Allograft and overall survival of patients with posttransplant skin cancer.

BACKGROUND: Little is known about the possible association between nonmelanoma skin cancer (NMSC) and allograft survival and overall patient survival. OBJECTIVE: To determine the association between posttransplant NMSC and early to mid-term allograft survival and overall patient survival after kidney, liver, or heart transplantation. METHODS AND MATERIALS: We retrospectively reviewed patients identified from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. The study included adult recipients of kidney (n=46,216), liver (n=8,049), and heart (n=8,519) transplants from 1996 to 2001. RESULTS: Multivariate analysis showed that kidney recipients with NMSC had a significantly lower risk of allograft loss (relative risk (RR)=0.55, p<.001) and death (RR=0.55; p<.001) within 5 years of transplantation than recipients without NMSC. Significantly lower risk of death was also observed for liver recipients (RR=0.28, p<.001) and heart recipients (RR=0.25; p<.001) with NMSC. CONCLUSIONS: Longer early to mid-term allograft and overall survival was seen in patients with NMSC, but long-term survival rates must be examined to determine whether mortality rates increase later for patients with NMSC, as noted in previous studies.

A simple chemical free arsenic removal method for community water supply--a case study from West Bengal, India.

This report describes a simple chemical free method that was successfully used by a team of European and Indian scientists (www.qub.ac.uk/tipot) to remove arsenic (As) from groundwater in a village in West Bengal, India. Six such plants are now in operation and are being used to supply water to the local population (www.insituarsenic.org). The study was conducted in Kasimpore, a village in North 24 Parganas District, approximately 25 km from Kolkata. In all cases, total As in treated water was less than the WHO guideline value of 10 microg L(-1). The plant produces no sludge and the operation cost is 1.0 US$ per day for producing 2000 L of potable water.

Impact of the donor risk index on the outcome of hepatitis C virus-positive liver transplant recipients.

We have investigated the impact of the donor risk index (DRI) on the outcome of hepatitis C virus (HCV)-infected patients undergoing liver transplantation (LTx). Retrospective analysis was performed from the Organ Procurement and Transplantation Network database (January 1, 2000 to June, 2006). The DRI was calculated as described by Feng et al. (Am J Transplant 2006;6:783-790). Model for End-Stage Liver Disease (MELD) exceptions were excluded from the analysis. Relative risk (RR) estimates of patient and graft loss were derived from Cox regression models. The Wald test was used to test the effect of the MELD score at transplant on the HCV-DRI interaction. Of the LTx recipients (16,678), 76.1% were Caucasian, and 66.7% were male; the median age was 52 (range, 18-80 years), and the mean follow-up time was 1148 days (range, 0-2959 days). Forty-six percent (n = 7675) of LTx recipients were HCV(+). The median DRI was 1.3 (range, 0.77-4.27). Increasing DRI was associated with a statistically significant increase in the RR of graft failure and patient death for both HCV(+) and HCV(-) recipients. However, HCV(+) recipients demonstrated a significantly higher increase in the RR of patient and graft loss as a function of the DRI than HCV(-) subjects, even after adjustments for several recipient factors, including MELD. In conclusion, a synergistic interaction between donor DRI and recipient HCV status exists, such that an allograft from a high-DRI donor more adversely affects the outcome of an HCV(+) recipient than that of an HCV(-) recipient.

A review of studies relating to thyroid hormone therapy in brain-dead organ donors.

An acute decrease in cardiac performance can result from a reduced free triiodothyronine (FT3) level following (i) brain death (euthyroid sick syndrome), (ii) a period of cardiopulmonary bypass, and possibly (iii) regional or global myocardial ischemia. The two major pathophysiologic effects of brain death are (i) vascular injury associated with the hemodynamic consequences of the autonomic 'storm', and (ii) a generalized inhibition of mitochondrial function, which results in diminished organ function from the loss of energy stores from a rapid loss of circulating FT3. Deterioration of donor organ function can be reversed by hormonal replacement therapy, in which T3 plays a critical role. This results in (i) an increased number of organs being functionally acceptable, and (ii) increased early and intermediate graft survival. Cardiopulmonary bypass is associated with a reduction in the circulating level of FT3, and this can be associated with deterioration in cardiac function. The administration of T3 at the time of discontinuation of cardiopulmonary bypass reverses this state. In patients undergoing heart transplantation, T3 therapy to both donor and recipient is beneficial.

Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab.

Transplant patients are at the risk for posttransplant lymphoproliferative disease (PTLD), a virally-driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD suggesting that the T-cell depletion increases PTLD risk. We therefore studied 59 560 kidney recipients from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database for a relationship between induction agent use and PTLD. Two agents with comparable T-cell depletional effects, alemtuzumab and Thymoglobulin, were compared to nondepletional induction agents or no induction. The overall incidence of PTLD was 0.46% and differed significantly by induction strategy (p < 0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%) and alemtuzumab (0.37%). Thymoglobulin was associated with significantly increased PTLD risk (p = 0.0025), but alemtuzumab (p = 0.74), basiliximab (p = 0.33) and daclizumab, which trended toward a protective effect (p = 0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk although alemtuzumab is known to have a more pronounced B-cell depleting effect. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p < 0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, maintenance drug selection or perhaps the balance between B- and T-cell depletion may be more relevant determinants of PTLD risk.

Deceased donors with a past history of malignancy: an organ procurement and transplantation network/united network for organ sharing update.

Approximately 2% of deceased donor organ transplants result from donors with a past history of cancer. An analysis of Organ Procurement and Transplantation Network/United Network for Organ Sharing data on 39,455 deceased donors from 2000 to 2005 showed 1069 donors had a PHC, resulting in 2508 transplants, including 1236 kidneys, 891 livers, 199 hearts, 100 lungs, and 82 miscellaneous organs. The most common type of previous cancer in the donor was nonmelanoma skin cancer (n=776) followed by central nervous system malignancies (n=642) and carcinoma of the uterine cervix (n=336). One donor with a glioblastoma multiforme transmitted fatal tumors to three recipients. One donor with a history of melanoma 32 years earlier transmitted a fatal melanoma to a single recipient and, therefore, donors with a history of melanoma should not be used. Donors with a past history of cancer who have a nontraumatic cerebral hemorrhage cause concern because this hemorrhage may be the result of an unrecognized metastatic tumor.

Early mortality rates in older kidney recipients with comorbid risk factors.

BACKGROUND: There are over 60,000 candidates on the deceased donor kidney wait-list and the percentage of candidates over age 50 years continues to grow each year. National data have not previously been used to evaluate the association of comorbidities with mortality in older patients. METHODS: A multivariate analysis of 30,262 deceased donor primary kidney recipients aged 18-59 years and 8,895 aged >or=60 years evaluated the association of six recipient comorbidities on 90- and 365-day patient mortality rates. The additional effects of expanded criteria donors (ECD) and development of delayed graft function (DGF) were also evaluated. RESULTS: The 365-day mortality rate for recipients aged >or=60 years (10.5%) was more than twice that of recipients aged 18-59 years (4.4%) and comorbidities significantly increased mortality rates even higher (10.6-21.4%). The 365-day mortality rate for recipients aged >or=60 years who received an ECD kidney was 14.4% and who developed DGF was 15.9% while recipients with comorbidities but no DGF and no ECD ranged from 16.0 to 42.3%. The 365-day transplant mortality rate of recipients aged >or=60 years with comorbidities is higher than the 365-day wait-list mortality for patients with the same comorbidities, suggesting a lack of survival benefit from transplantation. CONCLUSIONS: Mortality rates for patients aged >or=60 years with comorbidities are higher than for those without comorbidities, significantly higher than for younger patients, and higher than for wait-listed patients. Thus, utility may be poorly served by allocating kidneys to older patients with comorbidities, and perhaps discussion of exclusionary listing criteria is warranted.

Resistance of quiescent and proliferating airway epithelial cells to H2O2 challenge.

Alveolar epithelial cell injury and recovery are important in the pathogenesis of oxidant-induced lung damage. The alveolar cell line A549 was used to study responses of proliferating and quiescent cells in culture to time- and dose-dependent hydrogen peroxide (H(2)O(2)) challenges. Recovery was monitored after 24 h of incubation in fresh medium with 10% serum. The adherent cells were counted and the resistance and recovery of the attached cells was assessed by appearance, by measuring the number of viable, apoptotic and necrotic cells using fluorescent-activated cell sorting, and by determining the intracellular free thiol content. A549 cells recovered from a 1-h challenge with up to 1 mM H(2)O(2) but could not sustain a more prolonged challenge (6 or 24 h) with 0.5 mM or 1.0 mM H(2)O(2). These more severe conditions resulted in: loss of cells by detachment from the plate surface; reduced numbers of viable cells primarily due to necrosis; and a strong reduction of the intracellular free thiol content. Quiescent cells proved to be more sensitive to oxidative stress than proliferating cells. Intracellular free thiol levels apparently play a decisive role in cell survival, preferentially protecting proliferating cells.

Hormonal therapy of the brain-dead organ donor: experimental and clinical studies.

Experiments in Cape Town in the 1980s demonstrated that acute brain death is followed by massive catecholamine release resulting in systemic hypertension, acute left ventricular failure, and multiple cardiac arrhythmias along with substantial decreases in cortisol, insulin, thyroid, and antidiuretic hormone levels, a change from aerobic to anaerobic metabolism, and increases in inflammatory cytokines. Hormonal replacement results in rapid recovery of cardiac function in both experimental animals and humans and enables significantly more organs to be transplanted. Organ Procurement and Transplantation Network/United Network for Organ Sharing multivariate studies on hormonal treatment of brain-dead donors revealed significant increases in organs transplanted and in one-year survival of kidneys and hearts.

Retransplantation after post-transplant lymphoproliferative disorders: an OPTN/UNOS database analysis.

Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication of immunosuppressive therapy. Retransplantation of survivors remains controversial. The Organ Procurement and Transplant Network/United Network for Organ Sharing database was reviewed for individuals who developed PTLD and underwent retransplant from 1987 through 2004. Sixty-nine retransplants have been performed: 27 kidney, 22 liver, 9 lung, 6 heart, 4 intestine and 1 pancreas. At first transplant, most subjects (63.8%) were <17 years of age and was similar at retransplant with 50.7% less than 17 years. Time from transplant to PTLD was <1 year in 33.3%, 1-3 years in 21.7%, 3-5 years in 21.7%, 5-10 years in 21.7% and >10 years in 1.4%. Time from PTLD to retransplant was <1 year in 24.6%, 1-3 years in 37.7%, 3-5 years in 17.4% and 5-10 years in 20.3%. Induction agents were used in 21.7% of first and 47.8% of retransplants. Immunosuppression for first transplant was cyclosporine (CSA) in 55.1%, tacrolimus (TAC) in 27.5% versus CSA in 26.1%, TAC in 66.7% of retransplants. At last follow-up, patient and graft survival are 85.5% and 73.9%, respectively. Most subjects retransplanted after PTLD are <17 years on TAC-based immunosuppression. Patient/graft survival is excellent and retransplantation in PTLD subjects should be considered acceptable.

No effects of probiotics on atopic dermatitis in infancy: a randomized placebo-controlled trial.

BACKGROUND: Studies have been performed suggesting that administration of probiotics may have therapeutic and/or preventive benefits in the development of sensitization and atopic disease, particularly in infants with atopic dermatitis (AD). OBJECTIVE: The purpose of this study was to evaluate the clinical and immunological effects of supplementation of a hydrolysed formula with two probiotic strains of bacteria on symptoms of AD in infancy. METHODS: We conducted a randomized, double-blind, placebo-controlled study. After 4-6 weeks of baseline and double-blind, placebo-controlled challenges for diagnosis of cow's milk allergy (CMA), infants less than 5 months old with AD received a hydrolysed whey-based formula as placebo (n = 17), or supplemented with either Lactobacillus rhamnosus (n = 17) or Lactobacillus GG (n = 16) for 3 months. Before, during and after intervention, the clinical severity of AD was evaluated using SCORing index Atopic Dermatitis (SCORAD). Allergic sensitization was evaluated by measurement of total IgE and a panel of food-specific IgEs as well as skin prick testing for cow's milk. Inflammatory parameters were blood eosinophils, eosinophil protein X in urine, fecal alpha-1-antitrypsin and production of IL-4, IL-5 and IFN-gamma by peripheral blood mononuclear cells after polyclonal stimulation. RESULTS: No statistically significant effects of probiotic supplementation on SCORAD, sensitization, inflammatory parameters or cytokine production between groups were found. Only four infants were diagnosed with CMA. CONCLUSION: We found no clinical or immunological effect of the probiotic bacteria used in infants with AD. Our results indicate that oral supplementation with these probiotic bacterial strains will not have a significant impact on the symptoms of infantile AD.

Post-transplant de novo malignancies in renal transplant recipients: the past and present.

Post-transplant de novo malignancies are reviewed in three time periods: (i) the azathioprine (AZA) era from 1962 to 1980-1981, (ii) the cyclosporine (CYA) era (1980 to present) in which the calcineurin inhibitors, CYA and tacrolimus (TAC), were the mainstay of recipient immunosuppression, and (iii) the TOR inhibitor era starting in the year 2000. Both transplant registry and transplant center reports on malignancies occurring in the AZA era are reviewed. Reports from transplant centers and from the Cincinnati Transplant Tumor Registry (CTTR) in both the early CYA era (1980s) and the 1900-2000 CYA era are reported. Cancer incidence associated with AZA versus CYA, CYA versus TAC, and AZA versus mycophenolate mofetil (MMF) is compared in both transplant center and registry reports including new, unreported Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data from 1998 to 2003. The malignancy incidence associated with lymphocyte-depleting antibody and corticosteroid immunosuppression is discussed. Reduced malignancy incidence recently reported with TOR inhibitors is compared with that of conventional immunosuppression. Important nondrug factors influencing the incidence of post-transplant malignancies from seven single and three registry reports are detailed. The substantial role that de novo malignancies play in post-transplant mortality is discussed. Finally, management recommendations for recipients who develop de novo post-transplant malignancies are briefly presented.

High ICAM-1 gene expression in pulmonary fibroblasts of COPD patients: a reflection of an enhanced immunological function.

Chronic obstructive pulmonary disease (COPD) is characterised by destruction of extracellular matrix (ECM) in parenchymal areas, whereas the bronchial walls can show fibrosis. In addition, an extensive inflammatory process is observed. CD8+ T-cells, located throughout the lung, and epithelial cells in centrally located airways, produce cytokines involved in the inflammatory process. These cytokines may influence the present fibroblasts, the key effectors in the defective ECM repair and maintenance in COPD. The current authors explored the effects of the cytokine microenvironment on cell-cell interaction gene expression in pulmonary fibroblasts of controls (n = 6), and Global Initiative for Chronic Obstructive Lung Disease stage II (n = 7) and stage IV (n = 7) COPD patients. The current authors simulated the in vivo microenvironment using supernatants of CD3/CD28 stimulated CD8+ T-cells isolated from peripheral blood of COPD patients, supernatant of a bronchial-epithelial cell line, or a combination of both. The present data show that fibroblasts of chronic obstructive pulmonary disease patients display an altered response to the cytokine microenvironment, depending on both the disease stage and the central or peripheral location in the lung. Especially adhesion-related genes are upregulated in fibroblasts of chronic obstructive pulmonary disease patients, which can indicate a more pronounced role of fibroblasts in the inflammatory process in chronic obstructive pulmonary disease, possibly resulting in reduced function as effectors of extracellular matrix repair.

Utilization of extended donor criteria liver allograft: Is the elevated risk of failure independent of the model for end-stage liver disease score of the recipient?

BACKGROUND: The goal of this analysis was to determine if outcomes from the use of extended criteria donor (ECD) livers were dependent upon the Model for End-Stage Liver Disease (MELD) score of the recipient. METHODS: The Organ Procurement and Transplantation Network (OPTN) database as of March 4, 2006 was used for the analysis. Data from 12,056 adult liver transplant (LTx) recipients between June 1, 2002 and June 30, 2005 was analyzed. The donor risk index (DRI) was calculated as previously reported. A DRI of > or =1.7 was classified as ECD. Relative risk (RR) estimates were derived from Cox regression models adjusted for DRI, recipient MELD, age, sex, ethnicity, diagnosis, and year of transplant. RESULTS: Data from 2,873 grafts falling in the ECD category (23.8%) and their recipients were analyzed. Recipients with low MELD scores (<15) received the highest proportion of ECD livers (33%). ECD livers were associated with a significant increase in the RR of graft failure within each MELD category. However, this effect held within each of the three MELD categories. CONCLUSION: The use of ECD grafts expands the organ pool at expense of increased RR of liver failure. Our analysis showed no significant interaction between DRI and MELD score of the recipient. The fact that there is no additional impact of ECD livers in recipients with high MELD scores suggests that this group of patients may benefit from this pool of grafts.

Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies.

BACKGROUND: Immunosuppressive drug therapy has been identified as one etiological factor in the increased incidence of and deaths from malignancies in renal transplant recipients. In animal models, calcineurin inhibitors have a positive growth effect, whereas target-of-rapamycin (TOR) inhibitors have a negative growth effect on malignant cells. METHODS: A multivariate analysis of posttransplant malignancies in 33,249 deceased donor primary solitary renal recipients reported by 264 kidney transplant programs to the Organ Procurement and Transplantation Network database from July 1, 1996 to December 31, 2001 was performed. Data were censored at 963 days to allow comparable follow-up time among drug treatment groups. The incidence and relative risks of any de novo malignancy (skin and solid) and for non-skin solid malignancies in patients receiving TOR inhibitors compared to patients receiving calcineurin inhibitors were the primary endpoints. RESULTS: The incidence rates of patients with any de novo posttransplant malignancy were 0.60% with sirolimus/everolimus alone, 0.60% with sirolimus/everolimus + cyclosporine/tacrolimus, and 1.81% with cyclosporine/tacrolimus (P<0.0001); the rates with a de novo solid tumor were 0%, 0.47%, and 1.00%, respectively. In the Cox regression model the relative risk associated with sirolimus/everolimus immunosuppression for any de novo cancer was 0.39 (95% CI: 0.24-0.64; P=0.0002) and for de novo solid cancer was 0.44 (0.24-0.82; P=0.0092). Other significant risk factors were male sex, adult age group, white race, and history of a malignancy. CONCLUSIONS: Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and non-skin solid malignancy.

Skin cancer in organ transplant recipients: effect of pretransplant end-organ disease.

BACKGROUND: Solid organ transplant recipients are at increased risk for posttransplant neoplasms. OBJECTIVE: Our purpose was to determine whether various diseases causing end-organ failure are associated with different degrees of risk of skin cancer development after transplantation. METHODS: The Organ Procurement and Transplantation Network/United Network for Organ Sharing Transplant Tumor Registry was searched for the incidence of skin cancer among kidney, liver, and heart transplant recipients in the United States between 1996 and 2001. Multivariate analysis was used to determine the association between disease diagnosis and posttransplant skin cancer. RESULTS: Transplant recipients with specific pretransplant diseases, such as polycystic kidney disease and cholestatic liver disease, were at increased risk for skin cancer. Patients with diabetes mellitus had a lower incidence of skin cancer after kidney transplantation. LIMITATIONS: The study had only a brief follow-up period, indirect assessment of photodamage, and possible underreporting. CONCLUSION: Transplant recipients with a history of certain diseases warrant intensive skin cancer surveillance and strict sun-protective practices.

Hepatic angiosarcoma and liver transplantation: case report and literature review.

Hepatic angiosarcoma is a rare malignant vascular tumor that accounts for up to 2% of all primary liver tumors. Accurate diagnosis of this tumor is difficult, especially if the patient has no history of exposure to specific carcinogens including thorotrast, arsenicals, and vinyl chloride monomer. Diagnosis of diffuse angiosarcoma by means of liver biopsy has been reported as treacherous and nondiagnostic. Herein, we present a case of a 61-year-old Caucasian male with history of cryptogenic cirrhosis, normal alpha-fetoprotein, and pretransplant abnormal liver MRI who underwent nondiagnostic liver biopsies followed by liver transplantation. High grade diffuse angiosarcoma was diagnosed in the explanted liver. The patient developed bone metastases at 8 months and is alive 1 year posttransplantation. Diffuse liver tissue infiltration seen pretransplant on CT scan or MRI, suggesting the possibility of diffuse liver lesions (HCC, angiosarcoma, etc) must be fully investigated with all techniques available including multiple open liver biopsies to avoid the sacrifice of a liver allograft in these patients.