Randomized, prospective trial of mycophenolate mofetil versus azathioprine for prevention of acute renal allograft rejection after simultaneous kidney-pancreas transplantation

BACKGROUND: In simultaneous kidney-pancreas (SPK) transplantation, manifestations of renal allograft rejection typically become evident before those of pancreatic rejection. This study compared mycophenolate mofetil (MMF) and azathioprine (AZA) in prevention of renal rejection after primary SPK transplantation. METHODS: In an open-label, randomized, multicenter study, patients received MMF 1.5 g twice daily (n=74) or AZA 1-3 mg/kg daily (n=76) for 1 year after transplantation. The incidence of rejection was assessed at 6 months. Adverse events were tracked through 1 year. Survival data are reported through 2 years. RESULTS: At 6 months, efficacy results for MMF vs. AZA patients, respectively, were the following: rejection (27% vs. 39%); rejection or death (34% vs. 42%); rejection, graft loss, death, or premature withdrawal (i.e., treatment failure; 41% vs. 55%). Six-month efficacy trends favored MMF, and time to rejection or treatment failure was significantly longer when compared with AZA (P=0.049). One-year efficacy results for MMF vs. AZA patients, respectively, were the following: treatment of renal rejection (35% vs. 47%); renal allograft loss or death (9% vs. 12%); pancreas allograft loss or death (15% vs. 14%). Five MMF patients (7%) and four (5%) in the AZA group died. More MMF than AZA patients developed opportunistic infections (54% vs. 38%), but the pathogens did not differ. CONCLUSIONS: Trends for most efficacy parameters favored MMF over AZA, and time to renal allograft rejection or treatment failure was statistically significantly longer for MMF. The use of MMF in the treatment of SPK recipients is a useful advance.     

Surgical risks and outcome of pancreas retransplants

BACKGROUND: The increased popularity of pancreas transplants has led to an increased number of potential candidates for retransplants after the initial graft has been lost to technical failure or rejection. We studied a group of recipients who underwent pancreas transplants at a single center to determine whether retransplant recipients were at higher risk of complications. METHODS: Between June 1, 1994, and Dec 31, 1997, a total of 213 pancreas transplants were performed at the University of Minnesota. Of these, 187 were primary transplants and 26 were retransplants. Demographically, the two groups were not significantly different. We analyzed and compared the two groups with respect to incidence of surgical complications, graft survival rates, and patient survival rates. RESULTS: Surgical complications such as bleeding and vascular thrombosis were slightly more common after retransplants, but this trend did not quite reach statistical significance. Infectious complications and leaks were equivalent between the two groups. The incidence of acute rejection was higher after retransplants (P =.02). At 3 years posttransplant, patient survival was no different between the two groups, but pancreas graft survival was lower after retransplants (P =.08). The incidence of early graft loss (by 6 months posttransplant) was significantly higher in retransplant recipients (27% vs 14%, P =.04). CONCLUSIONS: Pancreas retransplants can be performed with a minimal increase in surgical complications. However, graft survival after retransplants is slightly inferior to that after primary transplants, probably for both immunologic and nonimmunologic reasons. Retransplants can be offered to suitable candidates, but they may require more aggressive monitoring for rejection.     

Prolonged preservation increases surgical complications after pancreas transplants

BACKGROUND: Prolonged preservation of the donor organ may result in delayed graft function or nonfunction after most organ transplants. We studied whether or not prolonged preservation increases surgical complications after pancreas transplants. METHODS: Between January 1, 1994, and September 30, 1998, a total of 294 recipients underwent cadaver pancreas transplants at our institution. Recipients were analyzed in 2 groups: those with pancreas preservation time < or = 20 hours (n = 211) versus > 20 hours (n = 83). RESULTS: Demographic data were similar between the 2 groups, except that mean donor age in the prolonged preservation group was significantly lower. Despite use of younger donors, prolonged preservation was associated with an increased incidence of surgical complications, most notably leaks, thrombosis, and wound infections. Grafts with prolonged preservation were more often noted by the transplant surgeon to be edematous after reperfusion, although the incidence of hyperamylasemia posttransplant did not differ between the 2 groups. Graft and patient survival rates also did not differ between the 2 groups. The incidence of early graft loss (< 3 months) was, however, higher in the prolonged preservation group (20.5% versus 9.0%, P = .04). CONCLUSIONS: Prolonged preservation of the donor organ increases the incidence of surgical complications after pancreas transplants. All attempts should be made to minimize preservation time, keeping it below 20 hours, if possible.     

X-radiation induces 8-hydroxy-2'-deoxyguanosine formation in vivo in rat mammary gland DNA

Ionizing radiation is a carcinogen that induces oxidative DNA damage. 8- Hydroxy-2'-deoxyguanosine (8-OHdG) is a relatively abundant, mutagenic lesion that is widely regarded as a reliable index of oxidative DNA damage. The purpose of this study was to examine the effects of X- radiation on levels of 8-OHdG in the context of an experimental model for breast cancer in which chronic radiation exposure has been shown to be carcinogenic in Sprague-Dawley rats. A secondary objective of this study was to determine if the use of phenol during DNA isolation affected the concentration of 8-OHdG subsequently measured. Our results indicate that a profoundly carcinogenic dose of radiation induced a small but significant increase in 8-OHdG concentration in mammary gland DNA, and that the use of a phenol-based versus a salt-based method of DNA isolation had no significant impact on the levels of 8-OHdG detected in either control or irradiated tissue.      

Effects of dietary fat and a vegetable-fruit mixture on the development of intestinal neoplasia in the ApcMin mouse

The variation in colorectal cancer (CRC) incidence worldwide strongly suggests a role for dietary influences. Based on epidemiological data, protective effects of vegetables and fruit intake on CRC are widely claimed, while other data indicate a possible increased CRC risk from (higher) dietary fat intake. Therefore, we have investigated single and interactive effects of dietary fat and a vegetable-fruit mixture (VFM) in the ApcMin mouse, a mouse model for multiple intestinal neoplasia. In this study, four different diets (A-D) were compared, which were either low in fat (20% energy diets A/B) or high in fat (40% energy diets C/D). In addition, 19.5% (wt/wt) of the carbohydrates in diets B and D were replaced by a freeze-dried VFM. The diets were balanced so that they only differed among each other in fat/carbohydrate content and the presence of specific plant-constituents. Because the initiation of intestinal tumors in ApcMin mice occurs relatively early in life, exposure to the diets was started in utero. Without the addition of VFM, mice maintained at a high-fat diet did not develop significantly higher numbers of small or large intestinal adenomas than mice maintained at a low-fat diet. VFM added to a low-fat diet significantly lowered multiplicity of small intestinal polyps (from 16.2 to 10.2/mouse, 15 animals/group), but not of colon tumors in male ApcMin mice only. Strikingly, addition of VFM to female mice maintained on a low-fat diet and to both sexes maintained on a high-fat diet significantly enhanced intestinal polyp multiplicity (from 16.5 to 26.7 polyps/mouse). In conclusion, our results indicate that neither a lower fat intake nor consumption of VFM included in a high-fat diet decreases the development of polyps in mice genetically predisposed to intestinal tumor development.      

The effect of delta-9-tetrahydrocannabinol on forebrain ischemia in rat

The purpose of the study was to evaluate the effect of delta-9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, on ischemic neuronal injury. A 12-min ischemic insult was induced by a reduction in systolic blood pressure to a mean of 50 mm Hg, followed by bilateral carotid artery occlusion at a middle ear temperature of 37.5 degrees C. THC at either a low (0.1 mg/kg; n=8) or high (10 mg/kg; n=8) dose was injected i.p. every 12 h for 7 days prior to ischemia. Non-treated ischemic (n=8) animals formed the control group. The animals were sacrificed 3 weeks post-ischemia for quantitative histopathology. THC at either dose did not significantly reduce ischemic neuronal damage in the hippocampus. The high dose THC-treated group showed significantly less neocortical injury, compared to either the control or low-dose THC groups (p<0.05). The striatum was markedly protected by both low and high dose THC (p<0.001). This regionally specific protection implies that either the hippocampus undergoes suprathreshold ischemic injury or that mechanisms of ischemic injury vary in different brain regions.     

Decreased surgical risks of pancreas transplantation in the modern era

OBJECTIVE: To document the decreased incidence of surgical complications after pancreas transplantation in recent times. SUMMARY BACKGROUND DATA: Compared with other abdominal transplants, pancreas transplants have historically had the highest incidence of surgical complications. However, over the past few years, the authors have noted a significant decrease in the incidence of surgical complications. METHODS: The authors studied the incidence of early (<3 months after transplant) surgical complications (e.g., relaparotomy, thrombosis, infections, leaks) after 580 pancreas transplants performed during a 12-year period. Patients were analyzed and compared in two time groups: era 1 (June 1, 1985, to April 30, 1994, n = 367) and era 2 (May 1, 1994, to June 30, 1997, n = 213). RESULTS: Overall, surgical complications were significantly reduced in era 2 compared with era 1. The relaparotomy rate decreased from 32.4% in era 1 to 18.8% in era 2. Significant risk factors for early relaparotomy were donor age older than 40 years and recipient obesity. Recipients with relaparotomy had significantly lower graft survival rates than those without relaparotomy, but patient survival rates were not significantly different. A major factor contributing to the lower relaparotomy rate in era 2 was a significant decrease in the incidence of graft thrombosis; the authors believe this lower incidence is due to the routine use of postoperative low-dose intravenous heparin and acetylsalicylic acid. The incidence of bleeding requiring relaparotomy did not differ between the two eras. Older donor age was the most significant risk factor for graft thrombosis. The incidence of intraabdominal infections significantly decreased between the two eras; this decrease may be due to improved prophylaxis regimens in the first postoperative week. CONCLUSIONS: Although a retrospective study has its limits, the results of this study, the largest single-center experience to date, show a significant decrease in the surgical risk associated with pancreas transplants. Reasons for this decrease are identification of donor and recipient risk factors, better prophylaxis regimens, refinements in surgical technique, and improved immunosuppressive regimens. These improved results suggest that more widespread application of pancreas transplantation is warranted.     

High-dose therapy and autologous hematopoietic stem-cell transplantation does not increase the risk of second neoplasms for patients with Hodgkin's lymphoma: a comparison of conventional therapy alone versus conventional therapy followed by autologous hematopoietic stem-cell transplantation.

PURPOSE: To determine the incidence of second malignancies among patients with Hodgkin's lymphoma (HL) treated with autologous hematopoietic stem cell transplantation (AHSCT) compared with patients receiving conventional therapy alone and to identify potential risk factors for their occurrence. PATIENTS AND METHODS: We analyzed data on 1,732 consecutive patients with HL treated at the British Columbia Cancer Agency from 1976 to 2001, including 202 patients undergoing AHSCT. The median follow-up duration was 9.8 years for the whole cohort, 9.7 years for those patients treated with conventional therapy, and 7.8 years from AHSCT. RESULTS: The cumulative incidence of developing any second malignancy 15 years after therapy for HL was 9% (risk ratio = 3.5; P < .001); however, the incidence did not differ between those patients receiving conventional therapy alone compared with those undergoing AHSCT (10% and 8%, respectively; P = .48). In multivariate analysis, the only factor significantly associated with an increased risk of developing any second neoplasm or solid tumor was age > or = 35 years (P < .0001). An increased risk of therapy-induced acute myeloid leukemia and therapy-induced myelodysplastic syndrome was seen for patients aged > or = 35 years (P = .03) and stage III/IV (P = .04). CONCLUSION: Patients with HL are at increased risk of developing a second neoplasm. However, those patients undergoing AHSCT do not seem to be at greater risk compared with those patients receiving conventional therapy alone, at least during the first decade after therapy.     

Bilobed oblong porous coated acetabular components in revision total hip arthroplasty

Thirty-eight oblong bilobed noncustom uncemented, porous-coated titanium acetabular components were used to reconstruct failed hip arthroplasties with large superior segmental acetabular bone deficiencies. No structural bone grafts were used. All patients were followed up for 2 to 5 years (mean, 3 years) after the operation. One patient (whose socket rested primarily on a structural bone graft from a previous procedure) had revision surgery for acetabular loosening. No other patients have had revision surgery or had another ipsilateral hip operation. At latest followup, 35 patients had no or mild pain and two patients had moderate pain. Two implants migrated more than 2 mm in the first year, then stabilized. On the latest radiographs, two implants had bead shedding, but there was no measurable migration or change in position. For selected patients with large superolateral acetabular bone deficiencies, this implant facilitated a complex reconstruction, provided good clinical results, and showed satisfactory stability at early to midterm followup in most patients.     

1-取代吡唑烷酮类抗惊构效关系的研究

1-正癸基吡唑烷-3-酮(Ⅱ结构式见表1)是欧洲专利报道的一种新型减肥剂。White等报道该化合物可通过血脑屏障,并对γ-氨基丁酸氨基转移酶(GABA-T)有强烈的抑制活性,但对谷氨酸脱羧酶的抑制作用较弱,因此可引起脑内γ-氨基丁酸(GABA)水平的升高,故我们相信应有抗惊活性。经我们合成后,发现Ⅱ确有良好的抗癲痫活性,抗小鼠最大电