Disease Relapse Research Articles

DNA Methylation in Recurrent Glioblastomas: Increased TEM8 Expression Activates the Src/PI3K/AKT/GSK-3β/B-Catenin Pathway.

Glioblastomas (GBM) are infiltrative malignant brain tumors which mostly recur within a year's time following surgical resection and chemo-radiation therapy. Studies on glioblastoma cells following radio-chemotherapy, have been demonstrated to induce trans-differentiation, cellular plasticity, activation of DNA damage response and stemness. As glioblastomas are heterogenous tumors that develop treatment resistance and plasticity, we investigated if there exist genome-wide DNA methylation changes in recurrent tumors. Utilizing genome-wide DNA methylation arrays, we compared the DNA methylation profile of 11 primary (first occurrence) tumors with 13 recurrent (relapsed) GBM, to delineate the contribution of epigenetic changes associated with therapy exposure, therapy resistance, and relapse of disease. Our data revealed 1,224 hypermethylated- and 526 hypomethylated-probes in recurrent glioblastomas compared to primary disease. We found differential methylation of solute carrier and ion channel genes, interleukin receptor/ligand genes, tumor-suppressor genes and genes associated with metastasis. We functionally characterized one such hypomethylated-up-regulated gene, namely anthrax toxin receptor 1/tumor endothelial marker 8 (ANTXR1/TEM8), whose expression was validated to be significantly up-regulated in recurrent glioblastomas compared to primary tumors and confirmed by immunohistochemistry. Using overexpression and knockdown approaches, we showed that TEM8 induces proliferation, invasion, migration, and chemo-radioresistance in glioblastoma cells. Additionally, we demonstrated a novel mechanism of β-catenin stabilization and activation of the β-catenin transcriptional program due to TEM8 overexpression via a Src/PI3K/AKT/GSK3β/β-catenin pathway. We report genome-wide DNA methylation changes in recurrent GBM and suggest involvement of the TEM8 gene in GBM recurrence and progression.

MYC translocation is a valuable marker for the development and relapse of extramedullary disease in multiple myeloma.

To study the cytogenetic characteristics of extramedullary disease (EMD) in patients with multiple myeloma (MM) and their impact on prognosis. Patients with newly diagnosed MM (NDMM) at Peking Union Medical College Hospital (Beijing, China) between June 2007 and December 2019 were recruited for this study. Demographic information, clinical data, fluorescence in situ hybridization (FISH) results of marrow and tissue samples, and survival outcome data were collected. A total of 439 patients with NDMM were divided into those without EMD (non-EMD, n = 339), those with EMD with primary paraosseous plasmacytoma (pEMD-B, n = 48), those with primary EMD with soft-tissue involvement (pEMD-S, n = 33), and those with secondary EMD (sEMD, n = 19). The incidence of EMD was 18.5% (81/439) at diagnosis and 22.8% (100/439) throughout the disease course. Comparison of FISH results showed a higher proportion of RB1 deletion (n = 20; 60.0% vs. 20.0%, p = .013) and MYC translocation (n = 12; 44.4% vs. 12.5%, p = .041) in the extramedullary tissues than in the paired bone marrow samples. At diagnosis, the percentage of MYC translocations in the sEMD group was notably higher than that in the non-EMD group (55.6% vs. 15.5%, p = .012). The median overall survival (OS) of patients with pEMD-S (32 months) and sEMD (17 months) was significantly shorter (both p = .001) than that of non-EMD patients (60 months). Soft-tissue EMD can be considered a high-risk condition, even in the era of novel agents. MYC translocation can serve as a valuable marker that correlates with extramedullary spread and relapse in patients with MM and should be considered for inclusion in routine FISH panels in clinical practice.

IVAC-XS15-CLL01: personalized multi-peptide vaccination in combination with the TLR1/2 ligand XS15 in CLL patients undergoing BTK-inhibitor-based regimens.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults in Western countries. Despite the introduction of targeted therapies, including first-line Bruton's tyrosine kinase inhibitor (BTKi) treatment, CLL remains largely incurable. Frequent disease relapses occur due to remaining treatment-resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD). Peptide-based vaccination targeting human leucocyte antigen (HLA)-presented CLL-associated antigens represents a promising, low-side-effect therapeutic option to optimize treatment responses and eliminate residual tumor cells by inducing an anti-leukemic immune response. The iVAC-XS15-CLL01 trial is an open-label, first-in-human (FIH) Phase I trial, evaluating the CLL-VAC-XS15 vaccine in CLL patients undergoing BTKi-based therapy. The vaccine was developed from HLA-presented CLL-associated antigen peptides, identified through comparative mass-spectrometry-based immunopeptidome analyses of CLL versus healthy samples in a previous study. To facilitate rapid and cost-effective deployment, vaccine peptides are selected for each patient from a pre-manufactured "peptide warehouse" based on the patient's individual HLA allotype and CLL immunopeptidome. The trial enrolls 20 CLL patients, who receive up to three doses of the vaccine, adjuvanted with the toll-like-receptor (TLR) 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. The primary objective of the iVAC-XS15-CLL01 trial is to assess the safety and immunogenicity of the CLL-VAC-XS15 vaccine. Secondary objectives are to evaluate the vaccine impact on MRD, progression-free survival, and overall survival, as well as comprehensive immunophenotyping to characterize vaccine-induced T-cell responses. This Phase I trial aims to advance CLL treatment by enhancing immune-mediated disease clearance and guiding the design of subsequent Phase II/III trials to implement a new therapeutic strategy for CLL patients.

Effects of donor-engrafted clonal hematopoiesis in allogeneic and autologous stem cell transplantation: a systematic review and meta-analysis.

Donor stem cell health may be critically important to the success of hematopoietic stem cell transplantation (HSCT). Herein, we performed this systematic review and meta-analysis including meta-regression to assess the impact of donor-engrafted clonal hematopoiesis (CH) in allogeneic HSCT (allo-HSCT) and impact of pre-transplant CH in autologous HSCT (auto-HSCT). We applied random-effects models to analyze 5 allo-HSCT studies with 3192 donor-recipient pairs and 9 auto-HSCT studies with 2854 patients. We found that donor-engrafted CH after allo-HSCT decreased the risk of disease relapse [Hazard Ratio (HR) = 0.79, 95% Confidence Interval (CI): (0.67, 0.93)], but did not affect overall survival (OS) [HR = 0.91, 95% CI: (0.75, 1.11)], progression-free survival (PFS) [HR = 0.94, 95% CI: (0.63, 1.41)], or non-relapse mortality [HR = 1.06, 95% CI: (0.81, 1.39)]. In contrast, pre-transplant CH in auto-HSCT recipients resulted in inferior OS [HR = 1.30, 95% CI: (1.16, 1.46)], inferior PFS [HR = 1.35, 95% CI: (1.18, 1.54)], and higher risk for therapy-related myeloid neoplasm [HR = 4.85, 95% CI: (2.39, 9.82)] when compared to auto-HSCT recipients without CH. This study sheds light onto the debate about prospective "CHIP screening" for stem cell donors and addresses the impact of CH as a transmissible phenomenon.

Polyautoimmunity and multiple autoimmune syndrome in patients with neuromyelitis optica spectrum disorder

BackgroundThe coexistence of neuromyelitis optica spectrum disorders (NMOSD) with other autoimmune diseases (AID) has been increasingly reported. The prevalence and significance of this association are not fully understood. ObjectivesThis study aimed to compare the clinical and laboratory characteristics in NMOSD patients with and without AID. MethodsRetrospective cross-sectional observational study was conducted involving adults meeting NMOSD criteria followed in a neuroimmunology clinic at a tertiary center. Descriptive analysis of clinical/paraclinical/treatment/outcome data collected from the medical records was compared between NMOSD patients with AID (polyautoimmunity) and those without AID. ResultsFrom a cohort of 46 NMOSD patients, 16 (34.8 %) patients, mostly women around 40 years of age, presented with polyautoimmunity: 10 anti-AQP4 positive, 4 anti-MOG positive, and 2 seronegative. Five different organ -specific AID, and six systemic AID were identified in the polyautoimmunity patients group, in addition to 6 cases of multiple autoimmune syndrome. The AID manifestation preceded NMOSD in 10 (62.5 %) patients, with a median interval of 7 years. The NMOSD with polyautoimmunity and NMOSD without AID groups had similar initial clinical manifestations with optic neuritis and/or myelitis being most frequent. Inflammatory CSF, namely elevated proteins, was more common in the polyautoimmunity group (13.0 % in NMOSD vs. 31.3 % in NMOSD+AID, p = 0.003). After a 10±6 years follow-up period, more patients with polyautoimmunity had a relapsing disease (75.0 % in NMOSD vs. 46.7 % in NMOSD+AID, p = 0.012) but no difference in the functional outcome evaluated by the EDSS score was identified. ConclusionsPolyautoimmunity was common in AQP4 positive NMOSD patients leading to a significantly higher risk of disease recorrence. The presence of polyautoimmunity and multiple autoimmune syndrome in NMOSD patients suggests the existence of common susceptibility factors or pathophysiological mechanisms, emphasizing the importance of a multidisciplinary approach to those patients.

BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice.

Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST) and Crh+ neurons in this region play a key role in chronic ethanol-induced increases in volitional intake, hypothesized to be driven by emergent negative affective behaviors. Excitatory N-methyl-d-aspartate receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. Specifically, GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. Male and female mice underwent a home cage chronic drinking forced abstinence model (CDFA) to assess the impact of 1 day or 2 weeks of ethanol abstinence on BNST synaptic transmission and BNST Grin gene expression. Constitutive and conditional BNST GluN2D knockout mice were used to assess the impact of GluN2D deletion on continuous access ethanol intake as well as negative affect behaviors, using the open field, elevated zero maze, and forced swim tasks. We report here that excitatory transmission undergoes time-dependent upregulation in BNST Crh+ cells. Further, knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in the dBNST or dBNST Crh+ neurons. Finally, we find that deletion of GluN2D fails to alter negative affect in ethanol-naïve female mice. These data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking but not ethanol abstinence, highlighting sex differences and behavioral specificity. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.

Advances and future directions in ROS1 fusion-positive lung cancer.

ROS1 gene fusions are an established oncogenic driver comprising 1%-2% of non-small cell lung cancer (NSCLC). Successful targeting of ROS1 fusion oncoprotein with oral small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment landscape of metastatic ROS1 fusion-positive (ROS1+) NSCLC and transformed outcomes for patients. The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Of note, resistance to ROS1 TKIs invariably develops, limiting the clinical benefit of these agents and leading to disease relapse. Progress in understanding the molecular mechanisms of resistance has enabled the development of numerous next-generation ROS1 TKIs, which achieve broader coverage of ROS1 resistance mutations and superior CNS penetration than first-generation TKIs, as well as other therapeutic strategies to address TKI resistance. The approach to subsequent therapy depends on the pace and pattern of progressive disease on the initial ROS1 TKI and, if known, the mechanisms of TKI resistance. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.

Tracking clonal evolution of drug resistance in ovarian cancer patients by exploiting structural variants in cfDNA.

Drug resistance is the major cause of therapeutic failure in high-grade serous ovarian cancer (HGSOC). Yet, the mechanisms by which tumors evolve to drug resistant states remains largely unknown. To address this, we aimed to exploit clone-specific genomic structural variations by combining scaled single-cell whole genome sequencing with longitudinally collected cell-free DNA (cfDNA), enabling clonal tracking before, during and after treatment. We developed a cfDNA hybrid capture, deep sequencing approach based on leveraging clone-specific structural variants as endogenous barcodes, with orders of magnitude lower error rates than single nucleotide variants in ctDNA (circulating tumor DNA) detection, demonstrated on 19 patients at baseline. We then applied this to monitor and model clonal evolution over several years in ten HGSOC patients treated with systemic therapy from diagnosis through recurrence. We found drug resistance to be polyclonal in most cases, but frequently dominated by a single high-fitness and expanding clone, reducing clonal diversity in the relapsed disease state in most patients. Drug-resistant clones frequently displayed notable genomic features, including high-level amplifications of oncogenes such as CCNE1 , RAB25 , NOTCH3 , and ERBB2 . Using a population genetics Wright-Fisher model, we found evolutionary trajectories of these features were consistent with drug-induced positive selection. In select cases, these alterations impacted selection of secondary lines of therapy with positive patient outcomes. For cases with matched single-cell RNA sequencing data, pre-existing and genomically encoded phenotypic states such as upregulation of EMT and VEGF were linked to drug resistance. Together, our findings indicate that drug resistant states in HGSOC pre-exist at diagnosis and lead to dramatic clonal expansions that alter clonal composition at the time of relapse. We suggest that combining tumor single cell sequencing with cfDNA enables clonal tracking in patients and harbors potential for evolution-informed adaptive treatment decisions.

Relapses in canine leishmaniosis: risk factors identified through mixed-effects logistic regression

BackgroundCanine leishmaniosis (CanL), caused by Leishmania infantum, is an important vector-borne parasitic disease in dogs with implications for human health. Despite advancements, managing CanL remains challenging due to its complexity, especially in chronic, relapsing cases. Mathematical modeling has emerged as a powerful tool in various medical fields, but its application in understanding CanL relapses remains unexplored.MethodsThis retrospective study aimed to investigate risk factors associated with disease relapse in a cohort of dogs naturally infected with L. infantum. Data from 291 repeated measures of 54 dogs meeting the inclusion criteria were included. Two logistic mixed-effects models were created to identify clinicopathological variables associated with an increased risk of clinical relapses requiring a leishmanicidal treatment in CanL. A backward elimination approach was employed, starting with a full model comprising all potential predictors. Variables were iteratively eliminated on the basis of their impact on the model, considering both statistical significance and model complexity. All analyses were conducted using R software, primarily employing the lme4 package, and applying a significance level of 5% (P < 0.05).ResultsThis study identified clinicopathological variables associated with an increased risk of relapses requiring a leishmanicidal treatment. Model 1 revealed that for each 0.1 increase in the albumin/globulin ratio (A/G) ratio, the odds of requiring treatment decreased by 45%. Conversely, for each unit increase in the total clinical score (CS), the odds of requiring treatment increase by 22–30%. Indirect immunofluorescence antibody test (IFAT) was not a significant risk factor in model 1. Model 2, incorporating individual albumin and globulins values, showed that dogs with high IFAT titers, hyper beta-globulinemia, hypoalbuminemia, anemia, and high CS were at increased risk of relapse. Both models demonstrated a good fit and explained a substantial amount of variability in treatment decisions.ConclusionsDogs exhibiting higher CS, dysproteinemia, anemia, and high IFAT titers are at increased risk of requiring leishmanicidal treatment upon clinical relapse in CanL. Regular monitoring and assessment of risk factors prove essential for early detection of relapses and effective intervention in CanL cases. The contrasting findings between the two models highlight the complexity of aspects influencing treatment decisions in this disease and the importance of tailored management strategies to improve outcomes for affected dogs.Graphical

Structural Basis for the Recognition of GPRC5D by Talquetamab, a Bispecific Antibody for Multiple Myeloma

Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal antibody production from plasma cells. Despite advances in the treatment, many patients experience disease relapse or become refractory to treatment. G-protein-coupled receptor class C group 5 member D (GPRC5D), an orphan GPCR predominantly expressed in MM cells, is emerging as a promising target for MM immunotherapy. Talquetamab, a Food and Drug Administration-approved T-cell-directing bispecific antibody developed for treatment of MM, targets GPRC5D. Here, we elucidate the structure of GPRC5D complexed with the Fab fragment of talquetamab, using cryo-electron microscopy, providing the basis for recognition of GPRC5D by the bispecific antibody. GPRC5D forms a symmetric homodimer with the interface between transmembrane helix (TM) 4 of one protomer and TM4/5 of the other protomer. A single talquetamab Fab interacts with the GPRC5D dimer with its orientation toward the dimer interface. All six complementarity-determining regions of talquetamab engage with extracellular loops and TM3/5/7. In particular, the side-chain of an arginine residue from the antibody penetrates into a shallow pocket on the extracellular surface of GPRC5D. The structure offers insights for optimizing antibody design against GPRC5D for relapsed or refractory MM therapy.

Evolution of transcriptomic profiles in relapsed inv(16) acute myeloid leukemia

Acute myeloid leukemia (AML) with inv(16) is typically associated with a favourable prognosis. However, up to 40 % of patients will eventually experience disease relapse. Herein, we dissected the genomic and transcriptomic profile of inv(16) AML to identify potential prognostic markers and therapeutic vulnerabilities. Sequencing data from 222 diagnostic samples, including 44 relapse/refractory patients, revealed a median of 1 concomitant additional mutation, cooperating with inv(16) in leukemogenesis. Notably, the mutational landscape at diagnosis did not differ significantly between patients experiencing primary induction failure or relapse when compared to the rest of the cohort, except for an increase in the mutational burden in the relapse/refractory group. RNA-Seq of unpaired diagnostic(n=7) and relapse(n=6) samples allowed the identification of oxidative phosphorylation (OXPHOS) as one of the most significantly downregulated pathways at relapse. Considering that OXPHOS could be targeted by Venetoclax/Azacitidine combination, we explored its biological effects on an inv(16) cell-line ME-1, but there was no additional advantage in terms of cell death over Azacitidine alone. To enhance Venetoclax efficacy, we tested in vitro effects of Metformin as a potential drug able to enhance chemosensitivity of AML cells by inhibiting the mitochondrial transfer. By challenging ME-1 with this combination, we observed a significant synergistic interaction at least similar to that of Venetoclax/Azacitidine. In conclusions, we identified a downregulated expression of oxidative phosphorylation (OXPHOS) at relapse in AML with inv(16), and explored the in vitro effects of metformin as a potential drug to enhance chemosensitivity in this setting.

Feasibility of co-transplantation of umbilical cord blood and third-party mesenchymal stromal cells after (non)myeloablative conditioning in patients with hematological malignancies

Umbilical cord blood (UCB) is an alternative source of stem cells for patients lacking a 9/10 or 10/10 HLA identical donor. However, after UCB transplantation, time to engraftment and immune recovery are prolonged, increasing the risk of fatal complications. Mesenchymal stromal cells (MSC) can support hematopoietic engraftment and have immunosuppressive effects.The primary objective of this phase I/II multicenter study was to determine the feasibility and safety of UCB transplantation with co-infusion of third party MSC, as assessed by treatment related mortality (TRM) at day 100. Secondary objectives were engraftment, immune recovery, occurrence of graft versus host disease (GVHD), infections, disease free survival, relapse incidence and overall survival.Eleven patients were grafted according to this protocol. Allogeneic transplantation after co-infusion appears feasible with 18 % TRM at day 100. Engraftment data show a median time of 16 days to neutrophil and 27 days to platelet recovery, which is shorter than what is usually reported after UCB transplantation. Only 1 episode of acute GVHD was reported.In conclusion, MSC and UCB co-transplantation is feasible and might help overcome some of the drawbacks of UCB transplantation.

Expression of p16INK4a, FLOT2, and EGFR in oropharyngeal carcinoma, prognostic significance and correlation with clinicopathological characteristics.

Various factors can affect the survival of patients with oropharyngeal cancer. We assessed the expression of protein p16INK4a, Flotillin2, epidermal growth factor receptor, and other clinicopathological features and their prognostic value for this type of cancer. We gathered patient data on demographics, clinicopathological characteristics, treatment patterns, and outcomes. Histologically and by immunochemistry staining we determined expression of prognostic factors and molecular biomarkers. The primary endpoints were overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Survival was assessed using the Kaplan-Meier method and Cox regression model analyses of potential prognostic parameters. After a median follow-up of 78 months, the median OS was 41 months, with an event recorded in 77.8% of patients. Median DFS was 22 months, 37 patients (51.4%) had disease relapse. The DSS survival rate was 58.3% with a median survival of 68 months. In regards to molecular biomarkers previously mentioned, there was no statistical significance for survival categories. After conducting a multivariate analysis of significant variables, we found that only recurrence, vascular invasion, and surgical intervention remained as factors with independent effects on both OS and DFS. Recurrence and the N stage were identified as independent prognostic factors for DSS. Our analysis underscores the complexity of factors that collectively influence survival following the diagnosis of OPSCC. Several factors were found to be statistically significant. These factors included the type of surgical procedure, disease relapse, vascular invasion, lymphatic invasion, perineural invasion, advanced T stage of the disease, N stage of the disease, and smoking status. The significance of these factors may vary across different types of survival. This analysis did not find any significant impact on survival from the growth factors tested, namely epidermal growth factor receptor, Flotillin2, and p16INK4a, in the applied regression models.

PrPC controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) benefit from treatment with tyrosine kinase inhibitors (TKI) targeting EGFR. Despite improvements in patient care, especially with the 3rd generation TKI osimertinib, disease relapse is observed in all patients. Among the various processes involved in TKI resistance, epithelial-to-mesenchymal transition (EMT) is far from being fully characterized. We hypothesized that the cellular prion protein PrPC could be involved in EMT and EGFR-TKI resistance in NSCLC. Using 5 independent lung adenocarcinoma datasets, including our own cohort, we document that the expression of the PRNP gene encoding PrPC is associated with EMT. By manipulating the levels of PrPC in different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrPC is mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrPC operates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrPC levels are elevated in EGFR-mutated versus wild-type tumours or upon EGFR activation in vitro. In addition, we provide evidence that PRNP levels increase with TKI resistance and that reducing PRNP expression sensitizes cells to osimertinib. Finally, we found that plasma PrPC levels are increased in EGFR-mutated NSCLC patients from 2 independent cohorts and that their longitudinal evolution mirrors that of disease. Altogether, these findings define PrPC as a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrPC levels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrPC-targeted therapies for EGFR-mutated NSCLC patients with TKI failure.

Impact of Rituximab on Remission Rates in Granulomatosis With Polyangiitis: A Systematic Review.

This systematic review evaluates the efficacy of rituximab in inducing and maintaining remission in patients with granulomatosis with polyangiitis (GPA). We conducted a comprehensive search across multiple databases, identifying 81 studies, of which 11 met our inclusion criteria after rigorous screening and assessment for relevance and quality. Our analysis shows that rituximab, compared to traditional treatments such as cyclophosphamide and azathioprine, significantly improves remission rates and reduces relapse frequency in GPA patients. Notably, rituximab's benefits extend across various patient demographics, including pediatric groups, and are evident in different dosing regimens, highlighting its versatility and potential as a first-line therapy. The review also underscores the importance of personalized medicine approaches in managing GPA, as rituximab's effectiveness was particularly pronounced in patients with relapsing disease forms. Future research should focus on long-term outcomes, optimal dosing strategies, and the economic implications of widespread rituximab use in clinical practice. Our findings advocate for the integration of rituximab into standard treatment protocols for GPA, offering new hope for patients afflicted with this challenging autoimmune disorder.

Risk Factors for the Development of Eating Disorders in Adolescents with Early-Onset Inflammatory Bowel Diseases.

Individuals with inflammatory bowel diseases (IBDs) have an increased risk of developing psychiatric comorbidities, including eating disorders (EDs). We aimed to investigate the potential association between key disease characteristics, including psychological features, and the development of EDs in a clinical sample of adolescents with IBDs. We enrolled 52 adolescents with IBDs, 83% of whom were in clinical remission, and systematically collected additional information on disease duration, the total number of relapses, the use of steroids, and the number of hospital admissions. All participants completed a validated psychometric battery assessing psychological symptoms (Symptom Checklist-90-Revised, SCL-90-R), alexithymia (Toronto Alexithymia Scale-20, TAS-20), and ED symptomatology (Eating Disorders Inventory-3rd edition, EDI-3). About one in ten patients (9.6%) reported Eating Disorder Risk scores higher than the cut-off on the EDI-3 subscale, specifically addressing the risk of developing EDs. According to the EDI-3 scores, the risk of developing EDs directly correlated with the number of total relapses of IBDs (p < 0.05). The TAS-total scores also correlated with the number of total relapses (p < 0.01), as well as with the number of steroid cycles (p < 0.05), the number of hospital admissions (p < 0.05), and overall disease duration (p < 0.05). Our findings suggest that disease relapses increase the risk of developing both EDs and alexithymia in adolescents with IBDs. The recurrence of disease relapses should be identified and screened early on to prevent the onset of psychiatric disorders, including EDs. Research should be conducted on larger samples with different IBD phenotypes to further investigate the characteristics of patients with IBDs at risk of developing EDs.

Definitions of and Instruments for Disease Activity, Remission, and Relapse in Polymyalgia Rheumatica: A Systematic Literature Review.

To perform a systematic literature review on definitions and instruments used to measure remission, relapse, and disease activity in polymyalgia rheumatica (PMR), to inform an OMERACT project to endorse instruments for these outcomes. A search of Pubmed/MEDLINE, EMBASE, CINAHL, Cochrane, and Epistemonikos was performed May 2021 and updated August 2023. Qualitative and quantitative studies published in English were included if they recruited people with isolated PMR regardless of treatment. Study selection and data extraction was performed independently by two investigators and disagreement was resolved through discussion. Data extracted encompassed definitions of disease activity, remission and relapse, and details regarding the instruments used to measure these outcomes. From the 5,718 records, we included 26 articles on disease activity, 36 on remission, and 53 on relapse; 64 studies were observational and 15interventional, and none used qualitative methods. Some heterogeneity was found regarding definitions and instruments encompassing the domains pain, stiffness, fatigue, laboratory markers (mainly acute phase reactants), and patient and physician global assessment of disease activity. However, instruments for clinical signs were often poorly described. Whilst measurement properties of the polymyalgia rheumatica activity score (PMR-AS) have been assessed, data to support its use for measurement of remission and relapse is limited. Remission, relapse, and disease activity have been defined heterogeneously in clinical studies. Instruments to measure these disease states still need to be validated. Qualitative research is needed to better understand the concepts of remission and relapse in PMR. PROSPERO identification: CRD42021255925.

The role of the tonsils in the genesis of PFAPA syndrome: a modern view and description of two clinical cases

In ENT clinical practice, there are cases of a disease similar to those ones of chronic adenotonsillitis, but insensitive to the designated conservative therapy. This disease was first described in 1987 and is called PFAPA syndrome. Its symptoms periodicity and its regression when corticosteroids are prescribed were established. Adenotomy/adenotonsillectomy can eliminate the symptoms of the disease or significantly reduce the frequency of relapses. The histological features of the structure of the palatine and pharyngeal tonsils, as well as the characteristics of the PFAPA-syndrome, were revealed. Clinical Case Description: patient K., 3 years old, repeated cases of fever were recorded in the child from the age of 1 year 3 months. They were initially regarded as manifestations of acute respiratory viral infections, complicated by adenoiditis, pharyngitis, aphthous stomatitis and cervical lymphadenitis, with a frequency of 1.5–2 months, 6–7 episodes per year. The antiviral therapy was prescribed without any effect. A prednisolone test (1.5 mg/kg) was positive; it led to a rapid normalization of body temperature and condition improvement. The adenotonsillectomy was done. Surgical intervention and the postoperative period were uneventful. The follow-up period was without any recurrence of the disease for more than 1 year. Patient F., 6 years old, had, the recurrent (each 1.5–2 months), acute respiratory viral infections, adenotonsillitis, accompanied by lymphadenitis and febrile fever. A prednisolone test was positive. The patient was diagnosed with PFAPA syndrome by the age of 6. The adenotonsillectomy was done. No disease relapses were noted in the follow-up.

Minimal residual disease detection in lymphoma: methods, procedures and clinical significance.

Lymphoma is a highly heterogeneous lymphohematopoietic tumor. As our understanding of the biological and pathological characteristics of lymphoma improves, we are identifying an increasing number of lymphoma subtypes. Genotyping has enhanced our ability to diagnose, treat, and monitor the prognosis of lymphoma. Despite significant improvements in treatment effectiveness, traditional methods for assessing disease response and monitoring prognosis are imperfect, and there is no significant improvement in overall remission rates for lymphoma patients. Minimal Residual Disease (MRD) is often indicative of refractory disease or early relapse. For lymphoma patients, personalized MRD monitoring techniques offer an efficient means to estimate disease remission levels, predict early relapse risk, and assess the effectiveness of new drug regimens. In this review, we delve into the MRD procedures in lymphoma, including sample selection and requirements, detection methods and their limitations and advantages, result interpretation. Besides, we also introduce the clinical applications of MRD detection in lymphoma.

Analysis of proliferating Treg cells as a predictor for immunotherapy response using systemic longitudinal immune profiling: Biomarker analysis of the phase 3 CONTINUUM trial.

140 Background: The discovery of predictive biomarkers for immunotherapy is hindered by the lack of control groups in most translational studies, making it impossible to discern whether the identified biomarkers are merely prognostic or truly predictive for treatment outcomes. This study reported on prospectively designed biomarker analyses of the phase 3 CONTINNUUM trial (NCT03700476), the first trial that demonstrated prolonged event-free survival (EFS) with the addition of anti-PD-1 (aPD1) to chemoradiotherapy (CRT) in locoregionally-advanced nasopharyngeal carcinoma (LA-NPC). Methods: Mass cytometry was performed to generate a dynamic single-cell atlas on longitudinal peripheral blood mononuclear cell (PBMC) samples from 12 pairs of matched patients with or without relapse in the aPD1-CRT arm. The machine-learning algorithm CellCnn was applied to identify a cell subset that was most strongly associated with disease relapse, which was further confirmed by flow cytometry (n = 120). Single-cell RNA sequencing data from matched PBMC and tumor samples were analyzed and multiplex immunohistochemistry was performed on baseline tumor samples (n = 249) to verify the predictive value of the cell subset within tumors. Results: Baseline circulating regulatory T cells (Tregs), with a Ki67+ proliferating phenotype, were found to display a higher frequency in LA-NPC patients who developed posttreatment relapse ( P &lt; 0.001), which was further validated by flow cytometry. The intratumoral Ki67+ Tregs were also identified and correlated with an immunosuppressive tumor microenvironment. In patients with a low baseline level of Ki67+ Tregs, additional aPD1 significantly improved EFS compared with CRT alone (log-rank P = 0.011, HR = 0.22, 95% CI: 0.06−0.79), while EFS was almost identical in both treatment arms in patients with high Ki67+ Treg levels (log-rank P = 0.995, HR = 1.00, 95% CI: 0.49−2.05; interaction P = 0.047). This predictive value was further validated in datasets from two independent randomized trials in renal cancer. Conclusions: The frequency of Ki67+ Tregs can serve as a reliable predictive tool in selecting patients who are more likely to benefit from immunotherapy, potentially informing individualized immunotherapy strategies.