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Background/aim: Testicular cancers, particularly seminomas and non-seminomas, generally have a favorable prognosis, although a small subset of patients experience mortality. Current knowledge of clinical markers associated with relapse and poor prognosis in seminoma is limited. Chemokines, key proteins in the tumor microenvironment, are underexplored in seminoma prognosis. Additionally, tumor-infiltrating lymphocytes (TILs), which play a critical role in cancer prognosis, require further investigation in the context of seminoma., Patients and Methods: Samples from 25 seminoma patients and 24 control patients who underwent orchiectomy were immunohistochemically (IHC) stained for chemokines CXCR4, CXCR5, and their ligands CXCL12, CXCL13, and the proliferation marker Ki-67. The associations between IHC results and clinical presentations were examined., Results: Chemokine profiles differed between seminoma and normal testis. The expression of chemokines in TILs in seminoma samples was especially over-expressed. The cytoplasmic expression of CXCL13 in TILs multiplied by the percentage of TILs in each sample, appeared to approach statistical significance concerning the likelihood of relapse., Conclusion: The involvement of TILs in seminoma biology warrants further investigation, especially their role in the tumor micro-environment and pathogenesis. Chemokine and Ki-67 expression in TILs could serve as potential markers for assessing seminoma prognosis., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

To formulate a predictive model for assessing Ki-67 expression in breast cancer by integrating pre-treatment ultrasound features with non-morphological magnetic resonance imaging (MRI) parameters, encompassing functional and hemodynamic indicators. A retrospective study was conducted on 167 patients. All patients underwent a breast mass biopsy for histopathological and Ki-67 analysis prior to neoadjuvant chemotherapy (NAC) treatment. Additionally, all patients underwent ultrasonography and MRI examinations prior to the biopsy. The recorded variables were Ki-67, apparent diffusion coefficient (ADC) values, Max Slope, time to peak (TTP), signal enhancement ratio (SER), early enhancement rate (EER), time-signal intensity curve (TIC), tumor maximum diameter, tumor margins and boundaries, aspect ratio, microcalcification, color Doppler flow imaging grading, resistance index (RI), and axillary lymph node metastasis. Statistical analysis was performed using the R software package. Normally distributed continuous data are presented as mean ± standard deviation (SD), skewed continuous data as median, and categorical variables as frequency or percentage. The dataset was randomly divided into a modeling group and a validation group following a 7:3 ratio, employing a predetermined random seed. The selection of variables was conducted using the random forest algorithm. Specifically, in the initial analysis, we trained a random forest model using all available variables. By evaluating the Gini importance scores of each variable, we identified those that contributed the most to predicting Ki-67 expression. The predictive model for Ki-67 expression was constructed using selected variables: Maximum Diameter, ADC value, SER value, Max Slope value, TTP value, and EER value. Within the validation group, the evaluation metrics demonstrated an Area under the curve of 0.961 with a 95% confidence interval ranging from 0.865 to 0.995. The model achieved a kappa score of 1.00, precision of 0.949, recall of 1, an F1 score of 0.974, sensitivity of 100%, specificity of 85.71%, a positive predictive value of 94.87%, and a negative predictive value of 100%. The combination of non-morphological MRI parameters and pre-treatment ultrasound features in a breast cancer prediction model powered by RF machine learning demonstrated favorable clinical outcomes and improved diagnostic performance., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: To compare the clinicopathological characteristics of nonmetastatic breast cancer patients with and without BRCA variations and to investigate the impact of BRCA variations on prognosis., Methods: This retrospective single-center study involved an analysis of 938 patients with localized or locally advanced breast cancer who underwent BRCA variation testing. The patients were divided into three groups: 757 were without BRCA variation, 64 were with BRCA1 variation, and 117 were with BRCA2 variation., Results: In patients with BRCA1 variation, the Ki67, grade, and frequency of triple-negative breast cancer were significantly higher than in patients without BRCA variation and with BRCA2 variation. The 5-year disease-free survival in patients with BRCA1 variation was significantly worse than the other two groups (without BRCA, BRCA1, and BRCA2; 87.7%, 69.9%, and 95.3%, respectively, p = 0.049). Multivariate analysis detected no significant difference between groups. The pathological complete response rates with neoadjuvant therapy were significantly better in patients with BRCA variations than those without BRCA variations (49.2% vs. 29.6%, p = 0.024)., Conclusion: Patients with BRCA1 variation had more aggressive tumor characteristics, such as higher Ki67 and higher grade. Also, triple-negative breast cancer was more common. The presence of BRCA1 variation may worsen survival outcomes. Neoadjuvant treatment responses of patients with BRCA variations were significantly better, and neoadjuvant treatment may contribute to survival outcomes in nonmetastatic patients with BRCA variations., (© 2024 University College London (UCL) and John Wiley & Sons Ltd.)

Background: Chemotherapy is crucial for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and its survival benefits may outweigh adverse events. Oncotype DX (ODX) assesses this balance; however, it is expensive. Using nomograms to identify cases requiring ODX may be economically beneficial. We aimed to identify clinicopathological variables that correlated with the recurrence score (RS) and develop a nomogram that predicted the RS., Methods: We included 457 patients with estrogen receptor-positive, HER2-negative breast cancer with metastases in fewer than four axillary lymph nodes who underwent surgery and ODX at our hospital between 2007 and 2023. We developed nomograms and internally validated them in 310 patients who underwent surgery between 2007 and 2021 and validated the model's performance in 147 patients who underwent surgery between 2022 and 2023., Results: Logistic regression analysis revealed that progesterone receptor (PgR) level, histological grade (HG), and Ki67 index independently predicted the RS. A nomogram was developed using these variables to predict the RS (area under the curve [AUC], 0.870; 95% confidence interval [CI], 0.82-0.92). The nomogram was applied to the model validation group (AUC, 0.877; 95% CI, 0.80-0.95). When the sensitivity of the nomogram was 90%, the model was able to identify 52.3% low-RS and 41.2% high-RS cases not requiring ODX., Conclusions: This was the first nomogram model developed based on data from a cohort of Japanese women. It may help determine the indications for ODX and the use of nomogram to identify cases requiring ODX may be economically beneficial., (© 2024. The Author(s).)

Estrone and estradiol differentially modulate neuroplasticity and cognition. How they influence the maturation of new neurons in the adult hippocampus, however, is not known. The present study assessed the effects of estrone and estradiol on the maturation timeline of neurogenesis in the dentate gyrus (DG) of ovariectomized (a model of surgical menopause) young adult Sprague-Dawley rats using daily subcutaneous injections of 17β-estradiol, estrone or vehicle. Rats were injected with a DNA synthesis marker, 5-bromo-2-deoxyuridine (BrdU), and were perfused 1, 2, or 3 weeks after BrdU injection and daily hormone treatment. Brains were sectioned and processed for various markers including: sex-determining region Y-box 2 (Sox2), glial fibrillary acidic protein (GFAP), antigen kiel 67 (Ki67), doublecortin (DCX), and neuronal nuclei (NeuN). Immunofluorescent labeling or co-labelling of BrdU with Sox2 (progenitor cells), Sox2/GFAP (neural progenitor cells), Ki67 (cell proliferation), DCX (immature neurons), NeuN (mature neurons) was used to examine the trajectory and maturation of adult-born neurons over time. Estrogens had early (1 week of exposure) effects on different stages of neurogenesis (neural progenitor cells, cell proliferation and early maturation of new cells into neurons) but these effects were less pronounced after prolonged treatment. Estradiol enhanced, whereas estrone reduced cell proliferation after 1 week but not after longer exposure to either estrogen. Both estrogens increased the density of immature neurons (BrdU/DCX-ir) after 1 week of exposure compared to vehicle treatment but this increased density was not sustained over longer durations of treatments to estrogens, suggesting that the enhancing effects of estrogens on neurogenesis were short-lived. Longer duration post-ovariectomy, without treatments with either of the estrogens, was associated with reduced neural progenitor cells in the DG. These results demonstrate that estrogens modulate several aspects of adult hippocampal neurogenesis differently in the short term, but may lose their ability to influence neurogenesis after long-term exposure. These findings have potential implications for treatments involving estrogens after surgical menopause., (© 2024 The Author(s). Hippocampus published by Wiley Periodicals LLC.)

To study the effect of preoperative chemoradiotherapy combined with rehabilitation nursing in patients with rectal cancer surgery. 106 cases of rectal cancer patients in our hospital were selected. 53 cases in each group were treated with surgical treatment combined with rehabilitation nursing treatment and preoperative radiotherapy and chemotherapy combined with surgical treatment and rehabilitation nursing treatment in the study group. The T stage (ypT) and N stage (ypN) downgrading rates of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9 were compared between the two groups after treatment. The 5-year cumulative survival rate, recurrence rate and the positive rate of Bax and antigen identified by monoclonal antibody Ki-67 (Ki-67) expression were detected. T stage downgrading rate and N stage downgrading rate were 77.36% (41/53) 35.85% (19/53) in control group and 94.34% (50/53) 64.15% (34/53) in research group, respectively. The CEA and CA19-9 levels measured at the end of surgery and one month after nursing in both groups were lower than those before treatment. After treatment, scores of quality of life indicators in both groups increased. The positive rates of Bax and Ki-67Ki-67 were significantly different between the two groups after treatment ( P  < 0.05). Preoperative chemoradiotherapy combined with rehabilitation nursing has obvious effect on patients with rectal cancer surgery, and has obvious advantages in inhibiting tumor growth, destroying tumor survival immune environment and reducing surgical complications, which can improve the prognosis and is worthy of clinical application. It could provide a potential treatment for patients with rectal cancer.

Purpose: To identify the most effective combination of DCE-MRI (K trans ,K ep ) and IVIM (D,f) and analyze the correlations of these parameters with prognostic indicators (ER, PR, and HER2, Ki-67 index, axillary lymph node (ALN) and tumor size) to improve the diagnostic and prognostic efficiency in breast cancer., Methods: This is a prospective study. We performed T1WI, T2WI, IVIM, DCE-MRI at 3 T MRI examinations on benign and malignant breast lesions that met the inclusion criteria. We also collected pathological results of corresponding lesions, including ER, PR, and HER2, Ki-67 index, axillary lymph node (ALN) and tumor size. The diagnostic efficacy of DCE-MRI, IVIM imaging, and their combination for benign and malignant breast lesions was assessed. Correlations between the DCE-MRI and IVIM parameters and prognostic indicators were assessed., Results: Overall,59 female patients with 62 lesions (22 benign lesions and 40 malignant lesions) were included in this study. The malignant group showed significantly lower D values (p < 0.05) and significantly higher K trans , K ep , and f values (p < 0.05). The AUC values of DCE, IVIM, DCE + IVIM were 0.828, 0.882, 0.901. K trans , K ep , D and f values were correlated with the pathological grade (p < 0.05); K trans was negatively correlated with ER expression (r = -0.519, p < 0.05); K ep was correlated with PR expression and the Ki-67 index (r = -0.489, 0.330, p < 0.05); the DCE and IVIM parameters showed no significant correlations with the HER2 and ALN (p > 0.05). Tumor diameter was correlated with the K ep , D and f values (r = 0.246, -0.278, 0.293; p < 0.05)., Conclusion: IVIM and DCE-MRI allowed differential diagnosis of benign and malignant breast lesions, and their combination showed significantly better diagnostic efficiency. DCE- and IVIM-derived parameters showed correlations with some prognostic factors for breast cancer., Competing Interests: Declaration of competing interest One author of the study (Kai Ai) is a consultant for Philips Healthcare and provided some critical technical support in the manuscript. Other authors are not employees or consultants in the industrial fields and have reported any data or information that may present a conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This study aimed to establish risk groups on the basis of CPS-EG scores, independent of pCR status, in triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NACT) to identify the prognostic impact of the CPS-EG score., Methods: Patient characteristics included age, menopausal status, clinical stage, pathological stage, estrogen receptor (ER) expression, nuclear grade, Ki-67 proliferation index, residual cancer burden (RCB) score, HER2 status, and other tumor characteristics. The CPS-EG scoring system included clinical stage, pathological stage, ER status, and grade. Patients were divided into two groups on the basis of their CPS-EG scores ≤ 3 and > 3., Results: A total of 148 patients who were diagnosed with TNBC and treated with NACT were included in the study. A total of 52.0% of the patients had a CPS-EG score of ≤ 3, whereas 48.0% had a score of > 3. The rate of patients who achieved pCR was 29.7% (n = 44). CPS-EG score (HR: 2.331; 95%CI; 1.179-4.608; p = 0.015), pCR (HR: 0.348; 95%CI; 0.144-0.844; p = 0.019), pre-treatment mKi-67 proliferation index (HR: 0.467; 95%CI; 0.251-0.871; p = 0.017), and RCB score (HR: 0.401; 95%CI; 0.174-0.923; p = 0.032) were identified as significant prognostic factors for 5-year DFS. For 5-year OS, significant prognostic factors were CPS-EG score (HR: 2.30; 95%CI; 1.036-4.799; p = 0.040) and pre-treatment mKi-67 proliferation index (HR: 0.484; 95%CI; 0.246-0.954; p = 0.036)., Conclusions: The CPS-EG score, pre-treatment mKi-67 level, and the pCR and RCB score were practical prognostic markers for long-term survival. Conversely, the prognostic significance of pCR status was diminished, particularly in predicting OS. These findings underscore the importance of not only post-treatment pathological staging but also the initial tumor stage and biological characteristics of the tumor in predicting ultimate survival outcomes following neoadjuvant chemotherapy in TNBC patients., (© 2024. The Author(s).)

Background: To explore the value of dual-energy computed tomography (DECT) in differentiating pathological subtypes and the expression of immunohistochemical markers Ki-67 and thyroid transcription factor 1 (TTF-1) in patients with non-small cell lung cancer (NSCLC)., Methods: Between July 2022 and May 2024, patients suspected of lung cancer who underwent two-phase contrast-enhanced DECT were prospectively recruited. Whole-tumor volumetric and conventional spectral analysis were utilized to measure DECT parameters in the arterial and venous phase. The DECT parameters model, clinical-CT radiological features model, and combined prediction model were developed to discriminate pathological subtypes and predict Ki-67 or TTF-1 expression. Multivariate logistic regression analysis was used to identify independent predictors. The diagnostic efficacy was assessed by the area under the receiver operating characteristic curve (AUC) and compared using DeLong's test., Results: This study included 119 patients (92 males and 27 females; mean age, 63.0 ± 9.4 years) who was diagnosed with NSCLC. When applying the DECT parameters model to differentiate between adenocarcinoma and squamous cell carcinoma, ROC curve analysis indicated superior diagnostic performance for conventional spectral analysis over volumetric spectral analysis (AUC, 0.801 vs. 0.709). Volumetric spectral analysis exhibited higher diagnostic efficacy in predicting immunohistochemical markers compared to conventional spectral analysis (both P < 0.05). For Ki-67 and TTF-1 expression, the combined prediction model demonstrated optimal diagnostic performance with AUC of 0.943 and 0.967, respectively., Conclusions: The combined predictive model based on volumetric quantitative analysis in DECT offers valuable information to discriminate immunohistochemical expression status, facilitating clinical decision-making for patients with NSCLC., (© 2024. The Author(s).)

Objective: To explore the role of tumor necrosis factor receptor-associated factor 4 (TRAF4) in promoting the abnormal activation of epidermal growth factor receptor (EGFR) and its effect on lung cancer cell proliferation, migration and invasion. Methods: Tumor tissues from patients who underwent lung adenocarcinoma resection at The First Affiliated Hospital of Second Military Medical University, from January 2015 to May 2017 were collected, and the expressions of TRAF4 and Ki-67 in lung cancer tissues were detected by immunohistochemistry, the mRNA levels of Cyclin D and Vimentin were detected by real-time fluorescence quantitative PCR (qRT-PCR). The effect of TRAF4 on the tumor growth ability of lung cancer A549 cells was investigated by the xenograft model, the effect of TRAF4 or EGFR on the tumor proliferation ability was detected by using cell counting kit 8 (CCK8) and BrdU assay, and the migration and invasion abilities of tumor cells were detected by Transwell assay. Different structural domain deletion expression vectors of TRAF4 and EGFR were constructed to transfect cells, and the interaction mode of TRAF4 and EGFR was investigated by immunoprecipitation assay. Results: The expression of TRAF4 in non-small cell lung cancer (NSCLC) tissues was positively correlated with the expressions of Ki-67, cyclin D, and vimentin ( r 2 : 0.438, 0.695, and 0.736, respectively, all P ＜0.01). Immunohistochemical assay of tumor tissues from NSCLC patients showed that tissues with high expression of TRAF4 were also high in Ki-67. Patients with high TRAF4 expression (TRAF4 positivity >30%) had a shorter progression-free survival (PFS) time than that of patients with low TRAF4 expression (TRAF4 positivity ≤30%) (median PFS of 12 and 19 months, respectively; P =0.034). Traf4 -/- cells had a weakened proliferative capacity than traf4 +/+ cells and formed tumors with smaller size ( P ＜0.05). The expression level of Ki-67 in the tumor tissues formed by traf4 -/- cells [(45.6±8.7)%] was lower than that in the tumor tissues formed by traf4 +/+ cells [(62.3±10.3)%, P =0.015], the mRNA levels of cyclin D (1.01±0.15) and vimentin (1.01±0.12) in the traf4 -/- cells were lower than those of the traf4 +/+ cells (3.41±0.32 and 3.12±0.18, respectively, both P ＜0.05).The western blot results showed that, with the elevated intracellular expression level of TRAF4, phosphorylation level of EGFR was significantly increased in both wild-type EGFR and activation mutant EGFR-expression cells. The capacities of proliferation, migration and invasion of A549 cells was weakened after EGFR knockdown (all P ＜0.01). Immunoprecipitation experiments showed that TRAF4 binds to the peptide segment of the near-membrane region of EGFR through the TRAF structural domain, and the mutual binding between EGFR molecules was enhanced under TRAF4 overexpression conditions. Increasing TRAF4 expression promoted EGFR molecular phosphorylation and activation of downstream signaling. Conclusions: TRAF4 expression is elevated in NSCLC tissues and tumor cells, which promotes tumor proliferation, migration and invasion. TRAF4 directly binds to EGFR molecules, enhances its own phosphorylation and activates the downstream signaling pathway by promoting the interaction between EGFR molecules.

Marginal zone lymphoma (MZL) can have varied presentations and pathologic features, including high Ki-67 expression ( > 20%) as well as increased numbers of large B cells (LC). However, there are limited data available demonstrating the prognostic significance of these variables in patients with MZL. In this multi-institutional retrospective cohort study of patients with MZL treated at 10 centers, we evaluated the association between the presence of Ki-67 expression and increased LCs on survival and risk of histologic transformation (HT). A total of 785 patients were included (60% with extranodal MZL, 20% with nodal MZL, and 20% with splenic MZL). Among the 440 patients with Ki-67 staining, 22% had high Ki-67 (Ki-67 >20%). The median progression-free survival (PFS) for patients with high Ki-67 was 5.4 years compared to 7.0 years for patients with low Ki-67 (HR = 1.45, 95%CI = 1.03-2.05). Ki-67 > 20% strongly correlated with high LDH level. The risk of HT was higher in patients with increased Ki-67 than those without (5-year risk, 9.8% vs 3.87%, p = 0.01). Twelve percent of patients had LC reported on biopsy with 6% having >10% LC. The presence of LC was associated with high Ki-67 (p < 0.001), but not associated with shorter PFS or overall survival (OS). The cumulative risk for HT was higher in patients with LC compared to those without LC (5-year risk, 9.4% vs 2.9%, p = 0.04). Receipt of anthracycline-based therapy did not impact PFS or OS in either group. Ki-67 staining >20% was a prognostic factor for worse survival and strongly correlated with elevated LDH. Novel therapies should be investigated for their potential ability to overcome the high-risk features in MZL. Our data reinforce the importance of obtaining biopsies at relapse or progression, particularly in patients with baseline high Ki-67 and increased LCs, given their increased risk for HT., (© 2024. The Author(s).)

Most follicular lymphomas (FLs) demonstrate an indolent clinical course with favorable outcomes; however, a fraction of patients experiences progression of disease within 24 months (POD24) and has adverse outcomes. This study aimed to determine the predictive risk factors for POD24 in patients with FL, and the characteristics of the microenvironment in FL with POD24. By multivariate analysis, we revealed that increased Ki-67 expression was associated with POD24 events in patients with FL (hazard ratio [HR]: 6.29, 95% confidence interval [CI]: 1.96-20.22, p = 0.0020). Additionally, patients with FL with POD24 demonstrated immune cell reduction by immunohistochemistry analysis. Our results help better understand the therapeutic strategies for FL with POD24.

Aim: To characterize the immunohistochemical expression of MDM2, Bcl-2, SATB2 and Ki-67 in histological variants of unicystic ameloblastoma (UA)., Methodology: Following the ethical approval, forty (40) patients with unicystic ameloblastoma were retrieved from the archives and subjected to immunohistochemistry (IHC). Sociodemographic and clinical data were also retrieved. The results were entered into a Microsoft Excel spreadsheet and analyzed using SPSS software., Results: Human tooth germs, which served as the control, showed moderate expression of Bcl-2 and MDM2 with slight proliferative activity in ameloblasts and moderate expression of SATB2 in ectomesenchyme and odontoblasts. Luminal UA (Type 1) showed low Ki-67 index and negative to mild Bcl-2 and MDM2 expression, whilst Type 1.2 (luminal and intraluminal), Type 1.2.3 (luminal, intraluminal and mural), and Type 1.3 (luminal and mural), including the recurrent cases, showed moderate to intense expression with high mean Ki-67 index. The difference between the study groups was statistically significant (p value < 0.001). No expression of SATB2 was noted in any histological variant of UA. Furthermore, no significant differences were noted in age, gender, site and location between the groups., Conclusion: In contrast to luminal variant of UA, mural±intraluminal variants and recurrent cases demonstrate higher expression of Bcl-2 and MDM2 with higher mean Ki-67 index. It may thus be prudent to provide aggressive treatment for cases, not just with mural follicles but also for the patients with intraluminal plexiform proliferation, to prevent recurrence and improve patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To assess the capability of multimodal apparent diffusion (MAD) weighted magnetic resonance imaging (MRI) to distinguish between malignant and benign breast lesions, and to predict Ki-67 expression level in breast cancer., Methods: This retrospective study was conducted with 93 patients who had postoperative pathology-confirmed breast cancer or benign breast lesions. MAD images were acquired using a 3.0 T MRI scanner with 16 b values. The MAD parameters, as flow (f F , D F ), unimpeded (fluid) (f UI ), hindered (f H , D H , and α H ), and restricted (f R , D R ), were calculated. The differences of the parameters were compared by Mann-Whitney U test between the benign/malignant lesions and high/low Ki-67 expression level. The diagnostic performance was assessed by the area under the receiver operating characteristic curve (AUC)., Results: The f R in the malignant lesions was significantly higher than in the benign lesions (P = 0.001), whereas the f UI and D H were found to be significantly lower (P = 0.007 and P < 0.001, respectively). Compared with individual parameter in differentiating malignant from benign breast lesions, the combination parameters of MAD (f R , D H , and f UI ) provided the highest AUC (0.851). Of the 73 malignant lesions, 42 (57.5%) were assessed as Ki-67 low expression and 31 (42.5%) were Ki-67 high expression. The Ki-67 high status showed lower D H , higher D F and higher α H (P < 0.05). The combination parameters of D H , D F , and α H provided the highest AUC (0.691) for evaluating Ki-67 expression level., Conclusions: MAD weighted MRI is a useful method for the breast lesions diagnostics and the preoperative prediction of Ki-67 expression level., (© 2024. The Author(s).)

Objective: To investigate the clinicopathological, immunohistochemical, and molecular genetic characteristics of microsecretory adenocarcinoma (MSA) of the salivary gland, and to improve the understanding of this rare tumor. Methods: Cases originally diagnosed as MSA at the Department of Oral Pathology, the Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine were retrospectively collected. The cases of polymorphous adenocarcinoma and adenocarcinoma, not otherwise specified from January 2000 to January 2020 were reviewed to identify potential misdiagnosed MSA cases. Clinicopathological analysis and follow-up of all confirmed MSA cases were performed, and relevant literature was reviewed. Results: A total of 4 MSA cases were identified, including 2 screened from the polymorphous adenocarcinoma cohort. Of the 4 MSA patients, 3 were male and 1 was female, with an average age of 53 years (range, 37-67 years). Three cases occurred in the palate, and one in the buccal region. The clinical manifestation was usually a slow-growing painless mass. Tumors were generally small, with a maximum diameter ranging from 0.7 to 1.8 cm (average, 1.2 cm). Microscopically, the tumor was unencapsulated and showed an infiltrative growth pattern. The tumor cells appeared small in size and showed bland, cubic and flattened cytological features, forming microcystic lumens and glandular tubes. Significant basophilic secretions were seen in the lumens. Between the tumor nests there was fibro-myxoid stroma. Immunohistochemistry showed diffusely or partially positive staining for cytokeratin 7, S-100, SOX-10, p63 and vimentin and negative staining for p40, mammaglobin, and calponin. The proliferation index of Ki-67 was relatively low (1%-3%). Four MSA cases all harbored SS18 gene rearrangement as shown by fluorescence in situ hybridization (FISH), including 2 cases with MEF2C::SS18 fusion gene through RNA-targeted next generation sequencing. All 4 patients underwent surgical resection without any adjuvant treatments. Three patients were followed up for a period of 2 to 203 months. No tumor recurrence, metastasis, or disease-related death was found. Conclusions: Salivary gland MSA is a novel and rare low-grade carcinoma with unique and consistent histological morphology, immunophenotype, and molecular changes. Immunohistochemical staining and SS18 break apart FISH are useful for the diagnosis of the tumor with atypical morphology and high-grade transformation.

Ras homolog gene family member C (RhoC) is a GTPase involved in cell migration, implicated in epithelial-mesenchymal transition and treatment resistance and metastasis of cancer. For example, RhoC has been shown to be involved in resistance to radiation in cervical carcinoma. Here, the effect of X-ray irradiation on RhoC expression in prostate cancer (PCa) xenografts was investigated in both xenografts in regression and relapse. Male BALB/cAnNRj-Foxn1 nu/nu mice were inoculated with 4-6 million LNCaP-FGC cells and established xenografts were irradiated with X-rays (200 kV, 1 Gymin -1 ), 5, 10 or 15 Gy using a Gulmay Medical X-ray system. Expression of RhoC and Ki67, a known proliferation marker, was investigated in xenografts, given 15 Gy, 7 days (midst response as measured by size) or 3 weeks (relapse) post irradiation. Staining was quantified using the Halo software (v2.3.2089.34) with the Indica Labs - cytonuclear v1.6 algorithm. RhoC and Ki67 staining was divided into weak, medium, and strong staining and the percentage of cells stained, single and dual staining, was quantified. The HALO software was further used to classify the tissue in each section so that analysis of RhoC and Ki67 expression in cancer cells, stroma and necrotic areas could be done separately. The results showed that RhoC expression in cancer and stroma cells was significantly higher in relapsed xenografts than in those in regression. This was not seen for Ki67 staining, where the percentage of stained cells were the same in regressing and relapsing tumors. RhoC could be a useful biomarker to confirm relapse following external beam radiation therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Oskar Vilhelmsson Timmerand reports financial support was provided by RhoVac Aps. Jens Ceder reports financial support was provided by RhoVac Aps. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study is to construct models for predicting platinum resistance in high-grade serous ovarian cancer (HGSOC) derived from quantitative spatial heterogeneity indicators obtained from 18 F-FDG PET/CT images., Methods: A retrospective study was conducted on patients diagnosed with HGSOC. Quantitative indicators of spatial heterogeneity were generated using conventional features and Haralick texture features from both CT and PET images. Three groups of predictive models (conventional, heterogeneity, and integrated) were built. Each group's optimal model was the one with the highest area under curve (AUC). Postoperative immunohistochemical staining for Ki-67 and p53 was conducted. The correlation between the heterogeneity indicators and scores for Ki-67 and p53 was assessed by Spearman's correlation coefficient (ρ)., Results: A total of 286 patients (54.6 ± 9.3 years) were enrolled. And 107 spatial heterogeneity indicators were extracted. The optimal models for each group were obtained using the Gradient Boosting Machine (GBM) algorithm. There was an AUC of 0.790 (95% CI: 0.696, 0.885) in the conventional model for the validation set, and an AUC of 0.904 (95% CI: 0.842, 0.966) in the heterogeneity model for the validation set. The integrated model achieved the highest predictive performance, with an AUC value of 0.928 (95% CI: 0.872, 0.984) for the validation set. Spearman's correlation showed that HU&#95;Kurtosis had the strongest correlation with p53 scores with ρ = 0.718, while cluster site entropy had the strongest correlation with Ki-67 scores with ρ = 0.753., Conclusions: Adding quantitative spatial heterogeneity indicators derived from PET/CT images can improve the prediction of platinum resistance in patients with HGSOC. Spatial heterogeneity indicators were related to Ki-67 and p53 scores., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Triple-negative breast cancer (TNBC) is known to have the worst outcome compared to the other forms of breast cancer. Moreover, molecular markers identified basal-like breast cancer (BLBC) phenotypes to be also related to a worse prognosis. In this study, we evaluated by immunohistochemistry (IHC) the prognostic significance of combining Cytokeratin-19 (CK19), E-cadherin, and Ki-67 tissue expression in triple-negative breast cancer (TNBC) cases presenting a basal-like (BLBC) or a non-basal-like (n-BLBC) phenotype to improve the selection and the monitoring of BC patients with a more aggressive outcome. Herein, when compared to n-BLBC, patients with BLBC showed a positive correlation with lymph node metastasis occurrence and lower survival rates. Immunohistochemistry analysis revealed significantly lower E-cadherin prevalence and higher prevalence of both CK19 and Ki-67 in BLBC when compared to n-BLBC. Spearman correlation showed that E-cadherin is negatively and significantly correlated to CK19 and Ki-67 expressions. Moreover, in BLBC, expressing both CK19 and Ki-67 combined with E-cadherin loss was associated with the worst relapse-free and overall survival. In conclusion, TNBC/BLBC phenotypes simultaneously losing E-cadherin and overexpressing CK19 and Ki-67 markers are the most aggressive forms. This combined analysis could be a predictive marker of poor prognosis.

Background: Papillary thyroid carcinoma (PTC) occasionally invades the trachea and requires airway resection. Tracheal excision site recurrence (ESR) is a serious problem. We investigated predictors of ESR in patients with PTC who underwent airway resection for locally curative surgery., Methods: We enrolled 149 patients with PTC who underwent airway resection (median age at the initial surgery: 67 years), including partial-thickness resection (n = 73) or full-thickness resection (n = 76), for grossly curative surgery. The median postoperative follow-up period was 93 months., Results: To date, 11 patients (6.7%) underwent ESR: 6 underwent full-thickness resection and 5 underwent partial-thickness resection. The time to ESR ranged from 14 to 113 months (median: 57 months) after the initial surgery. None of the 11 ESR patients underwent adjuvant external beam radiotherapy (EBRT) and none of the 4 airway resection patients who underwent EBRT developed ESR. The 5- and 10-year ESR rates were 4.3% and 11.3%, respectively. In the multivariate analysis (forward-backward stepwise selection method), a Ki-67 labeling index (LI) ≥5% (p = 0.048) and the thyroglobulin doubling rate (Tg-DR) >0.33/year (p = 0.009) (for Tg-antibody negative cases) were independent predictors of ESR. Nine of the 11 patients underwent ESR resection and only one developed a second recurrence., Conclusions: A high Ki-67 LI was a static predictor, and high Tg-DR was a dynamic predictor, of ESR in patients with PTC following airway resection. In such patients, careful postoperative monitoring for ESR is necessary and adjuvant therapies, such as EBRT, may be considered., (© 2024 The Author(s). World Journal of Surgery published by John Wiley & Sons Ltd on behalf of International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Objective: To analyze the immunohistochemical expression of YAP and its correlation with markers involved in cell proliferation and apoptosis in benign epithelial odontogenic lesions., Study Design: The sample consisted of 95 cases of odontogenic lesions (25 dentigerous cysts, 30 non-syndromic odontogenic keratocysts, 30 conventional ameloblastomas, and 10 unicystic ameloblastomas) and 10 dental follicles used as normal odontogenic tissue. The histological sections were submitted to immunohistochemistry with YAP, cyclin D1, Ki-67, and Bcl-2 antibodies. Immunoexpression was analyzed qualitatively and quantitatively using an adapted method. The collected data were analyzed descriptively and statistically (p ≤ 0.05)., Results: The highest YAP expression was observed in odontogenic keratocysts, followed by unicystic ameloblastomas and conventional ameloblastomas, which exhibited moderate immunoreactivity predominantly in peripheral cells. Furthermore, significant differences in YAP immunoexpression were observed between the groups analyzed, with significant positive correlations between YAP and cyclin D1 in dentigerous cysts and unicystic ameloblastomas and between YAP and Ki-67 in unicystic ameloblastomas (p < 0.05). However, there were no statistically significant correlations between YAP and Bcl-2 immunoexpression in the groups studied., Conclusion: YAP may influence epithelial cell proliferation in odontogenic cysts and tumors, suggesting its possible participation in the progression of the odontogenic lesions studied., (© 2024 Wiley Periodicals LLC.)

Aim: Ki-67 is a marker of cell proliferation and is increasingly being used as a primary outcome measure in preoperative window studies of endometrial cancer (EC). This study explored the feasibility of using apparent diffusion coefficient (ADC) values in noninvasive prediction of Ki-67 expression levels in EC patients before surgery, and constructs a nomogram by combining clinical data., Material and Methods: This study retrospectively analyzed 280 EC patients who underwent preoperative magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) in our hospital from January 2017 to February 2023. Evaluate the potential nonlinear relationship between ADC values and Ki-67 expression using the nomogram. The included patients were randomized into a training set (n = 186) and a validation set (n = 84). Using a combination of logistic regression and LASSO regression results, from which the four best predictors were identified for the construction of the nomogram. The accuracy and clinical applicability of the nomogram were assessed using the receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA)., Results: The results of this study showed a nonlinear correlation between ADCmin and Ki-67 expression (nonlinear P = 0.019), and the nonlinear correlation between ADCmean and Ki-67 expression (nonlinear P = 0.019). In addition, this study constructed the nomogram by incorporating ADCmax, International Federation of Gynecology and Obstetrics (FIGO), and chemotherapy. The area under the curve (AUC) values of the ROC for nomogram, ADCmax, FIGO, chemotherapy and grade in the training set were 0.783, 0.718, 0.579, 0.636, and 0.654, respectively. In the validation set, the AUC values for nomogram, ADCmax, FIGO, chemotherapy, and grade were 0.820, 0.746, 0.558, 0.542, and 0.738, respectively. In addition, the calibration curves and the DCA curves suggested a better predictive efficacy of the model., Conclusion: A nomogram prediction model constructed on the basis of ADCmax values combined with clinical data can be used as an effective method to noninvasively assess Ki-67 expression in EC patients before surgery., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: Ameloblastoma (AM), a locally aggressive tumor with extensive growth capacity, causes significant damage to the jaw and affects facial appearance. Although the high prevalence of BRAF V600E mutation in AM is known, its specific impacts on patients with AM remain unclear. Thus, the present study investigated the role of BRAF V600E mutation, thereby focusing on its impact on AM invasion and growth., Materials and Methods: Immunohistochemical analysis was used to compare BRAF V600E, MMP2, MMP9, and Ki-67 expressions in AM (n = 49), normal oral mucosa (NOM) (n = 10), and odontogenic keratocyst (OKC) (n = 15) tissues. AM was further classified according to the presence or absence of BRAF V600E. The relationship between BRAF V600E and invasion as well as growth was evaluated. In addition, correlation analysis was performed using immunohistochemistry and confirmed via double-labeling immunofluorescence. Finally, comparative analyses using mass spectrometry, immunohistochemistry, and immunofluorescence were performed to explore and identify underlying mechanisms., Results: AM exhibited a higher incidence of BRAF V600E mutation than NOM and OKC. BRAF V600E expression was positively correlated with the invasion-associated proteins MMP2 and MMP9 and the growth-related protein Ki-67. Proteomic data revealed that BRAF V600E primarily activates the MAPK signaling pathway in AM, particularly driving the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2)., Conclusions: In summary, the findings suggested that the BRAF V600E mutation enhances the invasion and growth abilities of AM via the MAPK/ERK signaling pathway. Thus, targeting BRAF V600E or the MAPK/ERK pathway may be a potential AM therapy., (© 2024 Wiley Periodicals LLC.)

Rationale and Objectives: To explore the feasibility of delta histogram parameters (including absolute delta histogram parameters (AdHP) and relative delta histogram parameters (RdHP)) in predicting the grade of meningioma and to further investigate whether delta histogram parameters correlate with the Ki-67 proliferation index., Methods: 92 patients with meningioma who underwent MRI examination (including T1-weighted (T1) and contrast-enhanced T1-weighted images (T1C)) were enrolled in this retrospective study. A total of 46 low-grade cases formed the low-grade group (grade 1, LGM), and a total of 46 high-grade cases formed the high-grade group (38 grade 2, 8 grade 3, HGM). Histogram parameters (HP) of T1 and T1C were extracted. Subsequently, morphological MRI features, AdHP (AdHP=T1CHP-T1HP), and RdHP (RdHP=(T1CHP-T1HP)/T1HP) were recorded and compared, respectively. Binary logistic regression analysis was used to obtain combined performance of the significant parameters. Diagnostic performance was identified by ROC. Spearman's correlation coefficients were taken to assess the relationship between delta histogram parameters and the Ki-67 proliferation index., Results: In morphological MRI features, HGM is more prone to lobulation and necrosis/cystic changes (all p < 0.05). In delta histogram parameters, HGM exhibits higher mean, Perc.01, Perc.25, Perc.50, Perc.75, Perc.99, SD, and variance of AdHP, maximum, mean, Perc.25, Perc.50, Perc.75, and Perc.99 of RdHP, compared to LGM (all p < 0.00357). The optimal predictive performance was obtained by combining morphological MRI features and delta histogram parameters with an AUC of 0.945. Significant correlations were observed between significant delta histogram parameters and the Ki-67 proliferation index (all p < 0.05)., Conclusion: Delta histogram parameter is a promising potential biomarker, which may be helpful in noninvasive predicting the grade and proliferative activity of meningioma., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The role of aquaporin proteins (AQPs) in tumor biology has attracted attention over the past 20 years. However, the expression profiles of AQPs in canine sebaceous gland tumors remain obscure. This study was performed to clarify the expression of AQP1, 3, 5, the most studied AQPs in tumor biology, in sebaceous adenoma and sebaceous epithelioma. Among these AQPs, only AQP3 was expressed in normal tissue and both tumor types and located to only undifferentiated sebocytes (basaloid cells). A cellular proliferation marker, Ki-67, was detected only in the area including basaloid cells in both tumor types. These findings suggest that AQP3 is useful for clarifying the origin of sebaceous gland tumors, and that AQP3 may be related to sebaceous gland development.

Background: Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach., Methods: Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed., Results: In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001)., Conclusions: G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up., (© 2024. The Author(s).)

Objective: Clinicopathologic features of patients with limited-stage mucosa-associated lymphoid tissue (MALT) lymphoma refractory to radiotherapy have not been fully elucidated. This study aimed to elucidate clinicopathologic features of localized conjunctival MALT lymphoma concerning radiosensitivity by analyzing cell proliferation and expression of mismatch repair proteins., Methods: We enrolled 26 patients with localized conjunctival MALT lymphoma treated with radiotherapy from November 2007 to March 2020. Monoclonal immunoglobulin H gene rearrangement was tested in addition to histopathologic evaluation. Thirty-six specimens were immunostained with antibodies to Ki-67 and MutL protein homologue 1 (MLH1), MutS protein homologue 2 (MSH2), and MutS protein homologue 6 (MSH6). Positive rates under a high-power field at a hot spot were counted manually., Results: After radiotherapy, 21 patients showed clinical disappearance of the tumour without recurrence (effective group). Three patients showed temporary disappearance of the tumour, which later recurred (relapse group). Two patients did not show disappearance of the tumour (ineffective group). The 2 ineffective patients were young, had bilateral lesions, and received x-ray beam therapy. The mean positive rates of Ki-67, MLH1, MSH2, and MSH6 were higher in tumours with complete remission (CR) than in those without CR (23.4% ± 4.0% and 18.7% ± 4.7%, 14.7% ± 2.3% and 7.1% ± 3.7%, 23.9% ± 4.7% and 14.4% ± 5.2%, and 11.5% ± 3.2% and 5.4% ± 2.2%; p > 0.05 for each, respectively)., Conclusions: A few patients could not achieve CR following radiotherapy, whereas there were no significant differences in proliferation activity and mismatch repair proteins between tumours with and without CR., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

The reporting of lung neuroendocrine neoplasms (NENs) according to the 2021 World Health Organisation (WHO) is based on mitotic count per 2 mm 2 , necrosis assessment and a constellation of cytological and immunohistochemical details. Accordingly, typical carcinoid and atypical carcinoid are low- to intermediate-grade neuroendocrine tumours (NETs), while large-cell neuroendocrine carcinoma (NEC) and small-cell lung carcinoma are high-grade NECs. In small-sized diagnostic material (cytology and biopsy), the noncommittal term of carcinoid tumour/NET not otherwise specified (NOS) and metastatic carcinoid NOS have been introduced with regard to primary and metastatic diagnostic settings, respectively. Ki-67 antigen, a well-known marker of cell proliferation, has been included in the WHO classification as a non-essential but desirable criterion, especially to distinguish NETs from high-grade NECs and to delineate the provisional category of carcinoid tumours/NETs with elevated mitotic counts (> 10 mitoses per mm 2 ) and/or Ki-67 proliferation index (≥ 30%). However, a wider use of this marker in the spectrum of lung NENs continues to be highly reported and debated, thus witnessing a never-subsided attention. Therefore, the arguments for and against incorporating Ki-67 in the classification and clinical practice of these neoplasms are discussed herein in detail., (© 2024 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Aims: Ulcerative colitis-associated neoplasia (UCAN) is characterised by multifocal tumourigenesis. A wide range of metachronous lesions have been reported to occur after endoscopic treatment of UCAN, which suggests the development of sporadic tumours in lesions treated as UCAN. Therefore, we aimed to evaluate differences of immunohistochemistry (IHC) in features and clinicopathological characteristics of intramucosal lesions in patients with ulcerative colitis (UC)., Methods and Results: We examined 35 intramucosal lesions resected for carcinoma or dysplasia by total colectomy from patients with UC and 71 sporadic adenomas (SAs) endoscopically resected from patients without UC. UC lesions were divided into the conventional UCAN group, defined as p53 mutant pattern and normal expression of β-catenin, and the non-conventional UCAN group, defined as the rest. Ki-67 distribution, α-methylacyl-CoA racemase (AMACR) expression and mucin phenotypes were compared using IHC, and clinicopathological characteristics were investigated. Conventional and non-conventional UCAN lesions were located in the left colon and rectum. Relative to the SA lesions, UCAN lesions occurred in much younger patients and exhibited more frequent basal distribution of Ki-67 in tumour crypts. Conventional UCAN lesions tended to be non-polyploid and exhibited a higher frequency of normal AMACR expression than SA lesions. UC lesions were heterogeneous-only two of the eight patients with multiple lesions had lesions (both non-conventional UCAN lesions) exhibiting concordant IHC staining features., Conclusions: The basal pattern of Ki-67 distribution, normal expression of AMACR and a non-intestinal mucin phenotype were determined as characteristic features suggestive of UCAN. Non-polypoid growth was another a key feature of UCAN., (© 2024 John Wiley & Sons Ltd.)

Borderline Brenner tumors (BBT) have a range of morphology that shows considerable overlap with that of malignant Brenner tumors (MBT). In particular, two histological patterns of BBT can be particularly challenging: 1) BBT with intraepithelial carcinoma (BBT-IEC) and 2) BBT with a small nested pattern (BBT-SNP). BBT-IEC is characterized by a tumor with the low-power non-infiltrative silhouette of a conventional BBT, but with increased cytological atypia and mitotic activity similar to that of MBT. Conversely, BBT-SNP is characterized by a complex proliferation of small tumor nests that closely resemble the infiltrative growth pattern of MBT, but without the obligate cytologic atypia and mitotic activity of MBT. We suggest that the combination of p16, p53 and Ki-67 may be helpful in distinguishing these 2 patterns of BBT from both conventional BBT and from MBT. While both conventional BBT and BBT-IEC show a null pattern of p16 expression, our case of BBT-IEC showed aberrant p53 overexpression, albeit with a maturation pattern similar to that described for TP53 mutant mucinous ovarian carcinoma and differentiated vulvar intraepithelial neoplasia (dVIN). Similarly, while BBT-SNP shows an infiltrative-like growth pattern similar to that of MBT, our case also showed a wild-type pattern of p53 expression and a Ki-67 proliferative index similar to areas with conventional BBT histology. In conclusion, in our small case series, we show that the use of immunohistochemistry for p53 and Ki-67 may help to distinguish challenging patterns of BBT from MBT. Further studies are needed to validate this finding in a larger case cohort., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aim: Even with advancement of medical technologies, liver transplantation still faces several major challenges. Hence, other treatment modalities are urgently needed for patients with end-stage liver disease. Stem cells from human exfoliated deciduous teeth (SHED) was discovered to have highly proliferative and pluripotent properties; including differentiation into hepatocyte-like cells. This study aims to investigate the capability of intrasplenic transplanted SHED and SHED-Hep cells in inducing proliferation of stem cells and native hepatocytes in order to accelerate liver regeneration in liver fibrosis mice models., Methods: Three carbon tetrachloride (CCl 4 )-injured male mice groups were used in this study. Two of those groups were transplanted with either SHED or SHED-Hep, while the other did not undergo transplantation. One age- and sex- matched healthy mice group was used as control. All specimens were immunohistochemically stained with anti-Ki-67 antibodies and anti-proliferating cell nuclear antigen (PCNA) antibodies before counter stained with hematoxylin-eosin., Results: Anti-Ki-67 antibodies staining: at both 8 and 12 weeks, proliferating activity was predominantly seen on both SHED- and SHED-Hep-transplanted CCl 4 -injured mice groups, while control and non-transplanted CCl 4 -injured mice group showed little to no sign of proliferation activity. Anti-PCNA staining: at both 8 and 12 weeks, significant proliferating activity was detected by PCNA staining, mainly on stem cells population area on SHED- and SHED-Hep-treated group., Conclusions: In conclusion, this study has provided the evidence that transplantation of SHED or SHED-Hep on liver-injured mice induced proliferation of both transplanted stem cells and native liver cells in order to accelerate liver regeneration., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Molecular beacons (MBs) based on hairpin-shaped oligonucleotides are captivating owing to their capability to enable effective real-time detection of cytosolic mRNA in living cells. However, DNase in the nucleus and lysosome could induce the degradation of oligonucleotides in MBs, leading to the generation of false-positive signals. Herein, a graphene oxide (GO) nanosheet was applied as a nanocarrier for MBs to greatly enhance the anti-interference of the easily designed nanoprobe. Advantageously, the absorption capacity of GO for MBs increased with the decrease in pH values, providing the MB-GO nanoprobe with the ability to detect the expression of cytosolic Ki-67 mRNA without interference from DNase Ⅱ in lysosomes. Moreover, the size of GO nanosheets was considerably higher than that of the nuclear pore complex (NPC), which prevented nanoprobes from transition through the NPCs, thereby avoiding the generation of false-positive signals in the nucleus. Altogether, the present work affords a convenient approach for the successful detection of Ki-67 mRNA expression in the cytosol without interference from DNase Ⅰ/Ⅱ in the nucleus/lysosome, which may be potentially further applied for the detection of other cytosolic RNAs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: To investigate the association of quantitative parameter (apparent diffusion coefficient [ADC]) from diffusion-weighted imaging (DWI) and various quantitative and semiquantitative parameters from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) with Ki-67 proliferation index (PI) in cervical carcinoma (CC)., Methods: A total of 102 individuals with CC who received 3.0 T MRI examination (DWI and DCE MRI) between October 2016 and December 2022 were enrolled in our investigation. Two radiologists separately assessed the ADC parameter and various quantitative and semiquantitative parameters including (volume transfer constant [K trans ], rate constant [k ep ], extravascular extracellular space volume fraction [v e ], volume fraction of plasma [v p ], time to peak [TTP], maximum concentration [MaxCon], maximal slope [MaxSlope] and area under curve [AUC]) for each tumor. Their association with Ki-67 PI was analyzed by Spearman association analysis. The discrepancy between low-proliferation and high-proliferation groups was subsequently analyzed. The receiver operating characteristic (ROC) curve analysis utilized to identify optimal cut-off points for significant parameters., Results: Both ADC (ρ = -0.457, p < 0.001) and K trans (ρ = -0.467, p < 0.001) indicated a strong negative association with Ki-67 PI. Ki-67 PI showed positive correlations with TTP, MaxCon, MaxSlope and AUC (ρ = 0.202, 0.231, 0.309, 0.235, respectively; all p values<0.05). Compared with the low-proliferation group, high-Ki-67 group presented a significantly lower ADC (0.869 ± 0.125 × 10 -3  mm 2 /s vs. 1.149 ± 0.318 × 10 -3  mm 2 /s; p < 0.001) and K trans (1.314 ± 1.162 min -1 vs. 0.391 ± 0.390 min -1 ; p < 0.001), also significantly higher MaxCon values (0.756 ± 0.959 vs. 0.422 ± 0.341; p < 0.05) and AUC values (2.373 ± 3.012 vs. 1.273 ± 1.000; p < 0.05). The cut-offs of ADC, K trans , MaxCon and AUC for discrimating low- and high-Ki-67 groups were 0.920 × 10 -3  mm 2 /s, 0.304 min -1 , 0.209 and 1.918, respectively., Conclusions: ADC, K trans , TTP, MaxCon, MaxSlope and AUC are associated with Ki-67 PI. ADC and K trans exhibited high performance to discriminate low and high Ki-67 status of CC., Competing Interests: Declaration of competing interest All the other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Pulmonary tuberculosis (PTB) is a well-known disease caused by Mycobacterium tuberculosis. Its pathogenesis is premised on evasion of the immune system and dampened immune cells activity., Methods: Here, the transcription pattern of immune cells exhaustion, inflammatory, and cellular activity markers were examined in peripheral blood mononuclear cells (PBMCs) from PTB patients at various stages of treatment. PBMCs were isolated, and RNA extracted. cDNA synthesis was performed, then amplification of genes of interest., Results: The T cell exhaustion markers (PD-L1, CTLA4, CD244 and LAG3) showed varied levels of expressions when comparing 0 T and 1 T to the other treatment phases, suggesting their potential roles as markers for monitoring TB treatment. IL-2, IFN-g and TNF-a expression at the gene level returned to normal at completion of treatment, while granzyme B levels remained undetectable at the cured stage. At the cured stage, the cellular activity monitors Ki67, CD69, GATA-3, CD8 and CD4 expressions were comparable to the healthy controls. Correlation analysis revealed a significantly strong negative relationship with CD244 expression, particularly between 1 T and 2 T (r = -0.94; p = 0.018), and 3 T (r = -0.95; p = 0.013). Comparing 0 T and 3 T, a genitive correlation existed in PD-L1 (r = -0.74) but statistically not significant, as seen in CTLA4 and LAG-3 expressions., Conclusion: Collectively, the findings of the study suggest that T-cells exhaustion marker particularly CD244, inflammatory markers IL-2, IFN-g and TNF-a, and cellular activity indicators such as Ki67, CD69, GATA-3, CD8 and CD4 are promising markers in monitoring the progress of PTB patients during treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

During the aging process, elastin is degraded and the level of elastin-derived peptides (EDPs) successively increases. The main peptide released from elastin during its degradation is a peptide with the VGVAPG sequence. To date, several papers have described that EDPs or elastin-like peptides (ELPs) affect human mesenchymal stem cells (hMSCs) derived from different tissues. Unfortunately, despite the described effect of EDPs or ELPs on the hMSC differentiation process, the mechanism of action of these peptides has not been elucidated. Therefore, the aim of the present study was to evaluate the impact of the VGVAPG and VVGPGA peptides on the hMSC stemness marker and elucidation of the mechanism of action of these peptides. Our data show that both studied peptides (VGVAPG and VVGPGA) act with the involvement of ERK1/2 and c-SRC kinases. However, their mechanism of activation is probably different in hMSCs derived from adipose tissue. Both studied peptides increase the KI67 protein level in hMSCs, but this is not accompanied with cell proliferation. Moreover, the changes in the NANOG and c-MYC protein expression and in the SOX2 and POU5F1 mRNA expression suggest that EDPs reduced the hMSC stemness properties and could initiate cell differentiation. The initiation of differentiation was evidenced by changes in the expression of AhR and PPARγ protein as well as specific genes (ACTB, TUBB3) and proteins (β-actin, RhoA) involved in cytoskeleton remodeling. Our data suggest that the presence of EDPs in tissue can initiate hMSC differentiation into more tissue-specific cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Aims/Background Immunohistochemistry (IHC) is the main method to detect human epidermal growth factor receptor 2 (Her-2) and Ki-67 expression levels. However, IHC is invasive and cannot reflect their expression status in real-time. This study aimed to build radiomics models based on visceral adipose tissue (VAT)'s 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) imaging, and to evaluate the relationship between radiomics features of VAT and positive expression of Her-2 and Ki-67 in gastric cancer (GC). Methods Ninety patients with GC were enrolled in this study. 18 F-FDG PET/CT radiomics features were calculated using the PyRadiomics package. Two methods were employed to reduce radiomics features. The machine learning models, logistic regression (LR), and support vector machine (SVM), were constructed and estimated by the receiver operator characteristic (ROC) curve. The correlation of outstanding features with Ki-67 and Her-2 expression status was evaluated. Results For the Ki-67 set, the area under of the receiver operator characteristic curve (AUC) and accuracy were 0.86 and 0.79 for the LR model and 0.83 and 0.69 for the SVM model. For the Her-2 set, the AUC and accuracy were 0.84 and 0.86 for the LR model and 0.65 and 0.85 for the SVM model. The LR model for Ki-67 exhibited outstanding prediction performance. Three wavelet transform features were correlated with Her-2 expression status ( p all < 0.001), and one wavelet transform feature was correlated with the expression status of Ki-67 ( p = 0.042). Conclusion 18 F-FDG PET/CT-based radiomics models of VAT demonstrate good performance in predicting Her-2 and Ki-67 expression status in patients with GC. Radiomics features can be used as imaging biomarkers for GC.

Background: Patients with pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) have better outcomes, potentially warranting less extensive surgical and systemic treatments. Early prediction of treatment response could aid in adapting therapies., Methods: On-treatment biopsies from 297 patients with invasive BC in three randomized, prospective neoadjuvant trials were assessed (GeparQuattro, GeparQuinto, GeparSixto). BC quantity, tumor-infiltrating lymphocytes (TILs), and the proliferation marker Ki-67 were compared to pre-treatment samples. The study investigated the correlation between residual cancer, changes in Ki-67 and TILs, and their impact on pathologic complete response (pCR) and disease-free survival (DFS)., Results: Among the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2-), 87 (29%) were triple-negative (TNBC), and 72 (24%) were HER2+. Invasive tumor cells were found in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2-: 84%, TNBC: 62%, HER2+: 51%; p < 0.001). Patients with residual tumor on-treatment had an 8% pCR rate post-treatment (HR+/HER2-: 3%, TNBC: 19%, HER2+: 11%), while those without any invasive tumor had a 50% pCR rate (HR+/HER2-: 27%; TNBC: 48%, HER2+: 66%). Sensitivity for predicting residual disease was 0.81, with positive and negative predictive values of 0.92 and 0.50, respectively. Increasing TILs from baseline to on-treatment biopsy (if residual tumor was present) were linked to higher pCR likelihood in the overall cohort (OR 1.034, 95% CI 1.013-1.056 per % increase; p = 0.001) and with a longer DFS in TNBC (HR 0.980, 95% CI 0.963-0.997 per % increase; p = 0.026). Persisting or increased Ki-67 was associated with with lower pCR probability in the overall cohort (OR 0.957, 95% CI 0.928-0.986; p = 0.004) and shorter DFS in TNBC (HR 1.023, 95% CI 1.001-1.047; p = 0.04)., Conclusion: On-treatment biopsies can predict patients unlikely to achieve pCR post-therapy. This could facilitate therapy adjustments for TNBC or HER2 + BC. They also might offer insights into therapy resistance mechanisms. Future research should explore whether standardized or expanded sampling enhances the accuracy of on-treatment biopsy procedures. Trial registration GeparQuattro (EudraCT 2005-001546-17), GeparQuinto (EudraCT 2006-005834-19) and GeparSixto (EudraCT 2011-000553-23)., (© 2024. The Author(s).)

Background: The risk of cervical cancer progression in high-risk human papillomavirus (HR-HPV)-positive women is associated with cervical lesion severity and molecular heterogeneity. Classification systems based on p16 and Ki67 expression cumulative scores (0-3 each)-p16/Ki67 collectively known as an immunoscore [IS]-are an accurate and reproducible method for grading cervical intraepithelial neoplasia (CIN) lesions. Meanwhile, DNA methylation is an early event in the development of cervical cancer. Hence, this study evaluated the relationship among CIN, p16/Ki-67 IS, and PAX1/ZNF582 methylation., Methods: In this study, 414 HPV-positive paraffin-embedded specimens were collected, and PAX1/ZNF582 methylation and the p16/ki67 IS were determined. A total of 43 invalid samples were excluded and 371 were included in the statistical analyses. There were 103 cervicitis, 95 CIN1, 71 CIN2, 89 CIN3, and 13 squamous cell carcinoma (SCC) cases. The association between PAX1/ZNF582 methylation and p16/Ki6 immunohistochemical staining scores was analyzed., Results: The ΔCp of PAX1 m (PAX1 methylation) and ZNF582 m (ZNF582 methylation) decreased with cervical lesion severity (Cuzick trend test, all P < 0.001). The severity of the cervical lesions and p16, Ki67, and p16/Ki67 IS showed an increasing trend (Multinomial Cochran-Armitage trend test, all P < 0.001). The prevalence of PAX1 m /ZNF582 m increased with an increase in the IS of p16, Ki67, and p16/Ki67 (Cochran-Armitage trend test, all P < 0.001). In cervical SCC, the IS was 5-6, and the PAX1 m /ZNF582 m was positive. Meanwhile, heterogeneity was observed in CIN lesions: 10 cases had an IS of 3-4 and were PAX1 m /ZNF582 m -positive in ≤ CIN1; 1 case had an IS of 0-2 and was PAX1 m /ZNF582 m -positive in CIN2/3., Conclusions: Significant heterogeneity was observed in CIN lesions for p16 and Ki67 immunohistochemical staining scores and PAX1/ZNF582 methylation. This may help clinicians personalize the management of CIN based on the predicted short-term risk of cancer progression, minimizing the rate of missed CIN1 diagnoses and incorrect treatment of CIN2/3., (© 2024. The Author(s).)

Stromal cells play a critical role in the tumor microenvironment of breast cancer (BC), as they are recruited by tumor cells and regulate the metastatic spread. Though high expression of α-parvin, a member of the parvin family of actin-binding proteins, is reported to be associated with a poor prognosis and metastasis in several cancers, its role in carcinogenesis has not been thoroughly explored. Therefore, we aimed to examine the expression of α-parvin in BC patients by compartmentalizing and quantifying tissues to determine whether α-parvin can be a potential therapeutic target. We performed immunohistochemical (IHC) staining of α-parvin in BC tissues, and the IHC scores were calculated in the overall tissue, stroma, and epithelium using image analysis software. The expression of α-parvin was significantly higher in BC tissues ( p = 0.0002) and BC stroma ( p < 0.0001) than in normal tissues. Furthermore, all α-parvin scores were significantly positively correlated with the proliferation marker Ki67. The overall and stroma scores are associated with the tumor, (lymph) node, and metastasis (TNM) classification, stage, and grade. These results suggest that high expression of α-parvin in stroma is associated with BCs and might be a new predictive marker for diagnosing BC.

Purpose: To investigate the application value of support vector machine (SVM) model based on diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) and amide proton transfer- weighted (APTW) imaging in predicting isocitrate dehydrogenase 1(IDH-1) mutation and Ki-67 expression in glioma., Methods: The DWI, DCE and APTW images of 309 patients with glioma confirmed by pathology were retrospectively analyzed and divided into the IDH-1 group (IDH-1(+) group and IDH-1(-) group) and Ki-67 group (low expression group (Ki-67 ≤ 10%) and high expression group (Ki-67 > 10%)). All cases were divided into the training set, and validation set according to the ratio of 7:3. The training set was used to select features and establish machine learning models. The SVM model was established with the data after feature selection. Four single sequence models and one combined model were established in IDH-1 group and Ki-67 group. The receiver operator characteristic (ROC) curve was used to evaluate the diagnostic performance of the model. Validation set data was used for further validation., Results: Both in the IDH-1 group and Ki-67 group, the combined model had better predictive efficiency than single sequence model, although the single sequence model had a better predictive efficiency. In the Ki-67 group, the combined model was built from six selected radiomics features, and the AUC were 0.965 and 0.931 in the training and validation sets, respectively. In the IDH-1 group, the combined model was built from four selected radiomics features, and the AUC were 0.997 and 0.967 in the training and validation sets, respectively., Conclusion: The radiomics model established by DWI, DCE and APTW images could be used to detect IDH-1 mutation and Ki-67 expression in glioma patients before surgery. The prediction performance of the radiomics model based on the combination sequence was better than that of the single sequence model., (© 2024. The Author(s).)

Aim: To define the role of clinical, endoscopic, laboratory and immunomorphological parameters in predicting the occurrence and course of colorectal cancer (CRC) in patients with diverticular disease of the colon (DDC)., Materials and Methods: One hundred and seventy five people with DDC were examined, divided into 3 groups: group 1 - 85 patients with DDC; group 2 - 45 with DDC in combination with adenomatous polyps (AP); 3rd group - 45 with DDC with established CRC (I or II stage). The control group consisted of 30 practically healthy people. Patients and healthy people were examined according to a single program: clinical, laboratory, instrumental data and immunomorphological research methods [use of primary antibodies to p53 (mAb clone DO-7 product no. PA0057, Leica Biosystems, Leica Bond III) and Ki-67 (Ab16667, Abcam, UK)]., Results: Among the main complaints in patients with DDC and CRC, constipation was more common than in patients with DDC and DDC with AP ( p< 0.05). In patients with DDC and colorectal neoplasia, a positive reaction to occult blood in the feces was more often verified, compared with the group with DDC ( p< 0.05). Higher levels of glucose and cholesterol in blood plasma, as well as body mass index were found in patients with DDC with AP and CRC, compared with the DDC group ( p< 0.05). A higher level of expression of Ki-67 and p53 was found in patients with DDC combined with AP and CRC, compared with patients with DDC without colorectal neoplasia ( p< 0.05). At the same time, in patients with DDC with CRC, the expression level of Ki-67 and p53 was higher than in patients with DDC with AP ( p< 0.05) Conclusion. In patients with DDC combined with AP and CRC, higher levels of glucose, plasma cholesterol, as well as body mass index were observed compared to the group of patients with DDC alone ( p< 0.05). Of note, the results of the determination of Ki-67 and p53 in the mucous membrane of the colon should be considered important prognostic markers for the development of CRC in patients with DDC.

Infantile hemangiomas (IHs) are benign vascular neoplasms of childhood (prevalence 5-10%) due to the abnormal proliferation of endothelial cells. IHs are characterized by a peculiar natural life cycle enclosing three phases: proliferative (≤12 months), involuting (≥13 months), and involuted (up to 4-7 years). The mechanisms underlying this neoplastic disease still remain uncovered. Twenty-seven IH tissue specimens (15 proliferative and 12 involuting) were subjected to hematoxylin and eosin staining and a panel of diagnostic markers by immunohistochemistry. WT1, nestin, CD133, and CD26 were also analyzed. Moreover, CD31 pos /CD26 pos proliferative hemangioma-derived endothelial cells (Hem-ECs) were freshly isolated, exposed to vildagliptin (a DPP-IV/CD26 inhibitor), and tested for cell survival and proliferation by MTT assay, FACS analysis, and Western blot assay. All IHs displayed positive CD31, GLUT1, WT1, and nestin immunostaining but were negative for D2-40. Increased endothelial cell proliferation in IH samples was documented by ki67 labeling. All endothelia of proliferative IHs were positive for CD26 (100%), while only 10 expressed CD133 (66.6%). Surprisingly, seven involuting IH samples (58.3%) exhibited coexisting proliferative and involuting aspects in the same hemangiomatous lesion. Importantly, proliferative areas were characterized by CD26 immunolabeling, at variance from involuting sites that were always CD26 negative. Finally, in vitro DPP-IV pharmacological inhibition by vildagliptin significantly reduced Hem-ECs proliferation through the modulation of ki67 and induced cell cycle arrest associated with the upregulation of p21 protein expression. Taken together, our findings suggest that CD26 might represent a reliable biomarker to detect proliferative sites and unveil non-regressive IHs after a 12-month life cycle.

Objective: To investigate the clinicopathological features and differential diagnosis of breast angiomatosis. Methods: Six cases of breast angiomatosis diagnosed at the Department of Pathology, the Seventh Medical Center, People's Liberation Army General Hospital and the Department of Pathology, Dongzhimen Hospital, Beijing University of Chinese Medicine from January 2011 to December 2023 were evaluated and reviewed. Results: All patients were female with an average age of 46 years at presentation, ranging from 25 to 62 years. The most common clinical presentation was a palpable unilateral breast mass with diameter ranging from 7 to 14 cm, and the average size was 11 cm. Histologically, all cases were composed of variably-sized ectatic, thin-walled blood vessels with minimal to no apparent smooth muscle, lined by flat normochromic endothelium without atypia, and diffusely infiltrating the breast stroma. Where present, the lesional vessels infiltrated between and around terminal duct lobular units but not into individual intralobular stroma. Immunohistochemical staining for CD31, CD34, Factor Ⅷ, Fli-1 and D2-40 revealed positive expression in vascular and/or lymphatic endothelial cells. Additionally, the Ki-67 proliferation index was found to be less than 1%. Conclusions: Angiomatosis of the breast is a rare benign vascular lesion. Distinguishing it from low-grade angiosarcoma requires careful consideration of the growth pattern, atypical features, and Ki-67 proliferation index.

The individualization of chromosomes during early mitosis and their clustering upon exit from cell division are two key transitions that ensure efficient segregation of eukaryotic chromosomes. Both processes are regulated by the surfactant-like protein Ki-67, but how Ki-67 achieves these diametric functions has remained unknown. Here, we report that Ki-67 radically switches from a chromosome repellent to a chromosome attractant during anaphase in human cells. We show that Ki-67 dephosphorylation during mitotic exit and the simultaneous exposure of a conserved basic patch induce the RNA-dependent formation of a liquid-like condensed phase on the chromosome surface. Experiments and coarse-grained simulations support a model in which the coalescence of chromosome surfaces, driven by co-condensation of Ki-67 and RNA, promotes clustering of chromosomes. Our study reveals how the switch of Ki-67 from a surfactant to a liquid-like condensed phase can generate mechanical forces during genome segregation that are required for re-establishing nuclear-cytoplasmic compartmentalization after mitosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Statins, inhibitors of HMG-CoA reductase, have been shown to have potential anti-carcinogenic effects through the inhibition of the mevalonate pathway and their impact on Ras and RhoGTAases. Prior studies have demonstrated a reduction in breast tumor proliferation, as well as increased apoptosis, among women with early-stage breast cancer who received statins between the time of diagnosis and the time of surgery. The aim of this study was to evaluate the impact of short-term oral high-potency statin therapy on the expression of markers of breast tumor proliferation, apoptosis, and cell cycle arrest in a window-of-opportunity trial. This single-arm study enrolled 24 women with stage 0-II invasive breast cancer who were administered daily simvastatin (20 mg) for 2-4 weeks between diagnosis and surgical resection. Pre- and post-treatment tumor samples were analyzed for fold changes in Ki-67, cyclin D1, p27, and cleaved caspase-3 (CC3) expression. Out of 24 enrolled participants, 18 received statin treatment and 17 were evaluable for changes in marker expression. There was no significant change in Ki-67 expression (fold change = 1.4, p = 0.597). There were, however, significant increases in the expression of cyclin D1 (fold change = 2.8, p = 0.0003), p27 cytoplasmic (fold change = 3.2, p = 0.025), and CC3 (fold change = 2.1, p = 0.016). Statin treatment was well tolerated, with two reported grade-1 adverse events. These results align with previous window-of-opportunity studies suggesting a pro-apoptotic role of statins in breast cancer. The increased expression of markers of cell cycle arrest and apoptosis seen in this window-of-opportunity study supports further investigation into the anti-cancer properties of statins in larger-scale clinical trials.

Purpose: Development of a computational biomarker to predict, prior to treatment, the response to CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy in patients with breast cancer., Experimental Design: A mechanistic mathematical model that accounts for protein signaling and drug mechanisms of action was developed and trained on extensive, publicly available data from breast cancer cell lines. The model was built to provide a patient-specific response score based on the expression of six genes (CCND1, CCNE1, ESR1, RB1, MYC, and CDKN1A). The model was validated in five independent cohorts of 148 patients in total with early-stage or advanced breast cancer treated with endocrine therapy and CDK4/6i. Response was measured either by evaluating Ki67 levels and PAM50 risk of relapse (ROR) after neoadjuvant treatment or by evaluating progression-free survival (PFS)., Results: The model showed significant association with patient's outcomes in all five cohorts. The model predicted high Ki67 [area under the curve; AUC (95% confidence interval, CI) of 0.80 (0.64-0.92), 0.81 (0.60-1.00) and 0.80 (0.65-0.93)] and high PAM50 ROR [AUC of 0.78 (0.64-0.89)]. This observation was not obtained in patients treated with chemotherapy. In the other cohorts, patient stratification based on the model prediction was significantly associated with PFS [hazard ratio (HR) = 2.92 (95% CI, 1.08-7.86), P = 0.034 and HR = 2.16 (1.02 4.55), P = 0.043]., Conclusions: A mathematical modeling approach accurately predicts patient outcome following CDK4/6i plus endocrine therapy that marks a step toward more personalized treatments in patients with Luminal B breast cancer., (©2024 American Association for Cancer Research.)

This study examined to evaluate the predictive value of a nomogram with Ki-67 in overall and disease-free survival in glioma patients, a total of 76 patients diagnosed with glioma by pathology in Tengzhou Central People's Hospital were enrolled. The baseline data and follow ups were retrospectively collected from medical records. The associations between Ki-67 and survival status were examined using log-rank test, univariate and multivariate Cox proportional hazard regression models. Calibrations were performed to validate the established nomograms. Ki-67 negative group showed of a longer OS survival time and a longer PFS survival time with log-rank test (x 2  = 16.101, P < 0.001 and x 2  = 16.961, P < 0.001). Age older than 50 years (HR = 2.074, 95% CI 1.097-3.923), abnormal treatment (HR = 2.932, 95% CI 1.343-6.403) and Ki-67 positive (HR = 2.722, 95% CI 1.097-6.755) were the independent predictive factors of death. High grade pathology (HR = 2.453, 95% CI 1.010-5.956) and Ki-67 positive (HR = 2.200, 95% CI 1.043-4.639) were the independent predictive factors of recurrence. The C-index for the nomogram of OS and PFS were 0.745 and 0.723, respectively. The calibration results showed that the nomogram could predict the overall and disease-free 1-year survival of glioma patients. In conclusion, the nomograms with Ki-67 as independent risk factor for OS and PFS could provide clinical consultation in the treatment and follow-up of malignant glioma., (© 2024. The Author(s).)

To determine if fluoride's established negative impact on adult kidney health begins during gestation, an intergenerational model of Wistar rats was exposed to two doses of fluoride (2.5 or 5.0 mg/kg/day via gavage) 20 days before mating and during gestation (20 days). The results revealed that fluoride was distributed to the amniotic fluid and fetus, resulting in lower weight, more pronounced fetal restriction, and decreased creatinine, osmolarity, and amniotic fluid volume. At the kidney level, less development in the nephrogenic and cortical zones was observed in the fluoride treatment groups, with an imbalance in the number of glomeruli and "S" shaped bodies, an increase in the immunoexpression of the marker of proliferation Ki-67 in the nephrogenic zone, an increase in the expression of Wnt4 and more maturation of the renal tubules, indicating that fluoride exposure during pregnancy alters kidney development and promotes early maturation of tubular segments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: The existence of insulin- or glucagon-expressing extra-islet endocrine cells scattered in the pancreas is well-known, but they have been sparsely characterized. The aim of this study was to examine their density, distribution, transcription-factor expression, and mitotic activity in young non-diabetic subjects., Methods: Multispectral imaging was used to examine PDX1, ARX, Ki67, insulin and glucagon in extra-islet endocrine cells in pancreatic tissue from organ donors aged 1-25 years., Results: Extra-islet insulin- or glucagon-positive cells were frequent in all donors (median 17.3 and 22.9 cells/mm 2 respectively), with an insulin:glucagon cell ratio of 0.9. The density was similar regardless of age. PDX1 localized mainly to insulin-, and ARX mainly to glucagon-positive cells but, interestingly, many of the cells were negative for both transcription factors. Double-hormone-positive cells were rare but found in all age groups, as were insulin-positive cells expressing ARX and glucagon-positive cells expressing PDX1. Extra-islet endocrine cells with Ki67 expression were present but rare (0-2%) in all age groups., Conclusions: Extra-islet endocrine cells are more frequent than islets. The preserved extra-islet cell density during pancreas volume-expansion from childhood- to adulthood indicates that new cells are formed, possibly from replication as cells with mitotic activity were discovered. The lack of transcription-factor expression in many cells indicates that they are immature, newly formed or plastic. This, together with the mitotic activity, suggests that these cells could play an important role in the expansion of beta-cell mass in situations of increasing demand, or in the turnover of the endocrine cell population., (© 2024. The Author(s).)

Purpose: To develop a nomogram using clinical features and the MRI parameters for preoperatively predicting the expression of Ki-67 in patients with hepatocellular carcinoma (HCC)., Methods: One hundred and forty patients (training cohorts: n = 108; validation cohorts: n = 32) with confirmed HCC were investigated. Mann-Whitney U test, independent sample t-test, and chi-squared test were used to analyze the continuous and categorical variables. Univariate and multivariate logistic regression analyses were performed to examine the clinical variables and parameters from MRI associated with Ki-67 expression. As a result, a nomogram was developed based on these associations in patients with HCC. The performance of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC) and calibration curves., Results: In the training set, multivariable logistic regression analysis revealed that lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) levels, protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels, and tumor shape were independent predictors for Ki-67 expression (p < 0.05). These three variables and the apparent diffusion coefficient (ADC) value were used to establish a nomogram, while the ADC value was found to be a marginal significant predictor. The model demonstrated a strong ability to discriminate Ki-67 expression in both the training and validation cohorts (AUC = 0.862, 0.877)., Conclusion: A non-invasive preoperative prediction method, which incorporates MRI variables and clinical features was developed, and showed effectiveness in evaluating Ki-67 expression in HCC patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)