Expansion of recipient-derived antiviral T cells may influence donor chimerism after allogeneic stem cell transplantation.

Donor chimerism (DC) analysis is an important marker in the hematopoietic stem cell transplant follow-up. Here, we present evidence for a possible relationship of infectious complications and declines in DC. We analyzed the DC in patients experiencing cytomegalovirus (CMV) reactivation. In addition, in some patients chimerism analyses of T-cell subsets were performed. CMV-specific cytotoxic T-lymphocytes (CMV-CTL) were monitored using human leukocyte antigen-restricted multimer staining. Interestingly, CMV reactivation was accompanied by changes in DC in 11 of 67 patients transplanted. For example, DC declined in a cord blood recipient, in both total leukocytes and CD4 and CD8 T-cell subsets upon CMV reactivation. The latter was controlled after only 5 days through expanding CMV-CTL of 96% recipient origin, according to chimerism analysis of CMV-CTL (enriched beyond 50%). In another patient, transplanted after reduced-intensity conditioning from a DQB1 mismatched, CMV seronegative donor, incipient CMV reactivation was completely aborted by CMV-CTL of recipient origin. However, at the same time, mixed chimerism dropped from 51% to 0% donor type, resulting in late graft rejection. Our data indicate that chimerism analyses in subset populations lead to a better understanding of declining total leukocyte chimerism. Furthermore, recipient-derived CMV-CTL may be able to control CMV reactivation after reduced-intensity conditioning. We speculate that autologous CMV-CTL may be instrumental to overcome recurrent CMV reactivations, especially in patients transplanted from CMV-seronegative donors. In addition, the expansion of recipient-derived CMV-CTL may contribute to both, graft failure or to conversion to full DC.

Solid organ transplantation after allogeneic hematopoietic stem cell transplantation: a retrospective, multicenter study of the EBMT.

To analyze the outcome of solid organ transplantation (SOT) in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT), a questionnaire survey was carried out within 107 European Group of Blood and Marrow Transplantation centers. This study covered HSCT between 1984 and 2007 in Europe. Forty-five SOT in 40 patients were reported. Fifteen liver, 15 renal, 13 lung, 1 heart and 1 skin transplantations were performed in 28 centers. Overall survival (OS) of patients after SOT was 78% at 5 years (95% confidence interval [CI], 64% to 92%). OS at 5 years was 100% for renal, 71% (95% CI, 46% to 96%) for liver and 63% (95% CI, 23% to 100%) for lung transplant recipients. The 2-year-incidence of SOT failure was 20% (95% CI, 4% to 36%) in patients with graft-versus-host disease (GvHD) and 7% (95% CI, 0% to 21%) in patients without GvHD before SOT. The relapse incidence for underlying malignant diseases was 4% at 5 years (95% CI, 0% to 12%). In summary, this study shows that selected patients receiving SOT after HSCT have a remarkably good overall and organ survival. These data indicate that SOT should be considered in selected patients with single organ failure after HSCT.

Allogeneic stem cell transplantation from related and unrelated donors for aplastic anaemia in adults--a single-centre experience.

Aplastic anaemia (AA) is a rare bone marrow failure syndrome treated either by immunosuppressive therapy or allogeneic stem cell transplantation (SCT). At present, no randomised clinical trials evaluating both treatment options, and in particular SCT from unrelated donors, are available. We here report the clinical course and outcome of allogeneic SCT for 20 consecutive adult patients with AA. Newly diagnosed and untreated patients (n = 8) or patients pre-treated by immunosuppressive therapy (n = 12) were transplanted either from human-leukocyte-antigen (HLA) identical family donors (n = 13) or matched (n = 6) and mismatched (n = 1) unrelated donors, respectively. Conditioning varied depending on donor type and included cyclophosphamide with or without anti-thymocyte globulin (ATG) and fludarabine-cyclophosphamide-ATG with or without low-dose total body irradiation. With a median follow-up of more than 40 months, all patients have had favourable outcomes with stable haematopoietic engraftment and high performance scores. Six patients developed acute (five I degrees -II degrees ; one >II degrees ) and four limited chronic graft-versus-host disease. In this group of AA patients, allogeneic SCT has proven very successful, independent of donor type and pre-treatment. Studies with greater cohorts of patients are warranted to better determine indication and timing of SCT especially from unrelated donors in AA.

Increased risk of complicated CMV infection with the use of mycophenolate mofetil in allogeneic stem cell transplantation.

Mycophenolate mofetil (MMF) is increasingly used for prophylaxis and therapy of GVHD in allogeneic stem cell transplantation. In some recent reports of use of MMF in solid organ transplantation a high incidence of CMV disease has been described. We evaluated the frequency and course of active CMV infection in patients who received MMF compared to those who did not receive MMF after allogeneic stem cell transplantation. We retrospectively analyzed 48 adult patients who consecutively underwent unmanipulated allogeneic bone marrow (n = 15) or peripheral stem cell transplantation (n = 33) from HLA-compatible family donors (n = 30) or unrelated donors (n = 18) from February 1997 to September 2000 at our institution. Only patients who were evaluable for the first 100 days were included in this analysis. Sixteen patients received MMF post transplant (MMF+). CMV-antigenemia was monitored by CMV-pp65 antigen. CMV-antigenemia occurred in 14 patients and was virtually only observed in CMV-IgG+ recipients (13/23, 56%). CMV-IgG+/MMF+ patients developed a higher incidence of CMV-antigenemia (8/9, 89%) compared to the CMV-IgG+/MMF- patients (5/14, 35%; P < 0.05). Moreover, five of six patients with persistent or recurrent CMV-antigenemia received MMF. No patient in either group developed CMV disease or died of CMV-related complications. In multivariate analysis including MMF treatment, unrelated vs related donor, GVHD, CMV-serostatus of the donor and stem cell graft type, only MMF treatment was found to be a significant risk factor for both overall and complicated CMV infection.

Donor cell-derived acute myeloid leukemia developing 14 months after matched unrelated bone marrow transplantation for chronic myeloid leukemia.

We report a patient with Ph-positive CML who developed a Ph-negative AML in donor cells 14 months after BMT from an HLA-identical male unrelated donor. The Ph translocation could not be detected by either conventional cytogenetics, FISH or RT-PCR analysis excluding relapse of CML in myeloid blast crisis. Chimerism studies were performed by variable number of tandem repeats (VNTR) analysis. These revealed donor-type hematopoiesis in both unseparated mononuclear cells and CD34+ selected blasts proving the leukemia to be of donor origin. The patient received three cycles of polychemotherapy with mitoxantrone, topotecan and ara-c resulting in CR after the first treatment cycle and reconstitution with donor hematopoiesis. A second transplant from a female alternative matched unrelated donor was performed after conditioning with fludarabine and 200 cGy TBI and was well tolerated. Nine months after the second transplant the patient is at home and in CR. T cell chimerism was studied by sex chromosome analysis and revealed complete female donor chimerism.

"The myth of mental illness:" continuing controversies and their implications for mental health professionals.

Since the publication of "The Myth of Mental Illness" in 1960, there has been an ongoing debate about Thomas Szasz's ideas concerning mental illness. In this paper, Szasz's views are summarized, as are the views of Szasz's critics. Specifically, the following areas are addressed: Szasz's definition of disease, his notions regarding the unconscious and rationality, his beliefs regarding culpability, his proposed differences between psychiatry and other branches of medicine, the uses of the term "mental illness," and the possibility of implicating physical lesions in some mental illnesses. With this discussion as a backdrop, the importance of these issues to mental health practitioners is addressed.

Proteomic peptide profiling for preemptive diagnosis of acute graft-versus-host disease after allogeneic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation is one curative treatment for hematological malignancies, but is compromised by life-threatening complications, such as severe acute graft-versus-host disease (aGvHD). Prediction of severe aGvHD as early as possible is crucial to allow timely initiation of treatment. Here we report on a multicentre validation of an aGvHD-specific urinary proteomic classifier (aGvHD_MS17) in 423 patients. Samples (n=1106) were collected prospectively between day +7 and day +130 and analyzed using capillary electrophoresis coupled on-line to mass spectrometry. Integration of aGvHD_MS17 analysis with demographic and clinical variables using a logistic regression model led to correct classification of patients developing severe aGvHD 14 days before any clinical signs with 82.4% sensitivity and 77.3% specificity. Multivariate regression analysis showed that aGvHD_MS17 positivity was the only strong predictor for aGvHD grade III or IV (P<0.0001). The classifier consists of 17 peptides derived from albumin, ß2-microglobulin, CD99, fibronectin and various collagen α-chains, indicating inflammation, activation of T cells and changes in the extracellular matrix as early signs of GvHD-induced organ damage. This study is currently the largest demonstration of accurate and investigator-independent prediction of patients at risk for severe aGvHD, thus allowing preemptive therapy based on proteomic profiling.

Prognostic factors in allo-SCT of elderly patients with AML.

The prognosis of elderly patients with AML after chemotherapy is poor. Allo-SCT is feasible in these patients, but data on prognostic factors and outcome are limited. We analyzed all 102 AML patients ≥55 years, who underwent allo-SCT at our institution from 1997 to 2008. OS and relapse-free survival (RFS) rates at 3 years are 39 and 37%, respectively. Multivariate analysis for OS revealed age ≥60 years and active (refractory or untreated before allo-SCT) or advanced (>CR1) disease as adverse prognostic factors. Patients transplanted in CR1 had a 3-year OS of 67 vs 27% for patients with active/advanced disease. Multivariate analysis for RFS revealed active/advanced disease as the only adverse factor. Patients transplanted in CR1 had a 3-year RFS of 70 vs 22% for patients with active/advanced disease. In all, 17% of patients suffered from acute GVHD ≥grade II. The risk for severe acute GVHD was increased after allo-SCT from mismatched donors. Nonrelapse mortality (NRM) was 23% at 1 year. The only risk factor for NRM was active/advanced disease. In conclusion, allo-SCT from related or unrelated donors yields very good results in elderly AML patients transplanted in CR1. Disease status at transplantation is the most important prognostic factor for transplantation success.

Laterality of interhemispheric inhibition depends on handedness.

There is some evidence that handedness is related to lateralisation of excitability in the motor system. We investigated lateralisation of interhemispheric inhibition (IHI), motor thresholds and short interval intracortical inhibition (SICI) and facilitation (SICF) in relation to handedness in 12 right (RH) and 13 left handed (LH) subjects. Because there is some controversy as to the optimal localisation to produce IHI we also compared IHI induced by conditioning the dorsal premotor cortex (dPM) versus primary motor cortex (M1) in ten RH. IHI was stronger following conditioning the motor dominant as compared to the motor non-dominant hemisphere in RH and LH. Motor thresholds were higher when elicited over the right hemisphere than over the left in both RH and LH, while SICI and SICF showed no differences between hemispheres or dependency from handedness. We hypothesize that IHI is a function of handedness perhaps reflecting predominant usage of the dominant hand, while lateralisation of thresholds and intracortical excitability are determined by other factors.

Activation of protein kinase A (PKA) by 8-Cl-cAMP as a novel approach for antileukaemic therapy.

Activation of PKA by cAMP agonists, such as 8-Cl-cAMP activation, selectively causes rapid apoptosis in v-abl transformed fibroblasts by inhibiting the Raf-1 kinase. Here we investigated whether 8-Cl-cAMP is useful for the treatment of chronic myelogenous leukaemia (CML), which is hallmarked by the expression of the p210(bcr/abl) oncogene. Autologous bone marrow transplantation is a feasible alternative for patients with no suitable donor, but hampered by the risk of relapse due to the persistence of leukaemia cells in the transplant. To study the effects of 8-Cl-cAMP on primary leukaemic cells, bone marrow cells (BMCs) from eight CML patients (one at diagnosis, three in chronic and four in accelerated phase) were treated. Ex vivo treatment of BMCs obtained in chronic phase of CML with 100 microM 8-Cl-cAMP for 24-48 h led to the selective purging of Philadelphia Chromosome (Ph1 chromosome) without toxic side effects on BMCs from healthy donors as measured by colony-forming unit (CFU) assays. BMCs from patients in accelerated phase showed selective, but incomplete elimination of Ph1 chromosome positive colony forming cells. The mechanism of 8-Cl-cAMP was investigated in FDCP-mix cells transformed by p210(bcr/abl), a cell culture model for CML. The results showed that 8-Cl-cAMP reduced DNA synthesis and viability independent of Raf inhibition as Raf inhibitors had no effect. MEK inhibitors interfered with DNA synthesis, but not with viability. In summary, our results indicate that 8-Cl-cAMP could be useful to purge malignant cells from the bone marrow of patients with CML and certain other forms of leukaemias.