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Background and aims. The aim of this study is to assess the lipid profile pattern of pediatric overweight and/or obese patients with Non-Alcoholic Fatty Liver Disease (NAFLD) in relation to IDF Consensus Criteria for Metabolic Syndrome (MetS).

A count was made of unhatched eggs and hatchling live and dead Podocnemis expansa turtles in 327 natural nests located on the beaches of the Environmental Protection Area (EPA) Meanders of the Araguaia River, to determine the percentage of hatching (94.63%), non-hatching (5.37%), survival (94.24%) and hatchling mortality (5.76%), and the average percentage of dead hatchlings during the 15 days in the nursery (0.97%). The mean number of hatchlings per nest was determined from the sum of the number of live and dead hatchlings divided by the total number of nests, while the mean number of eggs per nest was determined from the sum of live and dead hatchlings and unhatched eggs divided by the number of nests. These calculations yielded the following mean values: live hatchlings (88.98 ± 23.94), dead hatchlings (0.37 ± 0.93), unhatched eggs (5.07 ± 9.57), and total number of eggs (94.42 ± 21.30). The reproductive efficiency of the wild population of P. expansa can be affected by many environmental factors such as temperature, humidity and rainfall. In addition, man-made factors like the presence of chemicals in the water and the potential for infectious disease also have significant impact. The reproductive indices data obtained from this study are indispensable for future investigations of hatching anomalies.

Purpose: To evaluate the Stratipath Breast tool for image-based risk profiling and compare it with an established prognostic multigene assay for risk profiling in a real-world case series of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative early breast cancer patients categorized as intermediate risk based on classic clinicopathological variables and eligible for chemotherapy., Methods: In a case series comprising 234 invasive ER-positive/HER2-negative tumors, clinicopathological data including Prosigna results and corresponding HE-stained tissue slides were retrieved. The digitized HE slides were analysed by Stratipath Breast., Results: Our findings showed that the Stratipath Breast analysis identified 49.6% of the clinically intermediate tumors as low risk and 50.4% as high risk. The Prosigna assay classified 32.5%, 47.0% and 20.5% tumors as low, intermediate and high risk, respectively. Among Prosigna intermediate-risk tumors, 47.3% were stratified as Stratipath low risk and 52.7% as high risk. In addition, 89.7% of Stratipath low-risk cases were classified as Prosigna low/intermediate risk. The overall agreement between the two tests for low-risk and high-risk groups (N = 124) was 71.0%, with a Cohen's kappa of 0.42. For both risk profiling tests, grade and Ki67 differed significantly between risk groups., Conclusion: The results from this clinical evaluation of image-based risk stratification shows a considerable agreement to an established gene expression assay in routine breast pathology., (© 2024. The Author(s).)

Molecular profiling is central in cancer precision medicine but remains costly and is based on tumor average profiles. Morphologic patterns observable in histopathology sections from tumors are determined by the underlying molecular phenotype and therefore have the potential to be exploited for prediction of molecular phenotypes. We report here the first transcriptome-wide expression-morphology (EMO) analysis in breast cancer, where individual deep convolutional neural networks were optimized and validated for prediction of mRNA expression in 17,695 genes from hematoxylin and eosin-stained whole slide images. Predicted expressions in 9,334 (52.75%) genes were significantly associated with RNA sequencing estimates. We also demonstrated successful prediction of an mRNA-based proliferation score with established clinical value. The results were validated in independent internal and external test datasets. Predicted spatial intratumor variabilities in expression were validated through spatial transcriptomics profiling. These results suggest that EMO provides a cost-efficient and scalable approach to predict both tumor average and intratumor spatial expression from histopathology images. SIGNIFICANCE: Transcriptome-wide expression morphology deep learning analysis enables prediction of mRNA expression and proliferation markers from routine histopathology whole slide images in breast cancer., (©2021 The Authors; Published by the American Association for Cancer Research.)

Purpose: To determine the associations between lysosomal-associated transmembrane protein 4b (LAPTM4B) gene copy number and response to different chemotherapy regimens in hormone receptor negative (HR-) primary breast carcinomas., Patients and Methods: Two cohorts were analyzed: (1) 69 core biopsies from HR-breast carcinomas treated with neoadjuvant chemotherapy (anthracycline based in 72.5% of patients and non-anthracycline based in 27.5% of patients). (2) Tissue microarray (TMA) of 74 HR-breast carcinomas treated with adjuvant therapy (77.0% of the patients received anthracycline, 17.6% of the patients non-anthracycline-based therapy, and in 5.4% of the cases, no treatment data are available). Interphase FISH technique was applied on pretreatment core biopsies (cohort I) and on TMAs (cohort II) using custom-made dual-labelled FISH probes (LAPTM4B/CEN8q FISH probe Abnova Corp.)., Results: In the neoadjuvant cohort in the anthracycline-treated group, we observed a significant difference (p = 0.029) of average LAPTM4B copy number between the non-responder and pathological complete responder groups (4.1 ± 1.1 vs. 2.6 ± 0.1). In the adjuvant setting, the anthracycline-treated group of metastatic breast carcinomas was characterized by higher LAPTM4B copy number comparing to the non-metastatic ones (p = 0.046). In contrast, in the non-anthracycline-treated group of patients, we did not find any LAPTM4B gene copy number differences between responder vs. non-responder groups or between metastatic vs. non-metastatic groups., Conclusion: Our results confirm the possible role of the LAPTM4B gene in anthracycline resistance in HR- breast cancer. Analyzing LAPTM4B copy number pattern may support future treatment decision.

In this study, the reproducibility of Ki-67 proliferation index (KIPI) was investigated by comparing the semi-quantitative (SQ) results of three assessors with those of digital image-analysis (DIA) methods. The prognostic significance of the two approaches was also correlated with clinical outcome. Tissue microarrays of duplicate 2 mm cores were constructed from representative areas of formalin-fixed and paraffin-embedded tumor blocks of 347 breast cancer patients. SQ evaluation of Ki-67 (MIB1 clone) immunostained slides was performed independently by three pathologists. DIA was completed using a fully automated histological pattern and cell recognition module for KIPI detection (DIA-1) and an adjustable module (DIA-2) with the possibility of manual corrections. To compare SQ and DIA evaluations intra-class correlation (ICC) and concordance correlation coefficients (CCC) were determined. The three SQ evaluations demonstrated a remarkable ICC (0.853). Significant difference and poor concordance occurred between SQ-1 and SQ-2 as well as between SQ-1 and SQ-3 (p ≤ 0.001, CCC ≤ 0.827 for both comparisons). Thus, the reference KIPI value (SQ-RV) was generated from the mean values of SQ-2 and SQ-3. SQ-RV and DIA-2 results showed substantial concordance (CCC = 0.963, at p = 0.754), while SQ-RV and DIA-1 values differed (p ≤ 0.001) at only moderate concordance (CCC = 0.906). In multivariate analysis, lymph node status and SQ-2 assessment were significantly associated with clinical outcome (p ≤ 0.012 for both comparisons). Our results confirm that KIPI is a significant prognostic marker in breast cancer, which can be can be reliably reproduced by using an adjustable DIA-2 image analysis module.

Purpose: We aimed to compare the immunohistochemical expression of PD-1, PD-L1 and CTLA-4 of pregnancy-related breast cancer (PRBC) and early onset non-PRBC (YWBC), and their prognosis prediction potential was correlated to that of conventional clinicopathological factors., Methods: Twenty-one PRBC cases were paired with 21 YWBC in this matched case-control study. Immune-checkpoint markers (ICM) were evaluated with immunohistochemistry (IHC) on whole slides using the following antibodies: PD-1 (NAT-105), PD-L1 (28-8) and CTLA-4 (F-8). IHC score was defined as the percentage of positive cells, assessed separately among tumor cells, intratumoral lymphocytes and peritumoral lymphocytes., Results: The optimal threshold of PD-L1 expression of tumor cells occurred at 10% for overall survival (OS, AUC = 0.847, p = 0.009), and at 1% for disease-free survival (DFS, AUC = 0.795, p = 0.010). For PD-L1 expression on intratumoral lymphocytes, the optimal cut-off was 1% (AUC = 0.763, p = 0.048). Considering PD-1, PD-L1 and CTLA-4 expression, no significant difference occurred between PRBC and YWBC (p > 0.05 for all comparisons). PD-1, PD-L1 expressed on peritumoral lymphocytes and CTLA-4 failed, but PD-L1 expressed on tumor cells and on intratumoral lymphocytes was suitable to distinguish patient cohorts with different OS and DFS (p ≤ 0.011 for all comparisons). Higher PD-L1 expression was associated with poor prognosis. PD-L1 expressed on tumor cells represented an independent association with OS (p = 0.023) and DFS (p = 0.032)., Conclusions: Our results suggest that PRBC and YWBC do not differ in the expression of PD-1, PD-L1 and CTLA-4. However, our findings emphasize the relevance of PD-L1 expression in early-onset breast cancer, as an independent negative predictor of prognosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Although several antibodies are available for immunohistochemical detection of Ki-67, even the most commonly used MIB-1 has not been validated yet. Our aim was to compare 5 commercially available antibodies for detection of Ki-67 in terms of agreement and their ability in predicting prognosis of breast cancer. Tissue microarrays were constructed from 378 breast cancer patients' representative formalin-fixed, paraffin-embedded tumor blocks. Five antibodies were used to detect Ki-67 expression: MIB-1 using chromogenic detection and immunofluorescent-labeled MIB-1, SP-6, 30-9, poly, and B56. Semiquantitative assessment was performed by 2 pathologists independently on digitized slides. To compare the 5 antibodies, intraclass correlation and concordance correlation coefficient were used. All the antibodies but immunofluorescent-labeled MIB-1 (at 20% and 30% thresholds, P=.993 and P=.342, respectively) and B56 (at 30% threshold, P=.288) separated high- and low-risk patient groups. However, there were a significant difference (P values for all comparisons≤.005) and a moderate concordance (intraclass correlation, 0.645) between their Ki-67 labeling index scores. The highest concordance was found between MIB-1 and poly (concordance correlation coefficient=0.785) antibodies. None of the antibodies except Ki-67 labeling index as detected by poly (P=.031) at 20% threshold and lymph node status (P<.001) were significantly linked to disease-free survival in multivariate analysis. At 30% threshold, this was reduced to lymph node status (P<.001) alone. Our results showed that there are considerable differences between the different Ki-67 antibodies in their capacity to detect proliferating tumor cells and to separate low- and high-risk breast cancer patient groups., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of our retrospective study was to analyze patterns of subtype specific metastatic spread and to identify the time course of distant metastases. A consecutive series of 490 patients with breast cancer who underwent surgery and postoperative treatment at Semmelweis University, Hungary, and diagnosed between the years 2000 and 2007 was identified from the archives of the 2nd Department of Pathology, Hungary. Molecular subtypes were defined based on the 2011 St. Gallen recommendations. Statistical analysis was performed with SPSS Statistics for Windows, Version 22.0. Distant metastasis free survival (DMFS) was defined as the time elapsed between the first pathological diagnosis of the tumor and the first distant metastasis detection. Distant metastases were detected in 124 patients. Mean time to develop metastasis was 29 months (range 0-127 months). The longest DMFS was observed in the Luminal A (LUMA) subtype (mean 39 months) whereas the shortest was seen in the HER2-positive (HER2+) subtype (mean 21 months; p = 0.012). We confirmed that HER2+ tumors carry a higher risk for distant metastases (42.1%). LUMA-associated metastases were found to be solitary in 59% of cases, whereas HER2+ tumors showed multiple metastases in 79.2% of cases. LUMA tumors showed a preference for bone-only metastasis as compared with HER2+ and triple negative breast cancer (TNBC) cases, which exhibited a higher rate of brain metastasis. The most frequent second metastatic sites of hormone receptor (HR) positive tumors were the lung and liver, whereas the brain was the most affected organ in HR-negative (HR-) cases. Tumor subtypes differ in DMFS and in pattern of distant metastases. HER2+ tumors featured the most aggressive clinical course. Further identification of subtype-specific factors influencing prognosis might have an impact on clinical care and decision-making.

Background: Studies have partly demonstrated the clinical validity of Ki-67 as a predictive marker in the neoadjuvant setting, but the question of the best cut-off points as well as the importance of this marker as a prognostic factor in partial responder/non-responder groups remains uncertain., Methods: One hundred twenty patients diagnosed with invasive breast cancer and treated with neoadjuvant chemotherapy (NAC) between 2002 and 2013 were retrospectively recruited to this study. The optimal cut-off value for Ki-67 labeling index (LI) to discriminate response to treatment was assessed by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier curve estimation, log-rank test and cox regression analysis were carried out to reveal the association between Ki-67 categories and survival (DMFS = Distant metastases-free survival, OS = Overall survival)., Results: Twenty three out of 120 patients (19.2%) achieved pathologic complete remission (pCR), whereas partial remission (pPR) and no response (pNR) to neoadjuvant chemotherapy (NAC) was detected in 60.8% and 20.0%, respectively. The distribution of subtypes showed a significant difference in pathological response groups (p < 0.001). Most of the TNBC cases were represented in pCR group. The most relevant cut-off value for the Ki-67 distinguishing pCR from pNR cases was 20% (p = 0.002). No significant threshold for Ki-67 was found regarding DMFS (p = 0.208). Considering OS, the optimal cut-off point occurred at 15% Ki-67 (p = 0.006). The pPR group represented a significant Ki-67 threshold at 30% regarding OS (p = 0.001). Ki-67 and pPR subgroups were not significantly associated (p = 0.653). For prognosis prediction, Ki-67 at 30% cut-off value (p = 0.040) furthermore subtype (p = 0.037) as well as pathological response (p = 0.044) were suitable to separate patients into good and unfavorable prognosis cohorts regarding OS. However, in multivariate analyses, only Ki-67 at 30% threshold (p = 0.029), and subtype (p = 0.008) were independently linked to OS., Conclusions: NAC is more efficient in tumors with at least 20% Ki-67 LI. Both Ki-67 LI and subtype showed a significant association with pathological response. Ki-67 LI represented independent prognostic potential to OS in our neoadjuvant patient cohort, while pathological response did not. Additionally, our data also suggest that if a tumor is non-responder to NAC, increased Ki-67 is a poor prognostic marker.

A subgroup of triple-negative breast cancer (TNBC) shows epithelial-to-mesenchymal transition (EMT) features, which are sustained by the interaction between cancer cells and tumor-associated macrophages (TAMs). In this study, the clinical relevance of 30 EMT-related kinases and the potential cross-talk with TAMs were investigated in a cohort of 203 TNBC patients treated with adjuvant chemotherapy. The prognostic value of the evaluated markers was validated in two independent cohorts of TNBC patients treated with adjuvant chemotherapy ( N =95; N =137). In vitro , we investigated the potential synergism between cancer cells and TAMs. We found that the EMT-related kinase AXL showed the highest correlation with the frequency of CD163-positive macrophages ( r S =0.503; P <0.0001). Relapsing TNBC patients presented high expression of AXL ( P <0.0001) and CD163 ( P <0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, P =0.002; overall survival P =0.001). In vitro analysis demonstrated that AXL -expressing TNBC cells were able to polarize human macrophages towards an M2-like phenotype, and modulate a specific pattern of pro-tumor cytokines and chemokines. Selective AXL inhibition impaired the activity of M2-like macrophages, reducing cancer cell invasiveness, and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs. These data suggest that the EMT-related kinase AXL overexpressed in cancer cells has prognostic significance, and contributes to the functional skewing of macrophage functions in TNBC. AXL inhibition may represent a novel strategy to target cancer cells, as well as tumor-promoting TAMs in TNBC., Competing Interests: The authors declare no conflict of interest.

Background: Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) loss of function is frequently detected in advanced colorectal cancer. Its detection is thought to have prognostic significance and it is being considered to predict responsiveness to anti-EGFR therapy. Unfortunately, while immunohistochemical assessment of PTEN expression is widespread, it lacks standardization and the results are hardly comparable across the available publications., Methods: Retrospectively collected, formalin-fixed and paraffin-embedded colorectal tumor tissue samples from 55 patients were combined into tissue microarray (TMA) blocks. We used three different PTEN antibodies to determine the frequency, intensity and intracellular pattern of PTEN immunohistochemical labeling: Neomarkers, Dako and CellSignaling. We evaluated the aforementioned parameters in selected regions of colorectal cancers and in their lymph node metastases by using three scoring methods that take into consideration both staining frequency and intensity (H1-H3-score). We also evaluated intracellular localization., Results: The Dako and CellSignaling antibodies stained predominantly cytoplasms, while the Neomarkers antibody specifically stained cell nuclei. PTEN H-scores were significantly lower in all tumor areas as compared to the normal colonic mucosa based on staining with the DAKO and CellSignaling antibodies. Intratumoral regional differences or differences between matching tumors and metastases were not detected with any of the antibodies. Neither Dako, neither CellSignaling, nor the Neomarkers antibodies revealed a significant correlation between PTEN expression and pT, Dukes/MAC and clinical stage. KRAS status, histological grade correlated with PTEN H-scores based on staining with the Neomarkers antibody. PTEN H-scores did not correlate with MMR status. PTEN H-scores did not show any correlation with relapse-free survival based on staining with either antibody., Conclusions: While PTEN expression decreased in colorectal cancer according to two antibodies, neither of the three applied PTEN antibodies could justify significant correlation with clinicopathological data, nor had prognostic value. Thus, we might conclude that immunohistochemical PTEN investigation remains a challenge requiring more standardized evaluation on larger number of cases to clarify its utility as a prognostic and predictive tool in CRC. The standardization of immunohistochemical method is key in the evaluation process, which is further discussed.

A prognostic index (Petersen index, PI) was created for patients with pT3-4 pN0 M0 (Stage II, Dukes' B) colon cancers to distinguish between patients with better and worse outcome, and to help in recommending adjuvant chemotherapy for high risk patients in this stage. The prognostic value of the PI was evaluated in two independent retrospective series of stage II (Dukes' B) colon cancer patients. The parameters defining the PI (venous invasion, peritoneal involvement, circumferential margin involvement, perforation through the tumour) and performance of the PI were compared in two institutions. The two series of patients consisted of 127 and 87 patients. Venous invasion was more frequently detected at one of the centres (p<0.01) and tumour perforation was more frequent at the other (p<0.01). There were no significant differences in the 5-year survival estimates of all patients (p=0.19), and of either the low PI value groups (p=0.52) or that of the high PI value groups (p=0.99) between the two sites. In contrast, there were significant differences in the survival estimates between patients of the low PI category and those of the high PI category altogether (p<0.01) and in either centre. Although, it was expected that differences in the frequency of the parameters involved in the PI would influence its performance, this was not confirmed by the data. Our results suggest that using the PI may be of value in prognostic factor based therapy selection of colon carcinoma patients., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

In the second half of the 20th century research focusing to breast carcinomas at the Semmelweis University had been mostly linked to the 2nd Department of Pathology. Nowadays, following the rapidly improving treatment modalities in breast cancer there is an increasing need for defining new predictive and prognostic markers. The modern molecular pathological approach helps tremendously in mapping the biological behavior of individual cases of breast cancers and meanwhile, it is one of the prerequisites of a more efficient treatment both in neoadjuvant and adjuvant settings, as well as in metastatic disease. We provide a brief review of the relevant results we have obtained in breast cancer research between 2000 and 2015.

The transanal endoscopic microsurgery (TEM) provides lower relapse and complication rate for the the surgical treatment of the neoplasms of the middle and lower third of the rectum in selected cases. Hence, it can be an alternative method of the conventional approaches, if it does not compromise oncological radicality. The TEM procedure has been started at the 1st Department of Surgery, Semmelweis University in the fall of 2013. In this short study we have evaluated the clinicopathological characteristics of patients undergoing TEM between September 2013 and September 2014. Fourty-four patients were included in our retrospective analysis. 12 patients had low grade adenoma, 14 patients had high grade adenoma, 17 patients had invasive adenocarcinoma, while one was operated for a neuroendocrine tumor. There was no difference in the size of neoplasms between the low and high grade adenomas or adenocarcinomas (p = 0.210), tumors below the size of 30 mm or over 30 mm displayed no significant difference either (p = 0.424). The surgical margins were free of tumor in 41 cases (95.3%). In 13 out of 44 cases the preoperative histology proposed a lower grade neoplasm than the final report (p < 0.001). These results demonstrate that the surgical treatment of large adenomas with TEM technique, which involves excision of the whole bowel wall, is more appropriate than the fractionated removal or polypectomy supplemented by mucosectomy. The pT2 stage tumours might be subjected to the TEM method in selected cases (e.g. following neoadjuvant treatment or palliative care), but this has to be confirmed with prospecively evaluated large series clinical studies which are currently ongoing.

Background: Grade 2 breast carcinomas do not form a uniform prognostic group., Aim: To extend the number of patients and the investigated genes of a previously identified prognostic signature described by the authors that reflect chromosomal instability in order to refine characterization of grade 2 breast cancers and identify driver genes., Methods: Using publicly available databases, the authors selected 9 target and 3 housekeeping genes that are capable to divide grade 2 breast carcinomas into prognostic groups. Gene expression was investigated by polymerase chain reaction in 249 formalin-fixed, paraffin-embedded breast tumors. The results were correlated with relapse-free survival., Results: Histologically grade 2 carcinomas were split into good and a poor prognosis groups. Centroid-based ranking showed that 3 genes, FOXM1, TOP2A and CLDN4 were able to separate the good and poor prognostic groups of grade 2 breast carcinomas., Conclusion: Using appropriately selected control genes, a limited set of genes is able to split prognostic groups of breast carcinomas independently from their grade.

The aim of our study was to determine the radiographic prevalence of hip and knee osteoarthritis and compare our results with prevalence data reported by other studies, as no similar study had been performed in Hungary previously. Our aim was also to investigate the usefulness of the different radiological scoring methods for the definition of osteoarthritis. Patients who earlier reported complaints and gave written consent were asked to participate in a clinical follow-up. In the 682 participants Harris hip score, visual analogue pain scale values for both joints, Knee Society score and knee functional score were calculated. Weight-bearing radiographs were taken of both joints. Kellgren-Lawrence radiological evaluation was performed and osteoarthritis prevalence was defined. Hip osteoarthritis was found in 109 cases (16.49%), and knee osteoarthritis was found in 111 cases (16.54%). Harris hip score, Knee Society score, functional score and visual analogue scale values were significantly worse in people with radiographically proven osteoarthritis compared to the control group (p < 0.05). Significantly higher osteoarthritis prevalence of both joints was found in those with increased body mass index values. Age also plays a significant role in the development of both hip and knee osteoarthritis. No significant difference was observed between male and female participants regarding osteoarthritis prevalence. The Kellgren-Lawrence score with a cut-off value of 2 or more is a useful evaluation method for the detection of osteoarthritis prevalence in epidemiological studies; according to our observations, in clinical practice a cut-off value of three or more is more relevant.