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Biomedical subjects

K M Olthoff

Publications and source records attributed to K M Olthoff.

At least 19 recordsLinked to original sources
PubMed2006

Treatment of PTLD with rituximab or chemotherapy.

Information regarding treatment of post-transplant lymphoproliferative disease (PTLD) beyond reduction in immunosuppression (RI) is limited. We retrospectively evaluated patients receiving rituximab and/or chemotherapy for PTLD for response, time to treatment failure (TTF) and overall survival (OS). Thirty-five patients met inclusion criteria. Twenty-two underwent rituximab treatment, with overall response rate (ORR) 68%. Median TTF was not reached at 19 months and estimated OS was 31 months. In univariable analysis, Epstein-Barr virus (EBV) positivity predicted response and TTF. LDH elevation predicted shorter OS. No patient died of rituximab toxicity and all patients who progressed underwent further treatment with chemotherapy. Twenty-three patients received chemotherapy. ORR was 74%, median TTF was 10.5 months and estimated OS was 42 months. Prognostic factors for response included stage, LDH and allograft involvement by tumor. These factors and lack of complete response (CR) predicted poor survival. Twenty-six percent of the patients receiving chemotherapy died of toxicity. Rituximab and chemotherapy are effective in patients with PTLD who fail or do not tolerate RI. While rituximab is well tolerated, toxicity of chemotherapy is marked. PTLD patients requiring therapy beyond RI should be considered for rituximab, especially with EBV-positive disease. Chemotherapy should be reserved for patients who fail rituximab, have EBV-negative tumors or need a rapid response.

Adult↗
PubMed2005

Successful liver, kidney, and pancreas transplantation from a donor with cerebral emboli from a left atrial myxoma.

Although transmission and engraftment of donor-derived malignancies is rare in recipients of solid organ transplants, it is associated with unfavorable allograft and patient survival. Therefore, a recent history of malignancy is considered a contraindication to organ donation. Although atrial myxomas are benign cardiac tumors of stromal origin, they can lead to systemic embolization with ectopic myxoma formation. We report successful liver, kidney, and pancreas transplantation into 3 recipients from a donor with cerebral emboli from a left atrial myxoma. Eighteen months after transplantation, all 3 patients enjoy good allograft function and are free of donor-derived atrial myxoma. Although the duration of follow-up in this report is limited, we suggest that the presence of atrial myxoma should not be viewed as an absolute contraindication to organ recovery, particularly in view of the shortage of organ donors and the attendant morbidity and mortality for patients on waiting lists.

Adolescent↗
PubMed2001

Pattern of alloimmune response in second same donor allografts after induction of tolerance using CTLA4Ig.

BACKGROUND: The pattern of allograft acceptance in the presence of costimulatory blockade is manifested by the sequential appearance of Th1 cells, followed by Th2 cells. The aim of this study was to examine whether this phenomenon repeats itself after second same donor allotransplantation, hoping to determine whether acceptance in this setting provokes a predominance of the Th2 response. METHODS: Tolerance was achieved by transplantation of CTLA4Ig-transduced ACI liver allografts in Lewis recipients. Recipient long-term survivors received a second transplant, consisting of a cervical heterotopic heart from the same ACI donor strain. Animals were sacrificed at predetermined intervals following the second transplant and the heart and liver were processed for histology and cytokine mRNA expression. RESULTS: Recipients of CTLA4Ig-transduced livers survived indefinitely. Rechallenge with same donor strain second allograft was manifested by an anergic immune response in the second cardiac allograft, and a very mild transient infiltrate within the first accepted liver graft. Cardiac function was maintained with resolution of all infiltrates. The cytokine cascade was activated within the allografts; however, the pattern of acceptance was not associated with predominance of a specific Th subtype. CONCLUSIONS: The pattern of acceptance of an allograft following CTLA4Ig-mediated costimulatory blockade is not related to long-term predominance of Th2 cells, a phenomenon that may be unique to the setting of a tolerant liver. It may be likely that the infiltrating lymphocytes that are dominant in the second graft are suppressed by other memory mechanisms.

Abatacept↗
PubMed2001

Modified AdCTLA-4 vector blocks alloimmune response in vitro.

BACKGROUND: Gene transfer of the costimulatory blockade molecule CTLA-4Ig into cold-preserved rat liver allografts results in indefinite allograft survival. Despite local delivery, this mode of immunomodulation is associated with systemic immunosuppression. In an effort to restrict immunosuppression to the graft, we have constructed a novel adenoviral vector, AdCTLA-4ex-TAG, in which the Ig sequence of CTLA-4Ig DNA has been deleted to destabilize the gene product to promote rapid extrahepatic degradation while maintaining its immunosuppressive activity within the graft milieu. METHODS: (1) Vector construction. CTLA-4 extracellular binding domain (CTLA-4ex) was prepared by PCR-based cloning methods and fused in frame to a genetic element encoding an epitope TAG allowing identification of the transgene product CTLA-4exTAG. CTLA-4exTAG was subcloned into a shuttle vector enabling isolation of AdCTLA-4exTAG. (2) In vitro transfection: AdCTLA-4exTAG was transfected into MH(1)C(1) cells and then supernatant was recovered for Western blot analysis. (3) In vitro alloimmune response was characterized by CFSE proliferation assay. (4) Extrahepatic effect of AdCTLA-4exTAG was characterized by the ability to control tumor growth after implantation of a regressive, immune sensitive cancer cell line (REGb) in the skin of BDIX rats after liver transduction with AdCTLA-4exTAG. RESULTS: Expression and secretion of the recombinant protein were documented by Western blot after infection of the MH(1)C(1) cell line() with AdCTLA-4exTAG. Addition of infected MH(1)C(1) cell supernatant resulted in abrogation of alloimmune response as shown by markedly diminished division of CD4(+) T cells in a CFSE proliferation assay. Extrahepatic tumor regressed normally after liver transduction with AdCTLA-4exTAG. CONCLUSIONS: These results show efficient in vitro expression of CTLA-4exTAG after transfection with AdCTLA-4exTAG. The modified protein retains its ability to abrogate in vitro alloimmune response. Efficient control of extrahepatic tumor growth after liver-directed delivery of AdCTLA-4exTAG suggests that the immunosuppressive effect of this vector is restricted to the liver. These results set the ground for the utilization of this novel adenoviral vector in the transplant setting.

Abatacept↗
PubMed2001

Guidelines for the referral and management of patients eligible for solid organ transplantation.

Members of the Clinical Practice Committee, American Society of Transplantation, have attempted to define referral criteria for solid organ transplantation. Work done by the Clinical Practice Committee does not represent the official position of the American Society of Transplantation. Recipients for solid organ transplantation are growing in numbers, progressively outstripping the availability of organ donors. As there may be discrepancies in referral practice and, therefore, inequity may exist in terms of access to transplantation, there needs to be uniformity about who should be referred to transplant centers so the system is fair for all patients. A review of the literature that is both generic and organ specific has been conducted so referring physicians can understand the criteria that make the patient a suitable potential transplant candidate. The psychosocial milieu that needs to be addressed is part of the transplant evaluation. Early intervention and evaluation appear to play a positive role in maximizing quality of life for the transplant recipient. There is evidence, especially in nephrology, that the majority of patients with progressive failure are referred to transplant centers at a late stage of disease. Evidence-based medicine forms the basis for medical decision-making about accepting the patient as a transplant candidate. The exact criteria for each organ are detailed. These guidelines reflect consensus opinions, synthesized by the authors after extensive literature review and reflecting the experience at their major transplant centers. These guidelines can be distributed by transplant centers to referring physicians, to aid them in understanding who is potentially an acceptable candidate for transplantation. The more familiar physicians are with the exact criteria for specific organ transplantation, the more likely they are to refer patients at an appropriate stage. Individual transplant centers will make final decisions on acceptability for transplantation based on specific patient factors. It is hoped that this overview will assist insurers/payors in reimbursing transplant centers for solid organ transplantation, based on criteria for acceptability by the transplant community. The selection and management of patients with end-stage organ failure are constantly changing, and future advances may make obsolete some of the criteria mentioned in the guidelines. Most importantly, these are intended to be guidelines, not rules.

Adaptation, Psychological↗
PubMed2001

Activation of interleukin-6/STAT3 and liver regeneration following transplantation.

BACKGROUND: Every liver that is procured, stored, and transplanted experiences injury from cold ischemia and reperfusion. Most recover quickly, but some grafts sustain enough injury to result in prolonged organ dysfunction or require retransplantation. The molecular mechanisms involved in early graft function and recovery following cold ischemia and reperfusion (I/R) after liver transplantation have not been well defined. Interleukin (IL)-6 is a critical factor in the mitogenic response within the liver, and is important for cell cycle progression and protection from injury. Activation of the latent transcription factor, STAT3, is dependent on IL-6 release. The role of the IL-6/STAT3 pathway and hepatocellular regeneration in graft recovery and cell cycle progression following cold ischemia and reperfusion was studied in a rat liver transplant orthotopic (OLT) model. Methods. Rat OLT was performed in a syngeneic model. The presence, time course, and magnitude of expression of IL-6, STAT3 activation, and upregulation of target immediate early genes were determined in liver grafts with minimal (<1 h) and prolonged (12 h) cold preservation times followed by transplantation. Progression of the cell cycle and replication was confirmed by BrdU uptake. RESULTS: Prolonged cold ischemia resulted in increased IL-6 expression and STAT3 activation. This correlated with upregulation of junB, c-fos, c-myc, and c-jun, immediate early genes associated with hepatic regeneration. Extensive DNA replication was present in livers with 12-h ischemia, demonstrating successful completion of the cell cycle. CONCLUSIONS: The participation of the IL-6/STAT3 pathway leading to cell cycle progression and regeneration is an important component in the recovery of organs immediately following cold preservation and transplantation.

Animals↗
PubMed2001

Role of plasmapheresis in the management of acute hepatic failure in children.

OBJECTIVE: To assess the efficacy of plasmapheresis in the treatment of children with acute hepatic failure. SUMMARY BACKGROUND DATA: Acute liver failure is expressed with severe encephalopathy, coagulopathy, and subsequent multisystem organ failure, resulting in a high death rate. Liver transplantation is considered the best option, with long-term 1-year survival rates exceeding 88%. It has been suggested that plasmapheresis may improve coagulopathy and prevent bleeding complications while maintaining adequate fluid, electrolyte, and acid-base balance. METHODS: Forty-nine patients with acute liver failure underwent a total of 243 therapeutic plasma exchanges (TPE). Indications for treatment included candidacy for liver transplant and prolonged prothrombin time. Pheresis was performed daily until the patient recovered, died, or was transplanted. Four patients were anhepatic during pheresis. RESULTS: Coagulation profiles after TPE significantly improved compared with mean preexchange values while maintaining euvolemia. No bleeding episodes were observed during the course of treatment. There was no sustained improvement in neurologic function. Spontaneous recovery was observed in three patients; the remaining either underwent transplantation (32/49) or were not considered transplant candidates because of irreversible neurologic insults (11/49) or sepsis (3/49). CONCLUSION: For children with acute liver failure, TPE is extremely effective in preventing life-threatening bleeding while maintaining appropriate volume status in small children. This method of treatment has no effect on the neurologic complications of liver failure and has no impact on the ability of the liver to regenerate.

Acute Disease↗
PubMed2000

The fate of liver grafts declined for subjective reasons and transplanted out of a local organ procurement organization.

BACKGROUND: Decisions made by transplant surgeons to decline liver grafts for local use are based on both objective and ill-defined subjective parameters. These livers may be offered and subsequently transplanted at non-local centers. We analyzed the fate of these exported livers, focusing on the outcome of grafts declined for subjective reasons. The aim is to determine whether local surgeons' concerns about inferior graft function are justified. METHODS: Over a 3-year period, 13.3% of 555 livers in our organ procurement organization (OPO) were exported and transplanted out of the local area. Donor data and reason for decline were obtained from an extensive OPO database. Objective reasons for decline were based on no appropriate matched recipient due to donor size, serologies, or malignancy with potential for spread. Subjective parameters were related to the procuring surgeon's assessment and included variables such as medical and social history, abnormal liver enzymes, older age, organ visualization, and biopsy. Recipient data were obtained from questionnaires sent to outside transplant centers. RESULTS: There was a significantly higher rate of nonfunction in the subjective group (17.1%), compared to the objective group (0%). One-year graft and patient survival were 79 and 83% for the objective group and 59 and 68% for the subjective group (P=NS). When donors declined for medical/social history were excluded from the subjective group, leaving only grafts declined based solely on the surgeon's assessment of graft quality, there is a significant difference in graft survival (79% for objective and 46% for this subjective subgroup, P=0.03). CONCLUSIONS: Livers declined for local use based on subjective assessment by the procuring surgeon have a high nonfunction rate, associated with a high morbidity. Therefore, the use of these grafts should be restricted to recipients at the most urgent status.

Adolescent↗
PubMed2000

Successful reversal of recalcitrant hepatic allograft rejection by photopheresis.

Extracorporeal photopheresis (ECP) is an immunologic modality that has shown efficacy in the treatment of clonal T-cell diseases, including Sézary syndrome and allograft rejection. In this case report, we expand on this observation to include recalcitrant hepatic allograft rejection. A 14-year-old boy with hepatic allograft rejection refractory to high-dose corticosteroid and lymphocytolytic therapy was treated with 4 sessions of ECP over a 6-week period. After 2 sessions, a liver biopsy showed complete reversal of acute cell-mediated rejection. No opportunistic infections or other adverse events were noted. Photopheresis appears to be a safe and effective modality for the treatment of refractory hepatic allograft rejection.

Adolescent↗
PubMed1999

Supraceliac aortic pseudoaneurysms after liver transplantation in infants.

BACKGROUND: Reconstruction of the hepatic artery in infants undergoing liver transplantation presents challenging vascular situations. Microvascular techniques ensure arterial blood flow via small caliber vessels but are insufficient when inflow is poor. In these situations, the use of allogeneic grafts to the supraceliac aorta have been advocated. The development of a pseudoaneurysm at the supraceliac aortic suture line requires urgent repair and restoration of arterial flow to the graft. METHODS: Our study was based on case reports and review of the literature. RESULTS: Definitive diagnosis and successful repair of supraceliac pseudoaneurysm was accomplished in two infants after transplantation. CONCLUSION: We advocate a thoracoabdominal retroperitoneal approach, which provides safe control of the aorta and primary repair or patching of the diseased aortic segment, and also provides access for hepatic revascularization via placement of an infrarenal graft. Thrombosis of the artery and subsequent liver necrosis are indications for retransplantation.

Aneurysm, False↗
PubMed1999

Liver transplantation at the University of Pennsylvania and the Children's Hospital of Philadelphia.

The liver transplant program at the University of Pennsylvania and the Children's Hospital of Philadelphia experienced healthy growth in its clinical activity in the past 5 years. Patterns of referral and patient evaluation were established, care of patients while waiting on the list or being followed after transplantation was streamlined. We are now achieving excellent outcomes while transplanting relatively sicker patients. Innovative surgical procedures are implemented resulting in more efficient utilization of cadaveric and living-donor liver grafts. The protocols that are used for patient care are more standard, yet flexible and accommodate recent advancement in transplantation immunobiology. This progress of the clinical program was enhanced by careful preservation of the academic mission of the institution, which encourages the liver transplant faculty to be involved in NIH-supported clinical and basic science research.

Adult↗
PubMed1998

Adenovirus-mediated gene transfer into cold-preserved liver allografts: survival pattern and unresponsiveness following transduction with CTLA4Ig.

The immune response of liver transplant recipients was modulated via adenovirus-mediated transduction of the cold-preserved liver with sequences encoding CTLA4Ig. Transplanted allografts demonstrated rapid transient local expression and recombinant protein production shortly after revascularization, resulting in intact liver function, indefinite survival of the recipient, and the development of donor-specific unresponsiveness. Lymphocytic infiltration of the graft was mainly of the T helper 2 (Th2) subset and was not associated with injury to primary cellular targets of the alloimmune response. These findings demonstrate a successful outcome of a feasible and potentially clinically relevant system of gene delivery of sequences encoding proteins capable of inhibiting the alloimmune response.

Abatacept↗
PubMed1998

Indications for pediatric liver transplantation.

This review discusses the indications for orthotopic liver transplantation (OLT) in children and provides guidelines for the appropriate time to list children for transplant. The diseases for which OLT are indicated in children are divided into diagnostic categories with a focus on the natural history and appropriate medical and surgical therapy prior to transplantation. Contraindications to transplantation pertinent to specific diseases are outlined, with particular emphasis on complex metabolic defects with extrahepatic manifestations. The clinical conditions which indicate that listing for OLT is appropriate, as well as the relative and absolute contraindications, irrespective of diagnosis, are discussed. The importance of malnutrition and poor development as listing criteria is stressed. Special timing considerations for diagnoses relevant to the pediatric age group, e.g. urea cycle defects and Crigler-Najjar syndrome, are emphasized. Finally, the impact of co-existing extrahepatic disease on the decision to list children for OLT is reviewed.

Child↗
PubMed1998

Surgical options for hepatocellular carcinoma: resection and transplantation.

Surgical resection remains the best option for potential cure and long-term survival in patients with HCC. The question of to what extent transplantation for HCC should be performed remains controversial. There appears to be a definite role for OLT in the treatment of HCC, with many series showing improved survival over resection, especially with "favorable" tumors. What remains to be determined are the best patients and the best protocol. There is little question that patients with small unifocal tumors do well after OLT. It is the patient who falls outside of these narrow guidelines that poses a problem in clinical decision making and organ allocation. The ability to determine relative risk of recurrence of HCC would perhaps allow a more equitable allocation of a scarce resource. Currently, we evaluate each patient with HCC on an individual basis, making the best decision possible based on the patient's clinical status, our most advanced current imaging studies, and known clinical prognostic factors (Table 6). Adequate staging is essential to determine suitable candidates. Advances in multimodal adjuvant therapy are needed for patients with poor prognostic factors to achieve results similar to what is seen in those who receive transplants for nonmalignant diseases. Attempts at resection should be performed for those patients presenting with Child's class A cirrhosis, because these are the patients who would tolerate a resection with acceptable morbidity and mortality. Limited resections based on segmental anatomy may be consider in "good risk" Child's class B cirrhotics, considering the current organ shortage. Child's class C and decompensated Child's class B patients without significant risk factors should be evaluated for transplantation, and preoperative chemoembolization should be considered to prevent spread while the patient is on the waiting list. These patients should be monitored with imaging studies and by AFP levels on a regular basis while they await their transplant. After transplantation, chemotherapy should be considered for those patients with moderate to high risk of recurrence, within the guidelines of an institutional or multicenter protocol. In patients with multiple poor prognostic factors, or those who are too ill to undergo resection or transplantation, palliative measures may be used. As the need for organs increases, and the wait continues to grow, it becomes increasingly difficult to justify the use of a scarce resource for patients with a known less desirable outcome. On the other hand, we must be careful not to exclude an entire group of patients from a potentially curative procedure. We now have evidence that survival after transplantation for HCC in carefully chosen patients can equal that of benign disease. We need to be selective and cautious in our choice of recipients, but not exclusive, using prior experience and the knowledge we now possess regarding a set of fairly well-delineated risk factors.

Carcinoma, Hepatocellular↗
PubMed1997

Randomized controlled trial to evaluate flush and reperfusion techniques in liver transplantation.

To determine the impact of different flush and reperfusion techniques on postreperfusion syndrome (PRS) and postoperative graft function, 100 transplants were randomly assigned into four groups as follows: group 1 (n=31), portal vein flush, no vena caval venting; group 2 (n=21), hepatic arterial flush, no vena caval venting; group 3 (n=29), portal vein flush with vena caval venting; and group 4 (n=19), hepatic artery flush with vena caval venting. Donor and recipient characteristics were similar. Extensive intraoperative and postoperative monitoring was performed and measurements were documented immediately before reperfusion and at 1, 5, 15, and 30 min after reperfusion. PRS was defined by three criteria: mean arterial pressure (MAP) <60 mmHg at 1 min after reperfusion, MAP <60 mmHg at 5 min after reperfusion, and a decrease of 30% or more for the MAP percent area under the curve during the initial 5 min after reperfusion (%AUC). Using these definitions, the overall incidence of PRS was 21%, 8%, and 43%, respectively. Group 1 was the most hemodynamically stable; the incidence of PRS in group 1 was 2/31 (7%) at 1 min and 8/31 (25%) using %AUC criteria compared with 7/21 (33%) at 1 min and 12/21 (57%) using %AUC criteria for group 2 (P<0.05). The patients in groups 3 and 4 (vena caval venting) demonstrated smaller percentage increases in serum potassium levels (as determined by %AUC; 4.3+/-6.8 and 0.3+/-5.4, vs. 15.1+/-8.1 for group 1 and 22.9+/-8.2 for group 2). The difference between group 4 and group 2 was statistically significant (P<0.05). The increases in serum potassium did not translate into increased cardiac or hemodynamic instability. Combining all data obtained over the first 30 min after reperfusion, there was no statistically significant difference in hemodynamic or biochemical changes noted among the four groups. Postoperative liver function was similar among the four groups. We conclude that portal vein flush without vena caval venting provided a lower incidence of PRS than any other technique. Vena caval venting decreased the release of potassium into the circulation. Postoperative graft function was not significantly affected by flush and reperfusion techniques.

Adult↗
PubMed1997

Assessment of liver function: pre- and peritransplant evaluation.

Liver transplantation has been demonstrated to be a successful therapeutic modality for patients with end-stage liver disease. The high rate of survival for an otherwise terminal condition has resulted in significant expansion of the indications and diseases treated by this procedure, and is hampered only by the limited numbers of organs available for transplantation. Efforts in clinical and laboratory medicine should be directed to identify candidates who would benefit most from this procedure, to provide better means for accurate assessment of liver reserve and the appropriate timing for transplantation, to identify quality liver grafts that would have the potential to tolerate cold preservation and reperfusion injury, and to assist in accurate monitoring of graft function immediately after transplantation. The aim of this manuscript is to describe the existing pathways for clinical and laboratory assessment of pretransplant residual liver function, the donor liver graft, and immediate posttransplantation function.

Humans↗