Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors.

BACKGROUND: The signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule implicated in the regulation of growth and malignant transformation. Constitutive activation of STAT3 is seen in several tumour derived cell lines, and in a wide variety of human malignancies. AIMS: To examine the relation between p-STAT3 (activated form of STAT3) expression and clinicopathological factors in human colorectal adenocarcinoma and adenoma. METHODS: Immunohistochemical analyses were carried out on tissues from 44 colorectal adenomas and 95 colorectal adenocarcinomas, comprising 18 intramucosal carcinomas and 77 invasive carcinomas. RESULTS: Seventy seven of these 139 samples (55.4%) showed immunoreactivity for p-STAT3. Positive staining for p-STAT3 was seen in 69 of the 95 carcinomas. Only eight of the 44 adenomas showed immunopositivity for p-STAT3, resulting in a significant difference between total adenocarcinomas and adenomas (p < 0.001). Among the 95 cases of colorectal adenocarcinoma, p-STAT3 immunoreactivity was significantly correlated with the depth of tumour invasion (p < 0.05), venous invasion (p < 0.05), lymph node metastasis (p < 0.05), and increasing stages of the Dukes' classification (p < 0.01). Expression of p-STAT3 was detected by Western blot analysis in two different cultured human colorectal carcinoma cell lines and six colon carcinoma tissue samples obtained at surgery. CONCLUSION: This is the first study to report a significant correlation of p-STAT3 expression with the depth of tumour invasion. These findings suggest that p-STAT3 expression is an important factor related to carcinogenesis and/or tumour invasion of colorectal adenocarcinoma.

Effect of a selective Abl tyrosine kinase inhibitor, STI571, on in vitro growth of BCR-ABL-positive acute lymphoblastic leukemia cells.

By employing a new semi-quantitative assay system that includes co-culturing leukemia cells with the mouse bone marrow-derived stromal cell line MS-5, we examined the suppressive effect of a selective inhibitor of ABL tyrosine kinase, STI571, on acute lymphoblastic leukemia (ALL) cells with BCR-ABL fusion. Leukemic blast cells from eight patients with B-precursor ALL, including three patients with BCR-ABL-positive ALL, were cultured on monolayers of MS-5 cells for 3 weeks with or without addition of variable amounts of STI571. In all cases, cobblestone areas (CAs) were formed, showing clear linear cell dose-dependent curves, allowing quantitative assessment of blast cell growth. The progenitor frequencies obtained by this direct CA-forming cell (CAFC) assay were equivalent to ALL progenitor frequencies assessed by the standard limiting dilution assay. The number of CAFCs ranged from 12.3 to 140.3/10(4) cells. In BCR-ABL-positive ALL patients, CA-containing cells were examined by FISH, and all contained BCR-ABL fusion genes. STI571 inhibited CA formation of BCR-ABL-positive ALL cells virtually 100% at 0.1-1.0 micromol/l. None of the five BCR-ABL-negative ALL patients showed this growth inhibition by STI571 at 0.1-1.0 micromol/l. Our results indicate that STI571 selectively inhibits in vitro growth of BCR-ABL-positive ALL cells.

Recovery of hematopoietic progenitor cells in patients with severe aplastic anemia who obtained good clinical response with a combination therapy of immunosuppressive agents and recombinant human granulocyte colony-stimulating factor.

Seventeen patients with newly diagnosed acquired severe aplastic anemia were treated with a combination of immunosuppressive drugs consisting of anti-lymphocyte or anti-thymocyte globulin, cyclosporin A (CyA), methylprednisolone, and recombinant human granulocyte colony-stimulating factor (G-CSF). Fourteen (82%) of the 17 patients achieved good response (GR), and 3 (18%) had no response. Among the 14 GR patients, 5 (36%) later evolved clonal diseases, 1 developed myelodysplastic syndrome, and 4 developed paroxysmal nocturnal hemoglobinuria. The numbers of granulocyte-macrophage colony-forming units (CFU-GM) and erythrocyte burst-forming units were markedly low or absent in all cases before therapy. After therapy, those numbers in 13 patients among 14 responders recovered to the level of the normal control at the time of GR. However, the CFU-GM number substantially declined after that but gradually recovered again to reach a normal level over longer clinical courses. The positive rate for HLA-DRB1*1501 was 60% (3/5) among 5 CyA-dependent patients, which tended to be higher than the 20% (1/5) among 5 CyA-independent patients. Thus, immunosuppressive therapy combined with G-CSF provides a high rate of good hematological response accompanied by the apparent recovery of the hematopoietic progenitor compartments.

Successful treatment with a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) for a patient with relapsed mantle cell lymphoma who developed a human anti-chimeric antibody.

Mantle cell lymphoma (MCL) has a poor prognosis without cure; the median overall survival ranges only from 3 to 4 years irrespective of conventional therapeutic regimens. IDEC-C2B8 (rituximab), a chimeric monoclonal antibody against the B-cell-specific antigen CD20, induces an evaluable clinical response in patients with MCL with mild toxicities. However, the single agent rituximab cannot cure MCL. Due to its low immunogenicity, an antibody against IDEC-C2B8 (human antichimeric antibody [HACA]) has rarely been produced in vivo. We report a patient with relapsed MCL who was successfully treated with IDEC-C2B8 for over a year although she developed HACA 6 months after the initial administration of IDEC-C2B8 in the phase II clinical trial conducted by Zenyaku Kogyo Co. Ltd. We followed the pharmacokinetics of IDEC-C2B8, the serum HACA titer, and the number of B lymphocytes in the peripheral blood in relation to clinical response. The HACA became undetectable soon after subsequent administrations of IDEC-C2B8. When the serum level of IDEC-C2B8 was kept elevated, clinical responses were apparently observed and HACA disappeared during this response period. There were no significant clinical toxicities related to the appearance of HACA. The present findings suggested that IDEC-C2B8 is effective and safe even in patients who have developed HACA.

Acinar cell carcinoma of the pancreas associated with hypoglycemia: involvement of "big" insulin-like growth factor-II.

Apart from insulinomas, pancreatic tumors are rarely complicated by hypoglycemia and some may produce insulin-like growth factor II (IGF-II). To our knowledge, IGF-II-producing pancreatic tumors associated with hypoglycemia have not been reported previously. We describe what we believe to be the first case of "big" IGF-II-producing pancreatic acinar cell carcinoma. A 68-year-old man presented with a history of recurrent hypoglycemia. Abdominal computed tomography scan and magnetic resonance imaging showed a mass, approximately 5 cm in diameter, in the tail of the pancreas and two low-density areas in the liver. Low serum glucose was associated with low insulin levels and high levels of hormones (i.e., glucagon and IGF-II) that are functionally opposite to insulin. Although serum IGF-II level was within the normal range, most IGF-II was of the high molecular weight form, as determined by Western immunoblot analysis. Based on these findings, a diagnosis of hypoglycemia induced by IGF-II-producing pancreatic tumor was made. Surgery was not possible because of the patient's poor general condition. The patient ultimately died as a result of malignant cachexia. At autopsy, a yellowish-white tumor was found in the tail of the pancreas, and a histopathologic diagnosis of acinar cell carcinoma was made. Immunohistologically, the tumor cells contained IGF-II in an irregular staining pattern, suggesting that the hypoglycemia was caused by a pancreatic tumor producing "big" IGF-II.

[Treatment of acute lymphoblastic leukemia in adults by the modified protocol of L-10M (Sloan-Kettering): long-term outcome].

From January 1984 to April 1988, we treated 20 patients with adult lymphoblastic leukemia (ALL) and 2 patients with lymphoblastic lymphoma with a protocol which we modified L-10M of Sloan-Kettering Cancer Center. Since the median follow up time is now over 5 years, we report the most recent outcome. Thirteen patients were male and 9 were female. The median age was 31, ranging from 15 to 71 years of age, and there were no Ph1 positive patients. The complete remission (CR) rate was 81.8%. Median CR duration was 32 months and the 5-year continuous CR rate was 33.3%. No significant prognostic factor for CR rate was found. Age at achievement CR and duration were significant prognostic factors. The 5-year continuous CR rate of patients below 35 years old was 54.5%. In this group the leukocyte count was a significant prognostic factor. All patients with a leukocyte count above 1 x 10(4)/microliters relapsed. However, in patients with a WBC below 1 x 10(4)/microliters, the 5-year continuous CR rate was 75%. Based on these results, it seems reasonable to treat patients with ALL by different therapeutic strategies according to the risk factors.