Enhancement of delayed hypersensitivity reaction with varieties of anti-cancer drugs. A common biological phenomenon.

Delayed hypersensitivity reaction in mice was commonly enhanced with various anti-cancer agents administered as single or intermittent high doses but not consecutive divided doses. The effect of anti-cancer agents on the delayed hypersensitivity reaction was thought to be due to elimination of suppressor T cell activity.

Studies on delayed hypersensitivity in mice. III. Evidence for suppressive regulatory T1-cell population in delayed hypersensitivity.

T-T-cell interactions involved in delayed hypersensitivity (DH) response have been studied by employing delayed foot pad assay to methylated human serum albumin in C57BL/6J mice. The DH response, one of the T-cell manifestations of cell-mediated immune response is suppressively regulated by T cells and such observation was based on studies of age-associated kinetics of foot pad reaction and effects of cell transfer and adult thymectomy on developing DH response. These suppressively regulatory T cells in DH have a life span of less than 4 wk and a constant derivation from the thymus is required. Such cells are numerous in the young mouse thymus and few in the spleen and thymus of old mice. On the one hand, the presence of a long-lived effector T-cell population was suggested in DH. These cells are numerous in the spleen and are low responders to phytohemagglutinin in vitro. It is assumed that these suppressive T cells interact with antigen-reactive cells at their proliferating stage by recognition of the iodiotypic difference through surface receptors. As in the case of graft-vs.-host and humoral response in vivo, three different subsets of immune competent cells participate in the DH response. These cells consist of one specifically antigen-reactive T cell, one suppressive regulatory T cell, and one bone marrow-derived cell, a macrophage that responds to a chemical mediator from sensitized effector T cells and that develops a DH skin lesion nonspecifically.

Cyclophosphamide eliminates suppressor T cells in age-associated central regulation of delayed hypersensitivity in mice.

Effect of treatment of mice with cyclophosphamide (CY) on the delayed hypersensitivity (DH) response was investigated in C57BL/6 mice. DH to methylated human serum albumin (MHSA) could be enhanced with CY in young mice but not in aged ones. DH enhancement with CY appeared to be due to elimination of suppressor T cells involved in DH. Effector T cells were also sensitive to CY, the damaging effect of CY on these latter cells was, however, transient suggesting the rapid recovery of effector T cells. The overshooting recovery of the effector T cells required the presence of the thymus. It is more probably that there are at least two distinct subpopulations of T cells in DH, effector T cells, and suppressor T cells. The distinction is already apparent in the thymus stage. The suppressor T cells, categorized as a central regulator, seem to be antigen nonspecific and regulate the more effectively the DH in young mice, thus physiological role of these cells in age-associated immune alterations is implicated.

Doppler ultrasonography-aided early diagnosis of venous thromboembolism after total knee arthroplasty.

OBJECTIVES: Postoperative deep venous thrombosis (DVT) is usually asymptomatic but can result in a fatal pulmonary embolism (PE). To assess the ability of transcranial Doppler (TCD) ultrasound apparatus to detect venous emboli in patients who had undergone total knee arthroplasty (TKA). METHODS: Forty-eight patients undergoing TKA were examined postoperatively by using compression ultrasonography, computed tomographic angiography, and TCD ultrasonography that detected high-intensity transient signals (HITS) in femoral veins. An original scoring system based on both the number of HITS and the locations of DVT was tested for its accuracy in predicting PE development. RESULTS: Twenty-three of the 48 patients had DVT postoperatively, and 8 had an asymptomatic PE. The sensitivity and specificity of the HITS assessment alone in identifying PE development were 75% and 92.5%, respectively. The scoring system, however, had a sensitivity of 100% and a specificity of 85% and the area under the receiver operating characteristic (ROC) curve (AUC) was 0.96. CONCLUSIONS: Application of a scoring system based on the detection of both DVT and HITS may be an effective and efficient method of screening for PE after knee arthroplasty.

Development of a new surgical procedure for repairing tracheobronchomalacia.

We have developed a new surgical method for repairing tracheobronchomalacia. In experiments on dogs we tried external fixation of Marlex mesh (Bard Cardiosurgery Division, Bellerica, Mass.) on the trachea. We first made models of tracheomalacia by making fractures or resections in intrathoracic tracheal cartilages and then made an external fixation of Marlex mesh on the malacic segments of the trachea. In 11 dogs Marlex mesh was sutured onto the trachea with absorbable thread. The trachea was firmly supported after 2 to 6 months, compared with three controls in which no external fixation was made. However, mucosal defects associated with ischemia caused by the suture developed in four of the 11. In 13 more dogs Marlex mesh was bonded to the trachea with fibrin glue. After 3 to 8 months the supporting strength of the trachea increased up to the level of the normal trachea. There was no evidence of inflammation or of mucosal defects. Therefore Marlex mesh was applied to a 44-year-old-man who had experienced frequent attacks of cough syncope. After the operation the attacks of cough syncope and collapsing of his airway disappeared completely.

[Experimental and clinical results of tracheal prosthesis].

Prosthetic reconstruction of the trachea was performed experimentally in mongrel dogs. Neville's prosthesis, which we used initially, has insufficient elasticity and flexibility. As a result, migration was observed after the reconstruction. To prevent such migration, we wrapped the prosthesis in Marlex mesh. Nevertheless, dehiscence and local infection occurred at the anastomotic site. We have developed a new Katsura prosthesis which is made of silicone rubber and has good elasticity and flexibility. However, the Katsura prosthesis was also unable to prevent dehiscence and local infection at the anastomotic site in the experiment. We have thus tested successive models of the Katsura prosthesis (model I-model V). Recently, we wrapped the prosthesis of model V in pedicled omentum instead of Marlex mesh to prevent the spread of infection to the mediastinum. In clinical cases who had a large surgical defect of the trachea and difficulty of primary anastomosis, we performed prosthetic reconstruction. We used Neville's prosthesis in 7 cases and the Katsura prosthesis in 5 cases. Severe complications were observed, such as arterial erosion and migration of the prosthesis. All the cases have died, although 5 cases survived for more than 1 year, and the longest survival time was 43 months. In the future, we hope that an ideal substitute for the trachea will be found and that prosthetic reconstruction will be able to safely performed, as in the case of vascular prosthesis.

[Diagnosis and treatment of mediastinal teratoid tumors].

Among anterior mediastinal tumors affecting male patients of around 20 years old, mediastinal malignant teratoid tumor must be considered as one of the possibilities. Malignant teratoid tumor can be classified as seminoma, non-seminoma or mixed, according to clinical behavior. In the non-seminoma group, AFP and/or HCG can be the specific markers in the diagnosis or assessment of the effect of treatment. Chemotherapy with CDDP must be the first choice of treatment in these types of tumor, just as chemotherapy is the first choice of therapy in the treatment of small cell lung cancer, and surgery must be the adjuvant treatment to chemotherapy. On the other hand, seminoma can be treated by surgery and radiation, which has been proven to yield a good prognosis. In cases of seminoma which produces HCG and/or AFP, chemotherapy with CDDP must be added to surgery and radiation as in non-seminomatous mediastinal teratoid tumors, because the production of such markers in seminoma is considered to be one of the poor prognostic factors in the treatment of seminomatous mediastinal teratoid tumors.

[Malignant germ cell tumors in the mediastinum].

Mediastinal germ cell tumors are divided into seminomas and non-seminomatous germ cell tumors. The former is a radiosensitive tumor that can be successfully treated by surgery and radiation. The latter is much more malignant than the former, however, the therapy has been making remarkable progress owing to CDDP. Nevertheless, the median survival time of patients with mediastinal involvement is 14 months, much lower than that seen in patients with testicular involvement. From our 12 patients and a review of the literature, we drew the following conclusions. If malignant germ cell tumors are suspected among anterior mediastinal tumors affecting male patients of around 20 years old, tumor markers such as AFP and HCG must be investigated and then, tissue histology should be diagnosed from specimens obtained by mediastinoscopy or anterior mediastinotomy. In the case of NSGCT, or AFP and/or hCG producing seminoma, the first choice is the chemotherapy including CDDP. Seminomas, that do not produce either AFP or HCG, can be treated by surgery and radiation. If the patients have tumor markers such as AFP and/or HCG, these are very useful to evaluate the efficacy of the therapy. When the efficacy of chemotherapy reaches the maximum, adjuvant surgery may be indicated. Chemotherapy should be continued, when malignant tissues are present in the resected mass.

[Surgical treatment of metastatic lung tumors].

Surgical treatments were performed in 88 cases of metastatic lung tumors, where 5 years survival rate in all resected cases was 37.5%. We report our principles on the surgical treatment for metastatic lung tumors. First of all, the biological characteristics of the primary lesion is among the most important factors in considering the indication for the surgical treatment in metastatic lung tumors. For example, chemotherapy must be the first choice in treating lung metastasis of choriocarcinoma, and hormone therapy in lung metastasis of mammary carcinoma. On the other hand, such tumors as osteogenic sarcoma, soft tissue sarcoma, colorectal carcinoma and Grawitz's tumor, should be treated by surgery. Another point in the surgery of the metastatic lung tumor is the choice of the mode of operation for the solitary metastatic tumor according to tumor type. As a principle, partial or segmental resection is preferably chosen for metastatic lung tumor. However, the location of the lung tumor, tumor size, hilar lymph node metastasis and the pattern of invasion to the surrounding lung tissue must be considered to decide the surgical procedure. From these considerations, the segmental or partial resection for metastatic sarcomas and the lobectomy for the metastatic carcinomas are appropriate in general.

Lymphocyte subsets in human thymoma studied with monoclonal antibodies.

Lymphocyte subsets were investigated using OKT series monoclonal antibodies and flowcytometry in 16 cases of thymoma. From the viewpoint of lymphocyte subsets, thymoma could be divided into three types: thymus lymphocyte type, peripheral lymphocyte type, and intermediate type. In thymus lymphocyte type, the number of OKT-6+ cells exceed that of OKT-3+ cells, and are more than 50%. In peripheral lymphocyte type, the number of OKT-6+ cells are less than that of OKT-3+ cells and less than 10%. In intermediate type, OKT-6+ cells are between 10% and 30%. These three types correlate well with the histologic features with respect to the number and distribution of lymphocytes in thymoma tissue. Lymphocytes were infiltrating abundantly and intermingled in the tumor cell nests in thymus lymphocyte type, and were infiltrating rather scantly and outside the nests in peripheral lymphocyte type.

Lactate dehydrogenase isoenzyme-1 in the mediastinal yolk sac tumor.

LDH isozymes in both the serum and tumor tissues of 4 patients with mediastinal yolk sac tumors, and in the cystic content of tumors transplanted into nude mice was examined. Our findings suggested that LDH-1, along with AFP, is an important marker of this tumor, and that LDH isozyme study is necessary for its diagnosis.

[Non-Hodgkin's lymphoma arising from the wall of old tuberculous empyema--a surgical case report].

A 71-year-old male underwent therapeutic pneumothorax for left pulmonary tuberculosis 42 years ago. He visited our hospital in February 1988 with a complaint of hemosputum. In October, cytology of sputum revealed malignant cells, and the patient was admitted to our hospital for further examination. Because malignant cells were found by the left bronchial lavage, pan-pleuropneumonectomy was performed on January 12, 1989 under the diagnosis of left lung cancer. The tumor was partially left unremoved. Histological diagnosis was diffuse large cell type, B cell non-Hodgkin's lymphoma. Postoperatively, 2 courses of cyclophosphamide, adriamycin, vincristine, prednisone, etoposide (CHOP and VP-16) therapy were performed. However, the patient died of respiratory insufficiency on the 125th postoperative day. Recently, cases of malignant lymphoma involving the pleura after the old tuberculous empyema and therapeutic pneumothorax have been increased. Therefore, prompt diagnosis and treatment are recommended when tumor shadow is suspected as a result of imaging examination.

Delayed hypersensitivity in mice induced by intravenous sensitization with sheep erythrocytes: evidence for tuberculin type delayed hypersensitivity of the reaction.

Delayed hypersensitivity (DH) reaction can be induced in mice by intravenous sensitization with sheep erythrocytes (SRBC). However, as the sensitizing procedure is quite different from a usual mode of sensitization for DH using complete Freund's adjuvant (FCA), the nature of this reaction has been a matter of controversy. In an attempt to characterize this reaction, we placed special interest on two possibilities regarding the nature of this reaction; Jones-Mote reaction or tuberculin type DH. From the kinetics study on the DH after challenge, the DH reaction to SRBC in mice by intravenous sensitization was clearly distinguished from the Arthus reaction. The dose-response pattern of this reaction also suggested that the contribution of Arthus reactivity to delayed reactivity was negligible. Cell reconstitution experiments revealed this DH to be quantitatively thymus cell dependent. Furthermore, this DH required macrophages at its manifestation stage, and appearance of basophil infiltration at the lesion was absent. In addition, strain difference and ageing of host mice influenced the DH reaction in exactly the same fashion in which these factors influence the tuberculin type-DH induced by subcutaneous sensitization with methylated human serum albumin (MHSA) in FCA. Taken collectively, it was concluded that this DH reaction can be categorized as the tuberculin type.