Chronic kidney disease--a common and serious complication after intestinal transplantation

BACKGROUND: Chronic kidney disease after organ transplantation is a serious complication that negatively impacts on long-term patient survival. We describe long-term renal function after intestinal transplantation by serial measurements of glomerular filtration rates (GFR) with Chromium EDTA clearance. MATERIALS AND METHODS: Ten patients with at least 6 months survival form the basis of this report. Glomerular filtration rate measurements were performed at baseline, 3 months posttransplantation, and yearly thereafter. Median follow-up time for the cohort was 1.5 years (0.5-7.8 years). Tacrolimus (Prograf) was discontinued in four patients because of impaired renal function. These four patients were switched to sirolimus (Rapamune) at 11, 18, 24, and 40 months posttransplantation. RESULTS: Median baseline GFR was 67 (22-114) mL/min/1.73 m. In the adult patients, GFR 3 months posttransplantation had decreased to 50% of the baseline. At 1 year, median GFR in the adult patients was reduced by 72% (n=5). Two patients developed renal failure within the first year and required hemodialysis. One of the pediatric patients fully recovered her renal function, the second pediatric patient lost 20% of her baseline GFR at 6 months posttransplantation. Glomerular filtration rate calculated with the modified diet in renal disease formula consistently overestimated GFR by approximately 30% compared with measured GFR. CONCLUSION: Chronic kidney disease and renal failure are common after intestinal transplantation. These two factors significantly contribute to poor long-term survival rates. Measurements of GFR may help to identify those individuals at risk for developing chronic kidney disease to implement renal sparing strategies.     

H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase

It has been suggested that phosphorylation of the histone variant H2AX after ultraviolet light (UV) irradiation is triggered by DNA double-strand breaks induced as replication forks collide with UV-induced bulky lesions. More recently, it has been shown that UV-induced H2AX phosphorylation can also occur outside of S-phase, but the mechanism for this replication-independent induction is not well understood. In this study, we show that H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is induced in all phases of the cell cycle. Accumulation of DNA repair intermediates by inhibition of DNA repair synthesis resulted in a marked increase of H2AX phosphorylation in repair proficient but not repair-deficient xeroderma pigmentosum-A cells. Using chemical inhibitors of the PI(3)-like kinase family of protein kinases as well as ataxia telangiectasia mutated and Rad-3 related (ATR)-deficient Seckel syndrome cells and ataxia telangiectasia mutated-deficient ataxia telangiectasia cells, we show that the H2AX phosphorylation induced by accumulation of repair intermediates is mediated primarily by the ATR kinase. We suggest a model for UV light-induced phosphorylation of H2AX where in addition to replication blockage, DNA repair intermediates trigger H2AX phosphorylation via the ATR kinase.     

Compromised Fanconi anemia response due to BRCA1 deficiency in cisplatin-sensitive head and neck cancer cell lines

Head and neck cancers are commonly treated with the DNA-damaging agent cisplatin. While many tumors respond well to cisplatin treatment, some do not. The mechanism for this differential sensitivity of head and neck tumors to cisplatin is not understood in detail. In this study, we explored whether the functional status of the Fanconi anemia and BRCA pathway (FA/BRCA) would predict cisplatin sensitivity in head and neck cancer cells. The FA/BRCA pathway is critical for the orchestration of the cellular response to cisplatin and other DNA cross-linking agents. It was found that three out of four cisplatin-sensitive head and neck cancer cell lines showed defective formation of FANCD2 nuclear foci while all four cisplatin-resistant cell lines tested were proficient in FANCD2 foci formation following cisplatin treatment. The defect in FANCD2 foci formation in the cisplatin-sensitive cell lines was not due to defective monoubiquitylation of FANCD2 but appeared to be due to reduced expression or defective function of BRCA1 since expression of exogenous BRCA1 restored the ability of these cells to induce FANCD2 foci following cisplatin treatment and enhanced cisplatin resistance. These results suggest a possible role for BRCA1 in modulating cisplatin sensitivity in head and neck cancer cells.     

Pain in paediatric oncology: interviews with children, adolescents and their parents

Pain diagnostics and treatment are crucial components in the care of children with cancer. This study evaluated the extent and causes of pain, the use of methods for monitoring pain intensity, principles of pain management and adverse effects of pain treatment. In addition, care, support and information given to children and parents were evaluated. Structured interviews were conducted with 55 children with malignant disease and their parents. Pain was a common symptom and a major problem during different phases of cancer treatment and pain evaluation was unsystematic. Pain due to treatment and procedures was a greater problem than pain due to the malignant disease itself, and two thirds of the pain experienced by these children seemed to have iatrogenic origin. Younger children and children with short disease duration were more concerned about procedural pain. Parents and children thought that more efficient pain treatment was often possible. Parents claimed to judge their child's pain better than professionals, and children and parents wanted more information on different aspects of pain and pain treatment. Pain identification and treatment can be substantially improved through increased use of methods for pain evaluation and through giving enhanced information to families about pain and pain treatment.     

Bone marrow transplantation for acute non-lymphoblastic leukemia.

Most results obtained by different study and analytic designs favor that matched allogeneic BMT is superior to chemotherapy in young adults with ANLL in first remission. The place of ABMT is more difficult to assess and requires further study both compared to chemotherapy and allogeneic BMT. Furthermore, the question of purging needs further study in a controlled fashion. For older patients the choice is more difficult. Transplant related mortality increases with age which makes ABMT an attractive alternative to allogenic BMT. However, recent advances in prophylaxis and treatment of transplant related complications such as cytomegalovirus interstitial pneumonia and veno-occlusive disease of the liver might increase long-term survival after allogeneic BMT in older patients. The role of matched unrelated donors in the treatment of ANLL is unresolved but this procedure should probably be reserved for relatively young patients in second complete remission or later.     

Reduced susceptibility to penicillin of viridans group streptococci in the oral cavity of patients with haematological disease

The occurrence of oral penicillin-resistant viridans group streptococci (VGS) was studied in 50 patients with either newly diagnosed acute leukaemia or autologous peripheral stem cell transplants. One patient was excluded because of Staphylococcus aureus growth in the stem cell harvest. VGS were isolated from the oral cavity of 48 of the remaining 49 patients. Of these 48 patients, 12 (25%) yielded VGS resistant (MIC > 2 mg/L) to penicillin. These 12 patients had a higher frequency of septicaemia (p 0.04) and more days of treatment with trimethoprim-sulphamethoxazole (p 0.04) than patients who harboured susceptible or intermediately resistant VGS (MIC 2 mg/L). There were no other statistically significant differences between the two groups. It is important to be aware of the high level of penicillin resistance in oral VGS in patients with haematological disease, and this parameter should be considered when selecting antibiotic therapy for cases of septicaemia caused by VGS in immunocompromised patients.     

Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology

Summary Busulphan levels in plasma were measured in 27 patients during conditioning therapy (1 mg/kg×4 for 4 days) before bone marrow transplantation. The mean minimal concentration found in children aged <5 years (237 ng ml^–1) was lower than that observed in adults or older children (607 and 573 ng ml^–1, respectively). The AUC for the last dose was significantly lower in young children (2,315 h ng ml^–1) than in adults or older children (6,134 and 5,937 h ng ml^–1, respectively). The elimination half-life for the last dose in young children was shorter (2.05 h) than that in either adults (2.59 h) or older children (2.79 h). When the AUC was normalized for body surface area, the difference between young children and the other groups was smaller but remained statistically significant. The total body clearance was significantly higher in young children (7.3 ml min^–1 kg^–1) as compared with both older children and adults (3.02 and 2.7 ml min^–1 kg^–1, respectively). The plasma levels of busulphan showed circadian rhythmicity, especially in young children. The concentration measured during the night in some patients was up to 3-fold that observed during daytime. We conclude that the busulphan dosage for children must be reconsidered and that further studies are urgently needed to develop an optimal therapy.Abbreviations AML acute myeloblastic leukemia - ALL acute lymphatic leukemia - AUL acute undifferentiated leukemia - ABMT autologous bone marrow transplantation - BMT allogeneic bone marrow transplantation This work was supported by grant 2805-B90-01X from the Swedish Cancer Society     

Alpha-interferon maintenance treatment is associated with improved survival after high-dose treatment and autologous stem cell transplantation in patients with multiple myeloma: a retrospective registry study from the European Group for Blood and Marrow Transplantation (EBMT)

The purpose of this study was to evaluate the effect of alpha-IFN maintenance treatment after autologous stem cell transplantation (ASCT) for multiple myeloma in a retrospective registry analysis. 473 patients with multiple myeloma who received IFN maintenance treatment ASCT were compared with 419 patients who did not receive IFN-treatment. Patients who were evaluable for response and in complete or partial remission at 6 months after ASCT were eligible, after excluding patients with graft failure. Cox proportional hazards assumptions were checked and handled by stratification. The prognostic variables unevenly distributed between the two groups were statistically corrected for in the Cox analysis. 391 patients reached complete remission (CR) after ASCT (203 in the IFN group and 188 in the no-IFN group) and 501 were in partial remission (PR, IFN 270, no-IFN 231). Overall survival (OS) and progression-free survival (PFS) were significantly better in the IFN-group (OS, 78 vs 47 months, P = 0.007, and PFS, 29 vs 20 months, P = 0.006, respectively). The difference in OS and PFS was most strongly pronounced in the PR patients. 209 patients have died (IFN, 84; no-IFN, 125). Progressive myeloma was the cause of death in 94% of the IFN-treated patients and in 83% of the no-IFN group (P = NS). Thus, IFN maintenance treatment after ASCT was associated with better OS and PFS. Treatment seemed to be most beneficial in patients who did not achieve CR. The difference in median survival was as long as 2.5 years, and although part of this difference is attributable to differences in other prognostic factors, it might justify possible differences in quality-of-life due to adverse effects of interferon treatment.     

The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation

Busulfan (Bu) is an important component of some myeloablative regimens prior to stem cell transplantation (SCT). Over the last few years it has been shown that other drugs administered concomitantly can influence Bu pharmacokinetics. In the present study, we compared Bu concentrations (trough levels) in three groups of patients. Group A (n=5) received metronidazole as graft-versus-host disease prophylaxis during Bu treatment. Group B (n=9) received Bu only for 2 days followed by 2 days of Bu and metronidazole. Group C (n=10) was a control group that received Bu without metronidazole. The mean Bu levels for Group A receiving metronidazole during conditioning was significantly (P<0.001) higher (948+/-280 ng/ml), compared to those observed in the control group (507+/-75 ng/ml). In Group B, the administration of metronidazole resulted in a significant (P<0.001) increase in Bu levels (807+/-90 ng/ml) during the last 2 days, compared to 452+/-68 ng/ml during the first 2 days. In Group A, one patient died with multiorgan failure, three experienced veno-occlusive disease (VOD) and one developed hemorrhagic cystitis. Elevated liver transaminases (AST, ALT) and bilirubin were detected in all Group A patients. In Group B, six patients had elevated liver function tests but no VOD was observed. We conclude that metronidazole should not be administered simultaneously with Bu to avoid the high plasma levels of Bu, which may lead to severe toxicity and/or treatment related mortality.