Tumor Grade Research Articles

Machine Learning-Based Real-Time Survival Prediction for Gastric Neuroendocrine Carcinoma.

This study aimed to develop a dynamic survival prediction model utilizing conditional survival (CS) analysis and machine learning techniques for gastric neuroendocrine carcinomas (GNECs). Data from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2015) were analyzed and split into training and validation groups (7:3 ratio). CS profiles for patients with GNEC were examined in the full cohort. We utilized random survival forests (RSFs) and least absolute shrinkage and selection operator (LASSO) regression, alongside stepwise Cox regression, for variable selection. A CS-based nomogram was developed on the basis of key prognostic factors, followed by risk stratification and model validation. We included 654 patients with GNEC in our study, with 457 assigned to the training set and 197 to the validation set. The CS analysis demonstrated that the probability of achieving 5-year CS improved from 48% immediately after diagnosis to 68%, 81%, 88%, and 94% after surviving an additional year (i.e., at 1, 2, 3, and 4 years, respectively). Through the use of RSFs and LASSO regression, combined with multivariable regression analysis, we identified the optimal combination of prognostic factors, which included age, tumor grade, tumor stage, surgery, and chemotherapy. Utilizing these prognostic indicators, we successfully developed a nomogram model that incorporated CS and effectively stratified these patients by risk. Subsequent performance analyses further validated the superior efficacy of the nomogram. Our study highlights the value of CS in GNEC prognosis. The nomogram offers dynamic, individualized survival predictions, supporting personalized treatment strategies.

NETest and Gastro-Entero-Pancreatic Neuroendocrine Tumors: Still Far from Routine Clinical Application? A Systematic Review

Background: Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are the most prevalent subgroup among NETs and include heterogeneous tumors characterized by different clinical behavior and prognosis. The NETest is a tool based on real-time PCR combined with deep learning strategies to specifically identify tumors with a neuroendocrine genotype. Despite the promising results achieved regarding its utility in the field of GEP-NETs, the NETest has not yet entered into routine clinical practice. Methods: We performed a systematic review aimed at summarizing available evidence on the application of the NETest in both the diagnosis and the prognostic stratification of GEP-NETs. Results: We identified five studies evaluating the diagnostic role of the NETest and nine studies evaluating its prognostic value. The NETest emerged as a reliable biomarker for GEP-NET diagnosis with an accuracy higher than 90%, regardless of tumor stage and grade. However, according to some studies, the NETest showed a low specificity, mainly attributed to interferences with other gastro-intestinal malignancies. In terms of prognostic value, the NETest correlated with the detection of residual disease after surgery in six studies. The NETest was also associated with patients’ survival outcomes, namely progression-free survival (PFS) and overall survival (OS) in three studies. Conclusions: According to current systematic review, the value of the NETest both for diagnosis and for prognosis of GEP-NET emerged as robust across different studies. Further prospective analysis on larger GEP-NET series is encouraged to validate this tool, improving patients’ diagnosis, management, and follow-up.

CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis

The high mortality rate from hepatocellular carcinoma (HCC) is due primarily to challenges in early diagnosis and the development of drug resistance in advanced stages. Many first-line chemotherapeutic drugs induce ferroptosis, a form of programmed cell death dependent on ferrous iron-mediated oxidative stress, suggesting that drug resistance and ensuing tumor progression may in part stem from reduced ferroptosis. Since circular RNAs (circRNAs) have been shown to influence tumor development, we examined whether specific circRNAs may regulate drug-induced ferroptosis in HCC. Through circRNA sequencing, we identified a novel hsa_circ_0000195 (circTTC13) that is overexpressed in HCC tissues. This overexpression is linked to higher tumor grade, more advanced tumor stage, decreased ferroptosis, and poorer overall survival. Overexpression of CircTTC13 in HCC cell lines and explant tumors was associated with increased proliferation rates, enhanced metastatic capacity, and resistance to sorafenib, while also inhibiting ferroptosis. Conversely, circTTC13 silencing reduced malignant characteristics and promoted ferroptosis. In silico analysis, luciferase assays, and fluorescence in situ hybridization collectively demonstrated that circTTC13 directly targets and reduces miR-513a-5p expression, which in turn leads to the upregulation of the negative ferroptosis regulator SLC7A11. Moreover, the inhibition of SLC7A11 mirrored the effect of circTTC13 knockdown, whereas ferroptosis inhibition mimicked the effect of circTTC13 overexpression. Both circTTC13 and SLC7A11 were highly expressed in drug-resistant HCC cells, and circTTC13 silencing induced ferroptosis and reversed sorafenib resistance in explant tumors. These findings identify circTTC13 as a critical driver of HCC progression and resistance to drug-induced ferroptosis via upregulation of SLC7A11. The cicTTC13/miR-513a-5p/SLC7A11 axis represents a potential therapeutic target for HCC.

A multi-omics analysis reveals KDELR1 promotes malignant progression and correlates with tumor microenvironment in head and neck squamous cell carcinoma.

KDELR1, a constituent of the KDEL endoplasmic reticulum protein retention receptors family, is implicated in immune responses and cancers progression. In this study, we delineate the clinicopathological significance and oncogenic role of KDELR1 in head and neck squamous cell carcinoma (HNSCC) through a comprehensive multi-omics approach. KDELR1 expression is correlated with tumor grade, tumor stage, lymph node metastasis, clinical stage and poor prognosis in HNSCC. Moreover, our results indicate a marked upregulation of KDELR1 expression in primary tumor tissues compared to normal and dysplasia tissues. Furthermore, increased KDELR1 expression is associated with tumor progression and indicates an unfavorable prognosis in HNSCC. Functional enrichment analysis highlights the involvement of KDELR1 in HNSCC malignant progression. Depletion of KDELR1 inhibits proliferation, stemness, migration and invasion in HNSCC cells. Bioinformatics analysis results indicate that KDELR1 promotes HNSCC progression with regulating wnt signaling pathway and CTNNB1 expression. Of note, KDELR1 is associated with HNSCC tumor microenvironment compositions, especially positively correlating with cancer associated fibroblasts and negatively correlating with CD8+ T cells and B cells infiltration. Collectively, these findings indicate that KDELR1 as an oncogene in driving progression and correlates with tumor microenvironment, suggesting its potential as a promising biomarker and a therapeutic target in HNSCC.

The association between radiotherapy and the prognosis of follicular lymphoma patients with different characteristics in the rituximab era: a cohort study based on Surveillance, Epidemiology and End Results.

This retrospective cohort study examined the association between radiotherapy and prognosis in follicular lymphoma (FL) patients, with stratification by age, Ann Arbor stage, primary tumor site, surgical status, and grade. Using data from the SEER database, we employed Cox proportional hazards and competing risk models to assess the impact of radiotherapy on overall survival (OS) and cancer-specific survival (CSS) in 7,551 FL patients. The association between radiotherapy and second primary cancer (SPC) was explored using Logistic regression model. At the end of the 60-month follow-up, 6,053 patients were alive, while 1,498 had died. The overall result showed that radiotherapy was associated with the better OS [hazard ratio (HR): 0.70, 95% confidence interval (95%CI): 0.59-0.83, P < 0.001] and CSS (HR: 0.67, 95% CI: 0.52-0.87, P = 0.002)) in FL patients. Radiotherapy was associated with improved OS and CSS in patients aged ≥ 60 years [OS: HR: 0.65, CI: 0.53-0.79; CSS: HR: 0.63, CI: 0.52-0.77], early Ann Arbor stage (OS HR: 0.51, CI: 0.40-0.65; CSS HR: 0.51, CI: 0.40-0.65), primary sites at lymph nodes (OS HR: 0.76, CI: 0.62-0.93; CSS HR: 0.76, CI: 0.62-0.93) and skin/soft tissue (OS HR: 0.35, CI: 0.16-0.81; CSS HR: 0.36, CI: 0.16-0.82), and in both surgical (OS HR: 0.70, CI: 0.52-0.93; CSS HR: 0.70, CI: 0.52-0.93) and non-surgical patients (OS HR: 0.71, CI: 0.56-0.89; CSS HR: 0.69, CI: 0.55-0.87). Radiotherapy showed no significant association with second primary cancer (SPC) risk. These findings suggest radiotherapy improves 5-year survival outcomes in FL patients during the rituximab era.

Performance of Radiomics-based machine learning and deep learning-based methods in the prediction of tumor grade in meningioma: a systematic review and meta-analysis.

Currently, the World Health Organization (WHO) grade of meningiomas is determined based on the biopsy results. Therefore, accurate non-invasive preoperative grading could significantly improve treatment planning and patient outcomes. Considering recent advances in machine learning (ML) and deep learning (DL), this meta-analysis aimed to evaluate the performance of these models in predicting the WHO meningioma grade using imaging data. A systematic search was performed in PubMed/MEDLINE, Embase, and the Cochrane Library for studies published up to April 1, 2024, and reporting the performance metrics of the ML models in predicting of WHO meningioma grade using imaging studies. Pooled area under the receiver operating characteristics curve (AUROC), specificity, and sensitivity were estimated. Subgroup and meta-regression analyses were performed based on a number of potential influencing variables. A total of 32 studies with 15,365 patients were included in the present study. The overall pooled sensitivity, specificity, and AUROC of ML methods for prediction of tumor grade in meningioma were 85% (95% CI, 79-89%), 87% (95% CI, 81-91%), and 93% (95% CI, 90-95%), respectively. Both the type of validation and study cohort (training or test) were significantly associated with model performance. However, no significant association was found between the sample size or the type of ML method and model performance. The ML predictive models show a high overall performance in predicting the WHO meningioma grade using imaging data. Further studies on the performance of DL algorithms in larger datasets using external validation are needed.

Surgical Management of Gastroenteropancreatic Neuroendocrine Tumors

Background/Objectives: Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from enterochromaffin cells that can arise from the gastrointestinal (GI) tract and pancreas. Surgical management is the cornerstone of treatment, with the optimal approach tailored by tumor grade, size, location, and presence of metastasis. This review discusses the current strategies for the surgical management of NETs of the gastroenteropancreatic tract. Methods: A review of the available literature was conducted to evaluate surgical approaches to NETs. Consensus guidelines were incorporated to synthesize evidence-based recommendations. Results: For gastric NETs, surgical approach depends on Rindi Classification, WHO grade, and tumor size, with endoscopic approaches favored for smaller and low-grade lesions. Small bowel NETs can be multifocal and thus often require a surgical approach with careful evaluation of the entire intestine. Pancreatic NETs are categorized as functional or non-functional, with enucleation or formal resection strategies based on size, location, functional status, and risk of malignancy. Colorectal NETs are primarily treated with transanal localized or formal surgical resection, depending on lesion size and depth of invasion or presence of lymph node involvement. Appendiceal NETs are either treated with appendectomy or right hemicolectomy, depending on the size, location, and invasiveness of the lesions. For metastatic NETs, cytoreduction, liver transplantation, and targeted therapies offer symptom relief and possible survival benefits. Conclusions: Surgical resection provides curative potential for localized NETs and symptom control in metastatic cases. Future research is essential to refine guidelines for intermediate-risk lesions and multifocal tumors, ensuring optimal outcomes for patients with gastroenteropancreatic NETs.

Wnt/ β-catenin and CTNNB1 gene mutation in hepatocellular carcinoma, a case study in Egyptian patients

BackgroundWnt/β-catenin pathway has an important role in hepatocarcinogenesis. It has been involved in progression, growth, epithelial mesenchymal transition and metastasis of hepatocellular carcinoma (HCC). This pathway may represent a potential target for evolving treatment strategies. β-catenin gene (CTNNB1) has been identified as an important oncogene involved in hepatocarcinogenesis in previous trials to understand the pathogenesis of HCC. This study aimed to spot light on the role of Wnt/ β-Catenin and CTNNB1 gene mutation in HCC development and its relation with different clinicopathological features.Patients and methodsThis study was conducted on 121 HCC cases that were obtained from liver explants from pathology laboratory at Mansoura Gastroenterology center retrospectively in the period between 2006-2017. Tissue Microarray (TMAs) were prepared. β-Catenin and Wnt immunohistochemical (IHC) staining was performed on these blocks. Detection and scoring of CTNNB1 gene mutation were done by Chromogenic In Situ Hybridization (CISH). The relation between aberrant β-Catenin, Wnt2 IHC staining and CTNNB1 mRNA expression and different clinicopathological characteristics was studied.ResultsA significant association was detected between aberrent β-catenin IHC staining and larger tumor size (p = 0.011), multiple tumor nodules (p = 0.021), higher stages of the tumor (p = 0.03) and with presence of lymphovascular emboli (LVE) (p = 0.034). However, no significant association was detected with tumor site, presence of lymph node spread, distant metastasis, tumor necrosis, local recurrence and alpha-fetoprotein level. No significant association was seen between Wnt2 IHC staining with either tumor site, tumor size, number of tumor nodules, presence of LVE, tumor necrosis, tumor grade, TNM stage or presence of local recurrence. A significant association was seen between CTNNB1 mRNA expression and larger tumor size (> 5 cm) (p = 0.041), higher tumor stages (Stages III and IV) (p = 0.005) and presence of distant metastasis (p = 0.008).). No significant association between CTNNB1 mRNA expression and LVE, tumor necrosis, tumor grade or occurrance of local recurrence.ConclusionAberrant β-catenin IHC staining and CTNNB1 gene mutation in HCC correlate significantly with tumor size, number of tumor nodules, tumor stage and presence of LVE. All of these items confer poor prognosis in HCC. A highly significant correlation was detected between CTNNB1 gene mutation and aberrant β-catenin expression in HCC cases.

Circadian and Autophagy Markers Correlate with Poor Prognosis in Meningioma Patients.

Patients with meningiomas mostly present good outcomes and optimal prognosis, but different grades of tumors have very different symptoms and recurrence rates. Therefore, effective diagnosis is crucial for early intervention and controlling tumor development. Circadian cycle and autophagy have both been proven to be related to neoplasm formation and pathogenesis; however, there is limited exploration and discussion on the relationships between the circadian cycle and autophagy in patients with meningiomas. This study was undertaken to elucidate the relationship between two autophagy markers (Beclin1, LC3B) and one circadian marker (NR1D1) with clinicopathological parameters in patients with meningiomas. Clinicopathological data of 124 enrolled patients were collected. Tissue-sectioned slides were analyzed via immunohistochemical stains and the relationship between the markers was evaluated. Individually low expression of NR1D1 and Beclin 1 was associated with better prognosis, lower pathological grade, and longer survival. Although correlation analysis showed that NR1D1, Beclin 1 and LC3B were related to each other. However, the dual marker NR1D1-/Beclin 1- was effective in predicting good prognosis in meningiomas, whereas NR1D1-/LC3B- was not. NR1D1 and Beclin 1 could be adopted as a single marker or coupled as a combined marker to predict meningioma prognoses, pathological grades, and survival. This study provides insights into the association between autophagy and circadian cycles and may benefit future elucidation of molecular mechanisms.

MT1JP: A Pivotal Tumor-Suppressing LncRNA and its Role in Cancer Progression and Therapeutic Potential.

Metallothionein 1J pseudogene (MT1JP) is a long non-coding RNA (lncRNA) that functions as a tumor suppressor in various malignancies. Reduced MT1JP expression is associated with increased tumor proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and treatment resistance in nine cancers, such as gastric cancer, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, and breast cancer. Mechanistically, MT1JP acts as a competitive endogenous RNA (ceRNA) to regulate oncogenic microRNAs (miRNAs), including miR-92a-3p, miR-214-3p, and miR-24-3p. This regulation restores tumor suppressor genes, such as FBXW7, RUNX3, and PTEN, thereby disrupting oncogenic pathways, including PI3K/AKT, Wnt/βcatenin, and p53, promoting apoptosis, and inhibiting tumor progression. Clinically, MT1JP expression correlates with tumor grade, differentiation, TNM stage, lymph node metastasis, and patient prognosis, suggesting its potential as a diagnostic and prognostic biomarker. Furthermore, its therapeutic potential in RNA-based treatments has attracted significant attention. Despite these findings, questions remain regarding its role in epigenetic regulation, transcriptional control, and RNA delivery. This review explores the molecular mechanisms underlying MT1JP, highlighting its clinical relevance and potential as a therapeutic target. Future research should focus on elucidating its role in epigenetic regulation, overcoming challenges in therapeutic delivery, and validating its utility as a biomarker for different cancers. MT1JP holds promise for advancing precision oncology by providing innovative approaches for cancer diagnosis and treatment.

Outcomes for Gastrectomy During Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Non-Gastric Primaries: A 30-Year Experience.

Cytoreductive surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) can improve survival for patients with peritoneal surface malignancy. Completeness of cytoreduction correlates with prognosis. The role of gastrectomy in these patients is not well described. 1868 patients who underwent CRS+HIPEC for non-gastric primary between 1991-2024 were analyzed from a prospective database. Patients were stratified by gastrectomy extent and their outcomes compared with no-gastrectomy patients. Continuous variables are presented as mean (SD), categorical variables as N (%) and values considered statistically significant at < 0.05. There were no differences in baseline demographics between the gastrectomy and no-gastrectomy groups. There were 23 major, 45 distal, and 77 wedge gastrectomies (n=145, 7.76%). Appendiceal was the most common neoplasm in the gastrectomy groups (major: 96%, distal: 91%, wedge: 68%, no gastrectomy: 53%). Gastrectomy patients had higher median PCI [major: 27(7.0), distal: 24(7.0), wedge: 19(10.3), no-gastrectomy: 14(9.5); p<0.001], R2 resection (major: 96%, distal: 89%, wedge: 60%, no-gastrectomy: 45%; p<0.001), severe complications (major: 30%, distal: 27%, wedge: 19%, no-gastrectomy: 12%; p<0.001), LOS [major: 24(15.2) , distal: 23(25.7), wedge: 18(22.2), no-gastrectomy: 12 (12.5) days; p<0.001], and 30-day mortality (major: 17%, distal: 11%, wedge: 10%, no-gastrectomy: 5%; p<0.001). There was no difference in 30-day readmission or recurrence. On multivariate analysis, gastrectomy was not independently associated with overall survival (OS) (p=0.18). 8% of patients who underwent CRS+HIPEC for non-gastric primaries underwent gastrectomy. Gastrectomy patients were more likely to have higher PCI and incomplete resections with increased complications and mortality. PCI, resection status, LN's, tumor grade, and primary site, but not gastrectomy type, are significantly associated with OS.

VPS45 Contributes to the Progression of Hepatocellular Carcinoma by Triggering the Wnt/β-Catenin Signaling Pathway.

Vacuolar protein sorting 45 (VPS45) has recently been implicated in the development of ovarian cancer and non-small cell lung cancer. However, its role in the onset and progression of hepatocellular carcinoma (HCC) remains unclear. This study aims to elucidate the function of VPS45 in HCC. Bioassays were conducted to assess the prognostic significance of VPS45 in HCC. Techniques such as western blotting and real-time quantitative polymerase chain reaction (qRT-PCR) were used to confirm the expression levels of VPS45 in HCC tissues and cell lines, as well as to evaluate the expression of downstream effectors in its potential tumorigenic pathways. The impact of VPS45 on HCC cell invasion, proliferation, and migration was assessed using the Cell Counting Kit-8 (CCK-8), wound healing, and transwell assays. Furthermore, the effect of VPS45 on HCC tumorigenesis in vivo was evaluated through subcutaneous tumor formation assays in BALB/c nude mice. VPS45 is markedly overexpressed in both HCC tissues and cell lines. Its expression escalates with advancing tumor grade and clinical stage, and high VPS45 levels are indicative of poor prognosis. In vitro experiments revealed that VPS45 overexpression significantly boosts HCC cell proliferation, migration, and invasion. Conversely, VPS45 knockdown hindered HCC progression in vivo. Investigation into pathway protein expression suggests that VPS45 facilitates HCC progression through its involvement in the Wnt/β-catenin signaling pathway. The overexpression of VPS45 contributes to the development of malignant phenotypes in HCC cells, resulting in a poor prognosis. Targeting VPS45 may offer a viable therapeutic strategy for managing HCC.

Dual-center retrospective cohort analysis of high-risk cutaneous squamous cell carcinoma tumors.

High-risk cutaneous squamous cell carcinoma (hr-cSCC) tumors exhibit aggressive behavior, leading to local recurrence, metastasis, and mortality. The management of hr-cSCC tumors is not well-defined. To clarify the impact of clinical risk factors and management strategies on disease-related outcomes (DROs) in patients with hr-cSCCs. This dual-center retrospective cohort study reviewed patient records from 2007 to 2023, focusing on hr-cSCC tumors classified as high-risk according to two staging systems. 160 adult patients with hr-cSCC were included. Tumors > 2cm were associated with a higher risk of recurrence, metastasis, and mortality, with greater risk for tumors > 4cm. Nonsurgical therapies were linked to higher recurrence and mortality rates compared to surgical monotherapy. Patients whose initial treatment was delayed > 60 days following biopsy had increased incidence of DROs. Other variables associated with at least one DRO included female sex, higher tumor grade, lymphovascular invasion, and advanced AJCC-8 stages. Limitations of this study include its retrospective design, narrow demographics, and variable follow-up times. This study identifies increased tumor diameter, non-surgical treatments, delayed treatment > 60 days after biopsy, female sex, tumor grade, lymphovascular invasion, and advanced tumor stage as significant risk factors for DROs in hr-cSCC. Importantly, our study provides new clarifying evidence that delayed surgical treatment of hr-cSCCs > 60 days after biopsy is associated with elevated incidence of DROs.

First Clinical Experience of 68Ga-FAPI PET/CT in Tertiary Cancer Center: Identifying Pearls and Pitfalls.

Background/Objectives: Over the past four years, 68Ga-fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) has been established at a tertiary cancer care facility in Jordan. This retrospective study aims to explore tracer uptake metrics across various epithelial neoplasms, identify diagnostic pitfalls associated with 68Ga-FAPI PET/CT, and evaluate the influence of 68Ga-FAPI PET/CT staging results on changes in therapeutic intent compared to gold standard molecular imaging modalities. Methods: A total of 48 patients with biopsy-confirmed solid tumors underwent 77 68Ga-FAPI PET/CT examinations for molecular imaging assessment, encompassing neoplasms originating from the gastrointestinal tract, head and neck, hepatobiliary system, pancreas, breast, and lung. Results: Notably, pancreaticobiliary tumors exhibited the highest tracer uptake, with mean maximum standardized uptake values (SUVmax) and tumor-to-background ratios (TBR) surpassing 10. A comparative sub-analysis of 68Ga-FAPI PET metrics in 20 treatment-naïve patients revealed a significant correlation between 68Ga-FAPI uptake metrics and tumor grade (Spearman's rho 0.83; p = 0.00001). Importantly, the results from 68Ga-FAPI PET/CT influenced treatment decisions in 35.5% of the cases, primarily resulting in an escalation of management plans. A total of 220 diagnostic challenges were identified across 88.3% of the scans, predominantly within the musculoskeletal system, attributed to degenerative changes (99 observations). Conclusions: This comprehensive analysis highlights the potential significance of 68Ga-FAPI PET/CT in oncological imaging and treatment strategy, while also emphasizing the necessity for meticulous interpretation to mitigate diagnostic challenges.

Immunohistochemical expression of parathyroid hormone-related protein and ezrin in invasive breast carcinoma of no special type: a retrospective analysis

BackgroundGlobally, breast cancer ranks among the most common malignancies and has a high mortality rate. Invasive breast carcinoma of no special type (IBC-NST) presents a heterogeneous group with variable prognosis. Identifying reliable biomarkers is crucial for improving treatment strategies and predicting outcomes. This study investigates the immunohistochemical expression of parathyroid hormone-related protein (PTHrP) and ezrin in IBC-NST and their correlation with clinicopathological features and overall survival.MethodsThis retrospective study analyzed 160 paraffin-embedded tissue samples, including 123 IBC-NST and 37 normal breast tissues, collected from patients treated at Menoufia University Hospital during the period from January 2018 to January 2022. Immunohistochemical staining for PTHrP and ezrin was performed, and expression levels were quantified using the H score.ResultsPTHrP expression was significantly higher in IBC-NST than in adjacent DCIS and normal tissues (p < 0.001). High PTHrP percent of expression was associated with metastasis (p = 0.009), bone metastasis (p = 0.012), and lymphovascular invasion (p = 0.037). Ezrin expression was also significantly elevated in IBC-NST, with higher H score values correlating with high tumor grade (p = 0.002), high N stage (p = 0.045), advanced AJCC stage grouping (p = 0.0043) and metastasis (p = 0.001). A significant positive correlation was observed between PTHrP and ezrin expression (rs = 0.341, p < 0.001). Kaplan-Meier analysis showed that high ezrin expression, in terms of intensity (p = 0.007) and H score (p = 0.002), was linked to poorer survival.ConclusionThe study highlights the significant roles of PTHrP and ezrin in breast cancer progression. Elevated levels of these proteins are associated with more aggressive disease, suggesting their capability as prognostic indicators and treatment targets in breast cancer. Additional studies are required to investigate their interaction and collective influence on breast cancer metastasis and treatment.

68Ga-NOTA-RM26 PET/CT in the evaluation of glioma: a pilot prospective study

BackgroundGliomas are the most common malignant primary tumors of the central nervous system. There is an urgent need for new convenient, targeted and specific imaging agents for gliomas. This study aimed to firstly evaluate the feasibility of 68Ga-NOTA-RM26 PET/CT imaging in glioma and analyze the relationship between the imaging characteristics and glioma grade, classification and molecular alterations.ResultsTwenty-two patients were confirmed as glioma by surgery or biopsy. All patients exhibited 68Ga-NOTA-RM26 uptake. SUVmax was chosen as the imaging marker for analysis. For all glioma patients, there were significant differences between grades (P = 0.047). For primary gliomas, SUVmax had good discrimination for both tumor classifications (P = 0.045) and grades (P = 0.03). There was a positive correlation (P < 0.01) between GRPR expression level and SUVmax. P53 mutations caused significant differences in SUVmax (P = 0.03).ConclusionsThis study is the first application of 68Ga-NOTA-RM26 in glioma patients and confirmed the safety and efficacy in glioma patients. 68Ga-NOTA-RM26 PET/CT has potential value in tumor grade, classification, and molecular alterations.Trial registrationClinicalTrials.gov: NCT06412952. Registered 26 April 2024, https://clinicaltrials.gov/study/NCT06412952

Association of Structural Maintenance of Chromosome-1A Phosphorylation with Progression of Breast Cancer.

Structural maintenance of chromosome-1A (SMC1A) is overexpressed in various malignancies including triple-negative breast cancer (TNBC). As a core component of the cohesin complex, SMC1A was initially recognized for its involvement in chromosomal cohesion and DNA-repair pathways. However, recent studies have unveiled its pivotal role in epithelial-mesenchymal transition (EMT), metastasis, and chemo- and radio-resistance in cancer cells. In hepatocellular carcinoma, aberrant phosphorylation of SMC1A has been associated with enhanced cell proliferation and migration. Despite these insights, the precise role of SMC1A phosphorylation in breast cancer remains largely unexplored. This study represents the first investigation to test the phosphorylation status and subcellular localization of SMC1A (p-SMC1A) in breast cancer and normal breast tissues. Immunohistochemical (IHC) staining was conducted using previously validated phospho-SMC1A antibodies on a histological section and tissue microarray (TMA) comprising samples from primary, invasive, and metastatic breast cancer and normal breast tissues. Our results revealed that p-SMC1A staining intensity was lower in normal breast tissues compared to invasive or metastatic breast cancer tissues (p < 0.001). Approximately 40% of breast cancer tissue exhibited cytoplasmic/membranous localization of p-SMC1A, whereas nuclear expression was observed in normal breast tissues. Moreover, elevated phosphorylation levels were significantly associated with higher tumor grade and metastasis.

Evaluating the Effectiveness of Cyclin-Dependent Kinase 4/6 Inhibitors in Early- and Very Early-Onset Metastatic Breast Cancer: A Multicenter Study.

Background and Objectives: Early-onset breast cancer (EOBC), particularly in patients under 40, presents with distinct biological characteristics and worse survival outcomes compared to late-onset cases. Despite intensive treatments, EOBC patients, especially those with hormone receptor-positive, HER2-negative (HR+/HER2-) subtypes, show poorer prognosis. CDK4/6 inhibitors, combined with endocrine therapy (ET) have become the standard for HR+/HER2- metastatic breast cancer, yet younger patients are underrepresented in clinical trials. This study aims to evaluate the efficacy of ribociclib and palbociclib with ET in HR+/HER2- metastatic breast cancer, addressing the critical gap in understanding treatment outcomes in younger patient populations. Materials and Methods: This multicenter, retrospective study evaluated the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors, ribociclib, and palbociclib, in combination with endocrine therapy in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer. Results: A total of 198 patients treated between 2019 and 2023 were analyzed for progression-free survival, overall survival, and prognostic factors. Very early-onset breast cancer, which is diagnosed before the age of 35, was identified as an independent prognostic factor for poor progression-free survival. Additional factors associated with poorer outcomes included liver metastasis, progesterone receptor negativity, high tumor grade, and the concurrent use of fulvestrant with CDK4/6 inhibitors. Both ribociclib and palbociclib demonstrated similar efficacy, and dose reductions due to treatment-related adverse events did not compromise therapeutic outcomes. Conclusions: This study is the first to focus specifically on the treatment of early-onset breast cancer with CDK4/6 inhibitors, providing critical insights into the unique challenges faced by this patient population. The findings underscore the urgent need for personalized treatment strategies, routine genetic testing, and dedicated clinical trials designed to address the specific needs of these high-risk subgroups. By advancing our understanding of the clinical and molecular landscape of early-onset breast cancer and very early-onset breast cancer, this study lays the groundwork for improving outcomes in these underserved patients through tailored therapeutic approaches.

Immunohistochemical Profiling of Histone Modification Biomarkers Identifies Subtype-Specific Epigenetic Signatures and Potential Drug Targets in Breast Cancer.

Breast cancer (BC) subtypes exhibit distinct epigenetic landscapes, with triple-negative breast cancer (TNBC) lacking effective targeted therapies. This study investigates histone biomarkers and therapeutic vulnerabilities across BC subtypes. The immunohistochemical profiling of >20 histone biomarkers, including histone modifications, modifiers, and oncohistone mutations, was conducted on a discovery cohort and a validation cohort of BC tissues, healthy controls, and cell line models. Transcriptomic and cell growth analyses were conducted to evaluate the effects of the small-molecule G9a inhibitor in diverse BC models. Key histone biomarkers, including H3K9me2, H3K36me2, and H3K79me, were differentially expressed across BC subtypes. H3K9me2 emerged as an independent predictor for distinguishing TNBC from other less-aggressive BC subtypes, with elevated expression correlating with higher tumor grade and stage. G9a inhibition impaired cell proliferation and modulated epithelial-mesenchymal transition pathways, with the strongest impact in basal-like TNBC. The disruption of the oncogene and tumor suppressor regulation (e.g., TP53, SATB1) was observed in TNBC. This study highlights G9a's context-dependent roles in BC, supporting its potential as a therapeutic target. The findings provide a foundation for subtype-specific epigenetic therapies to improve outcomes in aggressive BC subtypes.

Cytokeratin-Based Assessment of Tumour Budding in Colorectal Cancer

Introduction: One of the most prevalent and major causes of cancer-related mortality is colorectal cancer (CRC). Unfortunately, despite being labelled as low-risk cancers based on their tumour, node, metastasis (TNM) stage, many tumours behave poorly. The independent forecasting tool for CRC, particularly in node-negative illness, is tumour budding (TB). The term ‘tumour buds’ (TB) refers to detached (epithelial) tumour cells, which are single or clusters (less than or equal to five cells) at the maximum invasive front. Background and Aims: The aim of this study was to evaluate TB using pan-cytokeratin immunostain and comparing it with haematoxylin and eosin (H&amp;E) staining and clinicopathological parameters. Methods: Resected specimens without presurgical therapy were analysed in the Department of Pathology for one year. Among histologically proven colorectal carcinoma, TB scores on H&amp;E and pan-cytokeratin immunostained slides were compared. Results: Among the various clinicopathological parameters evaluated in 83 cases of CRC, we emphasise from our study that there was a strong correlation of TB score with tumour type, grade of tumour and metastasis. There is a definitive chance of upgradation of TB score by cytokeratin immunostain. Conclusion: TB is a negative prognostic factor responsible for adverse outcomes in CRC patients. Regardless of the scoring method used, cytokeratin-based assessment of TB is superior compared with the TB score assessed by H&amp;E alone.