Shunichi Okushiba

CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.

Objective Recent studies have demonstrated the importance of tumor immunity for a cancer patients prognosis. In some types of cancer, it has been shown through immunohistochemical analysis that the existence of CD8+ tumor-infiltrating lymphocytes (TILs) is a crucial factor in determining prognosis. In an experimental model, CD4+ lymphocytes together with CD8+ lymphocytes contributed significantly to tumor immunity. Methods Specimens were taken from 80 surgically resected pancreatic adenocarcinomas between 1992 and 1999. Immunohistochemical staining of CD4, CD8, and S100 protein was performed, and the levels of these proteins were determined by microscopic analysis. The percentages of patients in the CD4(+) and CD8(+) groups were 59% (47/80) and 25% (16/80), respectively. When separated into 4 groups, CD4/8(+/+), CD4/8(+/−), CD4/8(−/+) and CD4/8(−/−), the overall survival rate was significantly higher in CD4/8(+/+) patients (13 cases) compared with those in all other groups combined (67 cases; P = 0.0098). CD4/8(+/+) status was negatively correlated with tumor depth and TNM stage. Multivariate analyses showed that CD4/8(+/+) status was an independent favorable prognostic factor. The number of tumor-infiltrating S100 protein positive cells was also significantly higher in the CD4/8(+/+) group than in others (P = 0.0084). Conclusions In pancreatic adenocarcinoma, the presence of CD4+ TILs together with CD8+ TILs serves as a good indicator of the patients outcome after surgical treatment.

Forty Consecutive Resections of Hilar Cholangiocarcinoma With No Postoperative Mortality and No Positive Ductal Margins: Results of a Prospective Study

Objective:Our objective was to perform a prospective study of surgical treatment of hilar cholangiocarcinoma according to newly established guidelines for performing safe and curative resections. Summary Background Data:The poor survival rate after resection of hilar cholangiocarcinoma is considered to be mainly the result of in-hospital death and positive ductal margins. Methods:Between July 1999 and December 2002, 40 of 42 surgically explored patients with hilar cholangiocarcinoma underwent resection. They were managed with preoperative biliary decompression, portal embolization, cholangiographic evaluation, and a choice of surgical procedures and techniques. Results:Hospital or 30-day mortality and morbidity rates were 0% and 48%, respectively. Hepatic failure was not encountered. Histopathologic examination revealed no positive ductal margins in all 40 patients, but 2 showed positive separation margins from the right hepatic artery. The overall 3-year survival rate and median survival time were 40% and 27 months. Survival of patients with Bismuth type III or IV tumors or of patients who underwent right hepatectomy was significantly better. Survival of patients who underwent concomitant vascular resection was similar to survival of those who did not. Univariate analysis indicated the type of hepatectomy, histopathologic grade, Bismuth classification, concomitant hepatic artery resection, and International Union Against Cancer stage as significant prognostic factors. Conclusions:No postoperative mortality and no positive ductal margins were achieved according to the above guidelines in a high-volume expert center. Long-term results, however, have not been significantly improved. A survival analysis of the patient series with homogeneous conditions derived from a short study period suggests the need for additional strategies including right hepatectomy for Bismuth type I or II tumors.

Expression of Pigment Epithelium-Derived Factor Decreases Liver Metastasis and Correlates with Favorable Prognosis for Patients with Ductal Pancreatic Adenocarcinoma

Pigment epithelium-derived factor (PEDF) is expressed in several normal organs and identified as an inhibitor of neovascularization. In the present study, we screened the expression of PEDF immunohistochemically and investigated its correlation with clinicopathological features in patients who underwent surgery for ductal pancreatic adenocarcinoma. Of the 80 patients, 22 cases (27.5%) were positive for PEDF. A significant association was found between the PEDF expression and low microvessel density (P = 0.0003). No correlation was found between PEDF expression and age, gender, depth of invasion, tumor diameter, lymphatic invasion, venous, invasion or histopathological grading. The patients in pathological stage II had a significantly higher incidence of PEDF-positive expression than those in pathological stage III or IVA (P = 0.0418). PEDF immunoreactivity was inversely associated with liver metastasis (P = 0.0422). The survival of patients that were PEDF positive was significantly longer than that of those with negative expression (P = 0.0026). Multivariate analysis using the Cox regression model indicated that PEDF-positive expression was an independent favorable prognostic factor (risk ratio, 0.394; P = 0.0016). We conclude that PEDF expression suggests a more favorable prognosis than in patients whose carcinomas lack PEDF expression.

Perineural invasion by ductal adenocarcinoma of the pancreas

The correlation between various levels of perineural invasion by pancreatic carcinoma and the patients prognosis has never been cleared. The authors carried out a histopathologic study of resected pancreatic carcinoma to elucidate the significance of a new histologic finding concerning perineural invasion, which we designated “ntrapancreatic, extratumoral perineural invasion (nex),” and also to determine its predictive value for prognoses of patients after surgical removal of the tumor.

The role of radiotherapy in the management of extrahepatic bile duct cancer: An analysis of 145 consecutive patients treated with intraluminal and/or external beam radiotherapy

PURPOSE To determine the feasibility of high dose radiotherapy and to evaluate its role in the management of extrahepatic bile duct (EHBD) cancer. METHODS AND MATERIALS Between 1983 and 1991, 145 consecutive patients with EHBD cancer were treated by low dose rate intraluminal 192Ir irradiation (ILRT) either alone or in combination with external beam radiotherapy (EBRT). Among the primarily irradiated, 77 patients unsuitable for surgical resection, 54 were enrolled in radical radiotherapy, and 23 received palliative radiotherapy. Fifty-nine received postoperative radiotherapy, and the remaining 9 preoperative radiotherapy. The mean radiation dose was 67.8 Gy, ranging from 10 to 135 Gy. Intraluminal 192Ir irradiation was indicated in 103 patients, and 85 of them were combined with EBRT. Expandable metallic biliary endoprosthesis (EMBE) was used in 32 primarily irradiated patients (31 radical and 1 palliative radiotherapy) after the completion of radiotherapy. RESULTS The 1-, 3-, and 5-year actuarial survival rates for all 145 patients were 55%, 18%, and 10%, for the 54 patients treated by radical radiotherapy (mean 83.1 Gy), 56%, 13%, and 6% [median survival time (MST) 12.4 months], and for the 59 patients receiving postoperative radiotherapy (mean 61.6 Gy), 73%, 31%, and 18% (MST 21.5 months), respectively. Expandable metallic biliary endoprosthesis was useful for the early establishment of an internal bile passage in radically irradiated patients and MST of 14.9 months in these 31 patients was significantly longer than that of 9.3 months in the remaining 23 patients without EMBE placement (p < 0.05). Eighteen patients whose surgical margins were positive in the hepatic side bile duct(s) showed significantly better survival compared with 15 patients whose surgical margins were positive in the adjacent structure(s) (44% vs. 0% survival at 3 years, p < 0.001). No survival benefit was obtained in patients given palliative or preoperative radiotherapy. Gastroduodenal complications increased in those receiving doses of 90 Gy or more, and serious biliary bleeding was experienced in three preoperatively irradiated patients. Complications in other patients was tolerable. CONCLUSIONS High-dose radiotherapy, consisting of ILRT and EBRT, appears to be feasible in the management of EHBD cancer, and it offers a survival advantage for patients not suited for surgical resection and patients with positive margins in the resected end of the hepatic side bile duct. Expandable metallic biliary endoprosthesis assists the internal bile flow and may lengthen survival after high dose radiotherapy.

Gene-expression profile changes correlated with tumor progression and lymph node metastasis in esophageal cancer

Purpose: The purpose of this research was to identify molecular clues to tumor progression and lymph node metastasis in esophageal cancer and to test their value as predictive markers. Experimental Design: We explored the gene expression profiles in cDNA array data of a 36-tissue training set of esophageal squamous cell carcinoma (ESCC) by using generalized linear model-based regression analysis and a feature subset selection algorithm. By applying the identified optimal feature sets (predictive gene sets), we trained and developed ensemble classifiers consisting of multiple probabilistic neural networks combined with AdaBoosting to predict tumor stages and lymph node metastasis. We validated the classifier abilities with 18 independent cases of ESCC. Results: We identified 71 genes of 1289 cancer-related genes of which the expression correlated with tumor stages. Of the 71 genes, 47 significantly differed between the Tumor-Node-Metastasis pT1/2 and pT3/4 stages. Cell cycle regulators and transcriptional factors possibly promoting the growth of tumor cells were highly expressed in the early stages of ESCC, whereas adhesion molecules and extracellular matrix-related molecules possibly promoting invasiveness increased in the later stages. For lymph node metastasis, we identified 44 genes with predictive values, which included cell adhesion molecules and cell membrane receptors showing higher expression in node-positive cases and cell cycle regulators and intracellular signaling molecules showing higher expression in node-negative cases. The ensemble classifiers trained with the selected features predicted tumor stage and lymph node metastasis in the 18 validation cases with respective accuracies of 94.4% and 88.9%. This demonstrated the reproducibility and predictive value of the identified features. Conclusion: We suggest that these characteristic genes will provide useful information for understanding the malignant nature of ESCC as well as information useful for personalizing the treatments.

Effectiveness of Radiation Therapy After Surgery for Hilar Cholangiocarcinoma

PurposeSome studies suggest that giving radiation therapy after surgery for hilar cholangiocarcinoma improves the survival rate; however, many of these studies did not specify numbers of subjects or provide an impartial analysis. Thus, we evaluated the effectiveness of radiation therapy as adjuvant treatment after surgery and attempted to establish appropriate adaptation standards.MethodsWe reviewed the records of 69 patients who underwent surgery for hilar cholangiocarcinoma between June 1980 and April 1998. Thirty-nine patients were treated with surgery followed by radiation therapy and 30 were treated with surgery alone.ResultsThe clinicopathologic features that might have influenced prognosis were similar in the patients who received radiation therapy and those who did not. Radiation as adjuvant therapy did not have a beneficial effect on overall survival (P = 0.554, log-rank test); however, it tended to improve survival in the group of patients who underwent curative resection for with p-stage III or IVa disease (P = 0.042, log-rank test).ConclusionsRadiation therapy after surgery did not show any clinical benefits for patients with hilar cholangiocarcinoma. However, it may be effective as adjuvant therapy after curative resection in a small subgroup of patients with p-stage III or IVa disease.

Ischemic gastropathy after distal pancreatectomy with celiac axis resection.

PurposeStomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric arteries is a radical operation performed for locally advanced cancer of the pancreatic body. However, it is not known whether the collateral pathways that develop immediately from the superior mesenteric artery to the gastroduodenal and hepatic arteries provide sufficient blood flow to support the hepatobiliary system and the stomach. This article examines the ischemic gastropathy that can occur after this procedure and identifies the predisposing conditions.MethodsBetween 1997 and 2001, nine patients underwent stomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric arteries. Concomitant resection of the right gastric artery or gastroduodenal artery was performed due to cancer infiltration in three patients.ResultsIrregular, shallow, and wide ulcerations thought to be ischemic in origin developed in these three patients, but all the ulcerations healed in 1–2 weeks with antiulcer medication. None of the other six patients had evidence of gastric ischemia.ConclusionsIschemic gastropathy is rare after distal pancreatectomy with celiac axis resection alone; however, division of additional arteries supplying the stomach may predispose to ischemic gastropathy.

Analysis of predictive factors for recurrence after hepatectomy for colorectal liver metastases.

Hepatectomy for liver metastases from colorectal cancer has recently received general acceptance as a safe, potentially curative treatment. Most patients, however, die of recurrent disease after hepatectomy. The predictive factors for recurrence after first resection of liver metastases have not yet been clarified. The authors aimed to determine the factors that can predict recurrence, especially hepatic-only recurrence after hepatectomy for colorectal liver metastases. Seventy-six patients who underwent liver resection of colorectal metastases were studied retrospectively. Forty-seven (61.8%) of the patients had a recurrence. The patients’ disease-free survival after first hepatectomy and the second recurrence sites were univariately and multivariately analyzed using 16 clinicopathologic variables. Wall invasion, lymph node metastases, lymphatic invasion, venous invasion of the primary tumor, 24 months or longer disease-free interval after resection of the primary colorectal cancer, and bilateral liver metastases significantly influenced the disease-free survival (log-rank test:p<0.05). The multivariate analysis revealed that venous invasion of the primary tumor and bilateral hepatic metastases were independent risk factors for recurrence after hepatectomy. The liver was the only site of second recurrence in 23 patients. Patients with lymph node metastases and venous invasion of the primary tumor had a significant difference between hepatic-only and extrahepatic recurrence after first hepatectomy (chi-square test or Fishers’ exact test:p<0.05). Recurrence after hepatectomy was influenced more by factors associated with the primary colorectal cancer than factors surrounding the first liver metastases. Venous invasion of the primary colorectal cancer was the most important predictable factor for hepatic-only second recurrence.RésuméOn considère que la résection de métastases hépatiques provenant de cancer colorectal est un procédé acceptable, sur et potentiellement curateur. La plupart des patients, cependant, meurent de récidives après résection hépatique. Les facteurs prédictifs de récidive, après une première résection de métastases hépatiques, ne sont pas encore établis. Le but ici a été de déterminer les facteurs qui peuvent prédire la récidive, surtout les récidives hépatiques seules, après résection de métastases de cancer colorectal. On a étudié 76 patients ayant eu une résection de métastases d’origine colorectale de façon rétrospective. Quarante-sept (61.8%) patients ont récidivé. On a réalisé une analyse mono et multifactorielle des facteurs de survie sans maladie après une première résection et la deuxième récidive, selon 16 variables clinicopathologiques. L’envahissement pariétal, les métastases lymphatiques, l’envahissement des vaisseaux lymphatiques, l’envahissement veineux de la tumeur primitive, un intervalle sans maladie de 24 mois ou plus après résection du cancer colorectal primitif, et la bilatéralité des métastases ont significativement influencé la survie sans maladie (test de Log-Rank; p<0.05). L’analyse multifactorielle a révélé que l’envahissement veineux de la tumeur primitive et la bilatéralité des métastases étaient des facteurs indépendants de récidive après résection pour métastases. Le foie a été le site de récidive secondaire chez 23 patients. On a trouvé une différence significative entre les patients ayant des métastases ganglionnaires et un envahissement veineux à partir de leur tumeur primitive en ce qui concerne le site de leur récidive (hépatique seule ou extrahépatique) après la première résection hépatique (test de chi2 ou test de Fisher; p<0.05). La récidive après hépatectomie a été influencée par les facteurs en rapport avec le cancer primitif colorectal plus que par les facteurs concernant les récidives hépatiques. L’envahissement veineux du cancer colorectal est le facteur principal et le facteur prédictif le plus important pour récidive hépatique secondaire seule.ResumenEn la actualidad, se acepta que la hepatectomia constituye el tratamiento más eficaz, potencialmente curativo, de las mestástasis hepáticas de un cáncer colorrectal. Sin embargo, bastantes pacientes fallecen tras las hepatectomia, por recidiva de la enfermedad cancerosa. Hasta ahora, no se conocen los factores predictivos de recidiva tras la primera resección por metástasis hepáticas. Los autores intentan determinar qué factores pueden predecir la recidiva, especialmente en casos de recidivas exclusivamente hepáticas, tras hepatectomia por metástasis del cáncer colorrectal. Se analizaron retrospectivamente 76 pacientes hepatectomizados por metástasis de cáncer colorrectal. En 47 (61.8%) casos, se constataron recidivas metastásicas en el higado. Se analizaron mediante test uni y mulivariables, utilizando 16 variables clinico-patológicas, la supervivencia de los pacientes libres de enfermedad, tras la primera hepatectomía y la localización de las segundas recidivas metastásicas. La invasión parietal, los ganglios metastásicos, la invasión linfática, la invasión venosa del tumor primario (colorrectal), el intervalo libre de enfermedad tras la resección del cáncer colorrectal igual o superior a 24 meses y, la existencia de metástasis bilaterales en ambos lóbulos hepáticos, influyen significativamente en la supervivencia libre de enfermedad (log-rank test: p<0.05). El análisis multivariante demuestra que la invasión venosa del tumor primario y las metástasis hepáticas bilaterales constituyen factores de riesgo independientes para la recidiva tras hepatectomia. El higado, en 23 pacientes, fue la única localización de la segunda recidiva. Pacientes en los que el tumor primario produjo metástasis ganglionares e invasión venosa, presentaron diferencias significativas por lo que a las recidivas sólo hepáticas y extrahepáticas (tras la primera hepatectomia) se refiere (test de la chi al cuadrado o test de Fischer: p<0.05). La recidiva tras hepatectomia se debe más a las caracteristicas del cáncer primario colorrectal que a otros factores dependientes de las primeras metástasis hepáticas. La invasión venosa del cáncer primario colorrectal es el factor predictivo más importante por lo que se refiere a las recidivas de metástasis localizadas exclusivamente en el higado.

The prognostic significance of RCAS1 expression in squamous cell carcinoma of the oesophagus.

Overexpression of RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) protects cancer cells from immune attack and might be related to poor prognosis in several cancers. We investigated the immunoreactivity of RCAS1 and its correlation with clinicopathological features in 95 patients who underwent surgical resection for oesophageal squamous cell carcinoma. Thirty-two of the 95 (33.7%) cases were strongly positive for RCAS1. RCAS1 showed significant correlations with age and stage grouping. Expression of RCAS1 was associated with shorter postoperative survival. Multivariate analysis indicated that RCAS1 positivity was an independent negative prognostic factor. Our study establishes RCAS1 as a novel prognostic marker for surgically resected oesophageal squamous cell carcinoma.