Prospective randomised controlled trial comparing trigone-sparing versus trigone-including intradetrusor injection of abobotulinumtoxinA for refractory idiopathic detrusor overactivity.

BACKGROUND: Botulinum toxin A is effective for treatment of idiopathic detrusor overactivity (IDO). The trigone is generally spared because of the theoretical risk of vesicoureteric reflux (VUR), although studies assessing injection sites are lacking. OBJECTIVE: Evaluate efficacy and safety of trigone-including versus trigone-sparing intradetrusor injections of abobotulinumtoxinA in patients with IDO. DESIGN, SETTING, AND PARTICIPANTS: Twenty-two patients from one centre were randomised to trigone-including or trigone-sparing injections. INTERVENTION: Injection of 500 U abobotulinumtoxinA diluted to 20ml into 20 trigone-including or trigone-sparing sites. MEASUREMENTS: The primary outcome measure was total overactive bladder symptom score (OABSS) at 6 wk. The OABSS questionnaire was completed at 0, 6, 12, and 26 wk. Baseline and postinjection urodynamic studies and micturating cystourethrograms were performed. Baseline values and subsequent time points were compared by t test. A mixed-effect model was used for repeated measures in time. RESULTS AND LIMITATIONS: For symptom scores at baseline compared with scores at 6 wk postinjection, the mean total OABSS improved from 22.4 to 8.7 (p<0.001) in the trigone-including group compared with 22.7 to 13.4 (p<0.03) in the trigone-sparing group. The difference in mean change from baseline was 4.4 points in favour of the trigone-including group (p=0.03). The total OABSS at 12 and 26 wk and the urgency subscale scores at 6, 12, and 26 wk showed significant improvement in favour of the trigone-including group. Mean postvoid residual volumes and clean intermittent self-catheterisation rates between the two groups were similar. No patients developed VUR. Performing injections under general anaesthetic was a limitation, as tolerability under local anaesthetic was not assessed. A further limitation is the lack of a trigone-only arm. CONCLUSIONS: Trigone-including injections are superior to trigone-sparing injections for the treatment of refractory IDO and did not cause VUR in this study.

Electroejaculatory stimulation for male infertility secondary to spinal cord injury: the Irish experience in National Rehabilitation Hospital.

OBJECTIVES: To examine the success rate of electroejaculatory stimulation in patients with acquired spinal injuries in a single Irish institution. The use of electroejaculatory stimulation is of benefit in patients with spinal cord injury who wish to have children. METHODS: A retrospective review of the Hospital In-Patient Enquiry scheme database and the patients' medical notes was performed. Any patient who had undergone electroejaculatory stimulation in the past 14 years was included. The quality of semen obtained and the pregnancy rate were assessed in relation to several variables, including patient age and level of spinal injury. RESULTS: From 1994 to 2008, 31 patients (29 patients with acquired spinal injury and 2 patients with a congenital spinal abnormality) had undergone electroejaculatory stimulation as a method of providing semen for assisted conception. Of the 31 patients, 6 had requested cryopreservation of their semen for future use and were therefore excluded from the pregnancy rate analysis. Of the 25 patients who had used the semen, 9 (36%) were successful in achieving pregnancy that resulted in living offspring. The semen analysis results were available for 15 patients. Three patients (one each with contaminated semen, poor semen quality, and an abandoned procedure) required testicular biopsy to extract viable sperm and subsequently achieved pregnancy. Lower spinal lesions (below T10) were associated with lower rates of pregnancy after electroejaculatory stimulation. One patient developed autonomic dysreflexia during the procedure, which was therefore abandoned. CONCLUSIONS: Electroejaculatory stimulation is an effective method of obtaining semen for reproductive purposes and is an option for fertility preservation in patients with spinal cord injury-related anejaculation.

Landmarks in the development of hematopoietic cell transplantation.

The field of bone marrow transplantation has evolved over a period of 50 years. Reports of beneficial treatment of murine leukemia by irradiation and injection of marrow cells from another mouse stimulated interest in attempting to use these techniques to treat patients with leukemia. The first few bold attempts at human application were generally met with a total lack of success except for a few transplants involving identical twins. Understanding the HLA system led to the ability to select compatible sibling donors. The first successful long-term survivors were reported at the end of the 1960s. During the 1970's patients were given transplants for leukemia after failure of all other treatment. Survivals were poor, but some patients were cured. Transplantation early in the course of the disease resulted in greatly improved survival. During the 1980s improved control of infections, the use of peripheral blood as the source of stem cells, and the ability to select donors other than family members resulted in wide application of hematopoietic cell grafting.

Historic landmarks in clinical transplantation: conclusions from the consensus conference at the University of California, Los Angeles.

The transplantation of organs, cells, and tissues has burgeoned during the last quarter century, with the development of multiple new specialty fields. However, the basic principles that made this possible were established over a three-decade period, beginning during World War II and ending in 1974. At the historical consensus conference held at UCLA in March 1999, 11 early workers in the basic science or clinical practice of transplantation (or both) reached agreement on the most significant contributions of this era that ultimately made transplantation the robust clinical discipline it is today. These discoveries and achievements are summarized here in six tables and annotated with references.

Bone marrow transplantation: a review.

Bone marrow transplantation has evolved over a period of 50 years. Laboratory observations and animal studies defined the essentials of transplantation biology. The first attempts to transfer these studies to patients met with little success. The definition of the complexities of the human leukocyte antigen (HLA) system made it possible to select compatible sibling donors and more recently unrelated donors. Transplantation of stem cells from marrow, blood, or cord blood is now the treatment of choice for a variety of hematological and genetic diseases. Transplantation using less toxic preparative regimens to induce mixed chimerism makes possible an application to autoimmune diseases. Laboratory and clinical research directed toward induction of tolerance and elimination of malignant cells point the way to a wider application of hematopoietic cell transplantation in the next decade.

Methotrexate and cyclosporine for graft-vs.-host disease prevention: what length of therapy with cyclosporine?

One hundred three patients with leukemia, aplastic anemia, or myelodysplastic syndrome were treated by marrow transplantation from genotypically HLA-identical siblings (n = 92) or HLA haploidentical family members differing for one HLA antigen on the nonshared haplotype (n = 11). To prevent graft-vs.-host disease (GVHD), they were administered postgrafting immunosuppression with a short course of intermittent methotrexate with daily cyclosporine for no more than 11 days. Customarily, we have given cyclosporine for 180 days after transplant. In the current study, we asked whether cyclosporine could be stopped earlier without affecting the risk of chronic GVHD. By day 60, patients who never had acute GVHD, or whose acute GVHD had resolved, were randomized to have cyclosporine stopped (n = 52) or continued for the usual 180 days (n = 51). Results were analyzed with a median follow-up of 9.3 years after transplant, and showed that patients in whom cyclosporine was discontinued on day 60 had a significantly more rapid onset (p = 0.001), but not a significantly higher overall incidence of chronic GVHD than those in whom the drug was stopped on day 180 (43 vs. 54%; p = 0.26). Transplant-related mortality was comparable among patients without preceding acute GVHD, regardless of when cyclosporine was discontinued (11% for both study arms). However, transplant-related mortality appeared to increase among patients with preceding acute GVHD in whom cyclosporine was stopped by day 60 (38 vs. 17%). Results suggest that cyclosporine can safely be discontinued early in patients who never had evidence of acute GVHD, while those with preceding acute GVHD would benefit from a longer course of the drug. Because of the relatively small sample sizes, these results would best be treated as promising preliminary findings that should be confirmed in larger randomized studies.

Pros and cons of stem cell transplantation for autoimmune disease.

The data and discussion at this symposium have provided a most useful analysis of the autoimmune diseases and their potential for therapy by stem cell transplantation. These diseases are characterized by threat to life and particularly by chronic, painful and debilitating courses that warrant aggressive therapy. Selection of patients will be difficult because of the variable disease course and the necessity to choose patients who still have reversible disease. The safety of both autologous and allogeneic stem cell grafting has progressed to the point where, in many cases, the risks of the disease far outweigh those of transplantation. In my opinion the data presented at this symposium show that we should proceed cautiously with both autologous and allogeneic stem cell grafts. Purified stem cells, which have the advantage of being free of lymphocytes, should be used for the first series of autologous studies. These studies are attractive because of the low risk of transplant related complications but are less likely to be curative. Allogeneic grafts from perfectly matched donors have the advantage of providing a completely new immunological environment. For this reason, I believe that curative results are most probable after allogeneic stem cell engraftment. Emphasis should be on the identification of patients with HLA matched siblings. Initially, these studies will be carried out in patients with advanced disease, as was the case in the early days of transplantation for leukemia. In considering more aggressive treatment for autoimmune diseases it appears there are 3 possible approaches. First, and most conservative, is to store peripheral blood stem cells for possible future marrow rescue and then to give higher doses of immunosuppressive agents, especially in combination, to see whether there is an improvement over conventional doses. Second, for those who prefer a conservative approach to stem cell transplantation, is to give myeloablative and lymphoablative chemotherapy followed by purified (lymphocyte-free) hematopoietic stem cells. Third, and most likely to be curative, is myeloablative and lymphoablative therapy followed by stem cells from an HLA matched family member with subsequent short methotrexate and cyclosporine treatment to control GVHD. As we have heard, there are differences of opinion about whether the preparative regimen should include irradiation. It should be pointed out that total body irradiation is the most effective way to destroy lymphoid cells throughout the body. Careful monitoring of accumulating clinical results will pilot future investigation.

Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation.

Thirty-six patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) were studied for the presence of the bcr-abl fusion mRNA transcript after an allogeneic matched related (N = 12), partially matched related (N = 4), matched unrelated (N = 14), autologous (N = 5), or syngeneic (N = 1) bone marrow transplant (BMT). Seventeen were transplanted in relapse, and 19 were transplanted in remission. Twenty-three patients had at least one positive bcr-abl polymerase chain reaction (PCR) assay after BMT either before a relapse or without subsequent relapse. Ten of these 23 relapsed after a positive assay at a median time from first positive PCR assay of 94 days (range, 28 to 416 days). By comparison, only 2 relapses occurred in the 13 patients with no prior positive PCR assays; both patients had missed at least one scheduled follow-up assay and were not tested 2 months and 26 months before their relapse. The unadjusted relative risk (RR) of relapse associated with a positive PCR assay compared with a negative assay was 5.7 (95% confidence interval 1.2 to 26.0, P = .025). In addition, the data suggest that the type of bcr-abl chimeric mRNA detected posttransplant was associated with the risk of relapse: 7 of 10 patients expressing the p190 bcr-abl relapsed, compared with 1 of 8 who expressed only the p210 bcr-abl mRNA (P = .02, log-rank test). The RR of p190 bcr-abl positivity compared to PCR-negative patients was 11.2 (confidence interval 2.3-54.8, P = 0.003), whereas a positive test for p210 bcr-abl was apparently not associated with an increased relative risk. In separate multivariable models, PCR positivity remained a statistically significant risk factor for relapse after separately adjusting for donor (unrelated and partially matched v matched, autologous, and syngeneic), remission status at the time of transplant, the presence of acute graft-versus-host disease (GVHD), and type of conditioning regimen (total body irradiation dose of < or = 1,200 cGy v > 1,200 cGy). The PCR assay appears to be a useful test for predicting patients at high risk of relapse after BMT and may identify patients who might benefit from therapeutic interventions. The finding that the expression of p190 bcr-abl may portend an especially high risk of relapse suggests a different clinical and biologic behavior between p190 and p210 bcr-abl.

Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation.

The influence of busulfan (BU) plasma concentration on outcome of transplantation from HLA identical family members for the treatment of chronic myelogenous leukemia (CML) was examined in 45 patients transplanted in chronic phase (CP) (n = 39) or accelerated phase (AP) (n = 6). All patients received the same regimen of BU, 16 mg/kg orally and cyclophosphamide (CY), 120 mg/kg intravenously. Plasma concentrations of BU at steady state (C(SS)BU) during the dosing interval were measured for each patient. The mean C(SS)BU was 917 ng/mL (range, 642 to 1,749; median, 917; standard deviation, 213). Of patients with C(SS)BU below the median, seven (five of 18 in CP and two of four in AP) developed persistent cytogenetic relapse and three of these patients died. There were no relapses in patients with C(SS)BU above the median. The difference in the cumulative incidence of relapse between the two groups was statistically significant (P = .0003). C(SS)BU was the only statistically significant determinant of relapse in univariable or multivariable analysis. The 3-year survival estimates were 0.82 and 0.64 for patients with C(SS)BU above and below the median (P = .33). There was no statistically significant association of C(SS)BU with survival or nonrelapse mortality, although the power to detect a difference in survival between 0.82 and 0.64 was only 0.24, similarly C(SS)BU above the median was not associated with an increased risk of severe regimen-related toxicity. We conclude that low BU plasma levels are associated with an increased risk of relapse.

Stem cell transplantation: past, present and future.

The early attempts at human allogeneic marrow transplants in the 1950's and 1960's were largely unsuccessful. The probability of success has improved steadily in the past two decades. Cure rates now range from 90% for non-malignant diseases transplanted early to 15% for patients with advanced leukemia. Most marrow transplants have involved an HLA matched sibling donor but, more recently, a matched unrelated volunteer marrow donor can be found for many patients without a family donor. Current research is focused on new preparative regimens for elimination of malignant cells, better prevention of graft-versus-host disease, and the use of hematopoietic growth factors and cytokines. Autologous transplants, which use the patient's own marrow, are increasing, particularly for breast cancer. The hematopoietic stem cells are responsible for marrow regeneration after a transplant. Sufficient numbers of stem cells for transplantation can now be obtained from the peripheral blood after mobilization of these cells by chemotherapy or hematopoietic growth factors. Transplants can also be achieved using stem cells obtained from cord blood at the time of delivery, tissue typed, and cryopreserved for later use. A variety of technological advances has reduced the hospitalization time for transplant patients with a corresponding saving in cost.

Bone marrow transplantation from bench to bedside.

Marrow grafting, now more appropriately called hematopoietic stem cell grafting, has come a long way from early bench studies and desperate bedside therapeutic attempts in terminal patients. Grafting of hematopoietic stem cells is now standard therapy for selected diseases and stages of disease, and increasing application on an outpatient basis is rapidly lowering the cost of the procedure. The combined efforts of the now many clinical marrow transplant teams and the interested basic science laboratories will undoubtedly make the coming decade an exciting and productive time for science and for the well-being of patients with otherwise incurable diseases.