Larval nutritional-stress and tolerance to extreme temperatures in the peach fruit fly, Bactrocera zonata (Diptera: Tephritidae).

Within the factors affecting insect tolerance to extreme environmental conditions, insect nutrition, particularly of immature stages, has received insufficient attention. In the present study, we address this gap by investigating the effects of larval nutrition on heat and cold tolerance of adult Bactrocera zonata - an invasive, polyphagous fruit fly pest. We manipulated the nutritional content in the larval diet by varying the amount of added yeast (2-10% by weight), while maintaining a constant sucrose content. Adults derived from the different larval diets were tested for their tolerance to extreme heat and cold stress. Restricting the amount of yeast reduced the efficacy of the larval diet (i.e. number of pupae produced per g of diet) as well as pupal and adult fresh weight, both being significantly lower for yeast-poor diets. Additionally, yeast restriction during the larval stage (2% yeast diet) significantly reduced the amount of protein but not lipid reserves of newly emerged males and females. Adults maintained after emergence on granulated sugar and water for 10 days were significantly more tolerant to extreme heat (i.e. knock-down time at 42 oC) when reared as larvae on yeast-rich diets (8% and 10% yeast) compared to counterparts developing on a diet containing 2% yeast. Nevertheless, the composition of the larval diet did not significantly affect adult survival following acute cold stress (exposure to -3°C for 2 hrs.). These results are corroborated by previous findings on Drosophilid flies. Possible mechanisms leading to nutrition-based heat-tolerance in flies are discussed.

Non-Oncological PET/CT imaging during SARS-CoV-2 pandemic.

In December 2019 a new ß-CoV, Severe Acute Respiratory Coronavirus- 2 (SARS-CoV-2), has been identified in Wuhan Hubei Province, China. Within a few months it spread rapidly to more than 114 countries and the disease, Coronavirus disease 2019 (COVID-19), was declared pandemic on 11th February 2020 by the World Health Organization (WHO). Until 20 June 2020 8:09 am, 8,465,085 cases of COVID-19 were confirmed globally, with 454,258 deaths. The first incidence in Greece was documented on 26 February 2020 in Thessaloniki and up to 20 June 2020 8:09 am, 3,227 confirmed cases of COVID-19 were reported, with 188 deaths. At the time of writing USA and Brazil, are the countries with the highest disease burden. Governments have imposed a variety of suggestions and restrictions in order to control the spread of the virus, focusing mainly on social distancing, self-isolation, personal hygiene and personal protective equipment (PPE). Greece was one of the countries that implemented early drastic measures thus succeeding in controlling the virus transmission; having a profound economical effect though.

Clinical, ultrasonographic, bacteriological, cytological and histological findings during uterine involution in ewes with pregnancy toxaemia and subsequent reproductive efficiency.

Objectives were to evaluate characteristics of uterine involution in ewes with pregnancy toxaemia during gestation and to study effects on subsequent reproductive performance. Pregnancy toxaemia was induced in ewes (A) by feeding an energy-deficient diet as confirmed by detecting ß-hydroxybutyrate concentrations in blood indicative of this disorder. There was also a control group (C). Animals were evaluated until the 60th day post-partum using clinical and ultrasonographic examinations. Vaginal swab samples and uterine biopsy tissue samples were collected for bacteriological and cytological examination; biopsy samples were prepared for histological examination. Ewes were subsequently placed with rams and reproductive performance was ascertained. Post-partum, during the ultrasonographic examination of the uterus, ewes of Group A had caruncle and uterine lumen diameters, as well as a uterine thickness greater than ewes of Group C. Post-partum uterine blood flow volume was greater in ewes of the A than C group. Neutrophils predominated in vaginal samples, with the neutrophil proportion being less in ewes of Group A than C. There were no differences in the uterine involution process between groups. During the subsequent reproductive season, all the ewes of Group A lambed normally and produced viable lambs. It is concluded that there were no adverse effects on subsequent reproductive performance of ewes previously affected with pregnancy toxaemia, when appropriate health management was performed.

How liquid biopsies can change clinical practice in oncology.

Cell-free DNA fragments are shed into the bloodstream by tumor cells. The analysis of circulating tumor DNA (ctDNA), commonly known as liquid biopsy, can be exploited for a variety of clinical applications. ctDNA is being used to genotype solid cancers non-invasively, to track tumor dynamics and to detect the emergence of drug resistance. In a few settings, liquid biopsies have already entered clinical practice. For example, ctDNA is used to guide treatment in a subset of lung cancers. In this review, we discuss how recent improvements in the sensitivity and accuracy of ctDNA analyses have led to unprecedented advances in this research field. We further consider what is required for the routine deployment of liquid biopsies in the clinical diagnostic space. We pinpoint technical hurdles that liquid biopsies have yet to overcome, including preanalytical and analytical challenges. We foresee how liquid biopsies will transform clinical practice: by complementing (or replacing) imaging to monitor treatment response and by detecting minimal residual disease after surgery with curative intent.

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer.

BACKGROUND: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

Factors increasing the risk for a severe reaction in anaphylaxis: An analysis of data from The European Anaphylaxis Registry.

BACKGROUND: Preventive measures to decrease the frequency and intensity of anaphylactic events are essential to provide optimal care for allergic patients. Aggravating factors may trigger or increase the severity of anaphylaxis and therefore need to be recognized and avoided. OBJECTIVE: To identify and prioritize factors associated with an increased risk of developing severe anaphylaxis. METHODS: Data from the Anaphylaxis Registry (122 centers in 11 European countries) were used in logistic regression models considering existing severity grading systems, elicitors, and symptoms to identify the relative risk of factors on the severity of anaphylaxis. RESULTS: We identified higher age and concomitant mastocytosis (OR: 3.1, CI: 2.6-3.7) as the most important predictors for an increased risk of severe anaphylaxis. Vigorous physical exercise (OR: 1.5, CI: 1.3-1.7), male sex (OR: 1.2, CI: 1.1-1.3), and psychological burden (OR: 1.4, CI: 1.2-1.6) were more often associated with severe reactions. Additionally, intake of beta-blockers (OR: 1.9, CI: 1.5-2.2) and ACE-I (OR: 1.28, CI: 1.05, 1.51) in temporal proximity to allergen exposition was identified as an important factor in logistic regression analysis. CONCLUSION: Our data suggest it may be possible to identify patients who require intensified preventive measures due to their relatively higher risk for severe anaphylaxis by considering endogenous and exogenous factors.

A Case of Cervical Carcinoid and Review of the Literature.

Uterine cervix carcinoids are distinct neuroendocrine cervical tumors, representing a comparatively small percentage of them. These well-differentiated neoplasms are far less prevalent than small- and large-cell carcinomas, characterized by a more favorable biological course. We report a case of a 43-year-old woman with a nonmetastatic cervical carcinoid, managed with radical hysterectomy. She still remains free of disease. Scant reports in the literature prohibit any reliable prediction of cervical carcinoid prognosis. Thus, prompt identification of the disease and subsequent therapeutic intervention could alter the final outcome.

Multi-morbidities of allergic rhinitis in adults: European Academy of Allergy and Clinical Immunology Task Force Report.

This report has been prepared by the European Academy of Allergy and Clinical Immunology Task Force on Allergic Rhinitis (AR) comorbidities. The aim of this multidisciplinary European consensus document is to highlight the role of multimorbidities in the definition, classification, mechanisms, recommendations for diagnosis and treatment of AR, and to define the needs in this neglected area by a literature review. AR is a systemic allergic disease and is generally associated with numerous multi-morbid disorders, including asthma, eczema, food allergies, eosinophilic oesophagitis (EoE), conjunctivitis, chronic middle ear effusions, rhinosinusitis, adenoid hypertrophy, olfaction disorders, obstructive sleep apnea, disordered sleep and consequent behavioural and educational effects. This report provides up-to-date usable information to: (1) improve the knowledge and skills of allergists, so as to ultimately improve the overall quality of patient care; (2) to increase interest in this area; and (3) to present a unique contribution to the field of upper inflammatory disease.

Immunohistochemical expression of MTA1 and MTA3 in placental tissue of normal and preeclamptic pregnancies.

PURPOSE: The aim of this preliminary study was to evaluate and compare MTAI andMTA3 antigens expression in normal and preeclamptic placentas in order to demonstrate their possible functional relationship during pathogenesis of preeclampsia. MATERIALS AND METHODS: A series including 20 paraffin-embedded placentas, ten of which originated from normal patients and ten from preeclamptic patients, that were examined by immunohistochemistry using the polyclonal antibodies MTAI and MTA3. RESULTS: The results of this study showed a positive nuclear staining reaction against MTAI and MTA3 in both normal and preeclamptic placentas. However, in preeclamptic chorionic villi, cytotrophoblast and syncytiotrophoblast cells demonstrated increased expression of MTAI and MTA3 than in normal ones. CONCLUSION: The present observations indicate a potential role for MTAI and MTA3 for normal human placental function, playing an essential role in the pathogenesis of preeclampsia. Nevertheless, the precise relationship between these antigens' expression and pathological pregnancies remains to be elucidated.

A comparative immunohistochemical investigation of the consequences of chorioamnionitis on the developing human fetal spleen.

INTRODUCTION: The objective of this study was to determine the effects of chorioamnionitis on the extracellular matrix (ECM) structural glycoproteins of the developing human fetal spleen, and their influence on the haematopoiesis and spleen immune system compared to controls. MATERIALS AND METHODS: After elective induced pregnancy termination due to chorioamnionitis or voluntary abortion, paraffin-embedded specimens from the spleen and respective fetal membranes of 90 fetuses were investigated by immunohistochemistry for presence of ECM structural glycoproteins, haematopoietic, and lymphoid cells. Conventional histological examination of the relative fetal membranes was performed. RESULTS: The present results showed no quantitative variations in the expression of the ECM glycoproteins and haematopoietic lineages of the fetal spleen parenchyma at the end of first trimester (in both groups). At the second and third trimesters, acute chorioamnionitis showed a decreased number of the aforementioned proteins, with an increase of granulopoiesis and CD34 progenitor/stem haematopoietic cells. The immune system of the spleen during the third trimester demonstrated a decrease of both B and T lymphocytes, in comparison with controls. CONCLUSIONS: These results suggest that toxins and cytokines generated during chorioamnionitis, seem to influence ECM structural glycoproteins synthesis and release in fetal splenic parenchyma by reducing them, and probably cause further disorders of haematopoiesis and lymphopoiesis.

Impaired virus replication and decreased innate immune responses to viral infections in nasal epithelial cells from patients with allergic rhinitis.

The aim of this study was to assess the immune response to parainfluenza virus type 3 (PIV3), rhinovirus 1B (RV1B) and intracellular Toll-like receptors (TLR) agonists in nasal epithelial cells (NECs) from patients with allergic rhinitis and healthy controls. NECs were obtained from eight patients with allergic rhinitis (AR) and 11 non-atopic healthy controls (HC) by nasal scraping, grown to confluence and exposed to PIV3, RV1B infection or TLR-3 and TLR-7/8 agonists. Interferon (IFN)-λ1, IFN-α, IFN-ß and regulated on activation, normal T expressed and secreted (RANTES) release into the cell culture supernatants was assessed at 8, 24 and 48 h upon infection or 8 and 24 h after stimulation with poly(I:C) and R848. mRNA levels of IFNs, RANTES, interferon regulatory transcription factor (IRF)3, IRF7 and viral gene copy number were determined using real-time polymerase chain reaction (RT-PCR). PIV3 but not RV1B replication 48 h after infection was significantly lower (P < 0·01) in NECs from AR patients compared to HC. PIV3 infection induced significantly less IFN-λ1 (both protein and mRNA) in NECs from AR compared to HC. IFN-ß mRNA expression and RANTES protein release and mRNA expression tended to be smaller in AR compared HC cells in response to both viruses. Stimulation with TLR-3 agonist [poly (I:C)] induced similar IFN-λ1 and RANTES generation in AR and HC subjects. Viral infections in NECs induced IRF7 expression, which correlated with IFN and RANTES expression. These data suggest that virus proliferation rates and the immune response profile are different in nasal epithelial cells from patients with allergic rhinitis compared to healthy individuals.

Human rhinoviruses enter and induce proliferation of B lymphocytes.

BACKGROUND: Human rhinoviruses (HRVs) are one of the main causes of virus-induced asthma exacerbations. Infiltration of B lymphocytes into the subepithelial tissue of the lungs has been demonstrated during rhinovirus infection in allergic individuals. However, the mechanisms through which HRVs modulate the immune responses of monocytes and lymphocytes are not yet well described. OBJECTIVE: To study the dynamics of virus uptake by monocytes and lymphocytes, and the ability of HRVs to induce the activation of in vitro-cultured human peripheral blood mononuclear cells. METHODS: Flow cytometry was used for the enumeration and characterization of lymphocytes. Proliferation was estimated using 3 H-thymidine or CFSE labeling and ICAM-1 blocking. We used bead-based multiplex assays and quantitative PCR for cytokine quantification. HRV accumulation and replication inside the B lymphocytes was detected by a combination of in situ hybridization (ISH), immunofluorescence, and PCR for positive-strand and negative-strand viral RNA. Cell images were acquired with imaging flow cytometry. RESULTS: By means of imaging flow cytometry, we demonstrate a strong and quick binding of HRV types 16 and 1B to monocytes, and slower interaction of these HRVs with CD4+ T cells, CD8+ T cells, and CD19+ B cells. Importantly, we show that HRVs induce the proliferation of B cells, while the addition of anti-ICAM-1 antibody partially reduces this proliferation for HRV16. We prove with ISH that HRVs can enter B cells, form their viral replication centers, and the newly formed virions are able to infect HeLa cells. In addition, we demonstrate that similar to epithelial cells, HRVs induce the production of pro-inflammatory cytokines in PBMCs. CONCLUSION: Our results demonstrate for the first time that HRVs enter and form viral replication centers in B lymphocytes and induce the proliferation of B cells. Newly formed virions have the capacity to infect other cells (HeLa). These findings indicate that the regulation of human rhinovirus-induced B-cell responses could be a novel approach to develop therapeutics to treat the virus-induced exacerbation of asthma.

Respiratory hypersensitivity reactions to NSAIDs in Europe: the global allergy and asthma network (GA2 LEN) survey.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent drugs inducing hypersensitivity reactions. The aim of this analysis was to estimate the prevalence of NSAID-induced respiratory symptoms in population across Europe and to assess its association with upper and lower respiratory tract disorders. METHODS: The GA2 LEN survey was conducted in 22 centers in 15 European countries. Each of 19 centers selected random samples of 5000 adults aged 15-74 from their general population, and in three centers (Athens, Munich, Oslo), a younger population was sampled. Questionnaires including questions about age, gender, presence of symptoms of asthma, allergic rhinitis, chronic rhinosinusitis, smoking status, and history of NSAID-induced hypersensitivity reactions were sent to participants by mail. Totally, 62 737 participants completed the questionnaires. RESULTS: The mean prevalence of NSAID-induced dyspnea was 1.9% and was highest in the three Polish centers [Katowice (4.9%), Krakow (4.8%), and Lodz (4.4%)] and lowest in Skopje, (0.9%), Amsterdam (1.1%), and Umea (1.2%). In multivariate analysis, the prevalence of respiratory reactions to NSAIDs was higher in participants with chronic rhinosinusitis symptoms (Odds Ratio 2.12; 95%CI 1.78-2.74), asthma symptoms in last 12 months (2.7; 2.18-3.35), hospitalization due to asthma (1.53; 1.22-1.99), and adults vs children (1.53; 1.24-1.89), but was not associated with allergic rhinitis. CONCLUSION: Our study documented significant variation between European countries in the prevalence of NSAID-induced respiratory hypersensitivity reactions, and association with chronic airway diseases, but also with environmental factors.

Oral immunotherapy with low allergenic hydrolysed egg in egg allergic children.

BACKGROUND: A major drawback of oral immunotherapy for food allergy is the possibility of severe side-effects. We assessed both safety and efficacy of a low allergenic hydrolysed egg (HydE) preparation used in a double-blind placebo-controlled randomized study in egg allergic children. METHODS: In a pilot multicentre study, 29 egg allergic patients (aged 1-5.5 years) were administered daily for 6 months 9 g HydE or placebo in a blinded, randomized manner. Safety was verified by oral food challenge to assess tolerance towards HydE at the start and efficacy by an open oral food challenge (OFC, primary outcome) at the end. Additionally, changes in basophil activation and specific IgE and IgG4 were assessed. RESULTS: All egg allergic patients randomized to HydE (n = 15) tolerated the full dose at day 1 and received the maintenance dose from the start at home. No statistically significant difference was observed on the final OFC (36% and 21% had a negative OFC in the treatment and placebo groups, respectively). Specific IgG4 levels increased, while both CD203c+ and CD63+ basophils decreased significantly more over time in the treatment than in the placebo group. CONCLUSIONS: HydE can be regarded as a safe, low allergenic product to use in children allergic to egg. Although not significant, HydE given for 6 months increased numerically the proportion of patients becoming tolerant to egg. HydE induced a modulation of the immune response towards better tolerance. A longer treatment period and/or a higher dose may improve the clinical outcome and should be evaluated.

Clinical contraindications to allergen immunotherapy: an EAACI position paper.

Clinical indications for allergen immunotherapy (AIT) in respiratory and Hymenoptera venom allergy are well established; however, clinical contraindications to AIT are not always well documented. There are some discrepancies when classifying clinical contraindications for different forms of AIT as 'absolute' or 'relative'. EAACI Task Force on 'Contraindications to AIT' was created to evaluate and review current literature on clinical contraindications, and to update recommendations for both sublingual and subcutaneous AIT for respiratory and venom immunotherapy. An extensive review of the literature was performed on the use of AIT in asthma, autoimmune disorders, malignant neoplasias, cardiovascular diseases, acquired immunodeficiencies and other chronic diseases (including mental disorders), in patients treated with ß-blockers, ACE inhibitors or monoamine oxidase inhibitors, in children under 5 years of age, during pregnancy and in patients with poor compliance. Each topic was addressed by the following three questions: (1) Are there any negative effects of AIT on this concomitant condition/disease? (2) Are more frequent or more severe AIT-related side-effects expected? and (3) Is AIT expected to be less efficacious? The evidence, for the evaluation of these clinical conditions as contraindications, was limited, and most of the conclusions were based on case reports. Based on an extended literature research, recommendations for each medical condition assessed are provided. The final decision on the administration of AIT should be based on individual evaluation of any medical condition and a risk/benefit assessment for each patient.

Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer.

BACKGROUND: Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy. PATIENTS AND METHODS: This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8-10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS. RESULTS: Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8-10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (≥10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266). CONCLUSIONS: ctDNA is detectable in a high proportion of treatment naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.

Risk factors associated with adverse outcome following extracorporeal life support: analysis from 360 consecutive patients.

OBJECTIVE: Risk factors for adverse outcome after extracorporeal life support (ECLS) are yet to be defined. For this purpose, we reviewed our institutional data from more than a decade, focusing on patients with ECLS. METHODS: Between December 2001 and June 2013, 360 consecutive cardiac surgical patients received ECLS for post-cardiotomy cardiogenic shock, with high mortality risk despite optimal conventional therapy. Patient demographics, clinical characteristics, ECLS-related morbidity, as well as in-hospital and long-term mortality were analysed. Multivariate logistic regression analysis was performed to identify independent predictors of adverse outcome (failed ECLS weaning, in-hospital mortality). RESULTS: The mean age was 62±17 years, 76% were male and the mean preoperative ejection fraction was 35±16%. ECLS was established through peripheral (90%) or central thoracic cannulation. The mean duration of ECLS was 7±1 days. Intra-aortic balloon pumps were implanted in 22% of the patients. ECLS weaning was successful in 58% and 30% could be discharged from hospital. The main cause of death was sepsis (69%). Overall, major cerebrovascular events occurred in 12% (bleeding 3%, embolic 9%), limb ischaemia in 13%, gastrointestinal complications in 16% and renal replacement therapy in 61%. Independent risk factors for adverse outcome were prior cardiorespiratory resuscitation (OR: 4.1, 95%CI: 0.34-4.21, p=0.04), pH <7.1 (OR: 2.8, 95%CI: 0.45-3.28, p=0.01), serum lactate >120 mg/dL (OR: 2.6, 95%CI: 0.75-2.96, p< 0.01), norepinephrine dosage >0.5 µg/kg/min (OR: 2.4, 95%CI: 0.35-2.92, p=0.02) and age >75 years (OR: 2.0, 95%CI: 0.41-2.88, p=0.02). Kaplan Meier estimates for long-term survival were 26±3% at one year and 22±2% at five years. CONCLUSION: ECLS therapy offers one-year survival to one quarter of patients with an otherwise fatal prognosis. Procedural mortality is low and morbidity at the implantation site typically moderate. Thus, prolonged metabolic deterioration in combination with high-dose vasopressor support prior to ECLS therapy should be avoided, particularly in younger patients.

Is removal of calcium bar during mitral valve surgery safe? Long-term clinical outcome of 109 consecutive patients.

AIM: Risk factors for adverse outcome after decalcification and patch-reconstruction of the mitral annulus during mitral valve surgery are yet to be defined. For this purpose and for the report of long term results we reviewed our institutional data from over 10 years of mitral valve surgery in the presence of mitral annulus calcification. METHODS: A total of 109 consecutive patients with a mean age of 66.4±14 years (Mean logistic EURO-Score: 18.6%) underwent mitral valve surgery in the presence of extensive calcification of mitral annulus between 1996 and 2008. After decalcification and patch-reconstruction of the mitral annulus, mitral valve repair was performed in 53 cases (49%) and the remaining 56 patients (51%) received a mitral valve replacement. Multivariate logistic regression analysis was performed to identify independent predictors of adverse outcome. RESULTS: Inhospital-mortality was 8.3% and the actuarial survival rate at 8 years 76.2%. Echocardiographic follow up was complete. 65 survivors (94.5%) showed none or only trivial mitral valve insufficiency. The freedom of reoperation at 8 years was 91.8%. We found hypertension, diabetes mellitus, age older than 65 years, NYHA class IV, end stage renal failure, failure to preserve the subvalvular apparatus as well as concomitant aortic valve replacement to be associated with a significant increase of early or/and late mortality. CONCLUSION: Despite the complexity of this pathology, decalcification and patch-reconstruction of the mitral annulus during mitral valve surgery can be performed with low technical risk and acceptable long-term results.

A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations.

BACKGROUND: Melanoma cell lines treated with decitabine show upregulation of cancer antigens, and interferon-α upregulates MHC Class I antigens in cancer cells, leading to enhanced T-cell recognition and T-cell mediated tumor apoptosis. We evaluated the synergy between the hypomethylating effects of decitabine and the immunomodulatory effects of interferon in a combination regimen administered to advanced melanoma patients in a phase 1 trial. METHODS: Patients with one prior systemic therapy were eligible. Using a modified 3 + 3 design, patients received escalating doses of decitabine and pegylated interferon α-2b (PEG-IFN) during every 28-day treatment cycle. Global DNA methylation was measured on days 1 and 5 of cycles 1 and 3. Cytokine profiling and quantification of T-cell subpopulations by FACS were performed at baseline and cycle 3. RESULTS: Seventeen patients were assigned to one of four dose levels. Decitabine 15 mg/m2/d + PEG-IFN 3 µg/kg was the maximum tolerated dose (MTD). Grade 3/4 cytopenias were seen across all dose levels: anemia (1), neutropenia (7), and thrombocytopenia (2). One patient remained progression-free for 37 weeks. The other 16 patients progressed at or before 12 weeks. Median overall survival was 39 weeks. Hypomethylation was seen at all dose levels. Due to treatment-induced lymphocytopenia, absolute changes in T-cell populations post-treatment were too small to be meaningfully interpreted. CONCLUSIONS: The response to this combination regimen was characterized by significant myelosuppression, particularly neutropenia. Although disappointing efficacy and slow accrual led to early closure of the trial, hypomethylation showed pharmacodynamic evidence of a therapeutic effect of decitabine at all dose levels.

Simultaneous manifestation of pleural effusion and acute renal failure associated with dasatinib: a case report.

WHAT IS KNOWN AND OBJECTIVE: Dasatinib is a novel second-generation inhibitor of multiple tyrosine kinases, indicated for the treatment for Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy. Although dasatinib is a potent, efficacious and generally well-tolerated drug, patients are also subject to various adverse effects. The most common pulmonary-related side effect is pleural effusion (PE). Renal failure has been reported rarely as a side effect of dasatinib treatment. We report the first case of a patient with imatinib-resistant CML who developed PE and acute renal failure (ARF) simultaneously, after being placed on dasatinib therapy. CASE SUMMARY: We report a 58-year-old female dasatinib-treated patient with Ph+ chronic phase CML who was admitted to our hospital due to persisted dyspnoea and fever. After reviewing the laboratory and clinical findings, we determined our patient as having simultaneously ARF and PE related to dasatinib therapy. Dasatinib was discontinued, and after 10 days of treatment with ampicillin-sulbactam, allopurinol, amlodipine, furosemide and methylprednisolone, she was discharged home effusion free and with ameliorated renal function. WHAT IS NEW AND CONCLUSION: PE is the most common extra-haematological toxicity observed during dasatinib treatment whose pathogenesis is still unclear. A possible role of cytokines, such as platelet-derived growth factor receptor (PDGFR)-ß and vascular endothelial growth factor (VEGF), in causing endothelial permeability has been suggested. The aetiology of renal failure is also unclear in these patients, but two different possible mechanisms have been suggested such as tumour lysis syndrome and toxic tubular damage. In conclusion, here we describe the first case of simultaneous manifestation of PE and ARF associated with dasatinib. Thus, in patients treated with tyrosine kinase inhibitors, especially those with predisposing nephrological or haematological factors, serum creatinine levels should be monitored routinely.