Optimal Timing Of Transplantation Research Articles

In vivo and in silico studies on single versus multiple transplants for multiple myeloma

High-dose therapy and autologous stem cell transplantation (HDT-ASCT) have significantly improved survival in multiple myeloma (MM). However, patients are not cured, responses are variable and only about 40% of patients achieve a complete response (CR). Optimal timing of the procedure and knowledge of the relapse kinetics may assist physicians when they consider this therapeutic modality for their patients. We analyzed myeloma tumor burden and kinetics before and after HDT-ASCT in a cohort of 265 patients. Disease burden was estimated from serial M-spike measurements and the data fitted to the Gompertz function to determine the general parameters for all patients. Functions that couple disease burden and kinetics with time to progression (TTP) were derived and used to determine the optimal timing of transplantation. Patients who achieve CR with the first episode of HDT-ASCT should not be routinely offered tandem transplantation but carefully monitored and transplanted at an optimal disease burden. If CR is not achieved with a first trial of HDT-ASCT, the probability of CR after a tandem second trial is approximately 10%. TTP after tandem transplants (with its higher associated mortality) cannot be superior to TTP achieved with optimally timed serial transplants. Individualized HDT-ASCT for patients with MM is possible and may optimize results.

In vivo imaging of engrafted neural stem cells: its application in evaluating the optimal timing of transplantation for spinal cord injury

Neural stem/progenitor cells (NSPCs) hold promise in neural tissue replacement therapy after spinal cord injury. However, understanding the survival time of grafted NSPCs and determining the extent of migration away from transplantation sites are essential for optimizing treatment regimens. Here, we used in vivo bioluminescence imaging to noninvasively assess the survival and residence time of transplanted NSPCs at the injury sites in living animals, and we used histologic analyses to assess cell integration and morphology. Third-generation lentiviral vectors enabled efficient transduction and stable expression of both luciferase and a variant of green fluorescent protein in primary cultured NSPCs. Signals from these cells were detectable for up to 10 months or more after transplantation into the injured spinal cords of C57BL/6J mice. Histological and functional data supported the imaging data and suggest that the timing of NSPC transplantation may be a key determinant of the fates and function of integrated cells since cell survival and migration depended on the time of transplantation relative to injury. Optimization of cell therapies can be greatly accelerated and refined by imaging, and the methods in the present study can be widely applied to various research fields of regeneration medicine, including transplantation study.

Neocartilage from human mesenchymal stem cells in alginate: Implied timing of transplantation

Previous reports have demonstrated the suitability of alginate microencapsulation for chondrogenesis of human mesenchymal stem cells (MSCs) in vitro. This study examined the MSCs-alginate constructs that were transplanted beneath the dorsal skin of nude mice for 8 weeks after a variety of in vitro culture periods. The in vitro culture had great effects on gross morphology and histological characteristics of transplants. The integrity of alginate of transplants increased as the in vitro culture period increased. Transplants were characterized by an opaque and yellowish color, fair burnish, a firm to elastic texture, but without any evidence of calcification spots. Histological findings agreed with the clinical determination of hyaline cartilage, characterized by isolated cells with basophilic ground substance positive in Safranin-O staining and collagen type II immunohistochemistry. Transplants with exposure to TGF-beta1 for more than 2 weeks before transplantation, lost burnish, were flexible in texture, and had an increased formation of calcification spots. Accordingly, 1-week exposure to TGF-beta1 in vitro before transplantation is appropriate for neocartilage formation of human MSCs in alginate. These findings suggested that regeneration using cell therapy or tissue engineering should assist in ascertaining the optimal timing of transplantation.

The 6-Minute Walk Test Does Not Reliably Detect Changes in Functional Capacity of Patients Awaiting Cardiac Transplantation

Peak oxygen consumption (Vo(2)peak) is a strong independent predictor of prognosis in patients with severe chronic heart failure (CHF) and is used to guide optimal timing of transplantation. However, its assessment is relatively expensive and time-consuming and requires sophisticated equipment and highly trained personnel. The purpose of this study was to determine whether changes in 6-minute walk test (6WT) distance, a simple, inexpensive potential alternative measure of functional capacity, can predict changes in Vo(2)peak in patients with severe CHF. Sixteen subjects (ejection fraction 23+/-2%, Vo(2)peak 16.2+/-1.1 ml kg (-1)min(-1)) underwent repeated 6WT and Vo(2)peak assessments that included familiarization and 4 serial measures, 6 weeks apart (baseline and at Weeks 6, 12 and 18). Analysis compared baseline performance with each subsequent testing occasion. At baseline, mean (+/-SE) VO(2)peak was 16.3+/-1.1 ml kg(-1) min(-1) and 6WT distance was 458+/-21 m. 6WT and Vo(2)peak were strongly correlated at all timepoints (average r=0.82; all p<0.05). However, mixed model analysis, assessing the capacity of the changes seen in 6WT to predict changes in Vo(2)peak, showed no statistical significance (F=0.11; p=0.74). The 6WT is commonly used to assess functional capacity in patients with heart failure. This study demonstrates that, despite a strong cross-sectional correlation with Vo(2)peak, changes in the 6WT are not a reliable predictor of changes in Vo(2)peak within patients. Therefore, the 6WT has limited utility as a serial measure to assess changes in the clinical status of patients with severe heart failure.

Innovations in autologous transplantation for hematologic malignancy

Improvements in supportive care and the use of peripheral blood stem cells have increased the safety of autologous transplantation, making it an effective therapy for more patients with hematologic malignancies and some solid tumors. Although more patients, including older patients, are successfully undergoing transplantation, the major obstacle to long-term success remains relapse. In addition to relapse, there are some unresolved questions concerning the optimal timing of transplantation (first remission versus relapse) and the type of regimen (radiation based or chemotherapy based).

New concepts in organ transplantation

Over the past several decades, many factors have led to higher rates of patient and graft survival in organ transplantation. These factors include enhanced immunosuppressants available in recent years such as Neoral, Prograf, sirolimus, mycophenolate mofetil and anti–interleukin-2 receptor monoclonal antibodies. In addition, other new drugs, such as FTY 720, FK 778, anti-CD20, anti-CD40, and anti-CH52 monoclonal antibodies, are now being tested in clinical studies. Furthermore, there have been advances in surgical techniques, such as the piggyback method without venovenous bypass, side-to-side anastomosis of the hepatic veins, use of vascular staplers, biliary duct-to-duct anastomosis with or without tube drainage, microsurgical hepatic artery anastomosis and laparoscopic donor nephrectomy. Finally, better patient and donor selection criteria with regard to HBV- and HCV-seropositive donors, diabetic donors, donors with malignancies, older donors, ABO-incompatible donors, and non–heart-beating donors have been combined with optimal timing of transplantation, better options for treating early surgical and late medical complications, and improved management in intensive-care units. Other noteworthy scientific and social development are on the horizon namely genetic advances in xenografting and cell transplantation, and induction of immunologic tolerance. This article reviews the current developments that have significantly improved graft and patient survival among solid-organ transplants.

Cystic fibrosis and lung transplantation--determination of the survival benefit.

Cystic fibrosis is a well acknowledged indication for lung transplantation; however, the optimal timing for transplantation remains debatable. Liou et al. described a score for calculating 5-year probability of survival for patients with cystic fibrosis and concluded that only patients with a probability of survival < 30% gained a survival benefit from transplantation; those between 30% and 50% had equivocal survival effects from transplantation and those > 50% suffered negative effects. The aim of the present study was to determine the validity and applicability of this model. Data from patients with cystic fibrosis transplanted between January 1995 and July 2001 were retrospectively reviewed. Survival score according to Liou was calculated from data collected before transplantation. Patients were classified according to 5-year probability of survival (group 1: < 30%, group 2: 30%-50%, groups 3-5: > 50%). Actuarial survival rates were calculated separately for each group and compared with the predicted probability of survival. During the observation period 27 patients were transplanted for cystic fibrosis. Three patients had to be excluded from further analysis because of incomplete pretransplant data. Fifteen patients were classified as group 1 and nine patients as group 2. No patients were eligible for groups 3 to 5. There were nine female patients and six males in group 1, mean age 22.1 +/- 4.9 years. Mean survival time was 918 +/- 787 days; 1-, 3- and 5-year survival rates were 66.6%. Three male patients and six females were classified as group 2, mean age 26.2 +/- 12.2 years. Mean survival time for this group was 701 +/- 617 days, and 1-, 3- and 5-year survival rates were 66.6%. We found that only patients with a 5-year probability of survival < 50% had been transplanted. For patients in groups 1 and 2 we report identical 5-year survival rates of 66.6%. According to our experience, cystic fibrosis patients with a 5-year probability of survival < 30% and also those between 30% and 50% gain a clear survival benefit from bilateral lung transplantation.

Transplantation of neural stem cells into the spinal cord after injury.

Thanks to advances in the stem cell biology of the central nervous system (CNS), the previously inconceivable regeneration of the damaged CNS is approaching reality. The availability of signals to induce the appropriate differentiation of the transplanted and/or endogenous neural stem cells (NSCs) as well as the timing of the transplantation are important for successful functional recovery of the damaged CNS. Because the immediately post-traumatic microenvironment of the spinal cord is in an acute inflammatory stage, it is not favorable for the survival and differentiation of NSC transplants. On the other hand, in the chronic stage after injury, glial scars form in the injured site that inhibit the regeneration of neuronal axons. Thus, we believe that the optimal timing of transplantation is 1-2 weeks after injury.

Cystic fibrosis and lung transplantation - determination of the survival benefit

Introduction Cystic fibrosis is a well acknowledged indication for lung transplantation; however, the optimal timing for transplantation remains debatable. Liou et al. described a score for calculating 5-year probability of survival for patients with cystic fibrosis and concluded that only patients with a probability of survival 50% suffered negative effects. The aim of the present study was to determine the validity and applicability of this model.

Research agenda for pediatric gastroenterology, hepatology and nutrition: transplantation. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Research agenda for pediatric gastroenterology, hepatology and nutrition: transplantation. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Recent advances in pediatric liver transplantation.

Pediatric liver transplantation has matured into a well-established, highly successful treatment for advanced pediatric liver disease. Recent 1-year success rates range from 85% to 95%. This unprecedented achievement is the result of careful selection criteria and optimal timing of transplantation, technical advances in surgical technique, and improved treatment following transplant. This report highlights many recent published findings representing advances that have led to current successful approaches.

Progress in Renal Transplantation for Children

Renal transplantation continues to be the goal of therapy for children with end-stage renal disease. Patient age, primary renal disease, psychosocial status, living versus cadaver donor allograft, immunosuppressive therapy, urologic status, and maximization of growth and development must be considered in determining the optimal time for transplantation. Immunizations should be up to date, and the immune status of both the donor and the recipient with regard to Epstein Barr virus (EBV), cytomegalovirus (CMV), varicella, human immunodeficiency virus (HIV) and Hepatitis A, B, and C must be known. Prednisone; cyclosporine or tacrolimus; and mycophenolate mofetil or azathioprine remain the mainstays of immunosuppression. However, new therapies such as sirolimus are under investigation for use in pediatric renal transplantation. Induction therapies include T-cell antibodies as well as the more recent addition of interleukin-2 receptor blockers. Complications including infection, rejection, and malignancy continue to be problematic in pediatric renal transplantation. There continues to be a strong focus on optimizing growth and development after transplant. Although patient and graft survival have improved over time, outcomes in pediatric renal transplantation continue to lag behind those in adults.

Liver Transplantation in Primary Biliary Cirrhosis: Risk Assessment and 11-Year Follow-Up

Background/Aims: Liver transplantation (LTx) is the only established treatment in patients with end-stage primary biliary cirrhosis (PBC). Although short-term survival after LTx in this group of patients is usually good, few data exist on the long-term survival. The optimal timing of transplantation is difficult. Thus, the aims of this study were to assess the long-term survival of patients with PBC after LTx and to identify potential predictive factors for a positive outcome. Methods: Survival of 28 patients with PBC who underwent LTx between 1985 and July 1999 in a single center was studied by Kaplan-Meier analysis and was compared to predicted survival without LTx using established prognostic models for PBC, the Mayo and European risk scores. Potential prognostic parameters obtained before LTx were tested for correlation to survival. Rates of bone fractures as markers of hepatic osteodystrophy were compared before and after LTx. Results: Median follow-up after LTx was 90 months with a maximum of 140 months. Actuarial survival of patients with PBC was 89% after 1, 5, and 10 years and was significantly better than estimated survival without LTx after 1–7 years as calculated by the Mayo and European risk scores. Of several parameters tested, only serum bilirubin and the prognostic scores, but no other liver function tests obtained immediately prior to transplantation were significantly correlated with survival after LTx. The duration of intensive care after LTx was not associated with any parameters obtained before LTx. Bone fractures were diagnosed in 43% of patients of whom the vast majority were osteopenic before LTx as determined by osteodensitometry. Conclusion: Long-term survival of a well-defined group of patients with PBC was excellent after LTx and was inversely correlated with preoperative serum bilirubin levels as well as Mayo and European risk scores.

Early harvest and late transplantation as an effective therapeutic strategy in multiple myeloma.

Transplantation after high-dose chemotherapy prolongs survival in patients with multiple myeloma compared with standard therapy. It is unclear whether the optimal timing of transplantation is immediately after induction chemotherapy or whether stem cells may be cryopreserved for transplantation at subsequent progression or relapse. In this study, stem cells were collected within 6 months of diagnosis, followed by transplantation only at progression of myeloma. One hundred and eighteen patients with multiple myeloma had stem cells collected and cryopreserved. Eleven had transplants early in the disease after they demonstrated failure to respond to primary therapy. The remaining 107 were eligible for transplants when there was evidence of progressive disease. Of the 118 patients, 67 had transplants, nine died of progressive disease before transplantation, and 42 remain alive in plateau phase. The median survival of the group is 58.5 months; 67 are alive. Serum beta2-microglobulin, bone marrow labeling index (S phase), and hemoglobin level predicted overall survival (P < 0.006, P < 0.001, and P < 0.01, respectively). We conclude that early cryopreservation of blood stem cells followed by transplantation at progression is a feasible approach to therapy in patients with myeloma. The underlying biology of the disease has a greater impact on survival than the timing of transplantation. A prospective randomized trial is required to answer definitively the question of the optimal timing of blood cell transplantation.

Optimal timing of liver transplantation for patients with primary biliary cirrhosis: use of prognostic modelling

Background/Aims: Liver transplantation remains the only definitive treatment for patients with end-stage primary biliary cirrhosis, although the optimal timing of the procedure remains uncertain. The aim of the study was to use prognostic modelling to determine the optimal timing of transplantation for patients with primary biliary cirrhosis.Methods: A prognostic model for predicting the survival of patients after transplantation was generated using the Cox regression model with data from 312 patients transplanted for primary biliary cirrhosis at the Queen Elizabeth Hospital, Birmingham. The prognosis after transplantation was compared to that without transplantation (using a previously published prognostic index for non-transplantation) both in these patients and in 98 non-transplanted primary biliary cirrhosis patients dying from the liver disease, in order to establish at what stage the prognosis with transplantation was better than without transplantation.Results: The prognostic index for transplantation included the following significant prognostic variables: serum bilirubin, serum albumin, age, year of transplantation, and the presence of ascites or treatment with diuretics. Comparison of prognosis with and without transplantation showed that the predicted gain in survival after transplantation becomes increasingly positive when the 6-month survival probability in the absence of transplantation falls below 0.85. In the non-transplanted patients this occurs on average about 8 months before death.Conclusions: Comparison of the prognosis with and without transplantation provides a rational method for determining the optimum timing of the procedure which occurs approximately when the predicted 6-month survival probability without transplantation falls below 0.85.

Perfect timing, no remorse, and kidney transplantation.

Kidney transplantation is usually delayed until a patient has reached end-stage renal failure. When a living donor is used, earlier transplantation may be feasible. By averting the final stages of renal failure, early transplantation spares the patient the more pronounced effects of uremia. Unfortunately, lack of precision in predicting the future course of a patient's disease creates a dilemma: the kidneys could remain viable longer than anticipated. In that case, an early transplantation that leads to serious complications or graft failure will have caused harm by truncating the period of time the patient could have been sustained by his or her native kidneys. The present article introduces a theorem that helps solve the dilemma of early kidney transplantation. The theorem states that the timing decision depends only on the current burden of a disease relative to the risks of transplantation-that the future rate of progression of the disease is immaterial. The generality of the theorem makes it applicable, in principle, to any degenerative disease that can be treated by engraftment. The article also introduces a formula for the optimal timing of transplantation that depends on only four factors--a patient's perceived quality of life before transplantation as a function of time, the mortality associated with a transplant operation, the graft survival curve, and the quality of life in the event of a graft failure. The theorem and related formula should be helpful to patients and physicians in selecting the best time for transplantation.

Outcome of patients with cirrhosis requiring intensive care unit support: prospective assessment of predictors of mortality.

: Determinants of outcome and the utility of the Child-Pugh score and the acute physiology and chronic health evaluation (APACHE) II score as predictors of outcome were prospectively assessed in 54 consecutive patients with cirrhosis requiring intensive care unit (ICU) management. Overall mortality in the ICU was 43% (23/54). Child-Pugh scores did not differ between survivors or nonsurvivors (12.8 versus 12.3, P = 0.26), however APACHE II scores (P = 0.007), acute physiology scores (P = 0.006), and Karnofsky scores (P = 0.001) were significant predictors of outcome. By univariate analysis, requirement of mechanical ventilation analysis (P = 0.001), duration of mechanical ventilation (P = 0.001), pulmonary infiltrates (P = 0.0001), infections (P = 0.047), gastrointestinal bleeding (P = 0.005), and serum creatinine ≥1.5 mg/dl (P = 0.0005) were significantly associated with mortality. By logistic regression analysis only pulmonary infiltrates (P = 0.0001) and renal dysfunction (P = 0.041) were independent predictors of mortality. When controlled for the severity of illness (APACHE II scores), the mortality in patients with cirrhosis caused by alcohol was significantly lower than that in patients with liver disease not caused by alcohol (P = 0.01). Our study not only identified predictors of poor outcome in patients with cirrhosis requiring ICU care but also provided data that may have implications for optimal timing for transplantation.

Biliary malignancies in primary sclerosing cholangitis: Timing for liver transplantation

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease associated in 10% to 36% of those with hepatobiliary malignancies, which are, in the majority of cases, not known prior to transplantation. Diagnosis of carcinomas in a PSC setting at an early stage has not yet been achieved, because there are no differences in the age of patients or clinical course, particularly with regard to the time between diagnosis of PSC and detection of carcinomas. To assess optimal timing for transplantation in patients with PSC, we applied the Mayo survival model to 48 patients receiving transplants for that disease in our center between 1972 and 1994. Of these patients, 10 had a biliary malignancy, which was incidental in 9. According to the Mayo model, low-, moderate-, and high-risk groups of patients could be formed. The actuarial patient survivals at 1 and 7 years were 100% and 100% (low risk), 68.6% and 68.6% (moderate risk), and 54.6% and 46.8% (high risk), respectively. Patients with a biliary malignancy had a 30% survival at 1 year; none survived 6 years. Local recurrence of the tumor was found in 3 patients, 2 of them with low tumor stages at the time of transplantation. Analysis of the Mayo Model risk scores demonstrated a marked increase in the incidence of biliary malignancies at a score above 4.4. All patients with tumors were found to have a score above 4. Moreover, the prevalence rate rose from 14.3% in the low-risk group to 33.3% in the moderate-risk group. There was no difference in the clinical courses at 6 to 12 months prior to transplantation; in particular, the bilirubin levels (PSC alone, 250 +/- 230 mumol/L; PSC with carcinoma, 288 +/- 182 mumol/L) did not differ significantly (P > .05) between both patient groups. Because the outcome after transplantation is poor even in patients with low-grade malignancies, early timing of transplantation in patients with PSC is suggested to prevent formation of biliary malignancies. Therefore, regular scoring of patients with the Mayo Model risk score is suggested, and transplantation should be taken into consideration at scores above 4. (Hepatology 1996 May;23(5):1105-11)

Biliary malignancies in primary sclerosing cholangitis: Timing for liver transplantation

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease associated in 10% to 36% of those with hepatobiliary malignancies, which are, in the majority of cases, not known prior to transplantation. Diagnosis of carcinomas in a PSC setting at an early stage has not yet been achieved, because there are no differences in the age of patients or clinical course, particularly with regard to the time between diagnosis of PSC and detection of carcinomas. To assess optimal timing for transplantation in patients with PSC, we applied the Mayo survival model to 48 patients receiving transplants for that disease in our center between 1972 and 1994. Of these patients, 10 had a biliary malignancy, which was incidental in 9. According to the Mayo model, low-, moderate-, and high-risk groups of patients could be formed. The actuarial patient survivals at 1 and 7 years were 100% and 100% (low risk), 68.6% and 68.6% (moderate risk), and 54.6% and 46.8% (high risk), respectively. Patients with a biliary malignancy had a 30% survival at 1 year; none survived 6 years. Local recurrence of the tumor was found in 3 patients, 2 of them with low tumor stages at the time of transplantation. Analysis of the Mayo Model risk scores demonstrated a marked increase in the incidence of biliary malignancies at a score above 4.4. All patients with tumors were found to have a score above 4. Moreover, the prevalence rate rose from 14.3% in the low-risk group to 33.3% in the moderate-risk group. There was no difference in the clinical courses at 6 to 12 months prior to transplantation; in particular, the bilirubin levels (PSC alone, 250 +/- 230 mumol/L; PSC with carcinoma, 288 +/- 182 mumol/L) did not differ significantly (P > .05) between both patient groups. Because the outcome after transplantation is poor even in patients with low-grade malignancies, early timing of transplantation in patients with PSC is suggested to prevent formation of biliary malignancies. Therefore, regular scoring of patients with the Mayo Model risk score is suggested, and transplantation should be taken into consideration at scores above 4.

Progress in renal transplantation for children.

Renal transplantation continues to be the goal of therapy for children with end-stage renal disease. Patient age, primary renal disease, psychosocial status, living versus cadaver donor allograft, optimal immunosuppressive therapy, urologic status, and maximization of growth and development must be considered in determining the optimal time for transplantation. Immunizations should be up to date, and the immune status of both the donor and the recipient with regard to Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, and hepatitis A, B, and C must be known. Prednisone, imuran, cyclosporine, and T cell antibodies remain the mainstay of immunosuppression. However, new therapies, such as FK-506, rapamycin, mofetil, brequinar, leflunomide, and human leukocyte antigen-derived peptides, are under investigation for use in transplantation. Complications, including infection, rejection, and malignancy, continue to be problematic in pediatric renal transplantation. Although patient and graft survival has improved over time, outcomes in pediatric renal transplantation continue to lag behind those in young adults.