Intracerebral cell transplantation therapy for murine GM1 gangliosidosis

We performed a cell transplantation study to treat the brain involvement in lysosomal storage diseases. We used acid β-galactosidase knock-out mice (BKO) from C57BL/6 as recipients. To minimize immune responses, we used cells derived from transgenic mice of C57BL/6 overexpressing the normal human β-galactosidase. Fetal brain cells (FBC), bone marrow-derived mesenchymal stem cells (MSC), and mixed FBC and MSC cells were prepared and injected into the ventricle of newborn BKO mouse brain. The mice were examined at 1, 2, 4, and 8 weeks and 6 months after injection. In each experiment, the injected cells migrated into the whole brain effectively and survived for at least 8 weeks. Decrease in ganglioside GM1 level was also observed. FBC could survive for 6 months in recipient brain. However, the number of transplanted FBC decreased. In the brains of MSC- or mixed cell-treated mice, no grafted cells could be found at 6 months. To achieve sufficient long-term effects on the brain, a method of steering the immune response away from cytotoxic responses or of inducing tolerance to the products of therapeutic genes must be developed.     

Nuclear localization of immunoreactive beta-catenin is specific to familial adenomatous polyposis in papillary thyroid carcinoma.

Thyroid carcinoma is the first symptom in some patients with familial adenomatous polyposis (FAP). We evaluated the cellular localization of beta-catenin in thyroid carcinomas associated (n = 4) or not associated (n = 173) with FAP, since loss of functional protein of the adenomatous polyposis coli (APC) gene leads to nuclear accumulation of beta-catenin in adenomas and carcinomas of the FAP colon. Immunoreactive beta-catenin was demonstrated at the cell membrane of glandular cells of the non-neoplastic thyroid and non-FAP carcinomas. On the other hand, cytoplasmic and nuclear accumulation of beta-catenin is specific to FAP-associated papillary carcinomas. The abnormality in the APC / beta-catenin pathway is thus also important in FAP-associated thyroid carcinoma, and beta-catenin immunohistochemistry is a feasible screening method to identify occult FAP in young patients with thyroid tumors.     

CD70 expression in thymic carcinoma

CD70, a type II transmembrane glycoprotein, is a member of the tumor necrosis factor (TNF) family that mediates the interaction between B- and T-lymphocytes. CD70 has been shown to be expressed by malignant lymphoma, especially Hodgkin's disease, and by nasopharyngeal carcinoma, both of which are frequently associated with Epstein-Barr virus (EBV). In this study, we investigated the expression of CD70 in epithelial cells of various types of thymic epithelial tumors and its association with EBV. Immunohistochemical expression of CD70 was studied on frozen tissue. In a series of 27 thymic epithelial tumors, including thymic carcinomas (n = 8), atypical thymomas (n = 5), thymomas (n = 13), and thymic carcinoid (n = 1), 7 (88%) thymic carcinomas and 1 (20%) atypical thymoma showed positive immunoreactivity for CD70, whereas CD70 was not detected in other tumors. Twenty-four intrathoracic malignant epithelial tumors of nonthymic origin, including lung (n = 17), esophagus (n = 5), and mesothelium (n = 2), showed no immunoreactivity for CD70. Northern blot analysis also revealed that CD70 messenger RNA was expressed in 2 of 2 thymic carcinomas, 0 of 2 atypical thymomas. and 0 of 2 thymomas. All of the 27 thymic epithelial tumors were EBV-negative as assessed by EBV-encoded small RNA in situ hybridization. The expression of CD70 is closely related to the pathogenesis of thymic carcinoma but unrelated to EBV infection in the thymus.     

The potency of curative-intent treatment for advanced thymic carcinoma

Background

Heterogenous clinical or biological features are characteristic of thymic carcinoma. Well-defined clinical entities remain unclear because of rarity. The aim of this study was to clarify disease profiles, outcomes, and prognostic factors for survival among patients diagnosed with thymic carcinoma.

Patients and methods

A retrospective review was conducted of the medical records of 68 thymic carcinoma patients among 187 patients diagnosed with thymic epithelial tumors between 1980 and 2013 in our institution. Clinical demographics, histology, overall survival, and factors expected to predict survival were analyzed. Differences in survival were assessed using Kaplan–Meier analysis and uni- and multivariate Cox proportional hazards regression analyses.

Results

The study included 38 males (55.9%) and 30 females (44.1%). The median age at diagnosis was 63.5 years. The most common subtypes of thymic carcinoma were squamous cell carcinoma (69.1%), neuroendocrine carcinoma (16.2%), and mucoepidermoid carcinoma (5.9%). Masaoka-Koga staging of the 68 patients demonstrated no patients (0%) in Stage I, 3 (4.3%) in Stage II, 14 (20.6%) in Stage III, 12 (17.6%) in Stage IVa, and 39 (57.4%) in Stage IVb. The median survival time for all stages was 36.4 months (95% confidence interval 23.7–56.4); those for stages II, III, IVa, and IVb were: not reached, 65.8, 24.6, and 27.3 months, respectively. The difference by Masaoka-Koga staging was significant (p = 0.04). Overall survival rates at 1-, 5-, and 10-year were 76.3%, 36.0%, and 6.2%, respectively. By univariate analyses, the only favorable prognostic factor for overall survival was surgical intervention (p = 0.03), and, for Stage IVb, lymphatic metastasis without distant metastasis. However, clinically interesting variants did not differ significantly for predicting survival.

Conclusion

Surgical intervention results in better survival of thymic carcinoma, even in Stage IVb. The survival value of administration of curative-intent radiotherapy, or of identification of “resectability” in Stage IVb patients must continue to be discussed.     

Pancreatic cancer with a high serum IgG4 concentration

INTRODUCTION Autoimmune pancreatitis is a unique for m of pancreatitis, histopathologically characterized by dense lymphoplasmacytic infiltration and fibrosis of the pancreas with obliterative phlebitis[1,2]. Patients with this disease usually have a swollen pancreas with delayed enhancement on computed tomography (CT), irregular narrowing of the main pancreatic duct on endoscopic retrograde pancreatography, and a favorable response to steroid therapy[1-4]. Autoimmune pancreatitis has bee…     

Accumulation Profile of Frameshift Mutations During Development and Progression of Colorectal Cancer From Patients With Hereditary Nonpolyposis Colorectal Cancer

Purpose Role and timing of frameshift mutations during carcinogenesis in hereditary nonpolyposis colorectal cancer have not been examined. This study was designed to clarify the relationship between frameshift mutations and clinicopathologic features in colorectal cancer from patients with hereditary nonpolyposis colorectal cancer. Methods Thirty-one colorectal cancers from patients with hereditary nonpolyposis colorectal cancer at different clinicopathologic stages were analyzed for frameshift mutation in 18 genes. Results The frameshift mutations of the ACVR2 and PTHLH genes were found to have an extremely high frequency (94–100 percent) in all pathologic stages, and mutation of the MARCKS gene also was high (94 percent) in Dukes B and C cancers. These frequencies were higher than the frequency of TGFβRII gene inactivation (64–88 percent). Mutations of the hMSH3, TCF4, CASP5, RIZ, RAD50, and MBD4 genes were comparatively frequent (>35 percent) in all stages. Frequencies of inactivation of the MARCKS, BAX, IGFIIR, and PTEN genes were significantly higher in Dukes B and C cancers than in Dukes A cancer (P < 0.05). The number of accumulated frameshift mutations was larger in Dukes B and C cancers (9.4) than in Dukes A cancer (6.8) (P = 0.003). Conclusions The present data suggest that the disruption of the transforming growth factor-β super-family signaling pathway by the alteration of the ACVR2 and/or TGFβRII genes and the disruption of antiproliferative function by the PTHLH gene alteration contribute to the development of early colorectal cancer. Moreover, the further accumulation of alterations in the MARCKS, BAX, IGFIIR, and PTEN genes seem to be associated with progression from early to advanced colorectal cancer from patients with hereditary nonpolyposis colorectal cancer.     

A case of polymyositis in a chronic hepatitis C patient treated with peg-interferon-alpha 2b and ribavirin therapy

Hepatitis C virus (HCV) infection may result in progression to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Interferon-based treatment in patients with chronic hepatitis C may achieve viral clearance, and as a consequence improve liver histology and prevent progression to hepatocellular carcinoma. At present, the recommended therapy for chronic hepatitis C is peg-interferon-alpha (PEG-IFN-α) in conjunction with the oral nucleoside analog ribavirin. In the current study, we report a case of polymyositis associated with chronic hepatitis C following PEG-IFN-α and ribavirin therapy. The patient, a 64-year-old female who was treated with combination therapy, demonstrated elevated serum CPK, AST, ALT and LDH levels at 28 weeks after treatment onset. As there was an elevation of the serum HCV-RNA levels, combination treatment was ceased at 24 weeks. The patient had received IFN therapy twice previously (IFN-α 2a and IFN-α 2b with ribavirin therapy); however, no adverse side effects were observed. Further laboratory examination, muscle biopsy and imaging data suggested polymyositis, possibly triggered by the PEG-IFN-α treatment. The patient was subsequently administered prednisolone and the dose tapered over 7 months. As a result the polymyositis has remained in remission. Although many autoimmune diseases have been associated with IFN therapy, the development of polymyositis is extremely rare.     

Feasibility of intraoperative diagnosis of lung adenocarcinoma in situ to avoid excessive resection

BackgroundLimited lung resection is generally believed to be available for lung adenocarcinoma in situ (AIS). At our institute, intraoperative hematoxylin-eosin staining of frozen-section slides is routinely performed for evaluating tumor invasiveness after partial resection to avoid excessive lung resection. This study aimed to evaluate the feasibility and usefulness of intraoperative frozen-section diagnosis of AIS.MethodsWe retrospectively reviewed 143 patients with 151 AISs diagnosed by intraoperative frozen sections between 2012 and 2019 at our institute. All patients underwent limited resection because of the result of intraoperative frozen-section diagnosis.ResultsThe total concordance rate between the diagnoses of AIS by intraoperative frozen sections and postoperative paraffin-embedded sections was 82.7% for 151 nodules. Although 21 minimally invasive adenocarcinomas (MIA) and 5 invasive adenocarcinomas were diagnosed as AIS intraoperatively, no patient had tumor recurrence after resection. Among 125 pathologically proven cases of AIS postoperatively, there were 67 (53.6%) radiologically invasive tumors including ground-glass nodules (GGNs) with part-solid component or pure-solid nodules.ConclusionsThis intraoperative evaluation of frozen-section slides will help surgeons avoid excessive lung resection for AIS that was radiologically diagnosed as invasive adenocarcinoma. Intraoperative frozen-section diagnosis will provide to be clinically useful and lead to less invasive surgical treatment for lung nodules.