Neoplasms

All Conditions

Symptoms and General Pathology

Digestive System Diseases

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Heart and Blood Diseases

Rare Diseases

Carcinoma

Ischemia

Carcinoma, Hepatocellular

Liver Failure

Hepatic Insufficiency

Liver Diseases

Liver Neoplasms

Respiratory Tract Infections

Liver Failure, Acute

Primary Graft Dysfunction

Gastrointestinal Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Acute Graft Versus Host Disease

Pharmaceutical Solutions

All Drugs and Chemicals

Hematinics

Anti-Infective Agents

Respiratory System Agents

Ophthalmic Solutions

Liver Extracts

Acetylcysteine

N-monoacetylcystine

Antiviral Agents

Expectorants

Antioxidants

Protective Agents

The allocated organ, in addition to the standard procedure, was treated with a systemic NAC infusion before initiating the liver harvesting procedure, and a loco-regional infusion into the portal vein before cross-clamping.

Allocated organ was treated according to the centre's standard procurement procedure: a modified double perfusion technique, where donor livers are gravity-perfused in situ via the aorta and portal vein with Celsior solution at 4 °C. After hepatectomy, donor livers were further perfused at the back-table with Celsior solution and then stored in conventional bags containing the same solution at 4 °C until transplantation.

15 min systemic NAC infusion of the donor (30 mg/kg, maximum dose 3000 mg) diluted into 500 ml 5 % glucose solution, 30 min before initiating the liver harvesting procedure, and a loco-regional infusion (150 mg/kg of estimated liver weight, maximum dose 300 mg) into the portal vein 5 min before cross-clamping.

N-acetylcystein

Umberto Cillo, MD

Francesco D'Amico, MD

Randomized prospective study on the impact on the post-LT outcome by the infusion of N-acetylcysteine (NAC) during the liver procurement procedure, as an anti-oxidant agent to reduce the ischemia-reperfusion damage of organs for liver transplantation (LT).

Anti-oxidant agents have the potential to reduce the ischemia-reperfusion damage of organs for liver transplantation (LT). In this randomized prospective study, we seek to study the impact on the post-LT outcome of the infusion of N-acetylcysteine (NAC) during the liver procurement procedure.

Potential grafts, assigned to adult candidates with chronic liver disease enlisted for first LT, will randomly be included in a one-to-one ratio with a sequential closed envelope single-blinded assignation procedure to either the NAC protocol or in the standard procedure (without NAC).

The NAC protocol comprises: a systemic NAC infusion (30 mg/kg) one hour before the beginning of liver procurement; a loco-regional NAC infusion (300 mg through the portal vein) just before cross-clamping.

Use of N-Acetylcysteine During Liver Procurement

Infusione Sistemica e Loco-regionale di N-Acetilcisteina Nel Prelievo di Fegato: Uno Studio Prospettico Randomizzato Controllato. Fase II.

Azienda Ospedaliera di Padova

Director of the Hepatobiliary Surgery and Liver Transplantation Unit

Blood and Lymph Conditions

Immune System Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hematologic Neoplasms

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Leukemia, Myelomonocytic, Juvenile

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Non Lymphoblastic Leukemia

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Antineoplastic Agents

Antirheumatic Agents

Cyclophosphamide

Mycophenolic Acid

Tacrolimus

Busulfan

Immunosuppressive Agents

Mesna

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Calcineurin Inhibitors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Patients with AML and MDS:

Days -6 through -3: Busulfan q 5-6h IV q24h x 4 days

Days -2 and -1: Cyclophosphamide 50mg/kg/day IV x 2 days+ Mesna 40 mg/kg/day IV

For patients with ALL and lymphoblastic lymphoma:

Days -5 through -4: Cyclophosphamide 50mg/kg/day IV q24h x 2 days+Mesna 40 mg/kg/day IV

Days -3 through -1: TBI 200 Centigray (cGy) twice a day for 3 days

All patients Day 0: Infuse unmanipulated bone marrow

Day +3 and +4: Cyclophosphamide 50 mg/kg/day IV + Mesna 40 mg/kg IBW/day IV

Day +5: Begin tacrolimus 0.015mg/kg IBW/dose IV over 4 hours q 12h and mycophenolate mofetil (MMF)15mg/kg po/IV tid with maximum daily dose 3 gm/day

Day +30: Assess chimerism and disease status in bone marrow

Day +35: Discontinue MMF

Day +60: Assess chimerism and disease status in bone marrow

Day 180: Discontinue tacrolimus

Unmanipulated Bone Marrow

Mycophenolate mofetil

Heather Symons, MD, MHS

This is a multi-institutional phase II haploidentical T cell replete bone marrow transplant (BMT) study in children with high-risk leukemia. The myeloablative conditioning regimen prescribed will be Total body irradiation (TBI)-based for lymphoid leukemia and busulfan-based for myeloid leukemia. Our goal is to establish an easily exportable, inexpensive platform for haplotransplantation that has a safety profile equivalent to matched related and unrelated BMTs. The primary objective will be to estimate the incidence of 6-month non-relapse mortality (NRM), hypothesizing that NRM is \< 18%.

This is a phase II prospective study designed to evaluate the incidence of 6 month non- relapse mortality, safety, and feasibility of haploidentical bone marrow transplantation (BMT) after myeloablative conditioning with post-transplant Cy. Conditioning regimens include a total body irradiation (TBI)-based prep for lymphoid leukemias and a chemotherapy based prep for myeloid leukemias.

To estimate the incidence of non-relapse mortality at 180 days following myeloablative haploidentical BMT for children and young adults with high risk hematologic malignancies.

Myeloablative Haploidentical BMT With Post-transplant Cyclophosphamide for Pediatric Patients With Hematologic Malignancies

Pediatric Blood & Marrow Transplant Consortium (PBMTC) Phase II Myeloablative Haploidentical BMT With Post-transplantation Cyclophosphamide for Pediatric Patients With Hematologic Malignancies

Cumulative incidence (measured as a percentage) of non-relapse mortality at 180 days following myeloablative, Human Leukocyte Antigen (HLA)-mismatched bone marrow transplant (BMT) for patients with high risk hematologic malignancies.

Number of Participants with Donor Cell Engraftment at Day 60 following myeloablative, HLA-mismatched BMT.

Cumulative incidence (measured as a percentage) of acute GVHD grades 2-4 (overall) and grades 3-4 (severe).

Cumulative incidence (measured as a percentage) of chronic graft versus host disease (GVHD).

Incidence (measured as a percentage) of primary and secondary graft failure.

Number of participants who used steroid and non-steroid immunosuppressants to treat GVHD.

Duration of use of steroid and non-steroid immunosuppressants (in months) to treat GVHD.

Estimate incidence of overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), event-free survival, and relapse-free GVHD-free survival (GRFS) in patients receiving myeloablative, HLA-mismatched BMT for patients with high risk hematologic malignancies at 1 year. Incidence as a percentage.

Estimate incidence of overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), event-free survival, and relapse-free GVHD-free survival (GRFS) in patients receiving myeloablative, HLA-mismatched BMT for patients with high risk hematologic malignancies at 2 years. Incidence as a percentage.

Characterize immune reconstitution post myeloablative haploidentical BMT with Post transplantation cyclophosphamide (PT/Cy).

Time to neutrophil and platelet recovery in median days

Incidence of donor cell engraftment measured as the percentage of donor cell engraftment.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Adverse events reported at each visit during time at transplant center and up to 180 days post-transplantation.

Patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS):

Days -6 through -3: Busulfan q 5-6h IV q24h x 4 days Days -2 and -1: Cyclophosphamide 50mg/kg/day IV x 2 days+ Mesna 40 mg/kg/day IV

For patients with acute lymphocytic leukemia (ALL) and lymphoblastic lymphoma:

Days -5 through -4: Cyclophosphamide 50mg/kg/day IV q24h x 2 days+Mesna 40 mg/kg/day IV Days -3 through -1: total body irradiation (TBI) 200 Centigray (cGy) twice a day for 3 days All patients Day 0: Infuse unmanipulated bone marrow Day +3 and +4: Cyclophosphamide 50 mg/kg/day IV + Mesna 40 mg/kg IBW/day IV Day +5: Begin tacrolimus 0.015mg/kg IBW/dose IV over 4 hours q 12h and mycophenolate mofetil (MMF)15mg/kg po/IV tid with maximum daily dose 3 gm/day Day +30: Assess chimerism and disease status in bone marrow Day +35: Discontinue MMF Day +60: Assess chimerism and disease status in bone marrow Day 180: Discontinue tacrolimus Cyclophosphamide: Chemotherapy administration TBI: Radiation Therapy Busulfan: Chemotherapy Administered Unmanipulated Bone Marrow: Bone Marrow Transplant Tacrolimus: Immunosuppressive Drug Administered Mycophenolate mofetil: Immunosuppressive Drug Administered

Haploidentical BMT With PTCy for Acute Leukemias and MDS

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Region of Enrollment

Heather Symons, MD

Cumulative Incidence of Non-relapse Mortality

Patients with AML and MDS:

Days -6 through -3: Busulfan q 5-6h IV q24h x 4 days Days -2 and -1: Cyclophosphamide 50mg/kg/day IV x 2 days+ Mesna 40 mg/kg/day IV

For patients with ALL and lymphoblastic lymphoma:

Days -5 through -4: Cyclophosphamide 50mg/kg/day IV q24h x 2 days+Mesna 40 mg/kg/day IV Days -3 through -1: TBI 200 Centigray (cGy) twice a day for 3 days All patients Day 0: Infuse unmanipulated bone marrow Day +3 and +4: Cyclophosphamide 50 mg/kg/day IV + Mesna 40 mg/kg IBW/day IV Day +5: Begin tacrolimus 0.015mg/kg IBW/dose IV over 4 hours q 12h and mycophenolate mofetil (MMF)15mg/kg po/IV tid with maximum daily dose 3 gm/day Day +30: Assess chimerism and disease status in bone marrow Day +35: Discontinue MMF Day +60: Assess chimerism and disease status in bone marrow Day 180: Discontinue tacrolimus Cyclophosphamide: Chemotherapy administration TBI: Radiation Therapy Busulfan: Chemotherapy Administered Unmanipulated Bone Marrow: Bone Marrow Transplant Tacrolimus: Immunosuppressive Drug Administered Mycophenolate mofetil: Immunosuppressive Drug Administered

Number of Participants With Donor Cell Engraftment

Grades 2-4

Grades 3-4

Cumulative Incidence of Acute Graft Versus Host Disease (GVHD) Grades 2-4 and Grades 3-4

Cumulative Incidence of Chronic GVHD

Primary

Secondary

Primary and Secondary Graft Failure

Steroid immunosuppressants

Non-steroid immunosuppressants

Patients with AML and MDS:

Days -6 through -3: Busulfan q 5-6h IV q24h x 4 days

Days -2 and -1: Cyclophosphamide 50mg/kg/day IV x 2 days+ Mesna 40 mg/kg/day IV

For patients with ALL and lymphoblastic lymphoma:

Days -5 through -4: Cyclophosphamide 50mg/kg/day IV q24h x 2 days+Mesna 40 mg/kg/day IV

Days -3 through -1: TBI 200 Centigray (cGy) twice a day for 3 days

All patients Day 0: Infuse unmanipulated bone marrow

Day +3 and +4: Cyclophosphamide 50 mg/kg/day IV + Mesna 40 mg/kg IBW/day IV

Day +5: Begin tacrolimus 0.015mg/kg IBW/dose IV over 4 hours q 12h and mycophenolate mofetil (MMF)15mg/kg po/IV tid with maximum daily dose 3 gm/day

Day +30: Assess chimerism and disease status in bone marrow

Day +35: Discontinue MMF

Day +60: Assess chimerism and disease status in bone marrow

Day 180: Discontinue tacrolimus

Cyclophosphamide: Chemotherapy administration

TBI: Radiation Therapy

Busulfan: Chemotherapy Administered

Unmanipulated Bone Marrow: Bone Marrow Transplant

Tacrolimus: Immunosuppressive Drug Administered

Mycophenolate mofetil: Immunosuppressive Drug Administered

Steroid and Non-steroid Immunosuppressants

Four participants used immunosuppressants. Four used steroids and 2 of the 4 also used non-steroid. Duration of use for 3 participants using steroids was not recorded. One participant using non-steroid was not recorded.

Steroid and Non-steroid Immunosuppressants Use Duration

overall survival (OS)

progression-free survival (PFS)

disease-free survival (DFS)

event-free survival

Relapse-free GVHD-free survival (GRFS)

Survival

Blood samples collected were not analyzed due to lack of funding. No data was generated.

Immune Reconstitution

neutrophil

platelet

Time to Neutrophil and Platelet Recovery

Incidence of Donor Cell Engraftment

Overall Study

Recurrence

Antipyretics

Anti-Inflammatory Agents

Fibrinolytic Agents

Analgesics

Platelet Aggregation Inhibitors

Aspirin

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase Inhibitors

Outcome Analysis of Aspirin in liver transplantation

Christian E Oberkofler, MD

Henrik Petrowsky, MD

Henrik Petrowsky, Prof.

In the experimental setting inhibition of platelet activation was able to reduce immune-mediated necroinflammatory liver disease and consecutively hepatocellular carcinoma development. Therefore, antiplatelet therapy may not only have a preventive effect on hepatic artery patency but also on tumor recurrence.

So far and to the best of our knowledge, no study investigated the effect of antiplatelet therapy on hepatic arterial patency, tumor recurrence and graft survival after primary liver transplantation.

Outcome Analysis of antiplatelet therapy with Aspirin in Liver Transplantation

BACKGROUND Arterial complications after liver transplantation (LT) are still one of the most serious complications, which might result in liver necrosis, abscess formation, ischemic cholangiopathy, and eventually graft loss. The sequel of these adverse events has a negative impact on graft and patient survival and remains a life-threatening complication with a high mortality and retransplantation rate. Therefore, an uncompromised inflow of the hepatic artery is crucial to avoid any occlusion after LT.

In the literature, the incidence of hepatic artery thrombosis ranges between 2.5 and 10%. So far, the possibility of preventing hepatic artery thrombosis through specific pharmacological prophylaxis with antiplatelet agents (Aspirin) has been poorly investigated, which may be in part due to the impaired coagulative state at the time of transplantation and the early postoperative period. On the other hand, platelets, the chief effectors of vascular homeostasis, have been identified as important players in the pathogenesis of both acute and chronic liver diseases in animal models.

In the experimental setting inhibition of platelet activation was able to reduce immune-mediated necro-inflammatory liver disease and consecutively hepatocellular carcinoma development. Therefore, antiplatelet therapy may not only have a preventive effect on hepatic artery patency but also on tumor recurrence.

So far and to the best of our knowledge, no study investigated the effect of antiplatelet therapy on hepatic arterial patency, tumor recurrence and graft survival after primary liver transplantation.

STUDY OBJECTIVES The primary goal of this study is to conduct a multicentre cohort analysis to investigate whether antiplatelet therapy with Aspirin has an impact on hepatic arterial patency after primary liver transplantation.

Specific aim #1: To evaluate if antiplatelet therapy with Aspirin has a protective effect on arterial patency after primary LT.

Specific aim #2: To identify if antiplatelet therapy with Aspirin has a protective effect on acute cellular rejection.

Specific aim #3: To identify if antiplatelet therapy with Aspirin has protective effect on tumor recurrence (HCC).

Specific aim #4: To investigate whether antiplatelet therapy with Aspirin has a protective effect on graft survival.

STUDY DESIGN This will be a multicentre single cohort study including only cases of deceased donor primary liver transplantation. Primary endpoint is 30-day arterial patency in patients with or without antiplatelet therapy with Aspirin after liver transplantation. Secondary endpoints include postoperative complications, tumor recurrence, graft- and patient survival. The study protocol has received approval by the local ethics committee (2016-01889) as well as published here prior to data collection.

SETTING This multicentre cohort study will include several high-volume centres worldwide. Each participating centre requires a prospective database from that data can be extracted. All consecutive cases of deceased donor liver transplantation requiring from 1st of January 2013 until 31st of December 2015 are included allowing a minimum follow-up time of 24 months. Data collection at Aspirin4olt.org will be prospective, structured, anonymized, and encrypted.

PUBLICATION POLICY For upcoming publications, two authorships of the participating centres will be guaranteed as a group-authorship indexed in PubMed.

INSTITUTIONAL REVIEW POLICY / ETHICAL POLICY Each participating centre is responsible to contact their local ethics committee and receive approval for participation, if applicable. For example, this project is considered as an audit in some countries and thus there is no need for formal approval in the form of a protocol submission.

ELIGIBILITY CRITERIA

Inclusion criteria:

Adult Liver transplantation (age ≥18 years) Deceased donor after brain death (DBD) or deceased donor after circulatory death (DCD) Primary liver transplantation, whole graft Arterial anastomosis: end-to-end, back table reconstruction

Exclusion criteria:

Split liver and living donor liver transplantation Paediatric liver transplantation (recipient age \<18 years) Arterial conduits Multivisceral transplantations Retransplantations

ESTIMATED SAMPLE SIZE Each centre should provide at least 30 cases that meet the inclusion criteria to allow adequate event rates for each outcome.

Statistical methods The primary and secondary endpoints will be compared with patient and operation characteristics with univariate analysis. ROC Curve analysis will be performed to dichotomize continuous variables. Multivariable analysis (binary logistic and Cox regression) will be performed to identify independent risk factors. Statistical analysis will be performed using R Studio version 1.0.44 (RStudio, Inc. GNU Affero General Public License v3, Boston, MA, 2016) with the graphical user interface rBiostatistics.com beta version (rBiostatistics.com, London, UK, 2017, GNU License).

Christian E. Oberkofler Philip C. Müller Dimitri A. Raptis Henrik Petrowsky On behalf of the Aspirin4olt.org team Swiss HPB Center, Department of Surgery and Transplantation, University Hospital Zurich, Switzerland

Outcome Analysis of Aspirin in Liver Transplantation

Outcome Analysis of Antiplatelet Therapy With Aspirin in Liver Transplantation

We will look, if antiplatelet therapy with Aspirin has a protective effect on arterial patency after primary liver transplantation by looking at postoperative lab values and imaging, if they were perfromed.

We will analyze patients with and without postoperative cellular rejection and the intake of Aspirin.

We will look at post transplant tumor recurrence and if the recurrence does correlate with Aspirin intake.

We will look at the postoperative graft survival and devide graft survival in the group of patients who were under Aspirin postoperative with those who did not take Aspirin postoperative; both groups will be then compared.

University of Zurich

Liver Cirrhosis

Fibrosis

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Standard immunosuppression protocol with Tacrolimus, maintaining trough levels between 6 and 12 ng/ml in the first month, in association with steroids (20 mg/day with subsequent weaning within 3 months after transplantation).

Administration of Everolimus in association with Tacrolimus and steroids.

Administration of Everolimus within 24 hours from the time of randomization (7 days from the time of transplantation) in association with Tacrolimus and steroids. The first dose level of the trough will be performed at day 7 after initiation of therapy. After the reaching an Everolimus trough level of \>5ng/ml (final target 6-12 ng/ml), there will be a gradual weaning of tacrolimus (bringing Tacrolimus blood levels \<5 ng/ml) with discontinuation of Tacrolimus within 30 days after transplantation when possible.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Use of N-Acetylcysteine During Liver Procurement	NCT01394497	Liver Failure Liver Failure, ... Liver Diseases Carcinoma, Hepa... Liver Neoplasms	N-acetylcystein	18 Years -	Azienda Ospedaliera di Padova
Myeloablative Haploidentical BMT With Post-transplant Cyclophosphamide for Pediatric Patients With Hematologic Malignancies	NCT02120157	Myeloablative C... HLA-mismatched ... Graft Survival Transplantation...	Cyclophosphamid... TBI Busulfan Unmanipulated B... Tacrolimus Mycophenolate m...	6 Months - 25 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Outcome Analysis of Aspirin in Liver Transplantation	NCT04327427	Liver Transplan...	Aspirin	18 Years -	University of Zurich
Everolimus in de Novo Liver Transplantation: a Multicentre Randomized Study	NCT01423708	Liver Failure Liver Diseases Liver Cirrhosis Liver Neoplasms	Everolimus	18 Years - 70 Years	Azienda Ospedaliera di Padova
Everolimus in de Novo Liver Transplantation: a Multicentre Randomized Study	NCT01423708	Liver Failure Liver Diseases Liver Cirrhosis Liver Neoplasms	Everolimus	18 Years - 70 Years	Azienda Ospedaliera di Padova
Everolimus in de Novo Liver Transplantation: a Multicentre Randomized Study	NCT01423708	Liver Failure Liver Diseases Liver Cirrhosis Liver Neoplasms	Everolimus	18 Years - 70 Years	Azienda Ospedaliera di Padova

Spots Global Cancer Trial Database for graft survival