Ki-67 Expression Research Articles

Morphological and molecular changes of oestrogen receptor-positive breast cancer following bridging endocrine therapy: a United Kingdom multicentre study.

Standard neoadjuvant endocrine therapy (NAET) is used for 6-9 months to downstage hormone-receptor-positive breast cancer. Bridging ET was introduced during the COVID-19 pandemic to delay surgical intervention. There are no data in the literature on the effect of short course therapy on tumour response. We aimed to analyse the effect of bridging ET and validate the previously proposed neoadjuvant ET pathological reporting criteria. This was a multicentre cohort of 256 patients who received bridging ET between March and October 2020. Assessment of paired pre- and post-NAET hormone receptors and HER2 and posttherapy Ki67 expression was done. The median duration of NAET was 45 days. In all, 86% of cases achieved partial pathological response and 9% showed minimal residual disease. Histological response to ET was observed from as early as day 6 posttherapy. Central scarring was noted in 32.8% of cases and lymphocytic infiltrate was seen in 43.4% of cases. Significant changes associated with the duration of ET were observed in tumour grade (21%), with downgrading identified in 12% of tumours (P < 0.001), progesterone receptor (PR) expression with switch to PR-negative status in 26% of cases (P < 0.001), and HER2 status with a switch from HER2-low to HER2-negative status in 32% of cases (P < 0.001). The median patient survival was 475 days, with an overall survival rate of 99.6%. Changes characteristic of tumour regression and significant changes in PR and HER2 occurred following a short course of NAET. The findings support biomarker testing on pretreatment core biopsies and retesting following therapy.

Prognostic and clinicopathological value of Ki-67 in patients with oesophageal squamous cell carcinoma: a systematic review and meta-analysis

ObjectivesThe relationship between Ki-67 expression and the prognosis of patients with oesophageal squamous cell carcinoma (ESCC) has been extensively studied. However, their findings were inconsistent. Consequently, the present meta-analysis was...

Epithelial cell proliferation index in patients with atrophic gastritis depending on the presence of complete or incomplete intestinal metaplasia in the gastric antrum

Introduction. There is a debate about the significance of intestinal metaplasia (IM) subtypes for the development of gastric cancer. Therefore, determining the indicators of cellular renewal in individuals with complete and incomplete IM is certainly a topical issue.Aim. To study the proliferative activity of epithelial cells of the gastric antrum in patients with Helicobacter pylori-positive antral atrophic gastritis depending on the subtype of IM.Materials and methods. The study included 20 people with chronic antral non-atrophic gastritis (CNG; group A), 20 patients with chronic antral atrophic gastritis (CAG) without IM (group B), 20 patients with CAG with complete IM (group C) and 20 people with CAG with incomplete IM (group D). The stage of chronic gastritis was assessed by the morphological method in accordance with the modified Sydney classification. Typing of IM foci in the gastric mucosa was performed using the PAS reaction. Proliferation activity was studied by the expression of nuclear protein Ki67 using immunohistochemistry.Results. The proliferation index in the foci of complete BM in group C was 5%, and in group D in the foci of incomplete BM the Ki67 expression index was significantly higher and was 39% (p &lt; 0.001). Outside the foci of metaplasia, the proliferation index was 23.5% in group C and 19% in group D (p = 0.06).Conclusion. We have registered significantly higher proliferation indicators of gastric epithelial cells in foci with incomplete IM compared to foci with complete IM. Determination of proliferation indicators in foci of incomplete intestinal metaplasia may be a marker of an increased risk of developing gastric cancer.

Loss of CFTR Reverses Senescence Hallmarks in SARS-CoV-2 Infected Bronchial Epithelial Cells.

SARS-CoV-2 infection has been recently shown to induce cellular senescence in vivo. A senescence-like phenotype has been reported in cystic fibrosis (CF) cellular models. Since the previously published data highlighted a low impact of SARS-CoV-2 on CFTR-defective cells, here we aimed to investigate the senescence hallmarks in SARS-CoV-2 infection in the context of a loss of CFTR expression/function. We infected WT and CFTR KO 16HBE14o-cells with SARS-CoV-2 and analyzed both the p21 and Ki67 expression using immunohistochemistry and viral and p21 gene expression using real-time PCR. Prior to SARS-CoV-2 infection, CFTR KO cells displayed a higher p21 and lower Ki67 expression than WT cells. We detected lipid accumulation in CFTR KO cells, identified as lipolysosomes and residual bodies at the subcellular/ultrastructure level. After SARS-CoV-2 infection, the situation reversed, with low p21 and high Ki67 expression, as well as reduced viral gene expression in CFTR KO cells. Thus, the activation of cellular senescence pathways in CFTR-defective cells was reversed by SARS-CoV-2 infection while they were activated in CFTR WT cells. These data uncover a different response of CF and non-CF bronchial epithelial cell models to SARS-CoV-2 infection and contribute to uncovering the molecular mechanisms behind the reduced clinical impact of COVID-19 in CF patients.

Suppressing mitochondrial inner membrane protein (IMMT) inhibits the proliferation of breast cancer cells through mitochondrial remodeling and metabolic regulation

Metabolic reprogramming is widely recognized as a hallmark of malignant tumors, and the targeting of metabolism has emerged as an appealing approach for cancer treatment. Mitochondria, as pivotal organelles, play a crucial role in the metabolic regulation of tumor cells, and their morphological and functional alterations are intricately linked to the biological characteristics of tumors. As a key regulatory subunit of mitochondria, mitochondrial inner membrane protein (IMMT), plays a vital role in degenerative diseases, but its role in tumor is almost unknown. The objective of this research was to investigate the roles that IMMT play in the development and progression of breast cancer (BC), as well as to elucidate the underlying biological mechanisms that drive these effects. In this study, it was confirmed that the expression of IMMT in BC tissues was significantly higher than that in normal tissues. The analysis of The Cancer Genome Atlas (TCGA) database revealed that IMMT can serve as an independent prognostic factor for BC patients. Additionally, verification in clinical specimens of BC demonstrated a positive association between high IMMT expression and larger tumor size (> 2 cm), Ki-67 expression (> 15%), and HER-2 status. Furthermore, in vitro experiments have substantiated that the suppression of IMMT expression resulted in a reduction in cell proliferation and alterations in mitochondrial cristae, concomitant with the liberation of cytochrome c, but it did not elicit mitochondrial apoptosis. Through Gene Set Enrichment Analysis (GSEA) analysis, we have predicted the associated metabolic genes and discovered that IMMT potentially modulates the advancement of BC through its interaction with 16 metabolic-related genes, and the changes in glycolysis related pathways have been validated in BC cell lines after IMMT inhibition. Consequently, this investigation furnishes compelling evidence supporting the classification of IMMT as prognostic marker in BC, and underscoring its prospective utility as a novel target for metabolic therapy.

Multifaceted Impacts of Monosodium Glutamate on Testicular Health: Insights into Pyroptosis and Therapeutic Potential of Resveratrol.

Monosodium glutamate was considered one of the food additive and flavor enhancer in processed meat and soup that affects testicular tissues, the aim of this research to investigates the impact of monosodium glutamate (MSG) on testicular structure in rats and explores the potential protective effects of resveratrol. Four experimental groups involved in our study 10 rats of each.: the first group as control group; the second group (Resveratrol group: control rats received 20 mg/kg of resveratrol, via oral gavage); the third group (MSG group: rats received monosodium glutamate (MSG) with a dose 60 mg/kg body weight daily, via gastric tube, and the fourth group (MSG+ Resveratrol group). Serum level of testosterone, FSH, LH, were measured. Testicular tissues were prepared for measurement of oxidative stress markers, and gene expression of NLRP3, Caspase 3, and GSK-3β. Moreover, paraffin blocks contained testicular tissue used for histological and immunohistochemical examination. Additionally, seminal smear from epididymis were examined. MSG administration adversely affected testosterone production, hormonal levels, and sperm parameters, Histological examination revealed marked testicular degeneration, and oxidative stress assessments indicated elevated level of MDA a lipid peroxidation marker and decrease in SOD, CAT antioxidant enzymes. Moreover, MSG-induced apoptotic and pyroptotic markers and its gene expressions. Importantly. Administration of resveratrol reversed the detrimental effects of MSG, demonstrating its corrective influence on the hypothalamic-pituitary-gonadal axis disruption, improvement of sperm parameters, attenuation of oxidative stress, anti-apoptotic activity, and anti-pyroptotic effects. The expression of Ki-67 as a cell proliferation marker further supported the positive response to spermatogenesis dysfunction upon resveratrol treatment. This comprehensive exploration sheds light on the protective effect of resveratrol against MSG-induced testicular with exploration of its mechanistic role.

The correlation between Ki 67 and Oncotype Dx on HR+, HER2- early breast cancer management: Insights of molecular testing.

e12546 Background: Elevated Ki-67 expression serves as an indicator of tumoral proliferation in breast cancer (BC) and is used in Ecuador for survival estimation, recurrence risk assessment, and guiding chemotherapy decisions. The Oncotype DX Breast Recurrence Score (ODX RS) is a validated 21-gene assay for hormone receptor-positive, HER2-negative invasive BC. It predicts chemotherapy benefits and the risk of distant recurrence over 10 years and is a mortality indicator. ODX RS has the potential to reduce the need for chemotherapy, alleviate financial burdens, and enhance clinical outcomes. Despite conflicting evidence on the significance of Ki-67 in the ODX RS, there is a lack of exploration within Latin populations. This study aims to compare the correlation of immunohistochemical (IHC) measured Ki-67 to the ODX RS in the Ecuadorian population. Methods: A retrospective analysis included women with early BC who underwent ODX RS testing in Ecuador from May 2020 to January 2023. Inclusion criteria: early BC (T1-T3/N0-N1a); IHC estrogen receptor (ER) positive; HER2 negative; and availability of tumor size, grade, lymph node status, and Ki67 proliferation index data. Exclusion criteria: patients with recurrent BC, incomplete pathology, or lacking IHC data. Patients were categorized into low (≤5%), intermediate (6%–29%), and high Ki67 expression groups (≥30%). Using the statistical software SPSS, the correlation between ODX scores and Ki-67 expression was analyzed using Pearson’s correlation coefficient. For risk stratification groups, Spearman's correlation was employed. Results: Among 77 patients undergoing Oncotype DX testing, 64 (with a mean age of 55) met the inclusion criteria. Eighty-six percent of cases were invasive ductal carcinomas (IDC). Seventeen percent exhibited low Ki-67 expression, 61% intermediate, and 20% high. No statistically significant correlation was found between IHC Ki-67 expression and ODX RS (r=0.051; p=0.69), neither when stratified by categories (r=0.086; p=0.50). A subanalysis based on risk categories showed 82% correspondence in the low Ki-67 group, 18% in the intermediate group, and 31% in the high Ki-67 group. No significant correlation was observed when stratified by histological types (invasive ductal carcinoma and invasive lobular carcinoma), nor by sample origin (core biopsy, excisional biopsy). Conclusions: There was no correlation between IHC Ki-67 expression and ODX risk scores in this study involving Ecuadorian patients. Our findings emphasize that IHC Ki-67 expression should not be the sole determinant for guiding therapeutic decisions and predicting recurrence in early breast cancer.[Table: see text]

The predictive role of Ki67 in pathological complete response (pCR) and invasive disease-free survival (IDFS) in HER2-positive breast cancer: A retrospective study of 246 cases.

e12610 Background: While Ki67 is a routine diagnostic measure for early hormone receptor positive breast cancer, it is not integrated into the standard procedure for patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer patients, given the substantial risk linked to HER2 expression alone. Consequently, the predictive significance of Ki67 in achieving pathological complete response (pCR) or invasive disease-free survival (IDFS) in this subgroup remains uncertain. Methods: This retrospective, bi-centric analysis focused on HER2-positive early breast cancer patients undergoing neoadjuvant chemotherapy from 2015 to 2023. We assessed the correlation between Ki67 values and the achievement of pathological complete response (pCR, defined as ypT0/is, pN0). Multivariable logistic regression analyzed the independent association of various clinical parameters, including Ki67, with pCR. Ki67 values were categorized into risk groups (low &lt;15%, intermediate 15.1-35%, high &gt;35%) following the GepardTrio data [1]. Kaplan-Meier estimator calculated differences in overall and invasive disease-free survival. Results: The study included 246 HER2-positive early breast cancer patients with known Ki67 expression, followed for a median of 42 months. The median age was 52 years. Final nodal status was pN0 in 80.5%, pN1 in 15%, and pN2 in 3.3%. Hormone receptor positivity was observed in 66% of patients. 147 patients (60%) achieved pCR. Median Ki67 was 30. When categorized, 13% were low, 41.5% intermediate, and 45.5% high risk. No correlation between Ki67 and pCR was observed (p=0.25). HER2 IHC score 3+ significantly increased pCR compared to IHC 2+ (62.2% vs. 44.6%, p=0.023). Hormone receptor-positive tumors had a lower pCR rate (52.7% vs. 72.4%, p=0.0016. 5-year overall survival was 96.5% for pCR and 83.8% for non-pCR (p=0.008). 5-year invasive disease-free survival showed no difference between low Ki67 (89.5%), intermediate Ki67 (79.9%), and high Ki67 (80.9%) groups (p=0.77). Conclusions: In this study, Ki67 did not predict pCR in HER2-positive breast cancer, providing no additional clinical value. HER2 IHC score and hormone receptor status were predictive indicators for pCR. Ki67 expression appears to lack additional value in HER2-positive breast cancer, considering resource implications. 1. Denkert C et al: Ann Oncol. 2013 Nov;24(11):2786-93. doi: 10.1093/annonc/mdt350. Epub 2013 Aug 22. PMID: 23970015.

High Level of Adropin Promotes the Progression of Pancreatic Ductal Adenocarcinoma.

Preliminary experiments have revealed the abnormally high expression level of adropin in pancreatic ductal adenocarcinoma (PDA). This study investigated the role of adropin in the progression of PDA. The paraffin-embedded samples of 20 patients with PDA were obtained from the hospital biobank, and immunohistochemistry was used to evaluate adropin expression. PDA cell lines were cultured and treated with recombinant adropin or adropin knockdown. Cell behavior was assessed, and the expression of phospho-vascular endothelial growth factor receptor (p-VEGFR2) and other related proteins was detected. The cell-derived xenograft (CDX) of PDA was established, and the effects of adropin or adropin knockdown on tumor growth were observed. The PDA cancer tissues exhibited elevated adropin protein expression compared with the paracancerous tissues, and the expression was positively correlated with carbohydrate antigen 19-9 levels in patients. Adropin significantly promoted the proliferation and migration of PDA cells and upregulated the expression of p-VEGFR2, Ki67, cyclin D1, and matrix metalloprotein 2 (MMP2). After the knockdown of adropin expression or blockade of VEGFR2, the above effects of adropin were significantly reversed. Adropin supplementation significantly accelerated tumor growth in PDA CDX; upregulated the expression of p-VEGFR2, Ki67, cyclin D1, and MMP2; and promoted angiogenesis in tumor tissue microenvironment. However, CDX inoculated with adropin knockdown cells produced the opposite results. Adropin overexpression in PDA promotes cancer cell proliferation and angiogenesis in tumor microenvironment by continuously activating VEGFR2 signaling, thereby creating conditions for tumor progression. Thus, targeting adropin may be an effective anti-PDA strategy.

Effects of sinomenine on a rat orthotopic liver carcinoma model.

Liver carcinoma is a common malignant tumor. In this study, an orthotopic liver carcinoma model was established by B-ultrasound, and the therapeutic effect of sinomenine (Sin) on the disease was investigated. SD rats were randomly divided into control, Sin, Sorafenib (Sor), and combination (Sin+Sor) groups (n=8). An orthotopic liver carcinoma model was established by inoculating N1-S1 cells into the rat liver by B-ultrasound-guided, and tumor volume was monitored three times by B-ultrasound after inoculation. After drug treatment, the tumor tissues were stained with HE and TUNEL, and the levels of inflammatory cytokines, ALT and AST were detected by ELISA. The numbers of erythrocytes, leukocytes and platelets were detected. Immunohistochemistry and immunofluorescence were used to detect the expression of Ki-67, CD44, VEGF and CD31. The levels of cell cycle, apoptosis-related proteins were detected by western blot. B-ultrasound monitoring found that Sin reduced tumor volume. Moreover, Sin improved tissue lesions, and promoted cancer cell apoptosis. Sin decreased the levels of inflammatory cytokines, AST and ALT, and decreased the numbers of erythrocytes, leukocytes and platelets. Simultaneously, the expressions of Ki-67, CD44, VEGF and CD31 were decreased in the Sin group. Furthermore, Sin decreased the Bcl-2, Cyclin D1, CDK4, CDK6 and Survivin levels, but increased Bax, Cleaved-caspase3/pro-caspase3, P21 and P27 levels. More importantly, the combination of Sin and Sor treatment was more effective than treatment alone. A rat orthotopic liver carcinoma model was established under the guidance of B-ultrasound, and Sin had a therapeutic effect on orthotopic liver carcinoma.

The role of epithelial-mesenchymal transition markers in invasive breast cancer among patients of Arab descent.

e13166 Background: Epithelial-mesenchymal transition (EMT) is the process wherein polarized and cohesive epithelial cells lose their epithelial characteristics and acquire a mesenchymal phenotype and proceed to the invasive form of the tumor. Numerous regulators play a role in the complex signaling pathways that mediate the EMT process. This study aims to investigate the immunohistochemical (IHC) expression of several EMT-related markers and their implications on the diagnosis and prognosis of breast cancer in a cohort of Arab descent women. Methods: Patients of Arab descent treated surgically for invasive and in-situ breast cancer between 2017-2020 were included in the study. Expressions of Ki-67, Transforming growth factor- β (TGF-β), NF-kappaB (NF-kB), Snail, Vimentin, E-cadherin (E-Cad), and B-catenin (B-Cat) were evaluated by IHC in tissue microarray slides, as per guidelines in the literature. We examined the association between the tumor markers and other clinicopathological variables and prognosis. Fisher's exact tests were utilized to compare categorical variables between groups. Results: One hundred eleven patients were included, 65.8% had invasive ductal carcinoma (IDC); 19.8% had invasive lobular carcinoma (ILC); 13.5% had both ductal and lobular features, and 0.9% had ductal carcinoma in situ. 91 (54.1%) were grade 2 and 303 (41.4%) were grade 3 tumors. Most tumors were ER positive (81.8%), PR positive (75.7%), and HER-2 negative (77.5%). The median age at diagnosis was 52 years. High TGF- β expression was associated with higher frequency of grade 3 tumors (p=0.036), AJCC stage III (p=0.042), and larger tumor size (p=0.036) compared to those with low TGF-B expression. Patients with positive B-Cat expression had a higher risk of death compared to those with negative B-Cat expression (HR, 3.90; 95% CI, 1.19 to 15.93; p=0.024). IDC had a statistically significant increased expression of TGF-B (69.9% vs.45.5%, p=0.045), E-Cad (76.7% vs. 13.6%, p&lt;0.001), and B-Cat (P 39.7% vs. 0%, p&lt;0.001) when compared to ILC. The overall survival at 1 and 5 years were 96.3% (95% CI, 92.7-99.9) and 81.7% (95% CI, 73.8-90.3), respectively. Conclusions: Tumors with high expression for TGF- β and B-Cat exhibit more aggressive clinical behavior, suggesting the potential prognostic and therapeutic value of these markers. Due to the limited research focused on Arab descent women, findings from this study may provide the foundation for more extensive molecular and clinical studies to assess the validity and clinical utility of these biomarkers in breast cancer patients from diverse ethnic backgrounds.

Neoadjuvant dalpiciclib combined with aromatase inhibitors in stage I-III HER2 negative luminal B breast cancer (DANCER): Preliminary findings from an ongoing phase II study.

e12622 Background: CDK4/6 inhibitors, in combination with endocrine therapy, have shown efficacy as neoadjuvant treatment in HR+/HER2- breast cancer (BC). This study investigates the efficacy and safety of dalpiciclib, a CDK4/6 inhibitor, combined with aromatase inhibitors (AI) as a neoadjuvant treatment for luminal B BC (defined as ER+/HER2- BC, with either Ki67≥20% and/or PR&lt;20%). Methods: This single-arm, single-center, phase II study (NCT05640778) enrolled patients aged 18-75 with clinical stage I-III luminal B BC, primary tumor size ≥2 cm, and ECOG PS 0-1. Eligible patients, regardless of menopausal status, received AI therapy (either anastrozole 1 mg daily or letrozole 2.5 mg daily) combined with dalpiciclib (150 mg daily on days 1-21) starting from cycle 1 day 1 (C1D1), for four 28-day cycles, followed by surgery. Pre-/peri-menopausal patients received AI therapy 14 days prior to the first dose of dalpiciclib (C0D1-C0D14), concurrent with a GnRH agonist administered every 28 days from C0D1. Ki67 levels were assessed through serial biopsies at baseline, C1D15, and surgery. MRI assessments were performed at baseline, C2D28, and before surgery per RECIST v1.1. Serial plasma samples were collected for circulating tumor DNA (ctDNA) analysis. The primary endpoint was the complete cell cycle arrest (CCCA: Ki67≤2.7%) rate at 2 weeks (C1D15). Results: From Oct 2022 to Dec 2023, 23 patients with a median age of 52 years (range 38-73) were enrolled and received study treatment. Of these patients, 11 (47.8%) were pre-/peri-menopausal. Sixteen (69.6%) were diagnosed with stage II and the remaining had stage III disease. High Ki67 expression (≥20%) was observed in 21 patients (91.3%). As of Jan 7, 2024, all patients underwent the C1D15 Ki67 evaluation and the CCCA rate was 82.6% (95% CI: 60.5%-94.3%). The ctDNA concentration at C2D28 and post-surgery was significantly higher in patients who did not achieve CCCA compared to those who achieved CCCA ( P = 0.003 and 0.011, respectively). Ki67 expression decreased by a geometric mean of 93.1% (95% CI:76.0%-98.8%) from baseline to C1D15. Out of 20 patients who completed 2 cycles of treatment and received an MRI scan, 12 achieved a partial response, yielding an ORR of 60.0% at C2D28. Among 17 who completed all neoadjuvant therapy and underwent surgery, the ORR before surgery was 82.4% with 14 partial responses; none demonstrated residual cancer burden (RCB) 0/1, seven exhibited RCB 2, and 10 had RCB 3; one reached breast pathological complete response (ypTisN1). Grade ≥3 treatment-emergent adverse events included neutrophil count decreased (16, 69.6%), white blood cell decreased (9, 39.1%), and oral mucositis (1, 4.3%). Conclusions: Dalpiciclib plus anastrozole or letrozole exhibited biological and clinical activity with manageable toxicities in neoadjuvant treatment for stage I-III luminal B/HER2- BC. Clinical trial information: NCT05640778 .

Proliferation and apoptosis dynamics of the normal canine mammary gland during the oestrous cycle evaluated by Ki-67 and Caspase-3 indexes.

Understanding the normal physiology of the canine mammary gland (CMG) is crucial, as it provides a foundational reference for understanding canine mammary neoplasms. The relation between the Proliferation Index (PI) indicated by Ki-67 expression, along with the Apoptotic Index (AI) determined through Caspase-3 expression during the oestrous cycle, is inadequately documented in existing literature. This study seeks to offer insights into the interplay between PI and AI in the CMG across oestrous cycle phases. An extensive investigation was conducted on a diverse case series of bitches (n = 18). Oestrous cycle stages were determined through vaginal cytology, histological examination of the reproductive tract and serum progesterone and oestradiol concentrations. The entire mammary chain was histologically examined, and proliferation and apoptosis were assessed via double immunohistochemistry employing anti-Ki-67 and Caspase-3 antibodies. PI and AI were evaluated through a systematic random sampling approach, counting a minimum of 200 cells for each cell type. There was a significantly higher PI during early dioestrus in all mammary gland components, with a greater proportion of positive cells observed in epithelial cells compared to stromal cells. The highest PI was detected in epithelial cells within the end buds. Significant differences were found in Ki-67 labelling across the cranial mammary glands. A positive and strong correlation was noted between progesterone concentration and PI in epithelial cells. The AI remained consistently low throughout the oestrous cycle, with few differences observed across histological components. Caspase-3 labelling displayed the highest positivity in caudal mammary pairs. A negative and moderate correlation was identified between progesterone concentration and AI in interlobular mesenchymal cells. This study highlights the influence of endocrine regulation on cell proliferation indices in mammary tissue, emphasizing the need to consider these hormonal variations in toxicopathological studies involving canine mammary gland.

Clinical characteristics, prognosis, and immunotherapy outcome in pediatric melanoma: Analysis from a large Chinese cohort.

10050 Background: Malignant melanoma in children and adolescents is rare, with limited data on Chinese populations.To assess the clinical characteristics, survival, prognostic factors, and the efficacy of immunotherapy in a real-world cohort of Chinese pediatric patients with melanoma. Methods: This is a retrospective, cohort study included pediatric melanoma patients between February, 2005 and May, 2021, with a median follow-up time of 76.7 months. Data analyses were conducted in May, 2023. This study enrolled patients from Sun Yat-sen University Cancer Center, the biggest cancer institution in South China for cancer prevention, diagnosis and treatment. Inclusion criteria for this study were as follows: 1) histopathologically confirmed diagnosis of melanoma; 2) Age ≤18 year; 3) with complete clinical data on sex, age, histopathological features, etc. The exclusion criteria was secondary malignant melanoma. Main outcomes and measures were patient’s OS and EFS. Results: 43 patients were enrolled, with median age of 138.9 (range 13.1-215.0) months, including 30 cutaneous melanoma, 7 meningeal melanoma, 5 mucosal melanoma, and 1 uveal melanoma. The frequency of BRAF V600E mutation was 16.7% (4/24). Mismatch repair proteins were normally expressed (7/7), and the positive rate of programmed cell death ligand 1 expression was 55.6% (5/9). The event-free survival and overall survival of cutaneous, mucosal and meningeal melanoma were 46.7±9.1% vs 75.0±21.7% vs 16.7±15.2% ( P = 0.010), 65.5±8.9% vs 75.0±21.7% vs 16.7±15.2% (P&lt; 0.001), respectively. Survival of cutaneous melanoma were associated with pathological type, ulceration, Clark level, disease spread, sentinel lymph node status, tumor stage and Ki-67 expression. 5 of 9 patients who were treated with PD-1 inhibitors (5 with PD-1 inhibitors alone, 3 with PD-1 inhibitors plus angiogenesis inhibitors, 1 with combination of anti-PD1, anti-angiogenic inhibitors plus chemotherapy) were evaluable with the overall response rate of 20%. The most common immune-related adverse event was hypothyroidism. Conclusions: This is the largest real-world study in pediatric melanoma patients in Asia. The prognosis of mucosal melanoma was favorable, followed by cutaneous melanoma, and meningeal melanoma had the worst prognosis. PD-1 antibody combined with angiogenesis inhibitors maybe a promising choice in pediatric melanoma.

Clinical significance of circulating tumor DNA in neoadjuvant-treated HER2-negative luminal B breast cancer.

e12616 Background: Circulating tumor DNA (ctDNA) holds significant value in the comprehensive management of breast cancer (BC) patients, whereas long-standing questions have been raised concerning the practical utility of ctDNA in HR+/HER2- subtype. Herein, we evaluated the clinical activity of ctDNA in luminal B (HR+/HER2-, with either Ki67≥20% and/or PR&lt;20%) BC patients receiving neoadjuvant therapy. Methods: Patients received neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy combined with CDK4/6 inhibitors (NET) were enrolled. Tumor tissue and plasma samples were collected and subjected to sequencing. Blood was collected for ctDNA analysis before treatment (T0), 2-3 weeks after treatment (T1), at the midpoint of neoadjuvant treatment (T2), prior to surgery (S), and postoperatively (PO). The tumor tissues were biopsied or surgically excised at T0, T1, and S to assess somatic mutation profiling and pathological markers. NGS assays were performed with a custom-designed panel that covered 769 cancer-related genes. Results: As of Jan 7, 2024, 448 tumor tissue and plasma samples from 80 BC patients undergoing NCT (n = 57) or NET (n = 23) were sequenced and analyzed. At T0, positive ctDNA was detected in 62.8% (49/78, another two failed quality control) of the patients. Furthermore, ctDNA detection and the higher concentration had a significant correlation with clinicopathologic characteristics that confer aggressiveness, including larger tumor size, more lymph node metastases, and lower hormone receptor expression. There was also a certain relativity between ctDNA positivity and tumor grading as well as MammaPrint index ( P &lt; 0.1). With the progression of neoadjuvant therapy, the ctDNA positive rate decreased over time (T1: 32/80, 40.0%; T2: 11/61, 18.0%; S: 7/65, 10.8%; and PO: 6/64, 9.4%). Although no correlation was found between pretherapeutic Ki67 expression and T0 ctDNA status ( P = 0.871), the Ki67 expression in early cycles of neoadjuvant therapy (T1) was significantly higher in patients with inter-therapeutic detectable ctDNA. Moreover, the expression and decline of Ki67 after neoadjuvant therapy were significantly correlated with ctDNA positivity at T2, S, and PO. Among the patients who had undergone surgery, 8 patients were classified as RCB 0/1 and the rest 57 as RCB 2/3. All patients who exhibited RCB 0/1 were ctDNA negative at S and PO. Compared to RCB 2/3, patients with RCB 0/1 tumors showed a significant increase in ctDNA concentration at T0 ( P = 0.027). Subgroup analysis revealed similar trends in ctDNA status and concentration changes in the NCT group and NET group. Conclusions: We reported an unprecedented baseline ctDNA positivity in luminal B BC, and the ctDNA levels were closely associated with the clinicopathologic characteristics of patients. As the research progresses, more predictive and prognostic information is expected to be discovered. Clinical trial information: NCT05649475 .

Treatment (Tx) patterns, efficacy and safety of eribulin for advanced and heavily pretreated breast cancer (ABC): Updated results from a single-center, real-world study.

e13118 Background: We evaluated the Tx patterns, efficacy and safety of eribulin for heavily pretreated ABC in real-world practice. Previous results were reported at the 2023 ASCO (e13118), updated results for longer follow-up and additional enrollment are presented here. Methods: Patients (pts) with ABC who had progression on anthracycline taxane Tx and received eribulin (1.4 mg/m2 IV on Days 1 and 8 of a 21-day cycle) between April 2020 and October 2023 were enrolled. Response was evaluated using RECIST v1.1. Pts were considered as taxanes sensitive if taxanes treatment duration of last line use exceeds 6 months, otherwise were considered as taxanes resistant. Results: 89 pts were enrolled. Median (range) age was 54 (30–79) years; 80.9% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1, and 40.4% pts had a median of 3 prior lines of chemotherapy. 67.4% of pts had Ki67 &gt;30% and 46.0% had HR+/HER2− disease. 88.7% of pts had visceral metastasis. Eribulin was monotherapy in 30.3% of pts, and combined with bevacizumab, capecitabine, bevacizumab + capecitabine, and anti-HER2 agents in 28.1%, 9.0%, 3.4%, and 25.8%, respectively. The objective response rate was 22.5%; disease control rate was 84.3%. Median progression-free survival (PFS) overall was 6.0 (95% CI, [3.5–8.5]) months (mo). Univariate analysis indicated pts with HER2+ disease had longer PFS than pts with HR+/HER2− or triple-negative BC (median, 13.5, 4.5, and 3.7 mo, respectively; P = 0.011; Table). Pts with Ki67 expression ≤30% had longer PFS than pts with Ki67 &gt;30% (median, 8.0 vs. 4.0 mo; P = 0.02). Pts with grade I-II had longer PFS than pts with grade III (median, 10.5 vs. 4.0 mo; P = 0.003). Pts sensitive to Taxane had longer PFS than pts resistant to Taxane (median, 8.0 vs. 4.0 mo; P = 0.007). Among the 18 pts with a partial response, median PFS was 11.4 mo. The most common adverse events were leukopenia (44.9%), neutropenia (37.1%) and anemia (36.0%). Neurotoxicity was rare (6.7%). Conclusions: In this single-center study of pts with heavily pre-treated ABC in China, eribulin Tx resulted in favorable PFS irrespective of molecular subtype, with a manageable safety profile. In pts with a large tumor burden and a good PS, eribulin-based combinations may further improve outcomes. [Table: see text]

An MRI-based multi-parameter clinical decision support system (NeoMDSS) for early prediction of pathological complete response after the first cycle of neoadjuvant therapy in breast cancer: A multi-center prospective observational cohort study.

592 Background: Currently, there is no reliable and convenient way to predict response rates in early stages of neoadjuvant therapy (NAT) for breast cancer, which can affect the prognosis of non-responsive patients. Methods: In this prospective multi-center observational study, eligible participants who underwent NAT followed by radical surgery were recruited. All patients underwent magnetic resonance imaging (MRI) examination before and after the first cycle of NAT (1st-NAT). We analyzed the effects of clinicopathological features, such as histological grade, hormone receptor (HR) and HER2 status, Ki-67 expression, blood cell analysis, and MRI parameters including the reduction ratio of tumor diameter (ΔD%), apparent diffusion coefficient (ADC), and early enhancement ratio (EER) on NAT. By incorporating independent influencing factors, we developed a multiparametric clinical decision support system (NeoMDSS) model based on a retrospective cohort and validated its accuracy in both a prospective single-center internal cohort and a prospective multi-center external cohort. Relevant clinical trial details can be found under the identifier NCT04909554. Results: A total of 301 breast cancer patients were enrolled between January 2019 and December 2023, including 140 patients in the training cohort, 120 patients in the internal validation cohort, and 41 patients in the external validation cohort. The NeoMDSS model demonstrated excellent performance in predicting pathological complete response (pCR) at 1st-NAT, with an AUC of 0.874 (95% CI 0.813-0.935) in the training cohort, 0.845 (95% CI 0.771-0.919) in the internal validation cohort, and 0.867 (95% CI 0.742-0.992) in the external validation cohort. The NeoMDSS model exhibited a sensitivity, specificity, and accuracy of 80.0%, 81.3%, and 80.5%, respectively, in the internal validation cohort, and 87.0%, 83.3%, and 85.4%, respectively, in the external validation cohort. Calibration curves and decision curve analysis (DCA) further supported the clinical value of the NeoMDSS model. To facilitate the clinical application of the NeoMDSS model, a nomogram and an online website ( www.gdphneomdss.com ) were developed to calculate the probability of pCR, which the sensitivity, specificity, and accuracy of the NeoMDSS model were all 80.0% in the internal validation cohort and 80.0%, 81.3%, and 80.5% in the external validation cohort. Conclusions: The NeoMDSS model serves as a convenient tool in clinical practice at 1st-NAT to calculate and accurately predict the probability of pCR after NAT. This assists clinicians in determining whether to modify the treatment plan and improving personalized treatment for patients with poor response to NAT. Clinical trial information: NCT04909554 .

Overexpression of Extracellular Superoxide Dismutase 3 Inhibits Cancer Cell Growth and Migration in Colorectal Cancer.

Incidence of colorectal cancer is rapidly increasing worldwide. Extracellular superoxide dismutase (EcSOD; SOD3) is an antioxidant enzyme. However, SOD3 roles in colorectal cancer progression remain uncertain. Superoxide dismutase 3 expression was evaluated, and we analyzed clinical relevance of SOD3 expression in colorectal cancer. Subsequently, SOD3 roles in colorectal cancer progression were detected by gain of function experiments. Changes in subcutaneous tumor and liver nodule size after SOD3 overexpression were examined in nude mice. The expression of proliferation marker Ki67 was assessed by immunohistochemical staining. Supperoxide dismutase 3 was downregulated in colorectal cancer (P <.01). Downregulation of SOD3 was correlated with unfavorable outcomes (P < .05). Superoxide dismutase 3 upregulation limited the proliferative (P <.05), migrative (P <.01) and invasive actions of colorectal cancer cells (P <.01) by suppressing epithelial-mesenchymal transition. Moreover, SOD3 overexpression reduced Ki67 expression (P <.01) and blocked tumor growth (P <01) and liver metastasis (P <.001) in mouse tumor model. Superoxide dismutase 3 upregulation attenuates tumor growth and liver metastasis in colorectal cancer, suggesting that SOD3 has potential diagnostic and prognostic values regarding colorectal cancer treatment.

Immunohistochemical markers in the prognostic model for survival of patients with diffuse large B-cell lymphoma.

e19055 Background: Currently, relevant issues include the study of the role of immunohistochemical markers in patients with diffuse large B-cell lymphoma (DLBCL) with extranodal involvement to predict the outcomes of the conducted therapy. Methods: A retrospective study included 81 patients with diffuse large B-cell lymphoma (DLBCL) involving the liver and spleen with extranodal manifestations, who underwent treatment and were under outpatient monitoring in a hospital setting. The average age of the patients was 60.7±7.5 years. The expression of pan-B-cell antigens CD20, CD79A, PAX 5 (monomorphic intense nuclear expression), CD5, CD45, CD30, BCL-2, BCL-6, Ki-67, MUM1, GCET1, FOXP1 was examined in the patients. To exclude the polymorphic blastoid variant of lymphoma with CD5 expression in mantle cells, the study of cyclin D1 expression was conducted. Results: All patients began treatment with R-CHOP chemotherapy. In 37 cases, this regimen had to be replaced with DHAP in 23 (62.2%) patients due to the low effectiveness of the 1st-line chemotherapy, and in 14 (37.8%) after completing the full course (6 cycles) of treatment. Over the 6-year observation period, despite identical treatment, the 5-year survival rate was 60.5%. Among 32 (39.5%) patients, there was a fatal outcome due to the progression of the pathological process during treatment. Moderate expression was characteristic for the markers CD5, CD30, PAX-5, FOXP1, and GCET1, while high expression was observed for CD10, CD45, CD79A, Bcl-6, MUM1, and Ki-67. High expression of Bcl-2, Bcl-6, GCET1, and Ki-67 exceeding 60% is a prognostically unfavorable factor significantly impacting the survival of patients. The most unfavorable outcomes were observed with the combination of Bcl-2 and Ki-67 expression exceeding 60% along with CD-45. The combination of Ki-67 expression exceeding 60%, CD-79, and MUM1 also resulted in an unfavorable outcome in all cases. The prognostic scale, using Cox's proportional hazard, allows predicting the prognosis of diffuse large B-cell lymphoma with extranodal involvement with a probability of 87.2%. Conclusions: In our studies, it has been demonstrated that adverse immunohistochemical characteristics of diffuse large B-cell lymphoma with extranodal involvement include high expression of Bcl-2, Bcl-6, GCET1, and a Ki-67 proliferation index exceeding 60% (p&lt;0.025).

Amide Proton Transfer-Weighted Imaging in Assessing the Aggressive and Proliferative Potential of Bladder Cancer.

Ki-67 and human epidermal growth factor receptor 2 (HER2) are known oncogenes involved in bladder cancer (BCa) patient risk stratification. Preoperative assessment of their expression level can assist in clinical treatment decision-making. Recently, amide proton transfer-weighted (APTw) MRI has shown promising potential in the diagnosis of several malignancies. However, few studies reported the value of APTw imaging in evaluating Ki-67 and HER2 status of BCa. To investigate the feasibility of APTw MRI in assessing the aggressive and proliferative potential regarding the expression levels of Ki-67 and HER2 in BCa. Retrospective. 114 patients (mean age, 64.78 ± 11.93 [SD] years; 97 men) were studied. APTw MRI acquired by a three-dimensional fast-spin-echo sequence at 3.0 T MRI system. Patient pathologic findings, included histologic grade and the expression status of Ki-67 and HER2, were reviewed by one uropathologist. The APTw values of BCa were independently measured by two radiologists and were compared between high-/low-tumor grade group, high-/low-Ki-67 expression group, and high-/low-HER2 expression group. The interclass correlation coefficient, independent sample t-test, Mann-Whitney U test, Spearman's rank correlation, and receiver operating characteristic curve (ROC) analysis were used. P < 0.05 was considered statistically significant. Significantly higher APTw values were found in high-grade BCa patients (7.72% vs. 4.29%, P < 0.001), high-Ki-67 expression BCa patients (8.40% vs. 3.25%, P < 0.001) and HER2 positive BCa patients (8.24% vs. 5.40%, P = 0.001). APTw values were positively correlated with Ki-67 (r = 0.769) and HER2 (r = 0. 356) expression status. The area under the ROC curve of the APTw values for detecting Ki-67 and HER2 expression status were 0.883 (95% CI: 0.790-0.945) and 0.713 (95% CI: 0.592-0.816), respectively. APTw MRI is a potential method to assess the biological and proliferation potential of BCa. Stage 2.