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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. [ABSTRACT FROM AUTHOR]

Background: The Ki-67 proliferative index (PI) is part of the diagnosis of nodal B-cell lymphoma (nBCL), but its determination in cytological samples is not standardized. We aimed to establish an approach for the accurate determination of the Ki-67 PI in cytological slides to differentiate between indolent and aggressive nBCLs. Methods: Patients diagnosed with nBCL by fine-needle aspiration biopsy and subsequent excision biopsy were included. Cell suspensions were prepared from biopsy samples for CD3/Ki-67 double immunocytochemical staining and flow-cytometric verification of lymphoma B-cell counts. The Ki-67 PI was assessed by manual counting and eyeballing in cytology and eyeballing in histology. The cut-off values for the differentiation between aggressive and indolent lymphomas were determined for each method. Results: A strong correlation between manual and flow-cytometric counting of lymphoma B cells was confirmed (interclass correlation coefficient (IC coef.) = 0.78). The correlation of the Ki-67 PI determined in cytological and histological slides was also strong (IC coef. > 0.80). Histologically, 55 cases were classified as indolent and 31 as aggressive nBCLs. KI-67 PI cut-off values of 28.5%, 27.5%, and 35.5% were established for manual counting and eyeballing in cytology and eyeballing in histology, respectively, with high sensitivity and specificity. Conclusions: The Ki-67 PI, assessed by manual counting and eyeballing in cytological samples, accurately differentiates between indolent and aggressive nBCLs. [ABSTRACT FROM AUTHOR]

Background: Ki-67 immunostaining is commonly used in neuroendocrine tumors to estimate the proliferative index and for grading. This study investigates its association with the invasiveness of follicular-derived thyroid carcinomas (TCs). Methods: A retrospective analysis of patients with TC at three McGill University teaching hospitals between January 2018 and November 2023 was conducted. The inclusion criteria included patients with malignant thyroid tumors and accessible Ki-67 LI data from final pathology specimens. The data collected included patient demographics, Ki-67 LI values, and different invasiveness attributes, such as molecular mutations, the histological subtype, lymphovascular invasion (LVI), extrathyroidal extension (ETE), and positive lymph nodes (LNs). Results: In total, 212 patients met the inclusion criteria, of which 80.7% were females and 19.3% were males. The Ki-67 LI ranged from 1% to 30%, with the majority of the cases within the range of 1–15%. A significant association was observed between higher Ki-67 LI and high-risk histological subtypes of thyroid carcinoma (p < 0.001). Similarly, Ki-67 LI was significantly associated with LVI and positive LN metastasis (p < 0.001 and p = 0.036, respectively). However, no significant association was found between the Ki-67 LI and gene mutations or ETE (p = 0.133 and p = 0.190, respectively). Using percentiles to establish a cutoff, patients with a Ki-67 LI higher than 6.7 showed a higher likelihood of being associated with invasive features. Conclusion: Elevated Ki-67 LI can serve as an indicator of aggressiveness in follicular-derived TC, especially when associated with distinct histological subtypes, LVI and positive LNs. [ABSTRACT FROM AUTHOR]

This study investigates the combined effects of the neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31-Pro34]NPY at a dose of 132 µg and Ketamine at 10 mg/Kg on cognitive functions and neuronal proliferation, against a backdrop where neurodegenerative diseases present an escalating challenge to global health systems. Utilizing male Sprague-Dawley rats in a physiological model, this research employed a single-dose administration of these compounds and assessed their impact 24 h after treatment on object-in-place memory tasks, alongside cellular proliferation within the dorsal hippocampus dentate gyrus. Methods such as the in situ proximity ligation assay and immunohistochemistry for proliferating a cell nuclear antigen (PCNA) and doublecortin (DCX) were utilized. The results demonstrated that co-administration significantly enhanced memory consolidation and increased neuronal proliferation, specifically neuroblasts, without affecting quiescent neural progenitors and astrocytes. These effects were mediated by the potential formation of NPY1R-TrkB heteroreceptor complexes, as suggested by receptor co-localization studies, although further investigation is required to conclusively prove this interaction. The findings also highlighted the pivotal role of brain-derived neurotrophic factor (BDNF) in mediating these effects. In conclusion, this study presents a promising avenue for enhancing cognitive functions and neuronal proliferation through the synergistic action of the NPY1R agonist and Ketamine, potentially via NPY1R-TrkB heteroreceptor complex formation, offering new insights into therapeutic strategies for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Dyslipidemia is a component of metabolic syndrome, having an important role in the carcinogenesis of different tumor types, such as prostate, ovarian, or renal cancer. The number of studies on the predictive potential of the different components of the lipid profile with a predictive potential in breast cancer is quite low. The evaluation of the lipid profile was carried out for the 142 patients who benefited from neoadjuvant therapy (NAC) in order to identify a potential predictive biomarker. The serological sample collection was performed sequentially according to a standardized protocol, pre-NAC, post-NAC and 6 months post-NAC after a 6-h pre-collection fast. We also investigated in the general group the presence or absence of the p53 mutation (TP53) and of the mitotic index ki-67, respectively, in relation to the molecular subtypes. The menopausal status, tumor size, family history, grading, Ki-67, p53 and LN metastases have a predictive nature regarding overall survival (OS) (p < 0.05), while for disease free survival (DFS), only tumor size, tumor grading, Ki-67 > 14, and p53+ are of predictive nature. The genetic and molecular analysis carried out in our group indicates that 71.67% have a Ki-67 score higher than 14%, and 39% of the patients have the positive P53 mutation. The multivariate analysis in the case of patients included in the TNBC subtype showed that the increased tumor volume (p = 0.002) and increased level of HDL (p = 0.004) represent predictive factors for the tumor response rate to NAC. High HDL-C levels before NAC and increased LDL-C levels after NAC were associated with the better treatment response in ER-positive and HER2+ breast cancer patients. Increased HDL-C values and tumor volume represent predictive factors as to the response rate to NAC in the case of patients included in the TNBC subtype. Regarding the ER+ and HER2+ subtypes, increased levels of HDL-C pre-NAC and increased levels of LDL-C post-NAC were associated with a better therapeutic response rate. Tumor grading, Ki-67, p53, and LN metastases have a predictive nature for OS, while tumor size, tumor grading, and Ki-67 > 14, and p53+ are predictive for DFS. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Nomogram for Predicting Recurrence-Free Survival of Primary Localized Gastrointestinal Stromal Tumor." The correction states that there were mistakes in Table 2 and Figure 3 of the original publication. The corrected versions of Table 2 and Figure 3 are provided in the document. The authors of the article state that these corrections do not significantly impact the overall findings and conclusions of the paper. [Extracted from the article]

Connections between vitamin D and psoriasis have been a matter of interest for the past decades, with its active metabolite, 1,25(OH)2 vitamin D, being valued for antiproliferative and immunomodulatory effects. However, none of vitamin D's actions could be possible without the CYP27B1 enzyme that bio-activates this metabolite of interest. In order to see if there is any link between the enzyme expression and the disease's particularities, we conducted a preliminary study that involved 11 skin biopsies of patients with mild (n = 4) or moderate to severe psoriasis (n = 7). The cell proliferation antigen Ki67 and the CD45RO+ marker were also assessed. Compared with healthy skin, in psoriasis, it is reported that the enzyme's expression seems to be more ubiquitous, but a clear correlation between the disease's severity and the CYP27B1 expression was, to our knowledge, lacking. We found that, in patients with very mild psoriasis, the enzyme expression was observed in the epidermal stratum basale in a similar manner as in healthy skin specimens. Contrary, for higher severity scores, a divergent result was observed, with the enzyme being either variably spread in the epidermal stratum spinosum or completely absent. Unlike malignant diseases, a significant connection between CYP27B1 and Ki67 (p = 0.313) or CYP27B1 and CD45RO+ (p = 0.657) does not seem to be relevant in psoriasis. [ABSTRACT FROM AUTHOR]

Simple Summary: This study reports on the use of Ki-67 and Ki-67 × AgNOR markers in cytological specimens of canine mast cell tumors. The research involved 45 dogs with cutaneous mast cell tumors. The cytological specimens were graded and assessed for these markers. The study suggests potential cut-off values for these markers in correlation with histopathological grading. The findings highlight the importance of cytological evaluation and the inclusion of Ki-67 and Ki-67 × AgNOR markers in assessing highly malignant mast cell tumors. A cytological grading system for canine mast cell tumors (MCTs) has been developed, but its integration into clinical routine has been hindered due to its diagnostic limitations. The aim of this study was to assess the prognostic value of Ki-67 and argyrophilic nucleolar organizing region (AgNOR) markers in cytological MCT samples and to determine cut-off values for these markers in correlation with histopathological grading. Cytological samples were collected prior to surgical excision, and histopathological samples were obtained postsurgery from 45 dogs diagnosed with cutaneous mast cell tumors (MCTs). The cytological specimens were classified using a two-tier grading system, and their Ki-67 (average immunopositive nuclei per 100 cells) and AgNOR (average AgNOR counts per 100 nuclei) signaling was assessed. Through receiver operating characteristic (ROC) analysis, cut-off values for Ki-67 and Ki-67 × AgNOR were determined to better align with histopathological grading (classified as low or high grade according to Kiupel's scoring system). Without the inclusion of proliferative markers, there was a 73% agreement between cytological and histopathological grading. The prediction of histopathological grade was slightly more accurate when assessing Ki-67 and Ki-67 × AgNOR signaling in cytological specimens (75% and 80%, respectively) compared to the initial cytological grading. The cytological assessment of canine MCTs proves beneficial for the initial evaluation, and the incorporation of the evaluation of Ki-67 and AgNOR markers may assist in identifying diagnostically highly malignant MCTs. [ABSTRACT FROM AUTHOR]

Background: Up to now, endometrial cancer (EC) treatments are mainly represented by surgery followed by adjuvant chemotherapy or radiotherapy. The updated guidelines give a 2A recommendation for the use of hormone therapy only in advanced low-grade ECs, underlying the need for more data on the role of hormone therapy in the adjuvant setting. Methods: The clinicopathological data of 158 early-stage EC patients was retrospectively collected. A Ki-67 cut-off value of 40% was established based on literature data. Disease-free survival (DFS) and Overall survival (OS) were evaluated. Results: Results: Multivariate analysis of DFS and OS showed a significantly increased risk of progression in patients with >40% Ki-67 [HR = 3.13 (95% CI; 1.35–7.14); p = 0.007] and a significantly higher relative risk of death [HR = 3.70 (95% CI; 1.69–8.33); p = 0.001]. The predictive role of the Ki-67 index was highlighted by the clinical benefit of adjuvant hormone in patients with high Ki-67. Conclusions: Our results suggest a positive role of the Ki-67 index as a prognostic and potentially predictive marker in EC, although further studies are warranted to reach a definitive conclusion. [ABSTRACT FROM AUTHOR]

The pathologic evaluation of a tumor tissue is an essential part of an acromegaly patient's assessment. This study aimed to analyze the pathologic characteristics of pituitary tumors in patients with acromegaly. The demographic data, in addition to the hormonal, imaging, and pathologic results of 120 patients with acromegaly after pituitary surgery, were extracted from the Polish Acromegaly Registry. We compared sparsely and densely granulated tumors, GH(+), mixed GH(+)/PRL(+) and plurihormonal tumors, α-subunit-positive and α-subunit-negative tumors, and tumors of various Ki-67 indices in terms of the abovementioned features. Sparsely granulated tumors were more frequent in women than in men (p = 0.001) and in younger patients (p = 0.011), and they were larger (p < 0.001) compared to densely granulated tumors. Tumors with positive α-subunit were smaller (p = 0.013), showed extrasellar extension less often (p = 0.039), and were more often densely granulated (p < 0.001) compared to α-subunit-negative tumors. Patients with a higher Ki-67 index were younger (p < 0.001) and more often diagnosed with genetic syndromes (p = 0.02); they had higher GH concentrations (p = 0.007), larger tumors (p = 0.006), and cavernous sinus invasions more frequently (p = 0.022). Conclusions: The pathologic characteristics of somatotroph pituitary tumors are associated with patient's age, sex, hormonal results, tumor size, and the degree of extrasellar expansion. [ABSTRACT FROM AUTHOR]

Microcystic, elongated, and fragmented (MELF) pattern of invasion has seldom been documented in endocervical adenocarcinoma (EAC). The aim of this study was to analyze the clinicopathological characteristics of EAC showing MELF pattern. We collected the clinicopathological information of 10 cases of EAC with the MELF pattern and conducted polymer-based immunostaining for Ki-67 (dilution 1:200, clone MIB-1) on these cases. Ki-67 expression was assessed using the average estimation within the hotspot method. All tumors were human papillomavirus-associated EAC with Silva pattern C. All except one tumor exceeded 3 cm in size. Five tumors involved the entire thickness of the cervical stroma, and four tumors extended into the parametrium. Lymphovascular space invasion was identified in six cases. Two patients developed metastatic recurrences in the para-aortic lymph nodes and lungs, respectively. The MELF area showed significantly lower Ki-67 labelling index than that of a conventional tumor area. We confirmed our previous observation that the MELF area displayed lower proliferative activity than the conventional tumor area of EAC. We also demonstrated that patients with EAC showing MELF pattern had several adverse clinicopathological characteristics reflecting aggressive behavior. On the other hand, since the frequencies of post-operative recurrence and disease-related mortality that occurred during the follow-up period were relatively low, further investigations are warranted to clarify the prognostic value of MELF pattern in EAC patients. [ABSTRACT FROM AUTHOR]

Our study aims to reveal clinically helpful prognostic markers using quantitative radiologic data from perfusion magnetic resonance imaging for patients with locally advanced carcinoma, using the Ki-67 index as a surrogate. Patients who received a breast cancer diagnosis and had undergone dynamic contrast-enhanced magnetic resonance imaging of the breast for pretreatment evaluation and follow-up were searched retrospectively. We evaluated the MRI studies for perfusion parameters and various categories and compared them to the Ki-67 index. Axillary involvement was categorized as low (N0–N1) or high (N2–N3) according to clinical stage. A total sum of 60 patients' data was included in this study. Perfusion parameters and Ki-67 showed a significant correlation with the transfer constant (Ktrans) (ρ = 0.554 p = 0.00), reverse transfer constant (Kep) (ρ = 0.454 p = 0.00), and initial area under the gadolinium curve (IAUGC) (ρ = 0.619 p = 0.00). The IAUGC was also significantly different between axillary stage groups (Z = 2.478 p = 0.013). Outside of our primary hypothesis, associations between axillary stage and contrast enhancement (x2 = 8.023 p = 0.046) and filling patterns (x2 = 8.751 p = 0.013) were detected. In conclusion, these parameters are potential prognostic markers in patients with moderate Ki-67 indices, such as those in our study group. The relationship between axillary status and perfusion parameters also has the potential to determine patients who would benefit from limited axillary dissection. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer is the most common cancer in women; its early detection plays a crucial role in improving patient outcomes. Ki-67 is a biomarker commonly used for evaluating the proliferation of cancer cells in breast cancer patients. The quantification of Ki-67 has traditionally been performed by pathologists through a manual examination of tissue samples, which can be time-consuming and subject to inter- and intra-observer variability. In this study, we used a novel deep learning model to quantify Ki-67 in breast cancer in digital images prepared by a microscope-attached camera. Objective: To compare the automated detection of Ki-67 with the manual eyeball/hotspot method. Place and duration of study: This descriptive, cross-sectional study was conducted at the Jinnah Sindh Medical University. Glass slides of diagnosed cases of breast cancer were obtained from the Aga Khan University Hospital after receiving ethical approval. The duration of the study was one month. Methodology: We prepared 140 digital images stained with the Ki-67 antibody using a microscope-attached camera at 10×. An expert pathologist (P1) evaluated the Ki-67 index of the hotspot fields using the eyeball method. The images were uploaded to the DeepLiif software to detect the exact percentage of Ki-67 positive cells. SPSS version 24 was used for data analysis. Diagnostic accuracy was also calculated by other pathologists (P2, P3) and by AI using a Ki-67 cut-off score of 20 and taking P1 as the gold standard. Results: The manual and automated scoring methods showed a strong positive correlation as the kappa coefficient was significant. The p value was <0.001. The highest diagnostic accuracy, i.e., 95%, taking P1 as gold standard, was found for AI, compared to pathologists P2 and P3. Conclusions: Use of quantification-based deep learning models can make the work of pathologists easier and more reproducible. Our study is one of the earliest studies in this field. More studies with larger sample sizes are needed in future to develop a cohort. [ABSTRACT FROM AUTHOR]

Simple Summary: This review aims to shed light on the proliferative markers important in the everyday clinical management of colorectal cancer (CRC), ranging from simple methods of assessing cellular proliferation (e.g., DNA ploidy, BrdUrd/IdUrd/tritiated thymidine binding index) to the use of immunohistochemistry (IHC) and modern molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing) for the detection of genetic and epigenetic markers. Among the examined markers, the prognostic utility was demonstrated for aneuploidy and the overexpression of IHC markers (e.g., TS, cyclin B1, and D1, PCNA, and Ki-67). Classical genetic markers of prognostic significance mostly comprise mutations in commonly examined genes such as APC, KRAS/BRAF, TGF-β, and TP53. Chromosomal markers include CIN and MSI, while CIMP is indicated as a potential epigenetic marker with many other candidates such as SERP, p14, p16, LINE-1, and RASSF1A. Modern technology-based approaches to study non-coding fragments of the human genome have also yielded some candidates for CRC prognostic markers among the lncRNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and miRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b). With growing knowledge of the human genome structure and the rapid development of molecular biology techniques, it is hoped that a panel of reliable prognostic markers could improve the assessment of survival as well as allow for the better estimation of the treatment outcomes for CRC patients. Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and detection of several molecular biomarkers associated with this cancer. Nonetheless, non-invasive and effective prognostic and predictive testing in CRC patients remains challenging. Classical prognostic genetic markers comprise mutations in several genes (e.g., APC, KRAS/BRAF, TGF-β, and TP53). Furthermore, CIN and MSI serve as chromosomal markers, while epigenetic markers include CIMP and many other candidates such as SERP, p14, p16, LINE-1, and RASSF1A. The number of proliferation-related long non-coding RNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and microRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b) that could serve as potential CRC markers has also steadily increased in recent years. Among the immunohistochemical (IHC) proliferative markers, the prognostic value regarding the patients' overall survival (OS) or disease-free survival (DFS) has been confirmed for thymidylate synthase (TS), cyclin B1, cyclin D1, proliferating cell nuclear antigen (PCNA), and Ki-67. In most cases, the overexpression of these markers in tissues was related to worse OS and DFS. However, slowly proliferating cells should also be considered in CRC therapy (especially radiotherapy) as they could represent a reservoir from which cells are recruited to replenish the rapidly proliferating population in response to cell-damaging factors. Considering the above, the aim of this article is to review the most common proliferative markers assessed using various methods including IHC and selected molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing, next-generation sequencing) as prognostic and predictive markers in CRC. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare the diagnostic accuracy of the Ki-67 labeling index (LI) between endoscopic ultrasonography-fine-needle aspiration cytology/biopsy (EUS-FNAC/FNB) and surgical specimens of pancreatic neuroendocrine neoplasms (PanNENs). Methods: Conventional meta-analysis and diagnostic test accuracy (DTA) reviews were performed on 17 eligible studies. The DTA review involved calculating the sensitivity, specificity, diagnostic odds ratio (OR), and area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve. In addition, subgroup analysis was conducted based on EUS-FNAC and FNB, tumor grade, and tumor size. Results: The overall concordance rate of WHO grade based on Ki-67 LI between the EUS-FNAC/FNB and the surgical specimen was 0.767 (95% confidence interval (CI), 0.713–0.814). Concordance rates of the EUS-FNAC and EUS-FNB subgroups were 0.741 (95% CI, 0.681–0.794) and 0.839 (95% CI, 0.738–0.906), respectively. In the DTA review for grade 3, the sensitivity and specificity were calculated to be 0.786 (95% CI, 0.590–0.917) and 0.998 (95% CI, 0.987–1.000), respectively. The diagnostic OR and AUC of the SROC curve were 150.220 (95% CI, 46.145–489.000) and 0.983, respectively. The sensitivity and specificity were observed to be highest in the grade 1 and 3 subgroups, respectively. Conclusions: Higher concordance of tumor grade based on Ki-67 LI was observed between EUS-FNAC/FNB and surgical specimens, indicating the potential usefulness of Ki-67 LI in predicting PanNEN tumor grade in EUS-FNAC/FNB. [ABSTRACT FROM AUTHOR]

Introduction: The identification of bladder detrusor muscle invasion in urothelial cancer is essential for prognosis and management. We studied the clinical, histological, and immunohistochemical expression of p16, p53, and Ki-67 in urothelial detrusor muscle-invasive bladder cancer (MIBC) and urothelial non-detrusor muscle-invasive bladder cancer (NMIBC) in Egyptian patients. Methods: Sixty-two bladder urothelial cancer cases obtained through TURBT were included and divided into two groups: (MIBC, stage T2) and NMIBC (T1). Tissue blocks were recut and re-examined microscopically; then, the immunostaining of p16, p53, and Ki-67 was performed to compare both groups and evaluate the 13% cut-off for Ki-67, 20% for p53, and p16 intensity in various conditions aided by telepathology technology. Results and conclusion: Hematuria was the main clinical first presentation, with no significant difference between either group. The mean age was 61.6 years, with male predominance (52 males and 10 females). The absence of papillary histological pattern was associated with a higher stage, including detrusor muscle invasion (p = 0.000). The overall average percent of p53 immunostaining was 12.9%, revealing no significant difference between MIBC and NMIBC when a cut-off of 20% was implicated. The Ki-67 expression was correlated with higher grade and muscle invasion; however, no association was found with the other two markers' expression. The negative immunostaining of p16 was associated with low grade and NMIBC in the case of the preservation of the papillary pattern. We recommend further studies on the cut-off of widely used markers and more immunohistochemical and genetic studies on the p16(INK4A), taking into consideration the histological pattern of conventional carcinomas. [ABSTRACT FROM AUTHOR]

Glioblastoma is an aggressive brain tumor with an average life expectancy between 14 and 16 months after diagnosis. The Ki-67 labeling index (LI), a measure of cellular proliferation, is emerging as a prognostic marker in GBM. In this study, we investigated the ultrastructure of glioblastoma tissue from 9 patients with the same molecular profile (adult IDH wild-type glioblastoma, wild-type ATRX, and positive for TP53 expression, GFAP expression, and EGFR overexpression) to find possible ultrastructural features to be used as biomarkers and correlated with the only parameter that differs among our samples, the Ki-67 LI. Our main results were the visualization of the anatomical basis of astrocyte-endothelial cells crosstalk; the ultrastructural in situ imaging of clusters of hyperactivated microglia cells (MsEVs); the ultrastructural in situ imaging of microglia cells storing lipid vesicles (MsLVs); the ultrastructural in situ imaging of neoplastic cells mitophagy (NCsM). The statistical analysis of our data indicated that MsEVs and MsLVs correlate with the Ki-67 LI value. We can thus assume they are good candidates to be considered morphological biomarkers correlating to Ki-67 LI. The role of NCsM instead must be further evaluated. Our study findings demonstrate that by combining ultrastructural characteristics with molecular information, we can discover biomarkers that have the potential to enhance diagnostic precision, aid in treatment decision-making, identify targets for therapy, and enable personalized treatment plans tailored to each patient. However, further research with larger sample sizes is needed to validate these findings and fully utilize the potential of ultrastructural analysis in managing glioblastoma. [ABSTRACT FROM AUTHOR]

The occurrence of worsening pulmonary function has been connected to hypothyroidism (HPO). Hesperidin (HES) was suggested to have antioxidant, anti-proliferative, and anti-inflammatory potential. Our study's objective was to determine whether HES could reduce carbimazole (CBZ)-induced lung injury more effectively than Eltroxin (ELT) in adult male albino rats or not. At random, 32 rats were distributed into four groups: Group I: normal control, to induce HPO, the remaining three groups were given CBZ (20 mg/kg/day) dissolved in distilled water for 1 week. They were then split up into three groups. Group II: orally administered CBZ (20 mg/kg b.w in water/day), Group III: HES (200 mg/kg/day) dissolved in 1% carboxymethyl-cellulose + CBZ treated, and Group IV: ELT (0.045 mg/kg/day) dissolved in distilled water + CBZ treated. All treatments were delivered for 12 weeks. Blood was collected to assess thyroid-stimulating hormone (TSH) and thyroid hormones (THs). Lung injury was evaluated based on the pulmonary content of interleukin (IL)-35, IL-6, and tumor necrosis factor-alpha (TNF-α), along with the estimation of lipid peroxidation, catalase, glutathione levels, superoxide dismutase, heme oxygenase-1 (HO-1), and nuclear factor erythroid 2-related factor 2 (Nrf2). The histological, ultrastructural, and immunohistochemical study of nuclear factor Kappa-B (NF-κB) and inducible nitric oxide synthase (iNOS), together with estimating the proliferation of cells using Antigen Ki-67 in lung tissue were performed. HES and ELT primarily suppressed variable lung damage mechanisms by suppressing TSH, the NF-κB/TNF-α pathway, iNOS, lipid peroxidation, Ki-67, and inflammatory mediators. On the other hand, they improved THs, antioxidant parameters, and the Nrf2/HO-1 pathway. HES and ELT exhibited an ameliorative effect that was reflected in the histopathological, immunohistochemical, and ultrastructural results. These results indicate that HES is a pneumoprotective agent that could be a promising treatment for oxidative stress, inflammation, and proliferation. [ABSTRACT FROM AUTHOR]

Staphylococcal enterotoxin B (SEB) is a protein produced by Staphylococcus aureus, which is toxic to humans. It is well known for its ability to stimulate the exacerbated activation of proinflammatory CD4+ T cells (Th1 profile), and in vitro studies have been conducted to understand its mechanism of action and its potential use as an immune therapy. However, the efficiency of the SEB1741 aptamer in blocking SEB has not been experimentally demonstrated. Methods: Enrichment CD4+ T cells were stimulated with SEB, and as a blocker, we used the SEB1741 aptamer, which was previously synthesised by an "in silico" analysis, showing high affinity and specificity to SEB. The efficiency of the SEB1741 aptamer in blocking CD4+ T cell activation was compared with that of an anti-SEB monoclonal antibody. Flow cytometry and Bio-Plex were used to evaluate the T-cell function. Results: In vitro, SEB induced the activation of CD4+ T cells and favoured a Th1 profile; however, the SEB1741 aptamer was highly efficient in decreasing the frequency of CD4+ T cells positive to ki-67 and CD69 cells, this means that proliferation and activation of CD4+ T cells was decreased. Moreover, the production of interleukin 2 (IL-2) and interferon-gamma (IFN-γ) was affected, suggesting that the Th1 profile is not present when the SEB1441 aptamer is used. Thus, the SEB1741 function was similar to that of anti-SEB. Conclusions: The SEB1741 aptamer is a valuable tool for blocking CD4+ T cell activation and the subsequent release of proinflammatory cytokines by SEB stimulation. [ABSTRACT FROM AUTHOR]

The implementation of high-risk human papillomavirus testing (hrHPV testing) as a screening method in substitute for cytology has evoked the need for more sensitive and less objective tests for the triage of HPV-positive women. In a cohort of 1763 HPV-positive women, the potential of immunocytochemical p16 and Ki-67 dual staining as compared to cytology, alone or in combination with HPV partial genotyping, was tested for triage of women attending a cervical cancer screening program. Performance was measured using sensitivity, specificity, and positive and negative predictive values. Comparisons were assessed using logistic regression models and the McNemar test. Dual staining was evaluated in a prospectively collected study cohort of 1763 HPV-screened women. For triage of CIN2+ and CIN3+, NPV and sensitivity, 91.8% and 94.2% versus 87.9% and 89.7%, respectively, were significantly higher using dual staining together with HPV 16/18 positive, as compared to cytology (p < 0.001). The specificities, however, were lower for dual staining as compared to cytology. Conclusions: Dual staining is safer for decision-making regarding HPV-positive women's need for follow-up with colposcopy and biopsy, as compared to cytology. [ABSTRACT FROM AUTHOR]

Medicinal plants have been commonly associated with chemotherapeutic treatments, as an approach to reduce the toxicological risks of classical anticancer drugs. The objective of this study was to evaluate the effects of combining the antineoplastic drug 5-fluorouracil (5-FU) with Matricaria recutita flowers extract (MRFE) to treat mice transplanted with sarcoma 180. Tumor inhibition, body and visceral mass variation, biochemical, hematological, and histopathological parameters were evaluated. The isolated 5-FU, 5-FU+MRFE 100 mg/kg/day, and 5-FU+MRFE 200 mg/kg/day reduced tumor growth; however, 5-FU+MRFE 200 mg/kg/day showed a more significant tumor reduction when compared to 5-FU alone. These results corroborated with the analysis of the tumor histopathological and immunodetection of the Ki67 antigen. In the toxicological analysis of the association 5-FU+MRFE 200 mg/kg/day, an intense loss of body mass was observed, possibly as a result of diarrhea. In addition, spleen atrophy, with a reduction in white pulp, leukopenia and thrombocytopenia, was observed in the 5-FU groups alone and associated with MRFE 200 mg/kg/day; however, there was no statistical difference between these groups. Therefore, the MRFE 200 mg/kg/day did not interfere in myelosuppressive action of 5-FU. In hematological analysis, body and visceral mass variation and biochemical parameters related to renal (urea and creatinine) and cardiac (CK-MB) function, no alteration was observed. In biochemical parameters related to liver function enzymes, there was a reduction in aspartate transaminase (AST) values in the 5-FU groups alone and associated with MRFE 200 mg/kg/day; however, there was no statistical difference between these groups. Therefore, the MRFE 200 mg/kg/day does not appear to influence enzyme reduction. The results of this study suggest that the association between the 5-FU+MRFE 200 can positively interfere with the antitumor activity, promoting the antineoplastic-induced reduction in body mass, while minimizing the toxicity of chemotherapy. [ABSTRACT FROM AUTHOR]

Acral melanoma (AM) is the most common melanoma in non-Caucasian populations, yet it remains largely understudied. As AM lacks the UV-radiation mutational signatures that characterize other cutaneous melanomas, it is considered devoid of immunogenicity and is rarely included in clinical trials assessing novel immunotherapeutic regimes aiming to recover the antitumor function of immune cells. We studied a Mexican cohort of melanoma patients from the Mexican Institute of Social Security (IMSS) (n = 38) and found an overrepresentation of AM (73.9%). We developed a multiparametric immunofluorescence technique coupled with a machine learning image analysis to evaluate the presence of conventional type 1 dendritic cells (cDC1) and CD8 T cells in the stroma of melanoma, two of the most relevant immune cell types for antitumor responses. We observed that both cell types infiltrate AM at similar and even higher levels than other cutaneous melanomas. Both melanoma types harbored programmed cell death protein 1 (PD-1+) CD8 T cells and PD-1 ligand (PD-L1+) cDC1s. Despite this, CD8 T cells appeared to preserve their effector function and expanding capacity as they expressed interferon-γ (IFN-γ) and KI-67. The density of cDC1s and CD8 T cells significantly decreased in advanced stage III and IV melanomas, supporting these cells' capacity to control tumor progression. These data also argue that AM could respond to anti-PD-1-PD-L1 immunotherapy. [ABSTRACT FROM AUTHOR]

Type I gastric neuroendocrine neoplasms (gNENs) are associated with atrophic gastritis and have a high recurrence rate, which means frequent endoscopies are required. The objective of this study was to identify factors predicting the local recurrence of type I gNENs. The clinical course and the pathological and biochemical data of patients with type I gNENs treated at Bnai Zion Medical Center between 2006 and 2022 were analyzed retrospectively. Twenty-seven type I gNENs were evaluated. The follow-up period was 41 months (range: 11–288 months). Recurrence of the tumor occurred in 13/27 (48%) patients after 35 months (median (M), interquartile range (IQR): 21–67.5). Serum gastrin levels were significantly higher in patients with recurrent disease versus patients with non-recurrent disease (788 vs. 394 ng/L; p = 0.047), while the Ki-67 index was significantly lower in patients with recurrent disease versus patients with non-recurrent disease (1% vs. 3.5%; p = 0.035). Tumor size, mitotic count, and serum chromogranin A levels did not correlate with recurrence. The present study emphasizes the role of gastrin in the pathogenesis of gNEN recurrence and highlights the debate regarding the ability of the Ki-67 index to predict the clinical course of this disease. [ABSTRACT FROM AUTHOR]

Background: Knowledge about the occurrence of processes such as proliferation, apoptosis and angiogenesis in healthy lung tissues with different bronchial epitheliums is limited, and further exploration can contribute to a better understanding of the physiological renewal of lung tissues. The processes mentioned above occur with the help of important tissue factors; therefore, the aim of the study was to determine the expression of markers Ki-67, nestin, CD34 and vascular endothelial growth factor (VEFG) and detect apoptotic cells in relatively healthy lung tissue. Methods: Samples of relatively healthy lung tissue were obtained from 19 patients and divided into groups of patients with non-changed and patients with metaplastic bronchial epithelium. Tissue samples were examined by hematoxylin and eosin staining. Ki-67, nestin, VEGF and CD34-positive cells were detected by the immunohistochemistry method. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay was carried out to detect apoptotic cells. The number of positive structures was counted semi-quantitatively by microscopy. Results: Ki-67-positive cells were detected in only one case. An occasional to moderate number of nestin-positive structures was found in various tissues of relatively healthy lungs with different bronchial epitheliums. No apoptotic cells were seen in non-changed bronchial epithelium, compared with few apoptotic cells in metaplastic bronchial epithelium. Metaplastic bronchial epithelium contained more VEGF-positive cells than non-changed bronchial epithelium. Samples with non-changed, and metaplastic bronchial epithelium both contained a similar number of CD34-positive structures. Conclusions: Proliferative activity and programmed cell death are not prominent events in normal lung tissue. A moderate number of nestin-positive cells in the alveolar epithelium and cartilage of bronchi with pseudostratified ciliated epithelium suggests a significant role of neuronal origin cells in these structures, to be intensified in metaplastic bronchial epithelium. A practically non-changed number of CD34-positive cells excludes any difference in stimulation of endothelial origin cells between lungs with different types of epithelium, while an increase in VEGF in structures with metaplastic epithelium suggests the presence/influence of tissue ischemia impact on possible development/maintenance of metaplasia. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) is a key player in the treatment of head and neck cancer (HNC). The RT response, however, is variable and influenced by multiple tumoral and tumor microenvironmental factors, such as human papillomavirus (HPV) infections and hypoxia. To investigate the biological mechanisms behind these variable responses, preclinical models are crucial. Up till now, 2D clonogenic and in vivo assays have remained the gold standard, although the popularity of 3D models is rising. In this study, we investigate the use of 3D spheroid models as a preclinical tool for radiobiological research by comparing the RT response of two HPV-positive and two HPV-negative HNC spheroid models to the RT response of their corresponding 2D and in vivo models. We demonstrate that HPV-positive spheroids keep their higher intrinsic radiosensitivity when compared to HPV-negative spheroids. A good correlation is found in the RT response between HPV-positive SCC154 and HPV-negative CAL27 spheroids and their respective xenografts. In addition, 3D spheroids are able to capture the heterogeneity of RT responses within HPV-positive and HPV-negative models. Moreover, we demonstrate the potential use of 3D spheroids in the study of the mechanisms underlying these RT responses in a spatial manner by whole-mount Ki-67 and pimonidazole staining. Overall, our results show that 3D spheroids are a promising model to assess the RT response in HNC. [ABSTRACT FROM AUTHOR]

Object: This study aimed to explore the relationship between the aggressiveness and immune cell infiltration in pituitary adenoma (PA) and to provide the basis for immuno-targeting therapies. Methods: One hundred and three patients with PA who underwent surgery at a single institution were retrospectively identified. The infiltration of macrophages and T-lymphocytes was quantitatively assessed. Results: The number of CD68+ macrophages was positively correlated with Knosp (p = 0.003) and MMP-9 expression grades (p = 0.00). The infiltration of CD163+ macrophages differed among Knosp (p = 0.022) and MMP-9 grades (p = 0.04). CD8+ tumor-infiltrating lymphocytes (TILs) were also positively associated with Knosp (p = 0.002) and MMP-9 grades (p = 0.01). Interestingly, MGMT expression was positively correlated with MMP-9 staining extent (p = 0.000). The quantities of CD8+ TILs (p = 0.016), CD68+ macrophages (p = 0.000), and CD163+ macrophages (p = 0.043) were negatively associated with MGMT expression levels. The number of CD68+ macrophages in the PD-L1 negative group was significantly more than that in the PD-L1 positive group (p = 0.01). The rate of PD-L1 positivity was positively correlated with the Ki-67 index (p = 0.046) and p53 expression (p = 0.029). Conclusion: Targeted therapy for macrophages and CD8+ TILs could be a helpful treatment in the future for aggressive PA. Anti-PD-L1 therapy may better respond to PAs with higher Ki-67 and p53 expression and more infiltrating CD68+ macrophages. Multiple treatment modalities, especially combined with immunotherapy could become a novel therapeutic strategy for aggressive PA. [ABSTRACT FROM AUTHOR]

Breast Cancer (BC) is the most common cancer among women worldwide and is characterized by intra- and inter-tumor heterogeneity that strongly contributes towards its poor prognosis. The Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67 antigen are the most examined markers depicting BC heterogeneity and have been shown to have a strong impact on BC prognosis. Radiomics can noninvasively predict BC heterogeneity through the quantitative evaluation of medical images, such as Magnetic Resonance Imaging (MRI), which has become increasingly important in the detection and characterization of BC. However, the lack of comprehensive BC datasets in terms of molecular outcomes and MRI modalities, and the absence of a general methodology to build and compare feature selection approaches and predictive models, limit the routine use of radiomics in the BC clinical practice. In this work, a new radiomic approach based on a two-step feature selection process was proposed to build predictors for ER, PR, HER2, and Ki67 markers. An in-house dataset was used, containing 92 multiparametric MRIs of patients with histologically proven BC and all four relevant biomarkers available. Thousands of radiomic features were extracted from post-contrast and subtracted Dynamic Contrast-Enanched (DCE) MRI images, Apparent Diffusion Coefficient (ADC) maps, and T2-weighted (T2) images. The two-step feature selection approach was used to identify significant radiomic features properly and then to build the final prediction models. They showed remarkable results in terms of F1-score for all the biomarkers: 84%, 63%, 90%, and 72% for ER, HER2, Ki67, and PR, respectively. When possible, the models were validated on the TCGA/TCIA Breast Cancer dataset, returning promising results (F1-score = 88% for the ER+/ER− classification task). The developed approach efficiently characterized BC heterogeneity according to the examined molecular biomarkers. [ABSTRACT FROM AUTHOR]

Recently, a population of "immature" neurons generated prenatally, retaining immaturity for long periods and finally integrating in adult circuits has been described in the cerebral cortex. Moreover, comparative studies revealed differences in occurrence/rate of different forms of neurogenic plasticity across mammals, the "immature" neurons prevailing in gyrencephalic species. To extend experimentation from laboratory mice to large-brained mammals, including humans, it is important to detect cell markers of neurogenic plasticity in brain tissues obtained from different procedures (e.g., post-mortem/intraoperative specimens vs. intracardiac perfusion). This variability overlaps with species-specific differences in antigen distribution or antibody species specificity, making it difficult for proper comparison. In this work, we detect the presence of doublecortin and Ki67 antigen, markers for neuronal immaturity and cell division, in six mammals characterized by widely different brain size. We tested seven commercial antibodies in four selected brain regions known to host immature neurons (paleocortex, neocortex) and newly born neurons (hippocampus, subventricular zone). In selected human brains, we confirmed the specificity of DCX antibody by performing co-staining with fluorescent probe for DCX mRNA. Our results indicate that, in spite of various types of fixations, most differences were due to the use of different antibodies and the existence of real interspecies variation. [ABSTRACT FROM AUTHOR]

The clinical evolution of solitary fibrous tumors (SFTs) is often uncertain and several risk stratification systems (RSS) have been proposed. The Demicco et al. RSS is the most frequently implemented. In this study we aim to validate two alternative RSS (Sugita et al. and G-Score) using results for the Demicco RSS from a previous study of 97 SFTs. In addition, we aim to determine whether reclassified cases had any distinctive molecular features. As the Sugita et al. system substitutes mitotic count with Ki-67 index we also investigated whether Ki-67 results for tissue microarrays are comparable to those obtained using whole tissue sections. In the present study we detected that many cases classified by Demicco RSS as low-risk were reclassified as intermediate risk using the new system (G-score RSS). Kaplan-Meier survival plots for G-Score RSS showed that the low-risk and intermediate-risk SFTs had a similar evolution that contrasted with the more aggressive high-risk group. Moreover, the similar evolution in both low and intermediate-risk groups occurred despite the G-score system being stricter in classifying low-risk tumors. We observed that Sugita RSS does not provide any better risk stratification in comparison with the Demicco RSS, and testing both RSS in our series produced similar Kaplan-Meier survival data. We found some discordant results when comparing whole sections and the corresponding tissue microarrays samples, finding the hotspot areas easier to locate in whole sections. Forty-one SFTs with initial low-risk assigned by the Demicco RSS were reclassified as intermediate-risk by G-score finding both TP53 and HTER mutations in four cases, only HTER mutation in 11 cases, and only TP53 mutation in 2 cases. All six cases of SFT classified as high-risk by both the Demicco and G-score RSS suffered recurrence/metastasis, and half showed both TP53 and HTER mutations. Five SFTs were categorized as low-risk by both Demicco and G-score, of which 4 cases revealed HTER mutation. Regarding the outcome of these 5 patients, two were lost to follow-up, and one of the remaining three patients suffered recurrence. We believe that although the presence of both TP53 and HTER mutations may confer or be related to poor evolution, the isolated presence of HTER mutation alone would not necessarily be related to poor outcome. The G-score RSS more accurately identified low-risk patients than the other two risk models evaluated in the present series. Late recurrence/metastasis may occasionally be observed even in low-risk SFTs categorized by stricter classification systems such as the G-score RSS. These findings support the possibility that additional, as yet unknown factors may influence the clinical evolution of SFTs. In conclusion, given the possibility of late recurrence, long-term follow-up is recommended for all SFT patients, even in cases classified as low risk by the stricter G-score system. An integration of clinical, radiological, pathological, and molecular findings may improve SFT risk stratification and better predict patient outcome. [ABSTRACT FROM AUTHOR]

We aimed to investigate the association between the radiomic features of contrast-enhanced spectral mammography (CESM) images and a specific receptor pattern of breast neoplasms. In this single-center retrospective study, we selected patients with neoplastic breast lesions who underwent CESM before a biopsy and surgical assessment between January 2013 and February 2022. Radiomic analysis was performed on regions of interest selected from recombined CESM images. The association between the features and each evaluated endpoint (ER, PR, Ki-67, HER2+, triple negative, G2–G3 expressions) was investigated through univariate logistic regression. Among the significant and highly correlated radiomic features, we selected only the one most associated with the endpoint. From a group of 321 patients, we enrolled 205 malignant breast lesions. The median age at the exam was 50 years (interquartile range (IQR) 45–58). NGLDM_Contrast was the only feature that was positively associated with both ER and PR expression (p-values = 0.01). NGLDM_Coarseness was negatively associated with Ki-67 expression (p-value = 0.02). Five features SHAPE Volume(mL), SHAPE_Volume(vx), GLRLM_RLNU, NGLDM_Busyness and GLZLM_GLNU were all positively and significantly associated with HER2+; however, all of them were highly correlated. Radiomic features of CESM images could be helpful to predict particular molecular subtypes before a biopsy. [ABSTRACT FROM AUTHOR]

(1) Background: The aim of the current study is to evaluate the immunohistochemical expression of Ki-67, CD-56, Cyclin-D1 and E-Cadherin in the tissues samples of pituitary adenomas (PAs) and its association with PAs clinical manifestation tumor size, invasiveness and the risk of recurrence. (2) Materials and Methods: Ninety-four patients who underwent endoscope transsphenoidal excision of PAs were included in our study. The immunohistochemical expression of the Cyclin-D1, CD-56, E-Cadherin and Ki-67 markers was analyzed in paraffin-embedded tissue samples. (3) Results: The expression of Cyclin-D1 and Ki-67 index levels was positively correlated with the size (p < 0.001, r = 0.56 and p < 0.001, r = 0.43, respectively), the recurrence (p < 0.001, r = 0.46 and p = 0.007 r = 0.3, respectively), the extrasellar extension (p < 0.001, r = 0.48 and p < 0.001, r = 0.4, respectively) and the cavernous sinus invasion of (p < 0.001, r = 0.39 and p < 0.001, r = 0.3, respectively). No correlation was found between CD-56 and E-Cadherin expression with the size, the invasiveness and the recurrence of PAs. (4) Conclusion: Cyclin-D1 and Ki-67 are promising immunohistochemical markers in predicting the invasive behavior and recurrence of PAs in contrast to E-Cadherin and CD-56 which did not seem to be associated with PAs behavior post-surgery. However, larger studies are required in order to establish their role in the routine evaluation of PAs. [ABSTRACT FROM AUTHOR]

Citicoline, presumed to be involved in the dopaminergic pathway, might play a role as a candidate agent in controlling myopia. However, its study with respect to myopia is limited. The aim of this study is to demonstrate the effect of citicoline on the expression of MMP-2, TGF-β1, and Ki-67, and on the thickness of scleral tissue of a rat myopia model. Immunohistochemistry was performed to evaluate the expression of MMP-2, TGF-β1, and Ki-67 as the markers for fibroblast proliferation. Hematoxylin and eosin staining were used to evaluate scleral thickness. An electronic digital caliper was used to evaluate the axial length. The treatment group administered with 200 mg/kg BW/day had the lowest mean MMP-2 expression, axial elongation, and fibroblast proliferation, but it had the highest mean scleral thickness. The treatment group administered with 300 mg/kg BW/day had the highest mean TGF-β1 expression. Citicoline is able to decrease MMP-2 expression and fibroblast proliferation and increase TGF-β1 expression and scleral tissue thickness significantly in the scleral tissue of rat models for myopia. [ABSTRACT FROM AUTHOR]

This research aimed to investigate the relationships between the parameters of glutathione metabolism and the immunohistochemical characteristics of glial tumors. Postoperative material from 20 patients with gliomas of different grades of anaplasia was analyzed. Bioinformatic analysis of the interactions between the gliomas' immunohistochemical markers and their glutathione-dependent enzymes was carried out using the STRING, BioGrid, while Signor databases revealed interactions between such glioma markers as IDH and p53 and the glutathione exchange enzymes (glutathione peroxidase, glutathione reductase, glutathione S-transferase). The most pronounced relationship with glutathione metabolism was demonstrated by the level of the nuclear protein Ki67 as a marker of proliferative activity, and the presence of the IDH1 mutation as one of the key genetic events of gliomagenesis. The glutathione system is an active participant in the body's antioxidant defense, involving the p53 markers and MGMT promoter methylation. It allows characterization of the gliomal cells' status at different stages of tumor development. [ABSTRACT FROM AUTHOR]

CD44 is the most frequently reported marker of the cancer stem cells in renal cell carcinoma (RCC). Matrix metalloproteinases MMP-2 and MMP-9 are key regulators of tumor invasion and metastasis. The aim of this study was to investigate the clinicopathologic and prognostic values of the immunohistochemical expression of CD44, MMP2, MMP9, and Ki-67 in papillary and chromophobe RCCs. In the case of papillary RCC, MMP-2 expression was positively correlated with patient age (p < 0.05), while CD44 expression was positively correlated with tumor stage (τ = 0.26, p < 0.05). Moreover, CD44 expression positively correlated with MMP-9 (τ = 0.39, p < 0.05). In the case of chromophobe RCC, only Ki-67 expression was negatively correlated with tumor stage (τ = −0.44, p < 0.05). During follow-up, a death was documented in 6 patients with papillary RCC. In these patients, CD44 expression was not a significant factor affecting the overall survival of patients (p > 0.05), whereas there was a positive correlation between increased MMP-9 expression and shorter overall survival (p < 0.05). Taken together, carcinogenesis in papillary RCC is probably dependent on both cancer stem cells and metalloproteinases activity. Expression of CD44 and MMP-9 can significantly improve the prediction of papillary RCC prognosis in the future. [ABSTRACT FROM AUTHOR]

Podoplanin and Ki-67 are two important markers of cancer progression. The aim of this study is to evaluate double immunostaining for Ki-67 and podoplanin in head and neck squamous cell carcinoma (HNSCC), and to observe the involvement of lymphagiogenesis in tumoral and peritumoral areas, as well as the density of tumor proliferation correlated with histopathological grading. A total of 50 patients with HNSCC were included in this study. We carried out a morphological evaluation of tissue samples, after that, cases were selected for double Ki-67 and podoplanin immunostaining. Podoplanin expression was significantly correlated with histopathological grade (p < 0.05; p = 0.037) and expression of Ki-67 (p < 0.05; p = 0.050). A high expression of podoplanin, as well as of the proliferation factor Ki-67, was observed in histopathological grade G3 and the correlation between these (p < 0.05; p = 0.028), and implication of LMVD and LVI was not significant (LMVD p = 0.577; LVI p = 0.976). This study demonstrated the importance of double immunolabeling in assessing lymphagiogenesis and tumor proliferation in correlation with histopathological grades in HNSCC. [ABSTRACT FROM AUTHOR]

Objectives: Histopathological tumor grade and Ki-67 expression level are key aspects concerning the prognosis of patients with hepatocellular carcinoma (HCC) lesions. The aim of this study was to investigate whether the radiomics model derived from Sonazoid contrast-enhanced (S-CEUS) images could predict histological grades and Ki-67 expression of HCC lesions. Methods: This prospective study included 101 (training cohort: n = 71; validation cohort: n = 30) patients with surgical resection and histopathologically confirmed HCC lesions. Radiomics features were extracted from the B mode and Kupffer phase of S-CEUS images. Maximum relevance minimum redundancy (MRMR) and least absolute shrinkage and selection operator (LASSO) were used for feature selection, and a stepwise multivariate logit regression model was trained for prediction. Model accuracy, sensitivity, and specificity in both training and testing datasets were used to evaluate performance. Results: The prediction model derived from Kupffer phase images (CE-model) displayed a significantly better performance in the prediction of stage III HCC patients, with an area under the receiver operating characteristic curve (AUROC) of 0.908 in the training dataset and 0.792 in the testing set. The CE-model demonstrated generalizability in identifying HCC patients with elevated Ki-67 expression (>10%) with a training AUROC of 0.873 and testing AUROC of 0.768, with noticeably higher specificity of 92.3% and 80.0% in training and testing datasets, respectively. Conclusions: The radiomics model constructed from the Kupffer phase of S-CEUS images has the potential for predicting Ki-67 expression and histological stages in patients with HCC. [ABSTRACT FROM AUTHOR]

Objective: The Ki-67 index is an indicator of the active proliferation and aggressive behavior of pituitary adenomas (PAs). Appropriate pre- and intra-operatives of the Ki-67 index can help surgeons develop better and more personalized treatment strategies for patients with PAs. This study aimed to investigate the influence factors for predicting the Ki-67 index in PAs. Methods: Data of 178 patients with PAs confirmed by pathology were retrospectively analyzed. According to the Ki-67 index, the patients were divided into the Ki-67 < 3% and Ki-67 ≥ 3% cohorts. Patient data, including age, sex, postoperative immunohistochemical pituitary hormone positive index, Knosp grade, tumor breaking through the sellar floor, rich blood supply to the tumor, tumor located inside the sella, erosion of the dorsum sellae bone, and pituitary-specific transcription factor, were collected. A univariate logistic analysis was used to evaluate the influence factors for a high Ki-67 index. Multiple regression and receiver operating characteristic (ROC) curve were used to analyze the factors with p < 0.05. The mutant status of Ki-67 index was predicted by nomogram. Results: Multivariate regression analysis showed that rich blood supply to the tumor and erosion of the dorsum sellae bone were independent risk factors for the Ki-67 proliferation index. The ROC curves demonstrated that age, rich blood supply to the tumor, and erosion of the dorsum sellae bone can predict the occurrence of a high Ki-67 index. Together, the three risk factors provide a stronger ability to predict the Ki-67 index. The nomogram was developed and validated. Conclusion: Age, rich blood supply to the tumor, and erosion of the dorsum sellae bone are influencing factors for predicting the Ki-67 index. Suitable nomogram prediction models were developed and validated, and there is potential for personalized treatment for PA patients. [ABSTRACT FROM AUTHOR]

Introduction: Studies have shown that the Ki-67 index is a valuable biomarker for the diagnosis, and classification of gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). We re-evaluated the expression of Ki-67 based on the intensity of the stain, basing our hypothesis on the fact that the Ki-67 protein is continuously degraded. Background: The aim was to evaluate whether a new scoring method would be more effective in classifying NETs by reducing staining heterogeneity. Methods: Patients with GEP-NET (n = 87) were analyzed. The classification difference between the two methods was determined. Results: The classification changed significantly when the Ki-67 semiquantal index was used. The percentage of G1 patients increased from 18.4% to 60.9%, while the G2 patients decreased from 66.7% to 29.9% and the G3 patients also decreased from 14.9% to 9.2%. Moreover, it was found that the traditional Ki-67 was not significantly related to the overall survival (OS), whereas the semiquantal Ki-67 was significantly related to the OS. Conclusions: The new quantification was a better predictor of OS and of tumor classification. Therefore, it could be used both as a marker of proliferation and as a tool to map tumor dynamics that can influence the diagnosis and guide the choice of therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Feline mammary neoplasias are highly prevalent in domestic cats and present many similarities to their human counterparts. Since information about benign feline mammary lesions is still scarce and often controversial, studies using a wider panel of oncological biomarkers are necessary to understand their potential contribution to malignant lesions. This study analyzed 47 benign lesions from 27 queens, regarding the expression of estrogen and progesterone receptors (ER and PR, respectively), fHER2 protein and two malignancy indicators (Ki-67 and CK 5/6). Our results showed that most of the lesions were ER positive (91.5%), PR negative (63.8%), fHER2 negative (64.4%), Ck 5/6 negative (76.6%) and with a low Ki-67 index (78.7%). Additionally, significant correlations were found between younger ages and ER positivity and between larger lesions and negative PR status. Our results highlight the importance of estrogen receptors in the development of benign feline mammary lesions, further contributing to the development of preventive and monitoring strategies in feline mammary oncology. Biomarkers are essential in the characterization of neoplastic lesions and aid not only in the classification of the nature of the lesions, but also in the understanding of their ontogeny, development and prognosis. In cats, while mammary carcinomas are increasingly being characterized, information on their benign lesions is still scarce. Indeed, a better characterization of benign lesions could have an important role in unravelling mammary oncogenesis, similar to that in human breast cancer. Thus, in this study, the expression of five markers was analyzed in 47 benign mammary lesions (hyperplasia, dysplasia and benign tumors) collected from 27 queens. Dysplastic and hyperplastic lesions were the most common (41/47, 81.7%). Most of the lesions were classified as ER positive (43/47, 91.5%), PR negative (30/47, 63.8%), fHER2 negative (29/47, 64.4%), CK 5/6 negative (36/47, 76.6%) and with a low Ki-67 index (37/47, 78.7%). Statistical analysis revealed a correlation between younger ages and ER positivity (p = 0.013) and between larger lesions and negative PR status (p = 0.038). These results reinforce the importance of evaluating the expression of the ER status, prevalent in benign lesions, as a putative precursor in cancer progression. [ABSTRACT FROM AUTHOR]

Oncocytic adrenal cortical neoplasms are rare cases and are divided into oncocytoma, oncocytic neoplasms of uncertain malignant potential and oncocytic adrenal cortical carcinomas, based on the Lin–Weiss–Bisceglia (LWB) histological system adopted in the current World Health Organization (WHO). We reported a 42-year-old female diagnosed with an oncocytic neoplasm of uncertain malignant potential initially, which turned out to be a carcinoma owing to distant metastasis to the scalp and lung. To our knowledge, this is the first published case of oncocytic adrenal cortical carcinoma with scalp metastasis. This case also highlights the limitation of the current diagnostic algorithm and emphasizes the importance of two parameters (PHH3 and Ki-67) for determining the malignant potential of oncocytic adrenal cortical neoplasms. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the relationship between tumor blood flow (TBF) measured by the pseudo-continuous arterial spin labeling (PCASL) method and IDH1 mutation status of gliomas as well as Ki-67 proliferative index. Methods. The study included 116 patients with newly diagnosed gliomas of various grades. They received no chemotherapy or radiotherapy before MRI. IDH1 status assessment was performed after tumor removal in 106 cases—48 patients were diagnosed with wildtype gliomas (Grade 1–2—6 patients, Grade 3–4—42 patients) and 58 patients were diagnosed with mutant forms of gliomas (Grade 1–2—28 patients, Grade 3–4—30 patients). In 64 cases out of 116 Ki-67 index was measured. Absolute and normalized tumor blood flow values were measured on 3D PCASL maps. Results. TBF and normalized TBF (nTBF) in wildtype gliomas were significantly higher than in IDH1-mutant gliomas (p < 0.001). ASL perfusion showed high values of sensitivity and specificity in the differential diagnosis of gliomas with distinct IDH1 status (for TBF: specificity 75%, sensitivity 77.6%, AUC 0.783, cutoff 80.57 mL/100 g/min, for nTBF: specificity 77.1%, sensitivity 79.3%, AUC 0.791, cutoff 4.7). TBF and nTBF in wildtype high-grade gliomas (HGG) were significantly higher than in mutant forms (p < 0.001). ASL perfusion showed the following values of sensitivity and specificity in the diagnosis of mutant HGG and wildtype HGG (for TBF: specificity 83.3%, sensitivity 60%, AUC 0.719, cutoff 84.18 mL/100 g/min, for nTBF: specificity 88.1%, sensitivity 60%, AUC 0.729, cutoff 4.7). There was a significant positive correlation between tumor blood flow and Ki-67 (for TBF Rs = 0.63, for nTBF Rs = 0.61). Conclusion. ASL perfusion may be an informative factor in determining the IDH1 status in brain gliomas preoperative and tumor proliferative activity. [ABSTRACT FROM AUTHOR]

Lung cancers are broadly divided into two categories: non-small-cell lung carcinoma (NSCLC), which accounts for 80–85% of all cancer cases, and small-cell lung carcinoma (SCLC), which covers the remaining 10–15%. Recent advances in cancer biology and genomics research have allowed an in-depth characterization of lung cancers that have revealed new therapy targets (EGFR, ALK, ROS, and KRAS mutations) and have the potential of revealing even more biomarkers for diagnostic, prognostic, and targeted therapies. A new source of biomarkers is represented by non-coding RNAs, especially microRNAs (miRNAs). MiRNAs are short non-coding RNA sequences that have essential regulatory roles in multiple cancers. Therefore, we aim to investigate the tumor microenvironment (TME) and miRNA tumor profile in a subset of 51 early-stage lung cancer samples (T1 and T2) to better understand early tumor and TME organization and molecular dysregulation. We analyzed the immunohistochemistry expression of CD4 and CD8 as markers of the main TME immune populations, E-cadherin to evaluate early-stage epithelial-to-mesenchymal transition (EMT), and p53, the main altered tumor suppressor gene in lung cancer. Starting from these 4 markers, we identified and validated 4 miRNAs that target TP53 and regulate EMT that can be further investigated as potential early-stage lung cancer biomarkers. [ABSTRACT FROM AUTHOR]

Background: [18F]FDG and [11C]methionine accumulate in lymph nodes draining S. aureus -infected foci. The lymph nodes were characterized by weight, [11C]methionine- and [18F]FDG-positron emissions tomography (PET)/computed tomography (CT), and immunohistochemical (IHC)-staining. Methods: 20 pigs inoculated with S. aureus into the right femoral artery were PET/CT-scanned with [18F]FDG, and nine of the pigs were additionally scanned with [11C]methionine. Mammary, medial iliac, and popliteal lymph nodes from the left and right hind limbs were weighed. IHC-staining for calculations of area fractions of Ki-67, L1, and IL-8 positive cells was done in mammary and popliteal lymph nodes from the nine pigs. Results: The pigs developed one to six osteomyelitis foci. Some pigs developed contiguous infections of peri-osseous tissue and inoculation-site abscesses. Weights of mammary and medial iliac lymph nodes and their [18F]FDG maximum Standardized Uptake Values (SUVFDGmax) showed a significant increase in the inoculated limb compared to the left limb. Popliteal lymph node weight and their FDG uptake did not differ significantly between hind limbs. Area fractions of Ki-67 and IL-8 in the right mammary lymph nodes and SUVMetmax in the right popliteal lymph nodes were significantly increased compared with the left side. Conclusion: The PET-tracers [18F]FDG and [11C]methionine, and the IHC- markers Ki-67 and IL-8, but not L1, showed increased values in lymph nodes draining soft tissues infected with S. aureus. The increase in [11C]methionine may indicate a more acute lymph node response, whereas an increase in [18F]FDG may indicate a more chronic response. [ABSTRACT FROM AUTHOR]

The meta-analysis aimed to compare the preoperative apparent diffusion coefficient (ADC) values between low-grade meningiomas (LGMs) and high-grade meningiomas (HGMs). Medline, Cochrane, Scopus, and Embase databases were screened up to January 2022 for studies investigating the ADC values of meningiomas. The study endpoint was the reported ADC values for LGMs and HGMs. Further subgroup analyses between 1.5T and 3T MRI scanners, ADC threshold values, ADC in different histological LGMs, and correlation coefficients (r) between ADC and Ki-67 were also performed. The quality of studies was evaluated by the quality assessment of diagnostic accuracy studies (QUADAS-2). A χ2-based test of homogeneity was performed using Cochran's Q statistic and inconsistency index (I2). Twenty-five studies with a total of 1552 meningiomas (1102 LGMs and 450 HGMs) were included. The mean ADC values (×10−3 mm2/s) were 0.92 and 0.79 for LGMs and HGMs, respectively. Compared with LGMs, significantly lower mean ADC values for HGMs were observed with a pooled difference of 0.13 (p < 0.00001). The results were consistent in both 1.5T and 3T MRI scanners. For ADC threshold values, pooled sensitivity of 69%, specificity of 82%, and AUC of 0.84 are obtained for differentiation between LGMs and HGMs. The mean ADC (×10−3 mm2/s) in different histological LGMs ranged from 0.87 to 1.22. Correlation coefficients (r) of mean ADC and Ki-67 ranged from −0.29 to −0.61. Preoperative ADC values are a useful tool for differentiating between LGMs and HGMs. Results of this study provide valuable information for planning treatments in meningiomas. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and prognostic information is essential in finding the right treatment. This study evaluated the prognostic significance of Ki-67 in patients with DLBCL. Methods: Patients with DLBCL, treated with first-line R-CHOP, were retrospectively analyzed in groups of high (>70%) and low (≤70%) Ki-67. Parameters of interest were the international prognostic index (IPI), treatment response, progression-free survival (PFS) and overall survival (OS). A chi-squared test or Fisher's exact test was conducted to analyze categorical variables. Kaplan-Meier and log-rank tests were applied for survival analyses. Finally, a multivariate linear regression analysis was performed, including gender, Ki-67 ≤ 70% or >70%, IPI and presence of B symptoms. Results: Overall, 58 patients were included. No significant association was found between Ki-67 status and IPI (p = 0.148) or treatment response (p = 0.373). Survival in patients with high Ki-67 was significantly inferior with respect to OS (p = 0.047) but not PFS (p = 0.138). Multivariate linear regression, however, yielded only IPI as a risk factor for OS. Conclusion: Future studies with larger patient cohorts are needed in order to elucidate the prognostic role of Ki-67 in patients with DLBCL treated with R-CHOP. [ABSTRACT FROM AUTHOR]

Modulated electro-hyperthermia (mEHT) is an adjuvant cancer therapy that enables tumor-selective heating (+2.5 °C). In this study, we investigated whether mEHT accelerates the tumor-specific delivery of doxorubicin (DOX) from lyso-thermosensitive liposomal doxorubicin (LTLD) and improves its anticancer efficacy in mice bearing a triple-negative breast cancer cell line (4T1). The 4T1 cells were orthotopically injected into Balb/C mice, and mEHT was performed on days 9, 12, and 15 after the implantation. DOX, LTLD, or PEGylated liposomal DOX (PLD) were administered for comparison. The tumor size and DOX accumulation in the tumor were measured. The cleaved caspase-3 (cC3) and cell proliferation were evaluated by cC3 or Ki67 immunohistochemistry and Western blot. The LTLD+mEHT combination was more effective at inhibiting tumor growth than the free DOX and PLD, demonstrated by reductions in both the tumor volume and tumor weight. LTLD+mEHT resulted in the highest DOX accumulation in the tumor one hour after treatment. Tumor cell damage was associated with cC3 in the damaged area, and with a reduction in Ki67 in the living area. These changes were significantly the strongest in the LTLD+mEHT-treated tumors. The body weight loss was similar in all mice treated with any DOX formulation, suggesting no difference in toxicity. In conclusion, LTLD combined with mEHT represents a novel approach for DOX delivery into cancer tissue.

Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC); the inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1β and IL-1RA in invasive BC and to evaluate their interaction with AKT signaling and proliferation. The study included two independent cohorts of n = 92 and n = 102 patients who underwent a radical cystectomy for BC. Specimen from BC and benign urothelium (n = 22 and n = 39) were processed to a tissue microarray and immunohistochemically stained for IL-1β, IL-1RA, AKT, and Ki-67. Expression scores were correlated to clinical variables and Ki-67 and AKT expression. An association with outcome was assessed using Wilcoxon Kruskal-Wallis tests, Chi-square tests or linear regression, dependent on the variable's category. Kaplan-Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Both IL-1β and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts ( p < 0.005). IL-1β was associated with vascular invasion (210 vs. 183, p < 0.02), lymphatic invasion (210 vs. 180, <0.05) and G3 cancer (192 vs. 188, <0.04). The survival analysis revealed favorable RFS, CSS, and OS in the case of high IL-1β expression ( p < 0.02, <0.03, and <0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1β expression on RFS, CSS, and OS. The IL-1β and IL-1β/IL-1RA ratios were positively correlated to the AKT expression ( p < 0.05 and <0.01, respectively). Additionally, the high expression of Ki-67 (>15%) correlated with higher levels of IL-1β ( p = 0.01). The overexpression of IL-1β and IL-1RA is frequently found in BC, with a prognostic significance observed for the IL-1β protein expression. The observed link between the IL-1β/IL-1RA axis and AKT signaling may indicate possible autophagy activation processes besides the known tumor-promoting effects of AKT.

Tyrosine kinase inhibitors (TKIs) may be combined with radiation therapy (RT) to enhance tumor control; however, increased incidences of gastrointestinal (GI) toxicity have been reported with this combination. We hypothesize that toxicity is due to compromised intestinal healing caused by inhibition of vascular repair and proliferation pathways. This study explores underlying tissue toxicity associated with abdominal RT and concurrent sunitinib in a mouse model. Four groups of CD-1 mice were treated with 12 Gy abdominal RT, oral sunitinib, abdominal RT + sunitinib, or sham treatment. Mice received oral sunitinib or the vehicle via gavage for 14 days. On day 7, mice were irradiated with 12 Gy abdominal RT or sham treated. Mice were euthanized on day 14 and intestinal tract was harvested for semiquantitative histopathologic evaluation and immunohistochemical quantification of proliferation (Ki67) and vascular density (CD31). Non-irradiated groups had stable weights while abdominal irradiation resulted in weight loss, with mice receiving RT + SUN having greater weight loss than mice receiving RT alone. Semiquantitative analysis showed significant increases in inflammation in irradiated groups. The difference in the density of CD31+ cells was significantly increased in RT alone compared to SUN alone. Ki67+ density was not significant. In summary, we identify a lack of angiogenic response in irradiated GI tissues when abdominal RT is combined with a TKI, which may correlate with clinical toxicities seen in canine and human patients receiving combined treatment.

Development of new techniques for multimodal treatment and diagnostics of various neoplasms and the improvement of current techniques can significantly increase the life expectancy of patients with carcinomas of the colon and abdominal-cavity organs, since prevention of various side effects of radiation therapy is one of the main problems of oncological care. Electron irradiation is one of the most promising types of radiation therapy. There are no data on proliferation and apoptosis of the colon epithelium after irradiation with electrons, especially in different modes (single and summary). Morphological evaluation of apoptosis and proliferation of colonic epithelium after local irradiation with electrons were conducted at doses of 2 Gy (Gray) and 25 Gy. Colon fragments from sexually mature Wistar rats ( n = 50, body weight 200 ± 10 g) were divided into three groups: I-control ( n = 10); II-experimental group ( n = 20; local single electron irradiation at a dose of 2 Gy); III-experimental group ( n = 30) with local fractional irradiation with electrons at a total dose of 25 Gy. They were studied using light microscopy using hematoxylin and eosin staining and immunohistochemical reactions with antibodies to Ki-67 and caspase-3 (Cas3). Morphological disorders were accompanied by increased expression of pro-apoptotic molecules (caspase-3), and the period of regeneration by proliferative marker (Ki-67). Colon electron irradiation led to disturbances in the histoarchitecture of varying severity, and an increase in cell apoptosis was observed (increased expression of caspase-3 and decrease in Ki-67). In addition, modulation of the PI3K/AKT and MAPK/ERK signalling pathways was detected. The most pronounced destructive changes were observed in the group of 25 Gy fractionated electron irradiation.

Background and Objectives: To investigate histopathological changes and serous carcinoma precursors such as secretory cell outgrowths (SCOUTs) and p53 signature in the bilateral tubal ligation (BTL) materials used during cesarean section (S/C). Materials and Methods : In total, 138 patients underwent S/C and tubal sterilization (TS) between October 2020 and May 2021 at Konya City Hospital. Patients' data were obtained from the hospital's system. All data and findings were investigated and statistically evaluated. Results: The mean age was 34.62 years (22-44), the mean gravity was 4.89 (2-15) and the mean parity was 3.46 (1-10). In total, 5.79% SCOUT, 7.24% atypia and 9.42% p53 signatures were observed. Significant correlations were shown between the epithelial cell lineage and age between Ki-67, SCOUT, and gravity; between the Ki-67 results and gravity and parity; and between the p53 score and age. Conclusions : TS is a common, safe, and effective method worldwide. Today, BTL is increasing along with increasing S/C ratios. In addition to the reduced risk of ovarian cancers with ligation alone, precursor lesions such as hyperplasia, SCOUT, p53 signature, and STIL/Serous tubal intraepithelial carcinoma (STIC) are encountered in the ampulla materials obtained. Considering the low rates of re-anastomosis, tubal excision may be recommended instead of ligation in women of relatively higher gravity and age.