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The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively) The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%

However, these 2 cases clearly indicate that it is not necessarily associated with thymoma but can also be associated with other malignancies. DLBCL cells ectopically express PIT-1, and the presence of PIT-1Creactive CTLs indicates the underlying mechanisms similar to those in patients with thymoma. B-cell lymphoma (DLBCL) of the bladder and case 2 was diagnosed with malignancy with multiple metastases of unknown origin. Because circulating antiCPIT-1 antibody was detected, both patients Rabbit polyclonal to NPAS2 were diagnosed with antiCPIT-1 hypophysitis. Circulating PIT-1Creactive T cells were detected in case 1 via enzyme-linked immunospot (ELISPOT) assay. TZ9 Interestingly, the PIT-1 protein was ectopically expressed in the DLBCL cells of case 1, whereas DLBCL tissues derived from patients without antiCPIT-1 hypophysitis were negative for PIT-1. In case 2, the materials were not available because of best supportive care was under way. These data show that antiCPIT-1 hypophysitis is associated not only with thymoma but also with other malignancies. Additionally, the ectopic expression of PIT-1 in the DLBCL tissues and presence of PIT-1Creactive T cells suggested that the underlying mechanisms were similar to those observed in thymoma. Thus, antiCPIT-1 hypophysitis is defined as a form of paraneoplastic syndrome. refers to symptoms and signs resulting from damage to organs or tissues that are remote from the site of a malignant neoplasm or its metastasis. In particular, most paraneoplastic neurological syndromes are immune mediated and are associated with ectopic antigen presentation in the tumor that induces humoral and/or cellular autoimmune responses. Various tumors are known to cause paraneoplastic neurological syndromes [3]. A recent study reported the association of lung cancer with a case of isolated adrenocorticotropin (ACTH) deficiency related to paraneoplastic syndrome. Lung cancer ectopically expressed proopiomelanocortin (POMC), which in turn promoted the production of POMC-specific CTLs [4]. These results suggested that pituitary injury can also occur as a form of paraneoplastic syndrome in addition to neuronal injury. We previously described a case of antiCPIT-1 hypophysitis with diffuse large B-cell lymphoma (DLBCL) briefly in the review literature [5]. In this study, we present the details of this case with further investigation for pathophysiology along with another novel case of malignancy and discuss a new definition of this disease. Case Presentation Case 1 A 79-year-old woman, hospitalized for the evaluation of chronic kidney disease, TZ9 was diagnosed with central hypothyroidism. Endocrinological evaluation revealed extremely low basal levels and blunted responses to the TZ9 provocative stimuli of GH, PRL, and TSH. However, the secretion of other anterior pituitary hormones was not impaired (Table 1). Pituitary magnetic resonance imaging revealed mild atrophy of the anterior pituitary (Fig. 1A). The patient was diagnosed with antiCPIT-1 hypophysitis by the detection of circulating antiCPIT-1 antibody (Fig. 2). Thereafter, she was treated with levothyroxine. At age 82 years, macroscopic hematuria and bladder tumors were detected. A biopsy of the tumor revealed the diagnosis of DLBCL. Computed tomography (CT) imaging revealed no evidence of thymoma (Fig. 1B) but multiple bilateral cervical, axillary, para-aorta, and internal and external peri-iliac lymphadenopathies (data not shown). Therefore, the patient was diagnosed with stage IV DLBCL and systemic chemotherapy was performed. Table 1. Endocrinological TZ9 data of cases 1 and 2 test or one-way analysis of variance with Bonferroni multiple comparison post hoc test was used to assess significance levels. Significance levels were set at *less than .05 and **less than .01. Ectopic expression of pituitary-specific transcription factor 1 in diffuse large B-cell lymphoma cells In previous cases of antiCPIT-1 hypophysitis associated with thymoma, ectopic expression of PIT-1 was observed in the tumor tissue [6]. Therefore, we examined the DLBCL tissue in case 1. Interestingly, the lymphoma cells clearly showed ectopic PIT-1 expression; however, the DLBCL tissues derived from other patients without antiCPIT-1 hypophysitis did not (Fig. 4). The expression of PIT-1 in TZ9 the DLBCL was also detected using the serum obtained from the patient with antiCPIT-1 hypophysitis containing antiCPIT-1 antibody [1]. Open in a separate window Figure 4. Ectopic pituitary-specific transcription factor 1 (PIT-1) expression in the diffuse large B-cell lymphoma (DLBCL) cells in case 1. Immunohistochemistry for PIT-1 using DLBCL tissues of case 1 and control cases without antiCPIT-1 hypophysitis. DLBCL cells in case 1 specifically expressed PIT-1 expression, whereas control DLBCL cells were negative for PIT-1. The serum of the patient [1] and a commercially available antiCPIT-1 antibody specifically showed the signal. Scale bars: 50.