Publications (8)24.77 Total impact
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Article: Safety analysis of ex vivo-expanded NK and NK-like T cells administered to cancer patients: a phase I clinical study.
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ABSTRACT: The chimeric state after allogeneic hematopoietic stem cell transplantation provides a platform for adoptive immunotherapy using donor-derived immune cells. The major risk with donor lymphocyte infusions (DLIs) is the development of graft-versus-host disease (GvHD). Development of new DLI products with antitumor reactivity and reduced GvHD risk represents a challenging task in cancer immunotherapy. Although natural killer (NK) and NK-like T cells are promising owing to their antitumor activity, their low concentrations in peripheral blood mononuclear cells reduces their utility in DLIs. We have recently developed a system that allows expansion of clinical-grade NK and NK-like T cells in large numbers. In this study, the safety of donor-derived long-term ex vivo-expanded human NK and NK-like T cells given as DLIs was investigated as immunotherapy for cancer in five patients following allogeneic stem cell infusion. Infusion of the cells was safe whether administered alone or with IL-2 subcutaneously. No signs of acute GvHD were observed. One patient with hepatocellular carcinoma showed markedly decreased serum alpha-fetoprotein levels following cell infusions. These findings suggest that the use of ex vivo-expanded NK and NK-like T cells is safe and appears an attractive approach for further clinical evaluation in cancer patients.Immunotherapy 09/2009; 1(5):753-64. · 1.85 Impact Factor -
Article: Long-term consequences of domino liver transplantation using familial amyloidotic polyneuropathy grafts.
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ABSTRACT: Domino liver transplantation (DLT) using grafts from patients with familial amyloidotic polyneuropathy (FAP) is an established procedure at many transplantation centers. However, data evaluating the long-term outcome of DLT are limited. The aim of the present study was to analyze the risk of de novo polyneuropathy, possibly because of amyloidosis, and the patient survival after DLT. At our department, 28 DLT using FAP grafts were conducted between January 1997 and December 2005. One patient was twice subjected to DLT. Postoperative neurological monitoring of peripheral nerve function was performed with electroneurography (ENeG) in 20 cases. An ENeG index based on 12 parameters was calculated and correlated to age and/or height. Three patients developed ENeG signs of polyneuropathy 2-5 years after the DLT, but with no clinical symptoms. The 1-, 3- and 5-year actuarial patient survival in hepatocellular carcinoma (HCC) patients (n = 12) and non-HCC patients (n = 15) was 67%, 15%, 15% and 93%, 93%, 80%, respectively (P = 0.001). Development of impaired nerve conduction in a proportion of patients may indicate that de novo amyloidosis occurs earlier than previously expected. Survival after DLT was excellent except in patients with advanced HCC.Transplant International 12/2007; 20(11):926-33. · 2.92 Impact Factor -
Article: Body growth after combined liver-kidney transplantation in children with primary hyperoxaluria type 1.
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ABSTRACT: Children with primary hyperoxaluria type 1 (PH1) often develop severe growth failure, which is related to metabolic and endocrine consequences of chronic renal failure, and/or oxalate deposition in bone and cartilage. Combined liver and kidney transplantation (LKT) corrects the underlying metabolic defect and restores renal function in these children. We therefore analyzed longitudinal growth of 24 children with PH1 who underwent LKT at nine European centers. Mean age at LKT was 8.9 years, and mean duration of follow-up was 5.7 years. After LKT mean standardized height tended to increase from -1.79 SD to -1.47 SD until last observation. Mean adult height amounted to 167 cm and 158 cm in boys and girls, respectively. At last observation, seven out of 24 patients were stunted. Within the whole study population, the degree of catch-up growth after LKT was positively associated with degree of stunting at the time of LKT and negatively associated with prednisolone dosage explaining together 39% of the overall variability. Combined LKT does not induce true catch-up growth in the majority of children with PH1. Due to the preexisting growth retardation at the time of LKT, one third of patients end up with a reduced final height.Transplantation 08/2006; 82(1):48-54. · 4.00 Impact Factor -
Article: A prospective, randomized, multi-centre trial of systemic adjuvant chemotherapy versus no additional treatment in liver transplantation for hepatocellular carcinoma.
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ABSTRACT: The role of adjuvant systemic chemotherapy in liver transplantation (LT) for hepatocellular carcinoma (HCC) is controversial. Here, we report the results of a Nordic prospective, randomized, multi-centre trial of systemic low-dose doxorubicin in patients with HCC. Between February 1996 and April 2004, 46 patients were randomized to receive either neoadjuvant doxorubicin in combination with LT (chemo group; n = 19) or LT alone (control group; n = 27). In the chemo group, doxorubicin was administered intravenously, 10 mg/m(2) weekly, starting from acceptance onto the waiting list for LT. One intraoperative dose of 15 mg/m(2) was given, and postoperatively doxorubicin was given weekly at a dose of 10 mg/m(2), depending on the clinical course, up to a cumulative dose of 400 mg/m(2). Actuarial, 3-year overall survival (OS) and disease-free survival (DFS) in the control group were 70% and 50%, respectively. In the chemo group, both OS and DFS were 63%. Freedom from recurrence at 3 years was 55% in the control group and 74% in the chemo group. None of the differences was statistically significant. Neoadjuvant treatment with systemic low-dose doxorubicin seems not to improve either survival or freedom from recurrence in patients with HCC undergoing LT.Transplant International 05/2006; 19(4):288-94. · 2.92 Impact Factor -
Article: Adriamycin cytotoxicity may stimulate growth of hepatocellular tumours in an experimental model for adjuvant systemic chemotherapy in liver transplantation.
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ABSTRACT: Adjuvant treatment with adriamycin has been suggested to improve results after liver transplantation for hepatocellular cancer. Here we have applied an animal model for evaluation of treatment with adriamycin and/or cyclosporine A on liver tumour growth. Three chemically induced rat liver tumours with various degree of differentiation were transferred to the spleens of syngenic rats. Each recipient group was divided into four subgroups, treated with adriamycin and/or cyclosporine A or none of the drugs. When the tumour was well differentiated no proliferation was found in any of the subgroups. When the tumour exhibited a more pronounced dysplasia, adriamycin stimulated tumour growth. This effect was further increased by cyclosporine. In the animals transplanted with the most aggressive tumour, adriamycin inhibited tumour growth. When given together with cyclosporine this inhibition was counteracted. These data suggest that adriamycin, especially when given together with cyclosporine, may have a stimulatory effect on liver tumour cell growth.Transplant International 09/2005; 18(8):992-1000. · 2.92 Impact Factor -
Article: Posttransplant lymphoma--a single-center experience of 500 liver transplantations.
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ABSTRACT: Posttransplant lymphoproliferative disease (PTLD) is a serious complication after organ transplantation associated with a high mortality, and is often caused by a primary or reactivated Epstein-Barr virus (EBV) infection. The incidence of PTLD ranges from 1% to 10%, depending on the type of organ transplanted and the immunosuppressive regimens used. In this retrospective study from a single center, 12 (2.4%) of 500 consecutive recipients of liver grafts developed lymphoma. Patient data were obtained by chart review. All diagnostic biopsies were reviewed by two hematopathologists. The median time between transplantation and the diagnosis of lymphoma was 19.5 (1.5-148) mo. Nine of the patients had been treated with OKT-3 and/or ATG after the transplantation. Two patients had a pretransplant diagnosis of lymphoma. The PTLD was of high grade in all patients, and was associated with EBV in 6 of 9 examined cases. No relation with human herpesvirus-8 could be detected. In all patients, immunosuppression was reduced at the time of lymphoma diagnosis. Chemotherapy was used in all patients, mostly upfront but in one patient after lymphoma progression after reduction of immunosuppression. Nine patients also got antiviral therapy. Immunotherapy with the monoclonal antibody rituximab was used in one patient. Half of the patients are alive, in complete continuous remission, more than 4 yr after the lymphoma diagnosis. Two patients died of neutropenic sepsis, three of persistent lymphoma, and one of recurrent cirrhosis while in complete remission. PTLD is a significant complication in liver-transplanted patients. Intensive chemotherapy can induce long-term remissions in a substantial number of patients. The role for monoclonal antibodies in this setting should be investigated further.Medical Oncology 02/2004; 21(3):273-84. · 2.14 Impact Factor -
Article: Liver transplantation followed by adjuvant nonmyeloablative hemopoietic stem cell transplantation for advanced primary liver cancer in humans.
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ABSTRACT: Tumor recurrence after orthotopic liver transplantation (OLT) in patients with advanced primary liver cancer is common. To achieve an adjuvant graft-versus-tumor effect, the authors investigated whether transplantation of allogeneic peripheral blood stem cells (PSCT) after OLT can induce sustained complete donor chimerism. Five patients with advanced primary liver cancer were included in the trial. None of the patients had signs of extrahepatic tumor before OLT. However, overall, the extent of surgery, as judged by morphologic examination of the explanted liver, was considered inadequate. A nonmyeloablative preparative regimen of fludarabine combined with total-body irradiation or cyclophosphamide preceded the allogeneic PSCT, which was then performed 16 to 135 days after OLT with human leukocyte antigen-matched donors. Mixed chimerism was monitored weekly by polymerase chain reaction of variable number tandem repeats after PSCT. In two patients, no engraftment of donor cells was seen, whereas one rejected the cells 2 months after PSCT. In two of the patients, a stable mixed donor chimerism was established. A mild transient graft-versus-host reaction was also noted in two patients. Three of the patients died of progressive disease 7 to 9 months after OLT. The other two are presently alive without recurrence at a follow-up of 26 and 10 months, respectively. These data suggest that PSCT after OLT is feasible, with low transplant-related morbidity. The rate of nonengraftment or rejection of the transplanted stem cells in this group of patients was three of five. An augmented pretreatment to prevent donor T-cell rejection seems to be necessary in this setting.Transplantation 05/2003; 75(7):1061-6. · 4.00 Impact Factor -
Article: Transplantation of Autologous and Allogeneic Bone Marrow With Liver From A Cadaveric Donor for Primary Liver Cancer1
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ABSTRACT: Background. In histocompatibility mismatched experimental animals, a combination of T-cell-depleted autologous and allogeneic marrow may induce mixed chimerism and tolerance. Patients with large primary liver tumors have a poor outcome. We investigated whether it were possible to induce mixed chimerism and obtain an antitumor effect in a patient with a large primary liver cancer after combined liver and bone marrow transplantation (BMT). Methods. A 46-year-old female with a primary non resectable liver cancer received a liver transplant from a cadaveric donor. Subsequently, she was conditioned with 4×2 Gy of total lymphoid irradiation, 120 mg/kg cyclophosphamide, and 7.5 Gy total body irradiation. Twelve days after liver transplantation, she received T-cell-depleted autologous : cadaveric 5/6 antigen HLA-mismatched marrow in a proportion of CD34+ cells of 0.5 : 3.0×106/kg. Chimerism status was determined with polymerase chain reaction amplification of variable number tandem repeats from DNA obtained from CD3+, CD19+, and CD45+ magnetic-bead-separated cells. Results. The early posttransplant period was uneventful; liver function was normal and the hematopoietic engraftment of donor and recipient origin was prompt. α-fetoprotein levels dropped from 440 to 35 μg/l. One month after marrow transplantation, donor T-cells decreased markedly. Monoclonal antibody OKT-3 and 105/kg donor T-cells were given. One month later, the patient developed diarrhea and abdominal pain. A colonoscopy showed moderate gastrointestinal acute graft-versus-host disease and a Cryptosporidium infection. Three months after BMT, she became a complete donor chimera. Chimera cells showed little, if any, reactivity in mixed lymphocyte cultures to recipient and donor cells, but reacted to third party. Five months after BMT, she developed progressive Aspergillus fumigatus pneumonia and died. No tumor was found at the autopsy. Conclusion. We obtained mixed donor-recipient hematopoietic chimerism without severe acute graft-versus-host-disease, after combined T-cell depleted autologous and allogeneic BMT and a transplantation of a liver from an HLA-mismatched cadaveric donor. Additional donor T-cells enhanced donor bone marrow engraftment, but rejected the autograft. On the basis of this first attempt, further clinical studies are warranted.Transplantation 05/2000; 69(10):2043-2048. · 4.00 Impact Factor
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Institutions
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2006–2007
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Karolinska University Hospital
Stockholm, Stockholm, Sweden
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