Highest Prognostic Significance Research Articles

Integrated multi-level omics profiling of disulfidptosis identifis SPAG4 as an innovative immunotherapeutic target in glioblastoma

ObjectiveTo investigate the association between disulfidptosis-related genes (DFRGs) and patient prognosis, while concurrently identifying potential therapeutic targets in glioblastoma (GBM).MethodsWe retrieved RNA sequencing data and clinical characteristics of GBM patients from the TCGA database. We found there was a total of 6 distinct clusters in GBM, which was identified by the t-SNE and UMAP dimension reduction analysis. Prognostically significant genes in GBM were identified using the limma package, coupled with univariate Cox regression analysis. Machine learning algorithms were then applied to identify central genes. The CIBERSORT algorithm was utilized to assess the immunological landscape across different GBM subtypes. In vitro and in vivo experiments were conducted to investigate the role of SPAG4 in regulating the proliferation, invasion of GBM, and its effects within the immune microenvironment.Results23 genes, termed DFRGs, were successfully identified, demonstrating substantial potential for establishing a prognostic model for GBM. Single cell analysis revealed a significant correlation between DFRGs and the progression of GBM. Utilizing individual risk scores derived from this model enabled the stratification of patients into two distinct risk groups, revealing significant variations in immune infiltration patterns and responses to immunotherapy. Utilizing the random survival forests algorithm, SPAG4 was identified as the gene with the highest prognostic significance within our model. In vitro studies have elucidated SPAG4’s significant role in GBM pathogenesis, potentially through the regulation of fatty acid metabolism pathways. Our in vivo investigations using a subcutaneous xenograft model have confirmed SPAG4’s influence on tumor growth and its capacity to modulate the immune microenvironment. Advanced research hints that SPAG4 might achieve immune evasion by increasing CD47 expression, consequently reducing phagocytosis.ConclusionsThese findings highlight SPAG4 as a potential GBM therapeutic target and emphasize the complexity of the immune microenvironment in GBM progression.

A gene module identification algorithm\xa0and its applications\xa0to identify gene modules and key genes of hepatocellular carcinoma

To further improve the effect of gene modules identification, combining the Newman algorithm in community detection and K-means algorithm framework, a new method of gene module identification, GCNA-Kpca algorithm, was proposed. The core idea of the algorithm was to build a gene co-expression network (GCN) based on gene expression data firstly; Then the Newman algorithm was used to initially identify gene modules based on the topology of GCN, and the number of clusters and clustering centers were determined; Finally the number of clusters and clustering centers were input into the K-means algorithm framework, and the secondary clustering was performed based on the gene expression profile to obtain the final gene modules. The algorithm took into account the role of modularity in the clustering process, and could find the optimal membership module for each gene through multiple iterations. Experimental results showed that the algorithm proposed in this paper had the best performance in error rate, biological significance and CNN classification indicators (Precision, Recall and F-score). The gene module obtained by GCNA-Kpca was used for the task of key gene identification, and these key genes had the highest prognostic significance. Moreover, GCNA-Kpca algorithm was used to identify 10 key genes in hepatocellular carcinoma (HCC): CDC20, CCNB1, EIF4A3, H2AFX, NOP56, RFC4, NOP58, AURKA, PCNA, and FEN1. According to the validation, it was reasonable to speculate that these 10 key genes could be biomarkers for HCC. And NOP56 and NOP58 are key genes for HCC that we discovered for the first time.

Prognostic effect of preoperative neutrophil-lymphocyte ratio is related with tumor necrosis and tumor-infiltrating lymphocytesin hepatocellular carcinoma.

Blood neutrophil-to-lymphocyte ratio (NLR) is one index representing systemic inflammation, and high preoperative NLR has been suggested as an independent prognostic factor in HCC. However, the NLR cutoff value with the highest prognostic significance is not consistent, and the mechanism of this phenomenon remains unclear. Preoperative NLR was calculated from complete blood counts obtained before 14days from operation day in 234 patients who underwent curative resection for primary HCC. The presence of tumor necrosis and degree of tumor-infiltrating lymphocytes (TILs) was determined histologically. High preoperative NLR (≥ 2.5) was observed in 28 (12.0%) of 234 HCCs and was significantly associated with younger age, larger tumor size, high Edmonson grade, microvascular invasion, major portal invasion, advanced AJCC T or BCLC stage, and low albumin level. Patients with high preoperative NLR showed shorter disease-specific survival (DSS) (p = 0.002) and a tendency for shorter recurrence-free survival (RFS) (p = 0.096). High preoperative NLR was associated with presence of tumor necrosis and low TIL. On multivariable analysis, preoperative NLR was an independent prognostic factor for DSS (hazard ratio: 2.050 (95% confidence interval 1.139-3.691), p = 0.017). However, the independent prognostic effect of NLR for DSS disappeared when tumor necrosis and TILs were added as co-variables. High NLR is an independent prognostic factor in patients with HCC who undergo curative resection. The prognostic effect of high NLR might originate from the prognostic effect of tumor necrosis or TILs.

Functional geometry of the left ventricle in dilated cardiomyopathy before and after resynchronization therapy

Aim. To analyse quantitative parameters of functional geometry of the left ventricle (LV) in patients with dilated cardiomyopathy (DCMP), to assess the changes in cardiac resynchronization therapy (CRT) and to reveal the relation of functional geometry of LV and its contractility. Material and methods. In DCMP patients group, who were directed to CRT according to the Guidelines of Russian Arhythmologists Society 2013, echocardiographic study was performed before and after CRT (at 5th day). Based on two-dimensional LV pictures the parameters were assessed in the cycle, as segmented kinetics of wall contraction, LV shape dynamics: sphericity index, Hibson, conicity of apical zone, Fourier shape complexity. Results. In DCMP patients the decrease of global ejection fraction <35% was followed with a decrease of systolic change of all sectoral squares of LV and enhancement of dimensional heterogeneity and asynchronicity of regional wall motion during cardiac cycle comparing to controls. There was negative correlation revealed between the proposed index of non-homogeneity and global ejection fraction. All shape indexes point to more spherical shape of LV in DCMP. However, opposite to controls, DCMP patients lack dynamical changes of shape indexes during cardiac cycle, that witnesses on significant disorders of wall motion coordination in cycle. After CRT there is significant re-coordination of LV wall motion, followed by restoration of non-homogeneity pattern of segmental kinetics, decrease of nonhomogeneity indexes and of asynchronicity and appearance of the dynamics of shape indexes changes during cardiac cycle. It was shown that end-systolic indexes of sphericity shape complexity of Fourier make it to separate patients who respond or does not on therapy, by clinical parameters. Changes of sphericity index between end diastole and end systole <3,5% selects patients with the highest prognostic significance comparing with other parameters. Conclusion. Disorders of functional geometry of the LV, particularly an increase of non-homogeneity and asynchronicity parameters of the regional motion of the wall, decrease of dynamical changes of LV sphericity indexes, might influence contractility and pumping function of the heart, and have diagnostic significance in selection of patients responding to CRT.

Reproducibility and Prognostic Variability of Grade and Lamina Propria Invasion in Stages Ta, T1 Urothelial Carcinoma of the Bladder

We assessed the reproducibility and prognostic variability of grade and lamina propria invasion in stages Ta, T1 urothelial carcinoma of the bladder. A total of 130 consecutive stages Ta, T1 urothelial carcinomas routinely diagnosed by 15 pathologists (original diagnosis) were reviewed by 3 independent experienced pathologists using 1999 WHO criteria (diagnoses 1 to 3 and reviewer consensus diagnosis). Interreviewer disagreement cases were blindly reviewed again. Each remaining disagreement case was discussed in a multihead microscope session to attempt to solve remaining disagreements. In cases of continuing disagreement the majority diagnosis on stage and grade was considered the consensus diagnosis. Stage progression at followup was the dependent variable. Stage progression-free Kaplan-Meier survival curves and hazard ratios of each stage and grade diagnosis were calculated and prognostic variability was determined. There was complete interobserver agreement on stage and grade among reviewers in 80% and 59% of cases, while it was 87.7% and 75.4%, respectively, after the second review. More than 1 grade difference occurred in 1.5% of cases (0% after the second review). The consensus and original diagnoses agreed on stage and grade in 68.5% and 62.3% of cases, respectively. Assignment of individual cases to 1 category of the 1999 WHO classification per reviewer varied considerably. The incidence of cases classified as stage T1 grade 3 by the reviewers was between 12.3% and 18.9% (average 14.1%). Consensus diagnosis grade had the strongest prognostic value (HR 68.8, range 8.9 to 528.0). Of the 63 original diagnoses of stage T1 tumors the consensus diagnosis down staged 35 (55.6%) to Ta and up staged 8 (12.7%) to T2-3. Progression was more common in the 20 consensus diagnosis stage T1 cases (5 or 25%) than in the 55 original diagnosis stage T1 cases (11 or 20%). Original diagnosis stage T1 tumors that were down staged by the consensus diagnosis showed less progression than consensus diagnosis confirmed stage T1 tumors (17% versus 25%). The prognostically worst subgroup (T1 grade 3) also showed considerable prognostic variation among reviewers (28% to 76% at 5 years of followup), in that the consensus diagnosis again had the highest prognostic significance (HR 3.5, range 1.2 to 10.2). At the end of the study all pathologists expressed that they were regularly uncertain about stage and grade assessment in an individual case in a considerable percent of all cases. Observer prognostic variability in staging and grading is considerable with potentially strong implications for patients. Interobserver variation did not decrease using the new 1999 WHO grading classification.

Rapid and prognostically valid quantification of immunohistochemical reactions by immunohistometry of the most positive tumour focus. A prospective follow-up study on breast cancer using antibodies against MIB-1, PCNA, ER, and PR.

The prognostic significance of immunohistochemical markers for cell proliferation [MIB-1, proliferating cell nuclear antigen (PCNA)] and hormone receptor analysis [oestrogen receptor (ER), progesterone receptor (PR)] was tested by means of immunohistometry in a series of 103 breast cancer patients in comparison with the lymph node status N, the tumour size T, histomorphological grading, and the biochemical ER and PR status. Immunohistochemical reactions were performed on 2 microns sections from paraffin-embedded tissue, using an indirect peroxidase method. The proportion of immunostained tumour cell nuclei was determined using a TV-image analysis system. Measurements were performed using a 20 x objective on 40 viewing fields (1.94 mm2, MIB-1 and PCNA) or 20 viewing fields (0.97 mm2, ER and PR). The mean immunopositivity of all viewing fields and the value of the most immunopositive viewing field (MIB-1max, PCNAmax, PRmax, ERmax) were calculated. The mean values and the maximal values were highly correlated (r = 0.903, P < 0.001). After 1:2:1 quantilization, 84.2 per cent of the 412 single measurements revealed mean and maximal values in the same category (P < 0.0001). For each of the four immunohistochemical markers, the prognostic significance of the maximal values was higher than that of the mean values. The highest prognostic significance was found for MIC-1max (P = 0.0002), followed by PRmax (P = 0.0046), ERmax (P = 0.0154), and PCNAmax (P = 0.0161). From the results of a Cox model, a 'prognostic index (PI)' was developed, ranging from -1 to 8: PI = 2 x N + T + MIB-1max-PRmax. The four groups of patients with PI values of < 2, 2-3, 4-5, and > 5 revealed significantly different 7.5-year survival probabilities (P < 0.0001). The simplicity of the PI makes it a clinically useful, routinely applicable, and understandable parameter in the surgical pathology of breast carcinoma.

Studies for Estimating the Biologic Behavior and Prognosis of Paragangliomas in the Head and Neck

Despite a large number of histopathologic and immunohistochemical studies, the biologic behavior and prognosis of paragangliomas (glomus tumors) of the head and neck still remain uncertain. In the present study 36 specimens from 32 patients who underwent surgery for a paraganglioma were examined. The examinations included routine histology, quantitative DNA analysis based on image cytometry, immunohistochemical detection of the proliferating cell nuclear antigen (PCNA) along with visualization of nucleolar organizer regions (AgNOR). According to LeCompte, the paragangliomas were histologically divided into three subcategories: 16 patients had a paragangliomatous tumor. 14 patients had an adenomatous tumor, and 6 patients had an angiomatous tumor. Quantitative DNA analysis revealed three categories of tumors with characteristical DNA pattern; DNA type I tumors were pure diploid, DNA type II tumors had stemlines at 2c and 4c and were therefore recognized as diploid-tetraploid. Aneuploid cells were not apparent in these two groups. DNA type III tumors had stemline ploidies exceeding 2c and 4c. Aneuploid cells were present in all of these tumors. The biologic behavior of these lesions therefore must be recognized as suspicious. DNA type III tumors and adenomatous tumors showed the highest values for the PCNA scores, indicating a higher proliferation rate and a more rapid growth pattern in these lesions. Twenty patients could be followed over a period of up to 110 months. Five of these patients developed a recurrent tumor. All of them had DNA type III tumors. The DNA indices showed significantly higher values in the recurrent tumor group. The 2c deviation index (DI) and the entropy value had the highest prognostic significance. No correlation to clinical follow-up was found for the AgNOR score. Based on these results, prognostic indices for paragangliomas were developed: patients with a tumor having a 2c DI exceeding 2.0, entropy value of more than 4.0. 5c exceeding rate more than 8.0, and a PCNA score more than 20.0% can be recognized as being at high-risk for developing recurrent disease.

The adenocarcinoma of the cervix: study of 81 cases (author's transl)

The present study deals with 81 primary adenocarcinomas of the uterine cervix diagnosed and treated in the departement of gynecology and obstetrics of the University of Zürich from 1950 through 1977. Clinical and morphological data such as patients age, character and duration of symptoms, clinical and anatomical stage, histological differentiation of the tumor and therapy were recorded and analysed in relation to patients survival. Of all these factors the stage of the tumor at time of diagnosis proved to have the highest prognostic significance.