Involvement of Krüippel-like factor 6 （KLF6） mutation in the development of nonpolypoid colorectal carcinoma

AIM： To examine Kruppel-like factor 6 （KLF6） mutations in nonpolypoid-type tumors and alterations of K-ras, p53, and B-raf in relation between mutation and morphologic type, particularly nonpolypoid-type colorectal carcinomas.
METHODS： Fifty-five early nonpolypoid colorectal carcinomas were analyzed. Loss of heterozygosity （LOH） of KLF6 and p53 was determined by microsatellite assay. Mutations of KLF6, K-ras, and B-raf were examined by polymerase chain reaction-single-strand conformation polymorphism followed by direct sequencing. In LOH- positive and/or mutation-positive tumors, multiple （4-7） samples in each tumor were microdissected and examined for genetic alterations, p53 expression was evaluated by immunohistochemistry. RESULTS： LOH of KLF6 and p53 was found in 14 of 29 （48.3%） and 14 of 31 （45.2%） tumors, respectively. In tO of the 14 （71.4%） KLF6 LOH-positive tumors and 9 of the 14 （64.3%） p53 LOH-positive tumors, LOH was found in all of the microdissected samples. In 1 of the tO （10.0%） KLF6 LOH-positive tumors, a single missense mutation was identified. K-ras and B-raf mutations were found in 5 of 55 （9.1%） and 6 of 55 （10.9%） tumors, respectively. However, these mutations were detected only in subsets of microdissected tumor samples.
CONCLUSION： These data suggest that KLF6 and p53 mutations are involved in the development of nonpolypoid colorectal carcinoma, whereas K-ras and B-raf mutations are not.     

Nuclear DNA content by cytofluorometry of stage I adenocarcinoma of the lung in relation to postoperative recurrence

Forty-six cases of adenocarcinoma of the lung, categorized as stage I (T1N0M0, T2N0M0) pathologically, were studied in terms of nuclear DNA content (NDC) determined by cytofluorometry. They comprised 23 cases each with and without tumor recurrence within five years postoperatively, and the NDC was compared in 23 pairs in which the tumor size and the degree of histologic differentiation were completely matched. The NDC was larger in the recurrent group than in the nonrecurrent group in terms of mean nuclear DNA content (MNDC), DNA histogram pattern, and occurrence of the aneuploid stem cell line, of which the difference in MNDC was statistically significant (p less than 0.05). When the comparison of NDC was made between the nonrecurrent and recurrent groups in the well differentiated (W/D), moderately to poorly differentiated (M.P/D), T1, and T2 subgroups, the NDC of the recurrent group was significantly larger than that of the nonrecurrent group in the W/D (MNDC, p less than 0.01 and DNA histogram pattern, p less than 0.005) and T1 subgroups (MNDC, p less than 0.05), but not in the M.P/D and T2 subgroups. The results indicate that the NDC is a good predictor of prognosis in stage I adenocarcinoma of the lung and its prognostic importance increases in more differentiated and smaller tumors, compared to less differentiated and larger tumors.     

Liver dysfunction due to apoptosis in a patient with systemic lupus erythematosus

We report on a 23-year-old Japanese female with a 13-year history of systemic lupus erythematosus (SLE), and two episodes of deterioration followed by treatment with high dose prednisolone. Although she had been recently treated with prednisolone (12.5 mg daily), her liver function became worse in July 1998. Results of a liver biopsy revealed multi-focal hepatic cell death in a severe fatty liver, without any inflammatory cell invasion. The biopsy also showed a positive TUNEL (Tdt-catalysed DNA nick end labelling) reaction indicating apoptosis. Her liver function recovered rapidly following steroid pulse therapy. Serum soluble Fas ligand (sFasL) was found to be elevated to a concentration of 0.395 ng/ml at the time of liver damage, but was less than 0.03 ng/ml before liver damage and after prednisolone treatment. The liver damage in this case appeared to be involved with apoptosis induced by sFasL. Although hepatitis associated with SLE is rare, apoptosis directly related to elevated sFasL levels might cause this complication.     

Cytotoxic T-Cell Lymphoma Arising in Behçet Disease

The case of a 49-year-old man with peripheral T-cell lymphoma arising in Behçet disease (BD) is reported. A diagnosis of incomplete BD was made, and the patient was treated with immunosuppressive agents for 9 months. A left perirenal mass emerged, and a computed tomography-guided needle biopsy of the tumor revealed the infiltration of small- and medium-sized lymphoma cells.The cells were positive for CD3, CD8, CD45RO, CD43, granzyme B, and T-cell intracellular antigen-1.A diagnosis of non-Hodgkin’s lymphoma (diffuse medium, T-cell) was made.A left orbital mass also appeared. Standard combination chemotherapy diminished the perirenal and orbital lesions.Lymphoma cell infiltration in the esophagus was detected after chemotherapy, and the patient died of massive bleeding from the gastrointestinal tract. Non-Hodgkin’s lymphoma is rarely associated with BD, and only 7 cases have been reported in the literature.We have summarized the published case reports of malignant lymphoma arising in BD.To our knowledge, this case report is the first to describe cytotoxic T-cell lymphoma arising in Behçet disease.     

Hemophagocytic syndrome as the primary clinical symptom of Hodgkin's disease

It is now well recognized that hemophagocytic syndrome (HPS) is occasionally associated with malignant lymphomas. However, its association with Hodgkin's disease has been only rarely reported. We present here a 72-year-old woman manifesting with HPS as the primary and solitary clinical symptom of Hodgkin's disease. She had been suffering from high-grade fever and anemia for more than a month. Based on the findings in bone marrow aspirates, she was diagnosed as having HPS. In spite of extensive surveys including various cultures, serological tests for collagen disease, abdominal and cardiac sonography, chest computed tomography (CT), and renal biopsy, the origin of the fever was not determined. She was treated with steroid pulse therapy and then referred. Radiological studies revealed only mild hepatosplenomegaly and small lymph node swellings around celiac and common hepatic arteries. Reevaluation of the bone marrow specimen revealed the infiltration of small numbers of CD30-, CD15-, and EBER-1-positive large-sized lymphocytes with bizarre nucleus. Under the diagnosis of Hodgkin's disease, she was treated with combination chemotherapy containing pirarubicin, cyclophosphamide, vincristine, and prednisolone. However, it was not effective and she died of rapidly progressive hepatic failure on the 5th day of the chemotherapy. Autopsy was performed, which showed proliferation of lymphoma cells in para-aortic lymph nodes. We believe that diagnostic survey to rule out the underlying lymphoma should be vigorously performed for patients with hemophagocytic syndrome of unknown origin.     

Encephalomyocarditis virus induced diabetes mellitus in mice: Long-term changes in the structure and function of islets of langerhans

Diabetologia - Adult male mice infected with the M variant of encephalomyocarditis virus develop hyperglycaemia acutely as a consequence of B cell injury. The severity of the metabolic disease is...     

Recognition of regional hypertrophy in hypertrophic cardiomyopathy using thallium-201 emission-computed tomography: Comparison with two-dimensional echocardiography

The configuration of the hypertrophied myocardium was evaluated by thallium-201 emission-computed tomography and 2-dimensional (2-D) sector scan in 10 patients with obstructive hypertrophic cardiomyopathy (HC), 10 with nonobstructive HC with giant negative T waves and 10 with concentric left ventricular (LV) hypertrophy. Thallium-201 myocardial imaging was reconstructed into multiple 12-mm-thick slices in 3 planes. The thickness ratio of the ventricular septum and the LV posterior wall in the short-axis plane and the ratio of the ventricular septum and the apical wall in the long-axis plane were analyzed. In the patients with obstructive HC the ventricular septal wall thickness index was increased, and the ratio of septal to posterior wall thickness index (1.45 ± 0.23) was greater than that in the patients with nonobstructive HC with giant negative T waves or in those with concentric LV hypertrophy (1.03 ± 0.20 and 0.98 ± 0.11, respectively; p <0.01 for each). In the patients with nonobstructive HC with giant negative T waves, increased apical wall thickness with apical cavity obliteration was characteristic, and the ratio of ventricular septal to apical wall thickness index (0.66 ± 0.14) was less than that in the patients with obstructive HC or in those with concentric LV hypertrophy (1.46 ± 0.38 and 1.04 ± 0.09, respectively; p <0.001 for each). In contrast, technically satisfactory 2-D sector scanning (83%) demonstrated various configurations of the hypertrophied ventricularseptum, but could not detect apical hypertrophy in 4 of the 10 patients with nonobstructive HC with giant negative T waves whose LV cineangiograms demonstrated apical hypertrophy. Thus, thallium-201 emission-computed tomography is useful in evaluating the characteristics of LV hypertrophy and assists 2-D sector scan, especially in patients with apical hypertrophy in HC.     

Synergistic anti-tumor efficacy by combination therapy of a self-assembled nanogel vaccine with an immune checkpoint anti-PD-1 antibody

Therapeutic strategies for cancer involving immune checkpoint inhibitors (ICIs) have been gaining widespread attention, but their efficacy remains limited. Thus, combination of ICI therapies with other therapeutic modalities may be required to improve their outcomes. In this study, we examined the improved efficacy of a CHP nanogel-based vaccine delivery system after combination with ICI therapy. For this, we evaluated the therapeutic efficacy of combining an anti-PD-1 antibody as an ICI with an OVA antigen-complexed CHP nanogel vaccine delivery system in a mouse E.G7-OVA tumor model. Mice were subcutaneously inoculated with E.G7-OVA tumor cells on one side of the back, and subcutaneously injected with OVA or the OVA/CHP nanogel vaccine on the other side of the back. Anti-PD-1 antibody was administered at defined intervals. Tumor volume, immune responses, and tumor-infiltrating cells were evaluated. Mice treated with OVA vaccine alone showed weak tumor suppression compared with untreated control mice. Mice receiving combined OVA/CHP nanogel vaccine and anti-PD-1 antibody therapy exhibited strong tumor growth suppression and markedly improved survival, suggesting that PD-1 signaling blockade by the anti-PD-1 antibody enhanced the anti-tumor efficacy of the OVA vaccine. Furthermore, tumor-infiltrating cells and immune responses were increased in the combined therapy group. No serious side effects were observed for any of the treatments. Taken together, the immune system activation induced by the CHP nanogel vaccine was synergistically enhanced by the anti-PD-1 antibody. The present findings suggest the potential for enhanced therapeutic efficacy by combining the CHP nanogel vaccine delivery system with ICI therapy for various cancer types.

Combination therapy of OVA/CHP nanogel vaccine with anti-PD-1 antibody synergistically improved anti-tumor effect and survival rate without side effects.     

Cribriform-Morular Variant of Papillary Thyroid Carcinoma: Ultrastructural Study and Somatic/Germline Mutation Analysis of the APC Gene

Cribriform-morular variant of papillary carcinoma is a distinctive histological variant of thyroid cancer, characterized by intermingled cribriform, follicular, papillary, trabecular, and morular architecture. These tumors are known to be associated with familial adenomatous polyposis (FAP), but are also encountered in non-FAP patients. The authors report on ultrastructural and genetic studies of 3 patients with this type of carcinoma-associated FAP. There were numerous microfilaments approximately 100?nm long at the nuclear clearing area of the morular regions. Two of the 3 patients showed germline APC mutations, and 1 had so somatic APC mutation. Both mutations were in previously unreported regions. The study provides new information for understanding the development of this rare tumor.