Update results of FEC followed by docetaxel neoadjuvant trials for primary breast cancer.

This study has been initiated to evaluate the safety, clinical and pathologic response as well as the relation of response (pCR or non-pCR) and survival (overall and relapse-free) of fluorouracil, epirubicin and cyclophosphamide (FEC) followed by docetaxel (DOC) as preoperative chemotherapy in patients with operable breast cancer. Japanese patients with primary breast cancer, Tlc-3N0M0 or T1-3NIM0, age 20-60, PS 0-1 were included in this study. Preoperative chemotherapy consisted of 4 cycles of FEC (500 mg/m(2), 100 mg/m(2), 500 mg/m(2)) every 3 weeks followed by 4 cycles of DOC (75 mg/m(2)) every 3 weeks. Since June 2002, 200 patients were enrolled in this study, and the time of this interim analysis, 80 patients were evaluable for safety and clinical efficacy. The overall clinical response rate was 71.4% (14% CR, 44% PR, 42% SD/PD), and the only G3,4 toxicities, neutropenia and febrile neutropenia were observed in 54% and 14% of patients, respectively. Eighty nine patients were evaluable for pathologic response by central review. Pathologic response was evaluated among invasive tumors on multiple cross-section specimens based on a modified version of the Japanese grading system for Japanese Breast Cancer Society. The pathologic response rate was 17%. In this ongoing trial, FEC followed by DOC was active and well tolerated.

Living-Donor Liver Transplantation for Hepatic Metastasis From Meningeal Hemangiopericytoma: A Case Report.

We report the case of a 58-year-old man referred to our hospital for liver tumor treatment. The patient had a history of neurosurgery for a meningeal hemangiopericytoma 16 years previously. Pre-operative imaging revealed a hypervascular tumor extending from Couinaud segment 4 to segment 8 of the liver, measuring 95 mm in diameter, indicating an atypical hepatocellular carcinoma. Because right trisectionectomy of the liver was considered to be high risk, living-donor liver transplantation (LDLT) was indicated. After transcatheter arterial embolization, LDLT was performed with the use of a left-lobe liver graft from the patient's son. Post-operative histological findings of the liver tumor were identical to those for meningeal hemangiopericytoma, therefore the patient was diagnosed with meningeal hemangiopericytoma that had metastasized to the liver. After LDLT, the patient had a healthy, active life for 2 years; then, a subcutaneous relapse was discovered in the left chest. The patient did not undergo any systemic chemotherapy in response to the relapse. After thoracic and orthopedic surgeries and radiotherapy for multiple metastases, the patient died 5 years and 5 months after LDLT. LDLT could be an effective treatment for localized metastatic hemangiopericytoma in the liver, but it should be indicated only for carefully selected patients.

Pathobiology of the senescence-accelerated mouse (SAM).

Routine postmortem examinations and the pathobiological features revealed by systematically designed studies have shown several pathologic phenotypes that are often characteristic enough to differentiate among the various SAM strains: senile amyloidosis in SAMP1, -P2, -P7, -P9, -P10, and -P11; secondary amyloidosis in SAMP2 and -P6; contracted kidney in SAMP1, -P2, -P10, and -P11; immunoblastic lymphoma in SAMR1 and -R4; histiocytic sarcoma in SAMR1 and -R4; ovarian cysts in SAMR1; impaired immune response in SAMP1, -P2, and -P8; hyperinflation of the lungs in SAMP1; hearing impairment in SAMP1; degenerative temporomandibular joint disease in SAMP3; senile osteoporosis in SAMP6; deficits in learning and memory in SAMP8 and -P10; emotional disorders in SAMP8 and -P10; cataracts in SAMP9; and brain atrophy in SAMP10. These are all age-associated pathologies, the incidence and severity of which increase with advancing age. The SAM model in which these pathobiological features have been carefully monitored will be a valuable tool in the clarification of the pathogenic mechanisms of age-associated pathologies and in the research for effective methods to modulate or ameliorate these pathologies.

Removal of a dimeric form of surfactant protein C from mouse lungs: its acceleration by reduction.

Clearance of hydrophobic surfactant-associated protein C (SP-C) and its dimeric form ([SP-C]2) was investigated. SP-C and [SP-C]2 obtained from proteinosis patients were fluorescently labeled and were instilled into mouse lungs as lipid-protein complexes. [SP-C]2 was removed more slowly than SP-C, with apparent half-lives of 30 and 18 h, respectively. A significant amount of [SP-C]2 was removed as SP-C, and the conversion rate was 0.22 micrograms.h-1.mouse-1. By correcting the removal as SP-C, we obtained 38 h for a possible half-life of [SP-C]2. Conversion from SP-C to [SP-C]2 seemed very slow. Decrease in glutathione (GSH) in the lung inhibited the conversion of [SP-C]2 to SP-C and GSH-treatment of liposomes accelerated clearance of [SP-C]2. These results suggest that the removal of [SP-C]2 from lung is accelerated by reduction and that GSH acts as a reducing agent in the lung.

Removal of disperse dyes by the fungus Cunninghamella polymorpha.

A disperse dye-removing fungus, Cunninghamella polymorpha, was isolated from soil. C. polymorpha efficiently removed an average 93% of 17 tested disperse dyes in 120 h, and 90% of C. I. Disperse Blue 60 was removed even at a high concentration of 500 mg/l. The dye removal was due to the sorption of dye to the fungal cells.

Neonatal tolerance induction in the thymus to MHC-class-II-associated antigens. V. Thymus medulla and the site for deletional signaling achievement in Mls tolerance.

Intravenous (i.v.) injection of Mls-1a peritoneal cavity (PerC) cells from (BALB/c x AKR)F1 (Mls-1b/a, H-2d/k) mice into newborn BALB/c (Mls-1b, H-2d) mice induced thymus cell tolerance by one week of age, accompanied by V beta 6+ cell elimination. The tolerant state is associated with intrathymic chimerism with MHC-class II(IA+) cells, confluent in the medulla and scattered in the cortex. To clarify the anatomical site for the deletional signaling, we injected Mls-1a PerC cells directly into the thymus lobe of BALB/c mice on the day of birth. Thus induced tolerant state was limited to the injected lobe and there was no penetration to the contralateral lobe. The tolerant state lasted less than 2 weeks, by which time donor-derived Ia+ cell had disappeared from the thymus. Thus, PerC cells seem to have little self-renewing ability. One week after the intrathymic injection of a small amount (0.3 microliter) of PerC cell suspension in several different sites, the thymus lobes were removed without killing the mice and serial cryostat sections were cut and stained immuno-histochemically for analysis of the donor cell distribution. Four weeks later, the functional activities of peripheral T cells in the spleens of the treated mice were tested. These experiments revealed that inoculated cells lodging in the medulla, but not in the cortex, induced tolerance to the Mls determinants. Target thymocytes for negative signaling are probably located in the medulla/juxta-medullary area in the thymus. Data are discussed in relation to Mls-bearing stroma cells in the thymus.

Age-related changes in lung structure and function in the senescence-accelerated mouse (SAM): SAM-P/1 as a new murine model of senile hyperinflation of lung.

Age-related changes in lung structure and function were investigated in murine models of accelerated senescence (SAM-P/1) and of normal aging (SAM-R/1). In morphometric studies, most of the parameters examined, including lung volume, mean linear intercept, total alveolar duct air volume, and total alveolar air volume, began to increase and the internal surface area per unit lung volume and total elastic fiber length per unit lung volume began to decrease from 2 months of age, and these changes continued to progress up to 10 months of age in SAM-P/1. In SAM-R/1, there were no significant changes in these parameters from 2 to 6 months of age, thereafter slight but steady changes were observed up to 25 months of age. Thus, significant differences in these parameters between SAM-P/1 and SAM-R/1 became evident in mice 6 to 17 months of age. Internal surface area and total elastic fiber length showed no age-related changes after 2 months of age, and total alveolar air volume showed no age-related changes after 6 months of age in either strain. All morphometric parameters examined showed similar levels at 17 months of age in SAM-P/1 and 25 months of age in SAM-R/1. Histologic observations revealed no evidence of destruction of the alveolar wall or elastic fibers in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients.

Recent experimental studies have revealed that tumour-associated stromal macrophages as well as tumour cells express vascular endothelial growth factor C (VEGF-C), which plays important roles in lymphangiogenesis, which is a critical factor in the progression of many malignant tumours including non-small-cell lung cancer (NSCLC). However, no clinical study on VEGF-C expression in both stromal macrophages and tumour cells has been reported, and we conducted the present study to address the issue in resected NSCLC. A total of 206 patients with completely resected pathologic stage I-IIIA NSCLC were retrospectively reviewed. Expression of VEGF-C in primary lung tumour was assessed immunohistochemically. Expression of VEGF-C in tumour cells was high in 125 patients (60.7%), and that in stromal macrophages was positive in 136 patients (71.2%). The status of VEGF-C in tumour cells or in stromal macrophages was not correlated with nodal status or angiogenesis. The 5-year survival rate of high tumoral VEGF-C patients (60.7%) was significantly lower than that of low tumoral VEGF-C patients (39.3%) (P=0.046), and a multivariate analysis confirmed that tumoral VEGF-C status was a significant and independent prognostic factor. Moreover, tumour showing high VEGF-A and VEGF-C expression in tumour cells showed the poorest prognosis (5-year survival rate, 45.1%). The status of VEGF-C in stromal macrophages was not correlated with the prognosis. In conclusion, tumoral VEGF-C status, not stromal VEGF-C status, was a significant prognostic factor in resected NSCLC.

Secretory meningioma: a case report with immunohistochemical and ultrastructural study.

Secretory meningioma is a new concept proposed with the progress on immunohistochemistry, and has not sufficiently been discussed in the literature. We report a case with this rare type of meningioma, in a 54-year-old female. The tumor had hyaline inclusions that showed not only carcinoembryonic antigen (CEA) on immunohistochemical study but some secreting organelles on ultrastructural study. The value of these findings are emphasized in the histological diagnosis for secretory meningioma.

Isolation and partial characterization of human low molecular weight protein associated with pulmonary surfactant.

A low molecular weight (MW) protein was isolated from the bronchoalveolar lavage fluid of a patient with alveolar proteinosis. The protein was isolated on DEAE-cellulose and CM-cellulose columns by a cross-reaction with the monoclonal antibody against pig low MW protein (15 kDa) used as a marker. Acidic ethanol-soluble proteins obtained from the fractions eluted by 0.09 to 0.16 M NaCl concentration from the CM-cellulose column migrated mainly as a 15-kDa band in the SDS-PAGE system without urea but mainly as a 5-kDa band in a system with 8 M urea. The isoelectric point of the protein was pH 10 to 11, and it contained a large proportion of hydrophobic amino acids (72%), especially leucine (17%). The arginine content was also high (9%). Two monoclonal antibodies were raised against this low MW protein, and immunohistochemical studies revealed that the antigen was located in the inclusions of alveolar wall cells in normal lungs and in lungs from a patient with alveolar proteinosis. These results indicate that the low MW protein originates from lamellar inclusions of alveolar wall cells (possibly type II epithelial cells) and is secreted into alveolar spaces.

Parotid gland lesions: diagnosis of malignancy with MRI and flow cytometric DNA analysis and cytology in fine-needle aspiration biopsy.

BACKGROUND: The purpose of this study was to assess the capability of magnetic resonance imaging (MRI) and cytology and flow cytometric (FCM) deoxyribonucleic acid (DNA) analysis in fine-needle aspiration biopsy (FNAB)-derived materials for diagnosing malignancy of the parotid lesions and the efficacy of FCM analysis in FNAB. METHODS: Magnetic resonance imaging findings and FCM results (ploidy and S + G2 + M phases [S + G2M] fraction) and cytology in FNAB-derived materials in 26 patients with 26 parotid lesions (12 benign lesions, 14 malignancies) were assessed for predicting malignancy. Flow cytometric results in aspirates were compared with those in surgically resected tissues. RESULTS: When a single predictor was used, cytology (92% accuracy) was most accurate for malignancy, followed by ill-defined margin (88% accuracy) and aneuploidy (88% accuracy). The combination of FCM and cytology raised the rate of sufficient materials from 92% to 100% and accuracy from 92% to 96% compared with cytology alone. The same highest accuracy (96%) was obtained with the combination of the ill-defined margin or other findings such as cytology, aneuploidy, or a high (S + G2M) fraction (6% <). Deoxyribonucleic acid ploidy in the FNAB showed full agreement with that in the surgical specimens. Receiver operating characteristic curves showed that the diagnosis of malignancy with (S + G2M) fraction in FNAB was superior to that in surgical specimens, but no significant difference was noted. CONCLUSIONS: A combination of MRI findings, cytology, and FCM results is optimal for diagnosing malignancies of the parotid lesions, and FNAB may replace the surgical specimens in FCM analysis.

[A case of thyroid medullary carcinoma-like tumor of the lung with amyloid stroma].

A 58-year-old man with history of productive cough and mild exertional dyspnea for several years was admitted to our hospital because of abnormal shadow on chest radiograph. Bronchofiberscopic examination revealed a polypoid tumor almost completely obstructing the right main bronchus. Bronchoscopic biopsy specimens showed amyloid-like deposits in the connective tissue surrounded by epithelium-like tumor cells with squamous metaplasia, but no diagnostic findings. Malignant tumor was suspected and right upper lobectomy was performed. The surgical specimen revealed nests of tumor cells surrounded by amorphous eosinophilic substance, which was confirmed to include amyloid fibrils by electron microscopy. A few tumor cells contained argyrophil granules by Grimelius staining, and some showed PAP staining for calcitonin. There was no evidence of involvement of other organs including the thyroid gland during the four year postoperative follow-up period. This case was diagnosed as thyroid medullary carcinoma-like tumor of the lung, which is a bronchopulmonary carcinoid-related tumor.

Neonatal tolerance induction in the thymus to MHC-class II-associated antigens. IV. Significance of intrathymic chimerism of blood-born Ia+ cells in Mls tolerance.

The significance of thymus cell chimerism in the induction and maintenance of tolerance was investigated. Mls-1b BALB/c mice were neonatally tolerized by the intravenous administration of either bone marrow (BM) cells or peritoneal cavity (PerC) cells from Mls-1b/a (BALB/c x AKR) F1 mice. Tolerance was long-lasting in the BM cell group, but transient in the PerC cell group, probably because PerC cells lack hemopoietic stem cells required for a continuous supply of tolerance-inducing cells. The degree of anti-Mls-1a responsiveness of these BALB/c thymus cells was correlated with the degree of intrathymic distribution of the inoculated F1 cells. The effect of BM cell inoculation, resulting in a year-long deletion of Mls-1a-reactive V beta 6-bearing T cells is in marked contrast to that of PerC cell inoculation which causes only a transient loss of V beta 6+ mature thymocytes (for about 1 week after birth). This functional profile of the tolerant state correlates well with the degree and persistence of the intrathymic presence of F1 type Ia+ cells. The long-lasting presence of donor-derived cells throughout the thymus tissue in the BM cell group is also in marked contrast to the early disappearance of Ia+ cells (within 2-3 weeks) from the cortex and then from the medulla in the PerC cell group, although these Ia+ cells were once spread throughout the thymus tissue 4 days after the tolerance-inducing cell inoculation. Taken together with a failure to induce consistent unresponsiveness to Mls-1a determinants in Mls-1b thymocytes regenerating in Mls-1a-thymic epithelial environments, all the above data indicate that intrathymic chimerism caused by hemopoietic stem cell-derived MHC-class II-bearing cells is a requisite for the induction and maintenance of unresponsiveness by means of clonal deletion in experimentally as well as naturally induced tolerance to Mls determinants.

[An epidemiologic study on patients with lung disease, using a data base management system and the histopathologic diagnosis].

A new pathologic data base management system was introduced in the Section of Pathology, Clinical Laboratory, of this hospital for an efficient sorting and searching past data and for the rapid epidemiological study of them. By the use of this system, the incidence and the age and sex distribution of various diseases were studied in a total of 1,264 patients received pathological examination for surgically operated specimens or biopsied materials at the Chest Disease Research Institute Hospital, Kyoto University, from January, 1986 to December, 1988. A gradual increase in the number of frozen section samples of surgically removed organs and of open lung biopsies was noted during this period. Adenocarcinoma, squamous cell carcinoma, small cell carcinoma and large cell carcinoma amounted to 42.5%, 32.9%, 12.2%, and 7.5% of primary lung cancers, respectively. The male-to-female ratio of patients with primary lung cancers was 2.9:1 but there was no significant difference in the age distribution among four types of the primary cancers in both sexes. Two hundred and ninety nine (32.6%) patients were diagnosed as non-neoplastic lung diseases: 121 infectious (13.2%), 69 granulomatous (7.5%), 62 pulmonary fibrotic (6.8%) and 47 miscellaneous non-neoplastic (5.1%) diseases.