Marker Of Prognosis Research Articles

Copeptin as an inflammatory marker in diagnosis and prognosis of neonatal sepsis

BackgroundCopeptin is an immediate biomarker of individual stress response; many life-threatening diseases are causing a high elevation of its concentration in plasma, such as myocardial infarction and cardiovascular shock. Moreover, copeptin is a promising marker in sepsis. We aimed to evaluate copeptin as a diagnostic and prognostic marker in neonatal sepsis for the early initiation of appropriate therapy and the prediction of mortality. A prospective case-control study involved 237 neonates (165 cases had neonatal sepsis, and 72 served as controls). Cases were admitted to the neonatal intensive care unit (NICU) and followed up for symptoms and signs of sepsis confirmed by laboratory data: complete blood count (CBC), c-reactive protein (CRP), and cultures. Serum copeptin level by the enzyme-linked immunosorbent assay (ELISA) was measured for all included neonates. We observed that the copeptin level was significantly higher in cases than control (3.51 ± 1.4, 1.61 ± 0.51 pmol/liter, respectively). The cut-off value of copeptin at which we can discriminate between cases and controls was above 2.065 pmol/liter. Among cases, copeptin was higher in early-onset sepsis (EOS) than late-onset sepsis (LOS) neonates, and there was a significant correlation between its level and all the following: age at admission, birth weight, gestational age, history of perinatal asphyxia, maternal chorioamnionitis, and premature rupture of membrane (PROM). Also, copeptin was strongly associated with CRP level and the poor prognosis of patients. Copeptin can predict the death of cases at a cut-off value above 2.995 pmol/liter.ConclusionSerum copeptin level can be used as a diagnostic and prognostic marker in neonatal sepsis.

Transpulmonary Plasma Endothelin-1 Arterial:Venous Ratio Differentiates Survivors from Non-Survivors in Critically Ill Patients with COVID-19-Induced Acute Respiratory Distress Syndrome.

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.

Potential use of SCAT1, SCAT2, and SCAT8 as diagnostic and prognosis markers in colorectal cancer

Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Despite advancements, the underlying mechanisms controlling CRC's etiology remain unclear, and reliable biomarkers for diagnosis and treatment are still lacking. Long noncoding RNAs (lncRNAs) are increasingly recognized for their role in cancer progression, though many remain unidentified and their functions poorly understood. In this study, we investigated the expression of SCAT1, SCAT2, and SCAT8 lncRNAs in both cancerous and adjacent non-cancerous tissues from CRC patients. Using cDNA synthesized from total RNA extracted from 100 tissue samples, we performed Real-Time PCR to measure the expression levels of these lncRNAs. In addition, their diagnostic potential was evaluated through ROC curve analysis. Our results demonstrate that SCAT1, SCAT2, and SCAT8 are significantly upregulated in CRC tissues, with ROC analysis suggesting SCAT1 as a moderate biomarker and SCAT2 and SCAT8 as promising biomarkers for CRC diagnosis. Moreover, we found strong correlations between SCAT1 and SCAT8, as well as SCAT2 and SCAT8. Collectively, our findings indicate that SCAT1, SCAT2, and SCAT8 may act as oncogenes in CRC, offering potential as novel biomarkers for diagnosis and prognosis.

Characterization and proteomic analysis of plasma-derived small extracellular vesicles in locally advanced rectal cancer patients.

Neoadjuvant chemoradiotherapy (nCRT) stands as a pivotal therapeutic approach for locally advanced rectal cancer (LARC), yet the absence of a reliable biomarker to forecast its efficacy remains a challenge. Thus, this study aimed to assess whether the proteomic compositions of small extracellular vesicles (sEVs) might offer predictive insights into nCRT response among patients with LARC, while also delving into the proteomic alterations within sEVs post nCRT. Plasma samples were obtained from LARC patients both pre- and post-nCRT. Plasma-derived sEVs were isolated utilizing the TIO2-based method, followed by LC-MS/MS-based proteomic analysis. Subsequently, pathway enrichment analysis was performed to the Differentially Expressed Proteins (DEPs). Additionally, ROC curves were generated to evaluate the predictive potential of sEV proteins in determining nCRT response. Public databases were interrogated to identify sEV protein-associated genes that are correlated with the response to nCRT in LARC. A total of 16 patients were enrolled. Among them, 8 patients achieved a pathological complete response (good responders, GR), while the remaining 8 did not achieve a complete response (poor responders, PR). Our analysis of pretreatment plasma-derived sEVs revealed 67 significantly up-regulated DEPs and 9 significantly down-regulated DEPs. Notably, PROC (AUC: 0.922), F7 (AUC: 0.953) and AZU1 (AUC: 0.906) demonstrated high AUC values and significant differences (P value < 0.05) in discriminating between GR and PR patients. Furthermore, a signature consisting of 5 sEV protein-associated genes (S100A6, ENO1, MIF, PRDX6 and MYL6) was capable of predicting the response to nCRT, yielding an AUC of 0.621(95% CI: 0.454-0.788). Besides, this 5-sEV protein-associated gene signature enabled stratification of patients into low- and high-risk group, with the low-risk group demonstrating a longer overall survival in the testing set (P = 0.048). Moreover, our investigation identified 11 significantly up-regulated DEPs and 31 significantly down-regulated DEPs when comparing pre- and post-nCRT proteomic profiles. GO analysis unveiled enrichment in the regulation of phospholipase A2 activity. Differential expression of sEV proteins distinguishes between GR and PR patients and holds promise as predictive markers for nCRT response and prognosis in patients with LARC. Furthermore, our findings highlight substantial alterations in sEV protein composition following nCRT.

Small Left Ventricular Chamber Size And Mortality In A Large General Population

Enlargement of the left ventricle (LV) is an important marker of adverse cardiac remodeling and poor prognosis. Previous studies demonstrated increased cardiovascular risk in small subsets of patients with small LV chamber size, however, the prognostic implications of small chamber size in a general population remains unclear. The objective of this study was to examine the prognosis of a small LV chamber in a large general cohort. All consecutive subjects that underwent echocardiography examinations from 2011 to 2023 were retrieved for analysis. Small chamber size was defined as end-diastolic diameter less than 42 mm for men and 37.8 mm for women as per ASE guidelines. The primary endpoint for the study was all-cause mortality. 46,529 subjects (mean age 60 ± 19 years, 56% males) were included of whom 3,787 had small LV chamber size. Clinical variables associated with small chamber included increasing age and lower BSA. Echocardiographic variables included higher relative wall thickness, and E/e' ratio. On multivariable analysis, the presence of a small LV was significantly associated with mortality (HR 1.34 with 95% CI 1.22-1.46; p <0.001). This finding was significant in both older (over 65 years) (HR 1.30 95% CI 1.19-1.41; p <0.001) and younger (HR 2.09 95% CI 1.81-2.41; p <0.001) subjects and in both males and females. In conclusion, in this retrospective large cohort study, small LV chamber size was significantly associated with mortality in a broad range of patients. Further study is necessary to elucidate mechanisms and design preventive strategies.

Leakage sign based on contrast-enhanced CT is a predictive marker for hematoma expansion and poor prognosis in primary brainstem hemorrhage

BackgroundAlthough hematoma expansion is a poor prognostic factor in patients with intracerebral hemorrhage (ICH), its effect on primary brainstem hemorrhage (PBSH) remains unclear. Since we previously observed the “leakage sign” (LS) on computed tomography (CT) to be a significant predictor for hematoma expansion, we herein investigated the effect of LS in PBSH. MethodsBetween January 2013 and August 2023, 515 patients with ICH were admitted to our institute. Thirty-six patients with PBSHs met the inclusion criteria, who were then divided into LS-positive (LS+) and LS-negative (LS-) groups based on the presence of LS. We evaluated hematoma expansion and prognosis at discharge. ResultsPatients in the LS+ group had larger baseline hematoma volume and lower Glasgow Coma Scale scores on admission and significantly poor prognosis at discharge. Subgroup analysis revealed that LS was frequently observed within 100 min after the onset of symptoms in patients with a hematoma size of >10 mm3 on CT; additionally, patients in the LS+ group more frequently experienced hematoma expansion and had poor prognosis at discharge. ConclusionLS is a significant predictive marker for disease severity at admission, hematoma expansion, and poor prognosis at discharge

Potential of Pre-Operative Serum Interleukin-6 as a Biomarker for Colorectal Cancers

The diagnosis of colorectal cancers (CRC) at its early stage is challenging due to lack of early markers. Current diagnostic tests are either invasive or show low sensitivity. Interleukins are known to elevate and play important roles in the development and progression of the CRC. The studies on interleukin profiles of CRC patients are mainly confined to Caucasian populations while South Asian data are sparse. Therefore, the aim of this study was to investigate the serum IL-6 and IL-10 levels in a cohort of Sri Lankan CRC patients and explore their potential to be used as markers for early diagnosis/prognosis of CRC. Blood samples from 35 CRC patients and 35 healthy volunteers were obtained after informed consent. Their clinical findings and carcinoembryonic antigen (CEA) levels were recorded. Concentrations of IL-6 and IL-10 were measured using ELISA according to manufacturer’s protocols. Mean serum [IL-6] was found to be significantly higher in CRC patients than controls (p&lt;0.05). The mean [IL-10]showed no difference to that of controls. (p&gt;0.05). Interestingly, the [IL-6] in CRC patients were correlated with the disease stage (Stage I-0.16pg/ml; stage II-7.01pg/ml; stage III-15.8pg/ml and stage IV-35.48pg/ml). CEA levels were not correlated with the disease stage or withIL-6 levels. This study provided preliminary evidence to use IL-6 as a potential biochemical marker for the diagnosis of CRC inaddition to CEA. Furthermore, IL-6 could be a marker for prognosis of CRC. Further studies with higher patient samples are needed to validate the results of this study.

The mechanism of L1 cell adhesion molecule interacting with protein tyrosine kinase 2 to regulate the focal adhesion kinase–growth factor receptor-bound protein 2–son of sevenless–rat sarcoma pathway in the identification and treatment of type I high-risk endometrial cancer

Objective: The objective of this study was to investigate how L1 cell adhesion molecule (L1CAM) interacting with protein tyrosine kinase 2 (PTK2) affects endometrial cancer (EC) progression and determine its association with the focal adhesion kinase (FAK)–growth factor receptor-bound protein 2 (GRB2)–son of sevenless (SOS)–rat sarcoma (RAS) pathway. EC is a female cancer of major concern in the world, and its incidence has increased rapidly in recent years. L1CAM is considered a reliable marker of poor prognosis in patients with EC. Material and Methods: A single-center and prospective study was conducted using data from the Cancer Genome Atlas and samples from normal and EC tissues to explore the differential expression of L1CAM. Additional experimental models included human immortalized endometrial epithelium cells (hEECs) and EC cell lines such as KLE, RL95-2, and Ishikawa. L1CAM expression was regulated using lentiviruses designed for either overexpression or interference, and PTK2/focal adhesion kinase (FAK) signaling was inhibited with PF431396. Transfected KLE cells were injected into mice, and tumor growth was monitored over 14 days. Cellular proliferation and survival were assessed using cell counting kit, colony formation, and terminal deoxynucleotidyl transferase-mediated 2’-deoxyuridine 5’-triphosphate (dUTP) nick-end labeling assays. Metastatic behavior was evaluated through Transwell assays for cell migration and invasion. The expression levels of matrix metallopeptidase (MMP) 2 and MMP9 were determined by Western blot. In addition, the activation of the FAK–GRB2–SOS–RAS pathway was examined by assessing the protein levels of FAK, GRB2, SOS, and RAS. Results: There was a significant difference in L1CAM expression between EC tumor tissues and normal tissues, and L1CAM messenger RNA (1.85-fold) and L1CAM protein (2.59-fold) were significantly more expressed in EC tissues (P &lt; 0.01) than in normal tissues. The tumor growth of L1CAM overexpressing EC cells was faster than that of negative control EC cells (6.43 fold; P &lt; 0.001). L1CAM promoted the expression of FAK (1.43-2.72-fold; P &lt; 0.001); enhanced EC cell proliferation (P &lt; 0.01), survival and motility (P &lt; 0.001), migration (P &lt; 0.001), and invasion (P &lt; 0.001); and activated the FAK–GRB2–SOS–RAS pathway, all of which were reversed when FAK expression was not upregulated (P &lt; 0.001). Conclusion: By upregulating PTK2 and its encoded protein FAK, L1CAM was found to promote tumor progression and increase the activation of the FAK–GRB2–SOS–RAS pathway. These findings establish L1CAM and PTK2 as reference genes for poor prognostic prediction in EC and as targets for EC therapy, providing a valuable basis for distinguishing between benign and malignant endometrial conditions and justifying the necessity of targeted therapeutic approaches.

The relation between socioeconomic status and invasive haemodynamics at evaluation for advanced heart failure.

Socioeconomic deprivation is a risk marker for worse prognosis in patients with heart failure (HF), and a potential barrier to referral for advanced HF evaluation. The relationship between socioeconomic status (SES) and invasive haemodynamics in patients undergoing evaluation for advanced HF therapies is unknown. We combined a consecutive clinical registry of patients evaluated for advanced HF with patient-level data on SES (household income, education, workforce status, cohabitant status and distance from home to tertiary HF centre) derived from nationwide registries. Using this information, the cohort was divided into groups of low-, medium- and high degree of socioeconomic deprivation. The associations between SES and invasive haemodynamics were explored with multiple linear regression adjusted for age and sex. A total of 631 patients were included. The median age was 53years, and 23% were women. Patients in the highest income quartile versus the lowest (Q4 vs. Q1) were older (median age 57 vs. 50years) and more often male (83% vs. 67%), both P<0.001. Increasing household income (per 100000 Danish kroner,1 EUR=7.4 DKK) was associated with lower pulmonary capillary wedge pressure (PCWP)[-0.18mmHg, 95% confidence interval (CI) -0.36 to -0.01, P=0.036] but not significantly associated with central venous pressure (CVP) (-0.07mmHg, 95% CI -0.21 to 0.06, P=0.27), cardiac index (-0.004L/min/m2, 95% CI -0.02 to 0.01, P=0.60), or pulmonary vascular resistance (PVR) (-0.003 Wood units, 95% CI -0.37 to 0.16, P=0.84). Comparing the most deprived with the least deprived group, adjusted mean PVR was higher (0.35 Wood units, 95% CI 0.02 to 0.68, P=0.04), but PCWP (0.66mmHg, 95% CI -1.49 to 2.82, P=0.55), CVP (-0.26mmHg, 95% CI -1.76 to 1.24, P=0.73) and cardiac index (-0.03L/min/m2, 95% CI -0.22 to 0.17, P=0.78) were similar. Most haemodynamic measurements were similar across layers of SES. Nevertheless, there were some indications of worse haemodynamics in patients with lower household income or a high accumulated burden of socioeconomic deprivation. Particular attention may be warranted in socioeconomically deprived patients to ensure timely referral for advanced HF evaluation.

Prognostic value of circulating proteins at diagnosis among patients with lung cancer: a comprehensive analysis by smoking status.

Improved prediction of prognosis among lung cancer patients could facilitate better clinical management. We aimed to study the prognostic significance of circulating proteins at the time of lung cancer diagnosis, among patients with and without smoking history. We measured 91 proteins using the Olink Immune-Oncology panel in plasma samples that were collected at diagnosis from 244 never smoking and 742 ever smoking patients with stage I-IIIA non-small cell lung cancer (NSCLC). Patients were recruited from nine centres in Russian Federation, Poland, Serbia, Czechia, and Romania, between 2007-2016 and were prospectively followed through 2020. We used multivariable Survey-weighted Cox models to assess the relationship between overall survival and levels of proteins by adjusting for smoking, age at diagnosis, sex, education, alcohol intake, histology, and stage. The 5-year survival rate was higher among never than ever smoking patients (63.1% vs. 46.6%, P<0.001). In age- and sex-adjusted survival analysis, 23 proteins were nominally associated with overall survival, but after adjustment for potential confounders and correcting for multiple testing, none of the proteins showed a significant association with overall survival. In stratified analysis by smoking status, IL8 [hazard ratio (HR) per standard deviation (SD): 1.40, 95% confidence interval (CI): 1.18-1.65, P=1×10-4] and hepatocyte growth factor (HGF) (HR: 1.45, 95% CI: 1.18-1.79, P=5×10-4) were associated with survival among never smokers, but no protein was found associated with survival among ever smokers. Integrating proteins into the models with clinical risk factors did not improve the predictive performance of NSCLC prognosis [C-index of 0.63 (clinical) vs. 0.64 (clinical + proteins) for ever smokers, P=0.20; C-index of 0.68 (clinical) vs. 0.72 (clinical + proteins) for never smokers, P=0.28]. We found limited evidence of a potential for circulating immune- and cancer-related protein markers in lung cancer prognosis. Whereas some specific proteins appear to be uniquely associated with lung cancer survival in never smokers.

Analysis of ALDOC Expression and Prognostic Value in Acute Myeloid Leukemiahe

Objective: This study aimed to investigate the expression pattern of ALDOC in patients with acute myeloid leukemia (AML) and to assess its potential as a prognostic marker. Methods: Data for this study were derived from the public databases TCGA and GTEx. Based on the expression levels of ALDOC in different age groups, the impact of ALDOC expression on the prognosis of AML patients was evaluated using univariate and multivariate Cox regression analyses, in conjunction with Kaplan-Meier survival curves. Bioinformatics methods were also employed to explore the possible mechanisms of ALDOC action in AML. Results: A significant difference in the expression of the metabolic gene ALDOC was found between AML patients and normal individuals (P &lt; 0.05). ALDOC was identified as a prognostic marker for patients under the age of 60. Bioinformatics analysis suggested that high expression of ALDOC could upregulate pathways involved in allograft rejection, response to IFN-α, response to IFN-γ, and phagocytosis, particularly indicating a poorer prognosis in patients under the age of 60. Conclusion: High expression of ALDOC is associated with poor prognosis in AML patients under the age of 60, and ALDOC may serve as a marker for AML prognosis and a promising potential therapeutic target for further research.

Integrative analysis of FADS3 as a marker for prognosis and immunity in head and neck squamous cell carcinoma

BackgroundLong-chain polyunsaturated fatty acid formation requires fatty acid desaturase (FADS), which is strongly linked to cancer progression. Nevertheless, it's unclear how FADS3 functions in head and neck squamous cell carcinoma (HNSCC). MethodsHNSCC cases were retrieved from TCGA and GEO databases, and FADS members with transcriptionally differential expression were identified. Clinical survival, tumor microenvironment (TME), and potential pathogenic mechanism in HNSCC were also investigated. These results were validated using tissue staining, flow cytometry and functional studies in HNSCC cell lines. ResultsWhen comparing HNSCC to normal epithelial tissues, FADS3 expression was much higher in the former. FADS3 upregulation was correlated with poor clinical outcomes. FADS3 was an independent prognostic factor for poor overall survival in HNSCC patients. KEGG, GO, and GSEA revealed that FADS3 expression correlated with several immune-related pathways and the epithelial-mesenchymal transition (EMT). Knocking down FADS3 restrained HNSCC cell proliferation, migration, invasion, and EMT. Single-cell dataset analysis showed an association between FADS3 and TME features. Further investigation revealed that FADS3high tumor was accompanied with less CD8+ T cells in situ tissue and peripheral blood. FADS3 was positively correlated with immune-related molecules and could predict the adverse efficacy of immunotherapy. Finally, we constructed a CYTOR/hsa-let-7c-5p axis regulating FADS3 expression in HNSCC progression. ConclusionsFADS3 may represent a target for treatment in HNSCC, which is linked to prognosis, EMT, immune infiltration, and ceRNA regulatory network of HNSCC.

Real-world treatment outcomes for Hodgkin lymphoma in South Africa: a prospective observational study

BackgroundProspective data from sub-Saharan Africa suggests that treatment outcomes for people living with HIV (PWH) with Hodgkin lymphoma (HL) are similar to those without HIV. However, real-world data from high-resource settings and retrospective studies from sub-Saharan Africa, suggest inferior outcomes. We set out to evaluate the real-world treatment outcomes for HL in South Africa to better understand the disparate outcomes.MethodsWe established a prospective, observational cohort of newly diagnosed, adult (≥ 18 years) HL cases recruited from Chris Hani Baragwanath Academic and Netcare Olivedale Hospitals in Johannesburg, South Africa between March 2021 and March 2023. Participants were followed for up to 18 months after enrollment with data censored on December 23rd, 2023. The primary endpoint was 1-year overall survival.ResultsWe enrolled 47 participants with HL including 31 PWH and 16 HIV-negative. Advanced stage disease and B symptoms were common at time of diagnosis irrespective of HIV status. Bone marrow biopsy, performed during the work-up and evaluation of cytopenias, provided the initial diagnosis of HL in 16/31 (52%) PWH. HIV status and bone marrow involvement were associated with early mortality (within 3 months of diagnosis) and a poorer 1-year overall survival from diagnosis (HIV: 55% vs. 88%; p = 0.03; bone marrow involvement: 50% vs. 80%; p = 0.02). Among evaluable participants, those that received at least 6 cycles of chemotherapy and underwent response assessment, there was no difference between those with and without HIV.ConclusionTraditional laboratory markers of poor prognosis including anemia, lymphopenia and hypoalbuminemia were more common among PWH and those with bone marrow involvement and suggest high risk disease. A better understanding of the drivers of these aggressive presentations is warranted to ensure more PWH are able to tolerate chemotherapy.

SURF2 is a MDM2 antagonist in triggering the nucleolar stress response

Cancer cells rely on high ribosome production to sustain their proliferation rate. Many chemotherapies impede ribosome production which is perceived by cells as “nucleolar stress” (NS), triggering p53-dependent and independent pathways leading to cell cycle arrest and/or apoptosis. The 5S ribonucleoprotein (RNP) particle, a sub-ribosomal particle, is instrumental to NS response. Upon ribosome assembly defects, the 5S RNP accumulates as free form. This free form is able to sequester and inhibit MDM2, thus promoting p53 stabilization. To investigate how cancer cells can resist to NS, here we purify free 5S RNP and uncover an interaction partner, SURF2. Functional characterization of SURF2 shows that its depletion increases cellular sensitivity to NS, while its overexpression promotes their resistance to it. Consistently, SURF2 is overexpressed in many cancers and its expression level is an independent marker of prognosis for adrenocortical cancer. Our data demonstrate that SURF2 buffers free 5S RNP particles, and can modulate their activity, paving the way for the research of new molecules that can finely tune the response to nucleolar stress in the framework of cancer therapies.

Spatial transcriptomics reveal tumor microenvironment and SLCO2A1 correlated with tumor suppression in hypopharyngeal squamous cell carcinoma

BackgroundHypopharyngeal squamous cell carcinoma (HSCC) is a type of head and neck tumor with malignant behavior and poor prognosis. Spatial transcriptomics is a method that spatially analyzes gene expression patterns in tissues and has been used to discover tumor microenvironment and molecular markers in various tumors. However, there are no published reports on spatial transcriptomic analysis of HSCC. MethodsIn this study, spatial transcriptomic analysis was performed on tumor tissues in situ, peritumoral tissues, and lymphatic metastatic tissues of four patients with HSCC. Morphological markers, including panCK, SMA, and CD45, were used to identify epithelial, fibroblast, and immune cells, respectively. By analyzing the expression of more than 18, 000 genes within the transcriptome of all ROIs, differentially expressed genes of three cell types in different tissues were identified, and differentially expressed signaling pathways and immune infiltration were analyzed. ResultsThe spatial distribution of cells suggests that fibroblast cells in tumor tissues may be involved in the genesis and development of tumors, and the immune infiltration of lymphatic tumor metastasis is lower than that of tumors in situ. For epithelial cells, SLCO2A1, which is a favorable prognosis marker in head and neck squamous cell carcinoma (HNSCC), was significantly down-regulated in tumor tissues and lymphatic metastatic tissues compared with adjacent normal tissues. For immune cells, KANK3, which is a favorable prognosis markers in HNSCC, was significantly down-regulated in lymphatic metastatic tissues compared with adjacent normal tissues. For fibroblast cells, AQP1, CLEC3B and SLCO2A1, which are favorable prognosis markers in HNSCC, were significantly down-regulated in tumor tissues compared with adjacent normal tissues. ITGA8, which is a favorable prognosis markers in HNSCC, was significantly down-regulated in lymphatic metastatic tissues compared with normal lymphatic tissues. CSRP1, DES, and SLCO2A1 positively correlate with immune infiltration in HNSCC. Moreover, SLCO2A1 overexpression suppressed Fadu cells proliferation and metastasis and significantly correlated with favorable survival overcome in HSCC. ConclusionsWe investigated tumor and fibroblast heterogeneity, as well as the immune microenvironment in HSCC by using spatial transcriptomics. SLCO2A1 may be a tumor suppressor gene and correlates with immune infiltration for HSCC and could serve as a potential target for its diagnosis and treatment.

Higher prevalence of poor prognostic markers at a younger age in adult patients with myelodysplastic syndrome – evaluation of a large cohort in India

BackgroundThe karyotype is a major determinant of prognosis in myelodysplastic syndrome (MDS). Details of the cytogenetic profile of MDS in South Asia are limited because cytogenetic services are not widely available.MethodsWe performed a retrospective analysis of the cytogenetic and clinicopathologic profile of adult primary MDS seen consecutively at a tertiary-care centre in South India between 2003 and 2017. Patients were re-categorised according to the 2022 World Health Organisation (WHO) and the International Consensus classifications (ICC).ResultsThere were 936 patients aged 18–86 years (median age 53, 65% males), with MDS with del 5q, low blasts and increased blasts in 7.5%, 58.4% and 34.1% respectively. Clonal abnormalities were seen in 55% of patients, with solitary abnormalities in 29.8% and complex karyotypes (CK, ≥ 3 abnormalities) in 15%. The most frequent abnormalities were monosomy 7/deletion 7q (16.1%), deletion 5q (14.5%), trisomy 8 (11.5%), and deletion 20q (5.1%). Cytogenetic prognosis groups were distributed as follows: very good, 2%; good, 55.6%; intermediate, 16.2%; poor, 15%; very poor, 11.2%. Clinical (IPSS-R) risk stratification (842 patients) showed: very low-risk, 3.9%; low-risk, 30.9%; intermediate-risk, 24.2%; high-risk, 21%; very high-risk, 20%. Age-adjustment (IPSS-RA) raised the very low-risk group to 12.4%; the other groups decreased by 1–3% each.ConclusionThe most significant finding of this cytogenetic analysis of MDS in India is that abnormal karyotypes with poor prognosis markers including monosomy 7 and CK were more frequent than in most other reports, among patients who were overall younger. Trisomy 8, deletion 20q, the IPSS-R intermediate-risk and both high-risk groups were more common than in the West. Trisomy 8 was less common than in South-East Asia while CK and deletion 20q were comparable. Evaluation of such large cohorts highlights the unique features of MDS in different parts of the world. These findings suggest that there could be differences in predisposing factors, environmental or genetic, and emphasise the need for further exploration to better understand the varied nature of MDS.

Hematological ratios as markers of lupus activity in Paraguayan patients with systemic lupus erythematosus

Introduction: The neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) are markers of inflammation and prognosis in systemic diseases. This study determined the association between hematological indices, and disease activity in patients with systemic lupus erythematosus (SLE). Methods: This prospective, observational and analytical cross-sectional study included 87 Paraguayan patients diagnosed with SLE, according to the ACR/EULAR 2019 criteria. We investigate four hematological indices: neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), eosinophil/lymphocyte ratio (ELR), and monocytes/lymphocyte ratio (MLR). Results: Eighty-seven percent were female, with a median age of 34.9 ±12.3 years. SLEDAI mean of 3.68 ± 4.76 was found. SLEDAI mean was 3.68 ± 4.76. Positivity of anti-DNAds was found in 52% of the patients. CRP mean was 3.5 ± 4.6. Regarding values of hematological indices, we found: NLR mean of 2.4 ± 1.6 was obtained, ELR 0.07 ± 0.09, MRL 0.07 ± 0.07 and PLR 155.89 ± 80.69. A significant positive correlation was found with SLEDAI and NLR (r=0.34, p=0.001). Based on the ROC curve, the best cut-off value for our patient cohort capable of predicting patients with high activity is for NLR values ? 2.283 (AUC: 0.66). Conclusion: NLR could be a valuable and accessible biomarker to identify elevated activity in patients with SLE.

Circulating tumor DNA (ctDNA) as a biomarker of response to therapy in advanced Hepatocellular carcinoma treated with Nivolumab.

Circulating tumor DNA (ctDNA) is a promising non-invasive marker for detection, diagnosis, treatment selection, and prognosis of hepatocellular carcinoma (HCC). This study aimed to examine the utility of ctDNA as a prognostic and predictive tool in HCC patients treated with nivolumab. We analyzed pre-treatment ctDNA from 44 HCC patients using comprehensive genomic testing on a commercially available platform. We utilized log rank test and univariate Cox models to correlate overall survival (OS) and progression-free survival (PFS) with ctDNA expressions. Of 44patients, 77.3% were men with median age of 67years. All but 3patients had at least one alteration identified, and TP53 was the most commonly altered gene (52.3%). Median OS was 17.5months (95% CI: 12.7, NA). Mutations involving PIK3CA, BRCA1, and CCND1 amplification were associated with shorter OS (P 0.0001, 0.0001 and 0.01, respectively). Median PFS time was 4.01months (95% CI: 3.06, 9.33). Mutations involving KIT and PIK3CA were associated with shorter PFS (P 0.0001 and 0.0004, respectively), while mutation involving CTNNB1 were associated with longer PFS (p= 0.04). ctDNA profiling may provide a benefit for prediction of survival and progression of HCC patients treated with nivolumab. Future studies are needed for confirmation.

Association of CYP7B1 expression with the prognosis of endometrial cancer: a retrospective study

BackgroundEndometrial cancer (EC) tissues express CYP7B1, but its association with prognosis needs to be investigated.MethodsImmunohistochemistry and image analysis software were used to assess CYP7B1 protein expression in paraffin-embedded endometrial tumor sections. Associations between CYP7B1 and clinical factors were tested with the Wilcoxon rank-sum test. Kaplan-Meier curves were employed to describe survival, and differences were assessed using the log-rank test. Cox regression analysis was used to assess the association between CYP7B1 expression and the prognosis of patients with EC.ResultsA total of 307 patients were enrolled with an average age of 52.6 ± 8.0 years at diagnosis. During the period of follow-up, 46 patients (15.0%) died, and 29 (9.4%) suffered recurrence. The expression of CYP7B1 protein is significantly higher in the cytoplasm than in the nucleus (P < 0.001). Patients aged < 55 years (P = 0.040), ER-positive patients (P = 0.028) and PR-positive patients (P < 0.001) report higher levels of CYP7B1 protein. Both univariate (HR = 0.41, 95% CI: 0.18–0.90, P = 0.025) and multivariate (HR = 0.35, 95%CI:0.16–0.79, P = 0.011) Cox regression analyses demonstrate that high CYP7B1 protein expression predicts longer overall survival (OS). When considering only ER-positive patients (n = 265), CYP7B1 protein expression is more strongly associated with OS (HR = 0.20,95%CI:0.08–0.52, P = 0.001). The 3-year OS and 5-year OS in the low-CYP7B1 subgroup are 81.6% and 76.8%, respectively; while in the high-CYP7B1 subgroup are 93.0% and 92.0%, respectively (P = 0.021).ConclusionsHigh CYP7B1 protein expression predicted longer OS, suggesting that it may serve as an important molecular marker for EC prognosis.

Abstract B051: Influence of MUC16 on the immune tumor microenvironment of PDAC

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease. In most cases, PDAC initiation results from oncogenic KRAS mutations, that act in part by directly increasing levels of a glycoprotein called Mucin-16 (MUC16). MUC16 is virtually absent in the normal pancreas, expressed on tumor cells in &amp;gt;65% of PDAC and is a marker of poor prognosis. The cell autonomous roles of MUC16 involve signaling through the ErbB-1/2/3 axes, and eliciting downstream AKT and GSK-3β activation to promote cell proliferation and survival. PDAC has a very interesting “immune cold” tumor microenvironment (TME) that is devoid of anti-tumor T cells and is instead flush with pro-tumor myeloid cells like macrophages. However, the role of MUC16 in influencing immune cells, particularly macrophages has not been investigated. Methods: We use immunohistochemistry to check for macrophage populations in spontaneous and orthotopic models of PDAC, KPC (LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx-1- Cre) and a derived KPC-MUC16 knockout (KPC-M16KO). Orthotopic implantation with KPC and KPC-M16- cells was done to assess survival. In vitro cytokine screening from M16+/- cells was done to understand cytokine players in MUC16-mediated immunosuppression. Clodronate liposomes (CL) and neutral control liposomes (NL) were used to deplete macrophages in orthotopically implanted KPC and KPC-M16- tumor-bearing mice, and flow cytometry was conducted to profile macrophages and T cells in the pancreas and spleens at the experimental endpoint. Results: We show that KPC-M16KO tumors have decreased M2-like macrophages, and a modest increase in M1-like macrophages, leading to a high M1/M2 ratio suggesting reduced immune suppressed cells in the KPC-M16KO models. KPC-M16KO tumor-bearing mice showed longer survival compared to the KPC group. In addition, we detect low levels of CCL2 and Serpin-E1 in cell lines and tumor tissues from KPC-M16KO models suggesting that they could serve as potential regulators of macrophage infiltration and M2-like polarization downstream of MUC16. Siglec-E (murine homolog of human Siglec-7/9) was also downregulated in KPC-M16KO tumors, suggesting MUC16-Siglec mediated immunosuppression as another mechanism. CL administration (versus NL) resulted in significant macrophage depletion in the spleens of mice with KPC and KPC-M16KO tumors, however, such depletion was not robust in the pancreas. Immune profiling studies showed a high M1/M2 ratio in the spleen and pancreas of mice treated with CL, suggesting a tumor cell-macrophage crosstalk, that could mediate M2-like macrophage states in a macrophage-rich TME. Mice treated with CL have smaller tumors, and KPC-M16KO+CL group had the smallest tumors, indicative that dual disruption of MUC16 and macrophages lowers tumor burden. Conclusions: These results suggest that MUC16 plays a crucial role in modulating the tumor immune microenvironment by increasing the accumulation of immunosuppressive macrophages in PDAC. Citation Format: Christabelle Rajesh, Satish Sagar, Prakash Radhakrishnan. Influence of MUC16 on the immune tumor microenvironment of PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B051.