Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Introduction: Chronic musculoskeletal pain is a major health, social, and economic problem. Most of the subjects who suffer from chronic musculoskeletal pain present processes of central sensitization. Temporal summation and conditioned pain modulation are the two most commonly used clinical measures of this. The objective of this review is to evaluate the effects of physical therapy on temporal summation (TS) and conditioned pain modulation (CPM) in patients with chronic musculoskeletal pain.Methods: This is a systematic review and meta-analysis. We searched the MEDLINE, EMBASE, CINAHL, EBSCO, PubMed, PEDro, Cochrane Collaboration Trials Register, Cochrane Database of Systematic Reviews, and SCOPUS databases. Different mesh terms and key words were combined for the search strategy, with the aim of encompassing all studies that have used any type of physical therapy treatment in patients with chronic musculoskeletal pain and have measured both TS and CPM.Results: Eighteen studies remained for qualitative analysis and 16 for quantitative analysis. Statistically significant differences with a 95% confidence interval (CI) were obtained for TS (–0.21, 95% CI = –0.39 to –0.03, Z = 2.50, P = 0.02, N = 721) and CPM (0.34, 95% CI = 0.12 to 0.56, Z = 2.99, P = 0.003, N = 680) in favor of physical therapy as compared with control. Manual therapy produces a slight improvement in TS, and physical therapy modalities in general improve CPM. No significant differences between the subgroups of the meta-analysis were found. The methodological quality of the studies was high.Conclusions: Physical therapy produces a slight improvement in central sensitization (CS)–related variables, with TS decreased and CPM increased when compared with a control group in patients with CMP. Only significant differences in TS were identified in the manual therapy subgroup.

Background: manual therapy (MT) has been shown to have positive effects in patients with osteoarthritis (OA)-related pain, and its use in clinical settings is recommended. However, the mechanisms of action for how these positive effects occur are not yet well understood. The aim of the present study was to investigate the influence of MT treatment on facilitatory nociception and endogenous pain modulation in patients with knee OA related pain. Methods: Twenty-eight patients with knee OA were included in this study. Pain intensity using the numerical pain rating scale (NPRS), temporal summation (TS), conditioned pain modulation (CPM), and local (knee) and distant (elbow) hyperalgesia through the pressure pain threshold (PPT), were assessed to evaluate the pain modulatory system. Patients underwent four sessions of MT treatments within 3 weeks and were evaluated at the baseline, after the first session and after the fourth session. Results: the MT treatment reduced knee pain after the first session (p = 0.03) and after the fourth session (p = 0.04). TS decreased significantly after the fourth session of MT (p = 0.02), while a significant increase in the CPM assessment was detected after the fourth session (p = 0.05). No significant changes in the PPT over the knee and elbow were found in the follow-ups. Conclusions: The results from our study suggest that MT might be an effective and safe method for improving pain and for decreasing temporal summation.

PI3Kδ inhibitors are active in patients with lymphoid neoplasms and a first series of them have been approved for the treatment of multiple types of B-cell lymphoid tumors, including marginal zone lymphoma (MZL). The identification of the mechanisms underlying either primary or secondary resistance is fundamental to optimize the use of novel drugs. Here we present a model of secondary resistance to PI3Kδ inhibitors obtained by prolonged exposure of a splenic MZL cell line to idelalisib. The VL51 cell line was kept under continuous exposure to idelalisib. The study included detailed characterization of the model, pharmacological screens, silencing experiments, and validation experiments on multiple cell lines and on clinical specimens. VL51 developed resistance to idelalisib, copanlisib, duvelisib, and umbralisib. An integrative analysis of transcriptome and methylation data highlighted an enrichment of upregulated transcripts and low-methylated promoters in resistant cells, including IL-6/STAT3- and PDGFRA-related genes and surface CD19 expression, alongside the repression of the let-7 family of miRNA, and miR-125, miR-130, miR-193 and miR-20. The IL-6R blocking antibody tocilizumab, the STAT3 inhibitor stattic, the LIN28 inhibitor LIN1632, the PDGFR inhibitor masitinib and the anti-CD19 antibody drug conjugate loncastuximab tesirine were active compounds in the resistant cells as single agents and/or in combination with PI3Kδ inhibition. Findings were validated on additional in vitro lymphoma models and on clinical specimens. A novel model of resistance obtained from splenic MZL allowed the identification of therapeutic approaches able to improve the antitumor activity of PI3Kδ inhibitors in B-cell lymphoid tumors.

Chronic neck pain is among the most common types of musculoskeletal pain. Manual therapy has been shown to have positive effects on this type of pain, but there are not yet many predictive models for determining how best to apply manual therapy to the different subtypes of neck pain. The aim of this study is to develop a predictive learning approach to determine which basal outcome could give a prognostic value (Global Rating of Change, GRoC scale) for Mulligan’s mobilization technique and to identify the most important predictive factors for recovery in chronic neck pain subjects in four key areas: the number of treatments, time of treatment, reduction of pain, and range of motion (ROM) increase. A prospective cohort dataset of 80 participants with chronic neck pain diagnosed by their family doctor was analyzed. Logistic regression and machine learning modeling techniques (Generalized Boosted Models, Support Vector Machine, Kernel, Classsification and Decision Trees, Random Forest and Neural Networks) were each used to form a prognostic model for each of the nine outcomes obtained before and after intervention: disability—neck disability index (NDI), patient satisfaction (GRoC), quality of life (12-Item Short Form Survey, SF-12), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI II), pain catastrophizing scale (ECD), kinesiophobia-Tampa scale of kinesiophobia (TSK-11), Pain Intensity Visual Analogue Scale (VAS), and cervical ROM. Pain descriptions from the subjects and pain body diagrams guided the physical examination. The most important predictive factors for recovery in chronic neck pain patients indicated that the more anxiety and the lower the ROM of lateroflexion, the higher the probability of success with the Mulligan concept treatment.

Purpose: Background: Evaluate whether the design of placebo control groups could produce different interpretations of the efficacy of manual therapy techniques. Methods: Nine databases were searched (EMBASE, CINAHL, PsycINFO, MEDLINE, PubMed, SCOPUS, WEB of SCIENCE, COCHRANE, and PEDro). Randomized placebo-controlled clinical trials that used manual therapy as a sham treatment on subjects suffering from pain were included. Data were summarized qualitatively, and meta-analyses were conducted with R. Results: 53 articles were included in the qualitative analysis and 48 were included in the quantitative analyses. Manipulation techniques did not show higher effectiveness when compared with all types of sham groups that were analyzed (SMD 0.28; 95%CI [−0.24; 0.80]) (SMD 0.28; 95%CI [−0.08; 0.64]) (SMD 0.42; 95%CI [0.16; 0.67]) (SMD 0.82; 95%CI [−0.57; 2.21]), raising doubts on their therapeutic effect. Factors such as expectations of treatment were not consistently evaluated, and analysis could help clarify the effect of different sham groups. As for soft tissue techniques, the results are stronger in favor of these techniques when compared to sham control groups (SMD 0.40; 95%CI [0.19, 0.61]). Regarding mobilization techniques and neural gliding techniques, not enough studies were found for conclusions to be made. Conclusions: The literature presents a lack of a unified placebo control group design for each technique and an absence of assessment of expectations. These two issues might account for the unclear results obtained in the analysis.