Pathological Stage Research Articles

Exosomal PSM-E inhibits macrophage M2 polarization to suppress prostate cancer metastasis through the RACK1 signaling axis

BackgroundIt is well-established that understanding the mechanism of prostate cancer (PCa)-associated metastasis is paramount for improving its prognosis. Metastasis is known to involve the communication between tumor-associated macrophages (TAMs) and tumor cells. Exosomes are crucial in mediating this intercellular communication within the tumor microenvironment. Nonetheless, the role of exosomal proteins in PCa metastasis is not yet fully understood. Here, we investigated the mechanisms of prostate cancer-derived exosomal PSM-E on regulating macrophage M2 polarization to suppress tumor invasion and metastasis.MethodsPSM-E levels in exosomes were detected by transmission electron microscopy and Western blotting analysis. The diagnostic value of urine-derived exosomal PSM-E in PCa were evaluated by LC-MS/MS, correlation analysis, and ROC curves analysis. The mechanisms underlying the inhibitory effect of exosomal PSM-E on the M2 polarization of macrophages was investigated by co-IP, IHC staining, and PCa tumorigenesis model, etc.ResultsWe revealed that exosomal PSM-E is upregulated in exosomes derived from the serum and urine of PCa patients. Clinically, an elevated exosomal PSM-E expression in urine is significantly correlated with an advanced pathological tumor stage and a high Gleason score. Our research also revealed that exosomal PSM-E inhibits prostate cancer cell proliferation, invasion, and metastasis by suppressing macrophage polarization in vitro and in vivo. Furthermore, we provided compelling evidence that exosomal PSM-E inhibits M2 polarization of macrophages by recruiting RACK1 and suppressing the FAK and ERK signaling pathways, consequently suppressing PCa invasion and metastasis. Furthermore, we found that the protease-associated domain of PSM-E and the fourth tryptophan-aspartate repeat of RACK1 are crucial for the interaction between PSM-E and RACK1.ConclusionsNotably, exosomes carrying PSM-E from PCa urine could potentially serve as a biomarker for PCa, and targeting exosomal PSM-E may represent a strategy for preventing tumor progression in this patient population.

Worse Clinical and Survival Outcomes in Breast Cancer Patients Living in Puerto Rico Compared to Hispanics, Non-Hispanic Blacks, and Non-Hispanic Whites from Florida.

Herein, we report the characterization of four cohorts of breast cancer patients including (1) non-Hispanic Whites in Florida, (2) non-Hispanic Blacks in Florida, (3) Hispanics in Florida, and (4) Hispanics in Puerto Rico. Data from female breast cancer patients were collected from cancer registry (n = 9361) and self-reported patient questionnaires (n = 4324). Several statistical tests were applied to identify significant group differences. Breast cancer patients from Puerto Rico were least frequently employed and had the lowest rates of college education among the groups. They also reported more live births and less breastfeeding. Both Hispanic groups reported a higher fraction experiencing menstruation at age 11 or younger (Floridian Hispanics [38%] and Puerto Ricans [36%]) compared to non-Hispanic Whites (20%) and non-Hispanic Blacks (22%). Non-Hispanic Black and Puerto Rican women were significantly older at breast cancer diagnosis than their non-Hispanic White and Floridian Hispanic counterparts. The Puerto Rican and non-Hispanic Black groups more frequently had pathology stage T2 or higher primary breast tumors at diagnosis (non-Hispanic Whites [29%], non-Hispanic Blacks [39%], Floridian Hispanics [33%], Puerto Ricans [46%]). The Puerto Rican (73%, 95% CI [66, 82]) and non-Hispanic Black (79%, 95% CI [75, 84]) groups demonstrate reduced 5-year survival compared to non-Hispanic Whites (89%, 95% CI [86, 92]) and Floridian Hispanics (89%, 95% CI [86, 90]). These findings demonstrate that Puerto Rican breast cancer patients suffer significant breast cancer health disparities relative to non-Hispanic Whites and Hispanics from Florida similar to the disparities observed for non-Hispanic Blacks. Future work must seek to better understand and address these disparities.

OGC SO15 - Utility of radiological re-staging following neo-adjuvant chemotherapy and its impact on oncological outcomes in resectable gastric adenocarcinoma

Abstract Background The current perioperative chemotherapy regimen that comprises the multimodal treatment strategy for gastric cancer consists of Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel. Despite improvement in outcomes at a population level, real-world data suggests that ≤40% of patients show a poor/no response to the neoadjuvant phase of treatment. Identification of these poor/non-responders may facilitate a re-evaluation of their treatment strategy and prevent potentially futile surgery. Radiological re-staging following neoadjuvant treatment is routinely performed despite its debatable accuracy and benefits. This study aimed to define the accuracy of radiological re-staging and its impact on survival following neoadjuvant treatment for resectable GC. Method Patients with resectable gastric cancer who completed 4 cycles of neoadjuvant FLOT and underwent resectional surgery with curative intent between 2018 and 2022 were retrospectively identified. All patients were clinically staged with gastroscopy, CT and staging laparoscopy. The index radiological/clinical stage at diagnosis was compared to the radiological re-staging following neoadjuvant treatment. Patient were re-staged with either a CT or PET-CT. Both were then compared with the final pathological stage to assess for correlation between the radiological and pathological stage. A survival analysis was then performed to evaluate the impact of radiological-pathological staging discrepancy on overall survival Results A total of 65 consecutive patients met the inclusion criteria of this study. On comparison of the index clinical stage with the radiological re-stage post-neoadjuvant treatment, 71% had concordant stages, 25% were downstaged, and 4% were upstaged. On comparison of the index clinical stage with the final pathological stage, 35% had concordant stages, 38% were upstaged and 27% were down staged (Cohen kappa = -0.224, 95% CI -0.390, -0.058). Discrepancy between clinical stage and radiological re-stage did not influence survival. However, discrepancy between clinical and pathological stage highlighted survival differences where upstaged patients had reduced survival (p = 0.018). Conclusion The accuracy of clinical staging compared to final pathological staging in the setting of aggressive tumour biology remains undefined. Radiological re-staging following neoadjuvant treatment proves to be an unreliable tool for assessing treatment response and does not predict long-term survival outcomes. These findings highlight the importance of accurate staging and the need for more precise methods of evaluating treatment response. This may enhance decision-making, individualise treatment regimens, and improve patient outcomes.

Integrated cerebellar radiomic-network model for predicting mild cognitive impairment in Alzheimer's disease.

Pathological and neuroimaging alterations in the cerebellum of Alzheimer's disease (AD) patients have been documented. However, the role of cerebellum-derived radiomic and structural connectome modeling in the prediction of AD progression remains unclear. Radiomic features were extracted from magnetic resonance imaging (MRI) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (n=1319) and an in-house dataset (n=308). Integrated machine learning models were developed to predict the conversion risk of normal cognition (NC) to mild cognitive impairment (MCI) over a 6-year follow-up. The cerebellar models outperformed hippocampal models in distinguishing MCI from NC and in predicting transitions from NC to MCI across both cohorts. Key predictors included textural features in the right III and left I and II lobules, and network properties in Vermis I and II, which were associated with cognitive decline in AD. Cerebellum-derived radiomic-network modeling shows promise as a tool for early identification and prediction of disease progression during the preclinical stage of AD. Altered cerebellar radiomic features and topological networks were identified in the subjects with mild cognitive impairment (MCI). The cerebellar radiomic-network integrated models outperformed hippocampal models in distinguishing MCI from normal cognition. The cerebellar radiomic model effectively predicts MCI risk and can stratify individuals into distinct risk categories. Specific cerebellar radiomic features are associated with cognitive impairment across various stages of amyloid beta and tau pathology.

OGC O01 - Stomach Cancer Elective Surgery Morbidity and Mortality at 90-Days (HOLD Study): A Prospective, International Collaborative Cohort Study

Abstract Background Data on multinational 90-day mortality and morbidity rates after surgery for gastric cancer is limited in the literature. This study aimed to understand the 90-day mortality and morbidity outcomes according to GASTRODATA Registry for elective gastric cancer surgery patients and identify risk factors. Method We conducted an international prospective study on ≥18 years patients undergoing elective surgery for gastric cancer with curative intent from 01 April 2022 to 30 September 2022. Known metastatic disease, concurrent secondary cancers, gastrointestinal stromal tumour (GIST) and Siewert type I/II oesophagogastric junction malignancies were excluded. Univariate and multivariate logistic regression was used to identify variables associated to 90-day outcome. Results 380 collaborators from 47 countries submitted data on 1538 patients. Mean age was 64.2 years and 58.5% were males. 90-day morbidity rate was 38.2% (n=587) and mortality rate was 2.9% (n=45). Pre-operative higher CCI or ASA score, pre-operative weight loss >10%, and surgical determinants such as type of gastric resection, positive specimen margin, number of harvested lymph nodes, longer surgery duration and post operative pathological IV staging (p value<0.05) were identified as predictors of postoperative severe complications and mortality. Conclusion Elective gastric cancer surgery has a 90-day morbidity of 38.2% and 90-day mortality of 2.9%, globally. This study identified several factors associated with higher morbidity and exemplified the importance of a unified language on surgical morbidity, pre-habilitation and ongoing audits to enhance patient outcomes.

Pathomic and bioinformatics analysis of clinical-pathological and genomic factors for pancreatic cancer prognosis

Pancreatic cancer exhibits a high degree of malignancy with a poor prognosis, lacking effective prognostic targets. Utilizing histopathological methodologies, this study endeavors to predict the expression of pathological features in pancreatic ductal adenocarcinoma (PAAD) and investigate their underlying molecular mechanisms. Pathological images, transcriptomic, and clinical data from TCGA-PAAD were collected for survival analysis. Image segmentation using unsupervised machine learning was employed to extract features, perform clustering, and establish models. The prognostic value of pathological features and associated clinical risk factors were evaluated; the correlation between pathological features and molecular mechanisms, gene mutations, and immune infiltration was analyzed. By clustering 45 effective pathological features, we divided PAAD patients into two groups: cluster 1 and cluster 2. Significant associations with poor prognosis were found for cluster 2 in both the training group (n = 113) and validation group (n = 75) (p = 0.006), with pathological stages II-IV identified as potential synergistic risk factors (HR = 2.421, 95% CI = 1.263–4.639, p = 0.008). Subsequently, through multi-omics correlation analysis, we further revealed a close association between cluster 2 and the oxidative phosphorylation mechanism. Within the cluster 2 group, 28 oxidative phosphorylation genes exhibited reduced expression, CDKN2A gene mutations were upregulated, and there was significant downregulation of Tregs infiltration and related immune gene expression. The pathomic model constructed using machine learning serves as a valuable prognostic target for PAAD. The histopathological features cluster 2 are closely associated with the downregulation of oxidative phosphorylation levels and Tregs immune infiltration.

OGC SO22 - Accuracy of CT and FDG/PET clinical staging within a dedicated multidisciplinary service for patients with oesophago-gastric cancer

Abstract Background Accurate staging for oesophago-gastric cancer is important in ensuring correct treatment pathways, avoiding unnecessary surgery and providing prognostication for patients. Previously, cross sectional imaging in accurately providing tumour (T) and nodal (N) staging has been variable for upper GI malignancies, with usage of invasive investigations such as EUS to provide more specific local staging. With the increased utilisation of specialist multidisciplinary involvement and improved technology, we aimed to assess whether CT and PET imaging may be able to provide sufficiently accurate staging required for treatment decision making. Method All patients who underwent oesoophagogastric resections between January 2022 and March 2024 were identified from our surgical database. Patients were included if they had oesophago-gastric cancer, and underwent curative resection without neo-adjuvant treatment. Data collected included age, gender, location of primary tumour, CT/PET staging, and final histology. Outcomes assessed included rate of understaging in clinical and pathological T and N staging, and sensitivity and specificity of imaging in identifying presence of nodal disease. Results 38 patients were included in this analysis. For oesophageal and GOJ cancers, T stage under-reporting occurred in 6/27 (22%) patients, and N under-reporting in 7/27 (27%) patients. Radiological staging correlated with final pathological staging in 55% of T staging and 59% of N staging. Sensitivity (55.56%, 95% CI 21-86%) and specificity (72.2%, 95% CI 46.5-90.3%) for nodal disease on CT/PET was low, however no tumour or nodal under-staging would have impacted management. Gastric cancer staging accuracy assessment was limited by small numbers (n=12), however T under-staging occurred in 5/12 (42%) patients and N under-staging occurred in 5/11 patients (45%). Conclusion Involvement of dedicated radiology services in multidisciplinary care for oesophago-gastric cancer provides adequate radiological staging to guide treatment. Gastric cancer clinical staging requires laparoscopic and endoscopic assessment for accurate tumour assessment and management guidance. Radiological under-staging is less common in oesophageal and GOJ tumours than gastric cancer and has minimal impact on patient management.

Abstract A055: Tumor muscle invasion promotes tumor heterogeneity and normal muscle reprogramming

Abstract Aggressive human prostate tumors traverse a contractile smooth muscle pseudo-capsule, in a process termed extracapsular extension (ECE), defining the pT3 pathologic stage associating with increased biochemical recurrence, bone metastases, and cancer-specific mortality. While T3 lesions can be detected by non-invasive mpMRI imaging, how the tumor invades into and through the contractile muscle is unknown. Using a mouse xenograft model system of ECE, we investigated the transcriptomic consequences of human tumor invasion into and through the contractile smooth muscle of the mouse diaphragm. Both human and mouse gene transcripts were documented and analyzed. Tumor cells were intraperitoneally injected into male NSG mice and 6 weeks later, three tumor compartments (pre-invasive, muscle-invasive, and super-invasive cells that had reached the superior diaphragm surface) were analyzed for differential bulk human and mouse gene expression. Whole genome transcriptomic sequencing and GO pathway analysis revealed that approximately 414 human genes were differentially expressed between the non- invasive, muscle-resident, and super-invasive tumor populations and at least 5 enriched pathways were involved. The unique expression gene patterns of muscle-resident tumor cells were reversible when compared to the pre-invasive and super-invasive expression patterns. Significant increases in g-H2AX and nuclear deformation were observed in the muscle-resident tumor clusters as compared to the non-invasive tumor mass. No differences in tumor cell proliferation, as detected by Ki67 staining, were found between the tumor clusters in the three compartments. Immunohistochemistry staining for a damage response cytokeratin (KRT6A) and integrin (CD49f) revealed heterogeneity within the muscle resident tumors as compared to the non- invasive cells. Taken together, these data suggest a hostile contractile muscle environment elicits specific responses by the invading tumor. Single cell analysis within each of the tumor compartments is currently underway to define the spatial heterogeneity of gene expression in invasive tumor cell clusters within the contractile muscle. A dynamic reciprocity of the tumor/muscle microenvironment is suggested by the analysis of the bulk transcriptomic sequencing demonstrating a significant increase in mouse muscle bio-synthetic gene transcription as a consequence of the human tumor penetrating the tissue. Taken together, these data indicate that human tumors, during the act of traversing the contractile muscle layer, respond to this unique microenvironment by transiently altering transcription, while sustaining nuclear damage which results in the reprogramming of the muscle. This new information suggests that novel tumor or muscle biomarkers might indicate early muscle invasion events and assist new high-resolution image analysis for precision diagnostic and/or therapeutic decisions. (Supported in part by P30 CA23074; F30 CA143924, UACC Team Science Award). Citation Format: Kendra D Marr, Beatrice S Knudsen, Rafael Sainz, Kelvin W Pond, Noel E Warfel, Belinda E Sun, Anne E Cress. Tumor muscle invasion promotes tumor heterogeneity and normal muscle reprogramming [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A055.

Pan-cancer landscape analysis of NOP58 and its oncogenic driving role in lung adenocarcinoma

Despite improvements in treatment in recent years, patients with lung adenocarcinoma (LUAD) still face poor prognoses. In this study, we elucidated the potential role of NOP58 ribonucleoprotein in pan-cancer and validated its oncogenic significance in LUAD using bioinformatics and in vitro and in vivo functional assays. NOP58 was found to be overexpressed in various types of tumors. It had great precision for predicting 20 distinct cancer types using receiver operating characteristic curve (ROC) as well as significant connections with the prognoses in particular cancers. In LUAD, NOP58 expression was correlated substantially with the TNM stage, pathologic stage, smoking status, and effectiveness endpoints, when we analyzed its association with clinical characteristics in LUAD. Elevated NOP58 expression was shown as connected with Th2 cell infiltration while also negatively linked with infiltrating other immune cells, such as CD8 T, cytotoxic, and Th1. By inhibiting NOP58 within the LUAD cells, we found a decrease in cells’ capability to proliferate, migrate, and invade. Knockdown of NOP58 inhibited tumor growth in mouse xenograft models. Furthermore, the tissue microarray study indicated that there was a greater expression of NOP58 in the tumor tissues compared to adjacent normal tissues in LUAD. Our findings revealed that NOP58 could be an outstanding bio-index for pan-cancer diagnosis and prognosis and an independent prognostic risk factor in LUAD.

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer’s disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology across 32 donors spanning the entire normal aging to severe AD continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across the AD-vulnerable neural network (spatial axis) or AD pathology stage (temporal axis). The proportion of homeostatic, intermediate and reactive astrocytes changed only along the spatial axis, whereas two other subclusters changed along the temporal axis. One of these, a trophic factor-rich subcluster, declined along pathology stages, whereas the other increased in the late stage but returned to baseline levels in the end stage, suggesting an exhausted response with chronic exposure to neuropathology. Our study underscores the complex dynamics of astrocytic responses in AD.

Expression and clinical significance of PIKFYVE gene in hepatocellular carcinoma analyzed based on TCGA database and experimental validation

Objective: To investigate the expression and clinical significance of human FYVE finger-containing phosphoinositide kinase (PIKFYVE) in hepatocellular carcinoma (HCC) on the basis of cancer genome atlas (The cancer genome atlas, TCGA) database analysis and clinical samples experimental validation. Methods: Based on the data information of 424 clinical samples (including 374 cases of HCC tissues and 50 cases of nontumorous liver tissues) in the TCGA database, Cox regression analysis and Kaplan-Meier method were used to analyse the relationship between the PIKFYVE mRNA expression and the clinical characteristics, prognosis for survival of HCC patients. The relationship between the PIKFYVE gene and immune cell infiltration was examined by correlation analysis between the PIKFYVE gene and 24 immune cells. In addition, we analysed the correlation between the mRNA expression of PIKFYVE gene and RAC-alpha serine/threonine-protein kinase (AKT1), phosphatase and tensin homolog (PTEN), protein kinase C, alpha (PRKCA), inositol polyphosphate-5-phosphatase (INPP5D), phosphoinositide-3-kinase regulatory subunit 1(PIK3R1), Inositol Polyphosphate 4-phosphatase Type II (INPP4B) and phospholipase-C4 gene (PLCB4) in HCC tissues. Meanwhile, paraffin sections of highly differentiated, moderately differentiated, poorly differentiated, and nontumorous liver tissue in the Department of Pathology of the First Affiliated Hospital of Xinjiang Medical University were collected, each of which was 30 cases, and the histopathological observation was carried out by HE staining, and the expression levels of PIKFYVE and Ki67 proteins were verified by immunohistochemistry in each clinical sample. Results: The expression level of PIKFYVE gene in HCC tumours was significantly higher than that in normal liver tissues (P=0.000 2, P<0.01), and the overall survival of patients in the low PIKFYVE expression group was significantly longer than that in the high expression group (HR=1.57, 95%CI: 1.10～2.25, P=0.014). The results of Univariate Cox regression analysis showed that there was an effect of TNM stage, pathological stage, tumour status and residual tumour on Overall survival (OS) (P<0.05), and the expression level of PIKFYVE had an effect on OS survival (P<0.05); the PIKFYVE prognostic risk model score ratio was HR=1.533 (1.077-2.181, P=0.018). Multivariate Cox regression analysis showed a PIKFYVE prognostic risk model score ratio HR=1.481 (0.886-2.476, P=0.134) and an area under the Receiver Operating Characteristic curve of 0.640, which was greater than 0.5, suggesting that the PIKFYVE prognostic risk model has a predictive value in survival prediction. Correlation analysis showed that the expression level of PIKFYVE was highly correlated with immune cell infiltration and TP53 (P<0.01). The immunohistochemistry staining results showed that the expression of PIKFYVE in HCC tissues was significantly higher than that of nontumorous tissues (P<0.05), and there was a negative correlation with the degree of differentiation. Conclusion: PIKFYVE, as an independent risk factor for HCC, is expected to be developed as a clinical diagnostic biomarker for HCC, which will provide a reference for new drugs for the treatment of HCC.

Safety and feasibility of robotic surgery in geriatric patients with rectal cancer.

The incidence of rectal cancer is increasing in the elderly population, yet the safety of surgical interventions in this group, particularly robotic surgery, is still debated. This study aims to investigate the safety and short-term postoperative outcomes of robotic surgery in geriatric patients (aged ≥ 70years) with rectal cancer. Patients diagnosed with rectal cancer and undergoing robotic surgery between March 2021 and September 2023 were divided into two groups based on age: the elderly group (aged ≥ 70years) and the younger group (aged < 70years), totaling 108 patients. The study included 80 younger patients in group 1 and 28 elderly patients in group 2. The groups had similar gender distribution and tumor characteristics. The elderly group had higher ASA scores and lower albumin levels and underwent the Miles procedure more frequently. The stoma rate was higher in the elderly group. Operation duration, tumor diameter, lymph node dissection numbers, pathological stage, and other histopathological features were similar in the two groups. Postoperative outcomes like hospital stay, complication rates, anastomotic leakage, reoperation rates, unplanned readmissions, and mortality were comparable between the groups. Robotic surgery for rectal cancer in elderly patients is technically feasible and safe. Age should not be a determining factor in patient selection for robotic surgery or be considered a risk factor for postoperative complications.

Exploration of the pattern of lymph node metastasis in esophageal cancer based on membrane anatomy theory.

To analyze the pattern of lymph node metastasis in esophageal cancer based on the theory of membrane anatomy. A retrospective analysis was conducted on 143 patients who underwent esophageal surgery at the Cancer Hospital of the Chinese Academy of Medical Sciences from March 2021 to March 2022. Lymph node metastasis was observed and categorized according to postoperative T staging. The characteristics and patterns of lymph node metastasis in different regions were observed, and the lymph node metastasis patterns in patients with clinical T3 esophageal cancer were analyzed using membrane anatomy theory. Among the 143 patients with esophageal squamous cell carcinoma, 21 were treated with surgery alone, while the rest received preoperative adjuvant therapy. A total of 5456 lymph nodes were cleared from the 143 patients, with 204 positive lymph nodes, resulting in a positive rate of 3.74%. In the thoracic lymph node dissection, the metastatic rates exceeded 5% for the following regions: 106recR (17.36%), 106recL (12.5%), 107 (10.42%), and 108 (5.56%) station. When analyzing the abdominal lymph node metastasis, the metastatic rates exceeded 5% for regions 7 (13.19%), 3a (7.64%), 2 (6.94%), and 1 (6.25%) station. Group analysis of patients with esophageal squamous cell carcinoma before postoperative pathological T3 stage revealed an increasing trend in tumor lymph node metastasis rate with later T staging. Lymph node metastasis in region 106recR can occur early, with a metastasis rate of 18.37% in T1 tumors. Analysis of lymph node metastasis characteristics in 103 patients clinically staged as T3 showed that 3966 lymph nodes were cleared, with 186 positive nodes, resulting in a positive rate of 4.69%. Lymph node metastasis rates were higher in regions 106recL, 106recR, 107, 108, 110, 1, 2, 3a, and 7, all exceeding 5%. The theory of membrane anatomy can effectively explain the pattern of lymph node metastasis in esophageal cancer.

Exploring Intratumoral Budding in Colorectal Cancer Using Computational Pathology: A Biopsy-Based Evaluation

Owing to insufficient evidence, tumor budding (TB) is not currently evaluated in colorectal cancer (CRC) biopsies. This study investigates TB in CRC by establishing the value of intratumoral budding (ITB) in resection specimens and assessing the feasibility and clinical value of TB in biopsies. TB was assessed using an algorithm in all cases. In a test cohort of 555 primarily surgically treated CRC patients, we assessed the prognostic impact of ITB compared with peritumoral budding (PTB). The distribution of ITB in the uppermost 5 mm of resection specimens was analyzed to validate TB counting in biopsies. We further validated the prognostic and predictive impact of TB in biopsies of 285 rectal cancer patients, focusing on overall survival and response to neoadjuvant therapy. High-grade TB, whether intratumoral or peritumoral and in biopsies or resections, was associated with advanced pathological stage, lymphatic invasion, infiltrative tumor border, and poor overall survival in the test cohort. Superficial ITBs (0-3 mm from the lumen) accurately predicted the final TB grade based on PTB in 87% of tumors, with 87% of tumors having at least 1 superficial ITB hotspot. ITB (hazard ratio, 3.5; 95% CI, 1.1-10.8) was an independent predictor of overall survival, unlike PTB. In the validation cohort, TB presence in biopsies significantly reduced the likelihood of achieving a pathological complete response (odds ratio, 0.3; 95% CI, 0.1-0.7; P = .007). ITB is as prognostic as PTB, and evaluating both can improve risk stratification in CRC. TB assessment in biopsies can identify poor prognosis and predict response to neoadjuvant therapy.

SPP1 is a plasma biomarker associated with the dia gnosis and prediction of prognosis in sepsis

In this study, peripheral whole blood samples from 22 hospitalized patients and 10 healthy individuals were analyzed using a combination of Data Independent Acquisition (DIA) and Enzyme-Linked Immunosorbent Assay (ELISA) techniques to identify differentially expressed proteins (DEPs) in sepsis patients’ plasma. The aim was to provide accurate and detailed biomarkers, such as SPP1, for determining the pathological stages of sepsis. SPP1, known as osteopontin1 is a pleiotropic protein with a wide distribution and multifunctional effects. Its protein expression is associated with inflammatory changes, including variations in expression levels in infectious diseases, allergic diseases, and situations involving tissue damage. The registration number was ChiCTR1900021261.The full date of first registration year is 2018. In the affiliated hospital of southwest medical university, 22 sepsis patients were hospitalized from January 2019 to September 2020 and 10 normal healthy individuals were selected for DIA-based quantitative proteomics analysis. In addition to gene ontology analysis and Kyoto Encyclopedia of genes and genomes analysis, enrichment analysis of data was performed and target protein network was screened through joint protein–protein interaction and visualization techniques. The selected protein targets were then validated by Elisa kit. The software was used to analyze the differences comparing the control group to the sepsis group and the sepsis group, as well as between sepsis survivals and non-survivals, and a ROC curve was drawn to evaluate the diagnostic value and prognostic effect of the method of the corresponding target proteins. A total of 174 DEPs were screened by bioinformatics analysis. An analysis of go pathway enrichment revealed the following: These proteins were mainly involved in biological processes among them are the inflammation response, the metabolism of extracellular matrix, the secretion of cell secretions, the activation of cells, and the immune response. According to the Kegg pathway analysis, they were mainly involved in complement cascade polymerization, extracellular protease and glycosylase activation, protein synthesis process, biotin metabolism, leukocyte transmembrane migration, bacterial infection and phagosome formation. SPP1 was identified as a possible plasma biomarker and was therefore further validated using Elisa. As a result of experiments, it has been demonstrated that level in sepsis patients is significantly compared to the normal control group and the level is also higher in non-survivals of sepsis. The ROC curve can be used to see that it can diagnose sepsis more accurately and improve prognostic ability prediction. Cell experiments confirm that SPP1 is highly expressed in sepsis. There is a significant difference in the levels of SPP1 protein between the normal group and the sepsis group; it not only has good diagnostic significance for sepsis, but also provides corresponding reference value for patient prognosis; Therefore, it is more likely to become a biological marker of sepsis over time.

Clinical application of oral contrast-enhanced ultrasound in evaluating the preoperative T staging of gastric cancer.

Oral contrast-enhanced ultrasound (OCEUS) is widely used in the noninvasive diagnosis and screening of gastric cancer (GC) in China. To investigate the clinical application of OCEUS in evaluating the preoperative T staging of gastric cancer. OCEUS was performed before the operation, and standard ultrasound images were retained. The depth of infiltration of GC (T-stage) was evaluated according to the American Joint Committee on Cancer 8th edition of the tumor-node-metastasis staging criteria. Finally, with postoperative pathological staging as the gold standard reference, the sensitivity, specificity, negative predictive value, positive predictive value, and diagnostic value of OCEUS T staging were evaluated. OCEUS achieved diagnostic accuracy rates of 76.6% (T1a), 69.6% (T1b), 62.7% (T2), 60.8% (T3), 88.0% (T4a), and 88.7% (T4b), with an average of 75.5%. Ultrasonic T staging sensitivity exceeded 62%, aside from T1b at 40.3%, while specificity was over 91%, except for T3 with 83.5%. The Youden index was above 60%, with T1b and T2 being exceptions. OCEUS T staging corresponded closely with pathology in T4b (kappa > 0.75) and moderately in T1a, T1b, T2, T3, and T4a (kappa 0.40-0.75), registering a concordance rate exceeding 84%. OCEUS was effective, reliable, and accurate in diagnosing the preoperative T staging of GC. As a noninvasive diagnostic technique, OCEUS merits clinical popularization.

Spectrum of Gastric Carcinoma in a Tertiary Care Centre with Special Reference to PDL1 and Cyciln D1

Introduction: Gastric carcinoma is the fifth most frequently diagnosed tumor and the fourth leading cause of death. They represent a heterogenous group of tumors with multifactorial etiologies, both environmental and genetic. PD-L1 is a transmembrane protein, and a positive PD-L1 expression in gastric carcinoma may be a predictive biomarker of the response to PD-1/PD-L1 immune checkpoint inhibitors. Cyclin D1 is an important cell cycle regulatory protein and involved in the carcinogenesis of various cancers including gastric cancer. Aims: The aim of this study is to find out the clinicopathological spectrum of gastric carcinoma and to show the immunohistochemical expression of Cyclin D1 and PD-L1 to evaluate their prognostic importance and their therapeutic impact. Study Design: It is an observational cross-sectional study conducted in the Department of Pathology in collaboration with the Department of Surgery, in a tertiary care hospital. Partial and total gastrectomies were selected from January 2021 to July 2022 in a tertiary care hospital. Clinical history was collected in the study proforma. Immunohistochemical staining for Cyclin D1 and PD-L1 was performed. Material and Methods: The clinicopathological parameters like age, gender, histological type, regional lymph node status, lymphovascular invasion, perineural invasion, and pathological stage were compared and correlated with Cyclin D1 and PD-L1 expression. Results: Positive Cyclin D1 and PDL1 expression were found in 50% and 70% cases of gastric carcinoma, respectively. Cyclin D1 expression showed statistically significant correlation with anemia, regional lymph node status, and lymphovascular invasion. PD-L1 and Cyclin D1 expression showed statistically significant association between them (p value-0.0006). Conclusion: Cyclin D1 and PDL1 are important biomarkers in gastric carcinoma. Their contribution towards prediction of progression and prognosis, along with newer therapeutic modalities, is of immense importace in these patients. A statistically significant correlation was found between these two markers.

Nucleolar casein kinase 2 alpha as a prognostic factor in patients with surgically resected early‑stage lung adenocarcinoma.

Lung cancer remains a leading cause of global cancer‑related deaths, therefore the identification of prognostic factors for lung cancer is critical. Casein kinase 2 alpha (CK2α) is one of the driver kinases in various cancers, and it was previously demonstrated that CK2α localization was associated with a poor prognosis in invasive breast cancer. In the present study, the importance of CK2α in the nucleolus was explored as a potential prognostic marker for surgically resected early‑stage lung adenocarcinoma. The present study included 118 patients who underwent pulmonary lobectomy between 2014 and 2018 in Fukushima Medical University Hospital (Fukushima, Japan), and in whom CK2α localization in tumor samples was assessed by immunohistochemistry. Patient and tumor characteristics, including pathological stage, histological type and histological grade, were analyzed. Recurrence‑free survival (RFS) and overall survival were evaluated in relation to nucleolar CK2α staining. CK2α staining in the nucleoli was observed in 50.8% of lung adenocarcinoma tumors. Positive nucleolar CK2α staining was independent of pathological stage, histological type and histological grade. Patients with positive nucleolar CK2α staining exhibited significantly worse RFS compared with patients with negative staining. Multivariate analysis identified nucleolar CK2α staining and lymph node metastasis as independent poor prognostic factors. The results of the present study suggested that nucleolar CK2α staining is a novel and independent prognostic factor in surgically resected early‑stage lung adenocarcinoma. These findings indicated the potential of nucleolar CK2α as a predictive biomarker for future recurrence, and a guide to treatment decisions. Further research is required, particularly in understanding the molecular mechanisms linking nucleolar CK2α to recurrence.

Molecular Signatures of Resilience to Alzheimer's Disease in Neocortical Layer 4 Neurons.

Single-cell omics is advancing our understanding of selective neuronal vulnerability in Alzheimer's disease (AD), revealing specific subtypes that are either susceptible or resilient to neurodegeneration. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex and precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing RORB , CUX2 , and EYA4 . Layer 4 neurons in association neocortex also remained relatively preserved as AD progressed and shared overlapping molecular signatures of resilience. Early in the disease, resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotective factors, including GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1 , and CSMD1 . We also identified KCNIP4 , which encodes a voltage-gated potassium (Kv) channel-interacting protein that interacts with Kv4.2 channels and presenilins, as a key factor linked to resilience. KCNIP4 was consistently upregulated in the early stages of pathology. Furthermore, AAV-mediated overexpression of Kcnip4 in a humanized AD mouse model reduced the expression of the activity-dependent genes Arc and c-Fos , suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a valuable resource for investigating mechanisms underlying resilience to neurodegeneration.

Integrated pan-cancer analysis and experimental verification of the roles of ZBED3 in kidney renal clear cell carcinoma

The present study investigated the Zinc finger BED-type containing 3 (ZBED3) mRNA expression levels, diagnostic and prognostic values, co-expressed and differentially expressed genes, immune infiltration, and functional enrichment analysis in patients with kidney renal clear cell carcinoma (KIRC) using various public databases such as The Cancer Genome Atlas, Genotype-Tissue Expression Project, LinkedOmics, Gene Set Enrichment Analysis databases, and the Xiantao academic tool. Through extensive data mining, our study revealed differential expression of ZBED3 in various tumor and paired normal tissues. Specifically, ZBED3 expression was found to be significantly decreased in KIRC, particularly in advanced pathologic stages and histologic grades, when compared to corresponding control tissues. Our analysis revealed that the overexpression of ZBED3 is associated with a favorable overall survival outcome in KIRC patients. Moreover, functional enrichment analysis identified key pathways related to inflammation response and DNA methylation of ZBED3 in KIRC. Additionally, our findings suggest that the upregulation of ZBED3 leads to the inhibition of cell proliferation by modulating cell-cycle progression in KIRC cell lines. Taken together, these results suggest that ZBED3 may serve as a promising biomarker and prognostic indicator for individuals diagnosed with KIRC.