Influence of splenectomy in patients with liver cirrhosis and hypersplenism.

AIM: Splenectomy improves hypersplenic thrombocytopenia in cirrhotic patients with hypersplenism. However, the long-term influence of splenectomy has not been clarified. We examined whether splenectomy improved liver fibrosis and caused immunological changes. METHODS: We collected liver and spleen specimens and peripheral blood (PB) from 26 patients with hepatitis C virus-related liver cirrhosis. An immunohistochemical examination of CD4, CD8, forkhead box P3, granzyme B and transforming growth factor-ß1, and Masson-trichrome stain were performed in spleen and liver tissues and in seven cases of follow-up liver biopsy sections obtained after splenectomy. We obtained PB before and at various intervals after splenectomy. We also examined the ratio of CD4(+) and CD8(+) lymphocytes in PB using flow cytometry. RESULTS: We observed improvements in liver fibrosis in four biopsy specimens obtained after splenectomy, in which fibrotic areas significantly decreased from 19.5% to 8.2% (P < 0.05). Increases were also observed in the ratio of CD8(+) cells in PB after splenectomy, which resulted in a significant decrease in the CD4(+) /CD8(+) ratio (P < 0.001). The carcinogenic rate in patients with a CD4(+) : CD8(+) ratio that decreased by more than 0.5 at 1 month after splenectomy was significantly lower than that in patients with a ratio that decreased by less than 0.5 (P < 0.05). CONCLUSION: Splenectomy may improve liver fibrosis and cause beneficial immunological changes in cirrhotic patients with hepatitis. Improvements in antitumor mechanisms can be also expected.

Side population cell fractions from hepatocellular carcinoma cell lines increased with tumor dedifferentiation, but lack characteristic features of cancer stem cells.

BACKGROUND AND AIM: Cancer stem cells (CSCs), a minority population with stem cell-like characteristics, play important roles in cancer development and progression. Putative CSC markers, such as CD13, CD90, CD133, and epithelial cell adhesion molecule (EpCAM), and side population (SP) technique are generally used in an attempt to isolate CSCs. We aimed to clarify the relationship between CSCs and clonal dedifferentiation in hepatocellular carcinoma (HCC). METHODS: We used a well-differentiated HCC cell line (HAK-1A) and a poorly differentiated HCC cell line (HAK-1B) established from a single nodule with histological heterogeneity. HAK-1B arose because of clonal dedifferentiation of HAK-1A. The SP cells and non-SP (NSP) cells were isolated from the two cell lines with a FACSAria II and used for the analyses. RESULTS: The SP cell fractions in HAK-1A and HAK-1B were 0.2% and 0.9%, respectively. CD90 or EpCAM was not expressed in either HAK-1A or HAK-1B, while CD13 and CD133 were expressed in HAK-1B alone. Although sphere forming ability, tumorigenicity, growth rate, and CD13 expression were higher in HAK-1B SP cells than HAK-1B NSP cells, there were no differences in drug resistance, colony forming ability, or cell cycle rates between HAK-1B SP and NSP cells, suggesting HAK-1B SP cells do not fulfill CSC criteria. CONCLUSIONS: Our findings suggested a possible relationship between the expression of CSC markers and clonal dedifferentiation. However, the complete features of CSC could not be identified in SP cells, and the concept of SP cells as a universal marker for CSC may not apply to HAK-1A and HAK-1B.

Noninvasive diagnosis of compensated cirrhosis using an analysis of the time-intensity curve portal vein slope gradient on contrast-enhanced ultrasonography.

PURPOSE: We measured the slope gradients (SGs) of the vascular time-intensity curves (TICs) of the intrahepatic vessels on contrast-enhanced ultrasonography (CEUS). The aim of this study was to assess the diagnostic accuracy of the SG of each hepatic vessel, particularly the portal vein (PV), for detecting cirrhosis and to compare this method with conventional modalities. METHODS: Fifty-one preoperative patients underwent CEUS, and the TICs were plotted. The SGs of the hepatic artery, PV and hepatic vein were obtained from the linear functions between the slope of the arrival time of the contrast agent and the peak enhancement time of each vessel. The transit times and levels of biochemical markers were also measured. The patients were divided into three groups according to the Metavir score: F0/1 group (n = 14), F2/3 group (n = 21) and F4 group (n = 16). RESULTS: The PVSG significantly decreased in the F4 group (F0/1: 29.1 ± 2.27, F2/3: 23.1 ± 1.86, F4: 14.7 ± 2.13). The PVSG demonstrated high accuracy for diagnosing cirrhosis and was correlated with the levels of ICG-R15 and hyaluronic acid (Spearman rank correlation; ρ = -0.5691, p < 0.001 and ρ = -0.4652, p = 0.0006). CONCLUSIONS: The PVSG has the potential to be a diagnostic marker for identifying patients with well-compensated cirrhosis.

[Current surgical management of cancer of the ampulla of Vater].

Pancreatoduodenectomy (PD) is the standard radical treatment for cancer of the ampulla of Vater. Among patients we have treated in whom lymph node metastasis of cancer of the ampulla of Vater occurred, more positive lymph nodes surrounding the superior mesenteric artery were seen in one (patient No. 14), whereas more positive lymph nodes surrounding the anterior and posterior pancreas head were seen in another (No. 13). Six patients with lymph node metastasis achieved long-term survival after PD with lymph node dissection. This appears to be an adequate surgical treatment for cancer of the ampulla of Vater. From the viewpoint of radical treatment, local resection (LR) of the ampulla of Vater cannot be selected as a less-invasive procedure. However, LR of the ampulla of Vater can be performed in very elderly patients and patients in poor general condition for whom PD is considered excessively invasive due to small tumor size.

Evaluation of magnifying endoscopy using narrow band imaging using ex vivo bile duct (with video).

BACKGROUND AND AIM: Detailed endoscopic findings of the bile duct mucosa, even of the non-neoplastic mucosa, have not yet been established. The aim of the present study was to compare a currently used video cholangioscope (CCS) with a magnifying endoscope (ME) that is commonly used for the gastrointestinal tract, for visualization of the bile duct mucosa. METHODS: Ten freshly resected common bile ducts were used in this study. We observed the non-neoplastic bile duct mucosa with CCS and ME, and carried out both conventional white light imaging and narrow band imaging. After histological diagnosis, the 10 specimens were classified into three categories according to the degree of histological inflammation: normal to mild, moderate, and severe. Then, we examined the relationship between the magnifying endoscopic findings and the histopathological findings. RESULTS: In eight of the 10 cases, the visualization obtained with CCS was inferior to that obtained by ME. Five specimens were classified as normal to mild inflammation, and many oval-shaped, depressed areas and a fine, regular network of the microvessels were observed by ME on the mucosal surfaces of these specimens. The remaining specimens were classified as moderate or severe inflammation, and the aforementioned findings could not be clearly visualized. CONCLUSION: CCS does not allow visualization of the bile duct mucosa with high sensitivity. Oval-shaped depressed areas and a fine, regular network of microvessels are characteristic endoscopic features of non-neoplastic bile duct mucosa without inflammation.

[A long-term survivor of advanced gallbladder carcinoma treated with curative operation and hepatic arterial infusion].

60-year-old woman was referred to us for epigastralagia under the diagnosis of chronic cholecystitis. Cholecystectomy was performed, and gallbladder carcinoma was pinpointed by postoperative pathological diagnosis. Because liver invasion should have been detected by pathological diagnosis, we conducted liver S4a+S5 resection, extrahepatic bile duct resection and D2 lymphadenectomy. The pathological diagnosis was advanced gallbladder carcinoma with liver metastasis. We treated a patient with curative operation and hepatic arterial infusion adjuvant chemotherapy by low-dose FP therapy for advanced gallbladder carcinoma, and she is doing well now without disease recurrence eight years after surgery.

Metastatic pulmonary adenocarcinoma 13 years after curative resection for pancreatic cancer: report of a case and review of Japanese literature.

CONTEXT: For the majority of patients, ductal adenocarcinoma of the pancreas remains a lethal disease. Currently, surgical extirpation for localized disease offers the only chance for long-term survival. CASE REPORT: We report a patient who underwent successful resection of isolated lung metastasis occurring 13 years after pancreatic cancer resection. A 59-year-old woman underwent distal pancreatectomy for pancreatic cancer 13 years previously, followed by adjuvant chemotherapy, and was followed-up at the outpatient clinic of a local hospital. From around June 2010, she noticed bloody sputum, so she visited a local hospital. Since her chest X-ray and CT revealed a 1.5 cm mass shadow in the segment 10 of her right lung and she was referred to the Respiratory Disease Center of our hospital. As a result of through examinations, she was strongly suspected of having lung metastasis of pancreatic cancer, and underwent partial pneumonectomy. Postoperative histopathological examination of the resected specimen was consistent with lung metastasis of pancreatic cancer. She is still alive and currently receives third line of chemotherapy. CONCLUSION: Patients who have achieved long-term survival after pancreatic cancer resection and can tolerate surgery may benefit from resection of a lung metastasis of pancreatic cancer in terms of survival, if it controls the metastasis.

[Endoscopic retrograde biliary drainage for the liver metastases from colorectal cancer and obstructive jaundice].

UNLABELLED: The success of biliary drainage in patients with liver metastases from colorectal cancer and obstructive jaundice influences its prognosis greatly. In this study, we report a retrospective evaluation of endoscopic retrograde biliary drainage in patients with liver metastases from colorectal cancer and obstructive jaundice. MATERIALS AND METHODS: From April 2004 to December 2011, 9 patients with liver metastases from colorectal cancer and obstructive jaundice who underwent endoscopic biliary drainage were evaluated retrospectively. RESULTS: The mean serum levels of total bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase improved significantly after biliary drainage. The median survival time after biliary drainage was 133 days. Only 4 cases were able to resume chemotherapy after biliary drainage, and their prognosis was significantly better than patients who were not able to resume chemotherapy(p=0.014). DISCUSSION: Endoscopic biliary drainage in patients with liver metastases from colorectal cancer and obstructive jaundice was effective, led to the resumption of chemotherapy, and improved prognosis. However, sufficient consideration of the patient's prognosis and performance status is required in order to perform biliary drainage.

Accuracy of differential diagnosis for pancreatic cancer is improved in the combination of RCAS1 and CEA measurements and cytology in pancreatic juice.

Improvement of diagnostic accuracy for pancreatic cancer in pancreatic disease patients was investigated by examining the combination of three diagnostic methods, i.e., measurements of RCAS1 and CEA levels in pancreatic juice and pancreatic juice cytology. Pancreatic juice was collected from 12 pancreatic cancer (PC) and 26 non-PC patients. RCAS1 and CEA levels were measured by using ELISA. RCAS1 expression on surgically resected tissue was immunohistochemically examined for 2 PC patients. By setting the cutoff level of RCAS1 at 10 U/ml and that of CEA at 18.5 µg/ml, sensitivity of RCAS1 was 42% and that of CEA was 50%. On the other hand, sensitivity and specificity increased from 42% and 85% of RCAS1 alone to 75% and 85% in the examination of RCAS1 + CEA + cytology, and the false-negative rate was also reduced to 25% in this combination. Immunohistochemically, a patient with a high RCAS1 level in pancreatic juice had numerous RCAS1-positive tumor cells in the pancreatic juice. We concluded that RCAS1 and CEA measurements together with cytology in pancreatic juice would be a useful combination method for making a differential diagnosis of PC from non-PC.

[A pilot study of intraperitoneal gemcitabine for reduction of peritoneal dissemination in advanced pancreatic cancer].

We schemed intraperitoneal gemcitabine (ipGEM) for reduction of peritoneal dissemination to three patients with unresectable and one patient with recurrent pancreatic cancer, followed by intraperitoneal catheter and subcutaneous port placement. Two locally advanced cases were performed for intra-operative radiotherapy, and one of 2 locally advanced cases was performed for gastrojejunostomy. And another locally advanced case had ileostomy. The recurrent case was resected for metastatic tumor of abdominal wall. In one of locally advanced cases, we couldn't perform ipGEM for progression of disease. In two remaining locally advanced cases, we could keep on doing ipGEM, and the patients did not experience with abdominal discomfort or hematological toxicity.

[An example case that chemoradiotherapy was succeeded for unresectable pancreas cancer].

BACKGROUND: Prognosis of pancreas cancer is extremely poor. For unresectable pancreas cancer, there has not been an effective method of treating. In our institution, the mean survival time was 13 . 6 months for a chemoradiotherapy case that used gemcitabine (GEM), but was 7.3 months for a non-treatment case in locally advanced and metastatic pancreas cancer. This time, we experienced a good case for unresectable pancreas cancer treated with chemoradiotherapy using GEM/S-1 that clearly exhibited a decrease in tumor size by tumor marker.

[A case of peritoneal recurrence of invasive carcinoma derived from IPMN after distal pancreatectomy].

The patient was a 62-year-old man who underwent distal pancreatectomy and partial resection of transverse colon with diagnosis of cystic tumor of pancreas tail in July 2006. In histology, the tumor was an invasive carcinoma derived from intraductal tumor. So, Chemotherapy using gemcitabine (GEM) was administered. Eleven months after the operation, abdominal contrast-enhanced CT showed a cystic tumor in the subdiaphragm and CEA increased to 15 .2 ng/mL. Combination chemotherapy using GEM and S-1 was administered under the diagnosis of peritoneal recurrence. CEA decreased to a normal level, but 19 months after the operation, CA19-9 increased to 187 .7 U/mL. Then, radiotherapy (a total of 40 Gy) was performed. Twenty two months after the radiotherapy, though chemotherapy using S-1 was continued, CA19-9 re- increased to 134 .2 U/mL. Abdominal contrast-enhanced CT and PET detected no other recurrent lesion. A tumor resection was performed in January 2010. In immunostaining MUC1(+), MUC2(-), MUC5AC(+), MUC6(+) and mucus expression forms as well as with previous specimen, and was diagnosed as recurrence of the invasive carcinoma derived from intraductal tumor.

[Liver histology and surgical outcomes after preoperative chemotherapy in colorectal cancer liver metastases].

We aimed to assess hepatic histopathological responses to preoperative chemotherapy in patients with colorectal liver metastasis. We selected all patients(n=34)with colorectal liver metastases between September 2006 and March 2009. The preoperative chemotherapy group was significantly associated with tumor regression, inflammatory response, sinusoidal dilatation compared with non-chemotherapy group. There was no difference in the rate of postoperative complications and hospital stay. Prolonged preoperative systemic chemotherapy alters liver parenchyma, but it does not increase postoperative complications. This should be taken into consideration before deciding a major liver resection in patients who have received preoperative chemotherapy.

Perioperative challenges associated with a pancreaticoduodenectomy and distal pancreatectomy for pancreatic cancer in patients with situs inversus totalis: report of two cases.

Situs inversus totalis is a rare anatomic variant of a complete mirror-image transposition of the thoracic and abdominal viscera. The performance of a pancreaticoduodenectomy and distal pancreatectomy in patients with situs inversus totalis is both rare and challenging. We herein present two cases of pancreatic cancer with situs inversus totalis. The abdominal anatomy was preoperatively assessed by multidetectorrow computed tomography, three-dimensional reconstruction, and angiography. We herein report that a pancreaticoduodenectomy and distal pancreatectomy with standard regional lymphadenectomy are feasible in patients with situs inversus totalis. Due to the transposition of the viscera and major blood vessels in such cases, preoperative knowledge of the exact anatomy, mapping of anomalies, and meticulous forward planning are essential for performing these technically difficult and complex hepatobiliary-pancreatic surgeries.

Comparison of liver regeneration after a splenectomy and splenic artery ligation in a dimethylnitrosamine-induced cirrhotic rat model.

AIM: A splenectomy and splenic artery ligation accelerate liver regeneration and improve liver function after a hepatectomy. However, there are no studies that directly compared the effects of a splenectomy and splenic artery ligation. In the present study, we compared the effects of a splenectomy and splenic artery ligation in cirrhotic rats. METHODS: Dimethylnitrosamine (DMN) was administered intraperitoneally for 4 weeks to induce cirrhosis. The rats were divided into three groups: sham operation (CT group), splenic artery ligation (SAL group) and splenectomy (SP group). Liver functions [alanine aminotransferase (ALT) and total bilirubin (T. Bil)], plasma TGF-beta1, histopathological changes, extent of liver fibrosis (fibrotic rate) and regeneration [Ki-67 labelling index(LI)] were investigated in each group. RESULTS: ALT and T. Bil levels were significantly lower in the SP group than the CT and SAL groups. TGF-beta1 levels were significantly lower in the SP group than in the CT and SAL groups. The fibrotic rate was significantly lower in the SP group than in the CT and SAL groups. The Ki-67 labelling index was significantly higher in the SP group than in the CT and SAL groups. DISCUSSION: A splenectomy significantly improved liver regeneration with reduction of plasma TGF-beta1 levels compared with splenic artery ligation in DMN-treated cirrhotic rats.

[Laparoscopic radiofrequency ablation for hepatocellular carcinoma].

We examined the case of laparoscopic radiofrequency ablation (L-RFA) to hepatocellular carcinoma (HCC), and then the method of this treatment was considered in terms of selection and adjustment. Between January 2008 and May 2010, L-RFC was performed on 18 cases (27 tumors). A total operation time was 203 minutes (± 85.5). The median survival time was 562 days (± 197 day). The amount of blood was 21.0 g (± 68.4), and 3 postoperative complications (pleural effusion) were observed. The average length of hospital stay after the operation was 8 days. There was no vestigial remnant in all cases after the operation. The prognosis of death due to a liver failure was one case on the 516th day after the operation. All other 17 cases were survived. If the tumors were identified by the naked eye and ultrasonography, and considering the position in relation to the main vas, the ablation would be possible for the troublesome part in case of the percutaneous approach. Therefore, we thought the application of RFA to HCC would be more expandable.

The effect of adjuvant and neoadjuvant chemo(radio)therapy on survival in 1,679 resected pancreatic carcinoma cases in Japan: report of the national survey in the 34th annual meeting of Japanese Society of Pancreatic Surgery.

BACKGROUND: Pancreatic carcinoma causes more than 20,000 deaths every year in Japan. The role of (neo-) adjuvant chemotherapy for pancreatic carcinoma is still controversial. METHODS: At the 34th Annual Meeting of the Japanese Society of Pancreatic Surgery in 2007, questionnaires were distributed regarding the use of (neo-) adjuvant chemo(radio)therapy for pancreatic carcinoma between 2001 and 2005. RESULTS: Sixty of the 146 member institutions responded to the questionnaires. There were a total of 1,846 cases of resected pancreatic carcinoma between 2001 and 2005. The study population had a greater proportion of males, and a mean age of 65.3 years (range 34-90 years). The lesion was located in the head of the pancreas in 1,204 cases (71.7%), in the body in 353 cases (21.0%), and in the tail in 111 cases (6.6%). Overall survival rates were 67.3% at 1 year, 36.0% at 2 years, and 23.9% at 3 years, respectively. Adjuvant chemotherapy (usually involving gemcitabine) was used in 66.0% of cases. The use of adjuvant chemotherapy was found to improve the overall survival rate. Interestingly, adjuvant chemotherapy only improved survival in late-stage (UICC stages IIB, III, and IV) but not early stage (IA, IB, and IIA) patients. Survival was treatment duration-dependent, with patients who received more than 12 months of therapy having a 3-year survival rate of 51.2%. CONCLUSION: This high volume retrospective data indicated the promising effect of gemcitabine-based adjuvant chemotherapy and the rational duration of adjuvant chemotherapy should be determined in the future prospective studies.

Pathomorphologic study of undifferentiated carcinoma in seven cases: relationship between tumor and pancreatic duct epithelium.

BACKGROUND/PURPOSE: By the time undifferentiated carcinoma is detected, it has formed a large mass, and it is reportedly difficult to pathologically observe its relationship with the pancreatic duct. In this study, we examined the pancreatic ducts of seven patients of surgical samples, and pathomorphologically investigated the relationship between the adenocarcinomatous and sarcomatous components and the pattern of tumor extension. In addition, we evaluated the usefulness of pancreatic juice cytology by comparison with the findings of the main pancreatic duct (MPD). METHODS: Seven primary undifferentiated carcinomas of the pancreas (from three male and four female patients with a mean age of 59 years) were analyzed. Histopathological evaluation was based on the WHO diagnostic criteria. Pancreatic juice cytology was performed and evaluated in two patients. RESULTS: All the undifferentiated carcinomas contained adenocarcinomatous and sarcomatous components, and two had a distinct glandular structure. However, we could not pathomorphologically confirm the continuity of the adenomatous with the sarcomatous components in any of the patients. Three undifferentiated carcinomas contained osteoclast-like giant cells. Pathological observation of the tumor and MPD was possible in three of the seven undifferentiated carcinomas. PanIN-3 was observed in the MPD of three patients, suggesting extension into the MPD. In one of these three, the tumor presented intraductal growth in the MPD, and preoperative pancreatic juice cytology revealed atypical cells with osteoclast-like giant cells. In the remaining two, the tumor extraductally compressed the MPD upward. CONCLUSIONS: Undifferentiated carcinoma showed two patterns of cancer extension: (1) invasion and expansive growth during the sarcomatous transformation of adenocarcinoma, and (2) intraductal extension. In addition, some undifferentiated carcinomas showed extension in the MPD. Of note, postoperative pancreatic juice cytology may be useful for the diagnosis.

Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis.

Cap43 has been identified as a nickel- and calcium-induced gene, and is also known as N-myc downstream-regulated gene 1 (NDRG1), Drg-1 and rit42. It is also reported that overexpression of Cap43 suppresses metastasis of some malignancies, but its precise role remains unclear. In this study, we asked how Cap43 could modulate the tumor growth of pancreatic cancer. Stable Cap43 cDNA transfectants of pancreatic cancer cells with Cap43 overexpression showed similar growth rates in culture as their control counterparts with low Cap43 protein level. By contrast, Cap43 overexpression showed a marked decrease in tumor growth rates in vivo. Moreover, a marked reduction in tumor-induced angiogenesis was observed. Gelatinolytic activity by matrix metalloproteinase-9 and invasive ability in Matrigel invasion activity were markedly decreased in pancreatic cancer cell lines with high Cap43 expression. Cellular expression of matrix metalloproteinase-9 and two major angiogenic factors, vascular endothelial growth factor and interleukin-8, were also significantly decreased in cell lines with Cap43 overexpression as compared with their parental counterparts. Immunohistochemical analysis of specimens from 65 patients with pancreatic ductal adenocarcinoma showed a significant association between Cap43 expression and tumor microvascular density (P = 0.0001) as well as depth of invasion (P = 0.0003), histopathologic grading (P = 0.0244), and overall survival rates for patients with pancreatic cancer (P = 0.0062). Thus, Cap43 could play a key role in the angiogenic on- or off-switch of tumor stroma in pancreatic ductal adenocarcinoma.