2.0 kcal/kg/day). The measured resting energy expenditure/predicted resting energy expenditure ratio, which reflects the stress factor, was 1.02 ± 0.10. After the pylorus preserving pancreatoduodenectomy, a significant increase in energy expenditure was observed, and the measured resting energy expenditure was 25.7 ± 3.5 kcal/kg/day on postoperative day 7 and 25.4 ± 4.9 kcal/kg/day on postoperative day 14. The measured resting energy expenditure/predicted resting energy expenditure ratio was 1.16 ± 0.14 on postoperative day 7, and 1.16 ± 0.18 on postoperative day 14 respectively. In conclusion, patients undergoing a pylorus preserving pancreatoduodenectomy showed a hyper-metabolic status as evaluated by their measured resting energy expenditure/predicted resting energy expenditure ratio. From our observations, we recommend that nutritional management based on 30 kcal/body weight/day (calculated by the measured resting energy expenditure×activity factor 1.2–1.3) may be optimal for patients undergoing a pylorus preserving pancreatoduodenectomy.

Prognostic role of CD10⁺ myeloid cells in association with tumor budding at the invasion front of colorectal cancer.

The expression of CD10 in tumor cells has been reported to correlate with liver metastasis in colorectal cancer (CRC). However, fibroblasts and immune cells positive for CD10 at the tumor invasion front have not been comprehensively studied. We classified CD10 expression patterns into three types of cells, tumor cells (tCD10), stromal myofibroblasts (sCD10), and immune cells (iCD10), and investigated their correlation with the expression of transforming growth factor‐β (TGF‐β1) protein and tumor budding grade. Several cell surface markers were stained to detect the phenotype of iCD10+ cells, including CD3, CD20, CD11b, CD14, CD15, and CD163. Specimens and follow‐up data of 206 CRC patients were examined. In multivariate analysis, iCD10 could be an independent prognostic factor for both recurrence‐free survival and overall survival in stage I–III CRC (hazard ratio, 2.522 [1.299–4.896], P = 0.006; 2.890 [1.357–6.157], P = 0.006, respectively). The expression of sCD10 and iCD10 was strongly correlated with TGF‐β1 expression in tumor cells and tumor budding grade. The phenotype of iCD10+ cells was CD11b+ and CD15+ granulocytes. The infiltration of sCD10+ fibroblasts and iCD10+ granulocytes at the tumor invasion front might interact with TGF‐β1 protein expression and enhance tumor budding grade. The expression level of iCD10 at the tumor invasion front represented an independent prognostic biomarker in stage I–III CRC and could be integrated into a new staging system. (Cancer Sci 2011; 102: 1724–1733)

Matrix metalloproteinase-3 secretion from human pancreatic periacinar myofibroblasts in response to inflammatory mediators.

Objectives: Matrix metalloproteinases (MMPs) play roles in the pathophysiology of pancreatic disorders. However, the regulation of MMP-3 secretion in the pancreas remains unclear. In this study, we assessed the expression of MMP-3 in human pancreatic periacinar myofibroblasts. Methods: MMP-3 secretion and MMP-3 mRNA expression were determined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. Results: In human pancreatic myofibroblasts, MMP-3 secretion and mRNA expression were induced by interleukin (IL)-17, IL-1&bgr;, and tumor necrosis factor (TNF) -&agr;, respectively. The effects of IL-17 were detected as similar in extent to those induced by IL-1&bgr; or TNF-&agr;. Costimulation by IL-17 plus IL-1&bgr; and/or IL-17 plus TNF-&agr; induced a synergistic increase in MMP-3 secretion, although the costimulatory effects of these combinations were not detected in tissue inhibitor of matrix metalloproteinase-1 secretion. Adenovirus-mediated transfer of a stable form of I&kgr;B&agr; markedly inhibited the effects of IL-17, IL-1&bgr;, and TNF-&agr;. Mitogen-activated protein kinase inhibitors (U0126, PD098059, and SB203580) also blocked MMP-3 secretion. These findings indicate a role for nuclear factor-&kgr;B and mitogen-activated protein kinases in cytokine-induced MMP-3 secretion. Conclusions: Pancreatic periacinar myofibroblasts actively secrete MMP-3 in response to IL-17, IL-1&bgr;, and TNF-&agr;. Pancreatic myofibroblasts may play an important role in extracellular matrix turnover via MMP-3 secretion in the pancreas.Abbreviations: IL - interleukin, TNF - tumor necrosis factor, ECM - extracellular matrix, NF-&kgr;B - nuclear factor-&kgr;B, MAP kinase - mitogen-activated protein kinase, ELISA - enzyme-linked immunosorbent assay, MMP - matrix metalloproteinase, TIMP - tissue inhibitor of matrix metalloproteinase