Shuichi Hashimoto

Lung Adenocarcinoma With Bronchioloalveolar Carcinoma Component Is Frequently Associated With Foci of High-Grade Atypical Adenomatous Hyperplasia

We assessed the occurrence of atypical adenomatous hyperplasia (AAH) in whole lung lobes with primary cancer lesions. Following surgical resection, tissue specimens were sliced to a thickness of 4 mm (3,641 specimens from 61 cases; mean = 59.7 specimens per case). A total of 119 AAH foci were found and an association was evident in 25 (57%) of 44 adenocarcinomas, 3 (30%) of 10 squamous cell carcinomas, and 2 (29%) of 7 other lung cancers. Histologic evaluation showed that 108 AAH foci were categorized as low-grade and the other 11 as high-grade AAH. These 11 foci of high-grade AAH were present in 7 patients with adenocarcinoma, and in 1 patient there was a synchronous double primary lung adenocarcinoma. High-grade AAH was closely associated with bronchioloalveolar carcinoma (BAC) type adenocarcinoma, and low-grade AAH with non-BAC adenocarcinoma. The mean +/- SD Ki-67 labeling index in high-grade AAH (3.5%+/-2.9%) was significantly higher than for the low-grade index (1.4%+/-1.6%). We propose that foci of high- but not low-grade AAH may be potential precursor lesions of lung adenocarcinoma, especially with the BAC component.

Recombinant Sendai virus vectors for activated T lymphocytes

T-lymphocyte-directed gene therapy has potential as a treatment of subjects with immunological disorders. One current limitation of this therapeutic strategy is low gene transfer efficiency, even when complex procedures are used. We report herein that a recombinant Sendai virus vector (SeV) was able to overcome this issue. Using jellyfish enhanced green fluorescent protein gene (EGFP), we found that SeV was able to transduce and express a foreign gene specifically and efficiently in activated murine and human T cells, but not in naive T cells, without centrifugation or reagents including polybrene and protamine sulfate; the present findings were in clear contrast to those demonstrated with the use of retroviruses. The transduction was selective in antigen-activated T cells, while antigen-irrelevant T cells were not transduced, even under bystander activation from specific T-cell responses by antigens ex vivo. Receptor saturation studies suggested a possible mechanism of activated T-cell-specific gene transfer, ie, SeV might attach to naive T cells but might be unable to enter their cytoplasm. We therefore propose that the SeV vector system may prove to be a potentially important alternative in the area of T-cell-directed gene therapy used in the clinical setting.

Heterogeneous distribution of P53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with P53 gene mutation.

Although the tumor suppressor p53 protein (P53) immunoreactivity and its gene (p53) mutation were reported to be significant prognostic indicators for human lung adenocarcinomas, little is known regarding the relationship between the heterogeneous distribution of P53 and its genetic status in each tumor focus and the clinicopathological significance. To determine how P53 is heterogeneously stabilized in patients, we compared P53 expression to both the p53 allelic mutation in exon 2 ∼ 9 by polymerase chain reaction‐single strand conformation polymorphism using microdissected DNA fractions, and the immunohistochemical MDM2 expression. Of the 48 positive to P53 in 118 lung adenocarcinomas examined, 10 with heterogeneous P53 expression were closely examined. The higher P53 expression foci in 7 of 10 cases were less differentiated, histologically in respective cases, and were frequently associated with fibrous stroma. Two had genetic mutations in exon 7 of the p53 gene in both the high and low P53 expression foci of cancer tissue indicating no apparent correlation between heterogeneous P53 expression and the occurrence of gene mutation. Immunohistochemical expression of MDM2 was significantly lower in high P53 expression areas (p < 0.05, the mean labeling indices of high and low P53 expression areas being 4.2 ± 5.4% and 13.6 ± 12.2%, respectively). In addition, among all the 118 cases examined, MDM2 expression was significantly suppressed in cases of p53 gene mutation, simultaneously with P53 overexpression, as compared with cases without both the p53 mutation and expression (p < 0.001). These findings suggest that the heterogeneous stabilization of P53 in human lung adenocarcinomas could be partly due to suppressed MDM2 expression. The overexpression of non‐mutated P53 may afford a protective mechanism in human lung adenocarcinomas.

Morphometric analysis of the immunohistochemical expression of Clara cell 10-kDa protein and surfactant apoproteins A and B in the developing bronchi and bronchioles of human fetuses and neonates

Abstract Morphometric analyses of the immunohistochemical expression of the Clara cell secretory 10-kDa protein (CC10) and surfactant apoproteins A and B (SP-A and -B) were carried out on the developing bronchi and bronchioles of human fetuses and neonates. We analysed the ratio of the number of CC10-positive cells per subepithelial length of the bronchial or bronchiolar basement membrane and found that both the bronchial and the bronchiolar population of CC10-positive cells was significantly higher than that of either SP-A or SP-B. In addition, CC10 was found to be distributed mainly in the bronchiole. CC10-positive cells began to be recognized in the late pseudoglandular phase (15 weeks of gestation) and thereafter gradually increased in the canalicular and terminal sac phases, which correspond to the active development period of the acini or peripheral airways. The earliest expression of SP-A was also noted at 15 weeks of gestation, but its positive epithelial cells were present mainly in the larger bronchi. Double immunohistochemical staining for CC10 and SP-A revealed that the CC10-positive cells lining both the bronchi and bronchioles were different from the SP-A-positive cells. This finding suggests that CC10-positive cells are functionally and developmentally heterogeneous in both fetal and neonatal lungs in humans

Case report: the first report of idiopathic hypereosinophilic syndrome involved with lung and middle ear.

It has been reported that various organs are involved in idiopathic hypereosinophilic syndrome. Frequently, the heart, lung, skin, and nervous system are involved. Involvement of the middle ear, however, has not yet been reported. In this article, the authors describe the first case of hypereosinophilic syndrome involving the lung and middle ear. A 39-year-old woman had a 4-month history of low grade fever, non-productive cough, and a feeling of fullness and hearing loss in both ears. Peripheral blood cell count showed eosinophilia. Bilateral tympanic cavities were obstructed with granulation tissue, and she was diagnosed as obliterative otitis media. The granulation tissue consisted of foamy histiocytes and eosinophils. Chest X-ray film and computed tomography showed patchy infiltrative shadow in the lung. Histologic examination of the open lung biopsied specimen showed alveolar spaces infiltrated by eosinophils. After treatment with 30 mg oral prednisolone daily, there was a rapid improvement in her clinical condition. Based on the clinical course and the histologic findings of this case, obliterative otitis media may be caused by eosinophilic infiltration and eosinophilic pneumonia.

Solitary Bronchioloalveolar Adenoma of the Lung

A case of an unusual pulmonary neoplasia, called bronchioloalveolar adenoma of the lung, is reported. The neoplasm presented as a solitary peripheral lesion of the left lung on computed tomography. Examination of the tumor revealed a focal proliferating lesion consisting of cuboidal or peg-shaped epithelial cells with slight nuclear atypia. Immunohistochemical study with anti-carcinoembryonic antigen antibody, anti-surfactant apoprotein antibody, and anti-Clara cell antibody suggested that this neoplasia has the characteristics of a type II pneumocyte. It is likely that more of these small peripheral lesions, which have potential for evolution to carcinoma, will now be encountered due to the introduction of helical CT of the chest.

Clinicopathologic Relevance of Apoptotic and Proliferative Factors in Human Lung Adenocarcinoma: Fas Expression Correlates with the Histologic Subtype, But Not with the Degree of Apoptosis

We immunohistochemically examined 141 surgically resected peripheral lung adenocarcinomas for the expression of Fas, single stranded (ss-) DNA and Ki-67, and statistically evaluated the relationship of these parameters with other clinicopathologic variables, including clinical stage, nodal involvement, and histopathologic subtypes classified according to WHO criteria. Fas expression by cancer cells was characteristically localized in the cytoplasm, and the extent of expression correlated well with the degree of Ki-67 reactivity (p = 0.0004), but not with the degree of apoptic occurrence, as assessed by ss-DNA reactivity. Cancer cells of the bronchioloalveolar carcinoma (BAC) subtype without invasive growth exhibited a significantly lower Fas expression than those of other subtypes (p < 0.0001). Positive expression of Fas was frequently associated with a high incidence of nodal involvement and advanced clinical stage, as compared with cases of negative expression (p = 0.0111 and p = 0.0439, respectively). Multivariate analysis revealed that Fas expression significantly correlated with the histologic subtype, but not with tumor size, nodal involvement, or clinical stage. Survival analysis determined by the log-rank test revealed that clinical stage and Ki-67 reactivity were poor prognostic variables, and Fas expression was not statistically significant. Based on these data, intracytoplasmic expression of Fas in cancer cells may participate in the development of resistance to fas-mediated apoptosis.