Unfavorable Prognostic Factor Research Articles

Оценка нутритивного статуса и рисков его нарушения у детей с болезнью Крона: одномоментное исследование

Children with Crohn's disease (CD) are at high risk for developing nutritional deficiencies. According to studies in adult patients with CD, loss of lean and skeletal muscle mass and decreased bone mineral density (BMD) are unfavorable prognostic factors for the course of the disease; among children, the prevalence of these changes has not been sufficiently studied as yet. The purpose of this research was to study the frequency and correlation between disorders of body composition and decreased bone mineral density in children with CD. Materials and methods used: medical records of 163 aged 5 to 17 y/o with a confirmed CD diagnosis were assessed for the risk of nutritional deficiency using STRONGkids screening tool, anthropometric parameters, body composition with bioimpedance measurements as well as the disease activity index with PCDAI and endoscopic activity with SES-CD. BMD was assessed in 145 using densitometry. Results: depending on the degree of risk of malnutrition, children were divided into 2 groups as follows: G1 with high and G2 with moderate risks for malnutrition. G1 patients had significantly lower values of both anthropometric indices (Z-scores BMI/age, mid-upper arm circumference/age) and lean and skeletal muscle mass (p<0.001) along with more severe course of CD according to PCDAI (p<0.001). According to bioimpedansometry data, a significant increase in catabolic processes was found in G1 children as a decrease in Z-scores for both the phase angle (p<0.001) and the active cell mass (p<0.001). A decrease in BMD was detected in 9 (37%) of G1 and 26 (21.4%) of G2. A correlation was found between Z-scores lean body mass/age and BMD/age (p<0.001, Rs=0.612). Among children with reduced BMD values, the indicators for BMI, lean, skeletal muscle and active cell mass according to bioimpedance measurements were significantly lower (p<0.001). Conclusion: the data obtained during the study proposes high incidence of decreased bone mineral density along with pathological changes in body composition in children with CD. The use of STRONGkids tool to identify children at high risk of developing malnutrition, especially in the absence of the technical ability to conduct a detailed assessment of nutritional status with determination of body composition and BMD indicators, makes it possible to timely identify patients requiring individual nutritional support aiming to optimizing diets and, if necessary, prescribing addition of specialized food supplements.

Prognostic Impact of Low Muscle Mass and Inflammatory Markers in Stage III Nonsmall Cell Lung Cancer Turkish Oncology Group and Turkish Society of Radiation Oncology Thoracic Cancer Study Group (08-005).

The aim of this retrospective multicenter study was to evaluate the prognostic significance of low muscle mass, and inflammatory markers in patients with stage III nonsmall cell lung cancer (NSCLC) who received definitive chemoradiotherapy (CRT). Furthermore, the study aimed to determine the threshold value of disease-specific low muscle mass. A total of 461 patients with stage III NSCLC were evaluated. Low muscle mass, prognostic nutritional index (PNI), and biochemical inflammatory markers were assessed. The Kaplan-Meier method and Cox regression analysis were used to analyze overall survival (OS) and progression-free survival (PFS). This study found a disease-specific low muscle mass threshold of LSMI <38.7cm²/m² for women and <45.1cm²/m² for men, with 25.2% of patients having disease-specific low muscle mass. Multivariate cox regression analysis revealed that low PNI was found to be an independent unfavorable prognostic factor for both PFS (HR=0.67; 95% CI: 0.48-0.92, P= 0.015) and OS (HR=0.67; 95% CI: 0.50-0.91, P=0.008). Other factors including ECOG PS 3 (HR=7.76; 95% CI: 1.73-34.76, P=0.007), induction CT (HR=0.66; 95% CI: 0.49-0.88, P= 0.004), and disease-specific low muscle mass (HR=1.40; 95% CI: 1.02-1.92, P= 0.038) also had independent effects on prognosis. The present study provides evidence that the presence of low muscle mass and low PNI significantly impacts the prognosis of patients with stage III NSCLC who undergo definitive CRT. Furthermore, our study is notable for being the first multicenter investigation to identify a disease-specific low muscle mass threshold.

Expression of interleukin-8 and integrin β3 predicts prognosis of patients with hepatocellular carcinoma after hepatectomy

As important components in the tumor microenvironment, interleukin-8 (IL-8) and integrin β3 play a key role in the progression and metastasis of hepatocellular carcinoma (HCC). This study aimed to determine the expression of IL-8 and integrin β3 and their prognostic value in patients with HCC after hepatectomy. We investigated the expression of IL-8 and integrin β3, their clinical significance, as well as their correlation in the cancer tissue of 130 patients with HCC using immunohistochemistry. The prognostic value of IL-8 and integrin β3 was investigated through the follow-up of patients with HCC after hepatectomy. In HCC, IL-8 expression had a positive correlation with integrin β3 expression. Increased expressions of IL-8 and integrin β3 were indicators of tumor progression and poor prognosis in patients with HCC after hepatectomy. IL-8 positive specimens exhibited a higher proportion of macrovascular invasion, larger tumor size, poor differentiation, and advanced tumor-node-metastasis (TNM) stage (P &lt; .05, respectively). Integrin β3 positive group exhibited a higher proportion of TNM III-staged tumors (P &lt; .05). The results indicated that macrovascular invasion, advanced TNM stage, and integrin β3 expression were independent unfavorable prognostic factors in HCC after hepatectomy. Integrin β3 expression was proved to be an independent unfavorable prognostic factor in HCC after hepatectomy. Targeting integrin β3 might be a potential therapeutic approach in preventing tumor progression in HCC.

Comprehensive analysis identifies YKT6 as a potential prognostic and diagnostic biomarker in lung adenocarcinoma

BackgroundLung cancer is the most common cause of cancer-related death worldwide. The most prevalent histological subtype of lung cancer is lung adenocarcinoma (LUAD), with incidence rising each year. Treating LUAD remains a significant issue due to a lack of early diagnosis and poor therapy outcomes. YKT6 is a member of the SNARE protein family, whose clinical value and biological function in LUAD has yet to be established.MethodsTCGA, HPA and UALCAN were used to analyze YKT6 mRNA and protein levels, the correlation between YKT6 expression and clinicopathological features and prognosis. YKT6 mRNA and protein expression were verified by qRT-PCR, immunohistochemistry (IHC) and tissue microarrays (TMA). Additionally, lung cancer cell lines were chosen for YKT6 silencing to explore the effects on cell proliferation and migration. The cBioPortal was used to select YKT6-related genes. Protein-protein interaction (PPI) network was created based on STRING database and hub genes were screened, with their expression levels and prognosis values in LUAD analyzed accordingly. YKT6-related genes were enriched by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses.ResultsIn LUAD, YKT6 was distinctly highly expressed with relation to clinical features of staging, smoking, lymph node metastasis, and TP53 mutation. Elevated YKT6 expression was linked to adverse prognosis, serving as an independent unfavorable prognostic factor. Moreover, YKT6 presented high diagnostic value in LUAD patients (AUC = 0.856). Experimental validation indicated that freshly collected LUAD tissues showed significantly high mRNA expression of YKT6. IHC and TMA verified increased YKT6 protein level in LUAD. Knockdown of YKT6 inhibited cell proliferation and promoted apoptosis, with mitigated capability of migration and invasion. The top ten hub genes screened by PPI network were highly expressed in LUAD, and significantly associated with poor prognosis. GO and KEGG analyses showed that YKT6-related genes were mainly involved in cell cycle.ConclusionElevated YKT6 expression is related to poor prognosis of LUAD patients. YKT6 can serve as a novel biomarker for LUAD diagnosis and prognosis. Cell proliferation, migration and invasion was impaired with increased apoptosis upon YKT6 silencing in lung cancer cells. In summary, this study comprehensively uncovered that YKT6 could be identified as a potential prognostic and diagnostic biomarker in LUAD.

Identification of potential core genes in lung cancer and therapeutic traditional Chinese medicine compounds using bioinformatics analysis.

Lung cancer (LC) remains the leading cause of cancer-related death. We identified potential therapeutic targets and traditional Chinese medicine (TCM) compounds for LC treatment. GSE43346 and GSE18842 were derived from the Gene Expression Omnibus (GEO) database and used to identify differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using The Database for Annotation, Visualization and Integrated Discovery (DAVID). Protein-protein interactions were analyzed using STRING and Cytoscape software. Hub gene expression was validated using Gene Expression Profiling Interactive Analysis and the Human Protein Atlas. Kaplan-Meier survival analysis was conducted to evaluate the prognostic value of hub genes in patients with LC. Therapeutic TCM compounds were screened using the Comparative Toxicogenomics Database, and DEGs were largely enriched in biological processes, including cell division and mitotic nuclear division, such as the cell cycle and p53 signaling pathways. Elevated expression of hub genes was observed in LC samples. Overexpression of CDC20, CCNB2, and TOP2A is an unfavorable prognostic factor for postprogressive survival in patients with LC. Paclitaxel, quercetin, and rotenone have been identified as active substances in TCM. CDC20, CCNB2, and TOP2A are novel hub genes associated with LC. Paclitaxel, quercetin, and rotenone can be used as therapeutic agents in TCM.

Neutrophil CD10 and CD16 as markers of generalized infection development in newborns

BACKGROUND: Neonatal sepsis remains a critical concern. Thus, predictors of infection development and generalization should be determined. AIM: This study aimed to determine novel neutrophil surface biomarkers for early prediction of the infections in newborns. MATERIALS AND METHODS: This observational, single-center, prospective, selective, uncontrolled, unblinded experimental study included 261 newborns, with a mean postconceptual age of 38.7 (38.4–39.0) weeks and a mean gestation age of 38.0 (37.7–38.2) weeks. Blood samples were collected into vacutainers on hospitalization day 1. Patients were enrolled between April 2022 and December 2023. The primary endpoints were length of stay in the ICU and total length of hospitalization in patients with normal and decreased values of CD16 and CD10 neutrophils and HLA-DR monocytes. The expression of CD16 on CD62Lhigh neutrophils, total neutrophil CD10, and monocyte HLA-DR were evaluated by flow cytometry. RESULTS: We assessed infants in the “control” (n = 96), “localized infection” (n = 95), and “generalized infection” (n = 70) subgroups. In all patients, a decrease in CD16 was associated with an increase in the median ICU stay from 4 to 8 days (p = 9.33 × 10–8) and total stay from 14 to 22 days (p = 1.58 × 10–7). A decrease in CD10 was associated with an increase in median ICU stay from 4 to 8 days (p = 3.01 × 10–6) and in the total stay from 14 to 19 days (p = 2.78 × 10–5). A decrease in monocytic HLA-DR was associated with a longer ICU and total hospital stay: 4 vs 8 days (p = 7.16 × 10–5) and 14 vs 21 days (p = 4.03 × 10–5), respectively. The median ICU stay in patients with a decrease in CD16 but normal CD10 was 4 days, whereas a decrease in both indicators was associated with prolonged hospital stay to 11 days (p = 2.13 × 10–5). The median hospital stay in patients with decreased CD16 but normal CD10 was 16 days, whereas the drop of both markers was related with increase of hospitalization stay to 23 days (p = 3.36 × 10–6). In the “localized infection” subgroup, low CD16 was associated with an increased median ICU stay from 4 to 6 days (p = 0.010) and the median hospital stay from 13 to 19 days (p = 4.14 × 10–4). In the “generalized infection” subgroup, decreased CD10 was related with prolongation of the median ICU stay from 7 to 11 days (p = 0.011) and the median total duration of hospitalization from 19 to 27 days (p = 0.037). CONCLUSIONS: A decrease in CD10 and CD16 on the neutrophils at the start of clinical is an unfavorable prognostic factor of infectious and septic complications in newborns.

RNF113A as a poor prognostic factor promotes metastasis and invasion of cervical cancer through miR197/PRP19/P38MAPK signaling pathway

It has been discovered that aberrant expression of RNF113A plays a significant role in various diseases, including esophageal cancer, hepatocellular carcinoma, and X-linked trichothiodystrophy syndrome. Nevertheless, its functional implications in cervical cancer (CC) remain unclear. The objective of this study was to investigate the role of RNF113A in both the development and prognosis of CC. To achieve this objective, a total of sixty cases were included in the follow-up investigation. The findings revealed a significant up-regulation of RNF113A protein in CC tissues compared to paired paracancerous tissues, and a high expression level of RNF113A was strongly associated with malignant phenotypes such as lymph node metastasis, differentiation degree, depth of invasion, and FIGO stage. Meanwhile, RNF113A was found to be an independent prognostic risk factor, with its high expression significantly correlating with a reduced overall survival period in patients. To elucidate the underlying cause and mechanism of the unfavorable prognosis associated with RNF113A, comprehensive functional investigations were conducted both in vitro and in vivo.Interestingly, it was revealed that RNF113A promoted migration and invasion while inhibiting apoptosis of CC cells, thereby contributing to a poor prognosis. Mechanistically, RNF113A regulated the progression and prognosis of CC through the miR197/Prp19/p38Mark signaling pathway. Overall, our findings underscore the potential clinical significance of RNF113A as an unfavorable prognostic factor in CC.

500. PRIMARY ESOPHAGEAL LYMPHOMA: UNDERSTANDING PROGNOSTIC FACTORS AND OUTCOMES

Abstract Background Primary Esophageal Lymphoma (PEL) represents a rare subtype of gastrointestinal lymphomas, posing unique diagnostic and therapeutic challenges. Given its rarity, comprehensive insights into its prognostic factors and outcomes remain limited. This study examines the epidemiology, treatment modalities, and outcomes of PEL, aiming to identify significant prognostic factors that influence patient survival. Methods A systematic review of the literature was conducted across PubMed/Medline and Scopus databases, focusing on cases of adult PEL. Data extraction included demographic information, treatment modality, and patient outcomes. Survival rates were calculated, and prognostic factors were analyzed through unifactorial analysis. Results Out of 56 studies, 69 cases of PEL were analyzed, with a male-to-female ratio of 2.8:1 and mean age of 55.5 years. Patients were predominantly treated with chemotherapy (52.1%) while 20% underwent surgical treatment. The mean survival reported was 49.3 months with one-, three-, and five-year survival rates of 84.5%, 72.3%, and 28.9%, respectively, exhibiting a less favorable prognosis compared to common lymphoma types. Survival analysis revealed that local lymphadenopathy had a significant impact on prognosis (p=0.008), while gender, age, treatment approach, and type of lymphoma were not significant determinants of survival. Immunocompromised status showed a marginally significant effect on survival (p= 0.053). Discussion The study highlights the less favorable prognosis of PEL compared to more common lymphomas, emphasizing the importance of recognizing patients with unfavorable prognostic factors such as local lymphadenopathy and immunocompromised status. The findings advocate for the establishment of an international patient registry to better understand and manage PEL, aiming to standardize diagnostic criteria and treatment strategies.

628. GUSTAVE ROUSSY IMMUNE SCORE IS A PROGNOSTIC MARKER IN PATIENTS WITH ESOPHAGEAL CANCER AFTER NEOADJUVANT THERAPY: A MULTICENTER RETROSPECTIVE STUDY

Abstract Background GRIm-Score (Gustave Roussy Immune Score), a novel nutritional and inflammatory-based prognostic score, is an unfavorable prognostic factor in patients with esophageal carcinoma (EC). However, the prognostic importance of GRIm-Scores after neoadjuvant chemo-radiotherapy in these patients remains unclear. Methods A retrospective study including 432 EC patients undergoing surgical resection was performed. The GRIm-Score was calculated by lactate dehydrogenase (LDH), neutrophil-lymphocyte ratio (NLR), and albumin (ALB). The over survival (OS) and disease-free survival (DFS) were analyzed for the current study with Cox regression analyses, Kaplan-Meier methods, and propensity score matching (PSM). Results There were 374 (86.6%) men and 58 (13.4%) women with a mean age of 62.1 ± 7.7 years (range: 39-80 years). After PSM, cohorts consisted of 55 patients in the high GRIm-Score group and 55 in the low GRIm-Score group. Patient with a high GRIm-Score had poor OS (Cohort: p = 0.001; PSM: p = 0.007) and DFS (Cohort: p = 0.001; PSM: p = 0.008). The GRIm-Score, instead of NLR, LDH, or ALB in multivariate analyses, was an independent prognostic factor for OS (p = 0.019) before PSM. However, after PSM, it was a powerful independent prognostic factor for both OS (p = 0.028) and DFS (p = 0.039). Subgroup analyses showed that GRIm-Score could identify cases with worse OS or DFS among pT3-4 patients, indicating the complementary role of GRIm-Score in the decision-making of adjuvant therapy. Conclusion The GRIm-Score was an independent prognostic marker in patients with EC undergoing surgical resection after neoadjuvant therapy. Our study is also the first to discuss the prognostic value of GRIm-Score in patients with EC after neoadjuvant treatment.

236. THE ROLE OF ADJUVANT THERAPY FOLLOWING NEOADJUVANT CHEMORADIOTHERAPY AND ESOPHAGECTOMY IN ESOPHAGEAL CANCER

Abstract Background The objective of this study was to assess the role of adjuvant therapy following neoadjuvant chemoradiotherapy and esophagectomy in esophageal squamous cell carcinoma (ESCC). Methods We conducted a retrospective analysis involving 506 ESCC patients who underwent trimodal therapy. The clinical significance of adjuvant therapy on overall survival and disease-free survival was evaluated using Kaplan–Meier curves with log-rank tests, the Cox regression model, and a forest plot displaying hazard ratios (HR) with 95% confidence intervals. Results Among the 506 patients who had clinically positive lymph nodes and no metastasis after neoadjuvant chemoradiotherapy and esophagectomy, those who received adjuvant therapy exhibited shorter post-resection overall survival (OS) and disease-free survival (DFS), with a statistically significant difference between the two groups (Log-Rank, OS: P = 0.002; DFS: P &amp;lt; 0.001). Adjuvant therapy was not identified as an independent prognostic factor for OS (HR: 1.249; 95% CI: 0.869-1.796; P = 0.230), but it was a significantly unfavorable independent prognostic factor for DFS (HR: 1.868; 95% CI: 0.349-2.586; P &amp;lt; 0.001). Conclusion Adjuvant therapy is associated with poorer overall survival (OS) and disease-free survival (DFS) outcomes in ESCC patients with ypTNM stage I and II on final pathology following neoadjuvant chemoradiotherapy and esophagectomy. However, there was no significant difference observed in patients with ypTNM stage III or IV. Therefore, it is not recommended to undergo postoperative adjuvant therapy for patients with ypTNM stage I and II ESCC. However, for patients with ypTNM stage III and IV ESCC, further research is needed to explore adjuvant treatment strategies.

Hyperleukocytosis in Pediatric Patients with Acute Lymphoblastic Leukemia: Demographic and Clinical Characteristics.

Background: Hyperleukocytosis, defined as a total leukocyte count of more than 50,000/mm3 leukocytes, occurs in almost one in five children with acute lymphoblastic leukemia (ALL). It represents an unfavorable prognostic factor in this disease. The aim of the following study was to describe demographic and clinical features in patients with hyperleukocytosis and their relationship with leukocyte count. Methods: We retrospectively analyzed the available medical data of patients with ALL diagnosed and treated at the University Children's Hospital in Lublin between 2017 and 2024. Results: Of the 97 patients, 10 (10.3%) had hyperleukocytosis. They were significantly more likely to be older boys diagnosed with T-ALL. The group with hyperleukocytosis had a higher mortality rate. The presence of hyperleukocytosis also correlated with the presence of petechiae, thrombocyte and neutrophil counts, and LDH activity. Patients with hyperleukocytosis also experienced a higher incidence of infections as a complication of therapy as leukocyte counts increased. Conclusions: Hyperleukocytosis, although rare, is an important factor in the course of ALL, both clinically and prognostically.

ZNF8 promotes progression of gastrointestinal cancers via a p53-dependent mechanism

p53 is a critical tumor suppressor, and the disruption of its normal function is often a prerequisite for the development or progression of tumors. Our previous works revealed that multiple members of Krüppel-associated box (KRAB) domain zinc-finger proteins (KZFPs) family regulate p53 transcriptional activity by interacting with it. But the tumor biology functions of these members have not been fully elucidated. Here, the pan-cancer analysis related to gastrointestinal cancers (GICs) revealed that ZNF8, a p53-interacting protein, is an unfavorable prognostic factor for patients with malignancies. ZNF8 interacts with p53 and further depresses its transcriptional activity in colon cancer cells. The knockdown of ZNF8 or the overexpression of ZNF8 inhibits or facilitates the in vitro colony formation, migration, invasion, and angiogenesis of p53+/+ colon cancer HCT116 cells, HepG2 cells and EC109 cells rather than p53−/− colon cancer HCT116 cells and p53-knockout HepG2 cells, respectively. Xenograft experiments conducted in vivo also showed that the knockdown of ZNF8 in p53+/+ but not in p53−/− HCT116 cells curbs the tumor growth and metastasis to lung, leading to an extended life span for tumor-bearing mice. Clinically, two independent immunohistochemistry cohorts of colon cancer and esophageal cancer also indicated that ZNF8 is higher expression in carcinoma tissues than adjacent tissues and this is associated with worse overall survival outcomes in patients without harboring p53 mutation. Together, our results provide insight into the p53-specific tumor oncogenic function of ZNF8. ZNF8 may prove to be a potential target for GICs treatment.

The intricate relationship between obesity, type 2 diabetes and female breast cancer: A retrospective study of 335 women.

Type 2 diabetes (T2D) is a risk factor for female breast cancer (FBC). Obesity has also been associated with FBC, also depending on menopausal status. This study aimed to evaluate the impact of obesity and T2D on the development, aggressiveness, and invasiveness of FBC. Demographic, clinical, and histopathological data from 335 women with FBC were collected, and analyzed according to weight category (102 normal weight, 117 overweight, and 116 living with obesity) and the presence/absence of T2D. Age at oncologic diagnosis was not statistically significantly different for body weight; women with overweight or obesity were more likely to have an oncologic diagnosis after menopause than normal weight (p<0.001). The presence of overweight/obesity and T2D seemed to be associated with a higher incidence of metastasis, recurrence, and triple-negative breast cancer (TNBC) subtype (p<0.001). Excess body weight was also associated with high histologic grade (G3) (p<0.005). These results confirm excess body weight and T2D as unfavorable prognostic factors in terms of the presence of the TNBC subtype, tumor metastasis, recurrence, and aggressiveness (G3 and Ki-67>20%). This study highlights the importance of prevention in all women, with early screening, and adequate nutritional programs.

Risk Factors for Rapid Cognitive Decline in Amyloid-Negative Individuals Without Cognitive Impairment or With Early-Stage Cognitive Loss in Screening Tests.

Although rapid cognitive decline (RCD) is an important unfavorable prognostic factor, not much is known about it, especially in amyloid-negative individuals. The purpose of this study was to investigate risk factors for RCD in amyloid-negative individuals. We retrospectively enrolled 741 individuals who were either cognitively unimpaired or had early-stage cognitive ability loss and who underwent 18F-florbetaben (FBB) (n = 402) or 18F-flutemetamol (FMM) (n = 339) PET/CT. Based on visual and semiquantitative (SUV ratio [SUVR]-based) analysis, the following amyloid-negative groups were established: visual-negative FBB (n = 232), visual-negative FMM (n = 161), SUVR-negative FBB (n = 104), and SUVR-negative FMM (n = 101). Univariable and multivariable logistic regression analyses were performed for RCD using 5 SUVRs, 5 cortical thicknesses, and 5 neuropsychological domains and clinico-demographic factors. In the amyloid-negative groups, a decline in language function was commonly identified as a significant risk factor for RCD (P = 0.0044 in the visual-negative FBB group, P = 0.0487 in the visual-negative FMM group, P = 0.0031 in the SUVR-negative FBB group, and P = 0.0030 in the SUVR-negative FMM group). In addition, declines in frontal/executive function, frontal SUVR, and parietal SUVR; a longer duration of education; and mild cognitive decline in the amyloid-negative groups were also significant risk factors for RCD. Even in amyloid-negative individuals without cognitive impairment or with early-stage cognitive ability loss, those with decreased language and frontal/executive functions on neuropsychological testing are at risk of progression to RCD.

IDH2 mutation accelerates TPO-induced myelofibrosis with enhanced S100a8/a9 and NFκB signaling in vivo.

IDH2 mutation is an unfavorable prognostic factor in patients with primary myelofibrosis (PMF) but its effect on myelofibrosis (MF) remains largely unclear. In this study, we aimed to elucidate the roles of IDH2 mutation in the development and progression of MF by transcriptomic and molecular techniques using the Idh2 R172K transgenic mice. We found that thrombopoietin (TPO)-overexpressed Idh2 R172K (Idh2 R172K +TPO) mice had accelerated progression to MF, compared with TPO-overexpressed Idh2-wild (WT +TPO) mice, showing activation of multiple inflammatory pathways, among which nuclear factor κB (NFκB) was the most significantly enhanced. Single-cell transcriptomes of the marrow cells in early MF showed that S100a8/a9 expression was mainly confined to neutrophil progenitors in the WT + TPO mice, but highly expressed in several types of myeloid precursor cells, including the megakaryocyte progenitors in the Idh2 R172K + TPO group. Furthermore, Idh2 R172K mice at age of 18 months had larger spleens, increased S100a8/a9-Tlr4 expression, and elevated serum S100a8/a9 levels compared with WT mice. PMF patients with IDH2 mutations had higher bone marrow plasma S100A8/A9 levels than those without IDH2 mutations. Overall, our findings showed that IDH2 mutation induced proinflammatory effects, which further exacerbated MF, as evidenced by the increase in S100a8/a9 levels and NFκB hyperactivation in Idh2 R172K + TPO mice.

MYCN in neuroblastoma: The kings' new clothes and drugs

Deregulated levels of the MYCN oncogene contribute to the tumorigenesis of several human tumors including neuroblastoma. MYCN amplification classifies neuroendocrine tumors as high-risk and as a consequence is an unfavorable prognostic factor. MYCN has long been primarily described as a transcription factor, which binds to active promoters after heterodimerizing with MAX and directly regulates gene expression programs. New findings show that MYC proteins have novel oncogenic functions that are tumor-promoting and go beyond the regulation of gene expression. This review describes how MYCN continuously drives tumor progression by forming various protein complexes, for example to resolve torsional stress, coordinate transcription and replication, repair DNA damage and regulate R-loops. Interfering with the described processes as well as interfering with MYCN chromatin binding emerge as novel treatment strategies to indirectly target the oncoprotein. Furthermore, we describe the role of MYCN in metabolism and we review how these newly described functions of MYCN could be used as vulnerabilities for MYCN-driven tumors. Recent studies show that MYC proteins are capable of multimerizing at sites of genomic instability to protect cancer cells from stress. Additionally, MYCN can bind aberrant RNA transcripts, another feature to enhance the stress resilience of cancer cells, once again highlighting the oncogenic potential of MYC. Taken together, we show that the diverse functions of MYCN depend on its temporal and spatial dynamic interactome, making those interaction partners and functions crucial factors in the treatment of MYCN-related cancer.

Pitfalls and complications in the treatment of clubfoot by the Ponseti method: A literature review

BACKGROUND: At every step of clubfoot treatment using the Ponseti method, pitfalls leading to complications, both minor and potentially dangerous, may occur. Any doctor involved in the treatment of clubfoot may encounter similar difficulties in their practice; however, publications devoted to this problem are limited, and in some cases, experts cannot reach a consensus regarding the interpretation of actions that entail undesirable consequences. AIM: This study aimed to analyze pitfalls and complications associated with the Ponseti method for the treatment of clubfoot using modern literature data. MATERIALS AND METHODS: Articles were searched for in PubMed, Science Direct, Google Scholar, and eLibrary databases using the following keywords: idiopathic clubfoot, Ponseti method, serial casting, bracing, Achilles tenotomy, pitfalls, and complications. The search was performed without language restrictions. Most of the studies included were published no more than 10 years ago. RESULTS: Current literature data present on the pitfalls and complications encountered in the treatment of clubfoot using the Ponseti method. The review also covered associated complications and unfavorable prognostic factors. The restrictive measures during the COVID-19 pandemic have affected the treatment of clubfoot. CONCLUSIONS: Analysis of the causes of pitfalls and complications and control of unfavorable prognostic factors will help reduce complications of clubfoot treatment using the Ponseti method and optimize orthopedic care for children.

HER2-negative or low expression as an unfavorable prognostic factor in patients with stage I/II uterine carcinosarcoma.

Uterine carcinosarcoma (UCS) is uncommon high-grade endometrial cancer with limited treatment options. We evaluated the prognostic significance of human epidermal growth factor receptor 2 (HER2) expression and HER2 gene amplification within large cohorts of UCS, and clarify clinicopathologic characteristics of HER2-low UCS. We examined HER2 protein expression in 148 patients of UCS using in vivo diagnostic HER2 immunohistochemistry (IHC) kits and HER2 gene amplification using fluorescence in situ hybridization (FISH) in 72 patients. HER2 IHC score was evaluated according to the latest American Society of Clinical Oncology/College of American Pathologists criteria for gastric cancer, which was negative in 41 patients, low expression of 1+ was observed in 57 patients, and HER2 high expression was observed in 50 patients (2+ in 38 and 3+ in 12 patients). There was no significant statistical difference in clinicopathological characteristics based on HER2 protein expression status. HER2 negative and low expression compared to high expression revealed poor overall survival in stage I/ II. The concordance between IHC and FISH results were relatively low compared to other cancer types (HER2 IHC score 1+, 2+, and 3+ were 5%, 15%, and 50%), and combining these results was not efficient as a prognostic factor in UCS. In contrast, the HER2 IHC score alone was a prognostic factor in stage I/II UCS. HER2 low group did not show specific clinicopathologic features. Since the HER2 IHC score low in advanced UCS is a predictive factor, stratification of UCS using HER2 IHC score for HER2 IHC score low group and developing adjuvant therapy may be proposed in the near future.

Analysis of the significance of echocardiographic signs of right ventricular dysfunction for predicting the outcome of heart failure with reduced left ventricular ejection fraction

Objective: to determine the ultrasound signs of right heart dysfunction, which increase the prognostic value of the recommended parameters of left ventricular (LV) dysfunction in patients with heart failure with reduced ejection fraction (HFrEF).Materials and methods. The prospective study included 79 patients with HFrEF LV with clinical manifestations of chronic heart failure functional class III according to the New York Heart Association (HF NYHA Class III) in 52 patients (65.8%) and HF NYHA Class IV in 27 (34.1%). The primary end point was death during a follow-up period of up to 3 years while waiting for heart transplantation.Results. Overall mortality was 33 patients (41.7%), 17 (21.5%) during the 1st year of follow-up. Regression analysis revealed the following independent ultrasound predictors of poor prognosis: LV ejection fraction on 3D-echocardiography (3DE LVEF), p = 0.014; global longitudinal strain of the LV (GLS LV), p = 0.010, and of the interventricular septum basal segment (IVSLS BS), p = 0.012; mean longitudinal strain of the basal segment of the right ventricle free wall (FWLS BS RV), p = 0.003. Changes in the configuration and dilatation of the LV cavity, an increase in LV end-diastolic pressure, impaired contractility, and strain of the LV myocardium can affect the function of the right ventricle (RV) through the common interventricular septum (IVS). Dilatation of the RV due to an increase in the end diastolic area (RV EDA) of more than 30 cm2 (p = 0.012) and end systolic area (RV ESA) of more than 25 cm2 (p = 0.001), an increase in the volume of the right atrium (3DE AKI) of more than 100 ml (p = 0.036), and a decrease in the % inspiratory collapse of the inferior vena cava (% IVC) less than 30% (p = 0.005) demonstrated a prognostic significance in the observed patients. A decrease in the deformation properties of the pancreas due to the longitudinal component and impaired strain of the basal segment makes a greater contribution to RV dysfunction (FWLS BS, % &lt; -15% (p &lt; 0.001)).Conclusions. RV dysfunction in patients with HFrEF is an unfavorable prognostic factor, independently associated with existing LV dysfunction. The most significant ultrasound sign for surveillance prediction of patients with LV HFrEF and RV dysfunction are indicators of ventricular myocardial deformation. Remodeling of the right chambers and dysfunction of the RV is a trigger for the separation of the RV and pulmonary artery, which ultimately leads to adverse outcomes.

Survival and lethal outcomes in Orenburg population of patients with systemic lupus erythematosus

Currently, the prognosis for systemic lupus erythematosus (SLE) has improved significantly, but the relative risk of death in these patients is stillhigher than in the general population. Thrombotic complications are one of the leading causes of death in SLE. Objective: to analyze the survival rate and structure of lethal outcomes in Orenburg population of patients with SLE, including deaths due to thrombotic complications. Material and methods. A two-stage study of SLE progression and patient survival was conducted from 2007 to 2022. Clinical signs of the diseasewere analyzed in all patients at baseline (n = 68) and in survivors (n = 50) after 15 years. The median age at the time of enrolment in the study was 35 [29; 45] years, the disease duration – 7.5 [3; 13.5] years. During the second stage, the characteristics of the course of the disease in the survived patients and the causes of death in those who died over 15-year period were determined. Results and discussion. The 10-, 15- and 20-year survival rates in Orenburg population of patients with SLE reached 98.5, 95.5 and 86.3%, respectively. During this period, 18 (26.5 %) deaths were registered, the median age of the deceased was 48.5 [39; 57] years, and the duration of the disease was 22 [16; 30] years. The most common causes of death were thrombotic complications (n = 14, 78 %) due to antiphospholipid syndrome, lupus nephritis, and arterial hypertension. Less frequently, infectious complications were the cause of death (n = 4, 22 %). Patients with thrombotic complications had a 20-year survival rate of 80.2% that was significantly lower than in the SLE group without thrombosis. Conclusion. The results obtained allow to consider the presence of thrombotic complications in patients with SLE in Orenburg population as an unfavorable prognostic factor.