Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL.

Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1-dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2-mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.

Shape of the anterior surface of the cornea after extended wear of silicone hydrogel soft contact lenses.

PURPOSE: To measure geometrical changes in the anterior surface of the cornea after wearing silicon hydrogel (SiH) soft contact lenses continuously for 1 week. METHODS: Forty-three eyes with 3.0D of myopia and 22 eyes with 3.0D of hyperopia were enrolled in the prospective, interventional study. All subjects underwent a general eye examination, corneal tomography with wavefront aberration analysis, corneal thickness measurements and epithelial thickness mapping before and after wearing SiH lenses (Acuvue Oasys) for 7 days. RESULTS: No significant changes in average keratometry were observed in either refractive group. In the myopic group, keratometry findings for the flat meridian (K1) and central corneal thickness decreased significantly. After +3.0 D lens wear in the hyperopic group, a significant decrease in epithelial thickness up to 3.19 µm was observed in the central and paracentral cornea, (p < 0.001). In both refractive groups, the largest epithelial thickness increase was seen in the periphery. A decrease in spherical aberration was noted in myopic eyes, while an increase of both higher order corneal aberrations and coma was found in hyperopic subjects. CONCLUSION: Extended wear of SiH lenses results in a significant change in epithelial thickness leading to alteration in the geometry of the anterior surface of the cornea, particularly in hyperopic patients. These epithelial thickness variations lead to changes in the higher order aberrations of the cornea.

Inhibition of IDO leads to IL-6-dependent systemic inflammation in mice when combined with photodynamic therapy.

It was previously reported that the activation of antitumor immune response by photodynamic therapy (PDT) is crucial for its therapeutic outcome. Excessive PDT-mediated inflammation is accompanied by immunosuppressive mechanisms that protect tissues from destruction. Thus, the final effect of PDT strongly depends on the balance between the activation of an adoptive arm of immune response and a range of activated immunosuppressive mechanisms. Here, with flow cytometry and functional tests, we evaluate the immunosuppressive activity of tumor-associated myeloid cells after PDT. We investigate the antitumor potential of PDT combined with indoleamine 2,3-dioxygenase 1 (IDO) inhibitor in the murine 4T1 and E0771 orthotopic breast cancer models. We found that the expression of IDO, elevated after PDT, affects the polarization of T regulatory cells and influences the innate immune response. Our results indicate that, depending on a therapeutic scheme, overcoming IDO-induced immunosuppressive mechanisms after PDT can be beneficial or can lead to a systemic toxic reaction. The inhibition of IDO, shortly after PDT, activates IL-6-dependent toxic reactions that can be diminished by the use of anti-IL-6 antibodies. Our results emphasize that deeper investigation of the physiological role of IDO, an attractive target for immunotherapies of cancer, is of great importance.

HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies.

Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective histone deacetylase inhibitors (HDACis). Because the use of pan-HDACis is associated with substantial adverse effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance. In this study, we demonstrate for the first time the role of HDAC6 in the regulation of CD20 levels. We show that inhibition of HDAC6 activity significantly increases CD20 levels in established B-cell tumor cell lines and primary malignant cells. Using pharmacologic and genetic approaches, we confirm that HDAC6 inhibition augments in vitro efficacy of anti-CD20 mAbs and improves survival of mice treated with rituximab. Mechanistically, we demonstrate that HDAC6 influences synthesis of CD20 protein independently of the regulation of MS4A1 transcription. We further demonstrate that translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition, as shown by the increase of CD20 mRNA within the polysomal fraction, indicating a new role of HDAC6 in the posttranscriptional mechanism of CD20 regulation. Collectively, our findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors.

The association between irisin and muscle metabolism in different thyroid disorders.

BACKGROUND: Irisin is a new adipo-myokine, encoded by the FNDC5 gene. Currently, there is a discussion regarding the relation between thyroid function and irisin concentration. This prospective study assesses the influence of thyrometabolic changes on serum irisin concentration in association with altered muscle metabolism. This is performed on a large cohort of patients affected by severe hypo- or hyperthyroidism, as well as by the expression of the FNDC5 gene in thyroid tissue affected by different pathologies. METHODS: The study group comprised 119 patients with newly diagnosed severe hyperthyroidism or hypothyroidism, and a control group of 45 healthy subjects. Body composition, serum irisin concentrations, and thyroid-related hormones, creatine kinase, dystrophin and titin concentrations were evaluated. FNDC5 expression was also analysed in tissue samples from 80 patients with nontoxic multinodular goitre, toxic goitre, Graves' disease and papillary thyroid cancer. RESULTS: Irisin concentration was lower in patients with prolonged hypothyroidism. There was a tendency towards lower dystrophin and titin concentrations in patients with hypothyroidism and hyperthyroidism. Restoration of euthyroidism in patients with hypothyroidism resulted in a decreased muscle mass with an increase in irisin concentrations, while the hyperthyroid group showed an increase in fat mass. Statistically significant overexpression of FNDC5 gene was found in patients with toxic goitre as compared to Graves' disease, papillary thyroid cancer and controls. CONCLUSIONS: The presented data support the theory that irisin concentration changes are associated with prolonged hypothyroidism and might primarily constitute the result of prolonged myopathy. These changes are most likely not related to the expression of the FNDC5 gene in the thyroid gland.

Inhibition of autophagy sensitizes cancer cells to Photofrin-based photodynamic therapy.

BACKGROUND: Accumulating evidence suggest that autophagy plays a pivotal role in various anticancer therapies, including photodynamic therapy (PDT), acting as a pro-death or pro-survival mechanism in a context-dependent manner. Therefore, we aimed to determine the role of autophagy in Photofrin-based PDT. METHODS: In vitro cytotoxic/cytostatic effects of PDT were evaluated with crystal violet cell viability assay. Autophagy induction was analyzed by immunoblotting and immunofluorescence using anti-LC3 antibody. Autophagy was inhibited by shRNA-mediated ATG5 knockdown or CRISPR/Cas9-mediated ATG5 knockout. Apoptosis was assessed by flow cytometry analysis of propidium iodide and anexin V-positive cells as well as by detection of cleaved PARP and caspase 3 proteins using immunoblotting. Protein carbonylation was evaluated by the 2,4-dinitrophenylhydrazine (DNPH) method. RESULTS: Photofrin-PDT leads to robust autophagy induction in two cancer cell lines, Hela and MCF-7. shRNA-mediated knockdown of ATG5 only partially blocks autophagic response and only marginally affects the sensitivity of Hela and MCF-7 cells to PDT. ATG5 knockout in HeLa cell line utilizing CRISPR/Cas9 genome editing results in increased PDT-mediated cytotoxicity, which is accompanied by an enhanced apoptotic response and increased accumulation of carbonylated proteins. CONCLUSIONS: Altogether, these observations imply that autophagy contributes to Photofrin-PDT resistance by enabling clearance of carbonylated and other damaged proteins. Therefore, autophagy inhibition may serve as a strategy to improve PDT efficacy.

Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy.

Lysosomes are conservative organelles with an indispensable role in cellular degradation and the recycling of macromolecules. However, in light of recent findings, it has emerged that the role of lysosomes in cancer cells extends far beyond cellular catabolism and includes a variety of cellular pathways, such as proliferation, metastatic potential, and drug resistance. It has been well described that malignant transformation leads to alterations in lysosomal structure and function, which, paradoxically, renders cancer cells more sensitive to lysosomal destabilization. Furthermore, lysosomes are implicated in the regulation and execution of cell death in response to diverse stimuli and it has been shown that lysosome-dependent cell death can be utilized to overcome apoptosis and drug resistance. Thus, the purpose of this review is to characterize the role of lysosome in cancer therapy and to describe how these organelles impact treatment resistance. We summarized the characteristics of typical inducers of lysosomal cell death, which exert its function primarily via alterations in the lysosomal compartment. The review also presents other anticancer agents with the predominant mechanism of action different from lysosomal destabilization, the activity of which is influenced by lysosomal signaling, including classical chemotherapeutics, kinase inhibitors, monoclonal antibodies, as well as photodynamic therapy.

Incidence of pituitary autoantibodies in idiopathic diabetes insipidus.

Diabetes insipidus is a disorder resulting from insufficient action of vasopressin (ADH) characterized by excretion of highly diluted urine in large amounts. Idiopathic diabetes insipidus is associated with the presence of both autoantibodies against ADH-secreting neurons and pituitary autoantibodies. The aim of the present study was to evaluate the occurrence of autoantibodies against the pituitary microsomal fraction. The study included 33 sera of diabetes insipidus patients and 10 control sera obtained from 10 healthy persons. In all patients the secretion of pituitary hormones and thyroid autoantibodies was assessed. Human pituitaries were obtained during autopsy and homogenized in 0.01 mol/l pH 7.4 phosphate buffer. In addition, for the autoantibody evaluation, the electrophoretic method of separation in polyacrylamide gel and western blot were employed. Among the 33 subjects, in 23 patients the presence of autoantibodies against the pituitary was shown. Sera of 15 patients reacted with the pituitary microsomal fraction protein of 55 kDa. In other cases, 10 sera reacted with the pituitary antigen of 67 kDa. In addition, 5 sera reacted with the 60 kDa antigen, 5 sera with 52 kDa protein, 3 sera with 105 kDa protein, 3 sera with the 97 kDa antigen and 2 sera with pituitary antigen of 92 kDa weight. In our study, based on the immunoblotting method, we observed that pituitary autoantibodies against 55, 60 and 67 kDa antigens occurred frequently.

Nicotinamide phosphorybosiltransferase overexpression in thyroid malignancies and its correlation with tumor stage and with survivin/survivin DEx3 expression.

Nicotinamide phosphorybosiltransferase (NAMPT) plays an important role in the regulation of cellular growth, angiogenesis, and apoptosis in mammalian cells. NAMPT overexpression has been recently found in colorectal, breast, prostatic, gastric, esophageal, pancreatic cancers, and specific NAMPT inhibitors might be adjuvant therapeutic modalities. In this study, we analyzed NAMPT expression in 40 malignant and in 67 benign thyroid tissue samples using qPCR. We also investigated relationships between NAMPT expression and survivin/survivin splicing variants DEx3 and 2B expressions. NAMPT expression was significantly higher in thyroid cancers (P < 0.0001), and it was positively correlated with tumor stage (P = 0.0012; r = 0.493). NAMPT expression was significantly higher in tumors staged pT3 or pT4 (16 cases) than in tumors staged pT1 or pT2 (24 cases) (P = 0.0106). Metastases to the lymph nodes were found in 12 out of 40 cases, and NAMPT expression was higher in the metastatic group (P = 0.0258). Multifocality was not associated with higher NAMPT expression (P = 0.3451). NAMPT expression in thyroid cancers significantly correlated with survivin and with survivin splice variant DEx3 expressions (P < 0.0001; r = 0.624 and P = 0.0239; r = 0.357, respectively). There was no correlation between NAMPT and survivin 2B expressions (P = 0.3508). This is the first study demonstrating NAMPT overexpression in thyroid malignancies using quantitative RT-PCR. Moreover, it shows that NAMPT is upregulated in patients with more advanced tumor stage and metastatic disease which may prove to be clinically relevant. Further studies are needed to explain the role of NAMPT in thyroid cancer biology and the possible use of NAMPT inhibitors in thyroid cancer.

Evaluation of survivin splice variants in pituitary tumors.

PURPOSE: Survivin is an apoptosis inhibitor, expressed in almost all types of human malignancies, but rarely in differentiated normal tissues. Recently, survivin gene splice variants with different anti-apoptotic activities have been reported. The current study was undertaken to examine the expression of survivin and its splice variants ∆Ex3 and 2ß in pituitary tumors, and to correlate the amount of particular transcripts with clinical staging in pituitary adenomas. Quantitative detection of survivin and its splice variants ∆Ex3 and 2ß transcripts in non-cancerous pituitary tissues (n = 12) and different types of pituitary tumor (n = 50). METHODS: Samples were collected from 50 pituitary tumors including 26 non-functional tumors, 21 GH-secreting tumors, 2 PRL-secreting tumors and 1 ACTH-secreting tumor. 12 normal pituitary glands received after autopsy served as a control of the study. 29 thyroid cancers tissues were used as a positive control. The RT-qPCR with TaqMan hydrolysis probes were used to determine the expression of analyzed splice variants of survivin. RESULTS: The obtained data showed that both survivin and its splice variants were expressed in different types of pituitary adenoma as well as in normal pituitary tissue. However, the level of its expression was similar in all studied cases. Patient age negatively correlated with tumor invasiveness. Moreover, our study showed a tendency for negative correlation between patient age and tumor diameter. CONCLUSIONS: No significant differences between survivin and its splice variants ∆Ex3 and 2ß expression in pituitary tumors and in normal pituitary glands as well as in invasive and in non-invasive tumors were found, suggesting that survivin does not play a significant role in pituitary tumorigenesis.

The role of antithyroglobulin, antiperoxidase and anti-TSH receptor autoantibodies in amiodarone-induced thyrotoxicosis and amiodarone-induced hypothyroidism (A two-center study).

OBJECTIVE: It has been reported that patients experiencing side effects of amiodarone (AM) therapy, such as amiodarone-induced thyrotoxocosis (AIT) or amiodarone-induced hypothyroidism (AIH), have changes in serum concentrations of anti-TSH receptor (TSHR), antithyroglobulin (Tg), and antiperoxidase (TPO) autoantibodies (Abs). The purpose of our study was to identify and analyze the changes in levels of listed antibodies in patients with several thyroid disorders. METHODS: 280 patients from two centers in Poland were included. Titers of TSHR-Abs, TPO-Abs and Tg-Abs were analyzed retrospectively in the following groups of patients: A - euthyroid patients with a history of hyperthyroidism prior to re-administration of AM; B - patients with AIT who discontinued the AM therapy; C - patients with AIT chronically treated with AM; D - hypothyroid patients. RESULTS: Serum Tg-Abs were not elevated in any of the studied groups. However, there were significant differences between A and B and also D and other groups (p<0.05). TPO-Abs titers were not elevated in most cases, there were no significant differences between groups. The serum titers of TSHR-Abs were not elevated in any group. We found statistically significant differences between B and D, C and other groups (p<0.05). CONCLUSIONS: Regardless of the statistically significant differences observed for Tg-Abs and TSHR-Abs levels, this observation have a limited clinical applicability. In almost all cases we observed normal to slightly increased titers of TPO-Abs, Tg-Abs, TSHR-Abs. Discontinuation or continuation of AM therapy had no influence on autoantibody titers. Furthermore, we found it impossible to differentiate between the type I and II of AIT based on autoantibody titers.

Familial syndromes associated with neuroendocrine tumours.

Neuroendocrine tumours may be associated with familial syndromes. At least eight inherited syndromes predisposing to endocrine neoplasia have been identified. Two of these are considered to be major factors predisposing to benign and malignant endocrine tumours, designated multiple endocrine neoplasia type 1 and type 2 (MEN1 and MEN2). Five other autosomal dominant diseases show more heterogeneous clinical patterns, such as the Carney complex, hyperparathyroidism-jaw tumour syndrome, Von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1) and tuberous sclerosis. The molecular and cellular interactions underlying the development of most endocrine cells and related organs represent one of the more complex pathways not yet to be deciphered. Almost all endocrine cells are derived from the endoderm and neuroectoderm. It is suggested that within the first few weeks of human development there are complex interactions between, firstly, the major genes involved in the initiation of progenitor-cell differentiation, secondly, factors secreted by the surrounding mesenchyme, and thirdly, a series of genes controlling cell differentiation, proliferation and migration. Together these represent a formula for the harmonious development of endocrine glands and tissue.

Patients with chronic hepatitis type C and interferon-alpha-induced hyperthyroidism in two-years clinical follow-up.

OBJECTIVES: Interferon-α (IFN-α) is a gold standard in the therapy of viral chronic hepatitis type C (CHC). However, such treatment might lead to thyroid dysfunction. Patients usually present hypothyroidism, but rarely also hyperthyroidism may develop. The aim of the study is to present two-year clinical follow-up of patients with CHC and IFN-α-induced hyperthyroidism (IIH), with special regard to the methods and efficacy of the therapy. METHODS: A group of 106 patients with CHC and IIH were analyzed. Subjects were divided into two groups according to etiology: group 1, with Graves' disease (GD) and group 2, with Hashitoxicosis (HT). The diagnosis of GD and HT was based on: clinical signs of hyperthyroidism, hormonal profile (TSH, fT4, fT3), level of thyroid autoantibodies (Tg-Abs, TPO-Abs, TSHRAbs). Treatment of hyperthyroidism was monitored by repeated clinical assessment and laboratory tests. RESULST: 28 patients (26 with GD of which 5 exhibited mild orbitopathy and 2 with HT) were treated with radioiodine [the average dose of was 17 mCi [668 MBq]. In adition 78 out of 80 patients with HT mostly ß-blocker therapy was successful (transient hyperthyroidism). At the end of the observation period, in group 1 remission was achieved in 17 (65.4%) cases, 6 (23.1%) patients showed hypothyroidism and 3 (11.5%) presented recurrence of hyperthyroidism. CONCLUSIONS: Most patients with IIH present Hashitoxicosis, while a minority of them develop Graves' disease. In a majority of patients with HT spontaneous remission of disease occurs. In patients with long-term hyperthyroidism, radioiodine therapy is an effective and well-tolerated.

The influence of radioiodine therapy on ocular changes and their relation to urine cotinine level in patients with Graves' Ophthalmopathy.

OBJECTIVES: Radioiodine therapy (RIT) is frequently used as the definitive treatment in patients with Graves' hyperthyroidism when remission is not achieved with anti-thyroid drugs (ATDs). In this observational study, we intended to examine whether the use of high doses of radioiodine (RAI) [22 mCi (814 MBq)] with prophylaxis of oral glucocorticoids (oGCS) does not exacerbate Graves ophthalmopathy (GO) in smokers and non-smokers, especially regards to the urine level cotinine and ocular changes before and after RIT. PATIENTS AND METHODS: The studied group consisted of 26 smokers, aged 28-61 years and 25 non-smoker patients, aged 21-54 years, respectively. The patients were enrolled to RAI after one-year of ineffective ATDs treatment. Criterion for inclusion in the study were patients with mild GO with hyperthyroidism at diagnosis based on the severity (NOSPECTS) and activity (CAS) scale. All the patients were subjected to RIT with oGCS prophylaxis and evaluated prospectively during a one-year follow-up. The ophthalmological examination was performed at various stages of RIT: initial pre-radioiodine administration, at the time of treatment 6, and 12 months after RAI. The present study is unique, because the urine cotinine measurement was employed to detect nicotine exposure, also in regard to smoking intensity. RESULTS: In smokers, the values of serum TPO-Abs were statistically significant in the second and six month (p<0.05) and in the second and after one year (p<0.005). The TSHR-Abs concentration was significantly higher in smokers (p<0.05), rising from 22.9±1.2 IU/L before therapy to 29.6±5.3 IU/L - 2 months, 32.6±8.6 IU/L - 6 months, and slightly decreased 28.9±10.6 IU/L - 12 months. These observed changes were statistically different between groups at baseline (p<0.05) and after one-year of follow-up (p<0.005). Mean urine cotinine were considerably higher in smokers comparing to non smokers in each point of observation [903.4±770.0 and 5.2±1.7 ng/mL at baseline (p<0.001), 412.8±277.3 and 3.0±0.6 ng/mL after 2 months (p<0.001), 452.0±245 and 6.6±3.6 after 6 months (p<0.001), 379.4±236.8 and 1.0±1.2 after one year (p<0.001)]. The CAS values in the smoking group before RIT increased statistically from 2.8±0.2 points at baseline to 4.3±0.3 after 6 months, and 4.0±0.5 (12 months), while in the non-smoking patients it was 1.4±0.2, 2.8±0.3 and 2.2±0.2, respectively. The level of urine cotinine correlated positively with CAS and TSHR-Ab in the smoking group (r=0.41; p<0.05) at baseline and during follow-up (2 months: r=0.46; p<0.001, 6 months: r=0.47, p<0.005; 12 months: r=0.46; p<0.005). In the NOSPECS classification, the symptoms changed from mild to moderate, mostly in smoking patients. CONCLUSIONS: 1) ablative RIT dose with prophylactic oral prednisone is a safe treatment in both smokers and non-smokers with mild GO; 2) The post hoc analysis showed that urinary level of cotinine can be very helpful in the assessment of exacerbation of ophthalmological clinical symptoms before and after RIT particularly in smokers.

Assessment of real-world usage of lanreotide AUTOGEL 120 in Polish acromegalic patients - results from the prospective 12-month phase of Lanro-Study.

AIM OF THE STUDY: To assess resource utilization and costs of treatment with lanreotide AUTOGEL 120 mg (ATG120) administered as part of routine acromegaly care in Poland. MATERIAL AND METHODS: A multicentre, non-interventional, observational study on resource utilization in Polish acromegalic patients treated with ATG120 at 4 weeks or extended (> 4 weeks) dosing interval. The study recruited adult acromegalic patients treated medically for ≥ 1 year including at least 3 injections of ATG120. Data on dosing interval, aspects of administration, and resource utilization were collected prospectively during 12 months. Costs were calculated in PLN from the public health-care payer perspective for the year 2013. RESULTS: 139 patients were included in the analysis. Changes in dosing regimen were reported in 14 (9.4%) patients. Combined treatment was used in 11 (8%) patients. Seventy patients (50%) received ATG120 at an extended dosing interval; the mean number of days between injections was 35.56 (SD 8.4). ATG120 was predominantly administered in an out-patient setting (77%), by health-care professionals (94%). Mean time needed for preparation and administration was 4.33 and 1.58 min, respectively, mean product wastage - 0.13 mg. Patients were predominantly treated in an out-patient setting with 7.06 physician visits/patient/year. The most common control examinations were magnetic resonance imaging of brain and brain stem (1.36/patient/year), ultrasound of the neck (1.35/patient/year), GH (1.69/patient/year), glycaemia (1.12/patient/year), IGF-1 (0.84/patient/year), pituitary-thyroid axis hormone levels assessment (TSH-0.58/patient/year, T4-0.78/patient/year). There were 0.43 hospitalizations/patient/year. For direct medical costs estimated at PLN 50 692/patient/year the main item was the costs of ATG120 (PLN 4103.87/patient/month; 97%). The mean medical cost, excluding pharmacotherapy, was PLN 1445/patient/year (out-patient care - 49%, hospitalization - 23%, diagnostics/laboratory tests - 28%). CONCLUSIONS: These results represent the current use of ATG120 in the population of Polish acromegalic patients in a realistic clinical setting. Findings that 50% of patients could be treated with dose intervals of longer than 28 days support the potential of ATG120 to reduce the treatment burden.

Is Cataract in Patients under 60 Years Associated with Oxidative Stress?

Oxidative stress is considered as a possible factor in the genesis of cataract. The study aimed to determine the systemic antioxidant status in cataract patients under 60 years. We studied 28 consecutive cataract patients, mean of 53 years (SD = 9.2), a range of 22-60 and 37 controls. In erythrocytes, activity of antioxidant enzymes was determined: superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), in contrast with plasma concentrations of vitamin A and E. Conjugated dienes (CD) level and protein carbonyls (PC) concentration were also determined in plasma. Malondialdehyde (MDA) concentrations in erythrocytes and plasma were also measured. SOD and GPx activity and vitamin A and E concentrations were lower in cataract patients (p = 0.000511, 0.02, 0.022, and 0.000006, respectively). MDA plasma and erythrocytes concentrations were higher in cataract patients (p = 0.000001 and 0.0000001, respectively). PC concentration was higher in cataract patients than in controls (p = 0.00000013). There were statistically significant correlations between oxidative stress markers both in the cataract patients group as well as in the control group. Cataract incidence in patients under 60 years seems to be accompanied by enhanced lipid peroxidation and protein oxidation, as well as antioxidant defense depletion. Thus, supplementation with antioxidants could be beneficial in this group of patients.

A rare case of Interferon-alpha-Induced Hyperthyroidism in patients with a chronic hepatitis C with granulocytopenia and transaminasemia treated successfully with radioiodine.

BACKGROUND: Conventional management of Interferon-α-Induced Hyperthyroidism (IIH) with radioactive iodine (RAI) may be used when treatment with beta blockers or antithyroid drugs (ATD), proves ineffective or is contraindicated. CASE PRESENTATION: We present a 38-year-old woman who has been treated with combined pegylated interferon alpha (INF-α) and Ribavirin for chronic hepatitis C. Destructive thyrotoxicosis appeared after four months of continuous IFN-α therapy and a beta blocker was prescribed. Initially, the patient presented normal TSH 2.4 µIU/mL, however during therapy with INF-α, TSH diminished to 0.05 and thyroid hormones were elevated: fT4 23.1 pmol/L, fT3 7.2 pmol/L. Ultrasound examination showed completely irregular and greatly decreased echogenicity of the thyroid gland. The radioiodine uptake (RAIU) was deeply decreased to 2 and 3% at 5 h and 24 h, respectively. The thyroid scintiscan showed lack of isotope accumulation. Hypothyroidism developed and L-thyroxine was prescribed. The following year, hyperthyroidism reoccurred with TSH 0.08 µIU/mL, fT4 26.4 pmol/L, fT3 8.2 pmol/L, positive TSHR-Abs 6.2 (normal <2 IU/L) and mild Graves' Ophthalmopathy (GO). RAIU values were 23% at 5 h and 46% at 24 h. Thyroid scintiscan showed diffuse goiter. At this point beta blocker was introduced and ATD was started. After three months of therapy an increased level of aminotransferases and granulocytopaenia were observed. Hence, the patient received RAI and glucocorticosteroid, while INF-α therapy was continued. After approximately 4 months, hypothyroidism reappeared with insignificantly raised TSH level. One year later the patient was euthyroid and required no further treatment. CONCLUSIONS: Our report suggests that: 1. Radioiodine therapy might be an effective and safe method of treatment in cases of IIH with mild GO. 2. IFN-α therapy need not be discontinued in patients with IIH.

Survivin--prognostic tumor biomarker in human neoplasms--review.

Accurate diagnosis and proper monitoring of cancer patients remain important obstacles for successful cancer treatment. The search for cancer biomarkers is carried out in order to quickly identify tumor cells and predict treatment response, ultimately leading to a favorable therapeutic outcome. One such prognostic marker seems to be survivin. Many studies have shown that survivin is strongly expressed in a vast majority of cancers. Its overexpression was demonstrated in breast and lung cancer prostate, gastric, colon, bladder and esophageal carcinomas, osteosarcomas, and lymphomas. In many of those tumors, high activity of the surviving gene was associated with a poor prognosis and worse survival rates. Moreover survivin expression was correlated with resistance to chemotherapy and radiotherapy-induced apoptosis. Since survivin may be identified as an independent prognostic factor and inhibitor of apoptosis, it may prove to be a useful therapeutic target in cancer therapy

Fatal course of cyclic Cushing's disease - lessons from a case.

We present a 56-year-old patient with cyclic Cushing's disease (CCD) observed for 28 months, who presented clinically and biochemically with alternating episodes of hyper-, normo- and hypocortisolemia. The course of the disease was fatal, the patient died due to severe hypokalemia.

Changes in the geometry of modern daily disposable soft contact lenses during wear.

The geometry of contact lenses can be altered by wear but determining the changes that occur in soft contact lenses (SCLs) is challenging. This study aimed to investigate the shape alterations of daily disposable SCLs after wear using swept-source optical coherence tomography (SS-OCT). Forty-five eyes with myopia of - 3.00 diopters (D) were enrolled. The participants wore three types of SCLs: hydrogel lens (nesofilcon A) and silicone hydrogel lenses (delefilcon A and stenfilcon A). The SCLs were scanned 3-6 min after lens removal. We found a significant decrease in the SCL anterior curvature: 0.24 ± 0.17 mm for nesofilcon A, 0.44 ± 0.21 mm for delefilcon A, and 0.53 ± 0.29 mm for stenfilcon A. The changes in the anterior curvature of SCLs correlated moderately with the mean corneal keratometry; Pearson's correlation coefficients for nesofilcon A and delefilcon A were 0.57 and 0.52, respectively (P < 0.001). A statistically significant change in the total diameter was observed in SCL made of stenfilcon A (0.39 mm, P < 0.001). To conclude, the central radii of curvature decreased after a wearing period for all three types of daily disposable SCLs to imitate the anterior corneal surface, however, the changes in other geometrical parameters measured with SS-OCT were lens-specific.