Topotecan in combination with radiotherapy in unresectable glioblastoma: a phase 2 study

Improving glioblastoma multiforme (GBM) treatment with radio-chemotherapy remains a challenge. Topotecan is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration. The present study assessed the combination of radiotherapy (60 Gy/30 fractions/40 days) and topotecan (0.9 mg/m²/day on days 1–5 on weeks 1, 3 and 5) in 50 adults with histologically proven and untreated GBM. The incidence of non-hematological toxicities was low and grade 3–4 hematological toxicities were reported in 20 patients (mainly lymphopenia and neutropenia). Partial response and stabilization rates were 2% and 32%, respectively, with an overall time to progression of 12 weeks. One-year overall survival (OS) rate was 42%, with a median OS of 40 weeks. Topotecan in combination with radiotherapy was well tolerated. However, while response and stabilization concerned one-third of the patients, the study did not show increased benefits in terms of survival in patients with unresectable GBM.     

Adaptation française et analyse des qualités psychométriques du questionnaire d’évitement et de fusion (AFQ) dans une population adulte

Objectives

The transdiagnostic approach of psychological disorders puts forward a set of psychological manifestations that would be responsible for the maintenance and aggravation of certain disorders such as depression, phobia, anxiety or addictive behaviors. One of these symptoms, the experiential avoidance, is characterized by the avoidance of internal events such as thoughts, emotions and sensations, as well as cognitive fusion (taking thoughts as real facts). The latter would engender psychological inflexibility in the individual and some psychological disorders. Tools such as the Avoidance and Fusion Questionnaire allows to detect this psychological inflexibility. This questionnaire, originally intended for a population of children and adolescents, was adapted and validated in an adult population but not in the French language. Then, we translated it in French and explored its psychometric qualities.

Epigenetics and autoimmunity

Advances in genetics, such as sequencing of the human genome, have contributed to identification of susceptible genetic patterns in autoimmune diseases (AID). However, genetics is only one aspect of the diseases that does not reflect the influence of environment, sex or aging. Epigenetics, the control of gene packaging and expression independent of alterations in the DNA sequence, is providing new directions linking genetics and environmental factors. Recent findings have contributed to our understanding of how epigenetic modifications could influence AID development, showing differences between AID patients and healthy controls but also showing how one disease differs from another. With regards to epigenetic abnormalities, DNA methylation and histone modifications could be affected leading to large spatial and temporal changes in gene regulation. Other epigenetic processes, such as the influence of the ionic milieu around chromatin and DNA supercoiling stresses may be suspected also. The newly described role of microRNAs in control of gene expression is important by promoting or suppressing autoreactivity in AID. As a consequence control of cellular processes is affected becoming conducive, for example, to the development of autoreactive lymphocytes in systemic lupus erythematosus, synoviocyte proliferation in rheumatoid arthritis, or neural demyelination in multiple sclerosis. Application of epigenetics to AID is in its infancy and requires new hypotheses, techniques, tools, and collaborations between basic epigenetic researchers and autoimmune researchers in order to improve our comprehension of AID. From this will arise new therapeutics, means for early intervention, and perhaps prevention.     

Geo-epidemiology and autoimmunity

Autoimmune disease (AD) affects approximately 3% of the population. This is an enormous number, but ironically the study of autoimmunity has not taken on the significance of many other diseases because so many of the ADs are relatively uncommon. Indeed, despite enormous advances in the diagnosis and the treatment of AD, there is still a paucity of data on the etiological events that lead to the clinical pathology. For most other human diseases, the etiology is addressed and often solved by the use of epidemiology. Epidemiology consists of the study of prevalence of a disease, coupled with analysis of genetic factors and detection of environmental agents. In the context of autoimmune conditions, preclinical epidemiology has recently been favored, as a consequence of the discovery that autoantibody precedes overt disease. The idea of a North–South gradient in the prevalence of ADs, with a reciprocal gradient in that of infectious injuries has proven to be debatable. More importantly, environmentally-induced changes have been shown to modify certain diseases giving rise to the key concept of epigenetics. However, it is clear that major voids exist. Some of these voids were hoped to be solved by the use of genome-wide associations. This, however, has proven very problematic, as the genetic basis of AD is considerably more complicated than once believed. We now base our hopes on next generational sequencing as a brut force undertaking to partially decipher the genetic code that predisposes individuals to AD. This volume is a compilation of papers in Autoimmunity Reviews and the Journal of Autoimmunity and presented as part of the 7th International Congress on Autoimmunity in Ljubljana, Slovenia. It is clearly impossible to present data on the geoepidemiology of all of the AD. Instead, we attempted to generate interest amongst immunologists to generate papers that are thought provoking but also contemporary reviews.     

Allogeneic hematopoietic stem cell transplantation allows long-term complete remission and curability in high-risk Waldenstr?m’s macroglobulinemia. Results of a retrospective analysis of the Société Fran?aise de Greffe de Moelle et de Thérapie Cellulaire

Background

Patients with poor-risk Waldenström’s macroglobulinemia have suboptimal response and early post-treatment relapse with conventional therapies. Hence, new therapeutic approaches such as allogeneic stem cell transplantation should be evaluated in these patients.

Design and Methods

We examined the long-term outcome of allogeneic stem cell transplantation in Waldenström’s macroglobulinemia by studying the records of 24 patients reported in the SFGM-TC database and one transplanted in the bone marrow unit in Hamburg.

Results

Median age at the time of transplant was 48 years (range, 24–64). The patients had previously received a median of 3 lines of therapy (range, 1–6) and 44% of them had refractory disease at time of transplant. Allogeneic stem cell transplantation after myeloablative (n=12) or reduced-intensity (n=13) conditioning yielded an overall response rate of 92% and immunofixation-negative complete remission in 50% of evaluable patients. With a median follow-up of 64 months among survivors (range, 11–149 months), 5-year overall survival and progression-free survival rates were respectively, 67% (95% CI: 46–81) and 58% (95% CI: 38–75). The 5-year estimated risk of progression was 25% (95% CI: 10–36%), with only one relapse among the 12 patients who entered complete remission, versus 5 in the 12 patients who did not. Only one of the 6 relapses occurred more than three years post-transplant.

Conclusions

Allogeneic stem cell transplantation yields a high rate of complete remissions and is potentially curative in poor-risk Waldenström’s macroglobulinemia.     

Severe Aplastic Anemia Associated With Eosinophilic Fasciitis: Report of 4 Cases and Review of the Literature

Diffuse eosinophilic fasciitis (Shulman disease) is a rare sclerodermiform syndrome that, in most cases, resolves spontaneously or after corticosteroid therapy. It has been associated with hematologic disorders, such as aplastic anemia. The clinical features and long-term outcomes of patients with eosinophilic fasciitis and associated aplastic anemia have been poorly described. We report the cases of 4 patients with eosinophilic fasciitis and associated severe aplastic anemia. For 3 of these patients, aplastic anemia was refractory to conventional immunosuppressive therapy with antithymocyte globulin and cyclosporine. One of the patients received rituximab as a second-line therapy with significant efficacy for both the skin and hematologic symptoms. To our knowledge, this report is the first to describe rituximab used to treat eosinophilic fasciitis with associated aplastic anemia.In a literature review, we identified 19 additional cases of eosinophilic fasciitis and aplastic anemia. Compared to patients with isolated eosinophilic fasciitis, patients with eosinophilic fasciitis and associated aplastic anemia were more likely to be men (70%) and older (mean age, 56 yr; range, 18–71 yr). Corticosteroid-containing regimens improved skin symptoms in 5 (42%) of 12 cases but were ineffective in the treatment of associated aplastic anemia in all but 1 case. Aplastic anemia was profound in 13 cases (57%) and was the cause of death in 8 cases (35%). Only 5 patients (22%) achieved long-term remission (allogeneic hematopoietic stem cell transplantation: n = 2; cyclosporine-containing regimen: n = 2; high-dose corticosteroid-based regimen: n = 1).