Poor Treatment Response Research Articles

Refining the clinical and therapeutic spectrum of granulomatous myositis from a large cohort of patients.

Granulomatous myositis (GM) is a rare entity whose precise clinical features and therapeutic outcomes have not yet been well defined. Given the limited evidence, data from a large cohort of patients is needed to aid in the recognition and management of this condition. We retrospectively analyzed our institutional databases to identify patients who had myositis and non-caseating granuloma on muscle biopsy (GM). We collected data on clinical and diagnostic features, management, and outcomes of these cases and compared them with inclusion body myositis (IBM) controls. 22 GM patients were identified and subdivided into 3 main groups:13 patients with GM and sarcoidosis (6 of whom subsequently developed suspected or confirmed IBM), 7 patients with idiopathic isolated GM (2 of whom subsequently developed confirmed IBM), 2 patients with GM and Crohn's disease. Patients with GM and sarcoidosis without IBM, as well as patients with isolated GM, exhibited variable clinical presentation ranging from myalgia to mostly symmetrical proximo-distal weakness, with most showing complete or at least partial response to therapies. Patients with GM associated with Crohn's disease had only mild clinical impairment and good therapeutic outcomes. Conversely, patients with GM and IBM presented more severe asymmetric proximo-distal muscle weakness, increased occurrence of dysphagia and poor treatment response, similar to IBM controls. A frequent association of GM with IBM and/or sarcoidosis was demonstrated in our cohort. When associated with IBM, GM led to treatment refractoriness and more severe clinical impairment, unlike the other GM groups which showed satisfactory outcomes in most cases.

Clinical characteristics and prognosis of acute erythroleukemia in children

To investigate the clinical characteristics and prognosis of acute erythroleukemia (AEL) in children. A retrospective analysis was conducted on the clinical data, treatment, and prognosis of 8 children with AEL treated at the First Affiliated Hospital of Zhengzhou University from January 2013 to December 2023. Among the 7 patients with complete bone marrow morphological analysis, 4 exhibited trilineage dysplasia, with a 100% incidence of erythroid dysplasia (7/7), a 71% incidence of myeloid dysplasia (5/7), and a 57% incidence of megakaryocytic dysplasia (4/7). Immunophenotyping revealed that myeloid antigens were primarily expressed as CD13, CD33, CD117, CD38, and CD123, with 4 cases expressing erythroid antigens CD71 and 2 cases expressing CD235a. Chromosomal analysis indicated that 2 cases presented with abnormal karyotypes, including +8 in one case and +4 accompanied by +6 in another; no complex karyotypes were observed. Genetic abnormalities were detected in 4 cases, with fusion genes including one case each of dup MLL positive and EVI1 positive, as well as mutations involving KRAS, NRAS, WT1, and UBTF. Seven patients received chemotherapy, with 6 achieving remission after one course of treatment; 2 underwent hematopoietic stem cell transplantation, and all had disease-free survival. Follow-up (median follow-up time of 6 months) showed that only 3 patients survived (2 cases after hematopoietic stem cell transplantation and 1 case during treatment). Children with AEL have unique clinical and biological characteristics, exhibit poor treatment response, and have a poor prognosis; however, hematopoietic stem cell transplantation may improve overall survival rates.

Subclonal TP53 and KRAS variants combined with poor treatment response identify ultra-high-risk pediatric T-ALL patients.

Variations in the TP53 and KRAS genes indicate a particularly adverse prognosis in relapsed pediatric T-ALL. We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined two cohorts of children diagnosed with T-ALL: one with 81 patients who relapsed and 79 matched non-relapsing controls, and another with 226 consecutive patients, 30 of whom relapsed. In cohort 1, targeted sequencing revealed TP53 clonal and subclonal variants in 6 of 81 relapsing patients but none in the non-relapsing group (p=0.014). KRAS alterations were found in 9 of 81 relapsing patients compared to 2 of 79 non-relapsing patients (p=0.032). Survival analysis showed that none of the relapsed patients with TP53 and/or KRAS alterations survived, whereas 19 of 67 relapsed patients without such variants did with a minimum follow-up time of 3 years (p=0.023). In cohort 2, none of the relapsing patients but 10 of 196 non-relapsing patients carried TP53 or KRAS variants, indicating that mutation status alone does not predict poor prognosis. All ten non-relapsing patients with mutations had a favorable early treatment response. Among the total cohort of 386 patients, 188 showed poor treatment response of whom 69 relapsed. Nine of these poor responders harbored TP53 or KRAS variants. In conclusion, subclonal TP53 and KRAS alterations identified at the time of initial diagnosis, along with a poor treatment response, characterize a subset of children with T-ALL who face a dismal prognosis and may benefit from alternative treatment approaches.

Prediction of treatment efficacy in psoriasis vulgaris using dermoscopic and capillaroscopic findings: a prospective cohort study.

Psoriasis is a chronic inflammatory skin disorder affecting millions worldwide. Dermoscopy and proximal nailfold capillaroscopy have emerged as valuable tools for understanding the pathophysiology and treatment response of psoriasis lesions. This study aimed to contribute to the limited literature on using dermoscopic findings to detect treatment effectiveness in patients with psoriasis vulgaris. This prospective, single-blinded, observational cohort study included 101 patients aged 18-71 years diagnosed with psoriasis vulgaris who initiated or altered systemic treatment. Monthly dermoscopic and capillaroscopic evaluations were performed alongside assessments of Psoriasis Area Severity Index (PASI), Body Surface Area (BSA), and Dermatology Life Quality Index (DLQI) scores. A significant relationship was found between first-month dermoscopic findings and third-month severity scores (PASI, BSA, DLQI). Patients with positive treatment responses exhibited changes from baseline regular capillary dilations to hemorrhagic spots or the absence of vascular findings during the first month. The correlations between dermoscopic changes and severity scores evolved over time, becoming stronger in the second and third months. Nailfold capillaroscopy findings at the third month of treatment showed significant differences from baseline. Dermoscopy is a fast, practical, and inexpensive tool for early prediction of treatment effectiveness in psoriasis vulgaris. The disappearance of regular capillary dilations or their change to hemorrhagic spots suggests treatment efficacy, while their persistence indicates poor treatment response. Early detection of treatment effectiveness using dermoscopic findings can facilitate timely adjustments, improving patient outcomes and reducing unnecessary treatment exposure.

Depression and cardiovascular reactions to acute psychological stress: Is anhedonia the driver?

Blunted cardiovascular reactions in response to acute psychological stress are predictive of future health risk. A large body of research has identified depression as an influential factor associated with blunted cardiovascular reactivity. Separately, there has been a resurgence in focus on anhedonia as a key feature of depression, responsible for poor treatment responses to non-improvement in cardiac event-free survival. In a re-analysis of a previously published study that found depression to be associated with blunted systolic blood pressure (SBP) and heart rate responses (HR), we used cross-sectional network models to examine if anhedonia symptoms were key drivers of this observation. Healthy young adults (N=180) completed measures of depression symptoms (Hospital Anxiety and Depression Scale (HADS)) and had their blood pressure and heart rate monitored throughout a standardized stress testing protocol. Using network analysis, a Walktrap algorithm identified two clusters of depressive symptoms: anhedonia and non-anhedonia. These anhedonia symptoms of depression, but not the non-anhedonia symptoms, were associated with blunted SBP and HR reactivity, such that those scoring higher on HADS-D items capturing anhedonia displayed more blunted cardiovascular response profiles. Moreover, these findings were robust to adjustment for several covariates. This study adds greater clarity on the depression-cardiovascular reactivity to stress association, by demonstrating that anhedonia is a key driver of this observation.

S100A4 contributes to colorectal carcinoma aggressive behavior and to chemoradiotherapy resistance in locally advanced rectal carcinoma

To investigate the functional role of S100A4 in advanced colorectal carcinoma (Ad-CRC) and locally advanced rectal carcinoma (LAd-RC) receiving neoadjuvant chemoradiotherapy (NCRT). We analyzed histopathological and immunohistochemical sections from 150 patients with Ad-CRC and 177 LAd-RC patients treated with NCRT. S100A4 knockout (KO) HCT116 cells were also used. S100A4 expression was absent in normal mucosa but increased progressively from colorectal adenoma to carcinoma, suggesting that S100A4 regulation is an early event in colorectal carcinogenesis. In Ad-CRC, high S100A4 expression correlated with high tumor budding and nuclear β-catenin, deep invasion, lymph-vascular involvement, and unfavorable prognosis. In NCRT-treated LAd-RC, high S100A4 expression was associated with poor treatment response and short progression-free survival. S100A4 KO decreased the proliferation of HCT116 cells through activation of the p53/p21waf1 axis, and sensitized cells to adriamycin-induced apoptosis. Levels of the apoptotic marker, cleaved poly (ADP-ribose) polymerase 1, were significantly higher in samples with low S100A4 and wild type p53. Finally, we observed a direct interaction between S100A4 and p53. In conclusion, S100A4 expression engenders aggressive behavior in Ad-CRC through association with β-catenin-driven tumor buddings. S100A4 exerts anti-apoptotic and proliferative effects via inhibition of p53 in LAd-RC patients receiving NCRT, which leads to chemoradioresistance and poor prognosis.

Clinicopathologic Features of a Rare and Underrecognized Variant of Early-stage Primary Biliary Cholangitis With Ductopenia.

Primary biliary cholangitis (PBC) with early cholestasis and extensive bile duct loss but no significant fibrosis or cirrhosis is rare and underrecognized. We aimed to clarify the clinicopathology features and prognosis of these variants of patients with early-stage PBC with ductopenia. From January 2009 to January 2023, we retrospectively collected the laboratory and pathologic data of patients with early-stage PBC and recorded their liver-related events with a median follow-up of 4.5 years. Finally, a total of 141 patients with PBC in the early stage were included and divided into 2 groups: one with ductopenia (n = 36) and the other without ductopenia (n = 105). The median age of the participants was 50 years, with 90.8% being female. The ductopenia group exhibited significantly elevated alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin, total bile acid, and total cholesterol (CHOL). Conversely, they showed a reduced biochemical response to ursodeoxycholic acid according to the Paris II, Barcelona, and Rotterdam criteria. A relatively poorer prognosis was observed in patients with early-stage PBC with ductopenia but with no statistical difference (11.8% vs 4.9%, P = 0.352). Baseline total CHOL levels were identified as an independent factor for the presence of ductopenia in early-stage PBC (odds ratio = 1.771, 95% CI: 1.264-2.479, P = 0.001). In conclusion, ductopenia was a significant risk factor for worse biochemical profiles and poor treatment response in patients with early-stage PBC. High levels of total CHOL at baseline are associated with the presence of ductopenia in early-stage PBC.

Developmental gene expression in skull-base chordomas and chondrosarcomas.

Chordomas are malignant tumors of the axial spine and skull base, and they are notorious for their poor treatment response. Differentiating these tumors from comparatively less malignant chondrosarcomas is crucial for treatment and prognostication. Both tumor types differ in their developmental origin. Chordomas are considered to be derived from notochordal remnants and chondrosarcomas from mesenchymal cells. Here, we evaluated the differential expression of developmental transcription factors in these skull base tumors. Histopathologically-confirmed tumor biopsies were obtained from 12 chordoma and 7 chondrosarcoma patients. Following RNA extraction, samples were submitted to real-time quantitative PCR (RT-qPCR) for the evaluation of 32 evolutionary conserved genes that are known to associate with notochord, mesoderm, and axial spine development. Gene expression levels were normalized to housekeeping genes ACTB and RS27a. Fifteen genes were either exclusively expressed (n = 12) or overexpressed (n = 3; 2.21-4.43 fold increase) in chordoma, compared to chondrosarcoma. Brachyury and CD24 were highly and exclusively expressed in chordoma. Other novel genes exclusive to chordomas included chordin, HOXA5 and ACAN. Vice versa, ten genes were either exclusively expressed (n = 2) or overexpressed (n = 8; 0.01-0.66 fold increase) in chondrosarcoma, compared to chordoma. As chordoma patients demonstrate a worse prognosis compared to chondrosarcoma patients, the differential expression of chordin, HOXA5 and ACAN and CD24 could be relevant for the pathophysiology of chordomas and may have diagnostic and treatment value. Further study on role of these genes in tumorigenesis is therefore warranted.

Are Pediatric Cancer Patients a Risk Group for Vitamin D Deficiency? A Systematic Review.

Background: Vitamin D deficiency is increasingly recognized as a global health concern, with potential implications for cancer development and progression. This systematic review investigated the prevalence of vitamin D deficiency in pediatric cancer patients and its potential impact on clinical outcomes. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, Web of Science, and Cochrane Library, to identify the relevant studies published between 2009 and July 2024. Studies were included if they assessed vitamin D status in pediatric cancer patients and reported on the clinical outcomes. Data extraction and quality assessment were performed independently by two reviewers. Results: The review included 20 original articles encompassing a diverse pediatric population with various cancer types. A high prevalence of vitamin D deficiency was observed across the studies. Deficiency was associated with older age and lower socioeconomic status. Several studies reported associations between vitamin D deficiency and the increased risk of infection, poorer treatment response, and decreased survival. Conclusions: Vitamin D deficiency is highly prevalent in pediatric cancer patients and may negatively impact clinical outcomes. Routine screening for vitamin D deficiency and personalized supplementation strategies should be considered in this population. Further research is needed to establish optimal vitamin D management protocols and evaluate the long-term benefits of vitamin D repletion in pediatric oncology.

The THE RELATIONSHIP OF TUMOUR BUDDING AND TUMOUR INFILTRATING LYMPHOCYTES IN DIAGNOSTIC BREAST CORE BIOPSIES WITH PATHOLOGICAL RESPONSE IN RESECTION SPECIMENS

Background: Breast cancer, ranks as the second-leading global cancer-related cause of death. This article highlights prognostic significance of tumour budding and tumour infiltrating lymphocytes, emphasizing their roles in guiding treatments. Recent discoveries support their pivotal contribution in enhancing risk assessments and refining management strategies in breast cancer. Methods: A retrospective study of 80 in house at Shaukat Khanum Memorial Cancer Hospital diagnosed with invasive ductal carcinoma in the year 2014. Patients were categorized into two groups based on receptor status: Group 1 (ER/PR positive, Her2 negative, or ER/PR/Her2 positive) and Group 2 (Triple negative and ER/PR negative, Her2 positive). Each group had 40 cases. Pathologists evaluated tumour budding, tumour infiltrating lymphocytes, Nottingham Grading, and receptor status on core biopsies. Study aimed to determine the relationship of TB and TILs assessed on core biopsies on corresponding resection specimen in terms of pathological tumour stage and overall survival after therapy. Results: In Group I, TILs >50% correlated with lower pathological tumour stage, while <50% correlated with higher post- treatment tumour stage. In Group II, most had <50% TILs, but some responded well. Low TB-Status in Group I linked to higher rates of ypT0, while in Group II, high TB-Status corresponded with high PT stage, i.e., yPT1 suggesting prognostic value for TILs and TB in breast cancer response and staging. Conclusions: Study suggests that higher TILs percentages correlate with improved treatment response and survival in contrast to lower TILs. Similarly, lower TB-status is associated with complete treatment response (y PT0) and higher TB- status is directly related to poor treatment response and higher tumour stage.

Identification of a novel immunosenescence-related genes and integrative analyses in patients with psoriasis.

Immunosenescence, characterized by age-related changes in the immune system, may contribute to the onset and progression of psoriasis, a condition whose incidence increases with age and often requires intensified medication in older patients. This study utilized bioinformatics analyses to identify differentially expressed immunosenescence-related genes in psoriasis patients from the GEO database. Enrichment, correlation, and interaction network analyses were conducted to explore their involvement in immune and inflammation pathways. Machine learning models were employed to predict psoriasis onset and validated using external datasets. Patient stratification based on gene expression patterns assessed differential responses to biologic inhibitors targeting specific genes. Immunosenescence emerged as a significant factor in psoriasis pathogenesis, with genes such as BACH2 potentially influencing T cell activation and disease outcomes. Lower BACH2 expression levels were associated with poorer treatment responses in psoriasis patients. This study sheds light on immunosenescence-related mechanisms in psoriasis, suggesting BACH2 as a potential disease diagnosis biomarker. Further research into BACH2's role in psoriasis pathophysiology is warranted to advance tailored treatment strategies.

C5aR2 in Breast Cancer and Its Relationship with Clinicopathological Features.

To determine the relation between C5aR2 and clinicopathological parameters of breast cancer. Study Design: Observational study. Place and Duration of the Study: Department of Histopathology, PNS Shifa Hospital, Karachi, from January to June 2023. Methodology: One hundred and twenty-eight women, aged 24-90 years with histologically proven diagnosis of breast cancer, were included in the study. Immunohistochemistry (IHC) was performed to evaluate the C5aR2 expression by its percentage and intensity. The C5aR2 staining was observed in membranes and/or cytoplasm. The immunoreactive score (IRS) was obtained and its association was analysed with clinicopathological parameters of breast cancer. SPSS version 27 was used to analyse the data. Results: The C5aR2 expression was higher in tumour cells (90.6%) compared to stromal cells (53.1%), predominantly exhibiting cytoplasmic localisation. Higher C5aR2 expression was observed in older age groups, higher-grade tumours, and ER/PR/HER2 and HER2 positive tumours. Moreover, tumours with poor treatment response also showed increased C5aR2 expression compared to those with good treatment response. Although no significant association was identified between C5aR2 expression and Ki67, increased C5aR2 expression has been found in tumours with high cell proliferation rates. In this study, an association between tumour and stromal cell C5aR2 expression and age, grade, receptor status, proliferation rate,andpost-treatment response was identified. Breast cancer, C5aR2, Cancer associated fibroblasts, Immunohistochemistry, Ki67.

Changing epidemiology and treatment responses in autoimmune liver diseases: a 14-year retrospective analysis from a tertiary care center

AimThis study aimed to retrospectively evaluate the epidemiological and clinical characteristics of patients diagnosed with autoimmune liver diseases (AILDs) over a 14-year period in a tertiary center. Additionally, we assessed factors influencing treatment response and relapse, with a particular focus on the rising incidence rates and gender distribution trends.Materials and methodsA total of 120 patients diagnosed with autoimmune liver diseases between January 2005 and December 2018 were included in this single-center study. Demographic, clinical, and laboratory data were retrospectively analyzed. Treatment responses were evaluated based on established criteria for autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC).ResultsThe study revealed an increasing trend in AIH diagnoses, particularly among males, over across the two 7-year periods analyzed (2005–2011 vs 2012–2018). Despite standard treatment, a notable proportion of patients experienced treatment failure or relapse. Cirrhosis at diagnosis and delayed diagnosis were associated with poorer treatment responses. Furthermore, portal plasma cell infiltration on liver biopsy was significantly associated with relapse.Discussion and conclusionOur findings indicate an increasing prevalence of AIH, particularly among males, highlighting the need for early diagnosis and improved predictive markers for treatment response. The significant association between portal plasma cell infiltration and relapse warrants further investigation. Although limited by the study’s retrospective design and sample size, these results suggest that multicenter studies could provide valuable insights into the management of AILDs.

Switching from ligand to receptor anti-calcitonin gene-related peptide (CGRP) antibodies or vice versa in non-responders: A controlled cohort study.

Limited options exist for migraine prevention after stopping anti-calcitonin gene-related peptide monoclonal antibodies. A systematic review examining the benefits of switching between different classes (ligand vs. receptor monoclonal antibody) is essential, alongside well-designed real-world studies. In this cohort study 67 patients were included, who discontinued their first treatment with erenumab or fremanezumab. Patients (n = 31) switched to another monoclonal antibody class within 3 months, whilst those in the control group (n = 36) received standard care. Allocation to either group relied largely on the availability of alternative monoclonal antibody treatments, introducing pseudo-random allocation. Changes in monthly migraine days were compared between groups 3 months post-discontinuation of the first monoclonal antibody or initiation of a different monoclonal antibody class. A multivariate regression model was conducted that accounted for potential confounding factors. The groups were comparable at baseline and poor treatment response was the main reason for treatment discontinuation of the first monoclonal antibody. The switching cohort experienced a reduction of 3.9 monthly migraine days (95% confidence interval -6.4, -1.3, p = 0.004) compared with the control group. Transitioning to a different anti-calcitonin gene-related peptide monoclonal class yields reduction in monthly migraine days compared to returning to standard care for patients with inadequate initial treatment response.

Clonal Hematopoiesis in Chronic Thromboembolic Pulmonary Hypertension.

The cause of chronic thromboembolic pulmonary hypertension (CTEPH) remains largely unknown. Recently, clonal hematopoiesis (CH) has been reported to be associated with cardiovascular and thromboembolic diseases. Here, we investigated the prevalence and clinical impact of CH in patients with CTEPH. Whole-exome sequencing and deep-panel sequencing were performed in 214 patients with CTEPH. Clinical data before and after treatment were compared between patients with and without CH. RNA sequencing and serum analysis were performed to explore the pathogenesis that CH contributes to CTEPH. Among the enrolled patients, 20.1%, notably 44.4% who were 80 to 89 years old, had variants in CH-associated genes. In regard to clinical impact, B-type natriuretic peptide levels and home oxygen therapy rate were significantly higher, and 6-minute walk distance was significantly shorter after treatment in patients with CH than in those without CH. Moreover, novel clot reformation in the pulmonary artery despite the use of anticoagulants and additional angioplasty events after treatment completion were more frequent in patients with CH. RNA sequencing analysis revealed that blood coagulation and neutrophil extracellular trap formation pathways were enriched in patients with CH. Additionally, serum citrullinated histone H3 levels were higher in patients with CH than those without CH. These results were consistent in the subgroup of patients who did not have the history of hematological disorders. The findings in this study raise the possibility that CH will induce a more prothrombotic state through neutrophil activation and neutrophil extracellular trap formation, contributing to pathogenesis and poor treatment response in patients with CTEPH.

Sustained Endocytosis Inhibition via Locally-Injected Drug-Eluting Hydrogel Improves ADCC-Mediated Antibody Therapy in Colorectal Cancer.

The epidermal growth factor receptor (EGFR) is a validated therapeutic target for RAS/RAF wild-type colorectal cancer (CRC). However, monoclonal antibody-based anti-EGFR therapies such as cetuximab have limited effectiveness. Herein, it is identified that EGFR internalization is associated with poor treatment response and prognosis in patients with CRC, based on a retrospective analysis of patients treated with cetuximab. It is further demonstrated that the endocytosis inhibitor prochlorperazine (PCZ) can move EGFR, which is hidden inside the cell, to the cell surface to improve therapeutic antibody binding. Thus, a thermosensitive hydrogel co-loaded with cetuximab and PCZ (Gel@Cmab/PCZ) is constructed for sustained inhibition of endocytosis and effective cetuximab delivery. Peritumoral injection of Gel@Cmab/PCZ shows strong antitumor efficacy in subcutaneous and orthotopic CRC tumor models and completely abrogated liver metastasis when combined with chemotherapy. In a humanized patient-derived xenograft model, a single injection of Gel@Cmab/PCZ with one-third of theconventional cetuximab dose achieved 91% tumor growth inhibition, which promoted NK cell infiltration into tumor tissues and their antibody-dependent cell-mediated cytotoxicity effect. This study represents a novel strategy to boost the monoclonal antibody-mediated anti-tumor response in CRC.

From microbes to medicine: harnessing the power of the microbiome in esophageal cancer.

Esophageal cancer (EC) is a malignancy with a high incidence and poor prognosis, significantly influenced by dysbiosis in the esophageal, oral, and gut microbiota. This review provides an overview of the roles of microbiota dysbiosis in EC pathogenesis, emphasizing their impact on tumor progression, drug efficacy, biomarker discovery, and therapeutic interventions. Lifestyle factors like smoking, alcohol consumption, and betel nut use are major contributors to dysbiosis and EC development. Recent studies utilizing advanced sequencing have revealed complex interactions between microbiota dysbiosis and EC, with oral pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum promoting inflammation and suppressing immune responses, thereby driving carcinogenesis. Altered esophageal microbiota, characterized by reduced beneficial bacteria and increased pathogenic species, further exacerbate local inflammation and tumor growth. Gut microbiota dysbiosis also affects systemic immunity, influencing chemotherapy and immunotherapy efficacy, with certain bacteria enhancing or inhibiting treatment responses. Microbiota composition shows potential as a non-invasive biomarker for early detection, prognosis, and personalized therapy. Novel therapeutic strategies targeting the microbiota-such as probiotics, dietary modifications, and fecal microbiota transplantation-offer promising avenues to restore balance and improve treatment efficacy, potentially enhancing patient outcomes. Integrating microbiome-focused strategies into current therapeutic frameworks could improve EC management, reduce adverse effects, and enhance patient survival. These findings highlight the need for further research into microbiota-tumor interactions and microbial interventions to transform EC treatment and prevention, particularly in cases of late-stage diagnosis and poor treatment response.

CSIG-28. DISSECTING THE FUNCTIONAL IMPAIRMENT OF WILD-TYPE P53 IN HUMAN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common malignant brain tumor in adults and is characterized by heterogeneous nature, invasive potential, and poor treatment response. Work from The Cancer Genome Atlas (TCGA) identified the tumor suppressor gene TP53 as a GBM driver. In contrast to several cancers, only ~35% of GBM cases carry mutations in TP53. Work from our lab showed that TP53 mutations emerge as ‘late’ events during GBM growth. Therefore, we hypothesized that wild-type (wt) p53 function is impaired in GBM. We used the TCGA data of 591 GBM patients to compare the clinical and molecular characteristics of wt and mutant TP53 patients. Gene expression data were analyzed to compare the correlation of TP53 with the expression of key p53 regulators and identify differentially expressed regulators between our groups. Furthermore, we evaluated the expression of p53 and selected regulators in patient-derived cells (PDCs) and control lines with known TP53 status. Our results show that wt TP53 patients live less than mutant patients and both groups respond similarly to treatment. No differences in age, sex, race, TP53 levels, and MGMT methylation status were observed between the groups. Gene expression analyses revealed that MAPK8, a p53 activator, negatively correlates with TP53 in the wt group. Moreover, ~21% of p53 regulators are differentially expressed between wt and mutant patients. Among these, we selected SIRT3, a p53 repressor, for experimental validation. We verified the p53 genetic status of PDCs through western blot and confirmed Sirt3 expression in wt and mutant TP53 PDCs. By CRISPR-Cas9-based genomic editing, we are currently evaluating the impact of SIRT3 knockout in GBM-PDC and patient-derived xenografts. We expect that SIRT3 knockout will restore p53 function in the wt group. In conclusion, our results suggest that p53 function is impaired in wt patients and provide insights into mechanisms affecting its activity.

Anhedonia is associated with a specific depression profile and poor antidepressant response.

Anhedonic features within major depressive disorder (MDD) have been associated with worse course and outcome and may predict nonresponse to treatment. However, a detailed clinical profile of anhedonia in MDD is still lacking. One thousand two hundred ninety-four patients with MDD were selected from the cross-sectional European multicenter Group for the Study of Resistant Depression study. Anhedonia was assessed through the Montgomery-Åsberg Depression Rating Scale anhedonia item "inability to feel." Clinical and demographic features were then analyzed. The presence of anhedonia related to a distinct demographical (living alone) and clinical profile (thyroid diseases, diabetes, suicide risk, high number of previous depressive episodes, more severe MDD, and more frequent inpatient status). Furthermore, anhedonia was associated with nonresponse to treatment and treatment resistance, even after adjusting for confounding variables. Our findings support the role of anhedonia as a modulating feature of MDD, being associated with a more severe depression profile. Moreover, anhedonic features are independent predictors of poor treatment response.

Role of ABCC5 in cancer drug resistance and its potential as a therapeutic target.

Over 90% of treatment failures in cancer therapy can be attributed to multidrug resistance (MDR), which can develop intracellularly or through various routes. Numerous pathways contribute to treatment resistance in cancer, but one of the most significant pathways is intracellular drug efflux and reduced drug concentrations within cells, which are controlled by overexpressed drug efflux pumps. As a member of the family of ABC transporter proteins, ABCC5 (ATP Binding Cassette Subfamily C Member 5) reduces the intracellular concentration of a drug and its subsequent effectiveness using an ATP-dependent method to pump the drug out of the cell. Numerous studies have demonstrated that ABCC5 is strongly linked to both poor prognosis and poor treatment response. In addition, elevated ABCC5 expression is noted in a wide variety of malignancies. Given that ABCC5 is regulated by several pathways in a broad range of cancer types, it is a prospective target for cancer treatment. This review examined the expression, structure, function, and role of ABCC5 in various cancer types.