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Objectives: This study aimed to analyze the clinicoradiologic features and Ki-67 proliferation indices between the histopathologic variants of ameloblastomas (ABs) for possible associations., Study Design: The diagnosis and histopathologic variant were confirmed for all cases by experienced Oral and Maxillofacial Pathologists. Immunohistochemistry for Ki-67 was performed on the most representative formalin-fixed paraffin-embedded tissue block. Demographic, clinical data and radiologic features were analyzed from patient records and available radiographic examinations. The investigators were blinded to the histopathologic variant and proliferation index when the clinicoradiologic features were assessed., Results: The current study included 116 cases of AB in the final sample. The indolent behavior of the unicystic variant was supported by their low proliferation index and slow growth paired with low frequencies of cortical destruction, loss of teeth, root resorption, and encroachment on anatomical structures. In contrast, the comparatively high proliferation index of the plexiform variant correlated with their fast growth and pain. Furthermore, high radiologic frequencies of cortical destruction, loss of teeth, and encroachment of surrounding anatomical structures supported their more aggressive clinical course., Conclusion: Statistically significant differences were noted between certain variants and Ki-67, location, borders, locularity, and cortical destruction, providing better insight into their biological behavior., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The addition of p16/Ki-67 dual immunostaining to human papilloma virus (HPV) screening tests has been shown to increase the detection rate of high-grade cervical intraepithelial neoplasia. Thus, the aim of this study was to evaluate the accuracy of p16/Ki67 dual staining in the detection of cervical intraepithelial neoplasia 2 (CIN2+) in women with high-risk HPV infection., Materials and Methods: A cross-sectional study was conducted between August 2017 and August 2019 at the Chulabhorn Hospital in Bangkok, Thailand. Women aged 20-70 years who underwent co-testing and tested positive for high-risk (HR) HPV (N = 215) were invited to participate in the study. P16/Ki67 testing was performed on residual cytological materials. Colposcopic biopsies were performed on all patients, and the results were correlated with positive or negative p16/Ki-67 test results., Results: The sensitivity and specificity of p16/Ki-67 dual staining in the detection of CIN2+ in the women with HR HPV infection were 74.4 % and 63.4 %, respectively. Compared with liquid-based cytology (LBC), p16/Ki67 cytology had similar sensitivity (p = 1.000) and specificity (p = 0.561) to LBC for detecting CIN2+., Conclusion: In this study, p16/Ki67 dual staining in HPV triage demonstrated a test performance similar to that of LBC., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest regarding the publication of this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Sacituzumab govitecan (SG), a novel antibody-drug conjugate (ADC) targeting TROP2, is approved for pre-treated metastatic triple-negative breast cancer (mTNBC). We conducted an investigator-initiated clinical trial evaluating neoadjuvant (NA) SG (NCT04230109), and report primary results., Patients and Methods: Participants with early-stage TNBC received NA SG for four cycles. The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) to SG. Secondary objectives included overall response rate (ORR), safety, event-free survival (EFS), and predictive biomarkers. A response-guided approach was utilized, and subsequent systemic therapy decisions were at the discretion of the treating physician., Results: From July 2020 to August 2021, 50 participants were enrolled (median age = 48.5 years; 13 clinical stage I disease, 26 stage II, 11 stage III). Forty-nine (98%) completed four cycles of SG. Overall, the pCR rate with SG alone was 30% [n = 15, 95% confidence interval (CI) 18% to 45%]. The ORR per RECIST V1.1 after SG alone was 64% (n = 32/50, 95% CI 77% to 98%). Higher Ki-67 and tumor-infiltrating lymphocytes (TILs) were predictive of pCR to SG (P = 0.007 for Ki-67 and 0.002 for TILs), while baseline TROP2 expression was not (P = 0.440). Common adverse events were nausea (82%), fatigue (76%), alopecia (76%), neutropenia (44%), and rash (48%). With a median follow-up time of 18.9 months (95% CI 16.3-21.9 months), the 2-year EFS for all participants was 95%. Among participants with a pCR with SG (n = 15), the 2-year EFS was 100%., Conclusions: In the first NA trial with an ADC in localized TNBC, SG demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed., Competing Interests: Disclosure LMS: consulting or advisory role—Avrobio; Novartis; Puma Biotechnology; research funding—Merck (Inst); Philips Healthcare (Inst). SMT: consulting or advisory role—4D Pharma, AstraZeneca, Athenex, BeyondSpring Pharmaceuticals, Blueprint Medicines, Bristol-Myers Squibb, Certara Inc., Chugai Pharma, CytomX Therapeutics, Daiichi Sankyo, Eisai, Ellipses Pharma, G1 Therapeutics, Genentech, Immunomedics/Gilead, Infinity Pharmaceuticals, Kyowa Hakko Kirin, Lilly, Merck, Mersana, NanoString Technologies, Nektar, Novartis, Odonate Therapeutics, OncoPep, OncoSec, OncXerna Therapeutics, Paxman, Pfizer, Puma Biotechnology, Reveal Genomics, Samsung Bioepis, Sanofi, Seagen, Zentalis, Zymeworks; research funding—AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Cyclacel (Inst), Eisai (Inst), Exelixis (Inst), Genentech/Roche (Inst), Immunomedics (Inst), Lilly (Inst), Merck (Inst), NanoString Technologies (Inst), Nektar (Inst), Novartis (Inst), Odonate Therapeutics (Inst), Pfizer (Inst), Sanofi (Inst), Seagen (Inst). LT: consulting or advisory role—Galera Therapeutics; research funding—Candel Therapeutics (Inst); AC: consulting or advisory role—Advance Medical, Applied Genetic Technologies Corporation (I), Beam Therapeutics (I), Biogen (I), Blue Cross Blue Shield Association (I), Crico, Editas Medicine (I), GenSight Biologics (I), Harvard Medical School, infiniteMD (I), Sanofi (I), Vedere Bio (I), WAVE Life Sciences (I). TM: consulting or advisory role—Outcomes4Me. ACG-C: research funding—AstraZeneca/MedImmune (Inst), Gilead Sciences (Inst), Merck (Inst). FL: consulting or advisory role—AmerisourceBergen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo/Astra Zeneca, OncoSec; research funding—AstraZeneca/Daiichi Sankyo (Inst), Bristol-Myers Squibb, CytomX Therapeutics (Inst), Immunomedics (Inst), Inivata (Inst). BM: consulting or advisory role—MOTUS (I); research funding—Puma Biotechnology (Inst); SJI: employment—Merus (I); consulting or advisory role—Novartis, Paxman, Puma Biotechnology, Seagen; research funding—Abbvie (Inst), AstraZeneca/MedImmune (Inst), Genentech (Inst), Merck (Inst), OncoPep (Inst), Outcomes4Me (Inst). NT: consulting or advisory role—AstraZeneca; research funding—AstraZeneca (Inst); EAM: honoraria—Physicans' Education Resource; consulting or advisory role—Exact Sciences, Merck, Roche, Roche/Genentech; research funding—GlaxoSmithKline; (OPTIONAL) uncompensated relationships—Bristol-Myers Squibb; Lilly. AB: consulting or advisory role—bioTheranostics, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Genentech, Genentech/Roche (Inst), Immunomedics, Immunomedics (Inst), Innocrin Pharma (Inst), Merck, Novartis, Novartis (Inst), Pfizer, Pfizer (Inst), Philips Healthcare, Puma Biotechnology, Radius Health;, Radius Health (Inst), Sanofi, Spectrum Pharmaceuticals; research funding—AstraZeneca/Daiichi Sankyo (Inst), Genentech (Inst), Immunomedics (Inst), Merck (Inst), Novartis (Inst), Pfizer (Inst), Radius Health (Inst), Sanofi (Inst). All other authors have declared no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Breast cancer (BC) is one of the malignancies threatening the woman's health. Our study aims to explore the underlying mechanism behind the anti-tumor function of Paris saponin VII (PS VII) in BC. Xenografting experiment was conducted to monitor the tumor growth. The Ki67 and 4-HNE expression were analyzed via immunohistochemical assay. After different treatments, the cell viability, proliferation, invasion, and migration capacity of BC cells were measured by the CCK-8, colony formation, transwell, and wound healing assays, respectively. The ratio of GSH/GSSG was measured by the GSH/GSSG ratio detection assay kit. The lipid ROS and Fe 2+ levels were quantified by flow cytometry analysis. The expressions of TFR1, ACSL4, Nrf2, and GPX4 were measured via western blotting. Compared with the Ctrl group, the tumor volumes, and Ki67 expression were markedly reduced in PS VII groups, and the BC cell viability was decreased by PS VII treatment in a dose-dependent manner. The colony numbers, invasive cells, and migration rates were also significantly decreased by PS VII treatment. Then, the Nrf2 as well as GPX4 expressions were decreased and TFR1 expression was increased by PS VII treatment in vitro and in vivo, while there was no difference in ACSL4 expression between Ctrl and PS VII groups. Moreover, the above effects of PS VII could not be observed in GPX4 knockdown cells. PS VII can promote ferroptosis to inhibit BC via the Nrf2/GPX4 axis, which innovatively suggests the pro-ferroptosis effect and therapeutic potential of PS VII in BC., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The heterogeneity of the somatotroph adenomas, especially for sparsely granulated (SG) and densely granulated (DG) subtypes, has attracted great attention in identifying their imaging biomarker. The purpose of the current study was to compare the diagnostic performance of diffusion-weighted and T2-weighted magnetic resonance imaging (MRI) sequences for preoperatively distinguishing the granulation patterns of somatotroph adenomas., Methods: Thirty-two patients with a clinical diagnosis of somatotroph adenomas from October 2018 to March 2023 were included in this study. Coronal diffusion-weighted imaging (DWI) and T2-weighted MRI sequence data were collected from 3.0T MRI and compared between SG and DG groups. The immunohistochemistry was used to confirm the electron microscopy pathologic subtypes and Ki67 expression levels of somatotroph adenomas postoperatively., Results: Patients in the SG group had significantly higher signal intensity (SI) ratio of DWI (rDWI) (P < 0.001), lower SI ratio of apparent diffusion coefficient (rADC) (P < 0.001), and higher SI ratio of T2-weighted imaging (P = 0.011). The combined diagnosis index of rDWI and rADC had the highest diagnostic efficiency in predicting SG adenomas (sensitivity, 93.3%; specificity, 88.2%; P < 0.001). The rDWI and rADC values had positive and negative correlations with the Ki67 index and tumor maximum diameter, respectively. Lower rADC×10 3 was an independent predictor for SG adenomas., Conclusions: Our results indicated that compared with previously used T2-weighted imaging, the DWI sequence, especially the combined diagnosis index of rDWI and rADC, could more efficiently distinguish the granulation patterns of somatotroph adenomas preoperatively., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pituitary carcinomas (PCa) are extremely rare, indistinguishable from pituitary adenomas on histopathological grounds and have a poor prognosis. Most PCa start as PRL or ACTH secreting tumors in males, with relapsing invasive behaviour, refractoriness to medical and radiotherapy and increasing hormonal levels. The presence of distant metastases is still required for the diagnosis of PCa. The association with genetic endocrine diseases must be taken into account, since it adds further risk of evolution towards malignancy. Intradural spinal metastases have also been reported, so a complete craniospinal MR evaluation is recommended, when clinically indicated. We report a case of PCa, associated with MEN1 syndrome, with evidence of meningeal spread to the tentorium cerebelli, clival dura and spinal drop metastases mimicking spinal nerves schwannomas.

Purpose: To determine the optimal cut-off value of Ki-67 for predicting the survival of patients with clear cell renal cell carcinoma (ccRCC) and tumor thrombus and to explore the correlation between Ki-67 expression and pathological features., Patients and Methods: We retrospectively analyzed Ki-67 immunohistochemical staining of ccRCC and tumor thrombus resected from February 2006 to February 2022. The survival rate was evaluated using the Kaplan-Meier method. The optimal cut-off value of the Ki-67 expression for predicting survival was determined by the minimum P-value method. Clinicopathological data were compared based on Ki-67 status (low versus high expression). Univariate and multivariate Cox regression analysis was used to explore independent predictors., Results: A total of 202 patients (median age, 58 years [IQR, 52-65 years], 147 men) with ccRCC and tumor thrombus were included in the study. The optimal cut-off value of Ki-67 for predicting survival was 30%. 159 (78.7%) and 43 (21.3%) patients were included in the low-expression and high-expression groups. Patients with Ki-67 high expression had significantly worse recurrence-free survival (P < 0.001) and cancer-specific survival (P < 0.001). Ki-67 high expression was associated with adverse pathological features, including tumor necrosis, ISUP nuclear grade, sarcomatoid differentiation, perirenal fat invasion, renal pelvis invasion, and inferior vena cava wall invasion (all P < 0.050). Ki-67 expression ≥ 30% (P = 0.016), tumor side (P = 0.003), diabetes (P = 0.040), blood loss (P = 0.016), inferior vena cava wall invasion (P = 0.016), and sarcomatoid differentiation (P = 0.014) were independent predictors of cancer-specific survival., Conclusion: The optimal cut-off level of Ki-67 in predicting the prognosis of ccRCC and tumor thrombus was 30%. The high expression of Ki-67 was associated with the aggressive pathological phenotype and poor prognosis., Competing Interests: Declaration of Competing Interest No potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Keratoacanthoma (KA) is a common keratinocyte neoplasm that is regularly classified as a type of cutaneous squamous cell carcinoma (cSCC) despite demonstrating benign behavior. Differentiating KA from well-differentiated cSCC is difficult in many cases due to the substantial overlap of clinical and histological features. Currently, no reliable discriminating markers have been defined, and consequently, KAs are often treated similarly to cSCC, creating unnecessary surgical morbidity and healthcare costs. In this study, we used RNA sequencing to identify key differences in transcriptomes between KA and cSCC, which suggested divergent keratinocyte populations between each tumor. Imaging mass cytometry was then used to identify single-cell tissue characteristics, including cellular phenotype, frequency, topography, functional status, and interactions between KA and well-differentiated cSCC. We found that cSCC had significantly increased proportions of Ki67+ keratinocytes among tumor keratinocytes, which were dispersed significantly throughout non-basal keratinocyte communities. In cSCC, regulatory T-cells were more prevalent and held greater suppressive capacity. Furthermore, cSCC regulatory T-cells, tumor-associated macrophages, and fibroblasts had significant associations with Ki67 + keratinocytes as opposed to avoidances with KA, indicating a more immunosuppressive environment. Our data suggest that multicellular spatial features can serve as a foundation to enhance the histological discrimination of ambiguous KA and cSCC lesions., (Copyright © 2023. Published by Elsevier Inc.)

Cadmium (Cd) is a heavy metal that has been widely reported to be linked to the onset and progression of breast cancer (BC). However, the mechanism of Cd-induced mammary tumorigenesis remains elusive. In our study, a transgenic mouse model that spontaneously develops tumors through overexpression of wild-type Erbb2 (MMTV-Erbb2) was constructed to investigate the effects of Cd exposure on BC tumorigenesis. The results showed that oral exposure to 3.6 mg/L Cd for 23 weeks dramatically accelerated tumor appearance and growth, increased Ki67 density and enhanced focal necrosis and neovascularization in the tumor tissue of MMTV-Erbb2 mice. Notably, Cd exposure enhanced glutamine (Gln) metabolism in tumor tissue, and 6-diazo-5-oxo-l-norleucine (DON), a Gln metabolism antagonist, inhibited Cd-induced breast carcinogenesis. Then our metagenomic sequencing and mass spectrometry-based metabolomics confirmed that Cd exposure disturbed gut microbiota homeostasis, especially Helicobacter and Campylobacter abundance remodeling, which altered the gut metabolic homeostasis of Gln. Moreover, intratumoral Gln metabolism profoundly increased under Cd-elevated gut permeability. Importantly, depletion of microbiota with an antibiotic cocktail (AbX) treatment led to a significant delay in the appearance of palpable tumors, inhibition of tumor growth, decrease in tumor weight, reduction in Ki67 expression and low-grade pathology in Cd-exposed MMTV-Erbb2 mice. Also, transplantation of Cd-modulated microbiota decreased tumor latency, accelerated tumor growth, increased tumor weight, upregulated Ki67 expression and exacerbated neovascularization as well as focal necrosis in MMTV-Erbb2 mice. In summary, Cd exposure induced gut microbiota dysbiosis, elevated gut permeability and increased intratumoral Gln metabolism, leading to the promotion of mammary tumorigenesis. This study provides novel insights into environmental Cd exposure-mediated carcinogenesis., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: HER2-low has emerged as a new predictive biomarker in metastatic breast cancer. However, its prognostic value in early-stage carcinomas needs to be revisited. We aimed to evaluate the association of HER2-low carcinomas with PAM50 risk groups combined with clinicopathological variables in early breast cancer., Methods: We conducted a retrospective analysis of 332 patients with early-stage breast cancer that underwent PAM50 signature analysis between 2015 and 2021at Hospital Universitario 12 de Octubre (Madrid, Spain). Clinical and pathological variables were collected from medical records. After adjusting for potential confounders, we estimated Odds Ratio (OR) and 95% confidence interval for high-risk PAM50 subgroup, comparing HER2-low versus HER2-zero carcinomas by multivariable logistic regression. P values below 0.05 were deemed statistically significant., Results: 192 (57%) patients were classified as HER2-low carcinomas. Median follow-up was 34 months. Adjusted OR for high-risk PAM50 when comparing HER2-low versus HER2-zero carcinomas was 1.31 (95% CI: 0.75-2.30, p = 0.33). The multivariable model detected significant associations for Ki-67% (≥20% vs. <20%: OR = 4.03, 95% CI: 2.15-7.56, p < 0.001), T staging category (T2/T3 vs. T1: OR = 3.44, 95% CI: 1.96-6.04, p < 0.001), progesterone receptor (PR ≥ 20% vs. <20%: OR = 0.44, 95% CI: 0.23-0.83, p = 0.01), nodal staging category (N+ vs. N0: OR = 3.8, 95% CI: 1.89-7.62, p < 0.001) and histological grade (grade 2 vs. 1: OR = 2.41, 95% CI: 1.01-5.73, p = 0.04; grade 3 vs 1: OR = 5.40, 95%CI: 1.98-14.60, p = 0.001)., Conclusions: In this early-stage breast cancer cohort, HER2-low was not associated with a high-risk PAM50 compared to HER2-zero carcinomas. Ki-67 ≥ 20%, T2/T3, histological grade 2/3, N+ and PR<20% were significantly associated to a high-risk PAM50., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Prostate specific membrane antigen (PSMA) directed radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) patients. However, it is still poorly understood why approximately 40% of the patients does not respond to PSMA-RLT. The aims of this study were to evaluate the pretreatment PSMA expression on immunohistochemistry (IHC) and PSMA uptake on PET/CT imaging in mCRPC patients who underwent PSMA-RLT. We correlated these parameters and a cell proliferation marker (Ki67) to the therapeutic efficacy of PSMA-RLT., Patients and Methods: In this retrospective study, mCRPC patients who underwent PSMA-RLT were analyzed. Patients biopsies were scored for immunohistochemical Ki67 expression, PSMA staining intensity and percentage of cells with PSMA expression. Moreover, the PSMA tracer uptake of the tumor lesion(s) and healthy organs on PET/CT imaging was assessed. The primary outcome was to evaluate the association between histological PSMA protein expression of tumor in pre-PSMA-RLT biopsies and the PSMA uptake on PSMA PET/CT imaging of the biopsied lesion. Secondary outcomes were to assess the relationship between PSMA expression and Ki67 on IHC and the progression free survival (PFS) and overall survival (OS) following PSMA-RLT., Results: In total, 22 mCRPC patients were included in this study. Nineteen (86%) patients showed a high and homogenous PSMA expression of >80% on IHC. Three (14%) patients had low PSMA expression on IHC. Although there was limited PSMA uptake on PET/CT imaging, these 3 patients had lower PSMA uptake on PET/CT imaging compared to the patients with high PSMA expression on IHC. Yet, no correlation was found between PSMA uptake on PET/CT imaging and PSMA expression on IHC (SUVmax: R 2  = 0.046 and SUVavg: R 2  = 0.036). The 3 patients had a shorter PFS compared to the patients with high PSMA expression on IHC (HR: 4.76, 95% CI: 1.14-19.99; P = .033). Patients with low Ki67 expression had a longer PFS and OS compared to patients with a high Ki67 expression (HR: 0.40, 95% CI: 0.15-1.06; P = .013) CONCLUSION: The PSMA uptake on PSMA-PET/CT generally followed the PSMA expression on IHC. However, heterogeneity may be missed on PSMA-PET/CT. Immunohistochemical PSMA and Ki67 expression in fresh tumor biopsies, may contribute to predict treatment efficacy of PSMA-RLT in mCRPC patients. This needs to be further explored in prospective cohorts., Competing Interests: Disclosure The authors have declared that no competing interest exists., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To examine correlations between shear-wave elastography (SWE) parameters with molecular subtype and axillary lymph node (LN) status of breast cancer., Methods: We retrospectively analyzed 545 consecutive women (mean age, 52.7 ± 10.7 years; range, 26-83) with breast cancer who underwent preoperative breast ultrasound with SWE between December 2019 and January 2021. SWE parameters (E max , E mean , and E ratio ) and the histopathologic information from surgical specimens including histologic type, histologic grade, size of invasive cancer, hormone receptor and HER2 status, Ki-67 proliferation index, and axillary LN status were analyzed. The relationships between SWE parameters and histopathologic findings were analyzed using an independent sample t-test, one-way ANOVA test with Tukey's post hoc test, and logistic regression analyses., Results: Higher stiffness values of SWE were associated with larger lesion size (>20 mm) on ultrasound, high histologic grade, larger invasive cancer size (>20 mm), high Ki-67, and axillary LN metastasis. E max and E mean were the lowest in the luminal A-like subtype, and all three parameters were the highest in the triple-negative subtype. Lower value of E max was independently associated with the luminal A-like subtype (P = 0.04). Higher value of E mean was independently associated with axillary LN metastasis for tumors ≤ 20 mm (P = 0.03)., Conclusion: Increases in the tumor stiffness values on SWE were significantly associated with aggressive histopathologic features of breast cancer. Lower stiffness values were associated with the luminal A-like subtype, and tumors with higher stiffness values were associated with axillary LN metastasis in small breast cancers., Competing Interests: Declaration of competing interest All other authors of the present study declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Soluble epoxide hydrolase (sEH) is a key enzyme for the hydrolysis of epoxyeicosatrienoic acids (EETs) and has been implicated in the pathogenesis of hepatic inflammation, fibrosis, cancer, and nonalcoholic fatty liver disease. However, the role of sEH in liver regeneration and injury remains unclear., Methods: This study used sEH-deficient (sEH -/- ) mice and wild-type (WT) mice. Hepatocyte proliferation was assessed by immunohistochemical (IHC) staining for Ki67. Liver injury was evaluated by histological staining with hematoxylin and eosin (H&E), Masson's trichrome, and Sirius red, as well as IHC staining for α-SMA. Hepatic macrophage infiltration and angiogenesis were reflected by IHC staining for CD68 and CD31. Liver angiocrine levels were detected by ELISA. The mRNA levels of angiocrine or cell cycle-related genes were measured by quantitative real-time RT-PCR (qPCR). The protein levels of cell proliferation-related protein and phosphorylated signal transducer and activator of transcription 3 (STAT3) were detected by western blotting., Results: sEH mRNA and protein levels were significantly upregulated in mice after 2/3 partial hepatectomy (PHx). Compared with WT mice, sEH -/- mice exhibited a higher liver/body weight ratio and more Ki67-positive cells on days 2 and 3 after PHx. The accelerated liver regeneration in sEH -/- mice was attributed to angiogenesis and endothelial-derived angiocrine (HGF) production. Subsequently, hepatic protein expression of cyclinD1 (CYCD1) and the downstream direct targets of the STAT3 pathway, such as c-fos, c-jun, and c-myc, were also suppressed post-PHx in sEH -/- compared to WT mice. Furthermore, sEH deficiency attenuated CCl 4 -induced acute liver injury and reduced fibrosis in both CCl 4 and bile duct ligation (BDL)-induced liver fibrosis rodent models. Compared with WT mice, sEH -/- mice had slightly decreased hepatic macrophage infiltration and angiogenesis. Meanwhile, sEH -/- BDL mice had more Ki67-positive cells in the liver than WT BDL mice., Conclusions: sEH deficiency alters the angiocrine profile of liver endothelial to accelerate hepatocyte proliferation and liver regeneration, and blunts acute liver injury and fibrosis by inhibiting inflammation and angiogenesis. sEH inhibition is a promising target for liver diseases to improve liver regeneration and damage., Competing Interests: Declaration of Competing Interest All authors declare that there are no financial or nonfinancial competing interests regarding the publication of this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To explore the repeated pain stimulation in neonatal rats affects their cognitive and memory abilities during puberty, and the proliferation expression of hippocampal neurons., Methods: Postnatal 1 day (P1) SD rats were randomly divided into two groups, and the skin of the needle group was pricked for seven days consecutively while the skin of the control group was stroked for the same period of time. The rats in both groups were weighed every week, and the Morris water maze experiment was performed from P44 to P49 to test the cognitive and memory abilities of the rats. On P50, the hippocampal tissue was extracted for observation of pathological features and the expressions of Ki-67 and caspase 3 were determined., Results: With the increase of the days, the body weight of the rats in the needle group increased slightly slower than that of the control group. The escape latency of the needle group was significantly higher than that of the control group in the water maze test at P45 and P48, and the number of times the rats crossing the platform in the needle group was lower than that of the control group. The HE staining of the hippocampal tissue showed that the cells in the needle group were disorganized, with irregular morphology. Under the electron microscope, the structure of neuron cells and organelles is changed in the hippocampal CA1 region of rats. It showed a decrease in the Ki-67 expression and an increase in caspase 3 in the needle group., Conclusion: Repeated experience of needle-pricking stimulation in neonatal rats can cause cognitive impairment and memory loss in puberty, disrupt hippocampal organization, and diminish neuronal proliferation., 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 © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The repeated-dose liver micronucleus (RDLMN) assay is a widely accepted method for detecting genotoxic substances. We investigated the effect of animal age on this assay. Proliferation activity in the liver tissue of untreated rats at age = 3.5, 6, 8, 10, or 12 weeks was measured via immunohistochemical expression of Ki-67 protein. The percentage of Ki-67-positive hepatocytes decreased markedly with age, reaching very low levels after 10 weeks, indicating decline with age of proliferative capacities in the liver. We calculated the area under the curve (AUC) of the approximate curve generated from the percentage of Ki-67-positive cells, to estimate the hepatocyte proliferation activity over the dosing period in the two regimens of the 4-week RDLMN assay: dosing initiated at age = 6 or 8 weeks. Hepatocyte proliferation activity of the former regimen was approximately double that of the latter. We also calculated the AUC for the juvenile-rat method, in which rats are treated for two days at age = 3.5 weeks. The AUC calculated for that method was approximately half of that for the 4-week repeated-dosing regimen initiated at 6 weeks of age. These findings suggest that the 4-week RDLMN assay with dosing initiated at age = 6 weeks could be approximately twice as sensitive as the other two methods., 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 © 2023 Elsevier B.V. All rights reserved.)

Purpose: To explore the clinical parameters and molecular biomarkers that can predict differential pathologic response to neoadjuvant chemohormonal therapy (NCHT) in prostate cancer (CaP)., Methods: A total of 128 patients with primary high-risk localized CaP who had received NCHT followed by radical prostatectomy (RP) were included. Androgen receptor (AR), AR splice variant-7 (AR-V7) and Ki-67 staining were evaluated in prostate biopsy specimens by immunohistochemistry. The pathologic response to NCHT in whole mount RP specimens was measured based on the reduction degree of tumor volume and cellularity compared to the paired pretreatment needle biopsy, and divided into 5 tier grades (Grades 0-4). Patients with Grades 2 to 4 (the reduction degree more than 30%) were defined as having a favorable response. Logistic regression was performed to explore the predictive factors associated with a favorable pathologic response. The predictive accuracy was evaluated by receiver operating characteristic (ROC) curve and area under the ROC curve (AUC)., Results: Ninety-seven patients (75.78%) had a favorable response to NCHT. Logistic regression showed that the preoperative PSA level, low AR expression and high Ki-67 expression in biopsy specimens were associated with a favorable pathologic response (P < 0.05). Furthermore, the AUC of the preoperative PSA level, AR and Ki-67 were 0.625, 0.624 and 0.723, respectively. Subgroup analysis revealed that the rate of favorable pathologic response to NCHT was 88.5% in patients with AR low Ki-67 high , which was higher than patients with AR low Ki-67 low , AR high Ki-67 low , and AR high Ki-67 high (88.5% vs. 73.9%, 72.9%, and 70.9%, all P < 0.05)., Conclusions: A lower preoperative PSA level was an independent predictive factor for a favorable pathologic response. Moreover, the expression status of AR and Ki-67 in biopsy specimens were associated with differential pathologic response to NCHT, and AR low/Ki-67 high was also associated with favorable response but warrants further evaluation in this patient subgroup and future trial clinical trial design., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Here, we aimed to investigate the clinical parameters affecting the recurrence of meningiomas, and to construct a predictive nomogram model, so as to predict the recurrence-free survival (RFS) of meningiomas more accurately., Methods: The Clinical, imaging, and pathological data of 155 primary meningioma patients treated surgically from January 2014 to March 2021 were retrospectively analyzed. Independent prognostic factors affecting postoperative recurrence of meningioma were identified by univariate and multivariate Cox regression analyses. A predictive nomogram was established based on independent influence parameters. Subsequently, time-dependent receiver operating characteristic curve, calibration curve, and Kaplan-Meier method were utilized to evaluate the predictive ability of the model., Results: The multivariate Cox regression analysis showed that tumor size, Ki-67 index, and resection extent had independent prognostic significance, and these parameters were subsequently used to construct a predictive nomogram. Receiver operating characteristic curves indicated that the model was more accurate in predicting RFS than independent factors. Calibration curves suggested that the predicted RFS were similar to the actual observed RFS. In the Kaplan-Meier analysis, the RFS of high-risk cases was obviously shorter than that of low-risk cases., Conclusions: The tumor size, Ki-67 index, and extent of resection were independent factors affecting the RFS of meningioma. The predictive nomogram based on these factors can be used as an effective method to stratify the recurrence risk of meningioma and provide a reference for patients to choose personalized treatment., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Pseudomyxoma peritonei (PMP) is a rare malignant disease. Adding of the Ki67 proliferation index to the PSOGI PMP classification provided two different subcategories of the extensive HG-PMP group (HG-PMP ≤15% and HG-PMP >15%) with different survival in a previous unicentric study. This study aims to carry out an external and multicentre validation of this new proposed classification., Method: It was a prospective analysis of samples from a historical and international cohort of patients. A representative area with higher cellular density was used to determine the Ki67%. The Ki67 proliferation index (%) was determined in all the HG-PMP patients. A Cox proportional hazard models and multivariable COX models were used. The Kaplan-Meier method and the two-tailed log-rank test were used to analyse the effect of different PSOGI-Ki67 categories on OS and DFS. Its predictive accuracy was analysed using Harrel's C-index and the ROC curve. The calibration was performed using the calibration plots matching., Results: After exclusions, 349 patients were available for analysis. The 5-years OS were 86% for LG-PMP, 59% for HG-PMP≤15, 38% for HG-PMP>15 and 42% for SRC-PMP (p = 0.0001). The 5-years DFS were 49% for LG-PMP, 35% for HG-PMP≤15, 16% for HG-PMP>15 and 18% SRC-PMP (p = 0.0001). The discrimination capability of PSOGI-Ki67 was validated., Conclusion: the PSOGI-Ki67 classification discriminates and predicts the OS and DFS in patients with PMP dividing the HG-PMP category into two well-defined sub-categories. The Ki67 proliferation index should be incorporated routinely in the pathology report for these patients., (Copyright © 2023 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: To improve understanding of the clinical features of renal angiomyolipoma (AML) accompanied by tumor thrombus (TT)., Methods: From January 2017 to February 2022, 18 patients with AML and TT were enrolled. We retrospectively analyzed them and there were 6 cases of epithelial AML (EAML) and 12 of classical AML (CAML). We compared the key variables between the two cohorts., Results: The mean age of the 18 cases was 42.0 (standard deviation [SD] 13.4) years and 14 (77.8%) were female. Eleven (61.1%) tumors were on the right side. Only two (11.1%) cases presented with flank pain. The mean follow-up time was 33.6 (IQR: 20.1-48.5) months. All participants were alive at the end of follow-up. One case developed lung metastases 21 months after operation but entered remission after 2 years of everolimus treatment. The imaging diagnoses of all CAML cases were consistent with the pathology, while all imaged EAML cases were diagnosed with carcinomas. Five EAML cases, but only one CAML case, exhibited necrosis (83.3 vs. 8.3%, P = 0.001). The Ki-67 index of the EAML group was significantly higher than that of the CAML group (7 vs. 2, P = 0.004)., Conclusions: Compared to CAML, EAML tended to be associated with a higher imaging misdiagnosis rate, and was more commonly associated with necrosis and a higher Ki-67 index. Surgery remains the prime treatment for nonmetastatic AML with TT; such cases have a relatively good prognosis despite the malignant potential., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: This study aims to evaluate Ki67 cut-off points for differentiating low and high-risk patients based on survival and recurrence and find the best Ki67 cut-off points in breast cancer patients undergoing adjuvant and neoadjuvant therapy using machine learning methods., Patients and Methods: Patients with breast cancer treated at 2 referral hospitals between December 2000 and March 2021 who had invasive breast cancer entered this study. There were 257 patients in the neoadjuvant group and 2139 in the adjuvant group. A decision tree method was used to predict the likelihood of survival and recurrence. The 2-ensemble technique of RUSboost and bagged tree were imposed on the decision tree method to increase the accuracy of the determination. 80 percent of the data was used to train and validate the model, and 20% was used as a test., Results: In adjuvant therapy breast cancer patients with Invasive ductal carcinoma (IDC) and Invasive lobular carcinoma (ILC) the cutoff points for survival were 20 and 10, respectively. For luminal A, luminal B, Her2 neu, and triple-negative adjuvant therapy patients' the cutoff points for survival were 25, 15, 20, and 20, respectively. For neoadjuvant therapy luminal A and luminal B group, survival cutoff points were 25 and 20, respectively., Conclusion: Despite variability in measurement and cut-off points, the Ki-67 proliferation index is still helpful in the clinic. Further investigation is needed to determine the best cut-off points for different patients. The sensitivity and specificity of Ki-67 cutoff point prediction models in this study could further prove its significance as a prognostic factor., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Breast cancer with fluorescence in situ hybridization (FISH) group 2 pattern (HER2 <4 and HER2/CEP17 ratio ≥2, a subset of monosomy CEP17) was historically considered HER2-positive, but mostly HER2-negative according to updated 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines unless 3+ by immunohistochemistry (IHC). Therapeutic relevance of this group remained elusive, therefore we assessed if repeat IHC and FISH can assist final HER2 classification., Patient and Methods: We retrospectively reviewed HER2 FISH performed at our institution from 2014 to 2018 and identified 23 of 3554 (0.6%) breast cancer cases with at least one-time measurement of HER2 FISH categorized as group 2. Repeat HER2 tests were performed for cases with available alternative tumor samples and compared with initial testing following 2018 ASCO/CAP guidelines., Results: Only 1 of 23 group 2 cases was HER2-positive, 0/18 in primary and 1/5 in metastatic/recurrent tumors. Of 13 primary tumors with repeat HER2 results; 10 (77%) remained HER2-negative; 3 (23%) changed from HER2-negative (group 2 and IHC 2+) to HER2-positive (group 1 and IHC 2+). Among 8 of these 13 patients receiving neoadjuvant systemic therapy containing anti-HER2 agent, 3 (38%) achieved pathologic complete response (pCR). Two of 3 pCR cases were HER2-positive converters on repeat testing. Three pCR cases were ER-negative or -low positive and Ki67 ≥40%, while 5 partial responders were ER-positive and Ki67 <40% (P < .05)., Conclusion: Breast cancer with HER2 FISH group 2 result may represent heterogeneous populations of tumor cells being originated de novo or preferentially selected secondary to therapy. Repeat HER2 tests on alternative samples may be considered to guide anti-HER2 therapy., Competing Interests: Disclosure All authors declare they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC), nanoparticle albumin-bound (nab)-paclitaxel showed promising efficacy versus solvent-based (sb)-paclitaxel in neoadjuvant trials; however, optimal patient and therapy selection remains a topic of ongoing research. Here, we investigate the potential of Oncotype DX® recurrence score (RS) and endocrine therapy (ET) response (low post-endocrine Ki67) for therapy selection., Patients and Methods: Within the WSG-ADAPT trial (NCT01779206), high-risk HR+/HER2- EBC patients were randomized to (neo)adjuvant 4× sb-paclitaxel 175 mg/m 2 q2w or 8× nab-paclitaxel 125 mg/m 2 q1w, followed by 4× epirubicin + cyclophosphamide (90 mg + 600 mg) q2w; inclusion criteria: (i) cN0-1, RS 12-25, and post-ET Ki67 >10%; (ii) cN0-1 with RS >25. Patients with cN2-3 or (G3, baseline Ki67 ≥40%, and tumor size >1 cm) were allowed to be included without RS and/or ET response testing. Associations of key factors with pathological complete response (pCR) (primary) and survival (secondary) endpoints were analyzed using statistical mediation and moderation models., Results: Eight hundred and sixty-four patients received neoadjuvant nab-paclitaxel (n= 437) or sb-paclitaxel (n = 427); nab-paclitaxel was superior for pCR (20.8% versus 12.9%, P = 0.002). pCR was higher for RS >25 versus RS ≤25 (16.0% versus 8.4%, P = 0.021) and for ET non-response versus ET response (15.1% versus 6.0%, P = 0.027); no factors were predictive for the relative efficacy of nab-paclitaxel versus sb-paclitaxel. Patients with pCR had longer distant disease-free survival [dDFS; hazard ratio 0.42, 95% confidence interval (CI) 0.20-0.91, P = 0.024]. Despite favorable prognostic association of RS >25 versus RS ≤25 with pCR (odds ratio 3.11, 95% CI 1.71-5.63, P ≤ 0.001), higher RS was unfavorably associated with dDFS (hazard ratio 1.03, 95% CI 1.01-1.05, P = 0.010)., Conclusions: In high-risk HR+/HER2- EBC, neoadjuvant nab-paclitaxel q1w appears superior to sb-paclitaxel q2w regarding pCR. Combining RS and ET response assessment appears to select patients with highest pCR rates. The disadvantage of higher RS for dDFS is reduced in patients with pCR. These are the first results from a large neoadjuvant randomized trial supporting the use of RS to help select patients for neoadjuvant chemotherapy in high-risk HR+/HER2- EBC., Competing Interests: Disclosure OG received consulting fees from Celgene, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, and Molecular health; honoraria from Genomic Health/Exact Sciences, Roche, Celgene, Pfizer, Novartis, NanoString Technologies, and AstraZeneca; payment for expert testimony from Genomic Health; and travel support from Roche, all outside of the submitted work; and co-director position at West German Study Group. SK received research funding from Roche and Novartis; consulting fees from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health/Exact Science, Lilly, MSD, Novartis, Seagen, Pfizer, pfm Medical, Roche, Somatex, and Gilead; travel support from Roche and Daiichi Sankyo; and other financial or non-financial interests for Non-Continuing Medical Education services from Somatex, Roche, Novartis, and Lilly, all outside of the submitted work; and co-director position at West German Study Group. UN received research funding paid to institution from Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Roche, and Sanofi; consulting fees from Genomic Health and Roche; honoraria from Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Novartis pharma, Pfizer Pharmaceuticals, Roche/Genentech, and Teva; payment for expert testimony from Genomic Health; travel support from Genomic Health, Pfizer Pharmaceuticals, and Roche; participation on a Data Safety Monitoring Board or Advisory Board at Roche, Seagen, and Exact Sciences, all outside of the submitted work; and co-director position at West German Study Group. MB received honoraria from AstraZeneca, Exact Sciences, Novartis, Pfizer, Roche, Teva, MSD; travel support from AstraZeneca, Celgene, Medac, Novartis, Roche, Daiichi Sankyo; and reports consulting/advisory role for AstraZeneca, Exact Sciences, Novartis, Puma, Roche, all outside of the submitted work. HF received honoraria from Roche and iOMEDICO (lecture); and travel support from Celgene and Amgen, all outside of the submitted work. CU received consulting fees from Tesaro, Novartis, Roche; research funding paid to institution from West German Study Group, German Breast Group, Novartis, AstraZeneca, Tesaro, Palleos Healthcare Services Gmbh, Pierre Fabre, AGO-Studiengruppe; travel support from German Breast Group, West German Study Group, AGO-Studiengruppe; and provided expert testimony for Pfizer, Novartis, Roche, PharmaMar, AstraZeneca, all outside of the submitted work. BA received honoraria from Pfizer, Roche Pharma, MSD, onkowissen.de, Novartis Pharma, AstraZeneca, PharmaMar, Lilly, promedicis, all outside of the submitted work. RK received consulting fees from AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Pfizer Pharmaceuticals, Roche/Genentech, Sandoz, and Seattle Genetics; and honoraria from Amgen, AstraZeneca, Genomic Health, Novartis, Pfizer Pharmaceuticals, Pierre Fabre, Roche/Genentech, and Zodiac Pharma, all paid to immediate family member and outside of the submitted work; and co-director position at West German Study Group. MG received consulting fees from AstraZeneca and travel support from Daiichi Sankyo, all outside of the submitted work. RW received consulting fees, honoraria, and travel support from Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Daiichi-Sankyo, Eisai, Exact Sciences/Genomic Health, Gilead, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnology, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Tesaro Bio, Teva, Veracyte, and Viatris; and other financial or non-financial interests from FomF (Forum for medical education in Germany), Aurikamed, Clinsol, Pomme Med, all outside of the submitted work. RB is a current employee of and owns stock in Exact Sciences Corporation. HHK received honoraria for lectures from Roche Pharma, Novartis, Genomic Health, AstraZeneca, Lilly, and Pfizer; and participation in Data Safety Monitoring Board or Advisory Board at Roche Pharma, Genomic Health, and AstraZeneca, all outside of the submitted work. NH received research funding paid to institution from Lilly, MSD, Novartis, Pfizer, and Roche/Genentech; honoraria for lectures and/or consulting from Amgen, AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer Pharmaceuticals, Roche/Genentech, Sandoz, Sanofi, and Seagen, all outside of the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Purpose: To assess the usefulness of amide proton transfer (APT) imaging to predict the biological status of breast cancers., Method: Sixty-six patients (age range 31-85 years, mean 58.9 years) with histopathologically proven invasive ductal carcinomas of 2 cm or larger in diameter were included in this study. 3D APT weighted imaging was conducted on a 3 T scanner. Mean APT signal intensity (SI) was analyzed in relation to biological subtypes, Ki-67 labeling index, and nuclear grades (NGs)., Results: The triple-negative (TN) cancers (n = 10; 2.75 ± 0.42%) showed significantly higher APT SI than the luminal type cancers (n = 48; 1.74 ± 0.83) and HER2 cancers (n = 8; 1.83 ± 0.21) (P = 0.0007, 0.03). APT SI had weakly positive correlation with the Ki-67 labeling index (r = 0.38, P = 0.002). The mean APT SIs were significantly higher for high-Ki-67 (>30%) (n = 31; 2.25 ± 0.70) than low-Ki-67 (≤30%) cancers (n = 35; 1.60 ± 0.79) (P = 0.0007). There was no significant difference in the APT SIs between NG 1-2 (n = 31; 1.71 ± 0.84) and NG 3 (n = 35; 2.08 ± 0.76%) cancers (P = 0.06)., Conclusions: TN and high-Ki-67 breast cancers showed high APT SIs. APT imaging can help to predict the biological status of breast cancers., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to explore the effects of bone marrow-derived Mesenchymal Stem Cell-Conditioned Medium (MSC-CM) treating diabetic foot ulcers in rats., Methods: Models of T2DM rats were induced by a high-fat diet and intraperitoneal injection of STZ in SD rats. Models of Diabetic Foot Ulcers (DFUs) were made by operation on hind limbs in diabetic rats. Rats were divided into four groups (n = 6 for each group), i.e., Normal Control group (NC), Diabetes Control group (DM-C), MSC-CM group and Mesenchymal Stem Cells group (MSCs). MSC-CM group was treated with an injection of conditioned medium derived from preconditioned rats' bone marrow MSCs around ulcers. MSCs group were treated with an injection of rats' bone marrow MSCs. The other two groups were treated with an injection of PBS. After the treatment, wound closure, re-epithelialization (thickness of the stratum granulosums of the skin, by H&E staining), cell proliferation (Ki67, by IHC), angiogenesis (CD31, by IFC), autophagy (LC3B, by IFC and WB; autolysosome, by EM) and pyroptosis (IL-1β, NLRP3, Caspase-1, GSDMD and GSDMD-N, by WB) in ulcers were evaluated., Results: After the treatment wound area rate, IL-1β by ELISA, and IL-1β, Caspase-1, GSDMD and GSDMD-N by WB of MSC-CM group were less than those of DM group. The thickness of the stratum granulosums of the skin, proliferation index of Ki67, mean optic density of CD31 and LC3B by IFC, and LC3B by WB of MSC-CM group were more than those of DM group. The present analysis demonstrated that the injection of MSC-CM into rats with DFUs enhanced the wound-healing process by accelerating wound closure, promoting cell proliferation and angiogenesis, enhancing cell autophagy, and reducing cell pyroptosis in ulcers., Conclusions: Studies conducted indicate that MSC-CM administration could be a novel cell-free therapeutic approach to treat DFUs accelerating the wound healing process and avoiding the risk of living cells therapy., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Pesticides can cause serious environmental and human health consequences such as metabolic disruption and even cancers. Preventive molecules such as vitamins can be an effective solution. The present study aimed to investigate the toxic effect of an insecticide mixture formulation of lambda cyhalothrin and chlorantraniliprole (Ampligo® 150 ZC), on the liver of male rabbits (Oryctolagus cuniculus) and the possible ameliorative effect of vitamins A, D3, E, and C mixture. For that, 18 male rabbits were divided into 3 equal groups: Control (distilled water), AP (20 mg/Kg bw of the insecticide mixture every other day, orally for 28 days), AP+ADEC (20 mg/Kg bw of the insecticide mixture + 0,5 ml of vitamin AD3E+ 200 mg/kg bw of vitamin C every other day). The effects were evaluated on body weight, food intake changes, biochemical parameters, liver histology, and immunohistochemical expression of AFP, Bcl2, E-cadherin, Ki67, and P53. Results indicated that AP reduced weight gain (6.71%) and feed intake, increased ALT, ALP, and TC plasma levels, and caused hepatic tissular damages such as dilatation and congestion of the central vein, sinusoidal dilatation, inflammatory cells infiltration, and collagen deposition. Hepatic immunostaining showed an increase in the tissular expression of AFP, Bcl2, Ki67, and P53 and a significant (p < 0,05) decrease in E-cadherin expression. In contrast, supplementation of vitamins A, D3, E, and C mixture improved the previous observed alterations. Our study revealed that a sub-acute exposure to an insecticide mixture of lambda cyhalothrin and chlorantraniliprole induced numerous functional and structural disorders in the rabbit liver and the addition of vitamins ameliorated these damages., 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., (Published by Elsevier B.V.)

Background: Neuroendocrine tumors (NETs) belong to a rare family of tumors whose incidence has increased significantly over the past 50 years., Purpose: To evaluate the prognostic value of volumetric arterial enhancement (VAE) on baseline magnetic resonance imaging (MRI) for patients with neuroendocrine liver metastasis (NELM) treated using transarterial chemoembolization (TACE)., Material and Methods: Between October 2012 and December 2018, VAE in 37 patients was measured with a semi-automatic volume of Interest (VOI) on subtracted T1 sequence in the arterial phase. Patients underwent 1-3 sectoral lipiodol TACE. Radiologic response using modified Response Evaluation Criteria in Solid Tumors (mRECIST) at the treatment cycle end and progression free survival were determined., Results: Median age was 68.0 (60.0; 73.0). Twenty-three patients (62%) had a partial response, 10 (27%) had stable disease, four (11%) had progressive disease. VAE was a significant (P<0.05) predictor of radiologic response. Median progression free survival was 13 months (IC 95: 8; 16). In univariate analysis, significant predictors of local progression were alkaline phosphatase (AP) (P=0.035), Ki-67 index (P=0.014), and VAE (P<0.01). VAE over 500ms and Ki-67 index over 3%were risk factors of progression (P=<0.01) in multivariate analysis., Conclusion: VAE before TACE could be predictive of radiologic response and could be related to oncologic outcomes in patients with NELM., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background and Aims: Neuroendocrine neoplasms (NENs) result from neuroendocrine cell neoplastic proliferation, with both characteristics of endocrine and nerve cells. NENs arise in different localizations but the most common site is the gastrointestinal tract, including the pancreas. The morphology and frequency of NENs in our hospital were evaluated, as well as the correlation between lymph node status and Ki67 proliferative index., Materials and Methods: Retrospectively, we analyzed NEN pathohistological reports of patients who underwent surgical excision of gastroenteropancreatic tumors in the Clinical Center of Vojvodina in Novi Sad, from 2011 to 2018. The descriptive and correlation statistics were done. Chromogranin A, synaptophysin, CD56, and Ki67 were usually used as immunohistochemical markers., Results: The study registered 78 surgical specimens. The average age of patients was 58.88 (±17) years, whereby 53.8% were males. The most frequent site was the pancreas (29.5%), followed by the large intestine (26.9%). The mean tumor size was 3.71 (±3.13) cm. No significance was found in tumor differentiation degree (G1 = 32.1%, G2 = 26.9%, and G3 = 29.5%). Lymph node metastases were found in 47.44%. Positive correlation was found between the Ki67 index and the percentage of positive lymph nodes (r = 0.343, p = 0.046, p < 0.05, respectively). The correlation between tumor size and lymph node metastases revealed no significance in our study (r = 0.015, p = 0.480, p > 0.05, respectively)., Conclusion: Most NENs lymph node metastases originated from tumors with a high Ki67 index. The results confirm the use of proliferative index Ki67 as a prognostic marker for the presence of metastases, disease progression, and neuroendocrine tumor prognosis., Competing Interests: Declaration of competing interests 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 © 2022 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Data on the occurrences of legacy and alternative per- and polyfluoroalkyl substances (PFASs) in glioma are scarce. It remains unclear if PFASs exposure is related to the prevalence of glioma. A total of 137 glioma and 40 non-glioma brain tissue samples from patients recruited from the Nanfang Hospital, South China were analyzed for 17 PFAS compounds. Perfluorohexanoic acid, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorooctane sulfonamide (FOSA), and 6:2 chlorinated polyfluorinated ether sulfonate were frequently detected (> 60 %) in glioma. The total concentrations (range; median) of 17 PFASs in glioma (0.20-140; 3.1 ng g -1 ) were slightly higher than those in non-glioma (0.35-32; 2.2 ng g -1 ), but without statistical significance. The PFAS concentrations in males were statistically higher (p < 0.05) than those in females. Elevated glioma grades were associated with higher concentrations of PFOA, PFOS, and FOSA. Positive correlations were observed between PFAS concentrations (especially for PFOA) and Ki-67 or P53 expression, pathological molecular markers of glioma. Our findings suggested that exposure to PFASs might increase the probability to develop glioma. This is the first case study demonstrating associations between PFASs exposure and brain cancer. More evidences and potential pathogenic mechanisms warranted further investigations., 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 © 2022 Elsevier B.V. All rights reserved.)

Primary cutaneous large B-cell lymphoma, leg-type (PCLBCL-LT) is the most aggressive primary cutaneous B-cell lymphoma (PCBCL). Tumor microenvironment has a crucial role in tumor development, and tumor-infiltrating lymphocytes (TILs) can be targeted by immunotherapies. We characterized TILs in 20 PCBCLs to identify the tumor microenvironment features associated with clinical outcomes. We developed a seven‒multiplex immunofluorescence panel using Opal staining and image analysis using HALO software. In PCLBCL-LT, TILs were sparsely intermingled within tumor infiltrate in contrast to those in indolent PCBCL where TILs were scattered around tumor nodule edges with variable tumor infiltration. In PCLBCL-LT, TILs were composed of CD8 and CD4, whereas CD4 was predominant in indolent PCBCL. Proliferative TILs (CD3+Ki-67+ cells) were more abundant in PCLBCL-LT (P = 0.0036) than in indolent PCBCL. In PCLBCL-LT, proliferative TILs' abundance tended to be associated with better progression-free survival. These data were confirmed in a second independent cohort of 23 cases showing that proliferative TILs were more abundant in PCLBCL-LT (P = 0.0205) and that in PCLBCL-LT, high CD3+Ki-67+ cell density was associated with better progression-free survival (P = 0.002). These distinct TILs composition and distribution among PCBCL suggest that proliferative T lymphocytes represent a good prognostic factor in PCLBCL-LT and that stimulating their functions may represent a therapeutic approach., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The incidence of thyroid cancer (TC) has increased considerably in the last few decades. Environmental factors, including plasticizers, are recognized as potential risks leading to thyroid cancer in humans. In this study, we used a transcriptome-metabolome-wide association study to find the unidentified carcinogenic mechanism of di-2-ethylhexyl phthalate (DEHP) in thyroid and biomarkers for non-invasive diagnosis. Rats were treated with different doses of DEHP (0, 0.3, 3, 30, 150 mg DEHP/kg bw/day) for 13 weeks. Then, the thyroids were processed for Ki67 staining and RNA-seq. Also, 17-h urine samples were collected for high-resolution metabolomics analysis. After a high dose of DEHP exposure, the terminal body weights and the thyroid and parathyroid glands weights were not altered. However, the liver weights and numbers of Ki67-positive cells were increased. Further, multivariate statistical analysis revealed that metabolic shifts were considerably altered above 30 mg DEHP/kg bw/day. In RNA-seq analysis, some cancer-related genes were altered, including 18 upregulated and 9 downregulated transcripts. These cancer transcripts and whole metabolome data were integrated to uncover thyroid cancer-related metabolic pathways, which revealed that cancer-related transcripts had a network structure linked to eicosanoids such as leukotriene D4 and prostaglandin. In brief, our study demonstrated that DEHP can induce thyroid hyperplasia through the eicosanoid-associated pathway, providing further insight into the mechanism of DEHP-associated thyroid cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Uterine scar was one of the long-term complications cesarean section. In this study, an thermo-responsive injectable hydrogel loaded with human umbilical cord mesenchymal stem cells (UCMSCs) and asiaticoside microspheres (AMs) was used for uterine scar repair, which was prepared by optimizing the mixed ratio of aldehyde-functionalized Pluronic F127 (F127-CHO) and adipic dihydrazide-modified hyaluronic acid (AHA). The asiaticoside was loaded in Poly (DL-lactide-co-gycolide) (PLGA) by emulsion- diffusion-evaporation method. The hydrogel had appropriate pore size, good mechanical property, and slow release ability of asiaticoside. In vitro cell experiments demonstrated that F127-CHO/AHA/AMs could effectively promote stem cell adhesion and proliferation, promote angiogenesis, and provide a suitable microenvironment for cell survival. The F127-CHO/AHA/AMs/UCMSCs hydrogel was further used to repair uterine scar in female SD rats. The results showed that the prepared hydrogel could promote the proliferation of rat endometrial cells, promote the regeneration of glands, reduce the degree of endometrial fibrosis and restore the morphology of uterine cavity. The hydrogel could upregulate expression of Ki67 and IGF-1, downregulate TGF-β1 expression and promote M1-M2 transition of macrophages. This study confirmed that the prepared hydrogel could be used as an effective transplantation strategy, which could be expected to achieve clinical transformation of uterine scar repair., Competing Interests: Declaration of competing interest No competing financial interests exist., (Copyright © 2022. Published by Elsevier B.V.)

Background: Complex interactions between cancer and the immune system have an impact on disease progression and therapeutic response. Our objective was to evaluate whether circulating immune-related determinants are associated with pathological complete response (pCR) in patients with locally advanced breast cancer (LABC) subjected to neoadjuvant chemotherapy (NACT)., Patients and Methods: Luminex technology was used to profile 22 cytokines, 10 chemokines, FGF2, PDGF-BB, VEGF, and Ca15-3/Ca125 glycoforms. Measurements were performed alongside standard hematological determinations on pretreatment plasma samples from 151 patients including 41 cases with pCR assessed following RECIST criteria., Results: Random Forest model analysis selected platelets, eotaxin, IFN-γ, IP10, and TGFβ2 as significant predictors of pCR. These immune-related features were combined into a quantitative score predictive of pCR. In patients who scored 0 or 1, none had pCR; the pCR frequency increased in relation to the score value (23.5%, 41.2%, and 78.6%, in score groups 2, 3, and 4, respectively). At multivariable logistic analysis, the pCR score was highly significant (odds ratio = 3.15 per unit increment; CI: 1.85-5.38; P < .0001); among clinical covariates (age, menopausal status, tumor stage, IHC subtype, Ki-67, CA15.3, and CA125), only Ki-67 was statistically significant (P = .013)., Conclusion: This explorative study aimed to lay the conceptual and practical foundation that a distinctive pattern of the immune determinant blood signature at diagnosis of LABC significantly correlates with the patient's response to NACT and provides the groundwork for larger studies that could lead to a minimally invasive tool for personalized medicine., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Inflammation plays a significant role in carcinogenesis and tumor growth. The current study was designed to test the hypothesis that resolvin E1 (RvE1) and overexpression of the receptor for RvE1 (ERV1) will prevent and/or reverse tumor generation in a gain-of-function mouse model of tumor seeding with lung cancer cells. To measure the impact of enhanced resolution of inflammation on cancer pathogenesis, ERV1-overexpressing transgenic (TG) and wild-type FVB mice were given an injection of 1 × 10 6 LA-P0297 cells subcutaneously and were treated with RvE1 (100 ng; intraperitoneally) or placebo. To assess the impact of RvE1 as an adjunct to chemotherapy, ERV1-TG and wild-type FVB mice were treated with cisplatin or cisplatin + RvE1. RvE1 significantly prevented tumor growth and reduced tumor size, cyclooxygenase-2, NF-κB, and proinflammatory cytokines in TG animals as compared to wild-type animals. A significant decrease in Ki-67, vascular endothelial growth factor, angiopoietin (Ang)-1, and Ang-2 was also observed in TG animals as compared to wild-type animals. Tumor-associated neutrophils and macrophages were significantly reduced by RvE1 in transgenics (P < 0.001). RvE1 administration with cisplatin led to a significant reduction of tumor volume and reduced cyclooxygenase-2, NF-κB, vascular endothelial growth factor-A, Ang-1, and Ang-2. These data suggest that RvE1 prevents inflammation and vascularization, reduces tumor seeding and tumor size, and, when used as an adjunct to chemotherapy, enhances tumor reduction at significantly lower doses of cisplatin., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: To explore the value of apparent diffusion coefficient (ADC) histogram analysis in preoperative evaluating intracranial solitary fibrous tumor (SFT) and further investigate the relationship between ADC histogram parameters and the Ki-67 proliferation index., Methods: From January 2014 to March 2022, 37 patients with intracranial SFT (grade 2, n = 20; grade 3, n = 17) who underwent preoperative diffusion-weighted imaging were enrolled in this study. For each tumor, nine histogram parameters were automatically extracted and selected using MaZda software based on the axial ADC maps of the whole tumor, including mean, variance, skewness, kurtosis, as well as the 1st, 10th, 50th, 90th, and 99th percentile ADC (Perc.01, Perc.10, Perc.50, Perc.90, Perc.99). Differences in ADC histogram parameters between grade 2 and 3 intracranial SFT were compared. Receiver operating characteristic (ROC) curves were drawn to determine the diagnostic performance, and Pearson's correlation coefficient was used to investigate the relationship between these parameters and the Ki-67 proliferation index., Results: The mean, Perc.01, Perc.10, Perc.50, Perc.90, and Perc.99 were significantly lower in grade 3 than in grade 2 intracranial SFT (all P &lt; 0.05). ROC analysis showed that these parameters can effectively distinguish between the two groups, with Perc.01 generating the best differentiation performance. Significant negative correlations were also observed between these parameters and the Ki-67 proliferation index (r = -0.436 ~ -0.522, all P &lt; 0.05). However, there was no significant difference in variance, skewness, or kurtosis between the two groups (all P &gt; 0.05)., Conclusions: ADC histogram analysis enables effective preoperative distinction of grade 2 and grade 3 intracranial SFT., (Copyright © 2022 Elsevier B.V. All rights reserved.)

To the best of our knowledge, artificial intelligence stain generation is an urgent requirement for histopathology images. Pathological examinations usually only utilize hematoxylin and eosin (H&E) regular staining to show histomorphological characteristics, but to accurately diagnose the disease, functional staining (such as oil red O and Ki67) are also required to provide important auxiliary information. However, the same tissue section is usually stained with one stain, and additional functional staining is not only time-consuming but also causes inevitable morphological misalignment due to manual manipulation. This brings difficulties to the development of artificial intelligence pathological image analysis tools. In this work, we propose a histopathology staining transfer framework to generate virtual functional staining images from H&E regular staining images. Compared with the framework that emphasizes generation diversity in the natural image field, we use KL loss and histo loss to align and separate style feature spaces in different domains to obtain domain-variant style features. The proposed multiple virtual functional stain (MVFStain) abstracts staining conversion to domain mapping and comprehensively utilizes multiple staining information. We evaluated the proposed method on four datasets (lung lesion, lung lobes, breast, and atherosclerotic lesion). The experiment involves the translation of H&E to nine other functional stains: CC10, Ki67, proSPC, HER2, PR, ER, oil red O, α-SMA, and macrophages. The major quantitative results are divided into image quality and positive signal prediction. MVFStain is close to or even surpasses one-to-one image translation on psnr and HTI image quality metrics. The best psnr reaches 26.1919, and HIT reaches 0.9430. We used mIOD to evaluate the optical density of positive signals, and CNR and gCNR to evaluate the lesion detectability. The results show that the mIOD of positive signals of virtual staining was slightly lower than the ground truth and close the lesion detectability of artificial staining. These results prove that the potential exists to develop a successful clinical alternative to artificial functional stains., 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 © 2022 Elsevier B.V. All rights reserved.)

Objectives: Ki67 is an important biomarker of pituitary adenoma (PA) aggressiveness. In this study, PA invasion of surrounding structures is investigated and deep learning (DL) models are established for preoperative prediction of Ki67 labeling index (Ki67LI) status using conventional magnetic resonance (MR) images., Methods: We reviewed 362 consecutive patients with PAs who underwent endoscopic transsphenoidal surgery, of which 246 patients with primary PA are selected for PA invasion analysis. MRI data from 234 of these PA patients are collected to develop DL models to predict Ki67LI status, and DL models were tested on 27 PA patients in the clinical setting., Results: PA invasion is observed in 46.8% of cases in the Ki67 ≥ 3% group and 33.3% of cases in the Ki67 < 3% group. Three deep-learning models are developed using contrast-enhanced T1-weighted images (ceT1WI), T2-weighted images (T2WI), and multimodal images (ceT1WI+T2WI), respectively. On the validation dataset, the prediction accuracy of the ceT1WI model, T2WI model, and multimodal model were 87.4%, 89.4%, and 89.2%, respectively. In the clinical test, 27 MR slices with the largest tumors from 27 PA patients were tested using the ceT1WI model, T2WI model, and multimodal model, the average accuracy of Ki67LI status prediction was 63%, 77.8%, and 70.4%, respectively., Conclusion: Preoperative prediction of PA Ki67LI status in a noninvasive way was realized with the DL model by using MRI. T2WI model outperformed the ceT1WI model and multimodal model. This end-to-end model-based approach only requires a single slice of T2WI to predict Ki67LI status and provides a new tool to help clinicians make better PA treatment decisions., (Copyright © 2022 Elsevier B.V. All rights reserved.)