Thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): Real world data of a Greek nationwide multicenter retrospective study.

Thrombosis is the most common and a life-threatening complication in patients with Paroxysmal Nocturnal Hemoglobinuria. One-third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death in these patients. The mechanism of thrombosis in PNH is complex and continues to be of great research interest. Since the introduction of C5 complement inhibitors in the treatment of PNH, the incidence of thromboembolic events has decreased substantially. We retrospectively analyzed data concerning the thrombotic episodes of 41 patients with PNH from 14 different national hematology centers in Greece. Sixteen patients (39%) experienced at least one episode of thrombosis, including, seven (43.8%) at diagnosis, seven (43.8%) during the course of the disease and two (12.5%) patients prior to PNH diagnosis. Nearly half of these individuals (n=7, 43.8%) had multiple episodes of thrombosis during the course of their disease. The most common sites of thrombosis were intra-abdominal veins. Three out of 26 patients developed thrombosis while on eculizumab. In none of the 16 patients, the thrombotic event was fatal. Our findings, despite the small number of patients, confirmed that thrombosis continues to be a significant complication of PNH affecting more than one third of the patients.

The Chronic Pain Grade Questionnaire: validity, reliability and responsiveness in Greek chronic hip pain sufferers.

BACKGROUND: The Chronic Pain Grade Questionnaire (CPGQ) was developed to assess the global severity of chronic pain based on pain intensity and pain-related disability. This study aimed to translate, culturally adapt, and validate the Greek version of the CPGQ (CPGQ-Gr).  Methods: Adaptation into Greek followed established guidelines. We invited orthopedic outpatients suffering from chronic hip pain to participate in the study. The validity, reliability, and responsiveness of the CPGQ-Gr were assessed. RESULTS: Factor analysis yielded two factors (subscales), disability score (DS) and characteristic pain intensity (CPI). CPGQ-Gr items, total and subscale scores were highly correlated with the 12-Item Short Form Health Survey (SF-12) physical component summary score, and slightly correlated or not correlated with the SF-12 mental component summary score. Cronbach's alpha correlation coefficients for the CPGQ-Gr total scale, DS, and CPI subscales were 0.90, 0.95, and 0.83 respectively. All measures showed excellent temporal stability (intraclass correlation coefficients of 0.84, 0.92, and 0.91, respectively). Cliff's delta effect sizes ranged from 0.47 to 0.82. The values of the area under the receiver operating characteristic curve were consistent with good to excellent discriminatory ability (range: 0.747-0.902). CONCLUSION: Our findings suggest that the Greek version of the CPGQ is a valid, reliable, and sensitive to changes, instrument for grading the severity of chronic hip pain. HIPPOKRATIA 2018, 22(1): 37-42.

Prolonged complete remission in a primary MALT lymphoma of the lung after rituximab monotherapy.

BACKGROUND: Primary pulmonary non-Hodgkin lymphoma (NHL) is a rare entity. Despite its favorable prognosis, an optimal treatment approach has not been established until today, as there are few debated heterogeneous data in the literature. Many therapeutic options such as surgery, radiotherapy, chemotherapy alone or in combination, immunotherapy and/or immunochemotherapy all with similar results, have been reported. CASE DESCRIPTION: We report the case of a 68-year-old man diagnosed with a primary marginal zone B-cell pulmonary NHL, with a durable complete response to rituximab monotherapy. CONCLUSION: We support the therapeutic application of rituximab monotherapy as an attractive option for this malignancy. This effective approach exhibits significant antitumor activity leading to long-term complete remission and minimal hematological toxicity in contrast to other intensive chemotherapies and/or radiotherapy, which might have serious side effects. HIPPOKRATIA 2017, 21(2): 108-110.

Impact of parental weight status on a school-based weight management programme designed for Mexican-American children.

BACKGROUND: While overweight and obese children are more likely to have overweight or obese parents, less is known about the effect of parental weight status on children's success in weight management programmes. OBJECTIVES: This study was a secondary data analysis of a randomized controlled trial and investigated the impact of having zero, one or two obese parents on children's success in a school-based weight management programme. METHODS: Sixty-one Mexican-American children participated in a 24-week school-based weight management intervention which took place in 2005-2006. Children's heights and weights were measured at baseline, 3, 6 and 12 months. Parental weight status was assessed at baseline. Repeated measures anova and ancova were conducted to compare changes in children's weight within and between groups, respectively. RESULTS: Within-group comparisons revealed that the intervention led to significant decreases in standardized body mass index (zBMI) for children with zero (F = 23.16, P < .001) or one obese (F = 4.99, P < .05) parent. Between-group comparisons indicated that children with zero and one obese parents demonstrated greater decreases in zBMI compared to children with two obese parents at every time point. CONCLUSIONS: The school-based weight management programme appears to be most efficacious for children with one or no obese parents compared to children with two obese parents. These results demonstrate the need to consider parental weight status when engaging in childhood weight management efforts.

Rifampicin-moxifloxacin interaction in tuberculosis treatment: a real-life study.

SETTING: Rifampicin (RMP) has been reported to reduce moxifloxacin (MFX) levels, which may interfere with the effectiveness of MFX in treating tuberculosis (TB). OBJECTIVE: To study the MFX-RMP interaction in patients receiving MFX with or without RMP as part of their anti-tuberculosis treatment regimen. DESIGN: Patients with pulmonary TB followed up by the Tuberculosis Out-patient Clinic of the Pulmonary Department, Aristotle University of Thessaloniki, Greece, who underwent treatment with MFX during the periods 1 May 2012-30 April 2014 and 1 January-31 March 2015, were included in the study. MFX levels were compared between 12 patients who were receiving RMP (Group 1) and 10 who were not (Group 2). RESULTS: The participants did not significantly differ in body mass index, days of MFX treatment or MFX dose/kg. Neither the peak concentration (Cmax) nor the 24 h area under the curve (AUC24) differed significantly between the two groups (Group 1, Cmax median 3.9 [range 1.9-4.5] mg/l; AUC24 29.1 [10-47.4] mg·h/l and Group 2, Cmax 4.1 [2-6.4] mg/l; AUC24 36.5 [14.6-54.2] mg·h/l). CONCLUSION: Although a decrease in MFX exposure was observed in the RMP-treated group, the effect was lower than previously reported in a real-life setting. The large variability observed in MFX pharmacokinetics in both groups may suggest the need for dose readjustment in some patients, regardless of RMP co-administration.

The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) elicits estrogenic-like microRNA responses in breast cancer cells.

The cooking of meat results in the generation of heterocyclic amines (HCA), the most abundant of which is 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Data from epidemiological, mechanistic, and animal studies indicate that PhIP could be causally linked to breast cancer incidence. Besides the established DNA damaging and mutagenic activities of PhIP, the chemical is reported to have oestrogenic activity that could contribute to its tissue specific carcinogenicity. In this study we investigated the effect of treatment with PhIP and 17-ß-estradiol (E2) on global microRNA (miRNA) expression of the oestrogen responsive MCF-7 human breast adenocarcinoma cell line. PhIP and E2 caused widespread and largely over-lapping effects on miRNA expression, with many of the commonly affected miRNA reported to be regulated by oestrogen and have been implicated in the initiation and progression of breast cancer. The regulatory activity of the miRNAs we show here to be responsive to PhIP treatment, are also predicted to mediate cellular phenotypes that are associated with PhIP exposure. Consequently, this study offers further support to the ability of PhIP to induce widespread effects via activation of oestrogen receptor alpha (ERα). Moreover, this study indicates that deregulation of miRNA by PhIP could potentially be an important non-DNA-damaging carcinogenic mechanism in breast cancer.

The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis.

Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16(INK4A), a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.

Long-term outcome of primary endocrine non-Hodgkin lymphomas: does the site make the difference?

AIM: Primary lymphomas of endocrine glands are extremely rare. Our study adds more data to the few published series regarding the incidence, clinical characteristics, management and overall survival (OS) by comparing the various diffuse large B-cell endocrine lymphomas. Moreover, it contributes to a better understanding of these neoplasms and provides concepts for future research. METHODS: We retrospectively evaluated the clinical profile and the patterns of outcome among patients who were treated in our center with the diagnosis of aggressive, B-cell, primary endocrine lymphoma. RESULTS: Between May 1980 and December 2011, 450 patients were diagnosed as primary extranodal non-Hodgkin lymphomas. Among them, 18 cases (4%) were primary testicular lymphoma (PTL), 8 cases (2%) were primary thyroid lymphoma (PTHL) and 4 cases (1%) were primary adrenal lymphoma (PAL). The therapeutic approaches employed were variable, including mainly chemotherapy in combination with radiotherapy and surgery. The median OS for the patients with PTL and PAL was 27 and 6 months, respectively. Better outcome was observed in patients with PTHL for whom the median OS has not been reached yet, whereas the PAL group had the worst prognosis. CONCLUSIONS: The discrepancies in the outcome among endocrine lymphomas could be partly attributed to their biologic variability, which might be determined by the initial site involved. We conclude that treatment decisions should be made according to a multi-disciplinary approach to avoid unnecessary surgery. Existing treatment strategies for PTL and PAL fail to provide long-term survival, rendering the application of novel therapeutic approaches essential.

Linezolid penetration into cerebrospinal fluid and brain tissue.

The aim of the study was to evaluate the penetration of linezolid into cerebrospinal fluid (CSF) and brain tissue after a single i.v. dose of 600 mg. The penetration of linezolid into cerebrospinal fluid and brain tissue was studied in 18 patients undergoing a neurosurgical procedure. Linezolid 600 mg i.v. was given with the induction of anesthesia. Mean concentrations of linezolid 2h after the final dose, in serum, cerbrospinal fluid and brain tissue were assayed by HPLC. CSF/serum and brain/serum ratios were 69.57% and 44.66% respectively. Concentrations of linezolid were above the MIC(90s )for staphylococci and streptococci. The concentrations obtained indicate good penetration of linezolid into CSF and brain tissue and support its use in the management of multidrug-resistant Gram-positive CNS infections.

Insulin receptor and IGF1R are not required for oocyte growth, differentiation, and maturation in mice.

In mammals, insulin and insulin-like growth factors (IGFs: IGF1 and IGF2) act through 2 structurally related receptors, the insulin receptor (INSR) and the type 1 IGF receptor (IGF1R), both of which are expressed in developing oocytes. IGF1 plays an important role in female reproduction, and female Igf1 knockout mice fail to ovulate and are infertile. On the other hand, little is known about the in vivo role of the insulin signaling pathway in oocytes during follicular development, although exposure to insulin or IGF1 in vitro improves oocyte maturation. To further address the significance of insulin/IGF signaling, we used conditional mutant mice and ablated the function of the genes encoding INSR, IGF1R, or both receptors specifically in developing mouse oocytes. Our genetic evidence showed unexpectedly that the female reproductive functions are not affected when Insr, Igf1r or both Insr;Igf1r are ablated in oocytes, as the female mice are fertile and exhibit normal estrous cyclicity, oocyte development and maturation, parturition frequency, and litter size. In view of these novel observations indicating that the insulin/IGF signaling is not essential in oocytes, the IGF1-dependent female fertility is re-evaluated and discussed.

Acute renal failure following intravenous immunoglobulin therapy in a HIV-infected patient.

Acute renal failure is a rare complication following the administration of intravenous immunoglobulin (IVIG). Only 114 cases have been reported in the literature. The exact mechanism of IVIG-associated acute renal failure remains unclear. Hereby we describe the first case of ARF in a HIV-infected patient, who received IVIG stabilized with maltose for the treatment of HIV-related thrombocytopenic purpura.

Addition of cyclosporin-A to chemotherapy in secondary (post-MDS) AML in the elderly. A multicenter randomized trial of the Leukemia Working Group of the Hellenic Society of Hematology.

In elderly patients with secondary leukemia, poor therapeutic response and low overall survival have been attributed mainly to age and to the primary resistance of leukemic cells to chemotherapy. Modulation of resistance has been attempted in different studies, but the results have been contradictory. We conducted an open, randomized multicenter clinical trial involving patients more than 60 years old with secondary leukemia preceded by a myelodysplastic syndrome. The induction chemotherapy regimen included idarubicin, cytarabine, and etoposide (group A); randomization involved simultaneous administration of cyclosporin-A per os (group B). Fifty-five patients were evaluated, 26 in group A and 29 in group B. Overall complete remission was achieved in 40% of the patients, 27% vs 52% in groups A and B, respectively (p=0.01). Leukemia-free survival was more favorable in patients who received cyclosporin-A, 12 vs 7 months for groups B and A, respectively (p=0.03). In a follow up period of 30 months, 7 out of 55 patients (13%) were alive, 4 of whom were in complete remission. Five out of the 7 alive patients were randomized in group B and had received cyclosporin-A. Treatment failure was higher in group A [19 of 26 patients (73%)] than in group B with CsA [14 of 29 patients (48%)] (p<0.0001). Treatment-related toxicity/mortality was 13%. Modulation of drug resistance by CsA in elderly people suffering from secondary acute leukemia may improve the outcome of chemotherapy without increasing drug toxicity and treatment-related mortality.

Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study.

BACKGROUND: High-dose chemotherapy with autologous stem cell transplantation after initial cytoreductive chemotherapy with the combination vincristine, doxorubicin and dexamethasone (VAD) is considered an effective therapy for many patients with newly diagnosed, symptomatic multiple myeloma. Response to initial cytoreductive chemotherapy is important for the long-term outcome of such patients. Thalidomide has recently shown significant antimyeloma activity. We studied the efficacy and toxicity of the combination of a liposomal doxorubicin-containing VAD regimen with thalidomide, administered on an outpatient basis, as initial cytoreductive treatment in previously untreated patients with symptomatic myeloma. PATIENTS AND METHODS: Thirty-nine myeloma patients were treated with vincristine 2 mg intravenously (i.v.), liposomal doxorubicin 40 mg/m(2) i.v. administered as single dose on day 1, and dexamethasone 40 mg per os daily for 4 days. Dexamethasone was also given on days 15-18 of the first cycle of treatment. The regimen was administered every 4 weeks for four courses. Thalidomide was given daily at a dose of 200 mg at bedtime. Response to treatment was evaluated after four cycles of treatment. After completion of four cycles, the patients were allowed to proceed to high-dose chemotherapy or to receive two additional cycles of the same treatment. RESULTS: On an intention-to-treat basis, 29 of the 39 patients (74%) responded to treatment. Four patients (10%) achieved complete and 25 (64%) partial response. Three patients (8%) showed minor response and seven (18%) were rated as non-responders. Major grade 3 or 4 toxicities consisted of neutropenia (15%), thrombocytopenia (15%), deep vein thrombosis (10%), constipation (10%), skin rash (5%) and peripheral neuropathy (5%). Two patients (5%) experienced early death due to infection. CONCLUSIONS: The combination of vincristine, liposomal doxorubicin, and dexamethasone (VAD doxil) with thalidomide is an effective and relatively well-tolerated initial cytoreductive treatment. Prospective randomized studies are required in order to assess the effect of this regimen on the long-term outcome of patients with multiple myeloma.

The combination of intermediate doses of thalidomide and dexamethasone reduces bone marrow micro-vessel density but not serum levels of angiogenic cytokines in patients with refractory/relapsed multiple myeloma.

The aim of the study was the evaluation of anti-angiogenic activity of the combination of intermediate doses of thalidomide and dexamethasone in patients with refractory/relapsed myeloma. Twenty-five patients were included in the study. Microvessel density (MVD) was evaluated in marrow biopsies before and after treatment. Serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), tumor necrosis factor-alpha (TNF-alpha), which have angiogenic potential and interleukin-6 (IL-6), IL-1beta, soluble IL-6 receptor (sIL-6R), and transforming growth factor-beta (TGF-beta) which are involved in the disease biology, were measured before treatment and then every 2 weeks for 8 weeks. Pretreatment levels of MVD, VEGF, b-FGF, IL-6, sIL-6R were increased in the patients compared to controls. The overall response rate to therapy was 72%. The administration of the combined regimen produced a significant reduction in MVD in responders. However, an increase in serum levels of VEGF, b-FGF, IL-6, sIL-6R was observed post-treatment in responders. In contrast, serum levels of TNF-alpha, TGF-beta, IL-1beta did not differ between patients and controls and remained unchanged during the study. These results suggest that the combination of thalidomide plus dexamethasone is an effective treatment for myeloma reducing MVD marrow levels but not serum levels of angiogenic cytokines or cytokines implicated in myeloma biology.

13q deletion in chronic lymphocytic leukemia: characterization of E4.5, a novel chromosome condensation regulator-like guanine nucleotide exchange factor.

We report the characterization of a new gene (E4.5) that maps at chromosome band 13q14.3, a chromosomal area frequently deleted in chronic lymphocytic leukemia (CLL) and in other lymphoid malignancies. E4.5 gene encodes for a 4 kb mRNA expressed in various tissues and has an open reading frame of 531 amino acids. The predicted E4.5 protein shows strong homology with the human regulator of chromosome condensation (RCC1) protein, the principal GTP exchange factor for Ran protein. The E4.5 protein contains a BTB domain in its N-terminus, a protein-protein interaction motif. Therefore, we propose that E4.5 is a new member of the RCC1-related guanine nucleotide exchange factor (GEF) family with potent interaction with other proteins and unknown function. Until now, no tumor suppressor genes have been mapped in the 13q14.3 minimal deleted region (MDR) in patients with CLL. It has been proposed that loss of the 13q14.3 MDR may contribute to lymphoid neoplasia by altering the expression/function of genes located on 13q14.3 outside the MDR. The E4.5 is one of these genes with a potential role in the pathogenesis of CLL.

Genetic heterogeneity underlies juvenile hemochromatosis phenotype: analysis of three families of northern Greek origin.

Hereditary hemochromatosis is a genetically heterogeneous disease. Common HFE mutations (C282Y and H63D) are related to the majority of hereditary hemochromatosis cases in populations of Northern European ancestry (HFE1). Juvenile hemochromatosis (JH) is a more severe iron overload disorder, usually presenting at the second decade of life. The gene responsible for JH lies on a genetic locus at chromosome 1q. We have performed a genetic linkage study in three families of Northern Greek origin with typical clinical features of JH. In two families results were in accordance with linkage to chromosome 1q. In one family linkage of the disease to the genetic loci at 1q21, 7q22, and 6p22 was excluded. We suggest that more than one gene may underlie the JH phenotype. This genetic type of hemochromatosis may be designated 1q unlinked juvenile hemochromatosis. Family studies are necessary to establish the genetic diagnosis of JH.