tacrolimus and Hepatoblastoma

This review presents the author's personal perspective and contributions to the first steps, the development, the current status, and the remaining issues of pediatric liver transplantation (LT). Innumerable children around the world who have undergone LT have reached adulthood. The techniques have reached maturity. As shown by my own group's experience, grafts donated by living donors might provide the best short-term and longterm results. Debate persists about the optimal immunosuppression (IS), although the place of tacrolimus remains unchallenged. Tolerance induction protocols aiming to induce microchimerism have been tried in clinical transplantation without convincing results. Withdrawal of maintenance IS is possible in some children who underwent liver transplantation who have excellent clinical status and normal liver function tests but is not without risk of rejection and subsequent worsening of histology. The current trend favored by the Brussels' group is to minimize IS as soon after transplant as possible, aiming to obtain a state of "prope" or "almost" tolerance. Liver grafts are threatened in the long term by increasing hepatitis-related fibrosis, resulting most likely from immunological assault. Nowadays, the focus is on the longterm survival, quality of life (growth, academic performance, employment, self-fulfillment, fertility, raising a family, etc.), induction of tolerance, prevention of risks bound to decades of IS (nephrotoxicity and neurotoxicity, cardiovascular risk, de novo malignancies, etc.), and prevention of graft fibrosis. All these issues are fertile fields for younger scientists. Liver Transplantation 22 1284-1294 2016 AASLD.

Topics: Achievement; Allografts; Biliary Atresia; Child; Drug Therapy, Combination; Fibrosis; Graft Rejection; Hepatitis, Autoimmune; Hepatoblastoma; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Living Donors; Patient Selection; Preoperative Care; Quality of Life; Risk Factors; Survival Rate; Tacrolimus; Withholding Treatment

We describe the successful pediatric liver transplant for unresectable hepatoblastoma in a 4-year-old male with COVID-19 prior to transplant. The first negative NP swab was documented 1 month after initial diagnosis, when SARS-CoV-2 antibodies were also detected. The patient was actively listed for liver transplant after completing four blocks of a SIOPEL-4 based regimen due to his PRETEXT IV disease which remained unresectable. Following three additional negative NP swabs and resolution of symptoms for 4 weeks, he underwent a whole-organ pediatric liver transplant. COVID-19 positivity determined via NP swab SARS-CoV-2 real-time RT-PCR (Hologic Aptima SARS-CoV-2 RT-PCR assay). IgG and IgM total SARS- CoV-2 antibodies detected by Ortho Clinical Diagnostics VITROS® Immunodiagnostics Products Anti-SARS-CoV-2 Test. Patient received standard prednisone and tacrolimus-based immunosuppression without induction therapy following transplant. Post-transplant course was remarkable for neutropenia and thrombocytopenia, with discharge home on post-transplant day #11. Surveillance tests have remained negative with persistent SARS-CoV-2 IgG antibodies at 6 weeks after transplant. We describe one of the earliest, if not the first case of liver transplant following recent recovery from COVID-19 in a pediatric patient with a lethal malignant liver tumor. A better understanding of how to balance the risk profile of transplant in the setting of COVID-19 with disease progression if transplant is not performed is needed. We followed existing ASTS guidelines to document clearance of the viral infection and resolution of symptoms before transplant. This case highlights that pediatric liver transplantation can be safely performed upon clearance of COVID-19.

Topics: Child, Preschool; COVID-19; COVID-19 Testing; Disease Progression; Hepatoblastoma; Humans; Immunoglobulin G; Immunoglobulin M; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Neutropenia; Prednisone; Tacrolimus; Thrombocytopenia; Treatment Outcome

SRL-based immunosuppressive strategies in pediatric liver transplantation are not clearly defined, especially within the first year after liver transplant. TAC is the more common, traditional immunosuppressant used. However, SRL may modulate TAC-associated kidney injury and may also have antiproliferative properties that are valuable in the management of patients following liver transplantation for HB. We sought to determine whether early conversion from TAC to SRL was safe, effective, and beneficial in a subset of liver transplant recipients with unresectable HB exposed to CDDP-based chemotherapy. Between 2008 and 2013, six patients were transplanted for unresectable HB. All patients received at least one cycle of CDDP-based chemotherapy prior to transplant. All patients were switched from TAC- to SRL-based immunosuppression within 1 year of transplant. Five patients had improvement in their mGFR, while one patient had a slight decline. The improvement in mGFR was statistically significant. No adverse events were identified. Three patients had BPAR that responded to pulsed steroids. Historical controls showed similar rates of BPAR within the first year after transplant. There were no identified HB recurrences in the follow-up time period. Conversion from TAC to SRL appears to be safe and effective in this selected group of pediatric liver transplant recipients without adverse reaction or HB recurrences.

Topics: Antineoplastic Agents; Child; Child, Preschool; Cisplatin; Female; Glomerular Filtration Rate; Hepatoblastoma; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Liver Neoplasms; Liver Transplantation; Male; Patient Safety; Pediatrics; Recurrence; Retrospective Studies; Sirolimus; Steroids; Tacrolimus; Treatment Outcome

LT from ABO-I donors requires preconditioning regimens to prevent postoperative catastrophic AMR. NAC for HBL is known to cause myelosuppression leading to a reduction in the number and function of lymphocytes. We investigated this chemotherapy-induced myelosuppression in HBL patients listed for LT from ABO-I donors with reference to the kinetics of B, T cells, and anti-ABO blood type isoagglutinin titers. Between 2005 and 2015, of the 319 patients who underwent LDLT at our institute, 12 were indicated for unresectable HBL. Three patients with unresectable HBL who underwent LDLT from ABO-I donors are included in this study. Immunosuppression consisted of a standard regime of tacrolimus and low-dose steroids as in ABO compatible/identical LDLT. No additional preoperative therapies for B-cell depletion were used. Absolute lymphocyte counts, lymphocyte subsets (including CD20+ B cells, CD3+CD4+ T cells and CD3+CD8+ T cells), and anti-ABO blood type isoagglutinin titers were measured before LDLT and postoperatively. The median age at diagnosis was 19 months (range, 3-31 months). The median follow-up was seven months (range, 6-15 months). The median interval from the last NAC to LDLT was 33 days (range, 25-52 days). The median interval from LDLT to adjuvant chemotherapy was 28 days (range, 22-36 days). The counts of CD20+ B cells before LDLT were depleted to median 5 cells/mm(3) (range, 0-6 cells/mm(3)). There was a transient rebound in the CD20+ B cell counts on day seven (maximum of 82 cells/mm(3)) followed by a decline starting at 14 days after LDLT that was sustained for the duration of adjuvant chemotherapy. Anti-ABO blood type isoagglutinin titers were lowered to between 1:1 and 1:16 before LDLT and remained low for the duration of follow-up in this study. All of the three patients remained in good health without either acute cellular or AMR after LDLT. The B-cell depletion that occurs after cisplatin-based chemotherapy for HBL may help accomplish safe ABO-I LDLT in children without the use of additional conditioning regimens for prevention of AMR.

Topics: ABO Blood-Group System; Antigens, CD20; Antineoplastic Agents; B-Lymphocytes; Blood Group Incompatibility; CD3 Complex; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chemotherapy, Adjuvant; Child, Preschool; Cisplatin; Cytomegalovirus Infections; Female; Hepatoblastoma; Humans; Immunity, Innate; Immunosuppression Therapy; Infant; Liver Neoplasms; Liver Transplantation; Living Donors; Lymphocyte Subsets; Male; Risk; Rituximab; Tacrolimus; Transplantation Conditioning; Treatment Outcome

BWS is one of the most well-known somatic overgrowth syndromes, which is characterized by macroglossia, organomegaly, abdominal wall defects, and predisposition to embryonal tumors, such as Wilms' tumor, hepatoblastoma, and adrenocortical carcinoma. We report a case of BWS in a girl with unresectable hepatoblastoma, who received a planned LVDT following neo-adjuvant chemotherapy. This is the first case report of liver transplantation for patients with BWS. Tumor surveillance after transplantation would be necessary to detect possible recurrence of the original disease and development of other malignancies.

Topics: alpha-Fetoproteins; Beckwith-Wiedemann Syndrome; Female; Hepatoblastoma; Humans; Immunosuppressive Agents; Infant; Liver Neoplasms; Liver Transplantation; Living Donors; Methylprednisolone; Mycophenolic Acid; Recurrence; Tacrolimus; Time Factors; Tomography, X-Ray Computed

Topics: Antineoplastic Agents; Child; Hepatoblastoma; Humans; Immunosuppressive Agents; Liver Transplantation; Medical Oncology; Neoplasm Metastasis; Peripheral Blood Stem Cell Transplantation; Recurrence; Tacrolimus; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Topics: Antineoplastic Agents; Child; Graft Rejection; Hepatoblastoma; Humans; Liver Neoplasms; Liver Transplantation; Medical Oncology; Peripheral Blood Stem Cell Transplantation; Prognosis; Recurrence; Risk; Tacrolimus; Transplantation Conditioning; Treatment Outcome

A four-yr-old boy developed a solitary metastasis nine months after living-related liver transplantation for unresectable hepatoblastoma. After resection of the metastatic lesion, he received an auto-PBSCT with a double-conditioning regimen consisting of melphalan and thiotepa. Auto-PBSCT could be safely performed without any serious regimen-related toxicity or infection. However, transient cessation of tacrolimus during myelosuppression resulted in graft rejection of the liver just after hematological engraftment, but rejection was resolved by tacrolimus and methylprednisolone. The patient is alive and free from disease two yr after auto-PBSCT without any signs of graft rejection. High-dose chemotherapy using this conditioning regimen may be feasible for recurrent hepatoblastoma after liver transplantation in terms of safety and anti-tumor activity.

Topics: Antineoplastic Agents; Child, Preschool; Graft Rejection; Hepatoblastoma; Humans; Liver Neoplasms; Liver Transplantation; Male; Peripheral Blood Stem Cell Transplantation; Prognosis; Recurrence; Tacrolimus; Transplantation Conditioning; Treatment Outcome

Despite aggressive chemotherapy, recurrence of disease remains the leading cause of death after liver transplantation (LTx) for hepatoblastoma (HB). Unfortunately, little is known about the effects of immunosuppression on recurrence and posttransplant outcomes. We hypothesized that minimal immunosuppression can be safely used in these recipients.. In 2004, we adopted a minimal immunosuppression regimen using daclizumab induction and tacrolimus monotherapy. Kaplan-Meier survival curves were generated.. From 2004 to 2006, 6 children underwent primary LTx for HB with neoadjuvant and adjuvant chemotherapy. Patient survival was 100% at 12 months and at 24 months, without graft loss. One patient died 28 months after transplantation. Recurrence-free survival was 83% at 12 months and at 24 months. Despite minimal immunosuppression (IS), 4 of 6 HB recipients remained rejection-free. When compared to other LTx recipients receiving minimal IS, HB recipients trended to have better rejection-free survival (HB, 83% at 12 months and 62.5% at 24 months vs all others, 36% and 36%, respectively; P = .19).. Our short-term patient and graft survival rates are comparable to those reported for all HB recipients in the United Network for Organ Sharing database. Although not statistically significant, our rejection-free survival data suggest that HB recipients may be less likely to reject than other recipients.

Topics: Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Daclizumab; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepatoblastoma; Humans; Immunoglobulin G; Immunosuppression Therapy; Infant; Kaplan-Meier Estimate; Liver Neoplasms; Liver Transplantation; Male; Probability; Registries; Retrospective Studies; Risk Assessment; Survival Analysis; Tacrolimus

Hepatoblastoma is the most common malignant liver tumor in children. Recently, liver transplantation has been indicated for unresectable hepatoblastoma. We retrospectively reviewed 14 children with a diagnosis of hepatoblastoma who had undergone living-donor liver transplantation (LDLT) at Kyoto University Hospital. During the period from June 1990 to December 2004, 607 children underwent LDLT. Of these interventions, 2.3% were performed for hepatoblastoma. Based on radiological findings, the pre-treatment extent of disease (PRETEXT) grouping was used for pre-treatment staging of the tumor. There were grade III in seven patients and grade IV in seven patients. Thirteen patients received chemotherapy, and seven underwent hepatectomy 11 times. Immunosuppressive treatment consisted of tacrolimus monotherapy in 11 patients. Actuarial 1- and 5-year graft and patient survival rates were 78.6% and 65.5%. The poor prognostic factors were macroscopic venous invasion and extrahepatic involvement with 1-year and 5-year survival rates of 33.0% and 0%. Pediatric patients without these factors showed an acceptable 5-year survival rate of 90.9%. LDLT provides a valuable alternative with excellent results in children with hepatoblastoma because it allows optimal timing of the liver transplantation, given the absence of delay between the completion of chemotherapy and planned liver transplantation.

Topics: alpha-Fetoproteins; Chemotherapy, Adjuvant; Child; Child, Preschool; Female; Graft Survival; Hepatoblastoma; Humans; Immunosuppressive Agents; Infant; Liver Neoplasms; Liver Transplantation; Living Donors; Male; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome