Cell surface expression of the endoplasmic reticular heat shock protein gp96 is phylogenetically conserved.
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In mammals, the heat shock protein gp96 complexed to antigenic peptides elicits T cell adaptive immunity. By itself, however, gp96 can evoke responses that are characteristic of innate immunity. Interestingly, this protein, which resides in the endoplasmic reticulum, is expressed on the surface of certain mouse tumor cells. Given that heat shock proteins are highly conserved, we investigated whether the cell surface expression of gp96 is also evolutionarily conserved. Our data reveal that gp96, most likely containing the endoplasmic reticulum retention motif (KDEL), is expressed on the surface of three different Xenopus lymphoid tumor cell lines, each derived from a different spontaneously arising thymic tumor. Levels of expression differ among the tumor lines tested, with more immunogenic tumors expressing greater amounts of surface gp96. Moreover, a high level of gp96 surface expression is detectable on a subset of Xenopus normal nontransformed splenic lymphocytes (mainly surface IgM+ B cells) but not on other normal cells, including macrophages and nucleated erythrocytes. Surface expression of a gp96 protein homologue occurs also on some, but not all, T and B cell clones derived from peripheral blood cells of the channel catfish, as well as on lymphocyte-like cells, but not on erythrocytes from the hagfish, a primitive agnathan vertebrate lacking markers of an adaptive immune system. gp96 is actively directed to and retained on the plasma membrane of Xenopus lymphocytes and tumor cells and hagfish lymphocyte-like cells by a process that requires vesicular transport. This selective surface expression of gp96 on some immune cells from different vertebrate classes is consistent with an ancestral immunological role of gp96 as danger-signaling molecule. (+info)
Cervical thymoma.
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CONTEXT: Cervical thymoma is a primitive thymic neoplasia. It is very rare. This disease presents higher incidence in female patients in their 4th to 6th decade of life. We present a case report of a cervical thymoma. CASE REPORT: 54-year-old female patient, caucasian, with no history of morbidity, presenting a left cervical nodule close to the thyroid gland. During the 30 months of investigation a left cervical nodule grew progressively next to the thyroid while the patient showed no symptoms, making accurate diagnosis difficult. Tests on her thyroid function did not show changes, nor were there changes in any subsidiary tests. The diagnosis of the disease was made intra-operatively through total thyroid individualization. The results were confirmed by the histological findings from the ressected material. Cervical thymoma is a very rare disease, with difficult preoperatory diagnosis. Some additional study methods which are employed today are thallium 201, technetium 99 and iodine 131 scintigraphy, magnetic nuclear resonance and especially histopathological findings and classification. (+info)
Differential diagnosis of thymic tumors using a combination of 11C-methionine PET and FDG PET.
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We assessed the usefulness of PET studies in making a differential diagnosis of thymic tumors by using 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG). METHODS: We examined 31 patients with thymic tumors, including 14 patients with thymic cancer, 9 with invasive thymoma, 5 with noninvasive thymoma and 3 with thymic cysts. The histological diagnosis was confirmed by either surgery or biopsy. MET PET and FDG PET were performed in 28 and 29 patients, respectively. Both the MET and FDG uptakes were evaluated by the standardized uptake value (SUV). RESULTS: MET uptake was not substantially different among thymic cancer (4.8 +/- 1.4), invasive thymoma (4.3 +/-1.1) and noninvasive thymoma (4.5 +/- 1.2), bat MET uptake in thymic cysts (0.9 +/- 0.1) was lower than that in the other three tumors (P < 0.01). The FDG uptake in thymic cancer (7.2 +/- 2.9) was higher than that in invasive thymoma (3.8 -/+ 1.3), noninvasive thymoma (3.0 +/- 1.0) and thymic cysts (0.9) (P < 0.01). MET uptake in thymic tumors correlated with the FDG uptake (r = 0.65), whereas MET uptake in thymic cancer was lower than FDG uptake (FDG/MET ratio = 1.52 +/- 0.52) but was higher than FDG uptake in both invasive and noninvasive thymoma (FDG/ MET ratio = 0.86 +/- 0.33). To differentiate thymic cancer from thymoma, a receiver operating characteristic (ROC) analysis was performed. The area under the curve of FDG PET was 0.90, whereas the FDG/MET ratio was 0.87. CONCLUSION: The MET PET, FDG PET and the FDG/MET ratios were unable to differentiate benign thymic tumors from malignant ones, although FDG PET was considered to be useful in the differential diagnosis between thymic cancer and thymoma. Although the difference in the uptake ratio between FDG and MET suggests a different origin of the tumors, the FDG/MET ratio is not considered to be useful as a complementary method for the differential diagnosis of thymic tumors. (+info)
Clinical and pathologic predictors of survival in patients with thymoma.
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OBJECTIVE: To evaluate the Johns Hopkins Hospital experience with 136 thymomas over the past 40 years. This number of patients allowed quantitative estimation of the independent influence of common clinicopathologic risk factors using multivariate analysis. SUMMARY BACKGROUND DATA: Thymomas vary widely in terms of recurrence and influence on overall survival. Several series have indicated the importance of initial tumor invasion, as well as the extent of surgical resection, as predictors of recurrence and survival after thymoma resection. However, findings have been equivocal when other predictors of prognosis were examined. METHODS: The authors evaluated 136 patients seen at the Johns Hopkins Hospital between 1957 and 1997 with a pathologic diagnosis of thymoma. Demographic information, clinical staging data, surgical and adjuvant treatment details, and patient follow-up data were obtained from the patient record and from detailed patient or family interviews. Microscopic sections of all 136 patients were reviewed by two pathologists blinded to the clinical data. All data were analyzed by multivariate Cox regression analysis, which allowed the quantification of the independent predictive value of 12 putative clinicopathologic prognostic indicators. RESULTS: Completeness of follow-up was 99%, 99%, and 98% of eligible patients at 5, 10, and 15 years, respectively. Forty percent of the patients had associated myasthenia gravis and 27% had a secondary primary malignancy. Overall patient survival rates were 71%, 56%, 44%, 38%, and 33% at 5, 10, 15, 20, and 25 years, respectively. Overall, the thymoma-related mortality rate was 14%; the nonthymoma-related mortality rate was 26%. Incomplete resection, preoperative absence of myasthenia gravis, and advanced Lattes/Bernatz pathologic class were found to be independent predictors of poorer overall survival. CONCLUSIONS: These findings support a policy of aggressive, complete surgical resection of all thymomas when feasible. Thymoma behaves as a rather indolent tumor, with most deaths from causes unrelated to thymoma or its direct treatment. Clinicians should have an increased awareness of the possibility of second primary malignancies in patients with thymoma. (+info)
Clonal acquisition of the Ly49A NK cell receptor is dependent on the trans-acting factor TCF-1.
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Families of clonally expressed major histocompatibility complex (MHC) class I-specific receptors provide specificity to and regulate the function of natural killer (NK) cells. One of these receptors, mouse Ly49A, is expressed by 20% of NK cells and inhibits the killing of H-2D(d) but not D(b)-expressing target cells. Here, we show that the trans-acting factor TCF-1 binds to two sites in the Ly49A promoter and regulates its activity. Moreover, we find that TCF-1 determines the size of the Ly49A NK cell subset in vivo in a dosage-dependent manner. We propose that clonal Ly49A acquisition during NK cell development is regulated by TCF-1. (+info)
CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism.
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A tumor-specific CD8+ T cell response was studied using adoptive transfer of OT-I TCR transgenic cells. Upon i.p. challenge with E.G7 tumor, OT-I cells undergo CD4+ T cell-independent expansion at the tumor site and develop lytic function. Before tumor elimination, however, they leave the peritoneal cavity (PC) and appear in the LN and spleen where they exhibit "split anergy" and cannot further proliferate to antigen. Administering anti-CTLA-4 mAb early caused sustained OT-1 expansion in the PC, and late administration caused the OT-I cells to return to the PC and further expand; in both cases, tumor was controlled. These effects required CD4+ T cells and IL-2 and appear to result from reversal of the nonresponsive state of the CD8+ T cells. (+info)
Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience.
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From 1990 to 1997, 16 consecutive patients with stage III and IVa invasive thymoma were treated in a single institution with primary chemotherapy consisting in adriamycin (40 mg m(-2)), cisplatin (50 mg m(-2)) administered intravenously on day 1, vincristine (0.6 mg m(-2)) on day 2 and cyclophosphamide (700 mg m(-2)) on day 4 (ADOC). The courses were repeated every 3 weeks. The aim was to evaluate the impact of this cytotoxic regimen with respect to response rate, per cent of patients radically resected, time to progression and overall survival. Two complete responses (one clinical and one pathological) and 11 partial responses were observed (overall response rate 81.2%); two patients had stable disease and one progressed. Toxicity was mild as only two patients developed grade III/IV neutropenia and one patient grade III nausea/vomiting. Nine patients were radically resected (five out of ten with stage III, and four out of six with stage IVa). Median time to progression and overall survival was 33.2 and 47.5 months respectively. Three patients were alive and disease free after more than 5 years. The ADOC scheme is highly active and manageable in the treatment of locally advanced thymoma. As a preoperative approach it should be offered to patients not amenable to surgery or to those surgically resectable but with a great deal of morbidity. (+info)
Thymoma: state of the art.
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Thymoma is the most common tumor of the anterior mediastinum. This tumor is associated with unique paraneoplastic syndromes, such as myasthenia gravis, hypogammaglobulinemia, and pure red cell aplasia. The rarity of this tumor, however, has somewhat obscured the optimal treatment for this disease. For the majority of patients who present with localized tumor, surgical extirpation remains the standard of choice. Adjuvant radiotherapy seems to improve local control and survival. In more advanced disease, systemic therapy has been demonstrated to produce a 50% to 80% objective response rate. These observations have led to the development of multimodality therapy for the treatment of patients with advanced thymoma. In this article, we will review the current perspectives on the management of early stage and advanced thymoma. (+info)