Aggressive Disease Course Research Articles

P219 Prognostic potential of mucosal proteins in Ulcerative Colitis

Abstract Background Better prognostic measures for ulcerative colitis (UC) could significantly advance patient care. While the prognostic capacity of circulating proteins in UC has been explored, the role of mucosal proteins remains largely unknown. We examined mucosal protein markers in patients with incident ulcerative colitis and evaluated their prognostic value. Methods Biopsies from macroscopically inflamed colonic/rectal mucosa of adult patients in the Swedish inception cohort of IBD (SIC IBD) were obtained at diagnosis of UC. Patients were followed prospectively, and clinical data were recorded after 3 and 12 months. Disease course was categorised as indolent or aggressive at 12 months, based on a composite outcome of colectomy, hospital admission for active disease, treatment refractoriness towards ≥2 biological agents; the use of >2 courses of corticosteroids, or a cumulative dose of >2.5 g. Relative estimates of 162 protein markers were assessed in homogenised tissue supernatants, using proximity extension assay technology (Olink Proteomics, Uppsala, Inflammation and Oncology II panel). Mann-Whitney U test, with Benjamini-Hochberg correction was used to identify differentially regulated mucosal proteins in aggressive vs indolent disease course, with a 5% false discovery rate (FDR). Smoothly clipped absolute deviation regularised logistic regression models were used to identify prognostic signatures distinguishing aggressive from indolent disease course. Performance was estimated in a leave-one-out cross-validation and reported as the area under the receiver operating characteristic (ROC) curve (AUC). Results 117 patients provided a macroscopically inflamed colonic/rectal biopsy at diagnosis of UC. Basic demographics and clinical characteristics are presented in Table 1. Relative protein levels of WFdc2 and CCL20 were significantly lower in lysates from patients developing an aggressive course vs patients developing an indolent course, while estimates of MMP1, CCL11, WISP-1, OPG, RSPO3 and VEGFR2 were higher (Figure 1A). Regularized logistic regression identified signatures restricted to 28 proteins, distinguishing aggressive from indolent UC courses, yielding an AUC of 0.68 (95% confidence interval (CI): 0.56-0.80) for left-out samples (Figure 1B). Incorporating extent of inflammation at diagnosis in the model improved the AUC to 0.71 (95% CI: 0.60-0.83). Conclusion We identified prognostic mucosal protein signatures associated with future course of ulcerative colitis by analysing inflamed mucosal biopsies that were obtained at diagnosis. These protein markers may highlight pathways of relevance for ulcerative colitis outcomes.

Prognostic factors affecting long-term outcomes in patients with concurrent IgA nephropathy and membranous nephropathy

BackgroundThe incidence of concurrent immunoglobulin A nephropathy and membranous nephropathy (cIgAN/MN) is low and rarely reported, and the prognosis of patients with cIgAN/MN remains unclear. This study was designed to compare the clinical and prognostic characteristics of cIgAN/MN with IgAN and MN and to identify crucial factors influencing the outcomes of patients with cIgAN/MN. MethodsWe included biopsy-proven cIgAN/MN patients between December 2012 and December 2020 at Xijing Hospital. In the same period, propensity score matching was employed to select an equal number of IgAN and MN patients according to the following criteria: age, sex, and follow-up time. The primary endpoint was defined as a composite of eGFR decline ≥30 %, end-stage renal disease, or death. The patient survival rate was examined using Kaplan–Meier survival curves. Univariate and multivariate Cox regression analysis models were utilized to identify the risk factors affecting renal prognosis. ResultsA total of 135 patients were finally included in this study and 35 (25.9 %) reached the primary endpoint. The median follow-up time of cIgAN/MN was 45.9 (24.0, 72.0) months. Compared to the IgAN group, the cIgAN/MN group exhibited a lower cumulative incidence rate of composite renal endpoints (P = 0.044), while no significant difference was found between MN and cIgAN/MN patients (P = 0.211). Univariate Cox analysis revealed that mean arterial pressure, serum potassium, blood urea nitrogen, serum IgA, segmental glomerulosclerosis (S1), and MN staging were associated with an increased risk of renal composite endpoints. The multivariate Cox regression analysis of clinical variables plus histological lesion scoring demonstrated that potassium (HR = 14.350, 95 % CI 2.637–78.090, P = 0.002), serum IgA (HR = 1.870, 95 % CI 1.109–3.153, P = 0.019), and S1 (HR = 11.965, 95 % CI 2.166–66.105, P = 0.004) were independent risk factors influencing renal outcomes in cIgAN/MN patients. ConclusionThe prognosis of cIgAN/MN patients may exhibit an intermediate pattern between IgAN and MN, leaning towards being more similar to MN in certain aspects. Within the cIgAN/MN cohort, potassium, and serum IgA may be more predictive of rapid progression of renal endpoints, and S1 may indicate a more aggressive disease course.

Clinical case of giant extramedullar plasmacytoma in a patient with multiple myeloma

One possible manifestation of multiple myeloma may be extramedullary plasmacytoma, manifested by infiltration of plasma cells outside the bone marrow. In the debut of the disease, bone plasmacytomas are most often diagnosed, in contrast to extramedullary ones, which are rare. According to the literature, the presence of extramedullary plasmacytoma is an unfavorable factor characterized by an aggressive disease course, the absence of an antitumor response to standard therapy, and low overall survival rates. Therefore, the pathogenesis, clinic, diagnosis and treatment of this variant of the disease require additional study. This article presents a clinical case of an aggressive course of extensive extramedullary plasmacytoma in a patient with multiple myeloma with an assessment of various combination therapy regimens efficacy.

The Novel CDK9/CDK4/6/PI3K Triple Inhibitor LCI139 for the Treatment of MYC-Driven Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive B cell malignancy with characteristic t(11;14)(q13;q32) translocation juxtaposing IGH and CCND1 gene loci. This chromosomal rearrangement leads to Cyclin D1 overexpression and cell cycle dysregulation at the G1/S phase transition. MCL is generally diagnosed at advanced stages and follows an aggressive course of disease. Although chemotherapy-based combination regimens are initially effective, most patients relapse with a median survival of only 2.5-5 years. While novel targeted therapeutics have shown promising activity in relapsed/refractory patients, inevitable relapse associated with progressively declining efficacy and increasing resistance to single agent targeted therapy is a major concern. To overcome this barrier, we designed in-silico based a novel multitarget small molecule inhibitor LCI139 which simultaneously blocks three oncogenic targets: cyclin-dependent kinase 9 (CDK9), CDK4/6, and phosphatidylinositol-3 kinase (PI3K). LCI139 is a potent CDK9/CDK4/6/PI3K inhibitor with IC 50s of 0.000039µM (CDK9), 0.0015µM/0.0036µM (CDK4/6) 0.070µM (p110α), 0.461µM (p110γ), and 0.214 (p110δ), as determined by cell free assay alpha screens. Dose-dependent screening of LCI139 against a panel of MCL cell lines revealed robust cytotoxic effects with maximal IC 50 of 86.67 nM in JeKo-1 cells, 64.8 nM in Mino cells, and 202.5 nM in Rec-1 cells. Compared with clinical single agent CDK9 inhibitor AZD4573, LCI139 is less toxic to normal human stromal cells (HS-5), whereas both LCI139 and AZD4573 have no significant cytotoxic effect on normal human foreskin fibroblast cells (Hs68). LCI139 treatment at various concentrations for 24hrs induced significant apoptotic response in two MCL cell lines, JeKo-1 (p<0.001 DMSO vs LCI139 100 nM, p<0.0001 DMSO vs LCI139 200 nM) and Mino (p<0.05 DMSO vs LCI139 100 nM, p<0.0001 DMSO vs LCI139 200 nM) as determined by Annexin V/7-AAD apoptosis staining. Similarly, LCI139-induced apoptotic cell death was further confirmed by increasing cl-PARP protein levels compared to control as assessed by Western blot analysis. LCI139 induced robust G2/M cell cycle arrest in JeKo-1 cells and G1 arrest in Mino cells. The mechanism of action of pan-CDK inhibitors has been associated with downregulation of the anti-apoptotic protein MCL-1 through inhibition of transcriptional CDKs. Our results show that short-term exposure of LCI139 (1hr and 3hr) significantly suppressed MCL-1 and MYC mRNA expression in JeKo-1 (p<0.00001 DMSO vs LCI139) and Mino cells (p<0.00001 DMSO vs LCI139). LCI139 suppressed pRpb1 (Ser2), MCL-1 and cMYC protein expression in IgM-stimulated JeKo-1 and Mino cells in a dose-dependent manner. Treatment with LCI139 had no significant effect on pAKT (Ser473) in Jeko-1 cells, whereas pAKT (Ser473) was completely abolished in Mino cells at 500nM of LCI139. Mechanistically, our findings also demonstrate that LCI139 decreased MCL-1 and cMYC protein stability and reduced half-life as accessed by cycloheximide chase assay. This decrease in cMYC stability is associated with decreased of cMYC phosphorylation at Ser62. Adaptive kinome remodeling via drug-induced transcriptional reprogramming is a known contributor to ibrutinib resistant (IR) MCL. RNA-sequencing analysis of JeKo-1 vs Jeko-1 IR cells revealed a total of 3468 differentially expressed genes (FC > 1.5 and FDR < 0.05) where 110 kinases display altered expression in JeKo-1 IR cells. Finally, we show that LCI139 overcomes chronic ibrutinib resistance by decreasing viability in JeKO-1 IR and Mino IR cells with an IC 50 of 79 nM and 89 nM, respectively. Therefore, the multitarget small molecule inhibitor LCI139 has superior potency against IR MCL cell lines and overcomes ibrutinib-resistance at nanomolar doses.

Outcomes of Lymphoma and Multiple Myeloma Patients Following Inpatient Antineoplastic Treatment

Introduction: Patients (pts) with hematologic malignancies receive more aggressive end-of-life care, including hospitalizations and antineoplastic therapy, compared to solid tumor. 1 In the modern era, treatment for lymphoma and multiple myeloma is mostly administered in the outpatient setting. Pts requiring inpatient treatment may have an aggressive disease course, decreased performance status, and comorbidities that impact clinical outcomes. Treatment decisions in the acute care setting are challenging due to the need to balance efficacy, toxicity, and cost. Given the paucity of data available to help guide decision-making, we sought to investigate the outcomes of inpatient administration of unplanned antineoplastic therapy. Methods: This retrospective cohort study included adults (≥18 years) with lymphoma and multiple myeloma who received unplanned inpatient antineoplastic therapy between June and October 2022. Pts who received planned chemotherapy or first cycle of treatment for newly diagnosed disease were excluded. Pts undergoing outpatient induction or salvage therapy admitted for complications who subsequently received their next cycle while admitted were included. Baseline characteristics, diagnosis, treatment, and clinical outcomes were abstracted from the electronic medical record. The primary endpoint was rate of treatment continuation or completion 60 days after first administration of inpatient therapy. Secondary endpoints included overall survival (OS); length of stay (LOS) following treatment; transfer to intensive care unit (ICU), emergency department (ED) visits, and readmissions within 30 days; and death within 30 and 60 days of inpatient treatment. Results: Of the 172 pts screened, 49 pts were included after excluding 122 pts (76 had planned chemo and 46 had newly diagnosed disease). Median age was 63 years (range, 34-88). Treatment was for a variety of diagnoses, including plasma cell neoplasm (53%), diffuse large B-cell lymphoma (18%), central nervous system lymphoma (14%), chronic lymphocytic leukemia (4%), as well as 1 pt each with T-cell prolymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, NK/T-cell lymphoma, and T-cell lymphoma. Most had relapsed/refractory disease (90%). Thirteen (26%) pts received inpatient only regimens; however, these were not planned admissions. Fifteen (31%) pts received drugs traditionally restricted to outpatient use only (daratumumab (10), carfilzomib (3), obinutuzumab (1), loncastuximab tesirine (1), polatuzumab vedotin (1)). At 60 days after first inpatient treatment, 15 (31%) pts continued or completed treatment, while treatment was discontinued in 34 (69%) pts. Of the 15 pts who continued treatment, 53% (8/15) received ≤ 3 additional cycles after discharge. Median time to discharge following inpatient treatment initiation was 5 days (range, 0-38). Fourteen (29%) pts were transferred to the ICU, 16 (33%) pts presented to the ED after discharge, and 14 (29%) were readmitted within 30 days of inpatient treatment. Overall survival was 26.5% at a median follow up of 157 days. The 30- and 60-day mortality rates were 18% and 31% respectively. Univariate and multivariate analysis to identify prognostic factors for survival will be conducted. Conclusions: In this retrospective analysis, about a quarter of pts with lymphoid and plasma cell malignancies were alive at 5 months after receiving unplanned inpatient antineoplastic therapy. Better tools are needed to select pts who may benefit from urgent inpatient treatment, as a small subset of our cohort experienced continued clinical benefit. Combining such tools with multidisciplinary discussions may help to maximize favorable outcomes while minimizing use of aggressive end-of-life antineoplastic treatment. Ongoing analysis in our population will aim to identify patient-specific factors associated with positive outcomes.

Dysregulation of Cellular Immunity in High-Risk Multiple Myeloma

Introduction: Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by the abnormal proliferation of plasma cells in the bone marrow. Approximately 20% of MM patients present with high-risk (HR) clinical and genetic features that are associated with aggressive disease course and poor prognosis. Novel immune therapies are changing the paradigm of MM treatment. A comprehensive understanding of immune dysregulation within the tumor microenvironment (TME) of HR vs standard risk (SR) MM patients could inform the development of targeted immunotherapeutic strategies for HR MM. Methods: 55 HR and 25 SR patients were selected from the Mt. Sinai Hematologic Malignancies Tissue Bank (IRB# STUDY-11-01978). HR included one or more cytogenic abnormalities (HRCA) such as translocations t(4;14), deletion of chromosome 17 (del17p), and gain/amplification of 1q (1q+/++) based on the Second Revised International Staging System (R2-ISS). We also included nine patients with t(14;16) translocation alone or combined with one or two of the other HRCA. We performed comprehensive immune phenotyping of the bone marrow micro-environment on specimens from HR and SR patients using mass cytometry (CyTOF) and single cell RNA sequencing (scRNASeq) of bone marrow mononuclear cells (BMMC) depleted of CD138 positive MM cells. Results: ScRNAseq of BMMC from HR MM patients revealed a robust cytotoxic and cytolytic signature on CD4+ T cells relative to SR, characterized by the upregulation of genes such as GNLY, NKG7, PRF1, and IFNG, and a higher frequency of Granzyme K-positive (GZMK+) CD8+ T cells, previously described as progenitors of exhausted cells. Both CD4 and CD8 T cells, along with monocytes, exhibited high expression of a group of Interferon-stimulated genes (ISGs) including IFI27, IFIT3, IFI44L, IFITM1/3, and OASL. Notably, high expression of this group of ISGs was associated with T cell exhaustion and poor prognosis in the setting of immune checkpoint inhibitor therapy for solid tumors. Mass cytometry analysis confirmed the activated state of T cells in HR MM patients, with increased expression of immune activation markers HLA-DR, CD38, and the senescence marker CD57. Furthermore, HR patients exhibited higher frequencies of mast cells, CD14+ Monocytes and plasmacytoid dendritic cells compared to SR, suggesting an inflammatory and immunosuppressive environment that may dampen effective antitumor immune responses. Conclusions: These results indicate distinct bone marrow microenvironments of HR and SR MM. CD4 and CD8 T cells appear to be more activated in HR patients compared to SR. However, the higher frequencies of mast cells and plasmacytoid dendritic cells, and the prominent expression of ISGs associated with inhibition of anti-tumor immunity suggest dysregulation and exhaustion of T cell activity in HR patients. Collectively, these findings highlight the complex immune dynamics in HR MM and provide insights into the underlying immune dysfunction which may contribute to disease progression and therapy resistance in HR MM. Such insights have the potential to inform the design of targeted therapeutic interventions aimed at modulating the immune response and improving treatment outcomes for HR MM patients.

Podcast on Identifying and Understanding Barriers to Care in Underserved Populations With MS in the United States.

Multiple sclerosis (MS) can affect people from all racial and ethnic backgrounds, but, historically, the incidence of MS in the United States was thought to be highest in White individuals. More recent data suggest that the incidence of MS in Black or African American individuals is comparable to that in White individuals. In Hispanic or Latino individuals, incidence of MS is lower, but age of onset may be earlier compared with White individuals. Additionally, there are important differences in MS disease severity, disease progression, and mortality in Black or African American and Hispanic or Latino populations. Compared with their White counterparts, individuals from these underrepresented groups are more likely to be affected by MS in specific areas of the nervous system, such as accelerated loss of retinal and brain tissue in Black or African American individuals and optic neuritis in Hispanic individuals. Additionally, Black or African American individuals with MS tend to have an aggressive disease course, earlier disability, and higher risk of requiring ambulatory assistance. Although these differences may be attributed to genetic factors, systemic racism and biases and barriers to accessing care may perpetuate health disparities. Moreover, non-White communities remain broadly underrepresented in clinical trials; however, it is vital that these populations are appropriately represented so that any potential differences in drug efficacy or safety implications are detected. Thus, it is important to increase awareness of MS in these populations. In this podcast, the authors discuss characteristics of MS in Black or African American and Hispanic or Latino populations, identify barriers to care, and propose solutions to improve access to MS care in these populations. MP4 (358385 KB).

STAT5-Feedback Controls Distinct Metabolic States for Dynamic Transitions between Cellular Activation and Quiescence in Acute Lymphoblastic Leukemia

Background and significance: B-cell acute lymphoblastic leukemia (B-ALL) is characterized by dynamic shifts between activation and quiescence. These cycles are predicated by fluctuations in oncogenic signaling, which mimic pre-BCR and cytokine receptor signaling, e.g. IL7 receptor signaling and phosphorylation of STAT5. These fluctuations in cytokine receptor and STAT5 signaling are mitigated by powerful feedback regulators, including CISH and SOCS (suppressors of cytokine signaling) family members. While B-ALL cells depend on oncogenic STAT5 signaling, CISH and SOCS2 negative feedback regulators of STAT5 are highly expressed in aggressive B-ALL and high expression levels are strongly linked to poor clinical outcome, positive MRD and increased likelihood of bone marrow relapse in children (COG P9906) and adults (ECOG E2993). To determine whether high levels of CISH and SOCS2 are biomarkers of high oncogenic STAT5 signaling or mechanistically contribute to clonal fitness and adaptability of B-ALL, we performed genetic experiments in mouse models for B-ALL. Here we examined the mechanisms and consequences of active and inactive states of STAT5 by studying constitutively active (CA) and non-phosphorylatable Y694F (YF) mutations of STAT5. Results: Consistent with a central role of STAT5-feedback control in B-ALL survival, inducible ablation of Cishfl/fl resulted in rapid depletion of B-ALL cells. Socs2-/- B-ALL cells rapidly underwent cellular senescence, lacked colony forming and leukemia-initiating capacity in serial transplantation experiments. Likewise direct interference with STAT5-function, by mutations resulting in constitutive activation (STAT5-CA) or an inactive state (STAT5-YF). Consistent with a requirement of adaptive STAT5-feedback control in B-ALL, both Stat5-CA and Stat5-YF resulted in rapid cell death. Induction of Stat5-CA caused accumulation of biomass indicated by their increased cell size, whereas Stat5-YF caused rapid cell shrinkage ( Figure A). To determine whether the mTOR cell growth pathway was responsible for cell death induced by Stat5-CA, we tested whether the genetic deletion of Mtor or pharmacological inhibition of protein synthesis were sufficient to rescue B-ALL cell death. As expected, B-ALL cells retaining intact Mtor rapidly underwent energy crisis and cell death, while genetic deletion of Mtor reversed the toxic effects of Stat5-CA, suggesting that Stat5-CA is associated with excessive protein synthesis and defective ER turnover. Indeed, Stat5-CA increased protein synthesis rate and ER content compared to EV control, and these effects were opposed by Stat5-YF. To compare the metabolic outcomes of Stat5-CA and Stat5-YF, we performed mass spectrometry-based metabolomic analyses ( Figure B). Consistent with the role of mTOR in promoting glycolysis, Stat5-CA increased the content of glycolytic intermediates in B-ALL cells. In contrast, Stat5-YF increased phospholipid intermediates and phosphatidylethanolamine (PtdEtn). Opposed by Myc, Stat5-YF increased the expression levels of Bcl6 and autophagic genes, suggesting that Bcl6-dependent programs promote PtdEtn-LC3B conjugation, thereby autophagosome formation. As expected, microscopic validation with LC3B-GFP reporter revealed that Stat5-YF increased the number of LC3B-GFP puncta, upon pharmacological inhibition of autophagosome-lysosome fusion ( Figure A). Consistent with STAT5-CA promoting Myc- as opposed to STAT5-YF driving Bcl6-dependent programs, a flow cytometry analysis of Myc-eGFP/Bcl6-mCherry dual reporter expression in murine B-ALL cells demonstrated that changes between glycolytic Myc+ and autophagic Bcl6+ states were the direct consequence of Stat5-CA and Stat5-YF induction, respectively. Conclusions: Our results demonstrate feedback regulators of STAT5, including SOCS2 and CISH are not only biomarkers of increased oncogenic STAT5 activity and a more aggressive course of disease linked to poor overall outcomes. Importantly, negative STAT5 feedback control mechanisms are essential to enable nimble adaptations of B-ALL cells in response to fluctuations of oncogenic signaling strength and availability of nutrients during distinct metabolic states of cellular activation (MYC) and quiescence (BCL6).

Arsenic Trioxide Combine with G-CSF Triggers Distinct TP53 Mutations Acute Myeloid Leukemia Cells Ferroptosis through TP53-SLC7A11-GPX4 Pathway

Abstract ： Background ： Acute myeloid leukemia (AML) is a complex disease with diverse molecular subtypes. Approximately 8% of AML patients carry the TP53 mutation, which is associated with an aggressive disease course and dismal survival rates. Arsenic trioxide (ATO) has been remarkably effective in treating acute promyelocytic leukemia (APL), but its clinical activity in other AML subtypes remains limited. Recent evidence indicates that ATO demonstrates potential in rescuing multiple TP53 mutations effectively, offering promise as an individualized therapeutic strategy targeting mutant TP53 in leukemic cells. Our previous study showed that the upregulation of AQP9 by G-CSF enhanced the effect of ATO in non-APL AML cells. This demonstrates that ATO holds therapeutic promise in AML cases harboring distinct TP53 mutations. Methods ： We conducted a comprehensive analysis of TP53 mutations in the Analysis of Whole Genomes cohort, encompassing patients from the TCGA and OHSU databases. The frequency and distribution of TP53 mutations were determined. Median overall survival (OS) was calculated using the Kaplan-Meier method. To functionally assess the effect of TP53 mutation on AML phenotype, various cell lines harboring distinct TP53 mutation types were used for this study, including KASUMI-1 TP53 R248Q THP-1 TP53frameshift_delHL-60 TP53 deletionMOLM13 TP53 wild-type. The cellular lipid oxidation levels were measured by a C11 BODIPY flow cytometry assay and it was also observed by fluorescence microscopy. Additionally, the RNA and protein expressions of GPX4 and SLC7A11 were analyzed by real-time quantitative Polymerase Chain Reaction (QRT-PCR) and Western Blot. Results ： In the OHSU cohort and TCGALAML database, including 1005 newly diagnosed patients with 120 TP53 mutations, we found that missense mutations are the most common TP53 mutations and R248Q has the highest mutation frequency. Furthermore, TP53 mutationwas significantly associated with lower survival ( P <0.001). ATO potently induced cell death in each cell line. The KASUMI-1 R248Q cell line was the most sensitive to ATO (IC50=0.3607) and showed the most pronounced change in the IC50 of ATO with the addition of ferrostatin-1(Fer-1, ferroptosis inhibitor). ATO induced cell death was prevented by the addition of lipophilic antioxidant ferrostatin-1, supporting the hypothesis that ATO induced cell death occurred by ferroptosis. In KASUMI-1 R248Q cell line, ATO increases the lipid oxidation levels (observed by C11 BODIPY flow cytometry assay and fluorescence microscopy), MDA levels and decreases the expression of GPX4 and SLC7A11 (including RNA level and protein level). Whereas, in MOLM13 TP53 wildtype cell line, ATO increases the lipid oxidation levels but cannot prevented by Fer-1. THP-1 TP53 frameshift_del and HL-60 TP53 deletion only decrease the RNA expression of GPX4 and SLC7A11, nothing else changed in ferroptosis. These suggest that ATO has a more pronounced effect on missense mutations such as TP53 R248Q. In KASUMI-1 R248Q cell line, associated with G-CSF can further promote lipid oxidation levels (observed by C11 BODIPY flow cytometry assay and fluorescence microscopy) and further reduce the expression of GPX4 and SLC7A11. These results suggest that G-CSF promotes ATO-induced ferroptosis in KASUMI-1 R248Q cell line. Conclusion: We have demonstrated that ATO induces AML with distinct TP53 mutation cell death by ferroptosis resulting from depletion of GPX4 and SLC7A11. ATO associated with G-CSF may be able to be a new therapeutic strategy for the treatment of AML with distinct TP53 mutation.

A prognostic model for tumor recurrence and progression after meningioma surgery: preselection for further molecular work-up.

The selection of patients for further therapy after meningioma surgery remains a challenge. Progress has been made in this setting in selecting patients that are more likely to have an aggressive disease course by using molecular tests such as gene panel sequencing and DNA methylation profiling. The aim of this study was to create a preselection tool warranting further molecular work-up. All patients undergoing surgery for resection or biopsy of a cranial meningioma from January 2013 until December 2018 at the University Hospital Zurich with available tumor histology were included. Various prospectively collected clinical, radiological, histological and immunohistochemical variables were analyzed and used to train a logistic regression model to predict tumor recurrence or progression. Regression coefficients were used to generate a scoring system grading every patient into low, intermediate, and high-risk group for tumor progression or recurrence. Out of a total of 13 variables preselected for this study, previous meningioma surgery, Simpson grade, progesterone receptor staining as well as presence of necrosis and patternless growth on histopathological analysis of 378 patients were included into the final model. Discrimination showed an AUC of 0.81 (95% CI 0.73 - 0.88), the model was well-calibrated. Recurrence-free survival was significantly decreased in patients in intermediate and high-risk score groups (p-value < 0.001). The proposed prediction model showed good discrimination and calibration. This prediction model is based on easily obtainable information and can be used as an adjunct for patient selection for further molecular work-up in a tertiary hospital setting.

Oligo-metastatic neoPlasms from the gastro-intestinal tract: iDentIfiCaTIon of cliNical and molecular drivers: the PREDICTION study

BackgroundMetastatic disease in tumors originating from the gastrointestinal tract can exhibit varying degrees of tumor burden at presentation. Some patients follow a less aggressive disease course, characterized by a limited number of metastatic sites, referred to as “oligo-metastatic disease” (OMD). The precise biological characteristics that define the oligometastatic behavior remain uncertain. In this study, we present a protocol designed to prospectively identify OMD, with the aim of proposing novel therapeutic approaches and monitoring strategies.MethodsThe PREDICTION study is a monocentric, prospective, observational investigation. Enrolled patients will receive standard treatment, while translational activities will involve analysis of the tumor microenvironment and genomic profiling using immunohistochemistry and next-generation sequencing, respectively. The first primary objective (descriptive) is to determine the prevalence of biological characteristics in OMD derived from gastrointestinal tract neoplasms, including high genetic concordance between primary tumors and metastases, a significant infiltration of T lymphocytes, and the absence of clonal evolution favoring specific driver genes (KRAS and PIK3CA). The second co-primary objective (analytic) is to identify a prognostic score for true OMD, with a primary focus on metastatic colorectal cancer. The score will comprise genetic concordance (> 80%), high T-lymphocyte infiltration, and the absence of clonal evolution favoring driver genes. It is hypothesized that patients with true OMD (score 3+) will have a lower rate of progression/recurrence within one year (20%) compared to those with false OMD (80%). The endpoint of the co-primary objective is the rate of recurrence/progression at one year. Considering a reasonable probability (60%) of the three factors occurring simultaneously in true OMD (score 3+), using a significance level of α = 0.05 and a test power of 90%, the study requires a minimum enrollment of 32 patients.DiscussionFew studies have explored the precise genetic and biological features of OMD thus far. In clinical settings, the diagnosis of OMD is typically made retrospectively, as some patients who undergo intensive treatment for oligometastases develop polymetastatic diseases within a year, while others do not experience disease progression (true OMD). In the coming years, the identification of true OMD will allow us to employ more personalized and comprehensive strategies in cancer treatment.Trial registrationClinicalTrials.gov ID NCT05806151.

Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targets

Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. Fresh frozen samples of MPNSTs (n=94) and benign neurofibromas (n=28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. "Immune active" MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P=0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P=0.003). "Immune deficient" MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P<0.01). Approximately half of MPNSTs belong to an "immune deficient" transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials. Research grants from non-profit organizations, as stated in the Acknowledgements.

Legg–Calvé–Perthes disease presenting with osteoarthritis: Mechanisms of the development and prospects of conservative therapy using bisphosphonates

BACKGROUND: Aseptic necrosis of the femoral head in children remains a subject of great interest among specialists, despite its long history of study. The LeggCalvPerthes disease is the most common form of aseptic necrosis of the femoral head in children. The necrotic lesion in the femoral head results from the blockage of the arterial blood supply to the epiphysis, leading to its infarction. Some children experience a more aggressive disease course, with signs of osteoarthritis, which can result in the early development of coxarthrosis. Numerous publications have demonstrated the successful use of bisphosphonates in adult patients with aseptic necrosis of the femoral head.&#x0D; AIM: To generalize data on the use of bisphosphonates in children with the LeggCalvPerthes disease presenting with signs of osteoarthritis through the analysis of contemporary global literature.&#x0D; MATERIALS AND METHODS: A literature search was conducted in the open databases of PubMed, Science Direct, and Google Scholar, and the analysis depth spanned 20 years. The search terms used included LeggCalvPerthes disease, aseptic (avascular) necrosis of the femoral head, and bisphosphonates. The review encompassed the literature on bisphosphonates, their biological action, effectiveness of their use in patients with aseptic necrosis of the femoral head, and results of our research.&#x0D; RESULTS: Studies on the efficacy of bisphosphonates in children with LeggCalvPerthes disease are limited. Currently, the effect of bisphosphonates on disease course and outcome is unknown. Despite this, mechanisms of chronic inflammation are increasingly mentioned in the literature, which may directly or indirectly influence the clinical course and outcome of the disease. The key is the hyperactivity of osteoclasts in osteonecrosis. The experience of using bisphosphonates in adult patients with aseptic necrosis of the femoral head had positive results in preventing the progression of the deformity of femoral head deformity.&#x0D; CONCLUSIONS: Bisphosphonates are specific inhibitors of osteoclast activity, which has been used in many diseases. The results and inferences of using bisphosphonates in children with LeggCalvPerthes disease will lead to the formulation of a new treatment algorithm.

Hairy cell leukemia with an aggressive outcome: A case report with a review of the literature

Abstract Hairy cell leukemia (HCL), an uncommon cancer affecting B-lymphocytes primarily in the bone marrow and spleen, is identified by abnormal projections on malignant B cells, which give the illness its name. This condition is less frequently observed in Asian populations compared with individuals from American and European backgrounds and tends to be diagnosed around the age of 55 years. The leading genetic association of this ailment is linked to the BRAFV600 mutation. Diagnosing HCL poses challenges due to its similarity to other conditions involving excessive lymphocyte growth. Here, we present a distinctive case of an aggressive disease course in a 46-year-old male.

Efficacy and outcomes of systemic chemotherapy in posttransplant and immunosuppression associated Kaposi sarcoma: Twenty years experience of a tertiary cancer center.

Kaposi sarcoma is a malignant angioproliferative disease, and human herpesvirus-8 plays a major role in its etiology. Iatrogenic Kaposi sarcoma (IKS) can occur in patients undergoing immunosuppressive therapy. The treatment strategy for patients with IKS is immunosuppressive therapy modification. However, it is unclear which chemotherapy drug is the most effective and safe in the treatment of IKS. Therefore, we investigated the efficacy and safety of systemic treatment in patients with IKS at our tertiary cancer center. This cross-sectional retrospective study analyzed the clinical data of 22 patients diagnosed with IKS between January 2000 and January 2020. The patients were divided into the following 2 groups according to the transplantation status: organ transplant recipient (OTR) group and non-organ transplant recipient (non-OTR) group. Of the 22 patients, 12 were included in the OTR group and 10 were included in the non-OTR group. The median patient age at diagnosis was 52.1 years in the OTR group and 68.1 years in the non-OTR group. The median overall survival (OS) was 65.4 months in the OTR group, while the median OS was not reached in the non-OTR group. There was no statistically significant difference in OS between the 2 groups (P = .45). The 5-year OS rate among all patients was 54%. In the OTR group, the objective response rate and disease control rate were 50% and 83%, respectively, and in the non-OTR group, the objective response rate and disease control rate were 60% and 90%, respectively. Chemotherapy was well tolerated in both groups. Hematological toxicities were the main dose-limiting adverse events. Grade III/IV leucopenia and neutropenia were observed in 5 and 4 patients, respectively; however, no patient experienced febrile neutropenia. No chemotherapy-related death occurred. Systemic chemotherapy is an effective treatment and can be considered for disease control in patients with an aggressive disease course, who do not experience regression with immunosuppressive therapy modification.

Interictal epileptiform discharges in Alzheimer's disease: prevalence, relevance, and controversies.

Alzheimer's disease (AD) is the most common type of dementia and remains an incurable, progressive disease with limited disease-modifying interventions available. In patients with AD, interictal epileptiform discharges (IEDs) have been identified in up to 54% of combined cohorts of mild cognitive impairment (MCI) or mild dementia and are a marker of a more aggressive disease course. Studies assessing the role of IEDs in AD are limited by the lack of standardization in the definition of IEDs or the different neurophysiologic techniques used to capture them. IEDs are an appealing treatment target given the availability of EEG and anti-seizure medications. There remains uncertainty regarding when to treat IEDs, the optimal drug and dose for treatment, and the impact of treatment on disease course. This review covers the state of knowledge of the field of IEDs in AD, and the steps needed to move the field forward.

The prognostic significance of lymphovascular invasion in cutaneous squamous cell carcinoma.

The majority of cutaneous squamous cell carcinomas (cSCC) have a favourable prognosis. However, a subset of cases follow an aggressive disease course with progression to metastasis and death. Several histopathological parameters are associated with poor outcomes, but lymphovascular invasion (LVI) has not been well studied. To assess the prognostic significance of LVI in cSCC and determine associations between LVI and cSCC. A retrospective review of 486 consecutive cases of cSCC over a 5-year period from a single centre was stratified by the presence or absence of LVI. Logistic regression and multivariate survival analysis were used to determine associations of LVI and prognostic significance of LVI, respectively. LVI was present in 41 cases (9.2%). LVI was significantly associated with increasing depth of invasion, microanatomical tumour location (subcutis vs. dermis), and tumour dimensions (P < 0.05). Univariate survival analysis revealed significantly lower 2-year overall survival rates for patients with LVI (37.1%) compared with those without (66.6%) (95% CI = 60.6-73.3, P < 0.001). LVI was also found to be an independent marker of poor disease-specific survival (HR = 0.232 (95% CI = 0.090-0.600), P = 0.003), poor overall survival (HR 0.338 (95% CI = 0.184-0.623), P < 0.001) and poor disease-free survival (HR 0.461 (95% CI = 0.230-0.923), P = 0.029) through multivariate analysis. This study confirms that LVI is an independent poor prognosticator in cSCC, with significantly worse survival indices at 2 years. Future systems of risk stratification for cSCC should incorporate LVI.

Decrease of left ventricular function measured by speckle-tracking echocardiography based on systemic lupus erythematosus severity in children.

Systemic lupus erythematosus in children generally manifests more severely with a more aggressive disease course. Cardiac involvement in systemic lupus erythematosus often does not show specific signs and symptoms, but speckle-tracking echocardiography can detect cardiac dysfunction. This study aimed to determine the differences in left ventricular function as measured by speckle-tracking echocardiography in children with various severity of systemic lupus erythematosus activity. A cross-sectional study of 49 children diagnosed with systemic lupus erythematosus are currently undergoing outpatient or inpatient care at Dr Hasan Sadikin General Hospital, Bandung, from May 2023 to June 2023. Disease activity was assessed by Mexican Version of the Systemic Lupus Erythematosus Disease Activity Index (MEX-SLEDAI) with a score of 2-5 classified as mild activity, 6-9 as moderate, and ≥10 as severe. Each subject underwent conventional echocardiography and speckle-tracking echocardiography with a Philips EPIQ machine performed by a Pediatric Cardiologist Consultant 10 days after inclusion. Fifteen (30.6%) subjects had mild disease activity, and 34 (69.4%) subjects had moderate disease activity. Most subjects (81.96%) were female with an average age of 15 years. The mean ejection fraction and fractional shortening as well as the median E/A ratio in the mild and moderate disease activity groups were not significantly different (65.76 versus 67.38%, 35.73 versus 37.11%, 1.6 versus 1.5%, respectively, p > 0.005). The global longitudinal strain in the moderate activity group was reduced more significantly than in the mild activity group (-16.58 versus -19.65, p = 0.008). Left ventricular function as measured by speckle-tracking echocardiography was lower in children with moderate systemic lupus erythematosus activity than those with mild disease activity.

What an adult multiple sclerosis registry can tell us about pediatric onset multiple sclerosis?

BackgroundMultiple Sclerosis (MS) is an immune-mediated, chronic disease of the central nervous system that affects mainly adults. However, it is increasingly recognized that MS may start in childhood resulting in a relentlessly progressive disability and cognitive impairment. Registries across the globe are reporting inconstant data about their Pediatric-Onset Multiple Sclerosis (POMS) patients. Moreover, newer lines of treatments are emerging and showing efficacy in controlling the MS disease regardless of the onset. Therefore, there is a requirement for more research into the clinical profile of POMS in different populations and ethnicities. MethodsThis study was a cross-sectional study that included MS patients who visited the MS unit at Alexandria University from January 2019 to January 2021. We analyzed their epidemiological, clinical, radiological data, and cerebrospinal fluid (CSF) results from their updated records as well as follow-up interviews. ResultsAnnual Relapse Rate (ARR) was marginally less in POMS than AOMS (0.72 ± 0.57 vs 1.04 ± 0.78 relapse/year, P =.008). POMS patients had a bigger gap to their first relapse (40.0 ± 47.35 vs 22.71 ± 34.33 months, p= .066). The difference in relapse rate between the two groups was abolished after the exclusion of patients who had a gap of more than 5 years to their first relapse. AOMS patients were significantly more likely to start with a second-line disease-modifying treatment (DMT) than POMS patients (11.5% vs 31%, p= .04), whereas POMS patients were more likely to be escalated to the second line (34.6% vs 19.3%, p= .07). ARR had a positive and significant correlation with expanded disability status scale (EDSS) progression per year (rs(24)= .57 p=.003). A Mann-Whitney test indicated that POMS patients who had infratentorial involvement in the initial MRI brain had higher EDSS (3.08 ± 1.99) than POMS who did not (1.07 ± 0.79) U=24 P =.013. IgG index had a significant and positive correlation with annual EDSS progression rate rs (8) = 0.8 p=.001. ConclusionEarly disease onset does not mean a higher relapse rate when including the full spectrum of POMS and longer follow-up duration. POMS patients relapsed more on the first-line DMT and escalation should be considered early. Infratentorial involvement in the initial magnetic resonance imaging (MRI) brain and high IgG index are potential predictors for aggressive disease course in POMS.

Fiber-Specific White Matter Alterations in Parkinson's Disease Patients with GBA Gene Mutations.

Patients with Parkinson's disease (PD) carrying GBA gene mutations (GBA-PD) have a more aggressive disease course than those with idiopathic PD (iPD). The objective of this study was to investigate fiber-specific white matter (WM) differences in nonmedicated patients with early-stage GBA-PD and iPD using fixel-based analysis, a novel technique to assess tract-specific WM microstructural and macrostructural features comprehensively. Fixel-based metrics, including microstructural fiber density (FD), macrostructural fiber-bundle cross section (FC), and a combination of FD and FC (FDC), were compared among 30 healthy control subjects, 16 patients with GBA-PD, and 35 patients with iPD. Associations between FDC and clinical evaluations were also explored using multiple linear regression analyses. Patients with GBA-PD showed significantly lower FD in the fornix and superior longitudinal fasciculus than healthy control subjects, and lower FC in the corticospinal tract (CST) and lower FDC in the CST, middle cerebellar peduncle, and striatal-thalamo-cortical pathways than patients with iPD. Contrarily, patients with iPD showed significantly higher FC and FDC in the CST and striatal-thalamo-cortical pathways than healthy control subjects. In addition, lower FDC in patients with GBA-PD was associated with reduced glucocerebrosidase enzyme activity, lower cerebrospinal fluid total α-synuclein levels, lower Montreal Cognitive Assessment scores, lower striatal binding ratio, and higher Unified Parkinson's Disease Rating Scale Part III scores. We report reduced fiber-specific WM density and bundle cross-sectional size in patients with GBA-PD, suggesting neurodegeneration linked to glucocerebrosidase deficiency, α-synuclein accumulation, and poorer cognition and motor functions. Conversely, patients with iPD showed increased fiber bundle size, likely because of WM reorganization. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.