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PURPOSE: This study investigated whether Ki-67 labeling index (LI) correlated with clinical outcomes after SRS for atypical meningiomas. METHODS: This retrospective study examined 39 patients with atypical meningiomas who underwent SRS over a 10-year study period. Ki-67 LI was categorized into 3 groups: low ( 10%). Local tumor control rates (LCRs), progression-free rates (PFRs), disease-specific survival (DSS) rates, and adverse radiation-induced events (AREs) were evaluated. RESULTS: The median follow-up periods were 26 months. SRS was performed at a median prescription dose of 18 Gy for tumors with a median Ki-67 LI of 9.6%. The 3-year LCRs were 100%, 74%, and 25% in the low, intermediate, and high LI groups, respectively (p = 0.011). The 3-year PFRs were 100%, 40%, and 0% in the low, intermediate, and high LI groups (p = 0.003). The 5-year DSS rates were 100%, 89%, and 50% in the low, intermediate, and high LI groups (p = 0.019). Multivariable Cox proportional hazard analysis showed a significant correlation of high LI with lower LCR (hazard ratio [HR], 3.92; 95% confidence interval [CI] 1.18-13.04, p = 0.026), lower PFR (HR 3.80; 95% CI 1.46-9.88, p = 0.006), and shorter DSS (HR 6.55; 95% CI 1.19-35.95, p = 0.031) compared with intermediate LI. The ARE rates were minimal (8%) in the entire group. CONCLUSION: Patients with high Ki-67 LI showed significantly more tumor progression and tumor-related death. Ki-67 LI might offer valuable predictive insights for the post-SRS management of atypical meningiomas.

Purpose To compare quantitative measures of tumor metabolism and perfusion using fluorine 18 (18F) fluorodeoxyglucose (FDG) dedicated breast PET (dbPET) and breast dynamic contrast-enhanced (DCE) MRI during early treatment with neoadjuvant chemotherapy (NAC). Materials and Methods Prospectively collected DCE MRI and 18F-FDG dbPET examinations were analyzed at baseline (T0) and after 3 weeks (T1) of NAC in 20 participants with 22 invasive breast cancers. FDG dbPET-derived standardized uptake value (SUV), metabolic tumor volume, and total lesion glycolysis (TLG) and MRI-derived percent enhancement (PE), signal enhancement ratio (SER), and functional tumor volume (FTV) were calculated at both time points. Differences between FDG dbPET and MRI parameters were evaluated after stratifying by receptor status, Ki-67 index, and residual cancer burden. Parameters were compared using Wilcoxon signed rank and Mann-Whitney U tests. Results High Ki-67 tumors had higher baseline SUVmean (difference, 5.1; P = .01) and SUVpeak (difference, 5.5; P = .04). At T1, decreases were observed in FDG dbPET measures (pseudo-median difference T0 minus T1 value [95% CI]) of SUVmax (-6.2 [-10.2, -2.6]; P < .001), SUVmean (-2.6 [-4.9, -1.3]; P < .001), SUVpeak (-4.2 [-6.9, -2.3]; P < .001), and TLG (-29.1 mL3 [-71.4, -6.8]; P = .005) and MRI measures of SERpeak (-1.0 [-1.3, -0.2]; P = .02) and FTV (-11.6 mL3 [-22.2, -1.7]; P = .009). Relative to nonresponsive tumors, responsive tumors showed a difference (95% CI) in percent change in SUVmax of -34.3% (-55.9%, 1.5%; P = .06) and in PEpeak of -42.4% (95% CI: -110.5%, 8.5%; P = .08). Conclusion 18F-FDG dbPET was sensitive to early changes during NAC and provided complementary information to DCE MRI that may be useful for treatment response evaluation. Keywords: Breast, PET, Dynamic Contrast-enhanced MRI Clinical trial registration no. NCT01042379 Supplemental material is available for this article. © RSNA, 2024.

This study examined to evaluate the predictive value of a nomogram with Ki-67 in overall and disease-free survival in glioma patients, a total of 76 patients diagnosed with glioma by pathology in Tengzhou Central People's Hospital were enrolled. The baseline data and follow ups were retrospectively collected from medical records. The associations between Ki-67 and survival status were examined using log-rank test, univariate and multivariate Cox proportional hazard regression models. Calibrations were performed to validate the established nomograms. Ki-67 negative group showed of a longer OS survival time and a longer PFS survival time with log-rank test (x2 = 16.101, P < 0.001 and x2 = 16.961, P < 0.001). Age older than 50 years (HR = 2.074, 95% CI 1.097–3.923), abnormal treatment (HR = 2.932, 95% CI 1.343–6.403) and Ki-67 positive (HR = 2.722, 95% CI 1.097–6.755) were the independent predictive factors of death. High grade pathology (HR = 2.453, 95% CI 1.010–5.956) and Ki-67 positive (HR = 2.200, 95% CI 1.043–4.639) were the independent predictive factors of recurrence. The C-index for the nomogram of OS and PFS were 0.745 and 0.723, respectively. The calibration results showed that the nomogram could predict the overall and disease-free 1-year survival of glioma patients. In conclusion, the nomograms with Ki-67 as independent risk factor for OS and PFS could provide clinical consultation in the treatment and follow-up of malignant glioma. [ABSTRACT FROM AUTHOR]

Purpose: To explore the value of deep learning-based multi-parametric magnetic resonance imaging (mp-MRI) nomogram in predicting the Ki-67 expression in rectal cancer. Methods: The data of 491 patients with rectal cancer from two centers were retrospectively analyzed and divided into training, internal validation, and external validation sets. They were categorized into high- and low-expression group based on postoperative pathological Ki-67 expression. Each patient's mp-MRI data were analyzed to extract and select the most relevant features of deep learning, and a deep learning model was constructed. Independent predictive risk factors were identified and incorporated into a clinical model, and the clinical and deep learning models were combined to obtain a nomogram for the prediction of Ki-67 expression. The performance characteristics of the DL-model, clinical model, and nomogram were assessed using ROCs, calibration curve, decision curve, and clinical impact curve analysis. Results: The strongest deep learning features were extracted and screened from mp-MRI data. Two independent predictive factors, namely Magnetic Resonance Imaging T (mrT) staging and differentiation degree, were identified through clinical feature selection. Three models were constructed: a deep learning (DL)-model, a clinical model, and a nomogram. The AUCs of clinical model in the training, internal validation, and external validation set were 0.69, 0.78, and 0.67, respectively. The AUCs of the deep model and nomogram ranged from 0.88 to 0.98. The prediction performance of the deep learning model and nomogram was significantly better than the clinical model (P < 0.001). Conclusion: The nomogram based on deep learning can help clinicians accurately and conveniently predict the expression status of Ki-67 in rectal cancer. [ABSTRACT FROM AUTHOR]

Proliferating cell nuclear antigen is a marker of cell proliferation and genomic maintenance. The protein undergoes several post-translational modifications that expand its playground and amplify its functions. Ubiquitylation, sumoylation, acetylation, phosphorylation, and nitrosylation are some of the modifications that confer a plethora of protein interactions with the antigen. These interactions regulate abundant functions like DNA replication, DNA damage control, and cell cycle control. Due to the versatile functions of the antigen, it may serve as a marker or target for therapeutic intervention for various diseases. This protein can be used as a marker for studies done to validate growth in medical and dental fields. The growth and proliferation of cells is a necessary factor for cancer to progress, both at primary and metastatic sites. It was proposed that PCNA can aid in not only the identification but also as a therapeutic agent for the disease due to its role in cell proliferation and DNA damage control. This review expounds on the structure and functions of PCNA. It discusses how the interactions of the antigen with other proteins can be used to block or enhance the functions of the cell being commanded by the antigen. [ABSTRACT FROM AUTHOR]

Background: Myxofibrosarcoma is a myxoid soft tissue sarcoma showing T2 high intensity on magnetic resonance imaging. However, myxofibrosarcoma is a heterogeneous sarcoma with both myxoid and cellular portions. Magnetic resonance imaging findings were obtained MRI findings for comparison with histological and Ki-67 immunohistochemical features, in different portions of one myxofibrosarcoma. Case presentation: Magnetic resonance imaging observations were compared with gross pathological and microscopic findings of a myxofibrosarcoma from a 50-year-old Japanese female. The Ki-67 labeling indices of different portions of the tumor, that is, the myxoid, cellular, and histologically confirmed infiltrative margin portions (pathological tail sign), were compared. The T2 low intensity area was more cellular than the T2 high intensity area, while the cellular portion had a significantly higher Ki-67 index than the myxoid portion (p = 0.0313). The portions with the pathological tail sign had a significantly higher Ki-67 labeling index than those without this sign (p = 0.0313). Conclusions: More cellular portions of a myxofibrosarcoma correspond to more areas of the tumor showing aggressive features. Furthermore, our data also support the hypothesis of high aggressiveness being associated with the pathological tail sign in myxofibrosarcoma. To our knowledge, this is the first case report to describe comparisons among the imaging findings, histological features, and Ki-67 immunohistochemistry results for different portions of one myxofibrosarcoma. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between expression levels of epidermal growth factor receptor (EGFR), proliferation marker protein Ki-67 (Ki-67), P53 and circulating tumor cell (CTC) and the prognosis of triple negative breast cancer. Methods A total of 95 patients with triple negative breast cancer were selected. The expression levels of EGFR, Ki-67 and P53 in pathological tissue specimens were detected by immunohistochemistry. All patients underwent 8 cycles of chemotherapy, and the expression of CTC was detected before and after chemotherapy by isolation epithelial tumor cells (ISET). The relationship between CTC expression before and after chemotherapy and efficacy of chemotherapy was analyzed. The correlation between CTC and expression levels of EGFR, Ki-67 and P53 was analyzed. Patients were followed up for progression free survival (PFS). Risk factors of progression for triple negative breast cancer were analyzed by COX regression. Results The positive detection rates of EGFR, Ki-67 and P53 were 44.21% (42/95), 63.16% (60/95) and 56.84% (54/95). The positive detection rate of CTC was lower in patients after chemotherapy than that before chemotherapy (14.74% vs. 61.05%, P＜0.05). The efficacy of chemotherapy was negatively correlated with the positive expression of CTC after chemotherapy (P＜0.001). COX regression analysis found that clinical stage Ⅲ, positive EGFR and CTC after chemotherapy were independent risk factors of progression of triple negatively breast cancer (P＜0.05). PFS of patients at clinical stage Ⅰ, stage Ⅱ, and stage Ⅲ decreased in order (P＜0.05). PFS of EGFR positive patients was shorter than that of EGFR negative patients (P＜0.05). PFS of CTC positive patients after chemotherapy was shorter than that of CTC negative patients after chemotherapy (P＜0.05). Conclusion The positive expression of EGFR before chemotherapy and the positive expression of CTC after chemotherapy are related to the poor survival prognosis of patients with triple negative breast cancer. The lower the positive detection rate of CTC after chemotherapy, the better the efficacy of chemotherapy. [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]

Morphological and immunohistochemical studies of solid arrangement canine mammary carcinomas have shown that the different histological types may be characterized by proliferation of epithelial and/or myoepithelial cells. However, little is known about immunophenotypes and the importance of inflammation as prognostic factors in these neoplasms. The objective of the present study was to characterize the immunophenotype and degree of inflammation in the solid type of canine mammary neoplasm and to investigate their association with metastasis, Ki-67 index, tumour size, necrosis and survival. Sixty-five carcinomas with solid pattern, basaloid carcinomas, solid papillary carcinomas, malignant adenomyoepitheliomas (MAMEs) or malignant myoepitheliomas (MMEs) were investigated. Luminal A, luminal B HER2 negative and HER2 positive, HER2 overexpressed and triple negative immunophenotypes were immunolabelled as were Ki-67 protein and cyclooxygenase-2 (Cox-2). Histological peritumoural and intratumoural inflammatory infiltrates were graded (distribution × intensity) and the presence of necrosis identified. We found a statistical difference between histological types and immunophenotypes, with MME and MAME having a higher occurrence of luminal A, whereas most neoplasms had the luminal B HER-negative immunophenotype. There was no correlation between immunophenotype and degree of peri- and intratumoural inflammation, nodal metastasis, necrosis or tumour size. An increased degree of peri- and intratumoural inflammation was significantly associated with lymph node metastasis, and more severe intratumoural inflammation was associated with the presence of tumour necrosis. Tumour size, Ki-67 index and Cox-2 score were not associated with inflammation in either peri- or intratumoural regions. No difference was observed in survival in relation to immunophenotype or degree of inflammation, but the Cox regression model revealed that nodal metastasis influenced the risk of death. [ABSTRACT FROM AUTHOR]

Mutations resulting in decreased activity of p53 tumor suppressor protein promote tumorigenesis. P53 protein levels are tightly regulated through the Ubiquitin Proteasome System (UPS). Several E3 ligases were shown to regulate p53 stability, including MDM2. Here we report that the ubiquitin E3 ligase XIAP (X-linked Inhibitors of Apoptosis) is a direct ligase for p53 and describe a novel approach for modulating the levels of p53 by targeting the XIAP pathway. Using in vivo (live-cell) and in vitro (cell-free reconstituted system) ubiquitylation assays, we show that the XIAP-antagonist ARTS regulates the levels of p53 by promoting the degradation of XIAP. XIAP directly binds and ubiquitylates p53. In apoptotic cells, ARTS inhibits the ubiquitylation of p53 by antagonizing XIAP. XIAP knockout MEFs express higher p53 protein levels compared to wild-type MEFs. Computational screen for small molecules with high affinity to the ARTS-binding site within XIAP identified a small-molecule ARTS-mimetic, B3. This compound stimulates apoptosis in a wide range of cancer cells but not normal PBMC (Peripheral Blood Mononuclear Cells). Like ARTS, the B3 compound binds to XIAP and promotes its degradation via the UPS. B3 binding to XIAP stabilizes p53 by disrupting its interaction with XIAP. These results reveal a novel mechanism by which ARTS and p53 regulate each other through an amplification loop to promote apoptosis. Finally, these data suggest that targeting the ARTS binding pocket in XIAP can be used to increase p53 levels as a new strategy for developing anti-cancer therapeutics. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma (NHL) that accounts for approximately 25–40% of all NHL cases. The objective of this study was to investigate the protein expression, clinical impact, and prognostic role of MYC, BCL2, and Ki-67 in Thai DLBCL patients. A retrospective analysis was conducted on 100 DLBCL patients diagnosed between January 2018 and December 2019. Immunohistochemistry was used to assess the expression of MYC, BCL2, and Ki-67. The study revealed a significant association between extranodal involvement and positive cases of MYC and BCL2. MYC expressions were associated with Ki-67 expression, while BCL2 positivity was associated with the non-germinal center B-cell (non-GCB) subtype. However, there were no significant differences in the three-year overall survival (OS) and three-year progression-free survival (PFS) rates when using cut-off points of ≥ 40% for MYC, ≥ 50% for BCL2, and ≥ 70% for Ki-67. Notably, DLBCL cases with co-expression of MYC and BCL2 exhibited significantly inferior three-year OS compared to other cases (0% vs. 53%; p = 0.020). Multivariate analysis identified age ≥ 60 years and Eastern Cooperative Oncology Group (ECOG) performance status as independent prognostic factors. In conclusion, MYC, BCL2, and Ki-67 expression can serve as prognostic biomarkers; however, their prognostic value may vary based on the specific cut-off values used. Therefore, determining the appropriate threshold for each biomarker based on individual laboratory analyses and clinical outcomes is crucial. [ABSTRACT FROM AUTHOR]

This research letter discusses the assessment of Ki-67 and mitoses in pituitary neuroendocrine tumors (PitNETs). The study found that there is an inverse relationship between the number of PitNET cells assessed and the Ki-67 proliferative index (PI) obtained. The authors suggest that digital Ki-67 PI and mitotic counts may have limited clinical value and question their efficacy as stand-alone tools for histopathological assessment and prognostication of PitNETs. They recommend consistent Ki-67 scoring approaches and re-evaluation of the recommended Ki-67 PI 3% cut-off to clarify this controversial topic. [Extracted from the article]

Aim: Tumor Ki‐67 expression reflects prognosis and cancer grade, and biopsy‐based preoperative assessment of Ki‐67 expression is key to treatment. Apparent diffusion coefficient (ADC) values obtained with this imaging may noninvasively predict Ki‐67 by reflecting tumor cell density and limited water molecule movement from irregular alignment. This study aimed to investigate the ability of ADC values to predict Ki‐67 expression in intrahepatic cholangiocarcinoma (ICC). Method: We retrospectively analyzed 39 cases of ICC confirmed by surgical pathology. All patients had undergone magnetic resonance imaging, and ADC values (mean, minimum, and maximum) were calculated. Ki‐67 expression was assessed by immunohistochemistry, and patients were divided into groups of high (n = 18) and low (n = 21) Ki‐67 expression. To assess the diagnostic performance of the ADC values for Ki‐67 expression, we used the receiver operating characteristic curve and compared the areas under the curve (AUC). Results: The mean and minimum ADC values were significantly lower in the group with high Ki‐67 expression. For predicting high Ki‐67 expression, the AUC values were 0.701 for mean ADC, 0.818 for minimum ADC, and 0.571 for maximum ADC. The diagnostic sensitivity and specificity of the minimum ADC values were 88.9% and 76.2%, respectively. In addition, with ADC values combined, the AUC increased to 0.831. Apparent diffusion coefficient is a useful predictor of Ki‐67 expression level in ICC. Conclusion: Apparent diffusion coefficient values, especially minimum ADC values, can noninvasively predict ICC associated with high Ki‐67 expression. [ABSTRACT FROM AUTHOR]

Ki‐67, a nuclear protein expressed in all stages of cellular proliferation, is a valuable tool to assess tumor proliferation and has been linked to more aggressive tumor behavior. However, interlaboratory staining heterogeneity and inter‐observer variability challenge its reproducibility. Round Robin tests are a suitable tool to standardize and harmonize immunohistochemical and molecular analyses in histopathology. The study investigates the interrater and interlaboratory reproducibility of Ki‐67‐scoring using both manual and automated approaches. Unstained TMA slides comprising diverse tumor types (breast cancer, neuroendocrine tumors, lymphomas, and head and neck squamous cell carcinoma) were distributed to six pathology laboratories, each employing their routine staining protocols. Manual and automated scoring methods were applied, and interrater and interlaboratory agreement assessed using intraclass correlation coefficients (ICC). The results highlight good‐to‐excellent reliability overall, with automated scoring demonstrating higher consistency (ICC 0.955) than manual scoring (ICC 0.871). Results were more variable when looking at the individual entities. Reliability remained good for lymphomas (ICC 0.878) and breast cancer (ICC 0.784) and was poor in well‐differentiated neuroendocrine tumors (ICC 0.354). This study clearly advocates standardized practices and training to ensure consistency in Ki‐67‐assessment, and it demonstrates that this can be achieved in a peer‐to‐peer approach in local quality‐circles. [ABSTRACT FROM AUTHOR]

This report describes the clinical, onychoscopic, nail clipping, and histopathologic features of a malignant onychopapilloma. A 71‐year‐old male presented to our outpatient clinic for a stable, asymptomatic lesion on his left middle finger that had been present for 2 years. Prior nail clipping histopathology showed nail plate thinning with subungual abnormal onychocytes. Clinical examination revealed a 2‐mm‐wide streak of longitudinal xanthonychia extending to the proximal nail fold, with distal hyperkeratosis and onycholysis. Onychoscopy showed irregular longitudinal nail plate ridging with scattered punctate hemorrhagic foci. An excisional nail unit biopsy demonstrated cellular atypia of the nail bed epithelium, matrix metaplasia, longitudinal abnormal onychocytes, increased Ki‐67 staining, and negative HPV immunoperoxidase staining, confirming the diagnosis of malignant onychopapilloma. [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]

Spinal clear cell meningiomas (CCMs) are a rare histological subtype of meningiomas that pose preoperative diagnostic challenges due to their radiographic similarities with other lesions. They are also more aggressive, exhibiting higher rates of recurrence, particularly in pediatric patients. Overcoming diagnostic challenges of these tumors can improve patient outcomes. In this report, we describe a case of a pediatric patient presenting with a lumbar CCM in whom we were able to obtain gross total resection. Our report reviews previously identified predictors of CCM recurrence, including the Ki-67 proliferation index, number of spinal segments involved, and hormonal influences related to age and sex. We describe the characteristic radiographic features that differentiate spinal CCMs from other tumors to improve pre-operative diagnosis. Furthermore, we provide our rationale for adjuvant therapy for pediatric patients to refine treatment protocols for these rare tumors. [ABSTRACT FROM AUTHOR]

Nuclear expression of β-catenin has been reported in canine intestinal epithelial tumors (IETs) and colorectal inflammatory polyps (CIPs) with dysplastic epithelia. However, the role of the Wnt/β-catenin signaling pathway in these lesions remains unclear. To investigate the association between the nuclear β-catenin expression and the activation of the Wnt/β-catenin signaling pathway, immunohistochemistry and mutation analyses were conducted on 64 IETs and 20 CIPs. IETs and CIPs with β-catenin nuclear and/or cytoplasm immunolabeling were classified as β-catenin (+). The immunostaining scores of c-Myc and Cyclin D1 and Ki-67 index were significantly higher in β-catenin (+) cases than in β-catenin (-) cases. Identical APC mutations (p.E154D and p.K155X) were detected in 6/41 β-catenin (+) IETs; all 6 of IETs with APC mutations were Jack Russell Terriers. CTNNB1 mutations were detected in 29/42 β-catenin (+) IETs, 3/11 β-catenin (+) CIPs, and 2/22 β-catenin (-) IETs, most of which were hotspots associated with human colorectal carcinoma. In one Miniature Dachshund diagnosed with a CIP that subsequently developed into an IET, the same CTNNB1 mutation was detected in both lesions. The immunohistochemical results suggest that cell proliferative activity in β-catenin (+) cases may be associated with activation of the Wnt/β-catenin signaling pathway. The mutation analysis results suggest that CTNNB1 mutations may be associated with cytoplasmic β-catenin accumulation in IET and CIP. Furthermore, the dysplastic epithelium in CIP may progress to IET through the activation of the Wnt/β-catenin signaling pathway by the CTNNB1 mutation. [ABSTRACT FROM AUTHOR]

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Canine splenic hemangiosarcoma has a high metastatic rate and short survival time. Currently, the main prognostic parameters are tumor stage and therapy, while data on histologic parameters, such as grade and Ki-67 expression, are scarce. The aims of this study were to compare two methods of assessment of Ki-67, verify their prognostic impact, and define a threshold value based on survival. Thirty-one cases of histologically diagnosed canine splenic hemangiosarcoma, which were treated with splenectomy and had full staging and follow-up information, were collected. Three were stage I, 17 stage II, and 11 stage III. The mean mitotic count (MC) was 23.9 (standard deviation [SD]: 22.1) and the median was 15 (range, 1–93). Immunohistochemistry for Ki-67 was performed, the Ki-67 labeling index (Ki-67LI) was assessed as a percentage of positive neoplastic nuclei per ≥500 cell, and the Ki-67 count (KI-67C) was defined as the average number of positive nuclei using a 1 cm2 optical grid performed in 5, 40× fields. The mean Ki-67LI and Ki-67C were 56.4% (SD: 38.7) and 27.2 (SD: 12.9) and medians were 51% (range, 8.2–55.2) and 26 (range, 5.5–148), respectively. Using a cut-off of 56% and 9, respectively, Kaplan-Meier survival curves showed an association of overall survival with Ki-67LI and MC. In addition to clinical stage, Ki-67LI maintained its prognostic value on multivariate analysis, supporting the role of Ki-67LI as an independent prognostic parameter. Based on these results, we propose a diagnostically applicable cut-off value of 56% for Ki-67LI as a prognostic parameter for canine splenic hemangiosarcoma. [ABSTRACT FROM AUTHOR]

To investigate the association of quantitative parameter (apparent diffusion coefficient [ADC]) from diffusion-weighted imaging (DWI) and various quantitative and semiquantitative parameters from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) with Ki-67 proliferation index (PI) in cervical carcinoma (CC). A total of 102 individuals with CC who received 3.0 T MRI examination (DWI and DCE MRI) between October 2016 and December 2022 were enrolled in our investigation. Two radiologists separately assessed the ADC parameter and various quantitative and semiquantitative parameters including (volume transfer constant [ K trans ], rate constant [ k ep ], extravascular extracellular space volume fraction [ v e ], volume fraction of plasma [ v p ], time to peak [TTP], maximum concentration [MaxCon], maximal slope [MaxSlope] and area under curve [AUC]) for each tumor. Their association with Ki-67 PI was analyzed by Spearman association analysis. The discrepancy between low-proliferation and high-proliferation groups was subsequently analyzed. The receiver operating characteristic (ROC) curve analysis utilized to identify optimal cut-off points for significant parameters. Both ADC (ρ = − 0.457, p < 0.001) and K trans (ρ = − 0.467, p < 0.001) indicated a strong negative association with Ki-67 PI. Ki-67 PI showed positive correlations with TTP, MaxCon, MaxSlope and AUC (ρ = 0.202, 0.231, 0.309, 0.235, respectively; all p values<0.05). Compared with the low-proliferation group, high-Ki-67 group presented a significantly lower ADC (0.869 ± 0.125 × 10−3 mm2/s vs. 1.149 ± 0.318 × 10−3 mm2/s; p < 0.001) and K trans (1.314 ± 1.162 min−1vs. 0.391 ± 0.390 min−1; p < 0.001), also significantly higher MaxCon values (0.756 ± 0.959 vs. 0.422 ± 0.341; p < 0.05) and AUC values (2.373 ± 3.012 vs. 1.273 ± 1.000; p < 0.05). The cut-offs of ADC, K trans , MaxCon and AUC for discrimating low- and high-Ki-67 groups were 0.920 × 10−3 mm2/s, 0.304 min−1, 0.209 and 1.918, respectively. ADC, K trans, TTP, MaxCon, MaxSlope and AUC are associated with Ki-67 PI. ADC and K trans exhibited high performance to discriminate low and high Ki-67 status of CC. • ADC and K trans were significantly and inversely correlated with Ki-67 proliferation index in cervical cancer. • In the high-Ki67 PI group, ADC and K trans were significantly lower than those of the low-Ki67 PI group. • DWI and DCE parameters could be used to predict the Ki-67 PI in cervical cancer. [ABSTRACT FROM AUTHOR]

Abstract Background We investigated the value of three-dimensional amide proton transfer-weighted imaging (3D-APTWI) in the diagnosis of early-stage breast cancer (BC) and its correlation with the immunohistochemical characteristics of malignant lesions. Methods Seventy-eight women underwent APTWI and dynamic contrast-enhanced (DCE)-MRI. Pathological results were categorized as either benign (n = 43) or malignant (n = 37) lesions. The parameters of APTWI and DCE-MRI were compared between the benign and malignant groups. The diagnostic value of 3D-APTWI was evaluated using the area under the receiver operating characteristic curve (ROC-AUC) to establish a diagnostic threshold. Pearson’s correlation was used to analyze the correlation between the magnetization transfer asymmetry (MTRasym) and immunohistochemical characteristics. Results The MTRasym and time-to-peak of malignancies were significantly lower than those of benign lesions (all p < 0.010). The volume transfer constant, rate constant, and wash-in and wash-out rates of malignancies were all significantly greater than those of benign lesions (all p < 0.010). ROC-AUCs of 3D-APTWI, DCE-MRI, and 3D-APTWI+DCE to differential diagnosis between early-stage BC and benign lesions were 0.816, 0.745, and 0.858, respectively. Only the difference between AUCAPT+DCE and AUCDCE was significant (p < 0.010). When a threshold of MTRasym for malignancy for 2.42%, the sensitivity and specificity of 3D-APTWI for BC diagnosis were 86.5% and 67.6%, respectively; MTRasym was modestly positively correlated with pathological grade (r = 0.476, p = 0.003) and Ki-67 (r = 0.419, p = 0.020). Conclusions 3D-APTWI may be used as a supplementary method for patients with contraindications of DCE-MRI. MTRasym can imply the proliferation activities of early-stage BC. Relevance statement 3D-APTWI can be an alternative diagnostic method for patients with early-stage BC who are not suitable for contrast injection. Key points • 3D-APTWI reflects the changes in the microenvironment of early-stage breast cancer. • Combined 3D-APTWI is superior to DCE-MRI alone for early-stage breast cancer diagnosis. • 3D-APTWI improves the diagnostic accuracy of early-stage breast cancer. Graphical Abstract

Purpose: Based on comparison of different machine learning (ML) models, we developed the model that integrates traditional hand-crafted (HC) features and ResNet50 network-based deep transfer learning (DTL) features from multiparametric MRI to predict Ki-67 status in sinonasal squamous cell carcinoma (SNSCC). Methods: Two hundred thirty-one SNSCC patients were retrospectively reviewed [training cohort (n = 185), test cohort (n = 46)]. Pathological grade, clinical, and MRI characteristics were analyzed to choose the independent predictor. HC and DTL radiomics features were extracted from fat-saturated T2-weighted imaging, contrast-enhanced T1-weighted imaging, and apparent diffusion coefficient map. Then, HC and DTL features were fused to formulate the deep learning-based radiomics (DLR) features. After feature selection and radiomics signature (RS) building, we compared the predictive ability of RS-HC, RS-DTL, and RS-DLR. Results: No independent predictors were found based on pathological, clinical, and MRI characteristics. After feature selection, 42 HC and 10 DTL radiomics features were retained. The support vector machine (SVM), LightGBM, and ExtraTrees (ET) were the best classifier for RS-HC, RS-DTL, and RS-DLR. In the training cohort, the predictive ability of RS-DLR was significantly better than those of RS-DTL and RS-HC (p< 0.050); in the test set, the area under curve (AUC) of RS-DLR (AUC = 0.817) was also the highest, but there was no significant difference of the performance between DLR-RS and HC-RS. Conclusions: Both the HC and DLR model showed favorable predictive efficacy for Ki-67 expression in patients with SNSCC. Especially, the RS-DLR model represented an opportunity to advance the prediction ability. [ABSTRACT FROM AUTHOR]

Single-cell-based methods such as flow cytometry or single-cell mRNA sequencing (scRNA-seq) allow deep molecular and cellular profiling of immunological processes. Despite their high throughput, however, these measurements represent only a snapshot in time. Here, we explore how longitudinal single-cell-based datasets can be used for deterministic ordinary differential equation (ODE)-based modelling to mechanistically describe immune dynamics. We derived longitudinal changes in cell numbers of colonic cell types during inflammatory bowel disease (IBD) from flow cytometry and scRNA-seq data of murine colitis using ODE-based models. Our mathematical model generalised well across different protocols and experimental techniques, and we hypothesised that the estimated model parameters reflect biological processes. We validated this prediction of cellular turnover rates with KI-67 staining and with gene expression information from the scRNA-seq data not used for model fitting. Finally, we tested the translational relevance of the mathematical model by deconvolution of longitudinal bulk mRNA-sequencing data from a cohort of human IBD patients treated with olamkicept. We found that neutrophil depletion may contribute to IBD patients entering remission. The predictive power of IBD deterministic modelling highlights its potential to advance our understanding of immune dynamics in health and disease. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. Methods: First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. Results: AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. Conclusion: Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the correlation between MRI findings and histological features for preoperative prediction of histological grading and Ki-67 expression level in alveolar soft part sarcoma (ASPS). Methods: A retrospective analysis was conducted on 63 ASPS patients (Jan 2017–May 2023). All patients underwent 3.0-T MRI examinations, including conventional sequences, dynamic contrast-enhanced scans with time-intensity curve analysis, and diffusion-weighted imaging with apparent diffusion coefficient (ADC) measurements. Patients were divided into low-grade (histological Grade I) and high-grade (histological Grade II/III) groups based on pathology. Immunohistochemistry was used to assess Ki-67 expression levels in ASPS. Statistical analysis included chi-square tests, Wilcoxon rank-sum test, binary logistic regression analysis, Spearman correlation analysis, and receiver operating characteristic curve analysis of various observational data. Results: There were 29 low-grade and 34 high-grade patients (26 males and 37 females) and a wide age range (5–68 years). Distant metastasis, tumor enhancement characteristics, and ADC values were independent predictors of high-grade ASPS. High-grade ASPS had lower ADC values (p = 0.002), with an area under the curve (AUC), sensitivity, and specificity of 0.723, 79.4%, and 58.6%, respectively, for high-grade prediction. There was a negative correlation between ADC values and Ki-67 expression (r = −0.526; p < 0.001). When the cut-off value of ADC was 0.997 × 10−3 mm²/s, the AUC, sensitivity, and specificity for predicting high Ki-67 expression were 0.805, 65.6%, and 83.9%, respectively. Conclusion: Qualitative and quantitative MRI parameters are valuable for predicting histological grading and Ki-67 expression levels in ASPS. Critical relevance statement: This study will help provide a more nuanced understanding of ASPS and guide personalized treatment strategies. Key Points: There is limited research on assessing ASPS prognosis through MRI. Metastasis, enhancement, and ADC correlated with histological grade; ADC related to Ki-67 expression. MRI provides clinicians with valuable information on ASPS grading and proliferation activity. [ABSTRACT FROM AUTHOR]

Objective: This study developed and validated a nomogram utilizing clinical and multi-slice spiral computed tomography (MSCT) features for the preoperative prediction of Ki-67 expression in stage IA lung adenocarcinoma. Additionally, we assessed the predictive accuracy of Ki-67 expression levels, as determined by our model, in estimating the prognosis of stage IA lung adenocarcinoma. Materials and methods: We retrospectively analyzed data from 395 patients with pathologically confirmed stage IA lung adenocarcinoma. A total of 322 patients were divided into training and internal validation groups at a 6:4 ratio, whereas the remaining 73 patients composed the external validation group. According to the pathological results, the patients were classified into high and low Ki-67 labeling index (LI) groups. Clinical and CT features were subjected to statistical analysis. The training group was used to construct a predictive model through logistic regression and to formulate a nomogram. The nomogram's predictive ability and goodness-of-fit were assessed. Internal and external validations were performed, and clinical utility was evaluated. Finally, the recurrence-free survival (RFS) rates were compared. Results: In the training group, sex, age, tumor density type, tumor-lung interface, lobulation, spiculation, pleural indentation, and maximum nodule diameter differed significantly between patients with high and low Ki-67 LI. Multivariate logistic regression analysis revealed that sex, tumor density, and maximum nodule diameter were significantly associated with high Ki-67 expression in stage IA lung adenocarcinoma. The calibration curves closely resembled the standard curves, indicating the excellent discrimination and accuracy of the model. Decision curve analysis revealed favorable clinical utility. Patients with a nomogram-predicted high Ki-67 LI exhibited worse RFS. Conclusion: The nomogram utilizing clinical and CT features for the preoperative prediction of Ki-67 expression in stage IA lung adenocarcinoma demonstrated excellent performance, clinical utility, and prognostic significance, suggesting that this nomogram is a noninvasive personalized approach for the preoperative prediction of Ki-67 expression. [ABSTRACT FROM AUTHOR]

To investigate whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has the potential to non-invasively detect microenvironmental condition by quantitatively measuring blood perfusion, vessel wall permeability, and vascularity, and to elucidate the possible correlations between DCE-MRI quantitative parameters and the expression level of hypoxia, vascularity, and cell proliferation related molecular biomarkers. In this prospective single center clinical study, 58 patients diagnosed with cervical cancer underwent DCE-MRI before anticancer treatment were enrolled. Ktrans, K ep , V e , and V p were generated from Extended Toft's model. Then patients conducted colposcopy biopsy within 1 week after DCE-MRI. Pretreatment expression levels of HIF-1α, VEGF and Ki-67 were assessed and scored by immunohistochemistry on colposcopy obtained tumor specimens. In HIF-1α low-expression group, Ktrans (p=0.031) and K ep (p=0.012) values were significantly higher than the high-expression group. In VEGF high-expression group, Ktrans (p=0.044) and V e values (p=0.021) were significantly higher than the low-expression group. In Ki-67 high-expression group, Ktrans (p=0.026) and K ep (p=0.033) were significantly higher than the low-expression group. Multiple linear regression analyses and Pearson correlation revealed that Ktrans independently negatively correlated with HIF-1α expression, V e independently positively correlated with VEGF, and K ep independently positively correlated with Ki-67. The area under the ROC curves of Ktrans for HIF-1α, V e for VEGF, and K ep for Ki-67 were 0.728, 0.743, 0.730, respectively. Our results suggest that DCE-MRI quantitative parameters could be potentially used as imaging markers for non-invasively detecting microenvironmental hypoxia, vascularity and proliferation in cervical cancer patients. • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) could non-invasively detect cancer related molecular biomarkers. • DCE-MRI could discriminate different molecular biomarker expression level. • Ktrans, V e , and K ep were correlated with hypoxia-inducible factors-1-alpha, vascular endothelial growth factor, and Ki-67 expression. [ABSTRACT FROM AUTHOR]

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

Objective: To evaluate the value of the malignant subregion-based texture analysis in predicting Ki-67 status in breast cancer. Materials and methods: The dynamic contrast-enhanced magnetic resonance imaging data of 119 histopathologically confirmed breast cancer patients (81 patients with high Ki-67 expression status) from January 2018 to February 2023 in our hospital were retrospectively collected. According to the enhancement curve of each voxel within the tumor, three subregions were divided: washout subregion, plateau subregion, and persistent subregion. The washout subregion and the plateau subregion were merged as the malignant subregion. The texture features of the malignant subregion were extracted using Pyradiomics software for texture analysis. The differences in texture features were compared between the low and high Ki-67 expression cohorts and then the receiver operating characteristic (ROC) curve analysis to evaluate the predictive performance of texture features on Ki-67 expression. Finally, a support vector machine (SVM) classifier was constructed based on differential features to predict the expression level of Ki-67, the performance of the classifier was evaluated using ROC analysis and confirmed using 10-fold cross-validation. Results: Through comparative analysis, 51 features exhibited significant differences between the low and high Ki-67 expression cohorts. Following feature reduction, 5 features were selected to build the SVM classifier, which achieved an area under the ROC curve (AUC) of 0.77 (0.68-0.87) for predicting the Ki-67 expression status. The accuracy, sensitivity, and specificity were 0.76, 0.80, and 0.68, respectively. The average AUC from the 10-fold cross-validation was 0.72 ± 0.14. Conclusion: The texture features of the malignant subregion in breast cancer were potential biomarkers for predicting Ki-67 expression level in breast cancer, which might be used to precisely diagnose and guide the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer is a significant cause of cancer-related mortality among men worldwide, necessitating the exploration of prognostic biomarkers to aid in accurate risk assessment and treatment decision-making. This cross-sectional study aimed to comprehensively evaluate the role of Ki-67 as a prognostic marker in prostate cancer by examining its association with clinicopathological parameters. A total of 102 archived cases of prostate core biopsy specimens, histopathologically reported as prostate carcinoma, were included in this study. Histopathological grading was conducted using Gleason's scoring and grading system based on morphology. The statistical software "R" was utilized for data analysis. Kruskal–Wallis test and Fisher's exact test were employed to analyze the association between Ki-67 expression and clinicopathological parameters. The study revealed significant correlations between Ki-67 expression and various clinicopathological parameters in prostate cancer cases. High Ki-67 expression levels were associated with higher Gleason scores, increased incidence of perineural invasion, advanced T stages, lymph node metastasis, presence of distant metastasis, and higher prognostic stage groups. The findings of this cross-sectional study support the potential of Ki-67 as a prognostic marker in prostate cancer. The significant associations observed between Ki-67 expression and clinicopathological parameters indicate its usefulness in risk stratification and treatment decision-making. The incorporation of histopathological grading, including Gleason scoring, and analysis of perineural invasion strengthens the validity of the study. Ki-67, in combination with morphological assessments, provides valuable prognostic information for prostate cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the predictive value of multi-parameters derived from advanced MR imaging for Ki-67 labeling index (LI) in glioma patients. Materials and Methods: One hundred and nine patients with histologically confirmed gliomas were evaluated retrospectively. These patients underwent advanced MR imaging, including dynamic susceptibility-weighted contrast enhanced MR imaging (DSC), MR spectroscopy imaging (MRS), diffusionweighted imaging (DWI) and diffusion-tensor imaging (DTI), before treatment. Twenty-one parameters were extracted, including the maximum, minimum and mean values of relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), relative mean transit time (rMTT), relative apparent diffusion coefficient (rADC), relative fractional anisotropy (rFA) and relative mean diffusivity (rMD) respectively, and ration of choline (Cho)/creatine (Cr), Cho/N-acetylaspartate (NAA) and NAA/Cr. Stepwise multivariate regression was performed to build multivariate models to predict Ki-67 LI. Pearson correlation analysis was used to investigate the correlation between imaging parameters and the grade of glioma. One-way analysis of variance (ANOVA) was used to explore the differences of the imaging parameters among the gliomas of grade II, III, and IV. Results: The multivariate regression showed that the model of five parameters, including rCBVmax (RC=0.282), rCBFmax (RC=0.151), rADCmin (RC= -0.14), rFAmax (RC=0.325) and Cho/Cr ratio (RC=0.157) predicted the Ki-67 LI with a root mean square (RMS) error of 0. 0679 (R2 = 0.8025). The regression check of this model showed that there were no multicollinearity problem (variance inflation factor: rCBVmax, 3.22; rCBFmax, 3.14; rADCmin, 1.96; rFAmax, 2.51; Cho/Cr ratio, 1.64), and the functional form of this model was appropriate (F test: p=0.682). The results of Pearson correlation analysis showed that the rCBVmax, rCBFmax, rFAmax, the ratio of Cho/Cr and Cho/NAA were positively correlated with Ki-67 LI and the grade of glioma, while the rADCmin and rMDmin were negatively correlated with Ki-67 LI and the grade of glioma. Conclusion: Combining multiple parameters derived from DSC, DTI, DWI and MRS can precisely predict the Ki-67 LI in glioma patients. [ABSTRACT FROM AUTHOR]

Background: Current diagnostic criteria of adrenocortical neoplasms are mostly based on morphology. The utility of immunohistochemistry (IHC) and histochemistry is limited. Materials and methods: To evaluate the diagnostic and prognostic utility of clinicopathological features, morphology, ancillary biomarkers, and reticular histochemistry in adrenocortical neoplasms. We examined 28 adrenocortical carcinomas (ACCs) and 50 adrenocortical adenomas (ACAs) obtained from pathology archives. Clinical data were retrieved from medical records. Two pathologists independently assessed hematoxylin and eosin-stained slides, employing modified Weiss criteria for all tumors and Lin-Weiss-Bisceglia criteria for oncocytic variants. Immunohistochemical markers (Calretinin, alpha-inhibin, MelanA, SF-1, Ki-67, PHH3, IGF-2, β-catenin, P53, CYP11B1, CYP11B2, MLH1, MSH2, MSH6, PMS2, EPCAM) and Gomori's Silver histochemistry were applied. Statistical analysis utilized SPSS Statistics 26. Results: ACCs exhibited larger tumor sizes (P<0.001) and symptomatic presentations (P = 0.031) compared to ACAs. Parameters of modified Weiss criteria and angioinvasion demonstrated diagnostic value for ACCs. Six immunohistochemical antibodies((MelanA, Ki-67, IGF-2, β-catenin, P53 and CYP11B1) and reticulin framework alterations showed diagnostic value. Notably, Ki-67 and reticulin staining were most recommended. Evident reticulin staining was frequently present in ACCs (P<0.001). Ki-67 was significantly higher in ACCs (P<0.001). Twenty-one conventional and seven oncocytic entities showed different necrosis frequencies. Symptoms and Ki-67 index ≥ 30% were prognostic for ACCs, correlating with shorter survival. Conclusions: This study emphasizes the diagnostic value of reticulin framework alterations and a high Ki-67 index. Markers such as CYP11B1, IGF2, P53, β-catenin and MelanA also contribute to the diagnosis of ACCs. Symptoms and Ki-67 index ≥ 30% predict shorter survival. These findings encourges the use of ancillary markers such as reticulin histochemistry and Ki-67 in the workup of evaluations of adrenocortical neoplasms. [ABSTRACT FROM AUTHOR]

Background: Oncotype-Dx (ODx) is a 21-gene assay used as a prognostic and predictive tool for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative, node-negative, or 1 to 3 lymph node-positive early breast cancers (EBCs). The cost of the test, which is not available in low-middle income countries (LMICs), is not within the means of most individuals. The Ki-67 index is a marker of tumor proliferation that is cost-effective and easily performed and has been substituted in many cases to obtain prognostic information. Objective: We aimed to identify the correlation between the ODx recurrence score (RS) and the Ki-67 index in HR-positive EBCs and to determine whether Ki-67, like the ODx, can help facilitate clinical decision-making. Design: Systematic review correlating Ki-67 index and ODx in HR-positive and HER2-negative EBCs as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data sources and methods: We searched different databases between January 2010 and May 2023 and included retrospective/prospective cohorts, clinical trials, case-control, and cross-sectional studies involving HR-positive and HER2-negative EBCs correlating the Ki-67 index and ODx RS categories. Results: Of the 18 studies included, 16 indicated a positive or weakly positive correlation between ODx and the Ki-67 index. The combined P value of the included studies is <0.05 (P =.000), which shows a statistical significance between the 2. Our review also discusses the potential of machine learning and artificial intelligence (AI) in Ki-67 assessment, offering a cost-effective and reproducible alternative. Conclusion: Even although there are limitations, studies indicate a favorable association between ODx and the Ki-67 index in specific situations. This implies that Ki-67 can offer important predictive details, especially regarding the likelihood of relapse in HR-positive EBC. This is particularly significant in LMICs where financial constraints often hinder the availability of costly diagnostic tests. Plain Language Summary: Comparing Ki-67 and Oncotype-Dx Tests for Predicting Early Breast Cancer Outcomes: A Comprehensive Review The study explored the correlation between the expensive Oncotype-Dx (ODx) test and the more affordable Ki-67 index in predicting outcomes for certain breast cancers. Results from 16 out of 18 studies indicated a significant link between the 2 tests, suggesting Ki-67 could be a cost-effective alternative, especially in low- to middle-income countries. [ABSTRACT FROM AUTHOR]

Introduction: Primary malignant hepatic vascular tumors with various malignant potentials include epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), which may overlap pathologically. This study aimed to compare the pathological findings of hepatic EHE with those of AS, in association with patient outcomes. Methods: Fifty-nine histologically confirmed patients with 34 EHE and 25 AS were admitted to a tertiary hospital from 2003 to 2020. Their EHE and AS pathological features were compared. Immunohistochemistry for CD31, ERG, CAMTA-1, TFE3, P53, and Ki-67 labeling was performed on paraffin-embedded blocks. Markers, along with histological findings, were analyzed for the purposes of diagnostic and prognostic significance by multivariate analysis. Results: CAMTA-1 was 91.2% positive in EHE, but negative in AS (p = < 0.001). AS was significantly correlated to an aberrant p53 expression, high Ki-67 labeling, and high mitotic activity, compared to EHE (all, p = < 0.001). EHE can be classified as low grade (LG) and high grade (HG) using the prognostic values of mitotic activity and ki-67 labeling (sensitivity = 1, specificity = 1). Low grade-EHE showed significantly better overall survival than high grade-EHE (p = 0.020). Conclusions: Immunohistochemistry for CAMTA-1, P53, and Ki-67 labeling may help distinguish EHE and AS in histologically ambiguous cases, especially small biopsied tissue. Moreover, the combination of mitotic activity and Ki-67 labeling can be a prognostic factor for EHE with various clinical features. [ABSTRACT FROM AUTHOR]

Background: Very well-differentiated gastric adenocarcinoma (VWDA) is a rare variant of gastric cancer, for which the diagnostic criteria and clinical behavior are not fully established. We reported a case of an intramucosal VWDA of gastric type with a lymphovascular invasion (LVI). Case presentation: A 67-year-old female was diagnosed as intramucosal gastric adenocarcinoma after a biopsy at the local hospital 3 weeks ago and then visited our hospital for further treatment. The endoscopic examination in our hospital showed a rough, slightly faded, 30-mm, flat, and elevated lesion on the lesser curvature of the middle gastric body. Histopathologically, the lesion consisted of superficial foveolar-type papillary adenocarcinoma and deep pyloric gland-type tubular adenocarcinoma. The immunostaining results showed that the foveolar-type papillary adenocarcinoma was positive for MUC5AC and had a high index of Ki-67, but the pyloric gland-type tubular adenocarcinoma was positive for MUC6 and had a low index of Ki-67. Both components were negative for MSH2 and MSH6, which suggested the high microsatellite instability phenotype. Moreover, a LVI was detected in the lesion. The pathological diagnosis was VWDA of gastric type. Conclusion: The case has unique histological and immunophenotypic characteristics, which not only indicates the importance of architectural features in the diagnosis of VWDA but also further proves that the aggressive behavior of VWDA is correlated with tumor histological type and immunophenotype. [ABSTRACT FROM AUTHOR]

Predicting the aggressiveness of meningiomas may influence the surgical strategy timing. Because of the paucity of robust markers, the systemic immune-inflammation (SII) index is a novel biomarker to be an independent predictor of poor prognosis in various cancers including gliomas. We aimed to investigate the value of SII as well as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) indices in predicting prognosis. Records including demographic, clinical, and laboratory data of patients operated on due to intracranial meningioma in 2017–2023 were retrospectively reviewed. A total of 234 patients were included in this study. All of SII index, NLR, and PLR values at presentation were significantly higher in grade ≥2 meningiomas. A positive correlation was observed between SII index and Ki67 index (r = 0.313; P < 0.001); between NLR and Ki67 index (r = 0.330; P < 0.001); and between PLR and Ki67 index (r = 0.223; P < 0.01). SII index (optimal cutoff level >618), NLR (optimal cutoff level >3.53), and PLR (optimal cutoff level >121.2) showed significant predictive values. This is the first study to assess the prognostic value of the SII index in patients with intracranial meningiomas. Increased SII index, NLR and PLR were correlated with higher grade and higher Ki-67 index. They also harbor the potential to screen patients that may need more aggressive treatments or more frequent follow-up examinations. [ABSTRACT FROM AUTHOR]

Objective: Tumor cell malignancy is indicated by histopathological differentiation and cell proliferation. Ki-67, an indicator of cellular proliferation, has been used for tumor grading and classification in breast cancer and neuroendocrine tumors. However, its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) remains uncertain. Methods: Patients who underwent radical pancreatectomy for PDAC were retrospectively enrolled, and relevant prognostic factors were examined. Grade of malignancy (GOM), a novel index based on histopathological differentiation and Ki-67, is proposed, and its clinical significance was evaluated. Results: The optimal threshold for Ki-67 was determined to be 30%. Patients with a Ki-67 expression level > 30% rather than = 30% had significantly shorter 5-year overall survival (OS) and recurrence-free survival (RFS). In multivariate analysis, both histopathological differentiation and Ki-67 were identified as independent prognostic factors for OS and RFS. The GOM was used to independently stratify OS and RFS into 3 tiers, regardless of TNM stage and other established prognostic factors. The tumor-nodemetastasis-GOM stage was used to stratify survival into 5 distinct tiers, and surpassed the predictive performance of TNM stage for OS and RFS. Conclusions: Ki-67 is a valuable prognostic indicator for PDAC. Inclusion of the GOM in the TNM staging system may potentially enhance prognostic accuracy for PDAC. [ABSTRACT FROM AUTHOR]

Purpose: To study the biomarkers present in primary pterygium samples of patients of Indian ethnicity and compare it with the samples obtained from the unaffected conjunctiva of the same eye. Methods: A prospective case-control study of 17 eyes in patients above 10 years of age with primary pterygium who underwent pterygium excision using limbal conjunctival autograft technique. The pterygium samples (cases) and conjunctival samples (controls) were sent for immunohistochemical (IHC) staining for the following biomarkers: p53, Bcl-2, Ki-67, and vascular endothelial growth factor (VEGF). Result: The immunohistochemistry of the samples and the controls revealed p53 positivity in 47.05% of pterygium samples and 29.4% of controls (P < 0.587). Nine cases each in pterygium and control samples were positive for Ki-67 expression. Differences in the staining pattern between the two groups were not statistically significant (P < 1.000). Bcl-2 positivity was seen in 10 pterygium samples (58.8%) and 12 controls (70.5%), with no statistical difference between the two groups (P < 0.455). VEGF expression was seen in both epithelial and endothelial cells of the samples and controls, with no statistical difference between the two groups, with P = 1.000 for the epithelial staining and P = 0.637 for endothelial staining. Conclusion: The expression of biomarkers was comparable in both groups. We conclude that pterygium, against common belief, might not be a localized disease process but a global ocular phenomenon where the apparently healthy tissue also has some ongoing disease process at a molecular level. [ABSTRACT FROM AUTHOR]

Purpose: To develop a contrast-enhanced ultrasound (CEUS) clinic-radiomics nomogram for individualized assessment of Ki-67 expression in hepatocellular carcinoma (HCC). Methods: A retrospective cohort comprising 310 HCC individuals who underwent preoperative CEUS (using SonoVue) at three different centers was partitioned into a training set, a validation set, and an external test set. Radiomics signatures indicating the phenotypes of the Ki-67 were extracted from multiphase CEUS images. The radiomics score (Rad-score) was calculated accordingly after feature selection and the radiomics model was constructed. A clinic-radiomics nomogram was established utilizing multiphase CEUS Rad-score and clinical risk factors. A clinical model only incorporated clinical factors was also developed for comparison. Regarding clinical utility, calibration, and discrimination, the predictive efficiency of the clinic-radiomics nomogram was evaluated. Results: Seven radiomics signatures from multiphase CEUS images were selected to calculate the Rad-score. The clinic-radiomics nomogram, comprising the Rad-score and clinical risk factors, indicated a good calibration and demonstrated a better discriminatory capacity compared to the clinical model (AUCs: 0.870 vs 0.797, 0.872 vs 0.755, 0.856 vs 0.749 in the training, validation, and external test set, respectively) and the radiomics model (AUCs: 0.870 vs 0.752, 0.872 vs 0.733, 0.856 vs 0.729 in the training, validation, and external test set, respectively). Furthermore, both the clinical impact curve and the decision curve analysis displayed good clinical application of the nomogram. Conclusion: The clinic-radiomics nomogram constructed from multiphase CEUS images and clinical risk parameters can distinguish Ki-67 expression in HCC patients and offer useful insights to guide subsequent personalized treatment. [ABSTRACT FROM AUTHOR]

Background: The grading of adult isocitrate dehydrogenase (IDH)-mutant astrocytomas is a crucial prognostic factor. Purpose: To investigate the value of conventional magnetic resonance imaging (MRI) features and apparent diffusion coefficient (ADC) in the grading of adult IDH-mutant astrocytomas, and to analyze the correlation between ADC and the Ki-67 proliferation index. Material and Methods: The clinical and MRI data of 82 patients with adult IDH-mutant astrocytoma who underwent surgical resection and molecular genetic testing with IDH and 1p/19q were retrospectively analyzed. The conventional MRI features, ADCmin, ADCmean, and nADC of the tumors were compared using the Kruskal–Wallis single factor ANOVA and chi-square tests. Receiver operating characteristic (ROC) curves were drawn to evaluate conventional MRI and ADC accuracy in differentiating tumor grades. Pearson correlation analysis was performed to determine the correlation between ADC and the Ki-67 proliferation index. Results: The difference in enhancement, ADCmin, ADCmean, and nADC among WHO grade 2, 3, and 4 tumors was statistically significant (all P <0.05). ADCmin showed the preferable diagnostic accuracy for grading WHO grade 2 and 3 tumors (AUC=0.724, sensitivity=63.4%, specificity=80%, positive predictive value (PPV)=62.0%; negative predictive value (NPV)=82.5%), and distinguishing grade 3 from grade 4 tumors (AUC=0.764, sensitivity=70%, specificity=76.2%, PPV=75.0%, NPV=71.4%). Enhancement + ADC model showed an optimal predictive accuracy (grade 2 vs. 3: AUC = 0.759; grade 3 vs. 4: AUC = 0.799). The Ki-67 proliferation index was negatively correlated with ADCmin, ADCmean, and nADC (all P <0.05), and positively correlated with tumor grade. Conclusion: Conventional MRI features and ADC are valuable to predict pathological grading of adult IDH-mutant astrocytomas. [ABSTRACT FROM AUTHOR]

Objectives: To develop and validate a contrast-enhanced computed tomography (CECT)–based radiomics nomogram for the preoperative evaluation of Ki-67 proliferation status in pancreatic ductal adenocarcinoma (PDAC). Methods: In this two-center retrospective study, a total of 181 patients (95 in the training cohort; 42 in the testing cohort, and 44 in the external validation cohort) with PDAC who underwent CECT examination were included. Radiomic features were extracted from portal venous phase images. The radiomics signatures were built by using two feature-selecting methods (relief and recursive feature elimination) and four classifiers (support vector machine, naive Bayes, linear discriminant analysis (LDA), and logistic regression (LR)). Multivariate LR was used to build a clinical model and radiomics-clinical nomogram. The predictive performances of the models were evaluated using area under receiver operating characteristic curve (AUC) and decision curve analysis (DCA). Results: The relief selector and LDA classifier using twelve features built the optimal radiomics signature, with AUCs of 0.948, 0.927, and 0.824 in the training, testing, and external validation cohorts, respectively. The radiomics-clinical nomogram incorporating the optimal radiomics signature, CT-reported lymph node status, and CA19-9 showed better predictive performance with AUCs of 0.976, 0.955, and 0.882 in the training, testing, and external validation cohorts, respectively. The calibration curve and DCA demonstrated goodness-of-fit and improved benefits in clinical practice of the nomogram. Conclusions: The radiomics-clinical nomogram is an effective and non-invasive computer-aided tool to predict the Ki-67 expression status in patients with PDAC. Clinical relevance statement: The radiomics-clinical nomogram is an effective and non-invasive computer-aided tool to predict the Ki-67 expression status in patients with pancreatic ductal adenocarcinoma. Key Points: The radiomics analysis could be helpful to predict Ki-67 expression status in patients with pancreatic ductal adenocarcinoma (PDAC). The radiomics-clinical nomogram integrated with the radiomics signature, clinical data, and CT radiological features could significantly improve the differential diagnosis of Ki-67 expression status. The radiomics-clinical nomogram showed satisfactory calibration and net benefit for discriminating high and low Ki-67 expression status in PDAC. [ABSTRACT FROM AUTHOR]

The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2 (MDM2, also termed HDM2 in humans) through a feedback mechanism. At the same time, TP53 is the most frequently mutated gene in human cancers. Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties, among which are deregulating cell proliferation, increasing chemoresistance, disrupting tissue architecture, and promoting migration, invasion and metastasis as well as several other pro-oncogenic activities. The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation. This cavity accommodates stabilizing small molecules that have therapeutic values. The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein. In this review, we summarize approaches that target p53-Y220C, including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future, which target tumor cells that express the p53-Y220C neoantigen. [ABSTRACT FROM AUTHOR]

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Integration of molecular data with histologic, radiologic, and clinical features is imperative for accurate diagnosis of pediatric central nervous system (CNS) tumors. Whole transcriptome RNA sequencing (RNAseq), a genome-wide and non-targeted approach, allows for the detection of novel or rare oncogenic fusion events that contribute to the tumorigenesis of a substantial portion of pediatric low- and high-grade glial and glioneuronal tumors. We present two cases of pediatric glioneuronal tumors occurring in the occipital region with a CLIP2::MET fusion detected by RNAseq. Chromosomal microarray studies revealed copy number alterations involving chromosomes 1, 7, and 22 in both tumors, with Case 2 having an interstitial deletion breakpoint in the CLIP2 gene. By methylation profiling, neither tumor had a match result, but both clustered with the low-grade glial/glioneuronal tumors in the UMAP. Histologically, in both instances, our cases displayed characteristics of a low-grade tumor, notably the absence of mitotic activity, low Ki-67 labeling index and the lack of necrosis and microvascular proliferation. Glial and neuronal markers were positive for both tumors. Clinically, both patients achieved clinical stability post-tumor resection and remain under regular surveillance imaging without adjuvant therapy at the last follow-up, 6 months and 3 years, respectively. This is the first case report demonstrating the presence of a CLIP2::MET fusion in two pediatric low-grade glioneuronal tumors (GNT). Conservative clinical management may be considered for patients with GNT and CLIP2:MET fusion in the context of histologically low-grade features. [ABSTRACT FROM AUTHOR]

Background: A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship between PD-L1 expression and the natural course of disease are controversial and sparse. Methods: To expand our understanding of the relationship between PD-L1 expression and parameters of cancer aggressiveness, PD-L1 was analyzed on tissue microarrays containing 2710 urothelial bladder carcinomas including 512 patients with follow-up data who underwent radical cystectomy and follow-up therapies in the pre-immune checkpoint inhibitor therapy era. Results: Tumor cell positivity in ≥10% of cells were seen in 513 (20%) and an immune cell positivity occurred in 872 (34%) of 2566 interpretable cancers. PD-L1 positivity in tumor cells increased from pTaG2 low grade (0.9% positive) to pTaG3 high grade (4.1%; p = 0.0255) and was even higher in muscle-invasive (pT2–4) carcinomas (29.3%; p < 0.0001). However, within pT2–4 carcinomas, PD-L1 positivity was linked to low pT stage (p = 0.0028), pN0 (p < 0.0001), L0 status (p = 0.0005), and a better prognosis within 512 patients with cystectomy who never received CPIs (p = 0.0073 for tumor cells and p = 0.0086 for inflammatory cells). PD-L1 staining in inflammatory cells was significantly linked to PD-L1 staining in tumor cells (p < 0.0001) and both were linked to a positive p53 immunostaining (p < 0.0001). Conclusion: It cannot be fully excluded that the strong statistical link between PD-L1 status and favorable histological tumor features as well as better prognosis could influence the outcome of studies evaluating CPIs in muscle-invasive urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to examine Ki-67’s correlation with clinicopathological characteristics of head and neck squamous cell carcinoma (HNSCC), evaluate its prognostic significance, and develop a Ki-67 integrated prognostic model. Methods: The retrospective study included 764 HNSCC patients hospitalized from 2012 to 2022. Data were sourced from medical records and immunohistochemical analysis of surgical specimens. Results: Ki-67 expression was significantly associated with sex, pathological grade, clinical stage, and metastasis, but not with age or recurrence. Higher Ki- 67 levels were linked to poorer prognosis, as indicated by Kaplan-Meier survival analysis. Utilizing a Cox proportional hazards model, four prognostic factors were identified: age, recurrence, metastasis, and Ki-67 expression. These factors were used to construct a prognostic model and a nomogram. The model’s predictive accuracy was confirmed by a high concordance index and a reliable calibration curve. Conclusion: Ki-67 expression in HNSCC patients correlates with several clinicopathological features and serves as a negative prognostic marker. A prognostic model incorporating Ki-67 was successfully developed, offering a new tool for patient prognosis assessment in HNSCC. [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]

Background: We investigated the value of three-dimensional amide proton transfer-weighted imaging (3D-APTWI) in the diagnosis of early-stage breast cancer (BC) and its correlation with the immunohistochemical characteristics of malignant lesions. Methods: Seventy-eight women underwent APTWI and dynamic contrast-enhanced (DCE)-MRI. Pathological results were categorized as either benign (n = 43) or malignant (n = 37) lesions. The parameters of APTWI and DCE-MRI were compared between the benign and malignant groups. The diagnostic value of 3D-APTWI was evaluated using the area under the receiver operating characteristic curve (ROC-AUC) to establish a diagnostic threshold. Pearson's correlation was used to analyze the correlation between the magnetization transfer asymmetry (MTRasym) and immunohistochemical characteristics. Results: The MTRasym and time-to-peak of malignancies were significantly lower than those of benign lesions (all p < 0.010). The volume transfer constant, rate constant, and wash-in and wash-out rates of malignancies were all significantly greater than those of benign lesions (all p < 0.010). ROC-AUCs of 3D-APTWI, DCE-MRI, and 3D-APTWI+DCE to differential diagnosis between early-stage BC and benign lesions were 0.816, 0.745, and 0.858, respectively. Only the difference between AUCAPT+DCE and AUCDCE was significant (p < 0.010). When a threshold of MTRasym for malignancy for 2.42%, the sensitivity and specificity of 3D-APTWI for BC diagnosis were 86.5% and 67.6%, respectively; MTRasym was modestly positively correlated with pathological grade (r = 0.476, p = 0.003) and Ki-67 (r = 0.419, p = 0.020). Conclusions: 3D-APTWI may be used as a supplementary method for patients with contraindications of DCE-MRI. MTRasym can imply the proliferation activities of early-stage BC. Relevance statement: 3D-APTWI can be an alternative diagnostic method for patients with early-stage BC who are not suitable for contrast injection. Key points: • 3D-APTWI reflects the changes in the microenvironment of early-stage breast cancer. • Combined 3D-APTWI is superior to DCE-MRI alone for early-stage breast cancer diagnosis. • 3D-APTWI improves the diagnostic accuracy of early-stage breast cancer. [ABSTRACT FROM AUTHOR]