Long-term survival outcomes of advanced gastric cancer patients who achieved a pathological complete response with neoadjuvant chemotherapy: a systematic review of the literature.

BACKGROUND: A pathologic complete response (pCR) can sometimes be induced by intensive or long-term neoadjuvant chemotherapy (NAC). This prognostic research study based on a systematic review of the literature evaluated the impact of a pCR on the long-term survival of gastric cancer (GC) patients. METHODS: Articles were extracted from PubMed and the Japanese medical search engine "Ichu-shi," using the terms "GC," "NAC," and "pCR." Articles were selected based on the following criteria: (1) full-text case report, (2) R0 resection following NAC for locally advanced GC, and (3) pathological complete response in both the primary stomach and in the lymph nodes. A questionnaire regarding the patients' prognoses was sent to the corresponding authors of the articles selected in July 2013. RESULTS: Twenty-four articles met the criteria. Twenty authors responded to the questionnaire. Finally, 22 patients from 20 articles were entered into the present study. The median follow-up time (range) of the survivors was 76 (range 13-161) months. Tumors that were stage III/IV (86%: 19/22) and of an undifferentiated histology (61.9%: 13/21) were dominant. An S1-based regimen was frequently selected for the NAC. All patients underwent R0 resection and D2/D3 lymphadenectomy. The overall survival and recurrence-free survival rates at 3 and 5 years were 96% and 85% and 91% and 75%, respectively. CONCLUSIONS: Although a pCR was a relatively rare event, a high pCR rate would be helpful to select the regimen and courses of NAC, especially when the pathological response rates are similar.

Does postoperative complication have a negative impact on long-term outcomes following hepatic resection for colorectal liver metastasis?: a meta-analysis.

BACKGROUND: The negative impact of postoperative complications (POCs) on long-term outcomes is well documented for several cancer surgeries, but conclusive evidence has yet to be provided on the influence of POCs on long-term oncological outcomes after hepatic resection for colorectal liver metastasis (CRLM). METHODS: Studies published through February 2012 evaluating the oncological impact of POCs after hepatectomy for CRLM were identified by an electronic literature search. Finally, 4 studies were identified and included in the meta-analysis. The main outcome measures were 5-year disease-free survival (DFS) and overall survival (OS). A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute odds ratio (OR) along with 95 % confidence intervals (95 % CI). RESULTS: The outcomes of 2,280 patients were studied. Meta-analysis of 5-year DFS data extracted from three studies demonstrated a significant reduction in 5-year DFS after POCs, with an OR of 1.98 (95 % CI = 1.33-2.96; P = .0008). Meta-analysis of 5-year OS data extracted from four studies demonstrated a significant reduction in 5-year OS after POCs, with an OR of 1.68 (95 % CI = 1.25-2.27; P = .0006). No differences between study heterogeneity were observed in either the DFS or the OS analyses. CONCLUSIONS: This study provides persuasive evidence that POCs following hepatic resection for CRLM have significant adverse oncological outcomes. These findings emphasize the need for meticulous surgical technique and careful perioperative management to minimize POCs.

Left paraduodenal hernia incidentally diagnosed during operation for transverse colon cancer.

We report the case of a patient with paraduodenal hernia diagnosed incidentally during an operation for transverse colon cancer. The patient was a 77-year-old woman who complained of dizziness. Laboratory data revealed no abnormal findings except slight anemia. Barium enema and colonoscopic examination revealed an irregular surfaced mass, about 5.0 cm in size, located near the flexure of the spleen of the transverse colon. A biopsy of the mass was performed, and a moderately differentiated adenocarcinoma was diagnosed. In April 2009, following the diagnosis of transverse colon cancer, laparotomy was performed, which revealed that a few loops of the jejunum were herniated through the orifice into the space posterior to the transverse mesocolon. Moreover, the jejunal loops were located right between a shifted left branch of the middle colic artery and ascending left colic artery. There were no ischemic changes in the jejunum. These findings were consistent with a left paraduodenal hernia associated with transverse colon cancer. The scheduled left hemicolectomy was performed in addition to a radical operation of the left paraduodenal hernia. The abdominal computed tomography (CT) images were reviewed postoperatively. The scan projection radiogram obtained by CT revealed a packing of jejunal loops in the middle of the abdomen. Abdominal CT revealed ascending left colic artery at the left edge of a packing of jejunal loops. The patient was discharged from our hospital 14 days after the surgery without any complications. Left paraduodenal hernias are rare and constitute less than 0.4% of all intestinal obstructions. Retrospectively reviewed, the preoperative CT is suggestive. In addition to the packing of jejunal loops in the middle of the abdomen, ascending left colic artery was clearly observed at the left edge of the packing of jejunal loops, which indicates left paraduodenal hernia.

A case of extrahepatic bile duct wall recurrence of gastric carcinoma that was treated with pancreaticoduodenectomy.

We report on a patient with obstructive jaundice caused by recurrence of gastric carcinoma in the wall of an extrahepatic bile duct more than 5 years after gastrectomy who was treated with pancreaticoduodenectomy. Histopathologic examination of the surgically resected specimen revealed a poorly differentiated adenocarcinoma with focal signet ring cells in the wall of the common bile duct which was histologically similar to the primary gastric carcinoma. To confirm the diagnosis, immunohistochemical staining was performed with antibodies against cytokeratins (CK7, CK20) and mucin peptide core antigens (MUC5AC, MUC6, MUC2). Based on the expression patterns of this monoclonal antibody panel, the final diagnosis of the common bile duct tumor was an isolated local recurrence of the gastric carcinoma. The patient has survived for more than 26 months after pancreaticoduodenectomy without recurrence.

Life-threatening bleeding from gastrointestinal stromal tumor of the stomach.

Here, we report on two patients with hemorrhagic shock due to hematemesis from a gastrointestinal stromal tumor (GIST) of the stomach. Patient 1 was a 64-year-old woman who was admitted to our hospital because of syncope due to hemorrhagic shock resulting from massive hematemesis. Emergent upper gastrointestinal (GI) endoscopy revealed a 5-cm-diameter submucosal tumor on the lesser curvature of the lower gastric body. In addition to the central ulceration of the tumor, a Dieulafoy-like lesion was present. Neither lesions showed active bleeding at the time of observation. Because the patient collapsed twice with fluminant hematemesis after admission, she underwent distal gastrectomy with Billroth-I reconstruction. Histological examination revealed a gastric GIST with no nodal metastasis and the mitotic count was less than 5 per 50 HPFs. Dilated vessels were prominent in the peritumoral submucosa, and a thrombus was seen in these vessels, which seemed to be a bleeding point. The patient had an uneventful postoperative course and has been alive without recurrence for 5 and a half years. Patient 2 was a 60-year-old man who presented with syncope due to hemorrhagic shock resulting from massive hematemesis. Because the source of the bleeding was not elucidated with an initial upper GI endoscopy, he was treated for a gastric ulcer. One week after admission, he suffered from hemorrhagic shock again, and a submucosal tumor 6 cm in size was revealed on the greater curvature of the upper stomach with upper GI endoscopy. The patient subsequently underwent wedge resection of the tumor. Histopathological findings were consistent with a GIST and the mitotic count was less than 5 per 50 high-power fields. The tumor showed no necrosis or intratumoral hemorrhage. A peritumoral submucosal artery, which was responsible for the massive hematemesis, was located at some distance away from the central ulceration. Postoperative recovery was without complications. After 4 years, the patient remains healthy and disease-free. Although hematemesis associated with gastric GIST has been said to originated from the central ulceration of the GIST, life-threatening, massive hematemesis is rare. The exact bleeding points of the gastric GISTs in these cases were submucosal vessels adjacent to the GIST, not the central ulceration. There have been no reports of peritumoral, submucosal vessels causing massive hematemesis from gastric GISTs. Because the origins and manner of bleeding varies in gastric GISTs, we must decide the methods of hemostasis immediately including the tumor excision.

Case of adenosquamous carcinoma of the ascending colon.

Adenocarcinoma accounts for most of the malignant tumors originating from the colon, whereas adenosquamous carcinoma is rare, accounting for about 0.1% of all colon cancers. We present herein a case of adenosquamous carcinoma of the ascending colon. The patient was a 94-year-old woman who presented with a chief complaint of lower abdominal pain. A barium enema examination and lower gastrointestinal endoscopy showed a type 3 tumor in the ascending colon, and a biopsy confirmed the diagnosis of adenosquamous carcinoma. Right hemicolectomy was performed, and the tumor was diagnosed as a stage III advanced colon cancer. The patient had postoperative aspiration pneumonia and died 35 days after surgery. A search of Japanese literature over the past 25 years yielded 70 patients with adenosquamous carcinoma of the colon, and the clinicopathological features are discussed herein.

Correlation between clinical pathologic factors and activity of 5-FU-metabolizing enzymes in colorectal cancer.

INTRODUCTION: Orotate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD), and thymidylate synthase (TS) are initial key enzymes in the 5-fluorouracil (5-FU) metabolic pathway. The expression levels and activities of these three enzymes play important roles in the response of cancer patients to 5-FU-based chemotherapy. PURPOSE: The purpose of this study was to investigate the relationship between the activities of 5-FU metabolic enzymes and clinicopathologic factors in colorectal cancer. METHODS: We measured the activities of OPRT, DPD, and TS in colorectal cancer tissues. We also investigated the correlations between the activities of these three enzymes and clinicopathologic factors (histological type, depth of tumor invasion, extent of lymph node metastasis, Dukes' stage, lymphatic invasion, and vascular invasion). We examined 100 patients with surgically resected colorectal cancer. RESULTS: Poorly differentiated adenocarcinoma showed significantly higher DPD activities than did moderately differentiated or well-differentiated adenocarcinoma. In patients with lymph-node metastasis, OPRT activity was significantly lower than in patients without lymph-node metastasis. No significant relation was found between TS activity and histological type, depth of tumor invasion, extent of lymph node metastasis, Dukes' stage, lymphatic invasion, or vascular invasion. CONCLUSION: The response to 5-FU may be poor in patients with lymph-node metastasis, because of low OPRT activity, and in patients with poorly differentiated adenocarcinoma, because of high DPD activity.

Male choriocarcinoma with metastasis to the jejunum: a case report and review of the literature.

We report on a patient with male choriocarcinoma. The patient was a 31-year-old male patient with jejunal choriocarcinoma that metastasized from the mediastinum. He was admitted complaining of melena and severe anemia. Upper and lower gastrointestinal endosocopy was performed, but no source of bleeding was seen. Chest X-ray and CT revealed a mediastinal tumor 7 cm in size anterior to the arotic arch. Superior mesenteric arteriography showed irregularities and macular opacity in the jejunal artery. An emergency laparatomy was performed because of massive gastrointestinal bleeding. A jejunal tumor approximately 4 cm in size was resected and numerous metastases were observed in the liver and mesentery. Histopathological examination showed metastatic jejunal choriocarcinoma. Gynecomastia was not present and the testes were normal. Serum beta-human chorionic gonadotropin (HCG) was at an abnormally high level of 4,396 ng/mL. Because of metastases to the brain and invasion to the trachea, he died on postoperative day 20. We report this rare case of a male patient with metastases of choriocarcinoma to the gastrointestinal tract from the mediastinum, together with a review of the literature.

[Antitumor effect of paclitaxel for gastric cancer is AUC dependent].

Paclitaxel (PTX), which is used for ovarian cancer, lung cancer, breast cancer and gastric cancer, is administered at a dose of 210 mg/m(2) once every three weeks. However, WHO grade 3-4 hematological and non-hematological toxicity occurred frequently in this manner. In recent studies about ovarian cancer and lung cancer, a schedule in which PTX was given weekly could have the same or better efficacy, with fewer side effects. The response rate of PTX administered every three weeks for gastric cancer, was 23.3 to approximately 28.0%, while that of PTX administered weekly was 24.0 to approximately 25.8%. Because of fewer adverse events, weekly PTX is widely used for gastric cancer in Japan. To prove the validity of PTX weekly administration, we performed a study using six specimens removed surgically and one specimen collected from ascites. A chemosensitivity test was performed on the basis of two assumptions: a high concentration for a short time, and a low concentration for a long time. A similar PTX effect was obtained when the AUC was equal. In this study, we demonstrated that the effect of low-dose PTX was equal to the effect of high-dose PTX in gastric cancer.

Identification of neovasculature using nestin in colorectal cancer.

CD34 is commonly used as an endothelial cell marker of tumor vessels. However, this marker detects not only newly formed, but also pre-existing large blood vessels. Nestin, a class VI intermediate filament protein, has recently received attention as a marker for detecting newly formed endothelial cells. In this study, whether nestin is a novel angiogenesis marker in colorectal cancer was examined. HCT-15, a human colon cancer cell line, was subcutaneously implanted into the dorsum of nude mice. After the tumor grew, the mice were perfused with fluorescent beads (Fluospheres). Then, the tumor tissues were used for immunofluorescence staining using nestin and the CD34 antibody. Immunohistochemistry was performed with nestin and CD34 on 101 human colorectal cancer tissue samples. Proliferating endothelial cells were detected immunohistochemically by a proliferating cell nuclear antigen (PCNA) antibody. Clinicopathological factors and prognosis were compared between two groups: that with a microvessel density (MVD) higher than the median MVD and that with MVD lower than the median MVD, as detected by nestin and CD34 labellings. Nestin was localized in endothelial cells in small blood vessels (median, 9.06 microm), whereas CD34 was localized in large blood vessels (median, 9.67 microm) in nude mice. The diameter of nestin-positive vessels was smaller than that of CD34-positive vessels in human colorectal cancer. The number ratio of PCNA-positive cells to nestin-positive vascular endothelial cells was higher than that of PCNA-positive to CD34-positive cells (p=0.002). There were no correlations between nestin-positive blood vessels and clinicopathological factors, but the prognosis was worse in the highly nestin-positive MVD group (p=0.071). Nestin is considered a novel angiogenesis marker of proliferating endothelial cells in colorectal cancer tissue.

A case of rectal metastatic tumor in the soft tissue of the hand.

Hand metastases occur infrequently, and metastatic tumors in the soft tissue of the hand caused by rectal cancer are extremely rare. We report a case here. The patient was a 76-year old man. He underwent Miles operation for rectal cancer located in the lower portion of the rectum. Histopathologically, the resected specimen showed well-differentiated adenocarcinoma. Six years postoperatively, a tumor involving the soft tissue of the palma was found in his left hand. The tumor was resected, and pathological examination showed a well-differentiated adenocarcinoma similar to the primary rectal carcinoma. Immunohistochemical examination demonstrated that this hand tumor had metastasized from rectal cancer. Fifteen cases of colorectal metastatic tumors in the hand have been documented, of which three were soft-tissue metastases. This report describes the fourth case.

Squamous cell carcinoma arising from recurrent anal fistula.

Here, we report on a patient with squamous cell carcinoma (SCC) arising from recurrent anal fistula. The patient was a 57-year-old woman who had 32-year history of having a recurrent perianal abscesses that ruptured spontaneously. Six months before her admission to our hospital, anal pain developed. She had no history of inflammatory bowel disease. Physical examination revealed three external fistulous openings at the two o'clock position, 2 cm from the anal verge. One internal opening in the lower rectum was found with proctoscopy. The patient underwent fistulectomy. Microscopic examination showed SCC arising from the anal fistula, which was accompanied by vessel invasion. The tumor was observed to be continuous from the external opening but was not exposed to the internal opening of the rectal mucosa. Because human papillomavirus (HPV) infection was suspected, immunohistochemical analysis was performed, but showed no HPV infection. Two weeks after fistulectomy, abdominoperineal resection with lymph node dissection was performed. Histopathological examination revealed no remnant cancer tissue or lymph node metastasis. She was discharged after surgery without complications. Eight years after the operation, she complained of constant pain during micturition. Urological examination revealed urinary bladder cancer, and transurethral resection of the bladder tumor was performed. Histopathological examination revealed transitional cell carcinoma of the urinary bladder. Two years later, the patient died of metastatic urinary bladder cancer, without recurrence of the fistula cancer. Because the patients mother had died of urinary bladder cancer and she herself had metachronous urinary bladder cancer in addition to fistula cancer, we investigated whether microsatellite instability (MSI) and chromosomal instability correlated with fistula cancer development. Immunohistochemical analysis of formalin-fixed, paraffin-embedded surgical tumor specimens for p53, MLH1, and MSH2 was performed. The tumor specimens showed no MLH1 expression but did show normal MSH2 expression. p53 was not expressed. Five microsatellite loci were examined using the tumor specimens to detect MSI, namely two loci with mononucleotide runs (i.e., BAT25 and BAT26) and three loci with dinucleotide repeats (i.e., APC, Mfd15, and D2S123). The tumor specimens showed alternations in the repeated sequences of two loci (i.e., BAT26 and D2S123). As a result, the tumor was classified as MSI-H (high) according to the Bethesda criteria. Our patient had MSI and one of the smallest reported SCCs arising from recurrent anal fistulae.

Mild hemophilia A diagnosed in a 55-year-old patient after pancreatoduodenectomy for carcinoma of the papilla of vater.

Hemophilia A is a sex-linked hereditary disease, and the total number of patients with this condition is small. It is quite rare for general surgeons to encounter a patient with hemophilia A. Moreover, it is extremely rare for surgeons to encounter adult patients with undiagnosed hemophilia. We describe a patient in whom intra-abdominal bleeding persisted after open abdominal surgery, leading to a diagnosis of hemophilia A. The patient was a 55-year-old man with carcinoma of the papilla of Vater who underwent pancreatoduodenectomy, during and after which hemostatic difficulties were encountered. Our initial diagnosis was complex coagulopathy; however, transfusion of a large volume of fresh frozen plasma did not improve the activated partial thromboplastin time, which led us to suspect hemophilia. Thorough personal and family histories and determination of coagulation factor VIII showed that the patient belonged to a family with hemophilia A, which had not been recognized by his parents, leading to a diagnosis of mild hemophilia A based on decreased coagulation factor VIII levels. After diagnosis, intermittent administration of a coagulation factor VIII product controlled the bleeding. The patient is currently being treated on an outpatient basis and remains free of cancer recurrence.

A case of multiple gastric carcinoids that could not be preoperatively diagnosed.

Here, we report the case of patient with multiple gastric carcinoids showing histopathological behavior similar to that of type I carcinoid tumors of the stomach. The patient was a 61-year-old man diagnosed as having a gastric tumor, which was revealed by follow-up computed tomography. Upper gastrointestinal endoscopy revealed a protruded tumor in the greater curvature and a small polyp in the anterior wall of the upper stomach. A biopsy revealed gastric carcinoid. Because he refused to be operated for gastric carcinoid, upper gastrointestinal endoscopy was performed 5 months later. A malignant transformation of the gastric carcinoid was strongly suspected. Therefore, the patient was admitted for operation. Laboratory findings were normal. With the diagnosis of type III gastric carcinoid, total gastrectomy was performed. Microscopic examination revealed that the carcinoid tumor was confined to the submucosa and that the small polyp mentioned earlier was also a carcinoid. Microcarcinoids and numerous enterochromaffin-like cell hyperplasias were observed along the muscularis propria of the fundus. The tumor differed from typical type I gastric carcinoids in several ways. Immunohistochemical staining for chromogranin A, synaptophysin, and cytokeratin was positive. However, p53 was absent, and the MIB-1 index was low. Two years after surgery, the patient is alive without recurrence.

Case of rectal malignant melanoma showing immunohistochemical variability in a tumor.

We report on a patient with rectal malignant melanoma. The patient was a 40-year-old man who complained of anal bleeding. His grandmother had died of pancreatic cancer and his mother had been operated for rectal cancer. Physical examination revealed a hard mass at the 12 o'clock position, 2 cm from the anal verge. A colonoscopic examination revealed an irregular surface mass, approximately 4.0 cm in size, located on the anterior wall of the lower rectum. A biopsy of the rectal tumor showed the proliferation of epithelioid cells with pleomorphic features. Immunohistochemical analysis was performed. S-100 protein, CD-56, and KIT expression were positive, but HMB-45 expression was negative. Abdominopelvic computed tomography (CT) revealed multiple liver and lymph node metastases. With the diagnosis of neuroendocrine carcinoma of the rectum, abdominoperineal resection was performed. After the operation, the serum lactate dehydrogenase level had rapidly increased. An abdominal CT showed progressive liver metastases. Thirteen days after the surgery, abdominal angiography was performed, which showed multiple hypervascular tumor stains in the liver. The reservoir was implanted transcutaneously with the aid of angiography and the catheter was fixed to the proper hepatic artery. Neoadjuvant chemotherapy using cisplatin and irinotecan via the subcutaneous reservoir port was performed and a partial response was obtained. However, the final pathological diagnosis of the surgically resected specimen was malignant amelanotic melanoma of the rectum. Immunohistochemical expression differed between rectal biopsy specimens and surgically resected specimens. HMB-45 expression was positive and KIT expression was negative in the resected specimen. As preoperative pathological diagnosis showed rare rectal tumor, we measured the chemosensitivity of the rectal tumor using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) to determine the most appropriate chemotherapy regimen for the patient. However, there were no anticancer drugs tested by CD-DST for malignant melanoma. With informed consent, the patient received two cycles of immunochemotherapy consisting of dacabazine, nimustine hydrochloride, vincristine sulfate, and interferon -beta. Although the patient was treated with immunochemotherapy for metastatic liver tumor, he died because of progression of metastases.

[Substance P and anticancer drug-induced emesis].

BACKGROUND: Cytotoxic drug-induced emesis is the side effect most feared by cancer patients. The Acute emesis has become well controlled by the emergence appearance of 5-HT3 receptor antagonist, but control of delayed emesis (DE) is insufficient. The mechanism of DE is different from acute emesis,and the existence of a mediator different from serotonin is contemplated. There were some reports suggesting the role of substance P (SP) and its receptor, neurokinin receptor 1 (NK 1), in the development of emesis. AIM: We investigated the relationship between DE and SP in patients treated with anticancer agents. PATIENTS AND METHOD: Digestive cancer and breast cancer patients, who were administered cytotoxic agents, were the objects of this study. We measured plasma levels of SP for 20 cases on the day before administration of anticancer agents and for five days after administration. RESULT: Plasma levels of SP increased significantly on the first and third days after administration. In the patient who experienced DE, the difference in plasma levels on the day before and the first day after chemotherapy was higher than that of who never experienced. CONCLUSION: The plasma levels of SP were transiently increased by chemotherapy. The difference in plasma levels between the day before and the first day after chemotherapy is important.

[Three advanced gastric cancer patients successfully treated by combination therapy of paclitaxel and cisplatin].

We report 3 gastric cancer patients with peritoneal dissemination who were successfully treated with weekly paclitaxel and cisplatin. The patients were 2 men and 1 woman from 57 to 70 years in age. The histological types were 2 poorly-differentiated adenocarcinomas and 1 moderately-differentiated adenocarcinoma. Intravenous infusion of PTX (80 mg/m(2)) and CDDP (25 mg/m(2)) after short premedication was continued for 3 weeks followed by 1 week rest. Ascites improved only after administration of 1 course in all patients.PTX/CDDP is thought to be an effective chemotherapy showing acceptable toxicity against advanced gastric cancer with ascites.

Neuroendocrine cell differentiation of poorly differentiated colorectal adenocarcinoma correlates with liver metastasis.

Poorly differentiated (PD) adenocarcinoma often retains the capacity for neuroendocrine (NE) cell differ-entiation; however, it is difficult to distinguish the NE cell differentiation by routine hematoxylin and eosin staining. It is important to detect the presence of NE cell differentiation in advanced colorectal carcinomas because these carcinomas have been shown to produce distant metastasis at the time of diagnosis and to have a particularly poor prognosis. In this study, the characteristics of PD adenocarcinoma with NE cell differentiation and its biological metastatic mechanisms were investigated. Forty-eight of 2204 colorectal cancer patients, diagnosed as having PD adenocarcinoma (2.2%) were enrolled in this study. Immunohistochemical analysis was performed with anti-chromogranin A anti-synaptophysin, anti-CD34, anti-D2-40, and anti-VEGF antibodies. The clinicopathological factors for PD adenocarcinoma with NE cell differentiation were compared with those for PD adenocarcinoma without NE cell differentiation. Microvessel density (MVD) was assessed using immunostained slides with anti-CD34 antibody and vascular endothelial growth factor (VEGF) expression in PD adenocarcinoma with NE cell differentiation was confirmed by in situ hybridization. By immunohistochemical staining for chromogranin A and synaptophysin, NE cell differentiation was detected in eight of 48 patients (16.7%) with PD adenocarcinoma. The frequency of liver metastasis at the time of diagnosis was significantly higher in patients having PD adenocarcinoma with NE cell differentiation (p=0.03). Moreover, MVD and VEGF expression level tended to be higher in patients having PD adenocarcinoma with NE cell differentiation (p=0.13 and 0.068, respectively). NE cell differentiation in PD adenocarcinoma may produce liver metastasis through microvessel formation in the tumor induced by VEGF. In PD colorectal adenocarcinoma, immunohistochemical analysis of NE markers is important for establishing the presence of NE cell differentiation and further study is necessary to evaluate the effectiveness of anti-angiogenic drugs to PD adenocarcinoma with NE cell differentiation.

Lumican expression in advanced colorectal cancer with nodal metastasis correlates with poor prognosis.

Lumican is a member of a small leucine-rich proteoglycan family, and it is reportedly overexpressed in human breast cancer. The expression of lumican in the extracellular matrix in breast cancer is associated with a high tumor grade, low estrogen receptor levels and young age. Lumican expression has been previously reported in colorectal cancer, but the role of lumican in the tumor is not well understood. In this study, we examined the expression and role of lumican in advanced colorectal cancer. Immunohistochemical staining was performed on 158 patients who underwent curative surgery for advanced colorectal cancer with lymph node metastasis. In the normal colorectal tissues, lumican immunoreactivity was observed in the fibroblasts and neural cells, but not in the colorectal epithelial cells. Lumican was localized in the cytoplasm of the cancer cells and its overexpression was detected in 99 of the 158 (62.7%) colorectal cancer patients. Clinicopathologically, there was no association of lumican expression with age, sex, histological typing, or venous and lymphatic invasion. However, lumican expression tended to correlate with the spread of lymph node metastasis and the depth of tumor invasion (p=0.136 and 0.135, respectively). Furthermore, the survival rate was significantly lower in patients with a high lumican expression level than in those with a low lumican expression level (p=0.048). These results indicate that lumican expression is a potential prognostic factor in patients with advanced colorectal cancer with nodal metastasis.

Ubiquitin-specific protease 14 expression in colorectal cancer is associated with liver and lymph node metastases.

Ubiquitin-specific protease 14, also known as the 60 kDa subunit of tRNA-guanine transglycosylase (USP14/TGT60 kD), belongs to the ubiquitin-specific processing protease (UBP) family. USP14/TGT60 kD expression in leukemic and colorectal cancer cell lines, and the suppression of such an expression after the induction of cell differentiation have been reported. In the present study, we attempted to clarify whether USP14/TGT60 kD overexpression affects the clinicopathological features of colorectal cancer. Immunohistochemically, USP14/TGT60 kD was absent or weakly localized in the cytoplasm of normal colorectal epithelial cells. In 18 of 99 (18.2%) colorectal cancer patients, USP14/TGT60 kD was strongly detected in the cytoplasm of cancer cells. USP14/TGT60 kD expression correlated with pathological stage (P=0.03), and lymph node (P=0.03) and liver (P=0.03) metastases. Furthermore, the percentage of patients strongly positive for USP14/TGT60 kD expression increased with pathological stage. The overall survival rate was worse in patients with a high USP14/TGT60 kD expression level than in those with a low USP14/TGT60 kD expression level. Our results suggest that USP14/TGT60 kD also controls the fate of proteins that regulate tumor invasion and metastasis.