[A Case of Early-Stage Cecal Cancer with Mesenteric Phlebosclerosis Requiring Laparoscopic Right Hemicolectomy of the Colon].

The patient was a 71-year-old woman diagnosed with mesenteric phlebosclerosis(MP)2 years earlier. CT performed to investigate her abdominal pain revealed an ascending colon obstruction. Colonoscopy(CS)revealed MP extending to the ascending colon hepatic flexure with stenosis and a cecal tumor(biopsy tub1). Although the cancerous lesion itself was potentially curable by endoscopic treatment, it was surgically resected because of the ascending colon stenosis caused by the MP that had also caused intestinal obstruction. Intraoperative findings revealed wall thickening and stiffening from the cecum to the ascending colon hepatic flexure. Postoperative pathological examination revealed cecal carcinoma pTis, N0, M0, pStage 0. The background mucosal tissue was consistent with MP, but no findings suggested a relationship between the MP and tumor. Although the relationship between MP and carcinogenesis is unknown, and no such relationship was identified in this case, we report this case because a further accumulation of cases of MP and carcinoma is necessary, considering the rarity of MP itself and the non-negligible number of cases with carcinoma.

Trimethyl-Substituted Carbamate as a Versatile Self-Immolative Linker for Fluorescence Detection of Enzyme Reactions.

Self-immolative linker is a useful building block of molecular probes, with broad applications in the fields of enzyme activity analysis, stimuli-responsive material science, and drug delivery. This manuscript presents N-methyl dimethyl methyl (i.e., trimethyl) carbamate as a new class of self-immolative linker for the fluorescence detection of enzyme reactions. The trimethyl carbamate was shown to spontaneously undergo intramolecular cyclization upon formation of a carboxylate group, to liberate a fluorophore with the second time rapid reaction kinetics. Interestingly, the auto-cleavage reaction of trimethyl carbamate was also induced by the formation of hydroxyl and amino groups. Fluorescent probes with a trimethyl carbamate could be applicable for fluorescence monitoring of the enzyme reactions catalyzed by esterase, ketoreductase, and aminotransferase, and for fluorescence imaging of intracellular esterase activity in living cells, hence demonstrating the utility of this new class of self-immolative linker.

[Two Cases of Neuroendocrine Carcinoma of Colon and Rectum].

We report 2 cases of neuroendocrine carcinoma(NEC)of colon and rectum with distant metastasis. The treatment of NEC with distant metastasis is based on the treatment of small cell lung cancer, but that is controversial because NEC is relatively rare. Case 1: A 75-year-old man who was admitted for anal pain. Physical examination showed the anal tumor and swelling inguinal lymph nodes. CT showed rectum tumor and multiple lymph node metastases to the pelvis and inguinal region. Colonoscopy showed a Type 3 tumor in the rectum. He was diagnosed with NEC based on biopsy and immunostaining. Colostomy was performed for pain relief and etoposide/cisplatin(EP)therapy was introduced. After 6 courses of the chemotherapy, CT showed progression of the tumor, then we made the shift to palliative treatment. Case 2: A 69-year-old man who was admitted for abdominal pain and back pain. CT showed transverse colon tumor with multiple metastases to the liver, lung, and lymph nodes. Colonoscopy showed a circumferential tumor in the transverse colon. He was diagnosed with NEC based on biopsy and immunostaining. He refused chemotherapy and died 2 months later.

[A Case of BRAF-Mutated Obstructive Colon Cancer with Liver Metastases Treated with Multidisciplinary Therapy].

A 39-year-old woman visited our hospital with complaints of nausea, vomiting, and lower abdominal pain for 2 weeks. Abdominal CT revealed thickening of the transverse colonic wall, dilated bowel, and a metastatic ischemic tumor in the liver (S7). We diagnosed her with obstructive colon cancer, clinical Stage Ⅳa(T, type 2, cT3, N0, M1a[liver]). At first, we placed a self-expanding metallic stent(SEMS)to decompress bowel obstructions. We planned a surgical resection of the primary tumor followed by partial resection of the liver. We performed a laparoscopic right hemicolectomy(D3)24 days after the stenting. Pathologically, we diagnosed her with BRAF-mutated colon cancer, pStage Ⅳa(pT4a, N1b[2/43], M1a[liver]). On completion of 4 courses of mFOLFOXIRI and bevacizumab, we confirmed a reduction of the S7 tumor but found a new tumor in S6. Since the tumors were potentially resectable, we performed partial liver resection(S6, S7)1 month later. A month following the hepatectomy, CT revealed a new tumor in S4. The patient has been receiving general chemotherapy (CapeOX and bevacizumab)without disease progression for 6 months. We experienced a challenging case of BRAF- mutated obstructive colon cancer with liver metastases.

[A Case of Long-Term Survival of a Postoperative Recurrence of Duodenal Papilla Adenosquamous Carcinoma Associated with the Annular Pancreas].

A woman in her mid-50's presented to our hospital with jaundice, fatigue, and fever. Jaundice, elevated tumor markers, and lower bile duct stricture suggested malignancy, for which subtotal stomach-preserving pancreaticoduodenectomy was performed. The patient also had annular pancreas as the second part of the duodenum was surrounded by pancreatic parenchyma. The histopathological diagnosis was adenosquamous carcinoma of the duodenal papilla associated with annular pancreas. Adjuvant chemotherapy with TS-1 was administered for 1 year. Although para-aortic lymph node metastasis was detected radiographically 3 years 9 months after surgery, the recurrence remains under control and she is alive at 5 years 9 months after surgery due to multidisciplinary therapy.

[A Case of Advanced Gastric Cancer with Right Gastroepiploic Vein Tumor Thrombus Treated by Preoperative S-1 plus CDDP That Resulted in Pathological Complete Response].

We report a case of advanced gastric cancer with right gastroepiploic vein tumor thrombus treated using preoperative S-1 plus cisplatin(CDDP)in which pathological complete response was achieved. A 78-year-old man was diagnosed with type 2 gastric cancer located at the greater curvature of the antrum, accompanied by right gastroepiploic vein tumor thrombus. Four courses of S-1 plus CDDP were administered as neoadjuvant chemotherapy. After 2 courses, computed tomography(CT) revealed the disappearance of the tumor in the right gastroepiploic vein thrombus. Distal gastrectomy with D2 lymphadenec- tomy was performed, and the diagnosis was pathological complete response(CR). Eight courses of S-1(100mg/day on days 1-28, followed by 2 weeks of rest)were administered as adjuvant chemotherapy. During the 1-year postoperative follow up, the patient showed no recurrence. An S-1 plus CDDP regimen can be a useful preoperative chemotherapy option for advanced gastric cancer with tumor vein thrombus.

[A Successful Case of Multimodal Therapy for Multiple Hypervascular Tumor of Unknown Primary Origin in the Liver].

We experienced a successful case in which the patient was treated with a combination of operation and transcatheter arterial chemoembolization for a hypervascular tumor of unknown primary origin in the liver; we report this case with a literature review. A 76-year-old man noticed an upper abdominal tumor and he visited our department for detailed examination. Enhanced CT scan showed multiple hypervascular tumors scattered across both lobes of the liver, and the pattern of contrast effect implied that the tumors were primary neuroendocrine tumors or endocrine metastases. Gastroscopy and colonoscopy showed no tumor in the intestine. TACE was performed mainly for the tumors in the right lobe. One month later, we performed left lateral segmentectomy and partial hepatectomy for segment 6. Histopathological findings showed that the tumors in the left lateral segment had neuroendocrine properties, and the tumor in segment 6 was necrosed. One year has passed since the surgery without recurrence of neuroendocrine tumors in the liver or other organs.

[Intrahepatic Bile Duct Metastasis from Rectal Adenocarcinoma Eight Years after Curative Operation].

A 60-year-old male undergoing pelvic evisceration with D3 lymph node dissection for pR0 in 2006f or carcinoma of the rectum was diagnosed pathologically with moderately differentiated adenocarcinoma, fStage ⅡA(UICC pT3, pN0, M0). Follow-up CT revealed hypovascular liver tumors with intrahepatic bile duct dilation in the right lobe 8 years after the pelvic evisceration. We conducted right lobe hepatectomy. The resected specimens showed that the tumor extended predominantly along the right intrahepatic bile duct. Histological findings and an immunohistochemical examination of CK7, CK20, and CDX2 revealed metastasis of the rectum cancer. We finally diagnosed him with intrahepatic bile duct metastasis from rectal adenocarcinoma.

[A Case of Cecal Cancer with Simultaneous Liver Metastases Successfully Treated with Multidisciplinary Therapy Including Two-Stage Hepatectomy].

We report a case of colon cancer with simultaneous liver metastases successfully treated with multidisciplinary therapy including two-stage hepatectomy. This is a case of a 72-year-old woman diagnosed with type 1 cecal cancer with 2 simulta- neous liver metastases(S4/8: 98mm, S3: 63mm). At first, laparoscopic resection of the primary site was performed to prevent colon ileus. Liver metastases rapidly grew and became unresectable; fortunately, 11 courses of mFOLFOX6 and bevacizu- mab were effective and liver metastases shrunk(S4/8: 85mm, S3: 67mm). At last, two-stage hepatectomy was performed as conversion surgery, and the patient survived without recurrence for more than 2 years.

[Two Cases of Aneurysm Rupture in Advanced Colorectal Cancer Successfully Treated with Selective Trans-Catheter Arterial Embolization].

We report 2 successful cases treated with trans-catheter arterial embolization(TAE)for hemorrhagic shock due to pseudoaneurysm rupture at the primary tumor site in advanced colorectal cancer. Case 1: A 73-year-old female underwent Hartmann surgery at another hospital for rectal perforation and peritonitis. Six months later, she had a massive bloody stool and was transferred to our hospital. She was diagnosed with bleeding from advanced rectal cancer that remained following the first surgery. Contrast computed tomography(CT)showed that a branch of the superior rectal artery(SRA)developed an aneurysm at the primary tumor site, and TAE was performed to stop bleeding on hospital day 3. Case 2: A 79-year-old male with type 2 sigmoid colon cancer and simultaneous multiple liver metastases developed copious blood in the stool before primary tumor resection and was transferred to our hospital. Contrast CT showed that a branch of the SRA developed an aneurysm at the primary tumor site, and TAE was immediately performed to stop bleeding.

[A Case of Perforated Gastric MALT Lymphoma with Total Gastrectomy].

A 62-year-old man presented with complaints of acute abdominal pain. Abdominal enhanced CT showed free air in the abdominal cavity, a thickened stomach wall accompanied by deep ulcer, and enlarged lymph nodes around the stomach. Emergent surgery was conducted, and a perforation in the upper part of the stomach was found. Total gastrectomy was performed. On pathological examination, a mucosa-associated lymphoid tissue lymphoma was diagnosed. Histologic examination revealed the absence of Helicobacter pylori in the gastric mucosa. After the operation, adjuvant chemotherapy was not administered. However, he has been well for 11 months without any recurrence. Gastric MALT lymphoma with spontaneous perforation is considered extremely rare. A brief review of the literature is presented.

[A Case of Extrarenal Retroperitoneal Angiomyolipoma].

We report a rare case of a extrarenal retroperitoneal angiomyolipoma. A 64-year-old female visited our hospital because of an abdominal mass in her lower right abdomen. Enhanced CT scan revealed a 67×52mm tumor in lower right retroperitoneal space. MRI revealed adipose component in the tumor on T1 weighted images and T2 weighted images. Our preoperative diagnosis was retroperitoneal liposarcoma, and we performed retroperitoneal tumor resection. At operation the tumor was on the fossa iliaca, which was covered with capsule. It did not invade surrounding tissues. The resected tumor measured 90× 60×45 mm, and tiny hemorrhage was seen in the tumor. Histopathological findings showed that the tumor was composed of a mixture of adipose tissue, vessels, and smooth muscle. Immunohistochemistry demonstrated the tumor was stained with asmooth muscle actin(aSMA). We diagnosed the tumor as extrarenal retroperitoneal angiomyolipoma.

[A Case of Non-Functioning Pancreatic Neuroendocrine Tumor Accompanied by Stenosis of the Main Pancreatic Duct].

We experienced a rare case of pancreatic neuroendocrine tumor(pNET)in which stenosis of the main pancreatic duct occurred despite the tumor diameter being less than 1 cm; therefore, here, we report this case with some literature review.A 41-year-old woman showed dilation of the main pancreatic duct on an abdominal ultrasound as part of a health examination, and she visited our department for a more detailed examination.Enhanced CT scan showed a 7mm subtle enhancing mass in the head of the pancreas and the upstream main pancreatic duct was dilated up to 7 mm.ERCP and MRCP images also showed a dilated main pancreas duct.We suspected that her tumor was a pNET.We decided not to perform surgery immediately. After 6 months of follow-up, the tumor size increased to 10 mm; therefore, we performed subtotal stomach-preserving pancreaticoduodenectomy considering the possibility of pancreatic cancer.Histopathological findings showed that the pancreatic tumor had the property of a neuroendocrine tumor and the proliferated fibrous stroma around it caused the pancreas duct stenosis.

[Resection of Pancreatic Metastasis from Renal Cell Carcinoma 21 Years after Nephrectomy].

We report a case where resection was performed for pancreatic metastasis from renal cell carcinoma 21 years after nephrectomy. A 72-year-old man had undergone total gastrectomy with distal pancreatomy and splenectomy for gastric cancer, and right nephrectomy for primary renal cell carcinoma in 1993. Incidentally, a CT scan performed in 2014 revealed a tumor in the head of the pancreas. Enhanced MRI suggested that the tumor contained some fat tissue. The tumor in the pancreatic body had sharp margins; therefore, we performed subtotal pancreatectomy. The tumor was considered pancreatic metastasis from renal cell carcinoma. Pathological findings indicated clear-cell type carcinoma(G1-G2), which is very similar to renal cell carcinoma. We diagnosed pancreatic metastasis from renal cell carcinoma. The patient has remained well, with no recurrence 20 months after the pancreatectomy.

A novel therapeutic combination sequentially targeting aurora B and Bcl-xL in hepatocellular carcinoma.

BACKGROUND: Effective therapeutic combinations targeting the oncogenic pathway still are unknown in human hepatocellular carcinoma (HCC). The authors previously identified aberrant expression of aurora B kinase as the independent predictor for the lethal recurrence of HCC, showing that AZD1152 induced in vitro and in vivo apoptosis with polyploidy in human HCC cells. In this preclinical study, the combined effects of molecular-targeted therapies were evaluated based on the cellular response of aurora B inhibition. METHODS: This study analyzed the expression of Bcl-2 family proteins in polyploidization induced by AZD1152 and the in vitro synergistic effects of AZD1152 with control of the Bcl-2 family pathway in human HCC cells. The in vivo effects of the combination therapy targeting the specific molecules were evaluated using subcutaneous tumor xenograft models. RESULTS: The findings showed that Bcl-xL was specifically overexpressed in AZD1152-induced polyploid HCC cells. The combination of AZD1152 followed by Bcl-xL/2 inhibitor ABT263 induced synergistically cellular apoptosis (p < 0.001) and growth inhibition (p < 0.0001). Interestingly, the reverse sequential administration of AZD1152 combined with pretreatment of ABT263 was less effective than the original one. In vivo studies using tumor xenografts of human HCC cells showed that combination therapy of ABT263 after AZD1152 pretreatment induced significant intratumoral apoptosis (p < 0.05) and remarkable anti-tumor effects (p < 0.05) without a severe adverse effect compared with the monotherapy. CONCLUSION: Based on Bcl-xL overexpression in polyploidy induced by aurora B inhibition, the rationale for therapeutic combinations targeting aurora B and Bcl-xL was demonstrated in the authors' preclinical studies, leading to a promising novel approach for the mechanism-based treatment of human HCC.

[A Case of Brain Metastases from Pancreatic Cancer That Had Been Treated Effectively with FOLFIRINOX].

We report a case of multiple brain metastases from pancreatic cancer, which had responded remarkably to FOLFIRINOX. A 47-year-old man had hypovascular tumors, 25 mm on the body and 23 mm on the uncus of the pancreas; multiple liver metastases; and skin metastasis. A diagnosis of unresectable pancreatic cancer, cT4N3M1 (HEP, LYM, PUL, SKI), cStage Ⅳb was made. We chose FOLFIRINOX for treatment because of his young age and good performance status. After 6 courses, he showed decreasing tumor marker levels, an almost complete disappearance of the primary lesion, and reduced liver metastases. After 8 courses, abnormal behaviors were noted and we performed a head contrast-enhanced MRI, which revealed diffuse enhancement of the cerebral and cerebellar hemisphere. Multiple brain metastases from pancreatic cancer were diagnosed. We made the shift to palliative treatment, but his general condition was worsening and he died a month later, 7 months after the first diagnosis.

Visualization of stem cell features in human hepatocellular carcinoma reveals in vivo significance of tumor-host interaction and clinical course.

UNLABELLED: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies because of recurrence and/or metastasis even after curative resection. Emerging evidence suggests that tumor metastasis and recurrence might be driven by a small subpopulation of stemness cells, so-called cancer stem cells (CSCs). Previous investigations have revealed that glioma and breast CSCs exhibit intrinsically low proteasome activity and that breast CSCs also reportedly contain a lower reactive oxygen species (ROS) level than corresponding nontumorigenic cells. Here we visualized two stem cell features, low proteasome activity and low intracellular ROS, in HCC cells using two-color fluorescence activated cell sorting to isolate cells with stem cell features. These cells were then analyzed for their division behavior in normoxia and hypoxia, expression of stem cell markers, tumorigenicity, metastatic potential, specific gene expression signatures, and their clinical implications. A visualized small subpopulation of HCC cells demonstrated asymmetric divisions. Their remarkable tumorigenicity in nonobese diabetic/severe combined immunodeficient mice suggested the cancer initiation potential of these HCC CSCs. Comprehensive gene expression analysis revealed that chemokine-related genes were up-regulated in the CSCs subpopulation. Our identified HCC CSCs facilitated the migration of macrophages in vitro and demonstrated metastatic potential by way of recruitment of macrophages in vivo. In patients who undergo curative operation for HCC, the CSC-specific gene signature in the liver microenvironment significantly correlates with recurrence. CONCLUSION: Based on these findings, the stem cell feature monitoring system proposed here is a promising tool to analyze the in vivo significance of CSC microenvironments in human HCCs.

Contrast-enhanced intraoperative ultrasonography for vascular imaging of hepatocellular carcinoma: clinical and biological significance.

UNLABELLED: Abnormal tumor vascularity is one of the typical features of hepatocellular carcinoma (HCC). In this study, the significance of contrast-enhanced intraoperative ultrasonography (CEIOUS) images of HCC vasculature was evaluated by clinicopathological and gene expression analyses. We enrolled 82 patients who underwent curative hepatic resection for HCC with CEIOUS. Clinicopathological and gene expression analyses were performed according to CEIOUS vasculature patterns. CEIOUS images of HCC vasculatures were classified as reticular HCC or thunderbolt HCC. Thunderbolt HCC was significantly correlated with higher alpha-fetoprotein levels, tumor size, histological differentiation, portal vein invasion, and tumor-node-metastasis stage, and these patients demonstrated a significantly poorer prognosis for both recurrence-free survival (P = 0.0193) and overall survival (P = 0.0362) compared with patients who had reticular HCC. Gene expression analysis revealed that a rereplication inhibitor geminin was significantly overexpressed in thunderbolt HCCs (P = 0.00326). In vitro knockdown of geminin gene reduced significantly the proliferation of human HCC cells. Immunohistochemical analysis confirmed overexpression of geminin protein in thunderbolt HCC (P < 0.0001). Multivariate analysis revealed geminin expression to be an independent factor in predicting poor survival in HCC patients (P = 0.0170). CONCLUSION: CEIOUS vascular patterns were distinctly identifiable by gene expression profiling associated with cellular proliferation of HCC and were significantly related to HCC progression and poor prognosis. These findings might be clinically useful as a determinant factor in the postoperative treatment of HCC.

EpCAM-targeted therapy for human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies and the identification of new effective therapies for HCC is urgently needed. We have previously identified EpCAM, one of the hepatic stem/progenitor markers, as a prognostic predictor of patients who received curative hepatectomy for HCC. In this preclinical study, the effects of VB4-845, an immunotoxin targeting EpCAM, were evaluated in HCC. METHODS: In vitro effects of VB4-845 on human HCC cells, the cytotoxic activity, sphere-forming ability, and expression of hepatic stem/progenitor markers were analyzed. In vivo effects of VB4-845 were evaluated using subcutaneous and orthotopic liver xenograft models. RESULTS: In all HCC cell lines expressing EpCAM, VB4-845 showed potent cytotoxicity and was significantly effective in combination with 5-FU (p < 0.05). Although 5-FU did not affect the sphere-forming ability and increased the populations expressing other stem/progenitor markers CD133 and CD13 (p < 0.05), VB4-845 strongly suppressed the sphere-formation and decreased the population expressing CD133 and CD13 (p < 0.0005, <0.01, respectively). In subcutaneous xenograft models, the combination of VB4-845 plus 5-FU showed significant regression of tumors compared with the control (p = 0.016). Moreover, in orthotopic liver xenograft models, the combination therapy dramatically decreased the tumor volume compared with the control (p = 0.0011). CONCLUSIONS: Our preclinical investigation suggests that EpCAM-targeted therapy may offer a promising and novel approach for the treatment of HCC with a poorer prognosis.

A Simple Index to Predict Liver Functional Reserve after Hepatectomy.

BACKGROUND/AIMS: It is difficult to estimate the functional reserve of the liver required for safe hepatectomy in patients with severe chronic liver disease The aim of this study was to retrospectively construct simple model based on routine laboratory data to predict both early liver failure (ELF) and mortality from recurrence-free liver failure (MLF) as an index for late liver failure after hepatectomy. METHODOLOGY: Between 2000 and 2004, 196 consecutive patients underwent curative hepatectomy, and data from 127 minor hepatectomies were included in this study. RESULTS: Mean survival time was [mean (SD)] 1252 (670) days after hepatectomy. ELF and MLF were observed in 29 and 13 patients, respectively. PT%, TB, and direct bilirubin (DB) were the best predictors in patients with both ELF and MLF. PT% alone was the best predictor of ELF and MLF with area under ROC curves of 0.70 and 0.81, respectively. By using a preoperative PT% of ≤ 70, we could accurately predict ELF and MLF in 77% and 87% of patients, respectively. ICG-R15 could not accurately predict both ELF and MLF for any cut-off values. CONCLUSIONS: Unlike ICG-R15, PT% is a simple noninvasive index for estimating liver functional reserve to predict both ELF and MLF.