Yoshihiko Maehara

Hypermethylation of FHIT as a prognostic marker in nonsmall cell lung carcinoma

Methylation of CpG islands in the promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes. The purpose of the current study was to determine the correlation between the aberrant promoter methylation of multiple genes and survival in patients with nonsmall cell lung carcinoma (NSCLC).

Predictive value of preoperative serum sialyl tn antigen levels in prognosis of patients with gastric cancer

Background. Expression of sialyl Tn antigen (STN) or serum STN levels were reported to be the independent prognostic factors of colon and ovarian cancers, respectively. The clinical significance of serum STN was evaluated as a tumor marker in gastric cancer.

Poorly differentiated medullary carcinoma of the stomach

Background. The biologic behavior of poorly differentiated medullary carcinoma of the stomach is unclear.

Interrelation between tumor-associated cell surface glycoprotein and host immune response in gastric carcinoma patients

Expression of changes in cell surface glycoprotein may correlate with the malignant potential and development of gastric carcinoma. Immunologic defense mechanisms of the host against the tumor can be effective in preventing the development of gastric carcinoma. The authors studied the effects of immunologic defense of the host against the tumor, using infiltration of S‐100 protein positive dendritic cells (DC) as a marker. In cases with or without changes in the surface glycoprotein of tumor cells, determinations were made by binding of Helix pomatia agglutinin (HPA).

Growth pattern and expressions of cell cycle regulator proteins p53 and p21WAF1/CIP1 in early gastric carcinoma

The growth pattern of early gastric carcinoma, as based on a volumetric analysis, reflects the biologic characteristics of a tumor. The penetrating growth (Pen) type tumor has an unfavorable prognosis, compared with the case of a superficially spreading (Super) type.

Increased proliferative activity caused by loss of p21WAF1/CIP1 expression and its clinical significance in patients with early‐stage gastric carcinoma

Recurrences of gastric carcinoma are likely to take on a variety forms, even after patients undergo curative resection for early‐stage gastric carcinoma. It is important to identify the biologic markers that predict tumor progression and survival in these patients. Proliferating cell nuclear antigen (PCNA) acts as a processivity factor for DNA polymerase δ, which is involved directly in DNA synthesis, and the PCNA level is correlated with the proliferative state of cells. p21WAF1/CIP1 interacts with PCNA to inhibit DNA synthesis and plays a central role in regulating the cell cycle. The authors investigated patients with early‐stage gastric carcinoma to determine the clinical significance of proliferative activity and p21 expression.

Postoperative chemotherapy for colorectal cancer by combining 5-fluorouracil infusion and 1-hexylcarbamoyl-5-fluorouracil administration after curative resection

Colorectal cancer is one of the major malignant diseases and, recently, its incidence appears to be increasing. Surgical resectability is an important prognostic determinant; however, recurrent tumors are commonly noted, even after apparently curative surgery. Because such metastatic disease cannot be cured, better adjuvant therapies are urgently called for.

Feasibility of ABO-incompatible living donor liver transplantation in the rituximab era

We read with interest the articles by Chan et al. (Queen Mary Hospital) and Hwang et al. (Asan Medical Center), who discussed the use of donor exchange programs for living donor liver transplantation (LDLT) to avoid ABO-incompatible (ABOi) LDLT because the outcomes of ABOi LDLT are very poor. However, it needs to be stressed that the outcomes of ABOi LDLT in adults have dramatically improved since 2003 with the application of rituximab, a novel anti-CD20 antibody terminating B lymphocytes. The Japan Study Group for ABO Blood Type Incompatible Transplantation reported that the 3-year survival rate of adults who underwent ABOi LDLT improved to a level as high as 70% between 2003 and 2006, although the overall 5-year survival rate since 1991 is 52%. The application of ABOi LDLT in adults has annually increased in Japan. At Kyushu University, the use of ABOi grafts in adult-to-adult LDLT has increased since 2008: 3 of 33 LDLT procedures (9%) used ABOi grafts in 2008, and 6 of 43 (14%) used ABOi grafts in 2009. The reason for this increase is increased confidence with the use of a rituximab-based immunosuppression protocol and with the abolishment of the classic graft local infusion (GLI) treatment, which delivers protease inhibitors, prostaglandin, and steroids via the portal vein or hepatic artery. We started ABOi LDLT with GLI in 2001, started the use of rituximab in 2005, and abolished the use of GLI in 2007. Moreover, although the administration of intravenous immunoglobulin was included in the ABOi LDLT protocol at Kyushu University in 2008, it is now reserved for cases with acute liver failure or posttransplant humoral rejection. Therefore, since 2009, our ABOi LDLT protocol for elective cases has included rituximab given 3 weeks before LDLT, pretransplant plasma exchanges to lower the isoagglutinin titer to less than 64, and conventional calcineurin inhibitor–based triple therapy. Because at least 1 week of treatment (preferably 3 weeks) is necessary for effective rituximab-induced termination of humoral reactions in ABOi LDLT, intravenous immunoglobulin is necessary for emergent cases, such as patients with acute liver failure. Thirteen ABOi LDLT procedures were performed at Kyushu University. The first 2 of these cases did not receive rituximab and had a survival rate of 50%. The other 11 cases were given rituximab and had a survival rate of 100%. However, the safety of rituximab in liver transplant recipients is still not established. In kidney transplantation, Tydén et al. recently reported that rituximab (375 mg/m) did not increase the incidence of infectious complications in a randomized trial. In our series, the patients receiving rituximab (n 1⁄4 11) had septic complications (n 1⁄4 1, 9%) and cytomegalovirus infections (n 1⁄4 6, 55%), although a direct association is unclear. A pharmacodynamic study of rituximab in liver transplant recipients is necessary to determine the appropriate dosage of the drug. As Hwang et al. described in their report, it is true that exchange donor LDLT is physically compatible, whereas ABOi LDLT is emotionally compatible. In clinical situations, it is impossible to perform identical surgeries or procedures. LDLT is a complicated surgical procedure that may be affected by various factors, and it is impossible to have 2 identical sets of procedures and results. Therefore, different outcomes with serious morbidity or mortality in donors or recipients in a exchange program could happen, so there are potential conflicts. Psychological incompatibility in an exchange program should be carefully evaluated. On the other hand, ABOi LDLT is emotionally compatible or close to identical in related situations, and the physical incompatibility has been addressed. ABOi LDLT is now a feasible option in Japan, and we believe that continued use of ABOi LDLT will allow further validation and general acceptance of emotionally compatible ABOi LDLT.

Fairly rare de novo inflammatory pseudotumor in a graft after living donor liver transplantation.

De novo solid tumors rarely occur in a graft after liver transplantation, although some de novo hepatocellular carcinomas have been reported. To the best of our knowledge, there have been no reports of de novo inflammatory pseudotumors (IPTs) in a liver graft. Here we report the first case of a de novo IPT in a liver graft after living donor liver transplantation (LDLT). The patient was a 54-year-old female with end-stage liver disease secondary to cryptogenic liver cirrhosis. She underwent LDLT with a left lobe graft donated by her 57-year-old husband. Her postoperative immunosuppression consisted of cyclosporine, mycophenolate mofetil, and steroids. This patient did not experience acute cellular rejection or biliary complications (eg, cholangitis, biliary leakage, or biliary strictures) after LDLT. One year after LDLT, routine abdominal ultrasound screening revealed an asymptomatic solid liver tumor in the transplanted graft that was adjacent to the umbilical portion. Enhanced computed tomography (CT) revealed a solid tumor in segment 3 and 4 of the graft with B2 (biliary duct in segment 2) dilatation (Fig. 1A,B). The levels of tumor markers were as follows: a-fetoprotein, 1.8 ng/mL (normal range<6.2 ng/mL); des-g-carboxyprothrombin, 49 mAU/mL (normal range<40 mAU/mL); carcinoembryonic antigen, 1.2 ng/mL (normal range<3.2 ng/ mL); and carbohydrate antigen 19-9, 82 U/mL (normal range<37 U/mL). Enhanced magnetic resonance imaging and CT angiography showed a hypovascular tumor consistent with cholangiocellular carcinoma. Endoscopic retrograde cholangiography revealed a B2 (biliary duct in segment 2) stricture that was caused by the tumor and distal dilation (Fig. 1C). F-fluorodeoxy glucose positron emission tomography demonstrated abnormal F-fluorodeoxy glucose uptake by the tumor (maximum standardized uptake value 5 23.3; Fig. 1D). Therefore, we diagnosed de novo cholangiocellular carcinoma in the graft just above the umbilical portion. Because the tumor location was very delicate, we planned to perform surgical tumor biopsy followed by partial hepatectomy. However, the biopsy sample indicated that the tumor was an IPT (Fig. 2). Therefore, we immediately suspended the procedure and treated the patient conservatively with antibiotics. IPTs of the liver are rare benign tumors. Although the etiology and pathogenesis of IPTs are unclear, they were initially histologically characterized by dense hyalinized fibrosis and/or infiltrating inflammatory cells, including large numbers of foamy histiocytes, lymphocytes, and plasma cells. Typical radiological findings from enhanced CT include hypoattenuation of the mass with respect to the hepatic parenchyma with a variable degree of enhancement in the internal septa or periphery in the portal or equilibrium phase. Therefore, it is difficult to distinguish IPTs from malignant tumors and especially cholangiocellular carcinomas. Ahn et al. reported that 78.2% of their patients with IPTs had symptoms, including abdominal pain (54.5%), febrile sensation (22.7%), and malaise (4.5%), although some patients were asymptomatic. Interestingly, they also found that carbohydrate antigen 19-9 and a-fetoprotein levels were elevated in 22.7% and 4.5% of their patients, respectively. IPTs can be treated conservatively with antibiotics with or without nonsteroidal anti-inflammatory drugs or with surgical resection. Surgical resection should be recommended for patients with poor responses to conservative therapy, tumor growth, increasing tumor marker levels, or an uncertain diagnosis.

Hyperthermia enhances the inhibition of tumor growth by 1-(2-tetrahydrofuryl)-5-fluorouracil/uracil (1:4) in tumors in mice and humans.

The cytotoxicity of several antitumor drugs is enhanced by hyperthermia (HT). Using mouse Sarcoma‐180 (S‐180) tumors, the authors examined the effects of 5‐fluoroura‐cil (5‐FU) and a combined oral preparation of l‐(Gtetra‐hydrofuryl)‐5‐fluorouracil (FT) and uracil in a molar ratio of 1:4 (UFT), in combination with HT. The antitumor effect of 5‐FU was not enhanced significantly by HT. Growth inhibition by UFT plus HT was significantly greater than that by UFT alone, whereas inhibition by UFT alone was significantly greater than that by 5‐FU. The intracellular metabolism of 5‐FU and FT in whole homogenates of S‐180 cells, human tumor cell lines (SC‐2 and Lu‐99), and five fresh human tumor tissues also was investigated. Conversion of FT to 5‐FU, phosphorylation, and degradation of 5‐FU were assayed with [3H]FT or [3H]5‐FU, and the products were separated by thin‐layer chromatography. The conversion of FT to 5‐FU and the phosphorylation of 5‐FU were more rapid at 43°C than at 37°C, whereas the degradation of 5‐FU to 2‐fluoro‐β‐alanine remained unchanged. This acceleration of the active metabolism of FT and 5‐FU may be one explanation for the enhanced effect of UFT by HT. Cancer 1992; 70:1177–1182.