Molecular insights into the development of hepatic metastases in colorectal cancer: a metastasis prediction study.

OBJECTIVE: Colorectal cancer is presently the third most commonly diagnosed cancer in the United States. In this study, we identified molecular differences between hepatic and non-hepatic metastases in colorectal cancer and evaluated their prognostic significance. MATERIALS AND METHODS: We downloaded primary data from the NCBI Gene Expression Omnibus (GSE6988, GSE62321, GSE50760, and GSE28722). To identify the molecular differences, we used the Significance Analysis of Microarray method. We selected nine prognostic genes (SYTL2, PTPLAD1, CDS1, RNF138, PIGR, WDR78, MYO7B, TSPAN3, and ATP5F1) with hepatic metastasis prediction score in colorectal cancer (hereafter referred to as LASSO Score). We confirmed the prognostic significance of the LASSO Score by using Kaplan-Meier survival analysis, multivariate analysis, the time-dependent area under the curve (AUC) of Uno's C-index, and the AUC of the receiver operating characteristic curve at 1-5 years. RESULTS: Survival analysis revealed that a high LASSO Score is associated with a poor prognosis in colorectal cancer patients with hepatic metastases (p = 0). Analysis of C-indices and AUC values from the receiver operating characteristic curve further supported this prediction by the LASSO Score. Multivariate analysis confirmed the prognostic significance of the LASSO Score (p = 1.13e-06). CONCLUSIONS: This study reveals the biological mechanisms underlying hepatic metastases in colorectal cancer and will help in developing targeted therapies for colorectal cancer.

Evolving affinity between Coulombic reversibility and hysteretic phase transformations in nano-structured silicon-based lithium-ion batteries.

Nano-structured silicon is an attractive alternative anode material to conventional graphite in lithium-ion batteries. However, the anode designs with higher silicon concentrations remain to be commercialized despite recent remarkable progress. One of the most critical issues is the fundamental understanding of the lithium-silicon Coulombic efficiency. Particularly, this is the key to resolve subtle yet accumulatively significant alterations of Coulombic efficiency by various paths of lithium-silicon processes over cycles. Here, we provide quantitative and qualitative insight into how the irreversible behaviors are altered by the processes under amorphous volume changes and hysteretic amorphous-crystalline phase transformations. Repeated latter transformations over cycles, typically featured as a degradation factor, can govern the reversibility behaviors, improving the irreversibility and eventually minimizing cumulative irreversible lithium consumption. This is clearly different from repeated amorphous volume changes with different lithiation depths. The mechanism behind the correlations is elucidated by electrochemical and structural probing.

Competitive Market Analysis of Transplant Centers and Discrepancy of Wait-Listing of Recipients for Kidney Transplantation.

BACKGROUND: There are over 250 kidney transplant programs in the USA. OBJECTIVE: To determine if highly competitive regions, defined as regions with a higher number of transplant centers, will approve and wait-list more end-stage renal disease (ESRD) candidates for transplant despite consistent incidence and prevalence of ESRD nationwide. METHODS: ESRD Network and OPTN data completed in 2011 were obtained from all transplant centers including listing data, market saturation, market share, organs transplanted, and ESRD prevalence. Herfindahl-Hirschman Index (HHI) was used to measure the size of firms in relation to the industry to determine the amount of competition. RESULTS: States were separated into 3 groups (HHI<1000 considered competitive; HHI 1000-1800 considered moderate competition; and HHI>1800 considered highly concentrated). The percentage of ESRD patients listed in competitive, moderate, and highly concentrated regions were 19.73%, 17.02%, and 13.75%, respectively. The ESRD listing difference between competitive versus highly concentrated was significant (p<0.05). CONCLUSION: When there is strong competition without a dominant center as defined by the HHI, the entire state tends to list more patients for transplant to drive up their own center's market share. Our analysis of the available national data suggests a discrepancy in access for ESRD patient to transplantation due to transplant center competition.

Nomogram for Predicting Time to Death After Withdrawal of Life-Sustaining Treatment in Patients With Devastating Neurological Injury.

Reliable prediction of time of death after withdrawal of life-sustaining treatment in patients with devastating neurological injury is crucial to successful donation after cardiac death. Herein, we conducted a study of 419 neurocritical patients who underwent life support withdrawal at four neurosurgical centers in China. Based on a retrospective cohort, we used multivariate Cox regression analysis to identify prognostic factors for patient death, which were then integrated into a nomogram. The model was calibrated and validated using data from an external retrospective cohort and a prospective cohort. We identified 10 variables that were incorporated into a nomogram. The C-indexes for predicting the 60-min death probability in the training, external validation and prospective validation cohorts were 0.96 (0.93-0.98), 0.94 (0.91-0.97), and 0.99 (0.97-1.00), respectively. The calibration plots after WLST showed an optimal agreement between the prediction of time to death by the nomogram and the actual observation for all cohorts. Then we identified 22, 26 and 37 as cut-points for risk stratification into four groups. Kaplan-Meier curves indicated distinct prognoses between patients in the different risk groups (p < 0.001). In conclusion, we have developed and validated a nomogram to accurately identify potential cardiac death donors in neurocritical patients in a Chinese population.

Native portal vein embolization for persistent hyperoxaluria following kidney and auxiliary partial liver transplantation.

Type 1 primary hyperoxaluria (PH1) causes renal failure, for which isolated kidney transplantation (KT) is usually unsuccessful treatment due to early oxalate stone recurrence. Although hepatectomy and liver transplantation (LT) corrects PH1 enzymatic defect, simultaneous auxiliary partial liver transplantation (APLT) and KT have been suggested as an alternative approach. APLT advantages include preservation of the donor pool and retention of native liver function in the event of liver graft loss. However, APLT relative mass may be inadequate to correct the defect. We here report the first case of native portal vein embolization (PVE) to increase APLT to native liver mass ratio (APLT/NLM-R). Following initial combined APLT-KT, both allografts functioned well, but oxalate plasma levels did not normalize. We postulated the inadequate APLT/NLM-R could be corrected by trans-hepatic native PVE. The resulting increased APLT/NLM-R decreased serum oxalate to normal levels within 1 month following PVE. We conclude that persistently elevated oxalate levels after combined APLT-KT for PH1 treatment, results from inadequate relative functional capacity. This can be reversed by partial native PVE to decrease portal flow to the native liver. This approach might be applicable to other scenarios where partial grafts have been transplanted to replace native liver function.

Early onset adenovirus infection after simultaneous kidney-pancreas transplant.

Adenoviruses (AdV) are increasingly recognized as important viral pathogens in immunocompromised hosts. The clinical spectrum ranges from asymptomatic viremia to allograft dysfunction, and death. Most of the medical literature is on AdV infection in children and bone marrow transplant recipients. We report a case of AdV in an adult recipient in the first month after simultaneous kidney-pancreas transplant with thymoglobulin induction. This is a rare report of adenovirus infection after multiorgan transplant, and is unique in that it exhibited tissue invasive disease without any localizing signs or allograft dysfunction, while other cases in medical literature had invasive disease of the allograft with allograft dysfunction, failure, or death. In addition, this is the first report of a radiologic presentation of AdV nephritis.

Induction with Rabbit Antithymocyte Globulin following Orthotopic Liver Transplantation for Hepatitis C.

BACKGROUND: Hepatitis C (HCV) is the most common indication for liver transplantation in the US. OBJECTIVE: Since steroids are the major stimulus of viral replication, we postulated that steroid-free immunosuppression might be a safer approach. METHODS: From January 1995 to October 2002, we used steroid plus calcineurin inhibitor (CNI) immunosuppression after liver transplantation for HCV (steroid group, n=81). From October 2002 to June 2007, rabbit antithymocyte globulin (RATG) induction, followed by CNI and azathioprine (RATG group, n=73) was utilized. RESULTS: There were no differences in 1- and 3-year patient/allograft survival rates. The incidence of acute rejection rate (19% vs. 28%), of biopsy-proven HCV recurrence (70% vs. 75%), and chronic rejection (6% vs. 9%) were comparable. The mean time to develop recurrent HCV was significantly longer in the RATG group (16.2 vs. 9.2 months, p=0.008). The incidence of severe portal fibrosis appears to be lower in RATG group compared to the steroid group; 14% vs. 4% (p=0.07). CONCLUSIONS: RATG induction is safe and effective after liver transplantation for HCV, but has no impact on the incidence of HCV recurrence and patient/allograft survival. However, a significant delay in time to HCV recurrence and a trend toward less rejection and portal fibrosis was observed.

Changing pattern of organ donation at a single center: are potential brain dead donors being lost to donation after cardiac death?

Donation after cardiac death (DCD) has proven effective at increasing the availability of organs for transplantation.We performed a retrospective examination of Massachusetts General Hospital (MGH) records of all 201 donors from 1/1/98 to the 11/2008, including 54 DCD, 115 DBD and 32 DCD candidates that did not progress to donation (DCD-dnp). Comparing three time periods, era 1 (01/98-12/02), era 2 (01/03-12/05) and era 3 (01/06-11/08), DCD's comprised 14.8,48.4% and 60% of donors, respectively (p = 0.002). A significant increase in the incidence of cardiovascular/cerebrovascular as cause of death was evident in era 3 versus eras 1 and 2; 74% versus 57.1% (p<0.001),as was a corresponding decrease in the incidence of traumatic death. Interestingly, we noted an increase in utilization of aggressive neurological management over time, especially in the DCD group.We detected significant changes in the make-up of the donor pool over the past decade. That the changes in diagnosis over time did not differ between DCD and DBD groups suggests this difference is not responsible for the increase in DCD rates. Instead, we suggest that changes in clinical practice, especially in management of patients with severe brain injury may account for the increased proportion of DCD.

Donor kidney recovery methods and the incidence of lymphatic complications in kidney transplant recipients.

BACKGROUND: Lymphatic leak and lymphocele are well-known complications after kidney transplantation. OBJECTIVE: To determine the incidence of lymphatic complications in recipients of living donor kidneys. METHODS: Among 642 kidney transplants performed between 1999 and 2007, the incidence of lymphatic complications was retrospectively analyzed in recipients of living donor kidneys procured by laparoscopic nephrectomy (LP, n=218) or by open nephrectomy (OP, n=127) and deceased donor kidneys (DD, n=297). A Jackson-Pratt drain was placed in the retroperitoneal space in all recipients and was maintained until the output became less than 30 mL/day. RESULTS: Although the incidence of symptomatic lymphocele, which required therapeutic intervention, was comparable in all groups, the duration of mean±SD drain placement was significantly longer in the LP group-8.6±2.7 days compared to 5.6±1.2 days in the OP group and 5.4±0.7 days in the DD group (p<0.001). Higher output of lymphatic drainage in recipients of LP kidneys could lead to a higher incidence of lymphocele if wound drainage is not provided. CONCLUSION: More meticulous back table preparation may be required in LP kidneys to decrease lymphatic complications after kidney transplantation. These observations also support the suggestion that the major source of persistent lymphatic drainage following renal transplantation is severed lymphatics of the allograft rather than those of the recipient's iliac space.

Live donor partial hepatectomy for liver transplantation: is there a learning curve?

BACKGROUND: Donor safety is the first priority in living donor liver transplantation (LDLT). OBJECTIVE: To determine the characteristics and outcome of live liver donors who underwent donor hepatectomy from January, 1997 to May, 2007 at Massachusetts General Hospital. METHODS: 30 patients underwent LDLT between January, 1997 and May, 2007 at our institution. RESULTS: The type of graft was the right lobe (segments 5-8) in 14, left lobe (segments 2-4) in 4, and left lateral sector (segments 2 and 3) in 12 patients. The mean donor age was 36 (range: 26-57) years. The mean follow-up was 48 (range: 18-120) months. No deaths occurred. Overall, 8 (26.6%) patients experienced a total of 14 post-operative complications. Donor complications based on graft type were as follows: left lateral sector (16.7%), left lobe (25%), and right lobe (35.7%). The experience was divided into two periods 1997-2001 (n=15) and 2002-2007 (n=15). Overall complications during 2 periods were 40% and 13.3%, respectively (p<0.001). The incidence of grade III complication also significantly decreased; 66.7% vs 33.3% (p<0.01). CONCLUSION: Partial hepatectomy in living donors has a learning curve which appears to be approximately 15 cases. This learning curve is not restricted to the surgeons performing the procedure but involves all aspects of patient care.

Deceased donor kidney transplantation in elderly patients: is there a difference in outcomes?

INTRODUCTION: There is a paucity of data on long-term outcomes of older kidney recipients. Our aim was to compare the early and long-term outcomes of deceased donor kidney transplantation in patients aged >or=60 years with outcomes in younger recipients. MATERIALS AND METHODS: From 1998 to 2005, we performed 271 deceased donor kidney transplants. There were 76 recipients (28.1%) >60 years old. Older candidates were carefully selected based on their physiologic, cardiac, and performance status. Demographic data, including clinical characteristics, early complications, mortality, and patient and graft survival rates, were collected and analyzed. RESULTS: Older patients had comparable perioperative mortality and morbidity, incidence of delayed graft function (DGF), length of stay, and readmissions compared with younger patients. The rates of acute rejection and major infections were also comparable between the 2 study groups. Among older recipients, 25/76 (32.1%) patients received extended criteria donor kidneys compared with only 35/195 (17.9%) of younger patients (P < .001). Nevertheless, equivalent 1-, 3-, and 5-year allograft survival rates were observed in elderly and young patients; 91.5% versus, 92.5%, 78.5% versus 81.9%, and 75.6% versus 78.5%, respectively. Overall patient survival was also comparable in both groups. CONCLUSION: Kidney transplantation in appropriately selected elderly recipients provides equivalent outcomes compared with those observed in younger patients. These observations support the notion that older recipients should not lose access to deceased donor kidney transplantation in the effort to achieve a perceived gain in social utility.

Impact of donor kidney recovery method on lymphatic complications in kidney transplantation.

INTRODUCTION: Prolonged lymphatic drainage and lymphocele are undesirable complications following kidney transplantation. We evaluated the impact of kidney recovery methods (deceased donor vs laparoscopic nephrectomy) on the lymphatic complications of the kidney transplant recipients. METHOD: The incidence of lymphatic complications was retrospectively analyzed in recipients of deceased donor kidneys (DD, n = 62) versus laparoscopically procured kidneys from living donors (LP, n = 61). A drain was placed in the retroperitoneal space in all recipients. The drain was maintained until the output became less than 30 mL/d with no evidence of fluid collection by ultrasound examination. RESULTS: There was no statistically significant difference in the patient demographics (age, gender, and original disease and procedure time) between two groups. The incidence of lymphocele that required therapeutic intervention was comparable in both groups (3.2%). However, the duration of drain placement was significantly longer in the LP group than in the DD group, 8.6 +/- 2.5 days versus 5.4 +/- 2.5 day, respectively (P < .05). CONCLUSION: The recipients of laparoscopically removed kidneys had a higher incidence of prolonged lymphatic leakage. More meticulous back table preparation may be required in LP kidneys to prevent prolonged lymphatic drainage after kidney transplantation. These observations may indicate that the major source of persistent lymphatic leakage is lymphatics of the allograft rather than severed recipient lymphatics.

Outcome of kidney transplantation using expanded criteria donors and donation after cardiac death kidneys: realities and costs.

Expanded criteria donors (ECDs) and donation after cardiac death (DCD) provide more kidneys in the donor pool. However, the financial impact and the long-term benefits of these kidneys have been questioned. From 1998 to 2005, we performed 271 deceased donor kidney transplants into adult recipients. There were 163 (60.1%) SCDs, 44 (16.2%) ECDs, 53 (19.6%) DCDs and 11 (4.1%) ECD/DCDs. The mean follow-up was 50 months. ECD and DCD kidneys had a significantly higher incidence of delayed graft function, longer time to reach serum creatinine below 3 (mg/dL), longer length of stay and more readmissions compared to SCDs. The hospital charge was also higher for ECD, ECD/DCD and DCD kidneys compared to SCDs, primarily due to the longer length of stay and increased requirement for dialysis (70,030 dollars, 72,438 dollars, 72,789 dollars and 47,462 dollars, respectively, p < 0.001). Early graft survival rates were comparable among all groups. However, after a mean follow-up of 50 months, graft survival was significantly less in the ECD group compared to other groups. Although our observations support the utilization of ECD and DCD kidneys, these transplants are associated with increased costs and resource utilization. Revised reimbursement guidelines will be required for centers that utilize these organs.

Spleen transplantation in miniature swine: surgical technique and results in major histocompatibility complex-matched donor and recipient pairs.

BACKGROUND: Spleen transplantation (Tx) between some strains of rodents can lead to donor-specific tolerance either spontaneously or after a short course of immunosuppression. This study developed a surgical technique for spleen Tx in miniature swine to investigate its immunologic impact in a large animal model. METHODS: The preferred surgical technique of spleen Tx (n=8) involved excision of the donor spleen with its vascular pedicle to the aorta and portal vein. Carrel patches of donor aorta and portal vein were anastomosed to the abdominal aorta and inferior vena cava, respectively, of the (splenectomized) recipient. The results in four major histocompatibility complex-matched pairs that were mismatched for the porcine allelic antigen are reported. Two recipients were untreated, one received a 12-day course of cyclosporine A (CsA) alone, and one received thymic irradiation (700 cGy) and CsA. Hematopoietic cell chimerism was followed by fluorescence-activated cell sorter, and graft survival was assessed by histology. RESULTS: Spleen Tx was technically successful. In two untreated pigs, chimerism was detected in the blood (maximum 5% for 17 and 25 days) and lymph nodes (maximum 6% for 28 and 56 days), but both grafts showed histologic rejection by day 28. In two treated pigs, chimerism was present in the blood for 47 and 57 days, and rejection was prevented, with follow-up for 57 and 217 days, respectively. CONCLUSION: Spleen Tx in major histocompatibility complex-matched pairs treated with CsA+/-thymic irradiation results in prolonged chimerism and is associated with the development of in vivo unresponsiveness to the transplanted spleen.

Long-term islet allograft function in the absence of chronic immunosuppression: a case report of a nonhuman primate previously made tolerant to a renal allograft from the same donor.

UNLABELLED: Development of mixed chimerism by donor bone marrow transplantation (DBMT) has led to long-term tolerance of solid organ allografts in nonhuman primates. As an initial attempt to extend this approach to cellular transplant, islet transplant from the same donor was attempted in the recipient previously made tolerant to a kidney allograft. METHODS: After the conditioning with ATG, total body irradiation, thymic irradiation, and splenectomy, DBMT was performed followed by 4 weeks of cyclosporine. Kidney transplantation and native nephrectomies were subsequently performed on day 89. After 2.8 years of DBMT, diabetes was induced by streptozocin (STZ) and islets from bone marrow and kidney donor were transplanted without immunosuppression. RESULTS: After DBMT, the recipient developed chimerism and no evidence of kidney rejection for more than 1000 days. STZ induced diabetes was reversed after the islet transplantation. Islet biopsies demonstrated insulin staining without rejection. Although the recipient became diabetic 300 days after islet transplantation, viable transplanted islets were found in the liver and under the kidney capsule without any evidence of rejection. CONCLUSION: Tolerance with a nonmyeloablative conditioning can allow successful pancreatic islet transplantation without immunosuppression. Because no histological evidence of rejection was identified, recurrent diabetes is presumed to be inadequate islet mass.

Association of natural killer cell depletion with induction of mixed chimerism and allograft tolerance in non-human primates.

BACKGROUND: Nonmyeloablative T cell depletion followed by donor bone marrow infusion has proved to be an effective approach to induction of mixed chimerism and tolerance of organ allografts in non-human primates. To help define the mechanisms involved we have compared T cell depletion with ATG versus anti-CD2 monoclonal antibody with respect to establishment of mixed chimerism and induction of tolerance. METHOD: Both nonmyeloablative regimens included low dose total body irradiation (1.5 Gy x 2), thymic irradiation (7 Gy), splenectomy and kidney plus donor bone marrow transplantation, followed by a 4-week posttransplant course of cyclosporine. In addition, the ATG group (13 recipients) received antithymocyte globulin, although the LOCD2b group (10 recipients) were treated with an anti-CD2 monoclonal antibody (LOCD2b). RESULTS: In the ATG group, 11 of 13 monkeys developed multilineage chimerism and 9 survived for more than 100 days without kidney allograft rejection. In contrast, 0/10 monkeys in the LOCD2b group developed chimerism, 5 died of infection and 5 suffered progressive rejection; only 1 recipient survived beyond 100 days. Sequential monitoring of peripheral blood mononuclear cells revealed greater T cell (CD3+) depletion in the LOCD2b-treated animals compared to those receiving ATG. However, NK cells (CD16+CD8+) were significantly more depleted in the ATG group and NK function remained abrogated longer after ATG than LOCD2b treatment (3 weeks vs. <5 days). CONCLUSION: Despite excellent T cell depletion by LoCD2b, ATG was more effective in inducing chimerism and tolerance. This difference correlated with anti-NK activity of the two reagents. These data suggest that NK cells may also resist engraftment of allogeneic bone marrow cells in this model.

Long-term outcome and alloantibody production in a non-myeloablative regimen for induction of renal allograft tolerance.

BACKGROUND: Multilineage chimerism and long-term acceptance of renal allografts has been produced in non-human primates conditioned with a nonmyeloablative regimen. Our study was undertaken to evaluate the immunological and pathological status of long-term survivors and to define the role of splenectomy and of the primarily vascularized kidney in the regimen. METHOD: Monkeys were treated with the basic regimen, including: total body irradiation, thymic irradiation, antithymocyte globulin, donor bone marrow transplantation, and a 4-week course of cyclosporine after which no further immunosuppression was given. They were divided into four groups according to the timing of kidney transplantation (KTx) and splenectomy as follows; group A (n=13): KTx and splenectomy on the day of donor bone marrow transplantation (day 0); group B (n=3): KTx on day 0 without splenectomy; group C (n=7): splenectomy on day 0 but delayed KTx until 3 to 16 weeks post-donor bone marrow transplantation; group D (n=3): both splenectomy and KTx delayed until day 120 post-donor bone marrow transplantation. RESULTS: In group A, 11 of 13 monkeys developed chimerism and 9 monkeys achieved long-term survival of 4 to 70 months without evidence of chronic vascular rejection. Alloantibodies were detected in only one long-term survivor. In contrast, all three monkeys in group B developed alloantibodies and rejected their allografts. In group C, long-term survival without alloantibody production was observed in two of three monkeys that had developed chimerism. In group D, all three recipients were sensitized and rejected the kidney allografts rapidly after transplantation. CONCLUSIONS: 1) Production of anti-donor antibody was prevented in most recipients that developed mixed chimerism in the regimens with splenectomy at the time of donor bone marrow transplantation. 2) If splenectomy is not included in the initial conditioning regimen, induction of B cell tolerance is less likely and the result is late onset of alloantibody production and allograft rejection. 3) Immediate transplantation of the kidney at the time of recipient conditioning is not essential for induction of donor specific hyporesponsiveness by bone marrow transplantation.