Graduate School of Medicine

Epithelioid hemangioendothelioma (EH) of the liver is a rare tumor and is difficult to differentiate from cholangiocellular carcinoma or metastatic liver tumor on image diagnosis. A case of curatively resected EH of the liver is reported. A 48-year-old woman was admitted because she had a mass in the liver. Cholangiocellular carcinoma was suspected preoperatively. Right trisegmentectomy of the liver, combined with bile duct resection and portal vein resection and reconstruction, was performed. Characteristic macro-and microscopic findings of the resected specimen revealed EH of the liver. The patient has survived for more than 6 years without recurrence. Because of the tendency of EH of the liver to appear in multiple or scattered forms, only 12 cases of resection for EH have been reported.

BACKGROUND. Chemoradiotherapy is widely used for patients with locally advanced pancreatic carcinoma. The purpose of this study was to clarify the efficacy and feasibility of chemoradiotherapy with more intensive radiotherapy in these patients, using a combination of intraoperative radiotherapy (IORT), conformal external-beam radiaotherapy (EBRT), and protracted 5-fluorouracil (5-FU).

The relationship between overexpression of glypican (GPC)-3 that is specific for hepatocellular carcinoma (HCC) and the prognosis has not yet been clarified. We attempted to determine the expression profile of GPC3 in association with the clinicopathological factors by immunohistochemical analysis in HCC patients and investigated the potential prognostic value of GPC3 by comparing the survival rate between the GPC3-positive and GPC3-negative HCC patients. Primary HCC tissue samples (n = 107) obtained from patients who had undergone hepatectomy between 2000 and 2001 were analyzed. GPC3 expression was less frequently observed in welldifferentiated HCC than in moderately and poorly differentiated HCC, the difference in the frequency being statistically significant. GPC3-positive HCC patients had a significantly lower 5-year survival rate than the GPC3-negative HCC patients (54.5 vs 87.7%, P = 0.031). Among 80 of the 107 (74.6%) patients with initial treatment who underwent hepatectomy, none of GPC3-negative HCC patients (n = 16, 20.0%) died during the follow-up period. No deaths were noted in the GPC3-negative HCC patients among the 71 (88.7%) patients with moderately and poorly differentiated HCC. Multivariate analysis identified GPC3 expression (P = 0.034) as an independent prognostic factor for the overall survival. We showed that GPC3 expression is correlated with a poor prognosis in

Tumor-associated macrophages (TAMs) are candidate histological factors in invasive ductal carcinoma (IDC) of the pancreas. Tumorassociated macrophages can be affected by cancer-related inflammation and pancreatitis and interact with important invasive behavior in a recurrent manner in pancreatic IDC. These features may help elucidate the aggressiveness of pancreatic IDC. The aim of this study was to characterize TAMs in pancreatic IDC in comparison with chronic pancreatitis (CP) and to reveal TAM-related factors and the clinical impact of TAMs. CD68 (a pan-macrophage marker) and CD204 (an M2 macrophage marker) immunohistochemistry was carried out in pancreas head specimens from 107 IDC cases and 11 CP cases. Immunopositive cell areas were calculated at the periphery and center of the tumor. The distributions of macrophages in IDC and CP and the relationship between TAMs and histological tumor factors, survival, and recurrence were evaluated. Macrophages were more frequently observed in the lesion periphery than the center in IDC and CP. The density of macrophages was elevated in IDC compared to CP. Dense M2 macrophages at the tumor periphery were frequently seen in large tumors and showed an independent impact on overall survival and disease-free time. Early recurrence in the liver or the local manipulated area was associated with high accumulation of peripheral M2 macrophages. More M2 macrophages were seen in IDC than in CP in both the periphery and the center. High numbers of peripheral M2 macrophages were associated with large tumor size, early recurrence in the liver, local recurrence, and shortened survival time in patients with pancreatic IDC. (Cancer Sci 2012; 103: 2012-2020 T he prognosis of patients undergoing resection for pancreatic invasive ductal carcinoma (IDC) remains poor. Histological studies have been carried out to elucidate the aggressiveness of pancreatic IDC and have revealed prognostic factors including tumor size, lymph node involvement, nerve plexus invasion, positive resected margin, and low tumor grade. Tumor-associated macrophages (TAMs) have recently been reported as a candidate factor in poor prognosis. Macrophages are the most abundant cancer stromal cells involved in the host immune system, and TAMs have been found to play important roles in tumorigenesis, angiogenesis, matrix remodeling, and metastasis. Tumor-associated macrophages have a prognostic impact in prostate, breast, and lung cancers, as well as pancreatic IDC. The heterogeneity of macrophages has been discussed with regard to their different responses to various microenvironmental stimuli. Macrophages are classically activated towards the M1 phenotype by lipopolysaccharide and interferon-c. M1 macrophages are characterized by high expression of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-12, and tumor necrosis factor. Alternatively, macrophages are activated towards the M2 phenotype by IL-4, IL-13, and IL-10. M2 macrophages are characterized by high expression of IL-4 and IL-10 and low expression of IL-12. Recent studies have revealed high CD204 expression in M2 macrophages and have shown that TAMs are polarized to the M2 phenotype. The distribution of TAMs was recently evaluated as a prognostic index in various cancers. A high number of TAMs in the peripheral area of the tumor is correlated with poor prognosis in gastric cancer, hepatocellular carcinoma, and non-small-cell lung cancer, although an increased number of TAMs in the invasive front of colon cancer is associated with favorable prognosis. Increased numbers of TAMs in many cancers are linked to reduced patient survival. In pancreatic IDC, high accumulation of TAMs in the periphery of the tumor is correlated with extrapancreatic invasion, lymph vessel invasion, lymph node involvement, and shortened survival time. (9) Tumor-associated macrophages may be a key to elucidating the aggressiveness of pancreatic IDC. Detailed clinicopathological studies should be carried out to estimate the role of TAMs. First, the distribution of macrophages should be compared between mass-forming chronic pancreatitis (CP) and pancreatic IDC. Macrophages accumulate at the inflammatory site and play crucial roles in the diverse phase. Pancreatitis is prevalent in pancreatic IDC and CP due to obstruction of the main pancreatic duct. Tumor-associated macrophages in pancreatic IDC can be affected by both pancreatitis and inflammatory mediators from tumor cells; macrophages in CP are affected by pancreatitis only. The comparison of macrophages between pancreatic IDC and CP may provide evidence that tumor cells mainly lead to TAM accumulation in pancreatic IDC. Second, TAM-related tumor factors should be examined in detail. Tumor-associated macrophages are attracted to and retained in avascular and necrotic areas where they are exposed to tumor hypoxia. Our previous clinicopathological study showed that tumor necrosis is frequent in large tumors. Tumor size may be associated with TAM accumulation. Identification of the precise TAM-related tumor factors is useful for estimating microenvironmental interactions between TAMs and pancreatic IDC. Third, the impact of TAMs on tumor relapse should be evaluated. The prognostic value of TAMs may indicate that TAMs are predictive markers of recurrence. The impact of TAMs on recurrence will reinforce the clinical significance of TAMs. Finally, multivariate analysis should be carried out to confirm the impact of TAMs on prognosis. The prognostic value of TAMs has only been tested with univariate analysis. Establishment of the prognostic importance needs to show independence among various tumor factors with multivariate analysis.

Because autonomous proliferating cancer cells are often exposed to hypoxic conditions, there must be an alternative metabolic pathway, such as autophagy, that allows them to obtain energy when both oxygen and glucose are depleted. We previously reported finding that autophagy actually contributes to cancer cell survival in colorectal cancers both in vitro and in vivo. Pancreatic cancer remains a devastating and poorly understood malignancy, and hypoxia in pancreatic cancers is known to increase their malignant potential. In the present study archival pancreatic cancer tissue was retrieved from 71 cases treated by curative pancreaticoduodenectomy. Autophagy was evaluated by immunohistochemical staining with anti-LC3 antibody, as LC3 is a key component of autophagy and has been used as a marker of autophagy. The results showed that strong LC3 expression in the peripheral area of pancreatic cancer tissue was correlated with a poor outcome (P = 0.0170) and short disease-free period (P = 0.0118). Two of the most significant correlations among the clinicopathological factors tested were found between the peripheral intensity level of LC3 expression and tumor size (P = 0.0098) or tumor necrosis (P = 0.0127). Activated autophagy is associated with pancreatic cancer cells, and autophagy is thought to be a response to factors in the cancer microenvironment, such as hypoxia and poor nutrient supply. This is the first study to report the clinicopathological significance of autophagy in pancreatic cancer. (Cancer Sci 2008; 99: 1813-1819) C ancers are abnormal tissue masses whose growth exceeds and is uncoordinated with that of adjacent normal tissues, and which persist in the same excessive manner after cessation of the stimulus that evoked them. (1) All cancers ultimately depend on the host for their nutrition and blood supply, but as the preexisting vasculature is obviously insufficient to support the cancers' unlimited requirements for energy and nutrition as a result of their unregulated growth, angiogenesis has been considered pivotal to providing proliferating cancer cells with an adequate source of oxygen, energy, and nutrients. However, recent studies have revealed that even after new blood vessels have formed, both the oxygen and glucose supply is insufficient for the aggressively proliferating cancer cells in locally advanced cancers. Tumor hypoxia has been used as a marker of poor prognosis; (5,6) however, how cancer cells become more malignant or survive with an extremely poor blood supply, as for example in pancreatic cancer, is poorly understood. (7) When cancer cells are exposed to hypoxia, anaerobic glycolysis increases and provides energy for cell survival, but as the glucose supply is also insufficient because of the poor blood supply, there must be an alternative metabolic pathway that provides energy when both oxygen and glucose are depleted. We have reported that several cancer cell lines, including pancreatic cancer-and colorectal cancer-derived cell lines, are resistant to nutrient-deprived conditions. We have named this starvation-resistant phenotype 'austerity' and speculated that austerity may contribute to cancer cell survival in a nutrient-deficient microenvironment. Autophagy has long been known to be a non-specific selfdegradation mechanism that is triggered by nutrient deprivation, but recently it has been shown to play an important role in removing redundant or faulty cell components, such as damaged mitochondria and other organelles that are targeted for lysosomal degradation. The autophagic process occurs in three steps: (1) autophagosome formation; (2) lysosomal fusion with the autophagosome; and (3) lysosomal degradation. In step 1, a cup-shaped lipid bilayer called the isolation membrane is formed and engulfs cytosolic components, including organelles. In step 2, the isolation membrane closes, forming an autophagosome. Cytosolic LC3 (microtubuleassociated protein 1 light chain 3), a mammalian homolog of yeast ATG8, is converted to LC3-I (soluble unlipidated form of LC3) during this step and LC3-I is then modified to form LC-3-II (a membrane-bound form) and becomes localized on autophagosomes. Autophagosomes fuse with lysosomes to form autolysosomes. In step 3, the contents of the autolysosomes are degraded rapidly by lysosomal hydrolases, including cathepsins B, D, and L. Intra-autophagosomal LC3-II is also degraded at the same time. Thus, LC3 is a key component of autophagy, and it has been used as a marker of autophagy.

For clinicians, the orthodox histological investigation of patients with invasive ductal carcinoma (IDC) remains important for predicting prognoses. The purpose of the present study was to determine the most important of the known prognostic histological parameters (including fibrotic focus and tumor necrosis), enabling the outcomes of 101 patients with IDC of the pancreas to be predicted accurately. Furthermore, we established a scoring classification consisting of important prognostic histological parameters examined in this study. Multivariate survival analyses showed that invasive tumor size of more than 3 cm, the presence of tumor necrosis, the presence of nerve plexus invasion and lymph vessel invasion scores of 2 or 3 were important prognostic factors. Our scoring classification, consisting of the above four parameters, accurately classified the outcome of patients independent of the invasive tumor size of IDC. We concluded that invasive tumor size of 3 cm or more, the presence of tumor necrosis, the presence of nerve plexus invasion and lymph vessel invasion scores of 2 or 3 are important histological prognostic parameters for patients with IDC of the pancreas. Furthermore, the scoring system consisting of the above four histological parameters is probably a very useful prognostic histological classification for patients with IDC of the pancreas. (Cancer Sci 2005; 96: 858-865)

The distance of nerve invasion is an important prognostic factor in pancreatic cancer. The extracellular matrix (ECM) of nerve, mainly composed of laminin, collagen IV and anchoring fibrils, might affect nerve invasion. However, this relationship has not been demonstrated. Our study aimed at discovering the promoting factor of nerve invasion within the tumoral ECM. An animal model was established to evaluate the distance of nerve invasion in murine sciatic nerves by intraneural injection of 6 human pancreatic cancer cell lines. mRNA expression of laminins and anchoring fibrils was compared to the distance of nerve invasion for each cancer cell line. A target molecule provided the strong association between mRNA expression and the distance of nerve invasion. To evaluate the role of a target molecule in nerve invasion, protein expression and function were examined using an animal model and surgical cases. Cancer cells with high laminin c2 mRNA and protein expression in their basement membranes were associated with long nerve invasion. Knockdown of laminin c2 in cancer cells significantly shortened nerve invasion in the animal model. In 75 patients with pancreatic cancer, a large distance of nerve invasion was associated with high expression levels of laminin c2 mRNA and basement membranous deposition of laminin c2 protein.

Background: Resections are effective for some patients with both hepatic and pulmonary metastases of colorectal cancer, but the best selection criteria for the resections and effective treatment for recurrence after the resections have not been determined. Methods: A retrospective analysis was performed for 30 consecutive patients who received aggressive multiple resections for both hepatic and pulmonary metastases of colorectal cancer. Recurrences after resections were surgically treated whenever resectable. Results: For the 30 patients, 45 hepatectomies and 40 pulmonary resections were performed and 17 patients received three or more resections. No mortality was observed. Overall survival after the first metastasectomy for the second organ (liver or lung) was 58% and nine 5-year survivors were observed. Multivariate analyses revealed that primary colon cancer, stage IV in TNM classification and maximum size of hepatic tumor .3 cm at initial hepatectomy were poor prognostic factors, but several long-term survivors were observed even among patients with those factors. Conclusions: Multiple resections for hepatic and pulmonary metastases of colorectal cancer are safe and effective. No single factor is considered to be a contraindication for the resections. For recurrence after the resections, surgical resection is also recommended if resectable.

Patients with testicular germ cell tumors who have disease-free remission for more than 2 years are usually considered to be cured of their disease. This report describes a case of a germ cell tumor recurring 12 years after initial diagnosis and its treatment in a 35-year-old man who developed a retroperitoneal mass adhering to the abdominal aorta with a boutof severe colic in the leftflank. Although tumor markers were notelevated and histology of the biopsy specimen was initially diagnosed as adenocarcinoma, we finally concluded thatthe retroperitoneal tumor wasteratoma developing as a recurrence of the germ cell tumor for the following reasons: (1) the histology of the specimen was similar to an epithelial component of teratoma found in the tissue resected 12 years before; (2) systemic survey failed to detect any other primary site; (3) the young age of this patient was consistent with germ cell tumor rather than adenocarcinoma; and (4) the retroperitoneum is the most frequent site of late recurrences of testicular cancer. He was treated successfully with combination chemotherapy of cisplatin, etoposide and bleomycin followed by surgery. It is important to differentiate thistreatable disease from metastasis from an unknown primary, because the latter responds poorly to therapy and survival is usually short.

Early recurrence is a major problem after hepatic resection of colorectal hepatic metastasis (CHM). Our aim was to investigate the relationship between time to recurrence after CHM resection and overall survival. A retrospective analysis was performed for 101 consecutive patients who underwent hepatic resection for CHM and have been followed more than 5 years. Among 101 patients, 82 (81%) had a recurrence. Overall survival of patients with recurrence within 6 months after CHM resection was significantly worse than that of patients with recurrence after more than 6 months (P < 0.01). Overall survival was poorer when time to recurrence was shorter. One of the reasons for poor prognosis of patients with recurrence within 6 months was that only a few patients could undergo a second resection for recurrence after CHM resection. Histological type, including poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor, bilobar metastases, microscopic positive surgical margin and carcinoembryonic antigen (CEA) above 15 ng/ml had predictive value for decreased recurrence-free survival after CHM resection. Short time to recurrence after CHM resection correlates with a poor prognosis. Histological type of poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor might be a predictor for early recurrence after CHM resection.

We encountered a patient with hepatocellular carcinoma (HCC) with peritoneal dissemination and needle tract implantation, both of which were strongly suspected to have been caused by percutaneous needle biopsy. The patient was a 65-year-old man. Partial hepatectomy of subsegment VI had been performed following the diagnosis of HCC by percutaneous needle biopsy in February 1997. After this first surgery, the patient additionally underwent five further surgeries for the treatment of intrahepatic recurrences, peritoneal recurrences and needle tract implantation caused by the percutaneous needle biopsy. The intrahepatic and peritoneal recurrences were surgically controlled for 3 years after the fifth operation. The needle tract implantation was first resected in February 2001. Since then, treatment by surgery and radiotherapy has been administered twice for local recurrences forming tumor thrombosis of the abdominal wall. Now, 7 years after the first surgery, the patient remains alive without any evidence of recurrence. This case report serves to emphasize that needle tract implantation and peritoneal seeding caused by percutaneous needle biopsy are rare but possible complications. When such iatrogenic spreading of malignant cells occurs, aggressive multimodal treatment is well worth considering. Wide resection of the tumor including the adjacent soft tissues should be performed in these cases, considering that the tumor spreads along the subcutaneous veins in needle tract implantation of HCC and repeated aggressive surgeries could provide good local control.

Background: There is no standard treatment for patients with extrahepatic spread from hepatocellular carcinoma. The aim of this retrospective study was to identify candidates for aggressive intervention or new drug trial among such patients. Methods: Retrospective exploration was performed to extract a patient cohort step by step using univariate and multivariate analyses. Results: There were 201 subjects from the past 12 years. The 1-, 3-and 5-year survival rates were 31.0, 9.2 and 4.5%, respectively. The upper limit of the 95% confidence interval of median survival time did not reach 3 months in patients with a performance status of 2 or worse, or with Child-Pugh grades B or C. After excluding those, univariate and multivariate analyses were performed in the remaining 124 subjects. Three independent prognostic factors-brain metastasis, number of metastatic tumors and primary tumor status-were identified. The final cohort was set at 121 after excluding three with brain metastasis. Among these 121, there were 11 with a solitary metastatic tumor and T1/2 primary tumor. In this subgroup, 10 underwent complete removal of the metastatic tumor, and the median survival time exceeded 5 years. Conclusion: Candidates for anti-cancer treatment should meet the following requirements: a performance status of 0 or 1, a Child-Pugh grade A and no brain metastasis. Among these, challenging locoregional intervention was acceptable only for patients with solitary metastatic tumor and T1/2 primary tumor.

Radical gastrectomy with regional lymphadenectomy is the only curative treatment option for gastric cancer. The extent of lymphadenectomy, however, is controversial. The two European randomized trials only reported an increase in operative morbidity and mortality, but failed to show survival benefit, in the D2 lymphadenectomy group. We conducted a randomized controlled trial to compare the Japanese standard D2 and D2 ϩ para-aortic nodal dissection.

Background The optimal surgical strategy for resectable, synchronous, colorectal liver metastases remains unclear. The objective of this study was to determine which patients could benefit from staged resections instead of simultaneous resection by identifying predictive factors for postoperative morbidity and anastomotic leakage after simultaneous resection of synchronous, colorectal liver metastases and the primary colorectal tumor. Methods This study involved 86 patients with synchronous colorectal liver metastases who underwent simultaneous resection of the primary colorectal tumor and the hepatic tumor. Postoperative mortality, morbidity, and other surgical outcomes, including survival and hospitalization, were assessed. Predictive factors for postoperative morbidity and for anastomotic leakage were evaluated. Results Postoperative morbidity and anastomotic leakage were found in 55 (64%) and 18 (21%) patients. Predictive factors for postoperative morbidity and for anastomotic leakage were intraoperative blood loss and operation time >8 h, respectively. The overall 5-year survival rate was 45%. Conclusions The frequency of morbidity and that of anastomotic leakage seemed to be high after simultaneous resection for synchronous colorectal liver metastases, especially when intraoperative blood loss or operation time increased greatly. Staged resections should be considered in cases in which excessive surgical stress from simultaneous resection of synchronous colorectal liver metastases would be expected.

Surgical treatment for locally advanced gastric cancer remains controversial, and many still question the benefits of extended resection. The aim of this study was to evaluate the effectiveness of combined resection of the involved organs with regard to survival in patients with gastric cancer. Between 1993 and 2000, among the 1638 patients with gastric cancer who underwent gastrectomy, 82 were found to have evidence of adjacent organ spread at laparotomy. A retrospective analysis of these patients was performed. Curative resections were carried out in 50 patients, whereas noncurative resections were performed in 32 patients. The 5-year survival rate in the group undergoing curative resection was 36.9%. The survival rate in the R0 group was significantly higher than the survival rate for patients undergoing noncurative resections. There was no significant difference in survival rates between patients with pT3 cancer and those with pT4 cancer. Seventy-one patients were pathologically proved to have lymph node metastasis, and the survival rate for patients with a lymph node ratio greater than 0.2 was lower than that in other groups. In multivariate analysis, peritoneal dissemination, lymph node ratio, and histologic findings were the predictors of survival. Patients with T4 gastric carcinoma, even with lymph node metastasis, might have benefited from aggressive surgery with curative intent. ( J GASTROINTEST SURG

We report a case of early duodenal cancer (2.5 cm in diameter, located in the proximal part) in a 65-year-old female whom segmental resection was performed and a 7-year disease-free survival was achieved. The surgical specimen, showed and a 2.5 x 1.5 • 1.0cm exophytic lesion histopathological examination revealed highly differentiated intramucosal adenocarcinoma. We also report or our review of 122 cases of early duodenal cancer reported in Japan. Intramucosal carcinoma was found in 66%, and submucosal carcinoma in 34% of the patients. The location of the lesion was bulbar in 73 patients (60%), supraampullary in 33 (27%), periamupllary in 5 (4%), and infraampullary in 11 (9%). Distal gastrectomy, including the bulb, was performed in 46 patients, pancreatoduodenectomy in 23, partial resection in 24, endoscopic polypectomy in 25, and segmental resection in 4, including our patient. The frequency of lymph node metastasis is low in early duodenal cancer, so that segmental resection appears to be a reasonable treatment method.