Publications by authors named "Giuseppe Colucci"

121 Publications

Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) 2.0.

Int J Mol Sci 2022 Jul 18;23(14). Epub 2022 Jul 18.

Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.

Nonalcoholic fatty liver disease (NAFLD) is among the most common liver diseases worldwide, affecting up to 20-30% of the human population [...].
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http://dx.doi.org/10.3390/ijms23147894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319880PMC
July 2022

Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial.

Lancet Haematol 2022 Aug 30;9(8):e585-e593. Epub 2022 Jun 30.

Department of Angiology, University Hospital Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland.

Background: COVID-19 is a viral prothrombotic respiratory infection. Heparins exert antithrombotic and anti-inflammatory effects, and might have antiviral properties. We aimed to investigate whether thromboprophylaxis with enoxaparin would prevent untoward hospitalisation and death in symptomatic, but clinically stable outpatients with COVID-19.

Methods: OVID was a randomised, open-label, parallel-group, investigator-initiated, phase 3 trial and was done at eight centres in Switzerland and Germany. Outpatients aged 50 years or older with acute COVID-19 were eligible if they presented with respiratory symptoms or body temperature higher than 37·5°C. Eligible participants underwent block-stratified randomisation (by age group 50-70 vs >70 years and by study centre) in a 1:1 ratio to receive either subcutaneous enoxaparin 40 mg once daily for 14 days versus standard of care (no thromboprophylaxis). The primary outcome was a composite of any untoward hospitalisation and all-cause death within 30 days of randomisation. Analysis of the efficacy outcomes was done in the intention-to-treat population. The primary safety outcome was major bleeding. The study was registered in ClinicalTrials.gov (NCT04400799) and has been completed.

Findings: At the predefined formal interim analysis for efficacy (50% of total study population), the independent Data Safety Monitoring Board recommended early termination of the trial on the basis of predefined statistical criteria having considered the very low probability of showing superiority of thromboprophylaxis with enoxaparin for the primary outcome under the initial study design assumptions. Between Aug 15, 2020, and Jan 14, 2022, from 3319 participants prescreened, 472 were included in the intention-to-treat population and randomly assigned to receive enoxaparin (n=234) or standard of care (n=238). The median age was 57 years (IQR 53-62) and 217 (46%) were women. The 30-day risk of the primary outcome was similar in participants allocated to receive enoxaparin and in controls (8 [3%] of 234 vs 8 [3%] of 238; adjusted relative risk 0·98; 95% CI 0·37-2·56; p=0·96). All hospitalisations were related to COVID-19. No deaths were reported during the study. No major bleeding events were recorded. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group.

Interpretation: These findings suggest thromboprophylaxis with enoxaparin does not reduce early hospitalisations and deaths among outpatients with symptomatic COVID-19. Futility of the treatment under the initial study design assumptions could not be conclusively assessed owing to under-representation of older patients and consequent low event rates.

Funding: SNSF (National Research Programme COVID-19 NRP78: 198352), University Hospital Zurich, University of Zurich, Dr-Ing Georg Pollert (Berlin), Johanna Dürmüller-Bol Foundation.
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http://dx.doi.org/10.1016/S2352-3026(22)00175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243568PMC
August 2022

Clinical Evaluation of Plasma Separation Cards as a Tool to Collect, Store, and Test Blood Samples for Hepatitis B and C Serological Markers.

Clin Chem 2021 12;68(1):214-217

Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: The plasma separation card (PSC) is a new device for collecting finger-pricking-derived small amount of blood in a solid support that is stable at room temperature and can be archived, mailed, and processed at a later time. This tool can facilitate screening at risk populations located in rural areas without local health care infrastructures. We evaluated the performance of PSC in the collection and preparation of blood samples for the determination of hepatitis B and C serological markers.

Methods: Blood obtained from 334 consecutive patients referred for the detection of hepatitis B surface antigens (HBsAg), hepatitis B surface antibodies (anti-HBs) and hepatitis C antibodies (anti-HCV) was analyzed in parallel using standard (STD) and PSC-based sample collection and preparation procedures. Results obtained from STD or PSC processed samples were compared for their detection rate and correlation.

Results: Using STD, we detected 5 samples positive for HBsAg, 150 for anti-HBs, and 23 for anti-HCV with a rate of concordance with PSC of 100%, 100%, and 91% respectively. The 100% concordance observed for anti-HBs was based on a cutoff of 2.6 IU/L for PSC-derived sample corresponding to the 10 IU/L threshold associated with immunity to hepatitis B. STD and PSC showed a good correlation (R2 = 0.85) in the detection of anti-HBs titers. The 2 anti-HCV PSC negative samples had no detectable viremia.

Conclusions: These data confirm the utility of PSC as a tool to support viral hepatitis screening programs in rural areas lacking local clinical infrastructures and testing facilities.
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http://dx.doi.org/10.1093/clinchem/hvab170DOI Listing
December 2021

Italian migrants study: An HCV and HBV micro-elimination pilot project.

Clin Res Hepatol Gastroenterol 2022 03 16;46(3):101852. Epub 2021 Dec 16.

EASL International Liver Foundation (EILF), Geneve, Switzerland.

Background: Migrants represent a key target population for viral hepatitis micro-elimination programs and are important targets for specific prevention, screening and treatment programs.

Aims: To raise awareness on viral hepatitis among migrants and key stakeholders, assess the prevalence of HBV and HCV among migrants, and determine an optimal and scalable viral hepatitis screening and treatment protocol.

Material And Methods: Unselected, consecutive migrants reaching the costs of Italy were screened for HBV, HCV, HDV and HIV markers. Anagraphic and anamnestic information were used to identify viral hepatitis endemic hotspots in the countries of birth or transit. Personal data, including migration route, test results and treatment, were collected and stored in a dedicated database RESULTS: 362 patients were recruited in 2019; median age was 28 years, 71% were male. Most of the patients were African (54%) or Asian (40%). 49% positive for at least one HBV marker: 2.2% HBsAg (asymptomatic carriers with low viremia); 10.6% anti-HBs; 28.5% anti-HBs and anti-HBc, 1.7% anti-HCV, 0.6% anti-HIV, with low or undetectable viral load. Libya was the nexus shared by most of the positive, reactive cases. HCV and HIV markers were only found in migrants already resident in Italy for more than 6-12 months.

Conclusion: Low to moderate prevalence of hepatitis B markers were observed in African and Asian first arrival migrants. Migrants positive for HCV and HIV likely acquired the infection after arrival in Italy, suggesting migrants are at risk of contracting viral infections once in Italy, highlighting the importance of ensuring access to prevention for migrant communities.
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http://dx.doi.org/10.1016/j.clinre.2021.101852DOI Listing
March 2022

The CCR5 and CXCR3 Pathways in Hepatitis C Virus Liver Transplanted Recipients Treated by a Direct Antiviral Agent Regimen: Informative Kinetics Profiles.

Viral Immunol 2021 10 12;34(8):542-551. Epub 2021 Jul 12.

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy.

The CC5 and CXC3 chemokines (CK) pathways are involved in the pathogenesis and outcome of several disease states, including chronic hepatitis C (CHC). The kinetics of Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) (CCL5) and IP-10 (CXCL10) during direct-acting antivirals (DAA) treatment was retrospectively analyzed in 18 liver transplant recipients (LT-R) compared with 20 patients with CHC and 49 healthy controls (HC). CK levels were determined at baseline, week 4, end of treatment, 24 weeks post-treatment (sustained virological response [SVR]), and later-on during follow-up (FU), 12 and 24 months post-DAA. At baseline, median RANTES levels were higher in HC than in both LT-R ( > 0.01) and CHC ( > 0.01), whereas IP-10 levels were higher in LT-R and CHC than in HC ( > 0.05 and  = 0.01), respectively. Mean RANTES values increased during DAA therapy to peak at SVR and FU with significantly higher levels than at baseline in LT-R ( < 0.01) and in CHC, but only at FU ( < 0.003). A subsequent return to baseline or lower levels was observed at extended FU. On the contrary, IP-10 values showed a significant decrease from baseline to SVR and FU in both LT-R ( < 0.03) and CHC ( < 0.01). RANTES profiles during the first 4 weeks of DAA treatment showed an increase or decrease from baseline according to baseline RANTES levels. CCR5 genotyping in LT-R showed the presence of 1 homozygous Δ32/Δ32 and 2 heterozygous WT/Δ32 haplotypes with a prevalence of 5.5% and 11.1%, respectively. In conclusion, although IP-10 showed the expected kinetics, the CC5 pathway appears extensively altered during CHC infection: monitoring these patients may be indicated as they may be at risk of other infections or immune-mediated disorders.
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http://dx.doi.org/10.1089/vim.2021.0035DOI Listing
October 2021

A case of CIDP concurrent with MGUS IgG kappa responsive to autologous stem cell transplantation.

Neurol Neuroimmunol Neuroinflamm 2020 11 15;7(6). Epub 2020 Sep 15.

From the Service of Hematology (G.C., C.M.), Clinica Luganese Moncucco, Lugano; Faculty of Medicine (G.C., C.G.), University of Basel; Department of Medical Oncology (T.P.) and Department of Hematology and Central Hematology Laboratory (U.B.), Inselspital, University Hospital and University of Bern; Neurocenter of Southern Switzerland (C.Z., C.G.), Ospedale Regionale di Lugano; and Faculty of Biomedical Sciences (C.Z., C.G.), Università della Svizzera Italiana (USI), Lugano, Switzerland.

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http://dx.doi.org/10.1212/NXI.0000000000000888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524574PMC
November 2020

Enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease-2019 (the OVID study): a structured summary of a study protocol for a randomized controlled trial.

Trials 2020 Sep 9;21(1):770. Epub 2020 Sep 9.

Clinic of Angiology, University Hospital Zurich, Zurich, Switzerland.

Objectives: The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation.

Trial Design: The OVID study is conducted as a multicentre open-label superiority randomised controlled trial.

Participants: Inclusion Criteria 1. Signed patient informed consent after being fully informed about the study's background. 2. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment. 3. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature >37.5° C. 4. Ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves 5. Ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. 6. Ability to walk from car to study centre or reach it by wheelchair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. 7. Ability to self-administer prefilled enoxaparin injections after instructions received at the study centre or availability of a person living with the patient to administer enoxaparin. Exclusion Criteria 1. Any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior venous thromboembolism (VTE), acute confirmed symptomatic VTE, acute coronary syndrome. 2. Anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis:  a. Any of the following events occurring in the prior 30 days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke,  b. previous VTE,  c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past 6 months, or recurrent, or metastatic, or inoperable. 3. Any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 30 days prior to randomization or sign of acute bleeding. 4. Intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial haemorrhage. 5. Haemoglobin <8 g/dL and platelet count <50 x 10 cells/L confirmed by recent laboratory test (<90 days). 6. Subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy. 7. Severe renal insufficiency (baseline creatinine clearance <30 mL/min calculated using the Cockcroft-Gault formula) confirmed by recent laboratory test (<90 days). 8. Contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity. 9. Current use of dual antiplatelet therapy. 10. Participation in other interventional studies over the past 30 days. 11. Non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment. 12. Cognitive impairment and/or inability to understand information provided in the study information. Patient enrolment will take place at seven Swiss centres, including five university hospitals and two large cantonal hospitals.

Intervention And Comparator: Patients randomized to the intervention group will receive subcutaneous enoxaparin at the recommended dose of 4,000 IU anti-Xa activity (40 mg/0.4 ml) once daily for 14 days. Patients randomized to the comparator group will receive no anticoagulation.

Main Outcomes: Primary outcome: a composite of any hospitalization or all-cause death occurring within 30 days of randomization.

Secondary Outcomes: (i) a composite of cardiovascular events, including deep vein thrombosis (including catheter-associated), pulmonary embolism, myocardial infarction/myocarditis, arterial ischemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischemic stroke within 14 days, 30 days, and 90 days of randomization; (ii) each component of the primary efficacy outcome, within 14 days, 30 days, and 90 days of randomization; (iii) net clinical benefit (accounting for the primary efficacy outcome, composite cardiovascular events, and major bleeding), within 14 days, 30 days, and 90 days of enrolment; (iv) primary efficacy outcome, within 14 days, and 90 days of enrolment; (v) disseminated intravascular coagulation (ISTH criteria, in-hospital diagnosis) within 14 days, 30 days, and 90 days of enrolment.

Randomisation: Patients will undergo block stratified randomization (by age: 50-70 vs. >70 years; and by study centre) with a randomization ratio of 1:1 with block sizes varying between 4 and 8. Randomization will be performed after the signature of the informed consent for participation and the verification of the eligibility criteria using the electronic data capture software (REDCAP, Vanderbilt University, v9.1.24).

Blinding (masking): In this open-label study, no blinding procedures will be used.

Numbers To Be Randomised (sample Size): The sample size calculation is based on the parameters α = 0.05 (2-sided), power: 1-β = 0.8, event rate in experimental group, pexp = 0.09 and event rate in control group, pcon = 0.15. The resulting total sample size is 920. To account for potential dropouts, the total sample size was fixed to 1000 with 500 patients in the intervention group and 500 in the control group.

Trial Status: Protocol version 1.0, 14 April 2020. Protocol version 3.0, 18 May 2020 Recruiting start date: June 2020. Last Patient Last Visit: March 2021.

Trial Registration: ClinicalTrials.gov Identifier: NCT04400799 First Posted: May 26, 2020 Last Update Posted: July 16, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04678-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479300PMC
September 2020

The complement system in liver diseases: Evidence-based approach and therapeutic options.

J Transl Autoimmun 2019 Dec 18;2:100017. Epub 2019 Sep 18.

Labormedizinisches Zentrum Dr. Risch, Waldeggstrasse 37, CH-3097, Liebefeld bei Bern, Switzerland.

Complement is usually seen to largely originate from the liver to accomplish its tasks systemically - its return to the production site has long been underestimated. Recent progress in genomics, therapeutic effects on complement, standardised possibilities in medical laboratory tests and involvement of complosome brings the complement system with its three major functions of opsonization, cytolysis and phagocytosis back to liver biology and pathology. The LOINC™ system features 20 entries for the C3 component of complement to anticipate the application of artificial intelligence data banks algorythms of which are fed with patient-specific data connected to standard lab assays for liver function. These advancements now lead to increased vigilance by clinicians. This reassessment article will further elucidate the distribution of synthesis sites to the three germ layer-derived cell systems and the role complement now known to play in embryogenesis, senescence, allotransplantation and autoimmune disease. This establishes the liver as part of the gastro-intestinal system in connection with nosological entities never thought of, such as the microbiota-liver-brain axis. In neurological disease etiology infectious and autoimmune hepatitis play an important role in the context of causative reactive complement activation. The mosaic of autoimmunity, i.e. multiple combinations of the many factors producing varying clinical pictures, leads to the manifold facets of liver autoimmunity.
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http://dx.doi.org/10.1016/j.jtauto.2019.100017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388403PMC
December 2019

Metronomic oral chemotherapy with cyclophosphamide plus capecitabine combined with trastuzumab (HEX) as first line therapy of HER-2 positive advanced breast cancer: A phase II trial of the Gruppo Oncologico Italia Meridionale (GOIM).

Breast 2020 Oct 5;53:18-22. Epub 2020 Jun 5.

Medical Oncology, Antonio Perrino Hospital, Brindisi, Italy.

Background: The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC.
Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied.

Results: Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1-98). ORR was 56.7% (95% CI, 44.1-68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3-4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt.

Conclusions: Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment.
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http://dx.doi.org/10.1016/j.breast.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375616PMC
October 2020

Thrombophilia screening revisited: an issue of personalized medicine.

J Thromb Thrombolysis 2020 May;49(4):618-629

Faculty of Medicine, University of Basel, Basel, Switzerland.

Clinical thrombophilia is the consequence of multiple gene and/or environment interactions. Thrombophilia screening requires a targeted patient with specific indication, in which a finding would have implications. Carrying out a thrombophilia examination in the physician's practice is often a cause of uncertainty and concern. The concerns begin in choosing the right patient to be examined, are associated with the time of investigation, with the choice of analysis, the test-material and with the correct interpretation of the results. Difficulties, which can influence the results, can occur with both organization and blood sampling. As common for any analysis, pre-analytical, analytical and post-analytical factors should be considered, as well as the possibility of false positive or false negative results. Finally, recommendation of correct therapeutic and prophylactic measures for the patient and his relatives is an additional focus. In this article we want to provide-on the basis of the evidence and personal experience-the theory of thrombophilia-investigation, the indications for testing, as well as practical recommendations for treatment options.
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http://dx.doi.org/10.1007/s11239-020-02090-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182628PMC
May 2020

Bevacizumab in Combination With Either FOLFOX-4 or XELOX-2 in First-line Treatment of Patients With Metastatic Colorectal Cancer: A Multicenter Randomized Phase II Trial of the Gruppo Oncologico dell'Italia Meridionale (GOIM 2802).

Clin Colorectal Cancer 2020 06 30;19(2):109-115. Epub 2020 Jan 30.

Medical Oncology Unit, Ospedale Garibaldi, Catania, Italy.

Introduction: Biweekly schedule of XELOX-2 (capecitabine plus oxaliplatin) showed interesting results in first-line therapy of patients with metastatic colorectal cancer (mCRC). Bevacizumab plus FOLFOX-4 (oxaliplatin, folinic acid, and infusional 5-fluorouracil) is among standard first-line treatment options in this setting. We performed a phase II randomized trial in order to evaluate the activity of bevacizumab plus either FOLFOX-4 or XELOX-2 in first-line therapy of patients with mCRC.

Materials And Methods: Patients with mCRC were randomized, in a 1:2 ratio, to first-line bevacizumab plus either FOLFOX-4 (Arm A), as calibration arm, or XELOX-2 (Arm B), up to 12 cycles. Patients without progression were further randomized to maintenance bevacizumab alone or with the same induction fluoropyrimidine. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival, overall survival, and toxicity. The study design was formally non-comparative, but exploratory comparison was performed.

Results: Forty-five patients were randomized in arm A and 87 in arm B with an ORR of 55.6% versus 48.3% (P = .43), respectively. After a median follow-up of 47.2 months, progression-free survival was 10.0 versus 9.9 months (hazard ratio, 0.96; 95% confidence interval, 0.65-1.41; P = .84) and overall survival was 29.8 versus 25.0 months (hazard ratio, 1.21; 95% confidence interval, 0.77-1.92; P = .41), respectively. The main grade 3 to 4 toxicities (% A/B) were: neutropenia 15/3 and nausea 9/5.

Conclusion: This exploratory analysis showed that biweekly XELOX-2 plus bevacizumab has a comparable ORR with FOLFOX-4 plus bevacizumab in patients with mCRC.
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http://dx.doi.org/10.1016/j.clcc.2020.01.003DOI Listing
June 2020

Combining micro-RNA and protein sequencing to detect robust biomarkers for Graves' disease and orbitopathy.

Sci Rep 2018 05 30;8(1):8386. Epub 2018 May 30.

Cardiff University, School of Medicine, Division of Infection & Immunity, Cardiff, UK.

Graves' Disease (GD) is an autoimmune condition in which thyroid-stimulating antibodies (TRAB) mimic thyroid-stimulating hormone function causing hyperthyroidism. 5% of GD patients develop inflammatory Graves' orbitopathy (GO) characterized by proptosis and attendant sight problems. A major challenge is to identify which GD patients are most likely to develop GO and has relied on TRAB measurement. We screened sera/plasma from 14 GD, 19 GO and 13 healthy controls using high-throughput proteomics and miRNA sequencing (Illumina's HiSeq2000 and Agilent-6550 Funnel quadrupole-time-of-flight mass spectrometry) to identify potential biomarkers for diagnosis or prognosis evaluation. Euclidean distances and differential expression (DE) based on miRNA and protein quantification were analysed by multidimensional scaling (MDS) and multinomial regression respectively. We detected 3025 miRNAs and 1886 proteins and MDS revealed good separation of the 3 groups. Biomarkers were identified by combined DE and Lasso-penalized predictive models; accuracy of predictions was 0.86 (±0:18), and 5 miRNA and 20 proteins were found including Zonulin, Alpha-2 macroglobulin, Beta-2 glycoprotein 1 and Fibronectin. Functional analysis identified relevant metabolic pathways, including hippo signaling, bacterial invasion of epithelial cells and mRNA surveillance. Proteomic and miRNA analyses, combined with robust bioinformatics, identified circulating biomarkers applicable to diagnose GD, predict GO disease status and optimize patient management.
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http://dx.doi.org/10.1038/s41598-018-26700-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976672PMC
May 2018

Standardized Management Protocol in Severe Postpartum Hemorrhage: A Single-Center Study.

Clin Appl Thromb Hemost 2018 Sep 18;24(6):884-893. Epub 2018 Apr 18.

1 Department of Hematology and Central Hematology Laboratory, University Hospital and University of Bern, Bern, Switzerland.

Severe postpartum hemorrhage (sPPH) is an obstetric emergency that needs prompt and effective therapy to reduce the risk of complications. In this study, women who developed sPPH (study cohort, n = 27) were treated according to a standardized management protocol prescribing sequential administration of uterotonic drugs, crystalloids, tranexamic acid, labile blood products, low-dose fibrinogen, and recombinant activated factor VII (rFVIIa). This group was compared to patients treated with different strategies during 2 preceding periods: an in-house guideline regulating the administration of rFVIIa (historical cohort 1, n = 20) and no specific guideline (historical cohort 2, n = 27). The management protocol was used over 33 months. The study cohort had a lower estimated blood loss ( P = .004) and required less red blood cell concentrates ( P = .007), fresh frozen plasma units ( P = .004), and platelet concentrates ( P = .020) compared to historical cohort 1 and historical cohort 2, respectively. The necessity of emergency postpartum hysterectomy was lower in the study group ( P = .012). In conclusion, in patients with sPPH treated with this standardized management protocol, we observed a decreased requirement of labile blood products and lower need to proceed to emergency postpartum hysterectomy.
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http://dx.doi.org/10.1177/1076029618758956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714733PMC
September 2018

Chemokine Receptor 5 Has No Major Role in the Severity of Hepatitis C Virus-Related Liver Damage.

Viral Immunol 2018 06 17;31(5):358-361. Epub 2018 Apr 17.

5 Traslational Research Center in Hepatology , Humanitas Research Hospital, Rozzano, Italy .

Total or partial inactivation of the chemokine 5 (CC5) pathway, as caused by the CC5 receptor Δ32 deletion (CCR5Δ32), may result in a profound manipulation of immune surveillance with significant consequences on the course and response to therapy of diverse human infections, including HIV. It has been postulated that in chronic hepatitis C (CHC), such a deregulation of CC5 pathway may compromise T cell-dependent antiviral immune responses, which in turn may favor viral persistence. To test this hypothesis, we investigated a cohort of 100 patients with CHC in whom 12 heterozygous and 1 homozygous CCR5Δ32 mutations were detected compared to 8 and none in 98 healthy controls (13% vs. 8.2%, p = 0.36). As patients with and without CCR5Δ32 mutations were similar in terms of histological activity (p = 0.84) and fibrosis stage (p = 0.20) as well as CCR5 tissue expression, we reasonably exclude that this CCR5 mutation is significantly involved in the pathogenesis of CHC and may be a potential therapeutic target. However, deleted patients showed a significantly higher response to pegylated interferon-alfa (PEG-IFN), suggesting that a dormant immune system is more readily primed by immunostimulation.
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http://dx.doi.org/10.1089/vim.2017.0190DOI Listing
June 2018

Prevalence of malnutrition in patients at first medical oncology visit: the PreMiO study.

Oncotarget 2017 Oct 10;8(45):79884-79896. Epub 2017 Aug 10.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology Sapienza, St. Andrea Hospital, Rome, Italy.

Background: In cancer patients, malnutrition is associated with treatment toxicity, complications, reduced physical functioning, and decreased survival. The Prevalence of Malnutrition in Oncology (PreMiO) study identified malnutrition or its risk among cancer patients making their first medical oncology visit. Innovatively, oncologists, not nutritionists, evaluated the nutritional status of the patients in this study.

Methods: PreMiO was a prospective, observational study conducted at 22 medical oncology centers across Italy. For inclusion, adult patients (>18 years) had a solid tumor diagnosis, were treatment-naive, and had a life expectancy >3 months. Malnutrition was identified by the Mini Nutritional Assessment (MNA), appetite status with a visual analog scale (VAS), and appetite loss with a modified version of Anorexia-Cachexia Subscale (AC/S-12) of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT).

Findings: Of patients enrolled (1,952), 51% had nutritional impairment; 9% were overtly malnourished, and 43% were at risk for malnutrition. Severity of malnutrition was positively correlated with the stage of cancer. Over 40% of patients were experiencing anorexia, as reported in the VAS and FAACT questionnaire. During the prior six months, 64% of patients lost weight (1-10 kg).

Interpretation: Malnutrition, anorexia, and weight loss are common in cancer patients, even at their first visit to a medical oncology center.
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http://dx.doi.org/10.18632/oncotarget.20168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668103PMC
October 2017

Epidemiology and characteristics of liver diseases in an immigrant population attending a nongovernmental organization (NGO) in Milan.

Dig Liver Dis 2017 Feb 24;49(2):229-230. Epub 2016 Dec 24.

Division of Gastroenterology-Hepatology, Fondazione Cà Granda-Policlinico, Milan, Italy.

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http://dx.doi.org/10.1016/j.dld.2016.12.021DOI Listing
February 2017

Thrombophilia Screening: Universal, Selected, or Neither?

Clin Appl Thromb Hemost 2017 Nov 4;23(8):893-899. Epub 2017 Jan 4.

2 Diagnostic Hematology, Department of Hematology, University Hospital Basel, Basel, Switzerland.

The utility of thrombophilia testing in clinical practice is still a matter of debate because studies have not shown a benefit in the reduction of recurrent venous thromboembolism (VTE) risk in patients with thrombosis, despite the clearly higher VTE risk for first thrombosis. Screening for thrombophilia is indicated in selected patients. Particularly in selected young patients, especially women of childbearing age, the knowledge of the genetic thrombophilic defect may help in specific situations to decrease the risk of VTE events. Avoidance of modifiable risk factors and/or prophylactic thromboembolic procedures may be evaluated in selected patients. A comprehensive workup including personal and familial history, clinical examination, and laboratory test results including hereditary thrombophilia remains helpful in assessing the cumulative risk and the management of this group of selected patients.
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http://dx.doi.org/10.1177/1076029616683803DOI Listing
November 2017

Prediction of Post-Weaning Fibrinogen Status during Cardiopulmonary Bypass: An Observational Study in 110 Patients.

PLoS One 2015 26;10(5):e0126692. Epub 2015 May 26.

Department of Anesthesiology and Pain Therapy, University Hospital Bern, Bern, Switzerland.

Background: After cardiac surgery with cardiopulmonary bypass (CPB), acquired coagulopathy often leads to post-CPB bleeding. Though multifactorial in origin, this coagulopathy is often aggravated by deficient fibrinogen levels.

Objective: To assess whether laboratory and thrombelastometric testing on CPB can predict plasma fibrinogen immediately after CPB weaning.

Patients/methods: This prospective study in 110 patients undergoing major cardiovascular surgery at risk of post-CPB bleeding compares fibrinogen level (Clauss method) and function (fibrin-specific thrombelastometry) in order to study the predictability of their course early after termination of CPB. Linear regression analysis and receiver operating characteristics were used to determine correlations and predictive accuracy.

Results: Quantitative estimation of post-CPB Clauss fibrinogen from on-CPB fibrinogen was feasible with small bias (+0.19 g/l), but with poor precision and a percentage of error >30%. A clinically useful alternative approach was developed by using on-CPB A10 to predict a Clauss fibrinogen range of interest instead of a discrete level. An on-CPB A10 ≤10 mm identified patients with a post-CPB Clauss fibrinogen of ≤1.5 g/l with a sensitivity of 0.99 and a positive predictive value of 0.60; it also identified those without a post-CPB Clauss fibrinogen <2.0 g/l with a specificity of 0.83.

Conclusions: When measured on CPB prior to weaning, a FIBTEM A10 ≤10 mm is an early alert for post-CPB fibrinogen levels below or within the substitution range (1.5-2.0 g/l) recommended in case of post-CPB coagulopathic bleeding. This helps to minimize the delay to data-based hemostatic management after weaning from CPB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126692PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444179PMC
January 2016

Cisplatin/Pemetrexed Followed by Maintenance Pemetrexed Versus Carboplatin/Paclitaxel/Bevacizumab Followed by Maintenance Bevacizumab in Advanced Nonsquamous Lung Cancer: The GOIM (Gruppo Oncologico Italia Meridionale) ERACLE Phase III Randomized Trial.

Clin Lung Cancer 2015 Jul 9;16(4):262-73. Epub 2014 Dec 9.

Gruppo Oncologico Italia Meridionale (GOIM), Bari, Italy.

Introduction: Cisplatin with pemetrexed (CP) and carboplatin with paclitaxel and bevacizumab (CbTB) are standard first-line treatments for patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC). Quality of life (QoL) is a key objective in the management of advanced NSCLC. Thus, effect on QoL could be an additional factor in the choice of treatment.

Patients And Methods: Patients with untreated stage IIIB/IV NS-NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomized to receive first-line chemotherapy with cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2), every 3 weeks, for 6 cycles followed by maintenance pemetrexed; or carboplatin area under the curve 6, paclitaxel 200 mg/m(2), and bevacizumab 15 mg/kg, every 3 weeks, for 6 cycles followed by maintenance bevacizumab. The primary end point was the difference in QoL between the 2 treatment arms after 12 weeks of maintenance, measured using the EuroQoL 5 Dimensions-Index (EQ5D-I) and EQ5D-visual analogue scale (EQ5D-VAS).

Results: One hundred eighteen patients were randomized to CP (n = 60) or CbTB (n = 58). Baseline characteristics were well balanced. The proportion of patients evaluable for the primary end point was lower than planned. After 12 weeks of maintenance, the difference between mean changes in EQ5D-I was 0.137, favoring CP (95% confidence interval [CI], -0.02 to 0.29, Wilcoxon P = .078), although not statistically significant; and the difference between mean changes in EQ5D-VAS was 0.97 (95% CI, -9.37 to 11.31, Wilcoxon P = .41).

Conclusion: Although the study was underpowered because of a small number of patients evaluable for the primary end point, QoL did not differ between treatment arms. Other factors such as comorbidities and schedule should be used when deciding on first-line treatment.
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http://dx.doi.org/10.1016/j.cllc.2014.12.002DOI Listing
July 2015

Biweekly combination of trastuzumab, docetaxel and gemcitabine for HER2-positive metastatic breast cancer: results of a Phase II GOIM study.

Future Oncol 2014 Apr;10(5):725-33

Division of Medical Oncology, Ospedale Antonio Perrino, Brindisi, Italy.

Aims: Clinical activity of chemotherapy plus trastuzumab in HER2 overexpressing advanced breast cancer has been documented. We report the activity and safety results of biweekly combination of trastuzumab, docetaxel and gemcitabine as first-line therapy in HER2-positive advanced breast cancer.

Patients & Methods: Patients were biweekly treated with trastuzumab (4 mg/kg), gemcitabine (1000 mg/m(2)) and docetaxel (50 mg/m(2)). The primary end point was overall response rate, secondary time to progression, clinical benefit rate (partial response plus complete response plus stable disease for ≥ 24 weeks) and tolerability.

Results: A total of 65 patients with HER2-positive advanced breast cancer have been enrolled. In total, 47 patients responded (73%; 95% CI, 60-84), 11 achieved complete response (17%; 95% CI: 8.9-28.7), 36 achieved partial response (56%; 95% CI: 43-68.6). The clinical benefit rate was 87.5% (95% CI: 77-94). Three patients (4.7%) experienced progressive disease. The median time to progression was 14.2 months (95% CI: 10.6-17.8), the median overall survival was 39.3 months and the 36-month survival rate was 55.5% (95% CI: 58-73). The worst toxicities were grade 3 neutropenia (12%), thrombocytopenia (6%) and diarrhea (6%). No cardiac toxicity was reported.

Conclusion: As first-line therapy, this combination allowed the delivery of polychemotherapy in association to targeted therapy, with clinical activity and mild toxicity. The promising results should be further explored in Phase III randomized clinical trials.
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http://dx.doi.org/10.2217/fon.13.186DOI Listing
April 2014

Decreased generation of procoagulant platelets detected by flow cytometric analysis in patients with bleeding diathesis.

Cytometry B Clin Cytom 2014 Nov 12;86(6):397-409. Epub 2014 Feb 12.

Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.

Background: A clinically relevant bleeding diathesis is a frequent diagnostic challenge, which sometimes remains unexplained despite extensive investigations. The aim of our work was to evaluate the diagnostic utility of functional platelet testing by flow cytometry in this context.

Methods: In case of negative results after standard laboratory workup, flow cytometric analysis (FCA) of platelet function was done. We performed analysis of surface glycoproteins Ibα, IIb, IIIa; P-selectin expression and PAC-1 binding after graded doses of ADP, collagen, and thrombin; content/secretion of dense granules; and ability to generate procoagulant platelets.

Results: Of 437 patients investigated with standard tests between January 2007 and December 2011, we identified 67 (15.3%) with high bleeding scores and nondiagnostic standard laboratory workup including platelet aggregation studies. Among these patients, FCA revealed some potentially causative platelet defects: decreased dense granule content/secretion (n = 13); decreased α-granule secretion induced by ADP (n = 10), convulxin (n = 4), or thrombin (n = 3); decreased fibrinogen receptor activation induced by ADP (n = 11), convulxin (n = 11), or thrombin (n = 8); and decreased generation of COAT platelets, that is, highly procoagulant platelets induced by simultaneous activation with collagen and thrombin (n = 16).

Conclusion: Our work confirms that storage pool defects are frequent in patients with a bleeding diathesis and normal coagulation and platelet aggregations studies. Additionally, FCA is able to identify discrete platelet activation defects. In particular, we show for the first time that a relevant proportion of these patients has an isolated impaired ability to generate COAT platelets--a conceptually new defect in platelet procoagulant activity, which is missed by conventional laboratory workup.
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http://dx.doi.org/10.1002/cyto.b.21157DOI Listing
November 2014

Decreased generation of procoagulant platelets detected by flow cytometric analysis in patients with bleeding diathesis.

Cytometry B Clin Cytom 2014 Jan 24. Epub 2014 Jan 24.

University Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital and University of Bern, Switzerland.

Background: A clinically relevant bleeding diathesis is a frequent diagnostic challenge, which sometimes remains unexplained despite extensive investigations. The aim of our work was to evaluate the diagnostic utility of functional platelet testing by flow cytometry in this context. Methods: In case of negative results after standard laboratory work-up, flow cytometric analysis (FCA) of platelet function was done. We performed analysis of surface glycoproteins (GP) Ibα, IIb, IIIa; P-selectin expression and PAC-1 binding after graded doses of ADP, collagen and thrombin; content/secretion of dense granules; ability to generate procoagulant platelets. Results: Out of 437 patients investigated with standard tests between January 2007 and December 2011, we identified 67 (15.3%) with high bleeding scores and non-diagnostic standard laboratory work-up including platelet aggregation studies. Among these patients FCA revealed some potentially causative platelet defects: decreased dense-granule content/secretion (n=13); decreased alpha-granule secretion induced by ADP (n=10), convulxin (n=4) or thrombin (n=3); decreased fibrinogen-receptor activation induced by ADP (n=11), convulxin (n=11) or thrombin (n=8); decreased generation of COAT-platelets, i.e. highly procoagulant platelets induced by simultaneous activation with collagen and thrombin (n=16). Conclusion: Our work confirms that storage pool defects are frequent in patients with a bleeding diathesis and normal coagulation and platelet aggregations studies. Additionally, flow cytometric analysis is able to identify discrete platelet activation defects. In particular, we show for the first time that a relevant proportion of these patients has an isolated impaired ability to generate COAT-platelets - a conceptually new defect in platelet procoagulant activity, that is missed by conventional laboratory work-up. © 2014 Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cytob.21157DOI Listing
January 2014

The effect of desmopressin on platelet function: a selective enhancement of procoagulant COAT platelets in patients with primary platelet function defects.

Blood 2014 Mar 17;123(12):1905-16. Epub 2014 Jan 17.

Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital and University of Bern, Switzerland.

1-deamino-8-d-arginine vasopressin (desmopressin [DDAVP]) is clinically efficacious in patients with mild platelet function disorders but it is not known which mechanisms mediate this effect. Our aim was to evaluate the impact of in vivo DDAVP administration in these patients. We assessed von Willebrand factor (VWF), factor VIII, platelet activation and aggregation, platelet-dependent thrombin generation, and platelet intracellular Na(+)/Ca(2+) fluxes, before and 2 and 4 hours after DDAVP (0.3 µg/kg). We found (1) no significant changes for P-selectin expression, PAC-1 binding, δ-granule content and secretion, and platelet-aggregation; (2) significant decreases of secretion of α-granules and GPIIb-IIIa activation induced by adenosine 5'-diphosphate, convulxin, and thrombin; (3) significant increases of procoagulant platelets induced by convulxin/thrombin and platelet-dependent thrombin generation; and (4) significant increases of intracellular Na(+)/Ca(2+) concentrations. We show that in vivo DDAVP selectively and markedly enhances the ability to form procoagulant platelets and increases platelet-dependent thrombin generation by enhancing Na(+)/Ca(2+) mobilization. This report indicates that the beneficial hemostatic effect of DDAVP is not limited to an increase in large VWF multimers. An enhancement of platelet procoagulant activity appears to be an additional and (at least in platelet disorders) -possibly clinically relevant mechanism of DDAVP's action.
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http://dx.doi.org/10.1182/blood-2013-04-497123DOI Listing
March 2014

Mediastinal mass following successful chemotherapy for ovary dysgerminoma: benign process or disease relapse? A case report.

J Pediatr Adolesc Gynecol 2013 Feb;26(1):e13-6

Medical Oncology Department, National Cancer Research Centre Giovanni Paolo II, Bari, Italy.

Background: Ovarian dysgerminoma is a rare tumor that affects adolescent girls and young women. Due to its high radio-chemosensitivity, prognosis is normally excellent. Relapses occur in less than 20% of early stage disease, but are more frequent in advanced disease. It is known that some benign mediastinal processes may mimic tumor relapse, particularly in young patients. This is the case of physiologic thymic hyperplasia, which occurs as a rebound phenomenon after chemotherapy in young women with ovarian dysgerminoma. Until now, no cases of dysgerminoma with benign mediastinal mass have been published.

Case: A young woman with bulky ovarian dysgerminoma, who obtained complete disease remission after chemotherapy, subsequently developed a mediastinal mass which was initially confused with a mediastinal relapse. CT scan features (close thymic location, homogeneous hypodensity, absence of infiltration of mediastinal structures) and subsequent PET/CT scan (homogeneous glucose uptake and a typical inverted V morphology) supported the diagnosis of thymic hyperplasia. No further invasive procedures were performed. 34 months from the diagnosis the patient is in good physical condition with no signs of relapse.

Conclusions: Our case underlines the importance of knowing the age- and treatment-related incidence of physiologic thymic hyperplasia in young women with ovarian dysgerminoma in order to reduce the potential pitfalls and to avoid unnecessary invasive diagnostic procedures.
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http://dx.doi.org/10.1016/j.jpag.2012.10.001DOI Listing
February 2013

Molecular diagnostic and predictive tests in the evolution of chronic hepatitis C anti-viral therapies.

Authors:
Giuseppe Colucci

BMC Infect Dis 2012 12;12 Suppl 2:S8. Epub 2012 Nov 12.

Roche Diagnostics, GCS, CH 6343 Rotkreuz, Switzerland.

Since the discovery of HCV, polymerase chain reaction (PCR) has significantly contributed to the understanding of the virus life cycle and its replicative kinetics during anti-viral therapy. Parallel to the progression of dual and triple combination treatment, real-time PCR molecular tests have constantly improved in their ability to monitor viral load and drive personalized management schedules. The current sensitivity, accuracy and dynamic range of the available assays fulfil the requirement of "companion diagnostics" and support the development of new directly acting antiviral (DAA)-based regimens.
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http://dx.doi.org/10.1186/1471-2334-12-S2-S8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495636PMC
June 2013
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