CD27/CD70 pathway activation in primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder.

Primary cutaneous CD4+ small or medium T-cell lymphoproliferative disorder (PCSM-LPD) is a clonal T-cell proliferation disease confined to the skin. PCSM-LPD shares expression of T follicular helper (Tfh) cell markers with various mature T-cell lymphomas. However, the benign presentation of PCSM-LPD contrasts the clinical behavior of other Tfh-lymphomas. The aim of our study was to delineate the molecular similarities and differences between PCSM-LPD and other Tfh-derived lymphomas to explain the clinical behavior and unravel possible pathological mechanisms. We performed targeted next-generation sequencing of 19 genes recurrently mutated in T-cell neoplasms in n = 17 PCSM-LPD with high and in n = 21 PCSM-LPD with low tumor cell content. Furthermore, gene expression profiling was used to identify genes potentially expressed in the PD1-positive (PD1+) neoplastic cells. Expression of some of these genes was confirmed in situ using multistain immunofluorescence. We found that PCSM-LPD rarely harbored mutations recurrently detected in other T-cell neoplasms. PCSM-LPD is characterized by the invariable expression of the T-cell-receptor-associated LCK protein. CD70 and its ligand CD27 are co-expressed on PD1+ PCSM-LPD cells, suggestive of autoactivation of the CD70 pathway. In conclusion, PCSM-LPD differs from disseminated lymphomas of Tfh origin by their mutation profile. Activation of CD70 signaling also found in cutaneous T-cell lymphoma represents a potential driver of neoplastic proliferation of this benign neoplasia of Tfh. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Cyclin D1 expression, cell proliferation, and clonal persistence characterize primary cutaneous CD4+ small or medium T-cell lymphoproliferative disorder.

AIMS: The aim was to gain insight into the biology of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-LPD). METHODS: We describe the histopathological and clinical characteristics of 177 PCSM-LPD diagnosed at our consultation centre. We performed immunohistochemical multistaining in a subset of cases (n = 46) including PD1, Cyclin D1, and multiple markers of proliferation. We evaluated clonal T-cell-receptor-(TCR) rearrangements and used tissue microdissection to analyse TCR-clonality of PD1(+) cells. RESULTS: The cohort of n = 177 PCSM-LPD included 84 males and 93 females (median age 57, range 13-85). Clinical presentation was as a solitary nodule or plaque (head and neck > trunk > extremities). Most patients were treated by local excision or steroids (96%, 69/72); relapses occurred in 12/65 (18%) of patients with follow up. Histopathology revealed the predominance of a nodular pattern (75%, 134/177) and frequent clustering of PD1(+) large cells (70%, 103/147). We detected Cyclin D1 and PD1 coexpression (>10% of PD1(+)-cells) in 26/46 (57%), which was not associated with CCND1 breaks or amplifications. PD1(+)-cells in PCSM-LPDs showed a significantly higher expression of proliferation-associated proteins compared to PD1(-)-cells. A clonal TCR-rearrangement was present in 176/177 (99%), with a clonal persistence in 7/8 patients at relapse including distant sites. Tissue-microdissection revealed PD1(+)-cells as the source of clonality, whilst PD1(-)-cells remained polyclonal. CONCLUSION: PCSM-LPD is a clinically indolent, albeit neoplastic, disease driven by clonal expansion of PD1(+)-cells. We demonstrate Cyclin D1-expression associated with accelerated proliferation as a surprising new biological feature of the disease.

Symptom change trajectories in patients with persistent somatic symptoms and their association to long-term treatment outcome.

OBJECTIVE: This study investigated symptom change trajectory for patients with persistent somatic symptoms (PSS) during psychotherapy and the association of these patterns with pre-treatment characteristics and long-term outcome. METHODS: Growth mixture modeling was used to identify trajectory curves in a sample of N = 210 outpatients diagnosed with PSS and treated either with conventional cognitive behavioral therapy (CBT) or CBT enriched with emotion regulation training (ENCERT). RESULTS: We identified three subgroups of patients with similar symptom change patterns over the course of treatment (a "no change," "strong response," and "slow change" subgroup). Higher initial anxiety symptoms were significantly associated with the no change and strong response subgroups; symptom-related disability in daily routine with no changes. Patients with a strong response had the highest proportion of reliable improvement at termination and at six-month-follow-up. CONCLUSION: Our results indicate that, instead of one common change pattern, patients with PSS respond differently to treatment. Due to the high association of symptom curves with long-term outcome, the identification and prediction of an individual's trajectory could provide important information for clinicians to identify non-responding patients that are at risk for failure. Selecting personalized treatment interventions could increase the effectiveness of psychotherapy.Trial registration: ClinicalTrials.gov identifier: NCT01908855..

Readiness to change as a moderator of therapy outcome in patients with somatoform disorders.

OBJECTIVE: A considerable amount of patients with somatoform disorders do not benefit from psychotherapy as much as expected. Our aim was to explore whether readiness to change moderates the relationship between the intensity of symptoms and therapy outcome in the early stages of psychotherapy. METHOD: 144 patients with somatoform disorders received an outpatient cognitive-behavioural intervention. Symptom intensity was measured with the Screening for Somatoform Disorders (SOMS-7). For readiness to change, a German modification of the Pain Stages of Change Questionnaire (PSOCQ) was used, which comprises four subscales (FF-STABS). Regression analyses were carried out, with baseline symptoms and the readiness to change subscales as predictors and symptom reduction as the outcome variable. RESULTS: Moderation analyses revealed significant interaction effects between baseline symptoms and the precontemplation subscale, as well as between baseline symptoms and the action subscale. For preparation and maintenance, no significant interaction effects were found. CONCLUSIONS: The results suggest that readiness to change is a variable that can be used to differentiate between patients, with low precontemplation and action scores indicating a better chance for positive outcome, even with high initial impairment. Rather than using readiness to change sum scores, the sub-aspects of this construct should be the subject of future research.

Defining early positive response to psychotherapy: An empirical comparison between clinically significant change criteria and growth mixture modeling.

Several different approaches have been applied to identify early positive change in response to psychotherapy so as to predict later treatment outcome and length as well as use this information for outcome monitoring and treatment planning. In this study, simple methods based on clinically significant change criteria and computationally demanding growth mixture modeling (GMM) are compared with regard to their overlap and uniqueness as well as their characteristics in terms of initial impairment, therapy outcome, and treatment length. The GMM approach identified a highly specific subgroup of early improving patients. These patients were characterized by higher average intake impairments and higher pre- to-posttreatment score differences. Although being more specific for the prediction of treatment success, GMM was much less sensitive than clinically significant and reliable change criteria. There were no differences between the groups with regard to treatment length. Because each of the approaches had specific advantages, results suggest a combination of both methods for practical use in routine outcome monitoring and treatment planning.

Lending an ear to feedback systems: evaluation of recovery and non-response in psychotherapy in a German outpatient setting.

Systems providing feedback on treatment progress have been implemented in outpatient psychotherapy. They are recognized as a helpful tool to identify possible treatment failures. This report presents the ideas underlying the planning of feedback interventions and the implementation of such programs into practice settings. Strategies to identify patients at risk for treatment failure (rationally- and empirically-derived decision rules) are presented. Additionally, evidence for the usefulness of feedback systems is discussed. The report ends with the description of an ongoing feedback intervention study in private practices in Germany (aimed at gathering information on 400 therapists with 2,000 patients).

Diabetes mellitus and the risk of preterm birth with regard to the risk of spontaneous preterm birth.

INTRODUCTION: It is internationally agreed that diabetes mellitus (DM) is associated with increased maternal and fetal morbidity and long-term complications. To avoid these complications, it is often necessary to induce birth before term. The impact of DM on spontaneous preterm birth (spontaneous labor, preterm premature rupture of membranes and/or cervical incompetence resulting in delivery before the completion of 37 gestation weeks) is still unexplained. Preterm birth accounts for the most neonatal deaths and infant morbidities, and therefore it still remains one of the biggest challenges in obstetrics. OBJECTIVE: Our study determined if there is an increasing tendency towards spontaneous preterm birth in mothers with gestational and preexisting DM. METHODS: In this retrospective cohort study, 187 pregnant women with gestational DM and preexisting DM were compared to a randomized control group consisting of 192 normoglycemic women concerning gestational age and perinatal outcome. Data were collected by the Medical University of Vienna. Multiple pregnancies and women with severe maternal diseases, such as preeclampsia, were excluded. RESULTS: Women with DM tended significantly more often to preterm births (P = 0.002). A significant difference in the incidence of spontaneous preterm birth was found (P = 0.047). CONCLUSION: DM affects the length of gestation and incidence of spontaneous preterm birth.

Patterns of early change and their relationship to outcome and follow-up among patients with major depressive disorders.

BACKGROUND: While highlighting the efficacy of different treatments for major depressive disorders (MDD), findings of the National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program (TDCRP) often are interpreted as supporting the idea of treatment non-specificity for MDD. However, heterogeneity in treatment courses and outcomes might be undetected when focusing only on types of treatment in terms of sample means without taking into account early change in treatment. METHOD: In this study, growth mixture models (GMM) were used in the completer sample of N=162 patients from the NIMH TDCRP to identify meaningful patterns of early change of depression severity that are shared by many individual patients. RESULTS: Results revealed three typical patterns of early change over the first 8 weeks of treatment irrespective of the type of treatment protocol provided: (a) moderate to severe depression with moderate early improvement, (b) moderate to severe depression with rapid early improvement, and (c) mild to moderate depression with moderate early improvement. In contrast to the type of treatment, these differential patterns of early response (together with overall pre-treatment symptom severity) predicted outcomes (i.e. depression severity) at treatment termination and over the 1.5-year follow-up period. LIMITATIONS: Due to the small sample size and the controlled setting of this study the degree to which these results can be generalized to clinical practice has to be further investigated. CONCLUSIONS: The findings provide further support for the assumption that early change is an important factor for the prediction of short- and long-term outcome in psychotherapy.