Disease Relapse Research Articles

Specific Mutation Predict Relapse/Refractory Diffuse Large B-Cell Lymphoma.

The application of rituximab has significantly enhanced the overall survival rates in patients with diffuse large B-cell lymphoma (DLBCL). Regrettably, a significant number of patients still progress to relapse/refractory DLBCL (rrDLBCL). Herein, we employed targeted sequencing of 55 genes to investigate if gene mutations could predict the progression to rrDLBCL. Additionally, we compared the mutation profiles at the time of DLBCL diagnosis with those found in rrDLBCL cases. Our findings highlighted significantly elevated mutation frequencies of TP53, MEF2B and CD58 in diagnostic biopsies from patients who progressed to relapse or refractory disease, with CD58 mutations exclusively observed in the rrDLBCL group. In assessing the predictive power of mutation profiles for treatment responses in primary DLBCL patients, we found that the frequency of CARD11 mutations was substantially higher in non-response group as compared with those who responded to immunochemotherapy. In addition, we revealed mutations in HIST2H2AB, BCL2, NRXN3, FOXO1, HIST1H1C, LYN and TBL1XR1 genes were only detected in initial diagnostic biopsies, mutations in the EBF1 gene were solely detected in the rrDLBCL patients. Collectively, this study elucidates some of the genetic mechanisms contributing to the progression of rrDLBCL and suggests that the presence of CD58 mutations might serve as a powerful predictive marker for relapse/refractory outcomes in primary DLBCL patients.

Can FDG-PET Imaging Identify Cardiac Sarcoidosis Disease Phenotypes?

Despite the scarcity of data, most guidelines have advocated for the treatment of cardiac sarcoidosis with corticosteroids. However, there is heterogeneity in disease presentation and response to treatment, which can make treatment challenging. The ability to identify disease phenotypes to allow for tailored therapy is therefore highly desirable. This review will seek to outline the disease phenotypes of cardiac sarcoidosis and the role that FDG-PET imaging can play in identifying these phenotypes to optimize disease diagnosis and treatment management. FDG PET can identify cardiac sarcoidosis and is being increasingly used to monitor therapeutic response to immunosuppressive therapy, to follow treatment response after discontinuation of corticosteroid therapy, and to evaluate for disease relapse. Modern quantitative techniques using FDG PET imaging may allow for even better phenotypic disease characterization and the ability to track the response to immunosuppression more accurately. FDG PET currently plays an important role in cardiac sarcoidosis diagnosis. However, it also affords us the opportunity to offer insights into cardiac sarcoidosis disease phenotypes to better understand the underlying disease process and in the future may allows us to tailor therapies accordingly.

Impact of positive CD4 cells on event-free survival in follicular lymphoma patients.

Previous results about prognostic value of CD4+ T cells in follicular lymphoma (FL) remain controversial. Immunohistochemistry was used to examine expression of positive CD4 cells in 103 patients with FL 1-3A. Early failure was described as failing to achieve event-free survival (EFS) at 12 or 24 months. There were 49 (47.6%) male and 54 (52.4%) females, with a median age of 54 years. Compared to patients with <20% of positive CD4 cells, patients with ≥20% of positive CD4 cells exhibited a significant lower risk of early failure (2-year EFS rate: 56.7% vs 73.5%, p = 0.047). When patients were stratified based on positive CD4 cell combined with FLIPI, the median EFS (p = 0.002) and median OS (p = 0.007) were significantly different. This study demonstrated that higher expression of positive CD4 cells predicts lower risk of early failure in follicular lymphoma, and combination analysis of CD4 and FLIPI could better predict disease relapse and survival outcome.

Uveitis as predictor of disease flare after the first anti-TNF withdrawal in oligoarticular and polyarticular juvenile idiopathic arthritis: a multicentric Italian experience.

TNF inhibitors (TNFi) have dramatically changed the prognosis of juvenile idiopathic arthritis (JIA), but it is not clear how and when to stop therapy. We aim to describe a multicentric cohort of JIA treated with adalimumab or etanercept who discontinued the treatment for persistent inactivity and to identify factors associated with relapse. In a multicentric Italian retrospective cohort study, medical records of patients with oligoarticular and polyarticular JIA were evaluated if they stopped therapy for persistent inactivity after the first TNFi. 136 patients were enrolled (102 female, median age at onset 3 years (range 1-15), of whom 55.9% had oligoarticular JIA, 40.4% uveitis and 72.8% ANA positivity. Adalimumab (59.3%) and etanercept (40.7%) were started at a median age of 6 years (range 1-16), TNFi were discontinued after a median time of 30 months (range 6-90), increasing the interval (76.5%), reducing the dose (18.4%) and abrupt discontinuation (16.9%). 79.4% of patients relapsed after a median time of 5 months (range 0.5-66). Patients with uveitis relapsed earlier (log rank χ² 16.4 p<0.0001), while patients who lengthened the interval of administration showed a later relapse (log rank χ² 6.95 p=0.008). Uveitis (HR 2.11 CI 1.34-3.31), age at onset (HR 0.909 CI 0.836-0.987), duration of tapering (HR 0.938 CI 0.893-0.985) and to have a persistent oligoarticular JIA (HR 0.597 CI 0.368-0.968) are significant predictors of disease relapse (Mantel-Cox χ² 34.23 p<0.001). Younger age at onset, uveitis, duration of tapering, and non-persistent oligoarticular JIA seem to be independent risk factors for earlier relapse after the first TNFi withdrawal.

The prophylactic application of low-dose rabbit antithymocyte globulin in matched siblings HSCT with high-risk factors for graft-versus-host disease

Relapse and graft-versus-host disease (GVHD) are currently the predominant causes of mortality post allogeneic hematopoietic stem cell transplantation (allo-HSCT). The contentious use of antithymocyte globulin (ATG) for preventing GVHD in matched sibling HSCT scenarios has been a topic of significant debate. A retrospective analysis was conducted on matched sibling HSCT cases with high-risk factors for GVHD in our center from January 2018 to June 2023. Our assessment revealed that the group administered with ATG exhibited a 30 % incidence of acute GVHD (aGVHD), in contrast to 81.8 % in the non-ATG cohort (P = 0.037) among matched sibling HSCT cases with high GVHD risk factors. Furthermore, chronic GVHD (cGVHD) occurred in 20 % of the ATG group and 72.7 % of the non-ATG group (P = 0.03). Notably, the administration of ATG did not significantly impact disease relapse (p = 0.149), infection rates (p = 0.64), granulocyte recovery time (p = 0.15), platelet recovery time (p = 0.12), overall survival (p = 0.889), or disease-free survival time (p = 0.787). The use of rabbit antithymocyte globulin (r-ATG) at a 5 mg/kg dosage demonstrated a notable reduction in aGVHD and cGVHD incidences within sibling matched HSCT cases with high-risk factors for GVHD, without increasing rates of disease recurrence or infections. These findings highlight the potential benefit of using low-dose r-ATG in high-risk of GVHD sibling matched allogeneic HSCTs, although further validation with a larger cohort is necessary.

Distinct Gene Expression Patterns Identify Patients who Relapse After Neoadjuvant Pembrolizumab and Radical Cystectomy in the PURE-01 Study

PurposeThe PURE-01 clinical trial reported the use of neoadjuvant treatment with pembrolizumab prior to radical cystectomy (RC) in patients with muscle-invasive bladder. Specific molecular subtypes and immune signatures were reported to be associated with a favorable survival. However, reports on the detailed tumor biology of patients relapsing after neoadjuvant pembrolizumab are lacking. Materials and MethodsMicroarray data from transurethral resection of the bladder tumor (TURBT; n = 102) and matched RC (N = 25) tissue from patients in PURE-01 who experience a disease relapse were analyzed, with gene expression signatures and molecular subtypes. The Kaplan–Meier method was used to estimate differences in patient outcomes. Immune-signatures were split by median for survival analysis. All significance testing used a two-sided t-test at a threshold of P < .05. ResultsThe study cohort consisted of 102 patients, of whom N = 19 (19%) experienced relapse. Molecular subtyping revealed that neuroendocrine-like tumors had the worst outcomes, while tumors classified as Claudin-low did show only one recurrence event. Differential gene expression analysis identified genes associated with relapse, including KRT20, H19, and immune-associated genes such as CXCL9 and CXCL11. ConclusionThis study provides a detailed characterization of patients who relapsed after neoadjuvant pembrolizumab and RC and identifies distinct gene expression patterns associated with relapse. These findings may have implications for predicting patient response and guiding treatment decisions in the neoadjuvant setting.

The prognostic significance of circulating tumor DNA in patients with positive lymph node disease after robotic-assisted radical cystectomy: A contemporary analysis

Background and objectiveNeoadjuvant therapy followed by radical cystectomy with lymphadenectomy remains the gold standard of treatment in patients with muscle-invasive bladder cancer. Pathologically positive lymph node (pN+) disease is known to convey a poor prognosis. Tumor-informed circulating tumor DNA (ctDNA) has emerged as a possible novel prognostic biomarker in the field. We seek to assess recurrence-free survival (RFS) for patients undergoing robotic-assisted radical cystectomy (RARC) with extended pelvic lymphadenectomy (ePLND) and to assess whether ctDNA status can be a prognostic marker for RFS outcomes in patients with pN+ disease. MethodsPatients who underwent RARC + ePLND during 2015 to 2023 were included. A sub-group analysis (n = 109) of patients who had prospectively collected serial-longitudinal tumor-informed ctDNA analyses during 2021-2023 was performed. Survival analysis and Cox-regression models were conducted. ResultsIncluded were 458 patients with a median age of 69 (IQR 63–76), and a median follow-up time of 20 months (IQR 10-37). RFS for pN0 (n = 353) and pN+ (n = 105) at 12, 24 and 36 months were 87% vs. 54%, 80% vs. 39%, and 74% vs. 35%, respectively (log-rank, P < 0.0001). On Cox multivariate analysis ≥pT3 disease (Hazzard ratio [HR] = 3.36 [2.18–5.18], P < 0.001), pN+ disease (HR = 2.39 [1.55–3.7], P < 0.001), and recipients of neoadjuvant treatment (HR = 1.61 [1.11–2.34], P = 0.013) were predictive of disease relapse. Patients with pN+ disease and undetectable precystectomy or postcystectomy ctDNA status had similar RFS to patients with pN0 with undetectable ctDNA. On Cox-regression multivariate sub-group analysis, detectable precystectomy ctDNA status (HR = 3.89 [1.32–11.4], P = 0.014), detectable ctDNA status in the minimal residual disease window ([MRD], HR = 2.89 [1.12–7.47], P = 0.028), and having ≥pT3 with pN+ disease (HR = 4.2 [1.43–12.3], P = 0.009) were predictive of disease relapse. ConclusionsPatients with pN+ .after RARC had worse oncological outcomes than patients with pN0 disease. Undetectable ctDNA status was informative of RFS regardless of nodal status at both the precystectomy and the MRD window. Patients with undetectable ctDNA status and pN+ disease may benefit from treatment de-escalation.

The expression of programmed cell death ligand 1 (PD-L1) involves in the clinicopathologic characteristics and prognostic implications of testicular germ cell tumor (TGCT): a systematic review and meta-analysis.

Testicular germ cell tumor (TGCT) is a type of tumor with relatively lower incidence but being more prevalent in young men. The expression of programmed cell death ligand 1 (PD-L1) serves as a potential biomarker for predicting the survival outcomes of other tumors. Some studies discovered higher prevalence of PD-L1 in TGCT patients who achieved favorable treatment outcomes, while other studies showed lower or absent expression of PD-L1 in TGCT with the better prognosis as well. Therefore, in order to address this controversy and clarify the association between the expression of PD-L1 and pathological features and prognosis of TGCT, this meta-analysis was conducted. A comprehensive literature search was performed using following search terms: "testis", "testicle", "testicular", "cancer", "carcinoma", "tumor", "neoplasm", "programmed cell death ligand 1", "programmed death ligand 1", "PD-L1", "PDL1", "B7 homolog 1", "B7-H1", "B7H1" and "CD274". Relevant studies were retrieved according to the inclusion criteria from reputable databases including PubMed, Embase, Web of Science, Cochrane Library and China National Knowledge Infrastructure (CNKI). These studies investigated the expression of PD-L1 in both tumor cells and tumor infiltrating immune cells (TIICs) in TGCT. The overall proportion of PD-L1 positivity was assessed using R programming. Pooled hazard ratio (HR) and odds ratio (OR) with corresponding 95% confidence interval (CI) were calculated using Revman software to evaluate the involvement of PD-L1 expression in TGCT. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality assessment of included studies. Sensitivity analysis and publication bias evaluation were subsequently performed. A total of eight eligible studies compromising 1,589 patients diagnosed with TGCT were finally included in this study. PD-L1 positivity was detected in 31% and 41% of TGCT patients' tumor cells and TIICs, respectively. The pooled data demonstrated a significant association between elevated PD-L1 expression levels in TIICs and a favorable prognosis characterized by the reduced disease progression and relapse events (HR =0.21, 95% CI: 0.13-0.33). Furthermore, PD-L1+ TIICs exhibited higher prevalence rates in seminoma (OR =2.11, 95% CI: 1.57-2.84) and embryonal carcinoma (OR =6.23, 95% CI: 2.42-16.02) patients. Notably, PD-L1 expression in TIICs displayed a tendency to increase in TGCT patients with lower stages or without lymph node metastasis. PD-L1 expression was observed in choriocarcinoma tumor cells, while yolk sac tumor and teratoma tumor cells exhibited lower or absent expression of PD-L1. Conversely, PD-L1 expression in TIICs was associated with seminoma and embryonal carcinoma, which was more commonly observed in TGCT patients with lower stages and better prognosis, thereby providing a theoretical foundation for the application of immunotherapy in relapsed/refractory TGCT patients.

Adjuvant modern radiotherapy in resected pN2 NSCLC patients: results from a multicentre retrospective analysis on acute and late toxicity on behalf of AIRO thoracic oncology study group: the RAC-TAC study.

Recently, the PORT-C and LUNG-ART trials, which evaluated the role of postoperative radiation therapy (PORT), have significantly altered the treatment landscape for NSCLC pN2 patients who previously underwent surgery. In response, the Italian Association of Radiotherapy and Oncology Thoracic Oncology study group has initiated an observational multicenter trial to assess both acute and late toxicities of PORT in pN2 NSCLC patients treated with modern techniques. Data on NSCLC patients submitted to PORT after radical surgery treated between 2015 and 2020 in six Italian Centers were collected. Heart, lung, and esophageal acute and late toxicities have been retrospectively analyzed and related to radiation therapy dosimetric parameters. Furthermore, loco-regional control, distant metastasis and overall survival have been analyzed. A total of 212 patients with a median age of 68years from six different centers were included in this analysis (142 males and 70 females). Prior to undergoing PORT, 96 patients (45.8%) had a history of heart disease, 110 patients (51.9%) had hypertension, and 51 patients (24%) had COPD. Acute toxicity was observed in 147 patients (69.3%), with lung toxicity occurring in 93 patients (G1 in 70 patients, G2 in 17 patients, and G3 in 4 patients), esophageal toxicity in 114 patients (G1 in 89 patients, G2 in 23 patients, and G3 in 1 patient), and cardiac toxicity in 4 patients (G1 in 2 patients and G3 in 2 patients). Late side effects were found in 60 patients (28.3%), predominantly involving the lungs (51 patients: 32 G1, 11 G2, and 1 G3) and the esophagus (11 patients: 8 G1 and 3 G2), with no reported late cardiac side effects. Various clinical and dosimetric parameters were found to correlate with both acute and chronic toxicities. Over a median follow-up period of 54months, 48 patients (22.6%) showed locoregional disease relapse, 106 patients (50%) developed distant metastases, and 66 patients (31.1%) died. RAC-TAC retrospective multicentric study showed the low toxicity of PORT when advanced technology is used. At the same time, it's noteworthy to underline that 50% of the patients develop distant recurrences in the follow up.

Cognitive performance in patients with neuromyelitis optica: clinical and imaging characteristics

This study aimed to identify the prevalence, clinical and radiographic characteristics, and risk factors for cognitive dysfunction in patients with Neuromyelitis optica spectrum disorder (NMOSD). Eighty-three participants who were diagnosed with NMOSD were recruited. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). The mean age of the patients was 47.78 ± 13.14 years, with an average of 12.05 ± 4.62 years of formal education. The majority (54%) exhibited cognitive impairment, defined by a MoCA score < 25 (mean: 22.96 ± 3.82). Disease severity (evaluated by the Expanded Disability Status Scale) and lower formal education levels were associated with cognitive impairment (p = 0.011 and < 0.001, respectively). The annualized relapse rate, disease duration, and AQP4 antibody status were not associated with cognitive impairment. Interestingly, informant-reported cognitive decline was associated with poorer cognitive performance (p = 0.027). Radiographic findings of lesion location and severity were associated with MoCA-assessed cognitive performance, particularly for lesions in the right parietal lobes (p = 0.023). Hippocampal atrophy was negatively correlated with FAB scores. In conclusion, approximately half of the Thai patients with NMOSD exhibited cognitive impairment, which was associated with age, formal education level, disease severity, relative perception, and specific radiological findings. Further studies incorporating comprehensive neuropsychological tests and subjective cognitive complaints are warranted.

Development of New Diffuse Large B Cell Lymphoma Mouse Models.

Diffuse large B cell lymphoma (DLBCL) is the most diagnosed, aggressive non-Hodgkin lymphoma, with ~40% of patients experiencing refractory or relapsed disease. Given the low response rates to current therapy, alternative treatment strategies are necessary to improve patient outcomes. Here, we sought to develop an easily accessible new xenograft mouse model that better recapitulates the human disease for preclinical studies. We generated two Luciferase (Luc)-EGFP-expressing human DLBCL cell lines representing the different DLBCL cell-of-origin subtypes. After intravenous injection of these cells into humanized NSG mice, we monitored the tumor growth and evaluated the organ-specific engraftment/progression period. Our results showed that human IL6-expressing NSG (NSG-IL6) mice were highly permissive for DLBCL cell growth. In NSG-IL6 mice, systemic engraftments of both U2932 activated B cell-like- and VAL germinal B cell-like-DLBCL (engraftment rate; 75% and 82%, respectively) were detected within 2nd-week post-injection. In the organ-specific ex vivo evaluation, both U2932-Luc and VAL-Luc cells were initially engrafted and expanded in the spleen, liver, and lung and subsequently in the skeleton, ovary, and brain. Consistent with the dual BCL2/MYC translocation association with poor patient outcomes, VAL cells showed heightened proliferation in human IL6-conditioned media and caused rapid tumor expansion and early death in the engrafted mice. We concluded that the U2932 and VAL cell-derived human IL6-expressing mouse models reproduced the clinical features of an aggressive DLBCL with a highly consistent pattern of tumor development. Based on these findings, NSG mice expressing human IL6 have the potential to serve as a new tool to develop DLBCL xenograft models to overcome the limitations of standard subcutaneous DLBCL xenografts.

Effectiveness of a Wilms tumour treatment guideline adapted to local circumstances in sub-Saharan Africa: A report from Wilms Africa Phase II-CANCaRe Africa.

Wilms tumour (WT) is one of the cancer types targeted by the Global Initiative for Childhood Cancer (GICC). The objective of this study was to describe the outcomes of Wilms Africa Phase II in sub-Saharan Africa. Wilms Africa Phase II used a comprehensive WT treatment protocol in a multi-centre, prospective study conducted in eight hospitals in Ethiopia (2), Ghana (2), Malawi, Cameroon, Zimbabwe and Uganda. Eligibility criteria were: age younger than 16years, unilateral WT, diagnosed between 1 January 2021 and 31 December 2022. We included 230 WT patients, median age 3years, 53% male. Median maximum tumour diameter at diagnosis was 13.6cm and 33% of patients had metastatic disease. Nephrectomy was performed in 71% of patients, of whom 21% had a tumour rupture. Two-year event-free survival (EFS) was 41.3%±3.9% after a median follow-up of 17months (range: 1-33months), with treatment abandonment considered an event. Treatment abandonment occurred in 26% and death during treatment in 14%. Disease relapse occurred in 10%. Two-year EFS of the 26 patients who received radiotherapy was 64.5%±9.7% with no reported disease relapse. Patients continue to present late with advanced WT in sub-Saharan Africa, and their survival is below the 60% GICC target. Prevention of treatment abandonment and treatment-related mortality remain important. Earlier diagnosis and access to radiotherapy are expected to decrease disease-related mortality.

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.