Mice conditionally expressing RET(C618F) mutation display C cell hyperplasia and hyperganglionosis of the enteric nervous system.

Medullary thyroid carcinoma (MTC) develops from hyperplasia of thyroid C cells and represents one of the major causes of thyroid cancer mortality. Mutations in the cysteine-rich domain (CRD) of the RET gene are the most prevalent genetic cause of MTC. The current consensus holds that such cysteine mutations cause ligand-independent dimerization and constitutive activation of RET. However, given the number of the CRD mutations left uncharacterized, our understanding of the pathogenetic mechanisms by which CRD mutations lead to MTC remains incomplete. We report here that RET(C618F), a mutation identified in MTC patients, displays moderately high basal activity and requires the ligand for its full activation. To assess the biological significance of RET(C618F) in organogenesis, we generated a knock-in mouse line conditionally expressing RET(C618F) cDNA by the Ret promoter. The RET(C618F) allele can be made to be Ret-null and express mCherry by Cre-loxP recombination, which allows the assessment of the biological influence of RET(C618F) in vivo. Mice expressing RET(C618F) display mild C cell hyperplasia and increased numbers of enteric neurons, indicating that RET(C618F) confers gain-of-function phenotypes. This mouse line serves as a novel biological platform for investigating pathogenetic mechanisms involved in MTC and enteric hyperganglionosis.

PD-1 and PD-L1 expression in thymic epithelial tumours and non-neoplastic thymus.

AIMS: We explored the relationships between programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression and the pathological and clinical features of thymic epithelial tumours and thymic hyperplasia. METHODS: We evaluated PD-1 and PDL-1 expressions within epithelial and microenvironmental components in thymic epithelial tumours (n=44) and thymic hyperplasias (n=8), immunohistochemically. We compared the results with demographic, clinical and histopathological features of the cases. RESULTS: We found 48% epithelial expression and 82.7% microenvironment expression for PD-1 and 11.5% epithelial expression and 34.6% microenvironment expression for PD-L1. There was no PD-1 expression, in either the epithelial or microenvironment, in the thymic hyperplasia group. PD-1 and PD-L1 positivity was more significant in thymic epithelial tumours than thymic hyperplasia. Patients with PD-1-positive microenvironments exhibited significantly shorter mean estimated survival time than their negative counterparts. CONCLUSION: These findings suggest that anti-PD-1 and anti-PD-L1 therapies may benefit patients due to high release of PD-1 and PD-L1 in thymic epithelial tumours.

Pathological Findings in Myasthenia Gravis Patients with Thymic Hyperplasia and Thymoma.

Thymectomy is routinely carried out in patients with myasthenia gravis (MG) and thymomas. However, there is still a dispute as to whether MG patients with thymic hyperplasia should undergo thymectomy. We aimed to investigate the pathological findings in the thymus in patients with co-existing MG and thymic hyperplasia or thymomas treated with thymectomy, as well as effects of immunosuppression. Thirty-three patients with MG were selected and grouped accordingly: patients with no thymic abnormalities, patients with thymic hyperplasia, and patients with thymomas. All patients were treated with methylprednisolone alongside immunosuppression. A separate cohort of 24 MG patients with thymic hyperplasia or thymomas and treated with thymectomy were selected. As controls, 5 patients with thymomas or thymic carcinoma without MG were selected. Expression of CD5, extracellular regulated protein kinases1/2 mitogen activated protein kinase (ERK1/2MAPKs) and CD95 ligand (FasL) in the thymus was examined. Methylprednisolone and immunosuppressive therapy are highly effective in MG patients with normal thymus tissue and MG patients with thymic hyperplasia compared to MG patients with thymomas alone. CD5 expression was highest in MG patients with thymic hyperplasia, correlating with expression of ERK1/2MAPKs. FasL expression was similar across all groups. Thymomas may be distinguished from thymic hyperplasia by expression of CD5 and ERK1/2MAPKs. Thymectomy is the preferred treatment for MG patients with thymomas but may not be necessary in MG patients with thymic hyperplasia who are treated with immunosuppressive therapy.

The thymidylate synthase enhancer region (TSER) polymorphism increases the risk of thymic lymphoid hyperplasia in patients with Myasthenia Gravis.

BACKGROUND: Myasthenia Gravis (MG) is caused, in approximately 80% of the patients, by autoantibodies against the nicotinic acetylcholine receptor (AChR). The disease is often associated with pathological changes of the thymus: thymic epithelial tumours are present in about 10-20% of the patients, while up to 80% of the patients with early disease onset have thymic hyperplasia. Folate metabolism is required for the production of DNA precursors and for proper DNA methylation reactions, and impaired folate metabolism has been often associated with cellular growth and cancer. METHODS: We investigated if major polymorphisms of folate-related genes, namely MTHFR c.677C>T, MTR c.2756A>G, MTRR c.66A>G and TYMS TSER (a 28-bp tandem repeat in the 5' promoter enhancer region of TYMS) increase the risk of pathological changes of the thymus in AChR+ MG patients. A total of 526 AChR+ MG patients, including 132 patients with normal (involuted) thymus, 146 patients with thymic hyperplasia, and 248 patients with a thymoma were included in the study. Allele and genotype comparisons were performed among the three study groups, after correcting for multiple testing. RESULTS: The frequency of the TYMS TSER 3R allele was significantly higher in MG patients with thymic hyperplasia (P=0.004), and the TYMS TSER 3R3R genotype was significantly associated with increased risk of thymic hyperplasia [OR 2.71 (95% CI: 1.34-5.47)]. CONCLUSIONS: The 3R allele in the thymidylate synthase promoter enhancer region results in increased protein production, required for the synthesis of DNA precursors. The present study suggests that the TYMS TSER 3R allele increases the risk of thymic lymphoid hyperplasia in AChR+ MG patients.

Analysis of TNF-related apoptosis-inducing ligand and receptors and implications in thymus biology and myasthenia gravis.

Myasthenia Gravis is an autoantibody-mediated, neuromuscular junction disease, and is usually associated with thymic abnormalities presented as thymic tumors (~10%) or hyperplastic thymus (~65%). The exact role of thymus in Myasthenia Gravis development is not clear, yet many patients benefit from thymectomy. The apoptotic ligand TNF-Related Apoptosis-Inducing Ligand is thought to be involved in the regulation of thymocyte counts, although conflicting results are reported. We investigated differential expression profiles of TNF-Related Apoptosis-Inducing Ligand and its transmembrane receptors, Nuclear Factor-kB activation status, and apoptotic cell counts in healthy thymic tissue and pathological thymus from Myasthenia Gravis patients. All tissues expressed TNF-Related Apoptosis-Inducing Ligand and its receptors, with hyperplastic tissue having the highest expression levels of death receptors DR4 and DR5. No detectable Nuclear Factor-kB activation, at least via the canonical Protein Kinase A-mediated p65 Ser276 phosphorylation, was evident in any of the tissues studied. Apoptotic cell counts were higher in MG-associated tissue compared to the normal thymus. Possible use of the TNF-Related Apoptosis-Inducing Ligand within the concept of an apoptotic ligand-mediated medical thymectomy in thymoma- or thymic hyperplasia-associated Myasthenia Gravis is also discussed.

Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.

Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

Chemical-shift MRI of rebound thymic hyperplasia with unusual appearance and intense (18)F-FDG uptake in adulthood: report of two cases.

Rebound thymic hyperplasia (RTH) with increased (18)F-FGD uptake at positron emission tomography (PET) computed tomography (CT) is typical of pediatric patients after chemotherapy, although it may occasionally occur in adults. At CT, RTH usually appears as a diffusely enlarged thymus with areas of fatty attenuation. We report two cases of RTH in adults detected at follow-up: both showed unusual morphology on CT and were confirmed at PET-CT as areas of strongly increased radiopharmaceutical uptake, which suggested disease recurrence. Chemical-shift magnetic resonance imaging, however, demonstrated fat infiltration within the tissue. Such finding was consistent with the diagnosis of RTH and was paramount in preventing unnecessary invasive procedures or treatments.

Increased number of Hassall's corpuscles in myasthenia gravis patients with thymic hyperplasia.

The thymus is implicated as an organ that contributes to autoimmunity in myasthenia gravis (MG) patients. Hassall's corpuscles (HCs) are assumed to represent the terminally differentiated stage of medullary thymic epithelial cells (mTECs). By using multicolor immunohistofluorescence analysis, we examined HCs in thymuses that were therapeutically excised from MG (+) and MG (-) patients. We found that the number of HCs per unit area of the thymic medulla was significantly elevated in the thymuses of MG (+) patients with thymic hyperplasia. CCL21 expression increased in the hyperplastic MG thymuses. We speculate that the altered differentiation of mTECs is associated with the thymic hyperplasia and the onset of MG.

The thymus in autoimmune Myasthenia Gravis: Paradigm for a tertiary lymphoid organ.

In autoimmune Myasthenia Gravis (MG), a neuromuscular disease generally mediated by autoantibodies against the acetylcholine receptor (AChR), the muscle is the target organ of the autoimmune attack, while the thymus seems to be the primary production site of the autoantibodies. In the majority of patients with anti-AChR antibodies, it is characterized by the presence of germinal centers, which contain B cells that produce anti-AChR antibodies. In this review, we summarize recent results regarding neoangiogenic processes, cell infiltration and modified chemokine expression in the MG thymus, which are typical features of secondary lymphoid organs. The structural and functional changes in the MG thymus therefore allow us to declare it to be an archetype for tertiary lymphoid neogenesis providing optimal settings for the interaction between lymphocytes and antigen presenting cells in order to elicit an immune response. We further discuss factors that may have a key role in the transformation of the MG thymus into a tertiary lymphoid organ, such as IFN type I and dsRNA signaling. These factors could also be of importance in other autoimmune diseases, especially those characterized by tertiary lymphoid neogenesis.

Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases.

PURPOSE: Understanding the molecular pathogenesis of medullary thyroid carcinoma (MTC) is prerequisite to the design of targeted therapies for patients with advanced disease. EXPERIMENTAL DESIGN: We studied by immunohistochemistry the phosphorylation status of proteins of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways in 53 MTC tissues (18 hereditary, 35 sporadic), including 51 primary MTCs and 2 cases with only lymph node metastases (LNM). We also studied 21 autologous LNMs, matched to 21 primary MTCs. Staining was graded on a 0 to 4 scale (S score) based on the percentage of positive cells. We also studied the functional relevance of the mTOR pathway by measuring cell viability, motility, and tumorigenicity upon mTOR chemical blockade. RESULTS: Phosphorylation of ribosomal protein S6 (pS6), a downstream target of mTOR, was evident (S ≥ 1) in 49 (96%) of 51 primary MTC samples. This was associated with activation of AKT (phospho-Ser473, S > 1) in 79% of cases studied. Activation of pS6 was also observed (S ≥ 1) in 7 (70%) of 10 hereditary C-cell hyperplasia specimens, possibly representing an early stage of C-cell transformation. It is noteworthy that 22 (96%) of 23 LNMs had a high pS6 positivity (S ≥ 3), which was increased compared with autologous matched primary MTCs (P = 0.024). Chemical mTOR blockade blunted viability (P < 0.01), motility (P < 0.01), and tumorigenicity (P < 0.01) of human MTC cells. CONCLUSION: The AKT/mTOR pathway is activated in MTC, particularly, in LNMs. This pathway sustains malignant features of MTC cell models. These findings suggest that targeting mTOR might be efficacious in patients with advanced MTC.

Ectopic and high CXCL13 chemokine expression in myasthenia gravis with thymic lymphoid hyperplasia.

Myasthenia gravis (MG) is an antibody and complement mediated autoimmune disease. Serum CXC chemokine ligand 13 (CXCL13) was found to be elevated in MG patients and high CXCL13 level was associated with severe clinical stages, especially in females with thymic lymphoid hyperplasia. Both protein and mRNA of CXCL13 and CXC chemokine receptor 5 (CXCR5) in the thymic tissues were significantly higher in MG patients with lymphoid hyperplasia than those with thymoma. Our data indicated that serum CXCL13 can be used as an index of disease severity and ectopic thymic expression of CXCL13 might be associated with aberrant cell trafficking to the thymus of MG.

CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia.

OBJECTIVE: Myasthenia gravis (MG), a neuromuscular disease mediated by anti-acetylcholine receptor (AChR) autoantibodies, is associated with thymic hyperplasia characterized by ectopic germinal centers that contain pathogenic antibody-producing B cells. Our thymic transcriptome study demonstrated increased expression of CCL21, a recruiter of immune cells. Accordingly, we are investigating its implication in MG pathogenesis. METHODS: The expression of CCL21 and its CCR7 receptor was analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting, respectively. Chemotaxis of T and B cells to CCL21 was measured by transwell assay. The nature of the thymic cells overexpressing CCL21 was investigated by immunochemistry and laser-capture microdissection combined with real-time PCR. RESULTS: We demonstrate that CCL21 is overexpressed specifically in hyperplastic MG thymuses, whereas there is no variation in CCR7 levels on blood cells. We show that although CCL21 attracts both human T and B cells, it acts more strongly on naive B cells. CCL21 overexpression is normalized in corticoid-treated MG patients, suggesting that targeting this chemokine could represent a new selective treatment, decreasing the abnormal peripheral lymphocyte recruitment. Moreover, we locate protein and messenger RNA overexpression of CCL21 to specific endothelial vessels. Investigation of the nature of these vessels demonstrated different angiogenic processes in MG thymuses: high endothelial venule angiogenesis and lymphangiogenesis. Unexpectedly, CCL21 overexpression originates from afferent lymphatic endothelial vessels. INTERPRETATION: We postulate that thymic overexpression of CCL21 on specialized lymphatic vessels results in abnormal peripheral lymphocyte recruitment, bringing naive B cells in contact with the inflammatory environment characteristic of MG thymuses, where they can be sensitized against AChR.

TGF-beta promotes thyroid epithelial cell hyperplasia and fibrosis in IFN-gamma-deficient NOD.H-2h4 mice.

IFN-gamma(-/-)NOD.H-2h4 mice given 0.05% NaI in their water develop severe thyroid epithelial cell (thyrocyte) hyperplasia and proliferation (TEC H/P) and fibrosis. Proliferating thyrocytes of IFN-gamma(-/-) mice with TEC H/P produce TGF-beta as demonstrated by immunohistochemical staining and in situ hybridization. Strong expression of activating phosphorylated Smad-2/3 and weak expression of inhibitory Smad-7 by proliferating thyrocytes correlate with the severity of TEC H/P. Splenocytes from IFN-gamma(-/-) mice with severe TEC H/P transfer severe TEC H/P to IFN-gamma(-/-)NOD.H-2h4.SCID mice. Mice given anti-TGF-beta had markedly reduced thyrocyte proliferation and decreased fibrosis compared with mouse Ig-treated controls, suggesting that TGF-beta plays an important role in development of TEC H/P induced by activated splenocytes. Moreover, transgenic IFN-gamma(-/-)NOD.H-2h4 mice expressing TGF-beta on thyrocytes all develop fibrosis and moderate to severe TEC H/P with accelerated kinetics, directly demonstrating a role for TGF-beta in severe TEC H/P and fibrosis.

Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1.

Tumor suppressor p53 is essential for checkpoint control in response to a variety of genotoxic stresses. DNA damage leads to phosphorylation on the Ser/Thr-Pro motifs of p53, which facilitates interaction with Pin1, a pSer/pThr-Pro-specific peptidyl prolyl isomerase. Pin1 is required for the timely activation of p53, resulting in apoptosis or cell cycle arrest. To investigate the physiological relationship between Pin1 and p53, we created Pin1-/-p53-/- mice. These p53-deficient mice spontaneously developed lymphomas, mainly of thymic origin, as well as generalized lymphoma infiltration into other organs, including the liver, kidneys and lungs. Ablation of Pin1, in addition to p53, accelerated the thymic hyperplasia, but the thymocytes in these Pin1-/-p53-/- mice did not infiltrate other organs. The thymocytes in 12-week-old Pin1-/-p53-/- mice were CD4(-)CD8(-) (double negative) and had significantly higher levels of the intracellular form of Notch1 (NIC) than the thymocytes of p53-/- or wild-type mice. Presenilin-1, a cleavage enzyme for NIC generation from full-length Notch1 was increased in the thymocytes of Pin1-/-p53-/- mice. Pin1 depletion also inhibited the degradation of NIC by proteasomes. These results suggest that both Pin1 and p53 control the normal proliferation and differentiation of thymocytes by regulating the NIC level.

The role of thymomas in the development of myasthenia gravis.

Thymic pathology occurs in 80-90% of myasthenia gravis patients. Significant associations between different thymic alterations and clinical findings are discussed. To highlight peculiarities in thymoma-associated myasthenia gravis, we briefly review myasthenia gravis associated with thymic lymphofollicular hyperplasia (TFH) and thymic atrophy.

Abnormalities of Th1 function in non-IgE food allergy, celiac disease, and ileal lymphonodular hyperplasia: a new relationship?

BACKGROUND: Non-IgE mechanisms may also be involved food allergy (FA). Our group has been studying the immunopathogenesis clinical entities in children with gastro-intestinal symptoms and in whom biopsies of the terminal ileum show lymphoid tissue masses referred to as ileal lymphonodular hyperplasia. Our more recent studies have demonstrated Th1/Th2 cytokine profiles associated with non-IgE FA and other clinical entities. OBJECTIVE: We investigated 12 subjects with non-IgE FA (group 1) and 4 subjects with celiac disease (group 2). Cytokine profiles and immunologic studies of lymphocytes in peripheral blood and from gastro-intestinal biopsy tissues from patients in groups 1 and 2 were also evaluated. METHODS: Group 1 consisted of 12 children with clinical symptoms of anorexia, diarrhea, and abdominal pain. The diagnosis of non-IgE FA was established by positive double-blind, placebo-controlled food challenge and reduced or negative immediate-type skin testing and negative IgE radioallergosorbent tests. Group 2 consisted of four patients with celiac disease and three adult females with biopsy-proven clinical symptoms of celiac disease. RESULTS: In group 1, peripheral blood CD4 and CD8 lymphocyte distributions were normal, with a predominance of CD4+ cells with a decreased intracellular Th1 cytokine pattern and a normal Th2 intracellular cytokine pattern. In contrast, all four patients in group 2 not only displayed abnormal CD4 and CD8 peripheral blood lymphocyte distributions (CD8 > CD4), but also an abnormal predominance of CD4+ cells with an increased Th1 and a normal Th2 cytokine pattern. A similar abnormal pattern of CD4 > CD8 ratio was observed in intestinal biopsies. All 12 patients in group 1 showed lymphonodular hyperplasia in each of the biopsies and by ileoscopy. CONCLUSIONS: These studies suggest that abnormalities in Th1 function may not only play a role in some patients with non--IgE-mediated FA in whom decreased Th1 function is seen, but also in patients with celiac disease in whom an increased Th1 function is seen. The studies also suggest that lymphonodular hyperplasia may be a hallmark histologic lesion in patients with non--IgE-mediated FA.

Immunolocalization of peripheral lymph node addressins in normal and neoplastic human thymuses.

Peripheral lymph node addressin is a specific L-selectin ligand of the high endothelial venules that plays an important role in lymphocyte homing to lymph nodes. Tissue selective migration of lymphocytes through this pathway to the thymus has also been proposed. In this work, peripheral lymph node addressin expression was investigated immunohistochemically with a monoclonal antibody, clone MECA-79, in formaldehyde-fixed, paraffin-embedded tissue sections of 5 normal neonatal thymuses, 25 thymomas, 3 thymic carcinomas, and 2 thymic lymphoid hyperplasias. In normal thymuses, peripheral lymph node addressin expression was found in the endothelium of corticomedullary and medullary vessels surrounded by perivascular space. In type B thymomas and thymic lymphoid hyperplasias, peripheral lymph node addressin was detected in the vessels with perivascular spaces, at the medullary differentiation areas, and in paralymphoid follicles, respectively. However, in type A thymomas and thymic carcinomas, MECA-79-positive vessels were restricted to the remnants of pre-existing thymic tissue, and they were absent from the neoplastic areas. These findings suggest that in normal and most neoplastic thymuses, peripheral lymph node addressin is expressed by regions of vascular endothelium corresponding to postcapillary venules that may serve as a pathway for homing of recirculating lymphocytes to the thymus.

Lack of effect of soy isoflavone on thyroid hyperplasia in rats receiving an iodine-deficient diet.

We have reported a dramatic synergism between soy intake and iodine deficiency regarding induction of thyroid hyperplasia in rats. Because isoflavones are active constituents of soybeans, in the present study, their possible contribution was examined. Female F344 rats were divided into 8 groups, exposed to diet containing a 0.2% soy isoflavone mixture (SI), 0.2% SI + iodine deficiency (ID), 0.04% SI, 0.04% SI + ID, 20% defatted soybean (DS) alone, 20% DS + ID, ID alone or basal diet alone for 5 weeks. Thyroid weight was not influenced by SI, but was increased by the ID and DS diets with a further significant increment in the DS + ID group (P < 0.01). Compared to the control value, serum T(4) was significantly (P < 0.01) increased by 20% DS alone and decreased in all groups given the ID treatment (P < 0.001). Serum thyroid stimulating hormone (TSH) level was increased by ID, and further enhanced by DS (P < 0.01) but not SI. Histopathologically, diffuse hypertrophy and / or hyperplasia of thyroid follicles were observed in the ID-treated groups, the severity being enhanced by DS but not SI. Proliferating cell nuclear antigen labeling indices (%) were elevated in the ID diet groups and again enhanced by DS, but not SI. These results thus suggest that isoflavones may not be involved in the mechanisms underlying the synergistic goitrogenic effect of soybean with iodine deficiency.

Cyclin D2 overexpression in transgenic mice induces thymic and epidermal hyperplasia whereas cyclin D3 expression results only in epidermal hyperplasia.

In a previous report, we described the effects of cyclin D1 expression in epithelial tissues of transgenic mice. To study the involvement of D-type cyclins (D1, D2, and D3) in epithelial growth and differentiation and their putative role as oncogenes in skin, transgenic mice were developed which carry cyclin D2 or D3 genes driven by a keratin 5 promoter. As expected, both transgenic lines showed expression of these proteins in most of the squamous tissues analyzed. Epidermal proliferation increased in transgenic animals and basal cell hyperplasia was observed. All of the animals also had a minor thickening of the epidermis. The pattern of expression of keratin 1 and keratin 5 indicated that epidermal differentiation was not affected. Transgenic K5D2 mice developed mild thymic hyperplasia that reversed at 4 months of age. On the other hand, high expression of cyclin D3 in the thymus did not produce hyperplasia. This model provides in vivo evidence of the action of cyclin D2 and cyclin D3 as mediators of proliferation in squamous epithelial cells. A direct comparison among the three D-type cyclin transgenic mice suggests that cyclin D1 and cyclin D2 have similar roles in epithelial thymus cells. However, overexpression of each D-type cyclin produces a distinct phenotype in thymic epithelial cells.

Functional imaging of thymic disorders.

Human thymomas are rare tumours which usually develop in the chest. The diagnosis via guided biopsy, the evaluation of the extent of the tumour and its boundaries with adjacent organs, the choice of the appropriate therapeutic option, and the assessment of response to treatment are usually made with computed tomography (CT) alone or in combination with magnetic resonance imaging (MRI). More recently, radiopharmaceuticals and nuclear medicine procedures have been used increasingly in the imaging and functional characterization of benign and malignant thymic disorders. Two groups of radiopharmaceuticals have been used. The first includes several oncotropic tracers, such as 201Tl-chloride, 99mTc-sestamibi and 18F-fluorodeoxyglucose, which are significantly concentrated in thymic tumours. Their uptake correlates with tumour grades and cellularity. The second class includes two radioligands: [(111)In-DTPA-D-Phe1]-octreotide (DTPA, diethylenetriamine penta-acetic acid) and [(111)In-DTPA-Arg1]-substance P, which bind to specific receptors. [(111)In-DTPA-Arg1]-substance P binds to its receptors that are largely expressed in the thymus of patients with autoimmune diseases. [(111)In-DTPA-D-Phe1]-octreotide recognizes the somatostatin receptor subtype 2. In patients with active disease investigated in our institution [(111)In-DTPA-D-Phe1]-octreotide has been shown to concentrate in the majority of thymoma deposits. Conversely, it is not concentrated in adult patients with benign lymphofollicular thymic hyperplasia. This finding has had a significant impact on the management of patients with myasthenia gravis as it differentiates early-stage thymoma from benign hyperplasia, unlike CT and MRI, which often fail to distinguish between the two. In addition to its role in diagnostic imaging, somatostatin receptor scintigraphy also enables us to select patients with advanced or metastatic thymoma unresponsive to conventional therapies, who might benefit from a somatostatin analogue-based treatment, serving thus as a link between diagnosis and therapy. In this article, we discuss and analyse the results of functional imaging with different radiopharmaceuticals, primarily those that we have obtained with [(111)In-DTPA-D-Phe1]-octreotide.