Shape of the art: TCR-repertoire after allogeneic hematopoietic cell transplantation.

The human adaptive immune repertoire is characterized by specificity and diversity to provide immunity against past and future tasks. Such tasks are mainly infections but also malignant transformations of cells. With its multiple lines of defense, the human immune system contains both, rapid reaction forces and the potential to capture, disassemble and analyze strange structures in order to teach the adaptive immune system and mount a specific immune response. Prevention and mitigation of autoimmunity is of equal importance. In the context of allogeneic hematopoietic cell transplantation (HCT) specific challenges exist with the transfer of cells from the adapted donor immune system to the immunosuppressed recipient. Those challenges are immunogenetic disparity between donor and host, reconstitution of immunity early after HCT by expansion of mature immune effector cells, and impaired thymic function, if the recipient is an adult (as it is the case in most HCTs). The possibility to characterize the adaptive immune repertoire by massively parallel sequencing of T-cell receptor gene rearrangements allows for a much more detailed characterization of the T-cell repertoire. In addition, high-dimensional characterization of immune effector cells based on their immunophenotype and single cell RNA sequencing allow for much deeper insights in adaptive immune responses. We here review, existing - still incomplete - information on immune reconstitution after allogeneic HCT. Building on the technological advances much deeper insights into immune recovery after HCT and adaptive immune responses and can be expected in the coming years.

Allogeneic Stem Cell Transplantation with Sequential Melphalan-Based Conditioning in AML: Residual Morphological Blast Count Determines the Risk of Relapse.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) during chemotherapy-induced aplasia may offer long-term survival in acute myeloid leukemia (AML) with otherwise poor prognosis including ELN adverse risk, relapsed or refractory disease. However, the value of residual morphologic disease prior HCT in this context has not been conclusively settled until yet. Therefore, we aimed to investigate variables predicting outcome in this unique setting of sequential conditioning therapy, with a focus on pretreatment morphologic blast count. In contrast to the most popular FLAMSA-RIC protocol, we used a melphalan-based conditioning regimen during aplasia. METHODS: We retrospectively analyzed data from 173 AML patients who underwent a sequential melphalan-based conditioning therapy between 2003 and 2015 at our centre. All patients participated either in the prospective Phase 2 BRIDGE trial (NCT01295307), the Phase 3 AML2003 study (NCT00180102) or were treated according to this protocol and underwent allogeneic HCT after melphalan-based conditioning in treatment-induced aplasia. RESULTS: Median bone marrow blast count prior to conditioning was 10% (range, 0-96%). Four year probabilities of EFS and OS were 34% (95% CI, 28-43%) and 43% (95% CI, 36-52%), respectively. In multivariate analysis, blast count >20% was associated with worse EFS (HR = 1.93; p = 0.009) and OS (HR = 1.80; p = 0.026). This effect was not significant anymore for HCT during 1st line therapy. CONCLUSION: Allogeneic HCT in aplasia with a melphalan-based conditioning regimen has the potential to cure a subset of adverse risk AML patients, even with persistent morphological disease prior HCT. However, a high pre-transplant blast count still indicates patients with a dismal prognosis, especially in the relapsed patient group, for whom post-transplant strategies should be considered to further optimize post HCT outcome.

T-cell receptor-α repertoire of CD8+ T cells following allogeneic stem cell transplantation using next-generation sequencing.

Alloreactivity or opportunistic infections following allogeneic stem cell transplantation are difficult to predict and contribute to post-transplantation mortality. How these immune reactions result in changes to the T-cell receptor repertoire remains largely unknown. Using next-generation sequencing, the T-cell receptor alpha (TRα) repertoire of naïve and memory CD8+ T cells from 25 patients who had received different forms of allogeneic transplantation was analyzed. In parallel, reconstitution of the CD8+/CD4+ T-cell subsets was mapped using flow cytometry. When comparing the influence of anti-T-cell therapy, a delay in the reconstitution of the naïve CD8+ T-cell repertoire was observed in patients who received in vivo T-cell depletion using antithymocyte globulin or post-transplantation cyclophosphamide in case of haploidentical transplantation. Sequencing of the TRα identified a repertoire consisting of more dominant clonotypes (>1% of reads) in these patients at 6 and 18 months post transplantation. When comparing donor and recipient, approximately 50% and approximately 80% of the donors' memory repertoire were later retrieved in the naïve and memory CD8+ T-cell receptor repertoire of the recipients, respectively. Although there was a remarkable expansion of single clones observed in the recipients' memory CD8+ TRα repertoire, no clear association between graft-versus-host disease or cytomegalovirus infection and T-cell receptor diversity was identified. A lower TRα diversity was observed in recipients of a cytomegalovirus-seropositive donor (P=0.014). These findings suggest that CD8+ T-cell reconstitution in transplanted patients is influenced by the use of T-cell depletion or immunosuppression and the donor repertoire.

TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.

Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.

Usefulness scale for patient information material (USE) - development and psychometric properties.

BACKGROUND: One economical way to inform patients about their illness and medical procedures is to provide written health information material. So far, a generic and psychometrically sound scale to evaluate cognitive, emotional, and behavioral aspects of the subjectively experienced usefulness of patient information material from the patient's perspective is lacking. The aim of our study was to develop and psychometrically test such a scale. METHODS: The Usefulness Scale for Patient Information Material (USE) was developed using a multistep approach. Ultimately, three items for each subscale (cognitive, emotional, and behavioral) were selected under consideration of face validity, discrimination, difficulty, and item content. The final version of the USE was subjected to reliability analysis. Structural validity was tested using confirmatory factor analysis, and convergent and divergent validity were tested using correlation analysis. The criterion validity of the USE was tested in an experimental design. To this aim, patients were randomly allocated to one of two groups. One group received a full version of an information brochure on depression or chronic low back pain depending on the respective primary diagnosis. Patients in the second group received a reduced version with a lower design quality, smaller font size and less information. Patients were recruited in six hospitals in Germany. After reading the brochure, they were asked to fill in a questionnaire. RESULTS: Analyzable data were obtained from 120 questionnaires. The confirmatory factor analysis supported the structural validity of the scale. Reliability analysis of the total scale and its subscales showed Cronbach's α values between .84 and .94. Convergent and divergent validity were supported. Criterion validity was confirmed in the experimental condition. Significant differences between the groups receiving full and reduced information were found for the total score (p<.001) and its three subscales (cognitive p<.001, emotional p=.001, and behavioral p<.001), supporting criterion validity. CONCLUSIONS: We developed a generic scale to measure the subjective usefulness of written patient information material from a patient perspective. Our construct is defined in line with current theoretical models for the evaluation of written patient information material. The USE was shown to be a short, reliable and valid psychometric scale.

Unipolar depression: diagnostic and therapeutic recommendations from the current S3/National Clinical Practice Guideline.

BACKGROUND: Depressive disorders are among the most common illnesses and reasons for obtaining health care. Their diagnosis and treatment are still in need of improvement. In Germany, a new S3/National Clinical Practice Guideline has been developed for this purpose. METHODS: The existing guidelines on unipolar depression from Germany and other countries were synoptically compared and supplemented with systematic literature searches. After 14 consensus conferences, a total of 107 evidence-based recommendations were issued. RESULTS: Unipolar depression should be diagnosed in accordance with ICD-10 criteria. Screening questionnaires are useful aids to diagnostic classification. When a treatment is chosen, shared decision-making with the patient is essential. Mild depressive episodes can be treated initially by watchful waiting for 14 days. For moderate depressive episodes, pharmacotherapy and psychotherapy are equally effective treatment options. For severe depression, a combination of pharmacotherapy and psychotherapy is recommended. If 4 to 6 weeks of acute therapy are insufficiently effective, lithium augmentation is recommended, rather than combination antidepressant therapy or a switch to another antidepressant. After remission, maintenance therapy should be continued for 4 to 9 months. In recurrent depression, pharmacotherapy and/or psychotherapy, where appropriate, should be continued for at least two years. Specific recommendations are given for patients who have somatic or mental comorbidities or are acutely suicidal, and recommendations are also given for coordination of care. CONCLUSION: This guideline is a comprehensive set of evidence- and consensus-based recommendations for the diagnosis and treatment of unipolar depression. An improvement in the care of patients with unipolar depression will require broad implementation of the guideline, both in the inpatient and outpatient setting.

[Evidence-based treatment of depression: what does the new S3- and national healthcare guideline Unipolar Depression really recommend?]. / Evidenzbasierte Behandlung bei depressiven Erkrankungen--was empfiehlt die neue S3-/Nationale Versorgungsleitlinie "Unipolare Depression" wirklich?

The paper reflects central recommendations and methodological issues of the new German guidelines for the treatment of depression, as discussed in the article New German Guidelines for the Treatment of Depression - The Central Role of Psychotherapy (Schauenburg et al. 2009). Members of the steering group for these guidelines disagree with the authors' description in several points, especially with reference to the efficacy of pharmacotherapy with antidepressants and psychotherapy, as well as the relationship between both strategies of therapy and their combination in diverse phases of treatment (acute/maintenance). Furthermore, we try to clarify some misunderstandings in matters of the guideline's methodology which arose in the paper cited.