Prognosis Of Patients Research Articles

Intracellular C5aR1 inhibits ferroptosis in glioblastoma through METTL3-dependent m6A methylation of GPX4

Glioblastoma (GBM) is the most common primary intracranial malignant tumor. Recent literature suggests that induction of programmed death has become a mainstream cancer treatment strategy, with ferroptosis being the most widely studied mode. Complement C5a receptor 1 (C5aR1) is associated with both tumorigenesis and tumor-related immunity. However, knowledge regarding the role of C5aR1 in GBM progression is limited. In the present study, we observed significant upregulation of C5aR1 in glioma tissue. In addition, C5aR1 expression was found to be closely associated with patient prognosis and survival. Subsequent experimental verification demonstrated that C5aR1 promoted the progression of GBM mainly by suppressing ferroptosis induction, inhibiting the accumulation of lipid peroxides, and stabilizing the expression of the core antiferroptotic factor glutathione peroxidase 4 (GPX4). Aberrant N6-methyladenosine (m6A) modification of GPX4 mRNA contributes significantly to epigenetic tumorigenesis, and here, we report that selective methyltransferase-like 3 (METTL3)-dependent m6A methylation of GPX4 plays a key role in C5AR1 knockdown-induced ferroptosis induction. Mechanistically, ERK1/2 signaling pathway activation increases the METTL3 protein abundance in GBM cells. This activation then increases the stability of METTL3-mediated m6A modifications on GPX4, enabling it to fulfill its transcriptional function. More importantly, in an intracranial xenograft mouse model, PMX205, a C5aR1 inhibitor, promoted alterations in ferroptosis in GBM cells and inhibited GBM progression. In conclusion, our findings suggest that C5aR1 inhibits ferroptosis in GBM cells and promotes MettL3-dependent GPX4 expression through ERK1/2, thereby promoting glioma progression. Our study reveals a novel mechanism by which the intracellular complement receptor C5aR1 suppresses ferroptosis induction and promotes GBM progression. These findings may facilitate the identification of a potential therapeutic target for glioma.

8523 An Unconventional Estrogen Receptor Conformation Induces SUMO Expression In Breast Cancer Cells

Abstract Disclosure: G.R. Hancock: None. K. Young: None. G.L. Greene: None. S.W. Fanning: None. An Unconventional Estrogen Receptor Conformation Induces SUMO Expression in Breast Cancer Cells Govinda Hancock, Kristen Young, Geoffrey L. Greene, Sean W. Fanning Competitive allosteric regulators, selective estrogen receptor modulators (SERMs)/degraders (SERDs) differentially manipulate receptor structure to treat and prevent metastatic breast cancers. However, their utility is limited by the ∼40% rate of disease progression due to acquired therapy resistance. In this study, a new SERM based on a tetrahydro-6-isoquinoline (T6I) scaffold reveals the relationship between ERα conformation and therapeutic transcriptional pathways in drug-resistant breast cancers. Optimization of structure-activity relationships produced unique lead compound that engages transcriptional programs similar to the clinically approved SERD fulvestrant. Notably, both drugs induce the expression of small ubiquitin-like modifier-1 (SUMO1), in opposition to the pathogenic hormone 17β-estradiol. SUMOylation is a post-translational modification affecting protein-protein interactions, localization, stability and functional properties. High expression of SUMO1 is associated with better patient prognosis in ERα+ disease. SUMOylation in breast cancer will be elucidated through understanding how it’s induced, its structural basis, and its role in therapeutic response of antiestrogen treatments. Presentation: 6/3/2024

The seven-day cumulative post-esophagectomy inflammatory response predicts cancer recurrence

BackgroundThe relationship between postoperative cumulative systemic inflammation and cancer survival needs to be investigated. We developed an approach to the prognostication of postoperative esophageal cancer by establishing low and high cut-off values for the C-reactive protein (CRP) area under the curve (AUC) at 7 and 14 days after esophagectomy.MethodsOne hundred and twenty-five consecutive patients with biopsy-proven invasive esophageal squamous cell carcinoma (SCC) who underwent esophagectomies were evaluated. Postoperative CRP levels were analyzed for the first 14 days after surgery. The AUC on days 7 and 14 were calculated and compared with clinicopathological features and survival. The cut-off values for CRP at 7 days (CRP 7 d) and 14 days (CRP 14 d) were 599 mg/L and 1153 mg/L, respectively.ResultsThe patients in the low CRP 7 d group had significantly better recurrence-free survival (RFS) and overall survival (OS), not that in the low CRP 14d group. The OS rates in the high CRP groups at PODs 1, 3, 10, and 14 were significantly lower than those in the low CRP groups. Postoperative complications were more common in the high CRP groups on PODs 3, 10, and 14. Univariate analyses revealed that pTNM stage, depth of tumor invasion, tumor location, lymph node involvement, and CRP 7 d were significant prognostic factors for both OS and RFS. The Cox proportional hazards model identified pTNM, tumor location, and CRP 7d as independent prognostic factors for the RFS and OS.ConclusionsEarly prediction of patients with postoperative complications, and adequate management will suppress the elevation of CRP 7 d and further suppress the CRP value in the late postoperative period, which may improve the prognosis of esophageal cancer patients after esophagectomy.

8213 A Splicing Modulator Inhibits Proliferation and Steroid Production of H295R Adrenocortical Cancer Cells

Abstract Disclosure: T. Tanaka: None. K. Ohe: None. T. Yanase: None. S. Kodama: None. Adrenocortical carcinoma (ACC) is a rare cancer, and treatment options are limited. The anti-tumor drug CX-4945 (Silmitasertib) is an inhibitor of Casein kinase 2 (CK2). It also inhibits cdc2-like kinase 2 (CLK2). CLK2 phosphorylates Serine/arginine rich splicing factors (SRSFs)/SR proteins and enhances exonic splicing enhancer (ESE) recognition during the pre-RNA splicing process. Anti-tumor agents targeting RNA splicing have been developed recently, and CLK inhibitors have shown anti-tumor effects against blood cancers. In this study, we analyzed the impact of CX-4945 on NCI-H295R cells. CX-4945 inhibited cell proliferation of H295R (IC50 = 6.4 µM, 72hr), and cortisol and aldosterone secretion in vitro. siRNA-induced CK2 inhibition did not alter H295R proliferation and steroid secretion. CX-4945 (150 mg/kg/day oral, 28 days) significantly reduced tumor weight in mice inoculated with H295R subcutaneously on the back. High-density microarray analysis showed reduced Nuclear receptor 5A1 (NR5A1) expression levels, indicating a possible splicing variant. RT-PCR, using a primer set that amplified the coding region, detected short variants of NR5A that were multiple exon-skipped and were not induced by suppression of CK2. The results of western blotting using an antibody that recognizes phospho-epitope of SRSFs/SR proteins showed that the phosphorylation of SRSF4 was reduced in H295R treated with CX-4945. These results suggest that CX-4945 inhibits CLK2 and decreases phosphorylated SRSF4 and ESE recognition, resulting in NR5A1 multiple exon-skipping. The prognosis of ACC patients with high NR5A1 expression levels is poor, independent of stage. CX-4945 may induce NR5A1 multiple exon-skipping, reduce full-length functional NR5A1, and suppress ACC growth and steroidogenesis, as a possible adjuvant in tackling this devastating cancer. Presentation: 6/1/2024

7615 Genomic Consequences of GRHL2 Overexpression in ER+ Breast Cancer Cells

Abstract Disclosure: K.O. Allen: None. C. Zheng: None. N. Solodin: None. M.S. Ozers: Owner/Co-Owner; Self; Proteovista, LLC. C.L. Warren: None. P.E. Messa: None. D.T. Vogt: None. E.T. Alarid: None. Breast cancer progression is characterized by the presence and prevalence of metastatic disease. At a genomic level, metastasis can be facilitated via rearrangement of the chromatin landscape to expose oncogenic genes for transcription. Grainyhead like protein 2 (GRHL2) is a nuclear transcription factor implicated in epithelial cell differentiation. The GRHL2 motif has been found near activated estrogen receptor (ER) binding sites, and elevated levels of GRHL2 have been linked to worse prognosis in hormone receptor positive breast cancer patients. In its capacity to contribute to a more severe disease state when overexpressed, GRHL2 may function as either a transcription or pioneer factor to aid in the expression of metastasis-associated genes. Our lab previously showed that GRHL2 genomic binding precedes ER binding at co-regulated binding sites. Also, overexpression of GRHL2 in MCF7 cells for 24 hours did not appreciably alter gene expression by RNA-Seq. These data taken together indicate that GRHL2 may be exhibiting pioneer factor activity. However, the specific role of GRHL2 overexpression in hormone positive breast cancer progression remains unknown. In order to examine the mechanism of GRHL2 action, GRHL2 genomic binding was investigated using a tetracycline-inducible MCF7 model that allows controlled overexpression of GRHL2. ChIP studies were performed to determine GRHL2 binding intensity at specific and genome wide GRHL2 binding sites. Specific focus was given to established GRHL2 binding sites near oncogenic genes responsible for epithelial to mesenchymal transition (EMT), dormancy, and proto-oncogenic behavior. A similar analysis examined H3K27 acetylation to validate active gene transcription. An orthogonal technology, Specificity and Affinity for Protein (SNAP) microarrays, which characterizes direct GRHL2 binding to tiled genomic regions identified in ChIP-Seq analyses from multiple labs, was utilized to discriminate direct and indirect GRHL2 binding sites. The requirement for GRHL2 transactivation function in regulation of EMT related genes was further interrogated using transactivation GRHL2 dominant negative mutants. This work aims to distinguish the transcriptional and non-transcriptional activities of GRHL2 in breast cancer cells on a genome wide level and thereby, provide a deeper understanding of how overexpressed GRHL2 contributes to hormone positive breast cancer. Presentation: 6/3/2024

Developing a prognostic model for hepatocellular carcinoma based on MED19 and clinical stage and determining MED19 as a therapeutic target

BackgroudMediator complex subunit 19 (MED19), a member of the mediator complex, has been demonstrated to involve in tumorigenesis of hepatocellular carcinoma (HCC). However, the regulation mechanisms of MED19, the immune landscape linking MED19 to HCC and its predictive value of immunotherapy treatment in HCC are so far unknown.MethodsHere, we analyzed data from The Cancer Genome Atlas and other databases to assess the expression of MED19 and its prognosis and therapeutical-targets impact in HCC.ResultsMED19 expression was upregulated in HCC tissues compared to non-tumorous liver tissues and that its upregulation was positively associated with advanced clinicopathology features. The multivariate analysis showed that MED19 was an independent predictor of outcome in HCC. In vitro experiments revealed that MED19 knockdown suppressed hepG2 cells proliferation, colony forming and invasion and induced apoptosis. Furthermore, MED19 inhibition resulted in G0/G1 phase arrest in hepG2 cells. We screened differentially expressed genes between low and high MED19 expression groups. Enrichment analyses showed that these genes were mainly linked to nuclear division and cell cycle. The pattern of tumor-infiltrating immune was demonstrated to be related with MED19 expression in HCC. TIDE analyses showed that patients in the low-expression group presented significantly better immunotherapy. Moreover, we developed a predicted model for HCC patient’s prognosis. Receiver operating characteristic analyses revealed that this model processed a favorable performance in predicting the prognosis of HCC patients. Finally, a nomogram was built for predicting survival probability of individual HCC patient.ConclusionThese findings suggest that MED19 as a novel biomarker that has significant association with immune landscape and immunotherapy response in HCC. The proposed prediction model composed of MED19 and pathological stage has a better role in determining prognosis and stratifying of HCC.

The clinical application of metagenomic next-generation sequencing in immunocompromised patients with severe respiratory infections in the ICU.

Early targeted antibiotic therapy is crucial for improving the prognosis of immunocompromised patients with severe respiratory infections (SRIs) in the intensive care unit (ICU). Metagenomic next-generation sequencing (mNGS) has shown significant value in pathogen detection, but research on lower respiratory tract microorganisms remains limited. This study enrolled 234 patients with SRIs in the ICU, and individuals were categorized into immunocompromised and immunocompetent groups. We compared the diagnostic performance of mNGS using bronchoalveolar lavage fluid (BALF) with conventional microbiological tests (CMTs) and analyzed the value of mNGS in immunocompromised patients with SRIs in the ICU. Among all patients, the pathogenic microorganism detection rate of mNGS was higher than that of CMTs (94.02% vs 66.67%, P < 0.05), both in the immunocompromised group (95.0% vs 58.75%, P < 0.05) and the immunocompetent group (93.51% vs 71.43%, P < 0.05). mNGS detected more pathogens than CMTs did (167 vs 51), identifying 116 organisms that were missed by CMTs. The proportion of antibiotic regimen adjustments based on mNGS results was significantly higher compared to CMTs in both the immunocompromised (70.00% vs 17.50%, P < 0.05) and immunocompetent groups (48.70% vs 15.58%, P < 0.05). In the immunocompromised group, patients who had their antibiotic treatment adjusted on mNGS results had improved prognosis, with significantly lower ICU mortality (8.93% vs 50%, P < 0.05) and 28-day mortality rates (30.36% vs 68.75%, P < 0.05) than CMTs. In the immunocompetent group, no statistically significant differences were observed in ICU mortality or 28-day mortality (20.00% vs 33.33%, P > 0.05; 42.67% vs 45.83%, P > 0.05). mNGS shows significant value in detecting pathogens in immunocompromised patients with SRIs in ICU. For immunocompromised patients who respond poorly to empirical treatment, mNGS can provide an etiological basis, helping adjust antibiotic regimens more precisely and thereby improving patient prognosis.

Interpretable machine learning model for predicting the prognosis of antibody positive autoimmune encephalitis patients

ObjectiveThe objective was to utilize nine machine learning (ML) methods to predict the prognosis of antibody positive autoimmune encephalitis (AE) patients. MethodsThe encephalitis data from the Global Burden of Disease (GBD) study is analyzed to reflect the disease burden of encephalitis. This study included 187 patients with AE. 121 patients as training set and 67 patients as validation set. Decision trees (DT), random forest (RF), extreme gradient boosting (XGBoost), k-nearest neighbor (KNN), support vector machine (SVM), naive bayes (NB), neural network (NN), light gradient boosting machine (LGBM), and logistic regression (LR) are ML methods used to construct predictive models. The constructed models were validated for discrimination, calibration and clinical applicability using validation set data. Shapley additive explanation (SHAP) analysis was used to explain the model. ResultsThe number of encephalitis worldwide deaths, incidence and prevalence is increasing every year from 2010 to 2021. The training set included 121 patients with AE. Univariate analysis and LASSO screening identified six variables. The results of constructing models using 9 ML methods showed RF had the highest accuracy (0.860), followed by XGBoost (0.826), with F1 scores of 0.844 and 0.807, respectively. Validation set data showed good discrimination, calibration and clinical applicability of the model. The SHAP values of infection, CSF monocyte percentage, and prealbumin were 0.906, 0.790, and 0.644, respectively. LimitationsAs a rare disease, the sample size of this study is relatively small. ConclusionThe model constructed using RF and XGBoost has good performance, good discrimination, calibration, clinical applicability, and interpretability.

8213 A Splicing Modulator Inhibits Proliferation And Steroid Production Of H295R Adrenocortical Cancer Cells

Abstract Disclosure: T. Tanaka: None. K. Ohe: None. T. Yanase: None. S. Kodama: None. Adrenocortical carcinoma (ACC) is a rare cancer, and treatment options are limited. The anti-tumor drug CX-4945 (Silmitasertib) is an inhibitor of Casein kinase 2 (CK2). It also inhibits cdc2-like kinase 2 (CLK2). CLK2 phosphorylates Serine/arginine rich splicing factors (SRSFs)/SR proteins and enhances exonic splicing enhancer (ESE) recognition during the pre-RNA splicing process. Anti-tumor agents targeting RNA splicing have been developed recently, and CLK inhibitors have shown anti-tumor effects against blood cancers. In this study, we analyzed the impact of CX-4945 on NCI-H295R cells. CX-4945 inhibited cell proliferation of H295R (IC50 = 6.4 µM, 72hr), and cortisol and aldosterone secretion in vitro. siRNA-induced CK2 inhibition did not alter H295R proliferation and steroid secretion. CX-4945 (150 mg/kg/day oral, 28 days) significantly reduced tumor weight in mice inoculated with H295R subcutaneously on the back. High-density microarray analysis showed reduced Nuclear receptor 5A1 (NR5A1) expression levels, indicating a possible splicing variant. RT-PCR, using a primer set that amplified the coding region, detected short variants of NR5A that were multiple exon-skipped and were not induced by suppression of CK2. The results of western blotting using an antibody that recognizes phospho-epitope of SRSFs/SR proteins showed that the phosphorylation of SRSF4 was reduced in H295R treated with CX-4945. These results suggest that CX-4945 inhibits CLK2 and decreases phosphorylated SRSF4 and ESE recognition, resulting in NR5A1 multiple exon-skipping. The prognosis of ACC patients with high NR5A1 expression levels is poor, independent of stage. CX-4945 may induce NR5A1 multiple exon-skipping, reduce full-length functional NR5A1, and suppress ACC growth and steroidogenesis, as a possible adjuvant in tackling this devastating cancer. Presentation: 6/1/2024

Role of Imaging in Screening for Hepatocellular Carcinoma

Primary liver cancer is among the most common cancers globally. It is the sixth-most common malignancy encountered and the third-most common cause of cancer-related death. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, accounting for about 90% of primary liver cancers. The majority of HCCs occur in patients with underlying cirrhosis, which results from chronic liver diseases such as fatty liver, hepatitis B and hepatitis C infections, and chronic alcohol use, which are the leading causes. The obesity pandemic has led to an increased prevalence of nonalcoholic fatty liver disease (NAFLD), which leads to nonalcoholic steatohepatitis and could progress to cirrhosis. As HCC is among the most common cancers and occurs in the setting of chronic liver disease in most patients, screening the population at risk could help in early diagnosis and management, leading to improved survival. Screening for HCC is performed using biochemical marker testing such as α-fetoprotein (AFP) and cross-sectional imaging. It is critical to emphasize that HCC could potentially occur in patients without cirrhosis (non-cirrhotic HCC), which can account for almost 20% of all HCCs. The lack of cirrhosis can cause a delay in surveillance, which could potentially lead to diagnosis at a later stage, worsening the prognosis for such patients. In this article, we discuss the diagnosis of cirrhosis in at-risk populations with details on the different modalities available for screening HCC in patients with cirrhosis, emphasizing the role of abdominal ultrasounds, the primary imaging modality in HCC screening.

Multiregional transcriptomic profiling provides improved prognostic insight in localized non-small cell lung cancer

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with survival) across different regions within a tumor were more prognostic than the average expression. Following that, we examined whether multiregional expression profiling can improve the performance of prognostic signatures. We investigated 11 gene signatures collected from previous publications and one signature developed in this study. For all of them, the prognostic prediction accuracy can be significantly improved by converting the regional expression of signature genes into sample-specific expression with a simple function—taking the maximal expression of hazardous genes and the minimal expression of protective genes. In the tumor microenvironment, we found a similar rule also seems applicable to immune ITH. We calculated the infiltration levels of major immune cell types in each region of a sample based on expression deconvolution. Prognostic analysis indicated that the region with the lowest infiltration level of protective or highest infiltration level of hazardous immune cells determined the prognosis of NSCLC patients. Our study highlighted the impact of RNA-ITH on the prognostication of NSCLC, which should be taken into consideration to optimize the design and application of expression-based prognostic biomarkers and models. Multiregional assays have the great potential to significantly improve their applications to prognostic stratification.

7775 Clinical Features of NKX2-1 Gene-Related Diseases

Abstract Disclosure: S. Fukui: None. E. Tanimoto: None. N. Ujita: None. H. Miyagi: None. K. Yoshii: None. N. Yasuhiro: None. R. Horikawa: None. Background: Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. The utilization of molecular genetic techniques has facilitated the detection of CH resulting from various single-gene mutations; NKX2-1 gene-related disease stands out as one etiology of symptomatic CH. We report the clinical course of three cases with CH caused by NKX2-1 pathogenic variants. Case 1: An 8-year-old boy. He was born at 40 weeks and six days of gestation, weighing 2845g, and was presented to our department by high TSH (76.1 µIU/mL) at newborn screening (NBS), and LT4 treatment was initiated. He showed motor developmental delay, and choreiform movements were exhibited at two years and 11 months without respiratory symptoms. Case 2: An 18-year-old female. She was born at 40 weeks and five days gestation, weighing 2680g, and was admitted to her previous hospital following poor weight gain at approximately six months. During hospitalization, she was initiated LT4 treatment with a TSH elevation(14.7μIU/mL). After receiving a diagnosis of idiopathic interstitial pneumonia, she was subsequently referred to our hospital. At the age of 11, an NKX2-1 mutation was identified. Case 3: An 18-year-old female. She was born at 41 weeks and three days of gestation, weighing 2364g.TSH elevation (27.9 µIU/ml) was detected at NBS, and LT4 treatment was started. Thyroid hormone levels were maintained within normal range. However, wheezing and tracheomalacia were noted around five months. Hypotonia and delayed motor development were evident, and an NKX2-1 mutation was identified at the age of 12 years. Discussion: Although NKX2-1 gene-related disorders can be readily suspected when typical symptoms of central nervous system, pulmonary, and thyroid dysfunction manifest concurrently, diagnosis is sometimes established later because of the diversity of the occurrence of these symptoms. Despite reports of choreiform movements being inevitable, they did not appear in Case 2.3 until the age of 18 years. Conversely, muscle hypotonia and delayed motor development were observed in all our cases. When atypical neurological symptoms combined with CH are observed, NKX2-1 gene-related disease should be considered since the disease is known to develop malignant tumors such as lung cancer and thyroid cancer, which can significantly affect the prognosis of patients. Conclusion: When muscle hypotonia and delayed motor development are observed in addition to hypothyroidism and respiratory symptoms, NKX2-1 gene-related disease should be suspected, and follow-up for complications, including malignancy, is essential after diagnosis. Presentation: 6/2/2024

8812 Incidence And Clinical Experience Of Immune Checkpoint Inhibitors-Induced Endocrine Side Effects Among Filipino Cancer Patients: A Single-Center Retrospective Study

Abstract Disclosure: N.B. Luna: None. E. Mendoza: None. S.A. Kho: None. Incidence And Clinical Experience Of Immune Checkpoint Inhibitors-Induced Endocrine Side Effects Among Filipino Cancer Patients: A Single-Center, Retrospective Study Immune checkpoint inhibitors (ICIs) serve as immunomodulatory antibodies, which enhance the immune system and substantially improve the prognosis for patients with advanced malignancies [1]. Referral to endocrinology have been increasing because ICIs were associated with endocrine-related adverse effects including hypothyroidism, hyperthyroidism, diabetes, hypophysitis and adrenalitis. Hence, the study aimed to retrospectively determine the local prevalence and profile of Filipino patients who developed endocrinopathies during ICI therapy at the University of Santo Tomas Hospital (USTH), Manila, Philippines from 2013-2019. A single-center retrospective study of ICI-treated cancer patients with serial biochemical and/or radiologic monitoring of endocrine adverse effects was done upon approval by the Research Ethics Committee. A total of 27 subjects were included with a median age of 60 years and male predominance. Pembrolizumab consisted 93% of the ICIs given. The incidence of thyroid dysfunction was 36% (18% overt hypothyroidism, 9% subclinical hypothyroidism, and 9% subclinical hyperthyroidism). The median time at risk for development of overt hypothyroidism is 4 weeks with median TSH level of 9.05 uIU/mL from baseline level of 3.77 uIU/mL. All patients who had baseline hypothyroidism worsened with increase from baseline levothyroxine dose by 50 to 230% in order to achieve euthyroidism (p 0.037). Serial monitoring was done every 2 weeks until euthyroidism. ICIs were temporarily put on hold in 75%. Diabetes (p 0.05), renal carcinoma (p 0.001) and dose of 200mg (p 0.42) were associated to developing overt hypothyroidism. Checking of glycemic levels was not routine among non-diabetic patients. Fifteen percent of diabetic patients had worsening of control (median HbA1c 8.5% [8-9] and 23% were newly diagnosed pre-diabetes (median fasting glucose 114mg/dL [104-120]). With the available imaging results, there were no abnormal adrenal metabolic uptake on PET scan and no evidence of hypophysitis in pituitary MRI. In conclusion, overt hypothyroidism is a common occurrence during ICI therapy (18%). Worsening occurred among all patients with hypothyroidism at baseline. New-onset pre-diabetes and worsening of glycemic control were seen in 15 and 23%, respectively. Serial clinical and biochemical monitoring is important and referral to endocrinology should be made if deemed necessary. [1] L Agrawal, A Bacal, S Jain, V Singh, N Emanuele, Ma Emanuele &amp; F Meah (2020) Immune checkpoint inhibitors and endocrine side effects, a narrative review, Postgraduate Medicine, 132:2, 206-214, DOI: 10.1080/00325481. 2019. 1709344 Presentation: 6/1/2024

Clinical outcomes in peritoneal dialysis with refractory peritonitis: significance of the day 5 cell count.

Peritoneal dialysis-associated peritonitis is a common and severe complication of peritoneal dialysis, associated with high morbidity and mortality. However, there's a lack of research on refractory peritonitis, which is difficult to manage and has a poor prognosis. Our study aimed to investigate factors affecting clinical outcomes in peritoneal dialysis patients with refractory peritonitis over a 12-year period at a medical faculty hospital in Turkey. We conducted a retrospective study at a single center from January 2009 to December 2020, involving 135 patients with 236 episodes of refractory peritonitis. The average age of the patient cohort was 53.0 ± 15.9years, and 72 (53.4%) of the patients were male. The leading identified causes of end-stage kidney disease were glomerulonephritis, hypertensive glomerulosclerosis, and diabetic nephropathy. Data on microbiological etiology, dialysate white blood cell counts, and patient demographics were analyzed to identify catheter removal risk factors. Statistical significance was set at p ≤ 0.05. Comparative analysis between patients with and without catheter loss revealed no significant differences in gender, age, presence of diabetes, prior hemodialysis, or duration of peritoneal dialysis. However, multivariate logistic regression analysis showed thata dialysate white blood cell count exceeding 1000/mm3 on day 5and hospitalization had a positive associationwith catheter loss, while the presence of gram-positive bacterial growth had an inverse correlation. Our study shows that fifth-day dialysate white blood cell count predicts refractory peritonitis outcomes. Future research should focus on developing tools to manage catheter removal proactively and enhance patient prognosis.

Synergistic effect of concurrent high molecular risk mutations and lower JAK2 mutant variant allele frequencies on prognosis in patients with myelofibrosis-insights from a multicenter study.

In addition to high-molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH, and U2AF1Q157), lower JAK2V617F variant allele frequencies (VAF) have been demonstrated to be associated with poor prognosis of myelofibrosis (MF) patients. Nevertheless, the relationship between JAK2V617F VAF and HMR mutations remains inconclusive. To address this, we analyzed the mutation status of 54 myeloid neoplasm-relevant genes using targeted next-generation sequencing in 124 MF patients. Three cohorts from multiple international centers were analyzed for external validation. Among JAK2-mutated patients, the presence of HMR mutations drove poor prognosis in patients with lower JAK2V617F VAF but not in those with higher JAK2V617F VAF. Survival analyses showed consistent results across validation cohorts. In multivariable analysis, concurrent HMR and a lower JAK2V617F VAF was identified as an independent adverse prognostic factor for survival, irrespective of age, MIPSS70, MIPSS70 + v2, and GIPSS risk groups. Mutation co-occurrence tests revealed no shared mutational pattern over different cohorts, excluding potential confounding effect from other concurrent mutations. Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics.

Development of biomarker signatures associated with anoikis to predict prognosis in patients with esophageal cancer: An observational study

Anoikis, a form of programmed cell death linked to cancer, has garnered significant research attention. Esophageal cancer (ESCA) ranks among the most prevalent malignant tumors and represents a major global health concern. To ascertain whether anoikis-related genes (ARGs) can accurately predict ESCA prognosis, we evaluated the predictive value and molecular mechanisms of ARGs in ESCA and constructed an optimal model for prognostic prediction. Using the Cancer Genome Atlas (TCGA)-ESCA database, we identified ARGs with differences in ESCA. ARG signatures were generated using Cox regression. A predictive nomogram model was developed to forecast ARG signatures and patient outcomes in ESCA. Gene set enrichment analysis (GSEA) was employed to uncover potential biological pathways associated with ARG signatures. Estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) and cell-type identification by estimating relative subsets of RNA transcripts analyses were used to assess differences in the immune microenvironment of the ARG signature model. Based on ARGs, the patients with ESCA were divided into high and low groups, and the sensitivity of patients to drugs in the database of genomics of drug sensitivity in cancer was analyzed. Finally, the correlation between drug sensitivity and risk score was then evaluated based on the ARG signatures. Prognostic relevance was significantly linked to the ARG profiles of 5 genes: MYB binding protein 1a (MYBBP1A), plasminogen activator, urokinase (PLAU), budding uninhibited by benzimidazoles 3, HOX transcript antisense RNA, and euchromatic histone-lysine methyltransferase 2 (EHMT2). Using the risk score as an independent prognostic factor combined with clinicopathological features, the nomogram accurately predicted the overall survival (OS) of individual patients with ESCA. Gene ontology (GO) enrichment analysis indicated that the primary molecular roles included histone methyltransferase function, binding to C2H2 zinc finger domains, and histone-lysine N-methyltransferase activity. GSEA revealed that the high-risk cohort was connected to cytokine-cytokine receptor interaction, graft-versus-host disease, and hematopoietic cell lineage, whereas the low-risk cohort was related to arachidonic acid metabolism, drug metabolism via cytochrome P450 and fatty acid metabolism. Drug sensitivity tests showed that 16 drugs were positively correlated, and 3 drugs were negatively correlated with ARG characteristic scores. Our study developed 5 ARG signatures as biomarkers for patients with ESCA, providing an important reference for the individualized treatment of this disease.

Effect of Preoperative Geriatric Nutritional Risk Index on Prognosis in Patients after Surgery for Lower Gastrointestinal Perforation.

Geriatric Nutritional Risk Index (GNRI) is a reliable index derived from serum al-bumin levels, height, and weight. Although various prognostic factors have been studied, the effect of preoperative nutritional status on surgical outcomes remains unexplored. This study aimed to evaluate the efficacy of the GNRI in predicting postoperative outcomes of lower gastro-intestinal perforation. Eighty patients treated at our institution between January 2016 and December 2022 were retrospectively analyzed. This study primarily focused on the correlation between pre-operative GNRI and two key outcomes: postoperative hospital stay duration and 1-year mortality rate. Our findings revealed a significant association between low GNRI scores and increased 1-year mortality (Odd ratio 4.0, 95% confidence interval [CI] 1.1-16, p=0.025). Kaplan-Meier analysis and log-rank test showed that patients in the low GNRI group had markedly poorer overall survival rates than those in the high GNRI group (12-month survival rate 0.88 [95%CI: 0.75-0.95] vs. 0.65 [95%CI: 0.47-0.78]; p=0.018). Additionally, both univariate and multivariate analyses indicated that lower GNRI scores were associated with prolonged hospital stays. We showed that a low GNRI score was associated with high mortality and pro-longed hospital stay after emergency surgery for lower gastrointestinal perforation.

Persistent acute kidney injury: Postoperative impact and predictors in patients undergoing liver resection.

Persistent acute kidney injury (AKI) has not been investigated in patients undergoing liver resection. We aimed to identify the predictors of persistent AKI, its effect on postoperative outcomes and long-term renal function in patients following liver resection, and its impact on survival in patients with hepatocellular carcinoma (HCC). We examined 990 patients who underwent liver resection, including a subgroup analysis of 384 patients with curative resection for initial HCC. Persistent AKI was defined as residual impairment of serum creatinine≥0.3mg/dL or≥50% from baseline 1month after surgery. The persistent AKI group had significantly worse postoperative outcomes, including overall morbidity, major morbidity, longer hospital stay, and 90-day mortality. In the subgroup analysis of patients with HCC, persistent AKI was associated with a significantly poorer overall survival (OS) rate (p<0.001), and the multivariate analysis confirmed persistent AKI as an independent poor prognostic factor for OS (p=0.005). The long-term postoperative estimated glomerular filtration rate decline was significantly greater in the persistent AKI group than in the no AKI and transient AKI groups (p<0.001 for both). Chronic kidney disease, albumin-bilirubin grade ≥2, and anatomical resection were independent predictors of persistent AKI (p=0.001, p=0.039, and p=0.015, respectively). Persistent AKI adversely affects postoperative outcomes and long-term renal function in patients undergoing liver resection. Furthermore, it is associated with poor prognosis in patients with HCC. Therapeutic strategies to prevent persistent AKI are critical for improving postoperative outcomes in these patients.

Mitotic spindle positioning protein serves as prognostic biomarker in patients with colorectal cancer

Background Colorectal cancer (CRC) ranks among the most aggressive types of cancer globally. Currently, clinical tumor prognostic biomarkers still lack accuracy. Mitotic spindle positioning (MISP) protein connects microtubules to the actin cytoskeleton and adhesive plaques, playing a critical role in spindle positioning, orientation, and the process of cell division. MISP can regulate the malignant biological functions of pancreatic cancer and intrahepatic cholangiocarcinoma and it acts as biomarker for prognosis, but its role in CRC remains unclear. Methods This study has collected 37 CRC tissue samples and 37 corresponding adjacent nontumor tissue samples, and 57 additional CRC tissues samples. Clinical data were obtained from the patients with CRC. MISP mRNA and protein expression levels were analyzed in normal control and CRC tissues using the GEPIA and Human Protein Atlas website. MISP protein levels in the collected tissues were analyzed using immunohistochemistry. Results MISP mRNA and protein expression levels were significantly increased in CRC tissues compared to adjacent nontumor tissues. Higher MISP protein levels were associated with distant metastasis, recurrence, and lower survival rates. Kaplan–Meier analysis showed that high expression levels of MISP protein were associated with recurrence and death in CRC patients. In addition, a high expression level of MISP protein, lymph node metastasis, and distance metastasis were risk factors for recurrence and a poor prognosis in patients with CRC. Conclusion Elevated MISP protein correlated with tumor metastasis, recurrence, and lower survival rates in patients with CRC, and thus, MISP has the potential to become a prognostic marker for CRC.

Cerebral venous thrombosis in elderly patients.

We aimed to report the characteristics of cerebral venous thrombosis (CVT) in elderly people (aged ≥65 years). This multicenter retrospective cohort included elderly patients hospitalized for a first CVT in nine Paris-Ile-de-France hospitals between 2011 and 2021. The estimated incidence was compared to CVT recorded by the French health insurance data system. Lariboisière Hospital's CVT registry allowed comparisons of our elderly cohort with individuals younger than 65 years. One hundred fourteen patients were included in this study (mean age = 74.2 years, range = 65-93, 61% female). The CVT annual incidence in Ile-de-France was 5.9-7.1 per million elderly individuals versus 8.5 per million nationwide. Headaches and focal deficits were the most common initial clinical features (50% and 51%, respectively), followed by seizures and confusion (40% and 27%). Treatment included anticoagulation (93%) and, rarely, endovascular procedure (2%) or craniectomy (1%). Compared with adult patients aged <65 years (younger adults), elderly patients presented fewer headaches (50% vs. 96%, p < 0.01) and intracranial hypertension (7% vs. 22%, p < 0.01) but more seizures and focal deficits (40% vs. 27% and 51% vs. 38%, respectively, p < 0.01). Underlying cancer, hemopathy, and locoregional infections were more frequent in elderly patients than among younger adults (p < 0.01). The prognosis of patients from our elderly cohort was poorer than that of younger adults; 8% died in the acute phase, and 73% had a favorable outcome at 1 year (vs. 1.7% and 87%, respectively, p < 0.01). CVT in elderly patients has a specific clinical presentation, epidemiology, and risk factors such as cancer or hemopathy, justifying specialized management.