Unusual Metastatic Spread of Follicular Thyroid Carcinoma: Report of a Case

Concurrent skull and liver metastases from follicular thyroid carcinoma is a very rare event. We herein present the case of a 72-year-old woman who initially presented with a swelling in the right supraorbital region that proved to be metastasis from a well-differentiated follicular thyroid carcinoma of clear-cell type. The metastatic workup disclosed a huge liver metastasis and an additional metastasis in the left iliac fossa. The treatment of this patient included a total thyroidectomy, an excision of the skull lesion, and the administration of radioiodine therapy, as well as thyroid-stimulating hormone (TSH) suppression therapy. However, the course of her disease was relentless. Although well-differentiated thyroid carcinoma tends to show an excellent course, the presence of metastatic disease leads to a very dismal prognosis.An erratum to this article can be found at     

Anthranilic acid based CCK1 receptor antagonists: preliminary investigation on their second "touch point"

In this phase of structure-affinity relationship study of VL-0395, a new anthranilic acid based CCK1 selective antagonist, we propose a series of unnatural aminoacidic derivatives. The result of this work is the identification of a new CCK ligand, which possesses an affinity (IC50 = 35 nm) one order of magnitude greater than the lead and, as a general rule, it points out how the hypothesized receptorial pocket which accommodates the Phe residue allows much more structural modification than that interacting with the N-terminal group. Hence, the modification of the C-terminal pharmacophoric group of our lead VL-0395 can not only enhance the affinity of anthranilic acid derivatives but can modulate the selectivity for one CCK receptor subtype or afford mixed antagonists.     

Histopathological and ultrastructural features of dermal telangiectasias in systemic sclerosis

AIMS: To investigate the histological, ultrastructural and immunohistochemical features of the vascular lining of dermal telangiectasia, a characteristic clinical finding in scleroderma. METHODS: Standard histological, electron microscopic and immunohistological techniques were used to examine dermal telangiectasias in five patients with limited scleroderma, the most common scleroderma variant in Caucasian populations. RESULTS: The telangiectasias were dilated postcapillary venules located in the papillary and superficial reticular dermis. The vessel walls consisted of non-fenestrated endothelial cells surrounded by a variable number of pericytes and smooth muscle cells. There were no unique ultrastructural features. Thickened collagen fibres in the reticular or deep dermis were seen in all but one patient, although in variable and generally minimal quantities. Surrounding infiltrating inflammatory cells were scarce. No enhanced endothelial staining was obtained with antibodies directed against endoglin, endothelin, E-selectin and ICAM-1 suggesting a resting or inactivated state. CONCLUSION: The immunohistological and ultrastructural features of the lining endothelium of established telangiectasias in long-standing, limited scleroderma appear benign. It would be of interest to examine telangiectasias in the early phase of their formation. Alternatively, other explanations need to be explored in understanding the aetiopathogenesis of telangiectasia in scleroderma.     

Expression of cyclins D1, D3 and p27 in thymic epithelial tumors

In this study, the expression of cyclins D1 and D3, as well as cyclin-dependent kinase inhibitor p27 in thymic epithelial tumors (thymomas) is examined. Histological specimens from 24 patients (11 males and 13 females) were submitted to classification according to WHO criteria. Staining for cyclins D1, D3 and p27 was applied and evaluation was performed for expression of D1, D3 and p27. Eighteen patients presented low-grade thymomas (nine B1, predominantly cortical; three B2, cortical; six B3, well-differentiated thymic carcinoma) and six patients benign thymomas (four A-medullary, two AB-mixed). The p27 expression in patients with benign thymomas was 42+/-26%, whereas in patients with low-grade thymoma, it was 11+/-13%. The expression of cyclins D1 and D3 was 2.8+/-2.7 and 10+/-6% for benign as well as 8.3+/-9.6 and 12+/-10% for low-grade thymomas, respectively. A statistically significant difference was revealed regarding the p27 expression through different grades (analysis of variance P-value 0.00076) and histopathological types of thymomas (P=0.0047). This finding of greater p27 expression in benign thymomas with progressive reduction in higher grades is compatible with observations on other soft tissue and solid tumors suggesting that p27 level decreases during tumor development and progression.     

The Varna-Thessaloniki telemedical collaboration in setting up a regional transborder transplantation network

In most Balkan countries, with the exception of Greece, transplantation is very rare and equality of access does not exist. In 2003, a Balkan partnership was established called SETNET (South-Eastern European Transplantation Network) for the promotion of transplantation. The objectives are to bring about the diffusion of transplantation techniques and practices in the Balkans, to increase public support for and participation in transplantation, and to eliminate the disparities in access to good health-care. SETNET is already beginning to generate data for an analysis of transplantation-related needs in the Balkans and to accelerate cross-border data exchange in transplantation-related emergencies. In the next few years, a regional training programme will be introduced for all health-care staff involved in transplantation. A regional organ procurement and transplantation network will be set up to utilize the existing telemedicine infrastructure. If successful, it will also prove that telemedicine infrastructures, however modest, can be the backbone for other, far-reaching human networks.     

SPRY2 is an inhibitor of the ras/extracellular signal-regulated kinase pathway in melanocytes and melanoma cells with wild-type BRAF but not with the V599E mutant

BRAF mutations result in constitutively active BRAF kinase activity and increased extracellular signal-regulated kinase (ERK) signaling and cell proliferation. Initial studies have shown that BRAF mutations occur at a high frequency in melanocytic nevi and metastatic lesions, but recent data have revealed much lower incidence of these mutations in early-stage melanoma, implying that other factors may contribute to melanoma pathogenesis in a wild-type (WT) BRAF context. To identify such contributing factors, we used microarray gene expression profiling to screen for differences in gene expression between a panel of melanocytic and melanoma cell lines with WT BRAF and a group of melanoma cell lines with the V599E BRAF mutation. We found that SPRY2, an inhibitor homologous to SPRY4, which was previously shown to suppress Ras/ERK signaling via direct binding to Raf-1, had reduced expression in WT BRAF cells. Using small interfering RNA-mediated SPRY2 knockdown, we showed that SPRY2 acts as an inhibitor of ERK signaling in melanocytes and WT BRAF melanoma cells, but not in cell lines with the V599E mutation. We also show that SPRY2 and SPRY4 directly bind WT BRAF but not the V599E and other exon 15 BRAF mutants. These data suggest that SPRY2, an inhibitor of ERK signaling, may be bypassed in melanoma cells either by down-regulation of its expression in WT BRAF cells, or by the presence of the BRAF mutation.     

Interaction pharmacokinetics of pegylated liposomal doxorubicin (Caelyx) on coadministration with paclitaxel or docetaxel

Purpose To investigate the pharmacokinetics of polyethylene glycol-coated liposomal doxorubicin (PLD, Caelyx) when given as a single agent and in combination with the taxanes paclitaxel or docetaxel in humans.Methods The plasma kinetics of PLD were studied in 19 cancer patients treated with PLD every 4 weeks combined with either paclitaxel (on a weekly basis in seven and as a single infusion in three patients) or docetaxel (weekly in seven and as a single infusion in two). Plasma concentrations of PLD were quantified in two sets of samples per patient to compare the same pharmacokinetic parameters in each subject when treated with single-agent PLD and again with the combination. Total doxorubicin concentrations in plasma were quantified by HPLC. Pharmacokinetics were evaluated by noncompartmental analysis and the data obtained were compared for differences by a matched-pairs nonparametric test.Results Coadministration of paclitaxel produced a median/mean 54/80% increase in PLD AUC_inf (95% confidence interval 23% to 136%, P=0.002). The observed increase was consistent among all subjects. PLD clearance was also decelerated in the presence of paclitaxel (P=0.013) while other pharmacokinetic parameters were affected modestly. A small increase in the AUC of PLD was observed in the docetaxel/PLD arm (mean increase 12%, P=0.039) while PLD clearance decreased marginally and other pharmacokinetic parameters remained unaffected. AUC extrapolated to infinity was below 8% in both arms.Conclusions This study showed the presence of a pharmacokinetic interaction that led to higher plasma concentrations of PLD when combined with paclitaxel and to a minor extent when combined with docetaxel. This pharmacokinetic information may be of value when planning combination therapies of PLD with taxanes.     

Successful treatment of refractory anemia with a combination regimen containing recombinant human erythropoietin, low-dose methylprednisolone and nandrolone

Myelodysplastic syndromes (MDS) are a heterogenous group of hematological clonal malignancies. Patients belonging to the refractory anemia (RA) subtype are usually treated with recombinant human erythropoietin (EPO). Not all patients respond to EPO administration and they are strictly dependent on supportive therapy with red cell blood (RBC) transfusions. The aim of this study was to investigate the efficacy of an alternative combination regimen containing EPO, low-dose methylprednisolone and nandrolone decanoate, in patients with RA unresponsive to EPO administration alone. Ten patients, 4 women and 6 men, median age: 70 years (range: 55-78 years) with refractory anemia unresponsive to EPO administration and RBC transfusion-dependent were included in the study. Median hematological data at baseline were Hb: 8.7 g/dl, (range 6.2-9.8), WBC: 3.35x10(9)/l (range 2.1-4), PLT: 82.5x10(9)/l (range 59-110). EPO 150 U/Kg three times/week subcutaneously, low-dose methylprednisolone 8 mg/day orally and nandrolone decanoate (Decadurabolin) 50 mg two-times/week intramuscularly were administered. As complete response (CR) to treatment was considered the normalization of the peripheral blood and bone marrow smears and biopsy. As partial response (PR) was considered increase in Hb level > or = 2 g/dl, or up to 10 g/dl and discontinuation of RBC transfusions. The response to therapy was evaluated on the 4th week after the initiation of the combination treatment. Bone marrow smear evaluation was carried out at baseline and every six months afterwards. After a 4-week treatment all patients achieved PR and discontinued RBC transfusions. Median and range hematological values on the 4th week after treatment initiation were Hb: 11.2 g/dl, (range: 9.8-12.8), WBC: 4.4x10(9)/l (3.5-6.6), PLT: 130x10(9)/l (95-160). The increase observed in hematological values was significant (p = 0.0001, 0.0004 and < 0.0001, respectively, for Hb, WBC and PLT counts). Treatment was well tolerated. Furthermore, two women, on treatment with the combination regimen, achieved CR one after six months and the second after 12 months. They are alive after 5 years from initiation of the combination treatment. After a median period of 18 months (range 12 to 20 months) in PR three men developed acute leukemia; they received intensive antileukemic chemotherapy without any response and died during the phase of pancytopenia. Three other men achieved CR, one after 6 and two after 12 months of therapy and they are on regular follow-up. Two women after 10 and 14 months in PR developed acute leukemia and died. In conclusion, combination therapy with EPO, nandrolone decanoate and low-dose methylprednisolone may be effective as an alternative treatment for RBC transfusion-dependent patients with RA unresponsive to EPO administration alone.     

BM88 is an early marker of proliferating precursor cells that will differentiate into the neuronal lineage

Progression of progenitor cells towards neuronal differentiation is tightly linked with cell cycle control and the switch from proliferative to neuron-generating divisions. We have previously shown that the neuronal protein BM88 drives neuroblastoma cells towards exit from the cell cycle and differentiation into a neuronal phenotype in vitro. Here, we explored the role of BM88 during neuronal birth, cell cycle exit and the initiation of differentiation in vivo. By double- and triple-labelling with the S-phase marker BrdU or the late G2 and M-phase marker cyclin B1, antibodies to BM88 and markers of the neuronal or glial cell lineages, we demonstrate that in the rodent forebrain, BM88 is expressed in multipotential progenitor cells before terminal mitosis and in their neuronal progeny during the neurogenic interval, as well as in the adult. Further, we defined at E16 a cohort of proliferative progenitors that exit S phase in synchrony, and by following their fate for 24 h we show that BM88 is associated with the dynamics of neuron-generating divisions. Expression of BM88 was also evident in cycling cortical radial glial cells, which constitute the main neurogenic population in the cerebral cortex. In agreement, BM88 expression was markedly reduced and restricted to a smaller percentage of cells in the cerebral cortex of the Small eye mutant mice, which lack functional Pax6 and exhibit severe neurogenesis defects. Our data show an interesting correlation between BM88 expression and the progression of progenitor cells towards neuronal differentiation during the neurogenic interval.