Sotto il Monte Giovanni XXIII, Italy
Sotto il Monte Giovanni XXIII, Italy

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PubMed | IRCCS Fondazione S. Maugeri, Hospital Papa Giovanni XXIII, Irccs Instituto Of Ricerche Farmacologiche Mario Negri, University of Milan and 5 more.
Type: | Journal: British journal of cancer | Year: 2017

Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN.Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedins effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines.On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models.Trabectedin could be good candidate for clinical studies in JMML/CMML patients.British Journal of Canceradvance online publication, 10 January 2017; doi:10.1038/bjc.2016.424 www.bjcancer.com.


Lacaille F.,Hepatogastroenterology Nutrition Unit | Gupte G.,Birminghams Children Hospital | Colomb V.,Hepatogastroenterology Nutrition Unit | D'antiga L.,Hospital Papa Giovanni XXIII | And 5 more authors.
Journal of Pediatric Gastroenterology and Nutrition | Year: 2015

Intestinal failure-associated liver disease is the most prevalent complication affecting children with intestinal failure receiving long-term parenteral nutrition. This paper reviews the definition, diagnostic criteria, pathogenesis, and risk factors. The authors discuss the role of enteral nutrition, parenteral nutrition, and its components, especially lipid emulsions. The authors also discuss the surgical treatment, including intestinal transplantation, its indications, technique, and results, and emphasise the importance of specialised intestinal failure centres. © 2015 by ESPGHAN and NASPGHAN.


Finazzi G.,Ospedale Papa Giovanni XXIII | De Stefano V.,Catholic University | Barbui T.,Ospedale Papa Giovanni XXIII | Barbui T.,Hospital Papa Giovanni XXIII
Current Hematologic Malignancy Reports | Year: 2013

A high risk of arterial and venous thrombosis is the hallmark of chronic myeloproliferative neoplasms (MPNs), particularly polycythemia vera (PV) and essential thrombocythemia (ET). Clinical aspects, pathogenesis and management of thrombosis in MPN resemble those of other paradigmatic vascular diseases. The occurrence of venous thrombosis in atypical sites, such as the splanchnic district, and the involvement of plasmatic prothrombotic factors, including an acquired resistance to activated protein C, both link MPN to inherited thrombophilia. Anticoagulants are the drugs of choice for these complications. The pathogenic role of leukocytes and inflammation, and the high mortality rate from arterial occlusions are common features of MPN and atherosclerosis. The efficacy and safety of aspirin in reducing deaths and major thrombosis in PV have been demonstrated in a randomized clinical trial. Finally, the Virchow's triad of impaired blood cells, endothelium and blood flow is shared both by MPN and thrombosis in solid cancer. Phlebotomy and myelosuppressive agents are the current therapeutic options for correcting these abnormalities and reducing thrombosis in this special vascular disease represented by MPN. © 2013 Springer Science+Business Media New York.


Marchetti M.,Hospital Papa Giovanni XXIII | Tartari C.J.,Hospital Papa Giovanni XXIII | Russo L.,Hospital Papa Giovanni XXIII | Panova-Noeva M.,Hospital Papa Giovanni XXIII | And 5 more authors.
American Journal of Hematology | Year: 2014

This study evaluates the functional procoagulant features of plasma microparticle (MP) to explore the MP contribution to the hypercoagulable state of patients with essential thrombocythemia (ET). Platelet-free plasma samples were obtained from 73 ET patients (37 positive for the JAK2V617F mutation) and 72 control subjects. The calibrated automated thrombogram (CAT) was performed in plasma samples to determine thrombin generation of MP-associated tissue factor (TF) and procoagulant phospholipid (PPL) activity, and the STA Procoag PPL assay to measure MP-PPL activity only. Both thrombin generation and PPL procoagulant activities were found significantly elevated in ET patients compared to controls, and were associated to significantly higher levels of TF antigen and FVIIa/AT complex. Thrombin generation was significantly greater in JAK2-V617F positive compared to JAK2-V617F negative patients and normal subjects. Significant correlations were found between the PPL-assay and the different parameters of the CAT assay. No difference was seen between the thrombosis and no thrombosis group. Prospective studies are needed to test whether MP-associated thrombin generation and procoagulant activity may predict for thrombosis in these patients. © 2013 Wiley Periodicals, Inc.


Nicastro E.,Hospital Papa Giovanni XXIII
Transplantation | Year: 2016

BACKGROUND: Most pediatric liver transplantation (LT) centers administer long courses of prophylaxis against Cytomegalovirus (CMV) without evidence of benefit and with significant drug exposure and costs. We aimed at evaluating overall outcomes, direct and putative indirect effects of CMV, possible impact of viremia and risk factors for CMV infection in pediatric LT recipients managed with ganciclovir-based preemptive therapy (PET). METHODS: The records of all the children who underwent LT between 2008 and 2014 were retrospectively analyzed. RESULTS: One-hundred children were included. Three children had CMV disease; no CMV-related death or graft loss was recorded. The only identified risk factor for CMV infection was the donor/recipient serostatus [OR: 17.23 (95%CI: 1.88-157.87); P=0.012], while viremia per se did not worsen LT outcomes, such as the incidence of acute rejection, EBV infection, sepsis, biliary and vascular complications, nor graft dysfunction/loss or death at 3 and 5 years after LT. When compared with a historical cohort of children receiving ganciclovir prophylaxis, PET did not differ from prophylaxis for any of the selected outcomes, but was rather associated with lower antiviral drug exposure (6.4 ± 13 vs 38.6 ± 14 days, P < 0.0001) and cost per patient (2.2 ± 3.9 vs 6.6 ± 8.2 k&OV0556;, P = 0.001). CONCLUSIONS: PET is effective in controlling CMV in children receiving LT, with lower costs and lower exposure to antivirals. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Falanga A.,Hospital Papa Giovanni XXIII | Russo L.,Hospital Papa Giovanni XXIII | Milesi V.,Hospital Papa Giovanni XXIII
Current Opinion in Hematology | Year: 2014

PURPOSE OF REVIEW: To provide an updated overview of the complex coagulopathy associated with malignancy, together with the advances in our knowledge of the interactions of cancer with the hemostatic system. Also, to offer an update of the recent progresses in the risk assessment, prevention, and treatment of thrombohemorrhagic complications in cancer patients. RECENT FINDINGS: Mechanisms underlying the hemostatic derangement caused by cancer include many prothrombotic properties of tumor tissues. Of extreme interest are the most recent findings that the regulation of tumor cell hemostatic protein expression is driven by oncogenes, the tumor-derived tissue factor-positive microparticles are an important player in thrombosis, and the changes in the tumor microenvironment in the presence of tissue factor affect 'dormant' cells to shift to a malignant phenotype.On the clinical side, risk assessment models, based on clinical and biological risk factors, are becoming very attractive to identify categories of cancer patients at different thrombotic risk. Unsuspected pulmonary embolism, incidentally discovered, is also opening an intensive area of research. Finally, new updates of the guidelines to help clinicians in the management of venous thromboembolism in cancer patient have been recently released. SUMMARY: The coagulopathy of cancer is complex. Thrombotic and bleeding complications significantly contribute to morbidity and mortality in this disease. The accrued knowledge of the underlying mechanisms is helping establish more accurate and appropriate interventions for the management of the thrombotic risk in these patients. Copyright © 2014 Lippincott Williams & Wilkins.


Alberti D.,Hospital Papa Giovanni XXIII | Colusso M.,Hospital Papa Giovanni XXIII | Cheli M.,Hospital Papa Giovanni XXIII | Ravelli P.,Hospital Papa Giovanni XXIII | And 4 more authors.
Journal of Pediatric Gastroenterology and Nutrition | Year: 2013

BACKGROUND:: The management of extrahepatic portal vein obstruction (EHPVO) in children is controversial. We report our experience with a prospective evaluation of a stepwise protocol based on severity of portal hypertension and feasibility of mesoportal bypass (MPB). METHODS:: After diagnosis, children with EHPVO underwent surveillance endoscopies and received nonselective β-blockers (NSBBs) or endoscopic variceal obliteration (EVO) when large varices were detected. In patients who failed NSBBs and EVO, we considered MPB as first-line and shunts or transjugular intrahepatic portosystemic shunt (TIPS) as second-line options. RESULTS:: Sixty-five children, median age 12.5 (range 1.6-25.8), whose age at diagnosis was 3.5 (0.2-17.5) years, were referred to our unit. Forty-three (66%) had a neonatal illness, 36 (55%) an umbilical vein catheterisation. Thirty-two (49%) presented with bleeding at a median age of 3.8 years (0.5-15.5); during an 8.4-year follow-up period (1-16), 43 (66%) had a bleeding episode, 52 (80%) were started on NSBBs, 55 (85%) required EVO, and 33 (51%) required surgery or TIPS. The Rex recessus was patent in 24 of 54 (44%), negatively affected by a history of umbilical catheterisation (P=0.01). Thirty-four (53%) patients underwent a major procedure: MPB (13), proximal splenorenal (13), distal splenorenal (2), mesocaval shunt (3), TIPS (2), and OLT (1). At the last follow-up, 2 patients died, 53 of 57 (93%) are alive with bleeding control, 27 of 33 (82%) have a patent conduit. CONCLUSIONS:: Children with EHPVO have a high rate of bleeding episodes early in life. A stepwise approach comprising of medical, endoscopic, and surgical options provided excellent survival and bleeding control in this population. Copyright 2013 by ESPGHAN and NASPGHAN.


Falanga A.,Hospital Papa Giovanni XXIII | Marchetti M.,Hospital Papa Giovanni XXIII | Russo L.,Hospital Papa Giovanni XXIII
Thrombosis Research | Year: 2015

Patients with cancer may display many types of hemostatic disorders that significantly contribute to morbidity and mortality in this disease. A complex coagulopathy develops in parallel with malignancy and is characterized by activation of clotting mechanisms to different extent in different patients and in different types of tumor. The pathogenesis of hemostatic alterations in cancer is multifactorial; however, the tumor tissue capacity to interact with and activate the host hemostatic system plays an important role. New molecular pathways of regulation of these properties have been recently demonstrated. Intervention strategies to prevent and treat venous thromboembolism (VTE) in cancer patients have been addressed by large RCTs and guidelines for VTE management have been updated. In this review, we will present an updated overview of the complex coagulopathy associated to malignancy and of recent advances in the thrombotic risk assessment of cancer patients. © 2015 Elsevier Ltd. All rights reserved.


Falanga A.,Hospital Papa Giovanni XXIII | Schieppati F.,University of Brescia | Russo D.,University of Brescia
Seminars in Thrombosis and Hemostasis | Year: 2015

Thrombosis is a major cause of morbidity and mortality in cancer patients. Many clinical factors contribute to the high thrombotic risk of this condition, including the type of malignancy, its disease stage, anticancer therapies, and comorbidities. However, the cancer cell-specific prothrombotic properties together with the host cell inflammatory response are important players in the pathogenesis of the cancer-associated hypercoagulability. Tissue factor (TF) is the most important procoagulant protein expressed by cancer cells, and with other cancer tissue procoagulant properties highly contributes to the procoagulant phenotype of malignant cells. Recent discoveries indicate that oncogenes determine the procoagulant protein expression, including TF, in cancer tissues. In addition, in malignancy, TF is also overexpressed by host normal blood cells triggered by cancer-derived inflammatory stimuli. As a consequence, a subclinical activation of blood coagulation is typically present in cancer patients, as demonstrated by abnormalities of circulating thrombotic biomarkers. The relevance of measuring these biomarkers to determine the patient thrombotic risk level is under active investigation. The goal is to identify the high-risk subgroups to establish more accurate and targeted anticoagulation strategies to prevent thrombosis in cancer patients. Ultimately, the clarification of specific molecular mechanisms triggering blood coagulation in specific cancer types may also indicate alternative ways to inhibit clotting activation in these conditions. © 2015 by Thieme Medical Publishers, Inc.


Barbui T.,Hospital Papa Giovanni XXIII | Finazzi G.,Hospital Papa Giovanni XXIII | Falanga A.,Hospital Papa Giovanni XXIII
Blood | Year: 2013

Major causes of morbidity and mortality in myeloproliferative neoplasms are represented by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. The pathogenesis of thrombosis results from a complex interplay of clinical and disease-related factors. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative changes but also qualitative modifications that characterize the switch of these cells from a resting to a procoagulant phenotype. According to age and previous thrombosis, patients are classified in a "high risk" or "low risk". Novel disease-related determinants such as leukocytosis and JAK2V617F mutational status and/or mutational burden are now under active investigation. In low-risk polycythemia vera patients, only phlebotomy and primary antithrombotic prophylaxis with aspirin is recommended, while in high-risk patients cytotoxic therapy is considered. Whether novel drugs targeting the constitutively active JAK2/STAT pathway will improve the management of thrombosis is a challenge for future studies. © 2013 by The American Society of Hematology.

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