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PurposeEstrogen receptor (ER) expression in breast cancer plays an essential role in carcinogenesis and disease progression. Recently, tumors with low level (1-10%) of ER expression have been separately defined as ER Low Positive (ERlow). It is suggested that ERlow tumors might be morphologically and behaviorally different from tumors with high ER expression (ERhigh).MethodsRetrospective analysis of a prospective cohort database was performed. Patients who underwent curative surgery for early breast cancer and had available medical records were included for analysis. Difference in clinicopathological characteristics, endocrine responsiveness and five-year recurrence-free survival was evaluated between different ER subgroups (ERhigh, ERlow, and ER-negative (ER-)).ResultsA total of 2162 breast cancer patients were included in the analysis, Tis and T1 stage. Among them, 1654 (76.5%) were ERhigh, 54 (2.5%) were ERlow, and 454 (21.0%) were ER- patients. ERlow cases were associated with smaller size, higher histologic grade, positive human epidermal growth factor receptor 2 (HER2), negative progesterone receptor, and higher Ki-67 expression. Recurrence rate was highest in ER- tumors and was inversely proportional to ER expression. Recurrence-free survival was not affected by hormonal therapy in the ERlow group (P = 0.418).ConclusionERlow breast cancer showed distinct clinicopathological features. ERlow tumors seemed to have higher recurrence rates compared to ERhigh tumors, and they showed no significant benefit from hormonal therapy. Future large scale prospective studies are necessary to validate the treatment options for ERlow breast cancer.

Summary Background Polycystic ovary syndrome (PCOS) is a multifactorial hormonal disorder accompanied by impairment of endometrial function and structure. Pomegranate is recognized for its role in normalizing the female sex hormones in PCOS with little known about its effect on the accompanying endometrial histological alterations. Aim of the work To assess the possible ameliorative role of pomegranate juice extract (PJE) on endometrial injury in a rat model of PCOS. Material and methods Forty adult albino rats were equally divided into 4 groups; control, PJE-treated (400 mg/kg/day for 3 weeks), letrozole-treated (PCOS) (1 mg/kg/day for 3 weeks), and PJE & PCOS groups. Serum Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), testosterone, estradiol, and tissue malondialdehyde (MDA) were assayed. Uterine samples were processed for histological staining with hematoxylin & eosin and Masson's trichrome stains, Ki67 and androgen receptor immunohistochemical staining, and scanning electron microscopy. Results PCOS group revealed a significant increase in serum FSH, LH, testosterone, estradiol, and tissue MDA. Uterine sections depicted various histological alterations in the endometrium with signs of inflammation. A significant increase in the endometrial collagen fiber content, as well as a significant upregulation in Ki67 and androgen receptor immunohistochemical expression were detected. Scanning electron microscopy showed a significant decrease in the mean number of pinopodes. Concomitant administration of PJE efficiently restored the studied biochemical, histological, and immunohistochemical parameters. Conclusion PJE ameliorated PCOS accompanying endometrial histological alterations through its antioxidant, anti-inflammatory, anti-fibrotic, anti-proliferative, and anti-androgenic effects most probably due to its polyphenols content.

Purpose A fast, reliable and non-invasive method is required in differentiating brain metastases (BMs) originating from lung cancer (LC) and breast cancer (BC). The aims of this study were to assess the role of histogram analysis of apparent diffusion coefficient (ADC) maps in differentiating BMs originated from LC and BC, and then to investigate further the association of ADC histogram parameters with Ki-67 index in BMs. Methods A total of 55 patients (LC, N = 40; BC, N = 15) with BMs histopathologically confirmed were enrolled in the study. The LC group was divided into small-cell lung cancer (SCLC; N = 15) and non-small-cell lung cancer (NSCLC; N = 25) groups. ADC histogram parameters (ADCmax, ADCmean, ADCmin, ADCmedian, ADC10, ADC25, ADC75 and ADC90, skewness, kurtosis and entropy) were derived from ADC maps. Mann–Whitney U-test, independent samples t-test, receiver operating characteristic (ROC) analysis and Spearman correlation analysis were used for statistical assessment. Results ADC histogram parameters did not show significant differences between LC and BC groups ( p > 0.05). Subgroup analysis showed that various ADC histogram parameters were found to be statistically lower in the SCLC group compared to the NSCLC and BC groups ( p mean and ADC10 for differentiating SCLC BMs from NSCLC, and ADC25 for differentiating SCLC BMs from BC achieved optimal diagnostic performances. Various histogram parameters were found to be significantly correlated with Ki-67 ( p Conclusion Histogram analysis of ADC maps may reflect tumoural proliferation potential in BMs and can be useful in differentiating SCLC BMs from NSCLC and BC BMs.

Odontogenic keratocysts (OKCs) and orthokeratinized odontogenic Cysts (OOCs) are distinct clinicopathological entities. OKC appears to behave in a way more similar to that of a neoplasm, such as ameloblastoma (AB). The aim of this study is to compare the influence of Ki-67, Cyclin D1 and COX-2 in the diagnosis and pathogenesis of OKC, OOC and AB.A cross-sectional observational study of 41 samples was organized into 3 groups: (1) OKC n=22; (2) AB n=13 and (3) OOC n=6. Paraffin blocks were sectioned and stained with hematoxylin and eosin (HE). Immunohistochemical study using Bond Polymer Refine Red Detection Kit, Leica, Wetzlar, Germany, was performed for the following antibodies: Ki-67, Cyclin D1 and COX-2. Double blind immunostaining was quantified subjectively. Staining: nuclear or cytoplasmic; nuclear (Ki-67 and Cyclin D15% positive) and cytoplasmic (COX-2; 1; 1-30 cytoplasm: 2; 31-60 cytoplasm; 3; 61-100 cytoplasm). Considering positive stained 61-100 cytoplasms.The expression of Ki-67 was higher in the OKC group than in the AB group (p0.05). Cyclin D1 showed a higher expression in OKC vs. OOC and OKC vs. AB (p0.05). Finally, expression of COX-2 was higher in OKC vs AB (p0.05).COX-2, Ki-67 and Cyclin D1 show statistically significant differences between the groups, suggesting that they could be useful tools in the differential diagnosis between OKCs and OOC and a predictive indicator for their biologic behaviour. The higher expressions of these 3 markers of OKC vs AB highlight once more the aggressive behaviour of this now re-considered cystic lesion. These markers could prove useful in the choice of more aggressive surgical treatment in OKCs as their behaviour appears to be similar to that of a neoplasm.

Background & Aims Microvascular invasion (MVI), a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma (HCC), is only detectable by microscopic examination of the surgical specimen. We aimed to define a transcriptomic signature associated with MVI in HCC than can be applied to formalin-fixed paraffin-embedded (FFPE) biopsies for use in clinical practice. Methods To identify a gene expression signature related to MVI by using NanoString technology, we selected a set of 200 genes according to the literature and RNA-sequencing data obtained from a cohort of 150 frozen HCC samples previously published. We used 178 FFPE-archived HCC samples, including 109 surgical samples for the training set and 69 paired pre-operative biopsies for the validation set. In 14 cases of the training set, a paired biopsy was available and was also analyzed. Results We identified a 6-gene signature (ROS1, UGT2B7, FAS, ANGPTL7, GMNN, MKI67) strongly associated with MVI in the training set of FFPE surgical HCC samples, with 82% accuracy (sensitivity 82%, specificity 81%, AUC 0.82). The NanoString gene expression was highly correlated in 14 paired surgical/biopsy HCC samples (mean R: 0.97). In the validation set of 69 FFPE HCC biopsies, the 6-gene NanoString signature predicted MVI with 74% accuracy (sensitivity 73%, specificity 76%, AUC 0.74). Moreover, on multivariate analysis, the MVI signature was associated with overall survival in both sets (hazard ratio 2.29; 95% CI 1.03-5.07; p = 0.041). Conclusion We defined a 6-gene signature that can accurately predict MVI in FFPE HCC biopsy samples, which is also associated with overall survival, although its survival impact must be confirmed by extensive study with further clinical data. Lay summary Microvascular invasion, a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma, is only detectable by microscopic examination of a surgical specimen. In this study, we defined a relevant surrogate signature of microvascular invasion in hepatocellular carcinoma that may be applied in clinical practice with routine tumor biopsy and integrated into the therapeutic strategy.

Background Myxopapillary ependymomas (MPE) with anaplastic features are rarely reported with only 21 cases identified to date, and long-term recurrence is rarely presented. The purpose of this case series is to expand understanding of this disease by describing three unique cases, including two that arose from myxopapillary ependymoma after a prolonged clinical course. Methods A review of literature and three cases of MPE with anaplastic features are described. Results Patient 1 is a 13-year-old male who presented with an avidly enhancing intradural lumbar mass. Upon gross total resection, the tumor was found to be a solid mass with areas of myxopapillary architecture and a MIB-1 (Ki-67) index of 12%. Patient 2 is a female who initially presented at age 22 with a lumbosacral tumor that treated with surgery and radiation. A recurrent tumor was resected at age 24. Twenty-six years later, at age 50, the patient presented with a large heterogeneous exophytic mass in the sacrum extending into the presacral space and Ki-67 index of 8%. This was treated with complete resection. Patient 3 is a male who initially presented at age 35 with a lower thoracic, upper lumbar mass at L2 extending into the sacrum. Following resection and radiation, a metastatic focus followed an indolent course until causing pain at the age of 48. The Ki-67 index was 16%. Conclusions The presented cases of MPE with anaplastic features make a total of 24 cases on record in the medical literature and demonstrate two examples of late recurrence.

This study evaluated the characteristics of vestibular schwannomas (VS) in young patients, including clinical features, treatment, prognosis, and histopathologic characteristics.We retrospectively reviewed medical records and follow-up data for 36 pediatric patients21 years of age who were surgically treated for VS in the Chinese PLA General Hospital between 2008 and 2019.Mean patient age was 17.4 years. Mean tumor size was 2.8 cm. Hearing loss (n = 32, 88.9%) and tinnitus (n = 20, 55.6%) were the most common symptoms. Ten patients (27.8%) had impaired facial nerve function after surgery. Gross total resection (GTR) was achieved in 26 cases (72.2%). The median tumor Ki-67 level was 5%. Tumor size was related to incomplete tumor resection (odds ratio, 0.2; 95% confidence interval, 0.1-0.9) and postoperative facial nerve dysfunction (odds ratio, 24.9; 95% confidence interval, 1.2-539.1). Tumor size was nonlinearly associated with prognosis and 2.2 cm corresponded to the inflection point at which the probability of tumor remnant and postoperative facial nerve dysfunction significantly increased. The GTR and low Ki-67 groups achieved better 3-year tumor control rate. Histopathologic findings confirmed the presence of cellular schwannoma subtype in young patients.Tumor size is an important factor affecting the prognosis of VS in young patients. For large VS, surgical treatment should be the first choice, rather than wait-and-scan. VS in young patients shows high tumor proliferation and a tendency to relapse. The cellular schwannoma subtype requires special attention; an accurate histopathologic diagnosis is necessary for young patients with VS, and a closer follow-up strategy should be adopted for cellular VS.

The choice of the anti-HER2 agent depends on country-specific availability, the specific, previously administered anti-HER2 therapy and the relapse-free interval, although there is not much published data on the use of lapatinib after progression on pertuzumab and/or T-DM1. The aim of this research is to determine efficacy of lapatinib in this setting. This research included 111 patients with metastatic HER2 positive breast cancer who received lapatinib with capecitabine at The Oncology Institute of Vojvodina. Lapatinib was given to 83 patients after trastuzumab without prior exposure to pertuzumab or T-DM1 while 28 patients received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1. In order to determine efficacy of lapatinib in both groups, we measured progression free survival (PFS) and overall survival (OS), as well as by subsets: hormonal status (ER-positive and/or PR-positive tumours versus ER-negative and PR-negative tumours), the number of positive axillary lymph nodes (four or more positive axillary lymph nodes versus less than four positive axillary lymph nodes), marker of proliferation (Ki-67 ≥ 30 versus Ki-67 30), disease free interval (metastatic recurrence ≤ 1 year after initial diagnosis versus metastatic recurrence1 year after initial diagnosis or de novo metastatic disease. Median PFS was 5.6 months (95% CI 4.6-6.6) in the group of patients who received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM 1 and 7.4 months (95% CI 6.1-10.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.79; 95% CI 0.61-0.98; P = 0.09). The patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes, marker of proliferation Ki 67 ≥ 30 and metastatic recurrence ≤ 1 year after initial diagnosis, had a similar PFS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Median OS was 10.1 months (95% CI 8.6-NR) in the group that received lapatinib after exposure to trastuzumab, pertuzumab and/or T-DM1 and 16.3 months (95% CI 14.4-20.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.76; 95% CI, 0.59-0.94; P = 0.04). Patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes and marker of proliferation Ki 67 ≥ 30, had no distinctly worse OS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Lapatinib with capecitabine is an effective therapeutic option, especially in patients with negative prognostic factors, who have received prior chemotherapy, trastuzumab, pertuzumab, T-DM1 and remains an acceptable option for HER2 positive metastatic breast cancer until the novel drugs are approved in developing countries.

OBJECTIVE To find the optimal threshold of Ki67 and evaluate its significance in predicting recurrence of stage I-II cervical cancer. METHODS A total of 1130 patients were included after screening. Univariate and multivariate Cox regression analysis were used to select factors associated with recurrence of cervical cancer. The receiver operating characteristic (ROC) curve was used to assess the optimal threshold of Ki67. The differences of clinicopathological parameters and the survival analysis between the two groups divided based on the optimal threshold of Ki67 were compared. RESULTS Multivariate Cox regression analysis showed that Ki67 (p

Although ependymomas (EPNs) have similar histopathology, they are heterogeneous tumors with diverse immunophenotypes, genetics, epigenetics, and different clinical behavior according to anatomical locations. We reclassified 141 primary EPNs from a single institute with immunohistochemistry (IHC) and next-generation sequencing (NGS). Supratentorial (ST), posterior fossa (PF), and spinal (SP) EPNs comprised 12%, 41%, and 47% of our cohort, respectively. Fusion genes were found only in ST-EPNs except for one SP-EPN with ZFTA-YAP1 fusion, NF2 gene alterations were found in SP-EPNs, but no driver gene was present in PF-EPNs. Surrogate IHC markers revealed high concordance rates between L1CAM and ZFTA-fusion and H3K27me3 loss or EZHIP overexpression was used for PFA-EPNs. The 7% cut-off of Ki-67 was sufficient to classify EPNs into two-tiered grades at all anatomical locations. Multivariate analysis also delineated that a Ki-67 index was the only independent prognostic factor in both overall and progression-free survivals. The gain of chromosome 1q and CDKN2A/2B deletion were associated with poor outcomes, such as multiple recurrences or extracranial metastases. In this study, we propose a cost-effective schematic diagnostic flow of EPNs by the anatomical location, three biomarkers (L1CAM, H3K27me3, and EZHIP), and a cut-off of a 7% Ki-67 labeling index. Supplementary Information The online version contains supplementary material available at 10.1007/s10014-021-00417-y.

Introduction Meningiomas are the most common benign intracranial neoplasms. CNS invasion in meningiomas has been integrated into the 2016 WHO classification of CNS tumors as a stand-alone criterion for atypia. Since then, its prognostic impact has been debated based on contradictory results from retrospective analyses. The aim of the study was to elucidate whether histopathological evidence of CNS invasion is associated with increased proliferative potential. Methods We have conducted a quantified measurement of the proliferation marker Ki67 and analyzed its association with CNS invasion determined by histology together with other established prognostic markers of progression. Routine, immunohistochemical staining for Ki67 were digitalized and automatic quantification was done using Image J software. Results Overall, 1718 meningiomas were assessed. Histopathological CNS invasion was seen in 108 cases (6.7%). Uni- and multivariate analysis revealed a significantly higher Ki67 proliferation rate in meningiomas with CNS invasion (p Conclusions Meningiomas with histopathological CNS invasion show a higher proliferative activity.

Bizarre (atypical/symplastic) cells have been described in various gynecologic normal tissues and benign neoplasms. This type of bizarre cytologic change is usually an incidental finding and is regarded as a benign process. We describe 17 cases of bizarre chorionic-type trophoblast in second-trimester and third-trimester placentas that created concern for an underlying/undersampled or incipient intraplacental trophoblastic neoplasm, predominantly found in intervillous trophoblastic islands (11/17), placental septae (6/17), chorionic plate (1/17), and/or the chorion layer of fetal membranes (2/17). The bizarre trophoblastic cells exhibited sheet-like or nested architecture, had a multifocal/patchy distribution, and/or were present as individual cells within hyaline stroma; they were characterized by large nuclei with smudgy chromatin and occasional intranuclear pseudoinclusions. The degree of atypia was classified as mild (0/17), moderate (3/17), or severe (14/17). Mitotic figures and necrosis were not identified. A dual immunohistochemical stain for trophoblast (hydroxyl-delta-5-steroid dehydrogenase) and a proliferation marker (Ki-67), performed in 15 cases, demonstrated 0% to very low proliferative activity within the bizarre trophoblast (0% to 2% [10/15], 3% to 8% [5/15]). Immunohistochemical stains for fumarate hydratase showed intact/retained expression in the bizarre cells in 7 of 7 cases. Clinical follow-up ranged from 1 to 45 months, and all patients were alive and well without subsequent evidence of a gestational trophoblastic or other neoplasms. We conclude that bizarre chorionic-type trophoblast in second-trimester or third-trimester placentas have the potential to mimic an intraplacental trophoblastic neoplasm but are likely a benign degenerative change. This study expands the spectrum of bizarre cells that occur in the gynecologic tract.

BACKGROUND: Ki-67 immunohistochemistry (IHC) staining is a widely used cancer proliferation assay; however, its limitations could be improved with automated scoring. The OncotypeDXTM Recurrence Score (ORS), which primarily evaluates cancer proliferation genes, is a prognostic indicator for breast cancer chemotherapy response; however, it is more expensive and slower than Ki-67. OBJECTIVE: To compare manual Ki-67 (mKi-67) with automated Ki-67 (aKi-67) algorithm results based on manually selected Ki-67 “hot spots” in breast cancer, and correlate both with ORS. METHODS: 105 invasive breast carcinoma cases from 100 patients at our institution (2011–2013) with available ORS were evaluated. Concordance was assessed via Cohen’s Kappa (κ). RESULTS: 57/105 cases showed agreement between mKi-67 and aKi-67 (κ 0.31, 95% CI 0.18–0.45), with 41 cases overestimated by aKi-67. Concordance was higher when estimated on the same image (κ 0.53, 95% CI 0.37–0.69). Concordance between mKi-67 score and ORS was fair (κ 0.27, 95% CI 0.11–0.42), and concordance between aKi-67 and ORS was poor (κ 0.10, 95% CI −0.03–0.23). CONCLUSIONS: These results highlight the limits of Ki-67 algorithms that use manual “hot spot” selection. Due to suboptimal concordance, Ki-67 is likely most useful as a complement to, rather than a surrogate for ORS, regardless of scoring method.

Summary Gastrointestinal lymphomas are uncommon in dogs and little is known about their distinct subtypes or proliferation rate. The aim of this study was to stratify 33 canine gastrointestinal lymphoma samples according to the latest World Health Organization classification and to determine the Ki67 proliferation index by manual counting, digital image analysis and visual estimation. The Ki67 index was then correlated with subtype, immunophenotype, mitotic index, grade and tumour location. The mitotic index correlated positively with the Ki67 index. A significantly higher number of Ki67-positive cells was found in enteropathy-associated T-cell lymphoma type I and in diffuse large B-cell lymphoma compared with enteropathy-associated T-cell lymphoma type II. There was also a significant difference in Ki67 immunolabelled cells between grade 1 and grade 2 lymphomas. Moderate agreement was found between the Ki67 index as obtained by manual counting and visual estimation, but there was strong agreement between manual counting and digital image analysis. The user-friendly digital imaging system used in this study could have potential for future determination of the Ki67 index in lymphoid neoplasms.

Ki67 labeling index (LI) has been proposed as a prognostic factor in uterine leiomyosarcoma (uLMS), although the evidence in this field is still unclear. We aimed to assess the prognostic value of ki67 LI in uLMS. A systematic review was performed by searching electronic databases from their inception to August 2020 for all studies assessing the prognostic value of ki67 LI in uLMS. Ki67 LI was assessed to the nearest 10% to define the most prognostically accurate threshold. Cox regression survival analysis with calculation of hazard ratio (HR) of death was performed; a p-value 0.05 was considered significant. Ten studies were included in the qualitative review, out of which 6 were suitable for quantitative review. The absolute risk of death was 0.29 for a ki67 LI 10%, remained stable at 0.49 in the 10%-39% LI range and increased to 0.65 for a LI ≥ 40%. On univariate analysis, both 10% and 40% thresholds were significantly associated with the hazard of death, with HRs of 3.349 (p = 0.007) and 3.172 (p = 0.001), respectively. On multivariate analysis, only the 10% threshold was significantly associated with the hazard of death (HR = 2.712; p = 0.028). In conclusion, a Ki67 LI ≥ 10% is a significant prognostic factor in uLMS.

Background: Familial forms of cavernous malformations (CMs) often occur as multiple lesions. Nevertheless, the presence of a single CM does not exclude the familiarity. The aim of this study is to establish which patients who undergo surgery for a single cerebral cavernous malformation (CCM), with no family history at initial diagnosis, should be investigated for familiarity through genetic testing and counseling. Methods: Eight families with 2 or more members affected by CCM have been studied. A control group of sporadic cases operated on, with no family history and followed up 10 years or more, was also included. Analyzed factors were patient age and sex, location, number and size of the lesions, associated developmental venous anomaly, presence of epileptic seizures, symptomatic hemorrhage, focal neurological deficits, and documented growth of the malformation and Ki67 MIB1 proliferation index. Results: The familial group of CCMs showed higher incidence of pediatric patients (P = 0.01), more frequent occurrence of multiple lesions (P = 0.0004), higher rate of large CCMs, and symptomatic hemorrhage; besides, all 3 cases with documented growth belonged to the familial group (14%). The expression of Ki67 MIB1 was positive in 79% of the familial cases versus 0% in the sporadic ones (P < 0.00001). Conclusions: Patients with CCM and no known family history at the time of the initial diagnosis who present specific features should be studied by genetic screening. The Ki67 MIB1 is a useful biomarker in favor of familial occurrence and may be studied in all patients with CMs to define the indication to the genetic tests.

BACKGROUND AND OBJECTIVES In the last decades, attention to the role of lymphangiogenesis in psoriasis has been paid. Our study was conducted to evaluate podoplanin-stained lymphatic vessels and the level of lymphangiogenesis in papular psoriatic lesions and psoriatic plaques and ascertain if podoplanin provides any additional prognostic information. MATERIALS AND METHODS Number of lymphatic vessels and total lymphatic vessel area were morphometrically analyzed in podoplanin-stained sections, using anti-D2-40, together with the immunohistochemical study of epidermal Ki-67 in psoriasis vulgaris (n = 20) (papules = 7 and plaques = 13) and control skin specimens (n = 20). RESULTS The number of lymphatic vessels and total lymphatic vessel area were higher in psoriasis cases compared with normal skin (p = 0.01, p = 0.01 respectively). In psoriatic plaques, the number of lymphatic vessels, total lymphatic vessel area, and epidermal Ki-67 immunoreactivity were higher than in papular lesions (p = 0.002, p = 0.008, and p = 0.01, respectively). CONCLUSIONS Psoriasis vulgaris is found to be a lymphangiogenesis-dependent disease, and the lymphatic vascular network is in remodeling and expanding process. Podoplanin may be implicated in the pathogenesis of psoriasis and could be used as a prognostic biomarker for disease severity and progression.

BACKGROUND: Twenty percent of women referred to colposcopy have a type 3 transformation zone—where colposcopic assessment for high-grade dysplasia (CIN2+) is not possible. This study examines the effectiveness of HPV biomarkers and genotyping in combination with techniques that sample an endocervical TZ. METHODS: A prospective diagnostic accuracy study. Women booked for large-loop excision (LLETZ) with squamous dyskaryosis, high-risk HPV and a TZ3 were recruited. Immediately prior to LLETZ samples were collected for p16/Ki-67 dual-stained cytology, HPV genotyping and H&E, p16- and Ki-67-stained endocervical curettings. RESULTS: In women with low-grade screening (n = 64), 35.9% had CIN2+; dual-stained cytology had the greatest effect on the PPV of routine screening (76.1% vs 35.9%) and perfectly predicted the absence of CIN2+. In women with a high-grade screening result (n = 37); 75.6% had CIN2+ and dual-stained curettings improved the PPV (96.5 vs 75.6%). CONCLUSIONS: With high-grade screening and a TZ3, LLETZ appears safest as three quarters have CIN2+ . Women with low-grade screening and a TZ3 have a twofold increased risk of CIN2+ when compared to women where the TZ is visible. The use of dual-stained cytology may help identify those women who can be safely offered surveillance and those who require treatment.

We report two pituitary neuroendocrine tumors (PitNETs) with very high Ki67 labeling indices, many mitoses and TP53 mutation (nearly all tumor cell nuclei were positive for p53). One of the tumors had bone and liver metastases. One was a corticotroph cell tumor; the other was a lactotroph tumor. The classification of these tumors is the subject of this discussion. Traditionally, pituitary carcinomas are only diagnosed by demonstration of metastases according to the 2017 WHO classification. In contrast, neuroendocrine neoplasms of the gastrointestinal tract and pancreas are classified as either well differentiated NETs that are graded as G1, G2, and G3 based on proliferation as determined by Ki67 indices of ≤ 3, 3–20 and > 20%, and/or 20 mitoses per 10 high-power field respectively, or as neuroendocrine carcinomas (NECs) that are poorly differentiated neoplasms with mitoses > 20/HPF and/or a Ki67 index > 20%. With the reclassificiation of PitNETs, in our opinion, the adequate term for the well-differentiated corticotroph tumor that we report is a PitNET G3, whereas the undifferentiated prolactin tumor should be classified as PitNEC. This report expands the spectrum of pituitary neuroendocrine neoplasms.

Aims: The biomarkers oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are routinely measured in patients with breast cancer with international consensus on how they should be interpreted. There is evidence to support use of other biomarkers to give more detailed predictive and prognostic information. Ki-67 is one example, and measures the proliferative activity of cancer cells. It is important that this can be performed at diagnosis of breast cancer for patients who do not have initial surgical treatment (mainly older women) and those receiving neoadjuvant therapies. Methods and results: A systematic review was performed to assess concordance of measurement of Ki-67 between core needle biopsy (CNB) samples and surgical excision (SE) samples in patients with invasive breast cancer. MEDLINE and Embase databases were searched. Studies were eligible if performed within the last 10years; included quantitative measurement of Ki-67 in both CNB and SE samples with no prior breast cancer treatment; measured concordance between two samples; and had full text available. A total of 22 studies, including 5982 paired CNB and SE samples on which Ki-67 was measured, were appraised. Overall, there appeared to be concordance; however, reliability was unclear. Where given, the Cohen’s kappa coefficient (κ) of correlation between samples ranged from 0.261 to 0.712. The concordance rate between CNB and SE where measured as a percentage had a range from 70.3 to 92.7%. Conclusions: Assessment of level of concordance of Ki-67 between CNB and SE samples is hampered by different methodologies. International consensus on Ki-67 measurement is urgently needed.

The expression of immunohistochemical markers has been extensively investigated in thymomas to assist in the differential diagnosis. We have studied six select markers to determine their utility in the evaluation of these tumors. A series of 126 thymomas including 33 type A, 27 type AB, 20 type B1, 22 type B2, and 24 type B3, were examined utilizing a tissue microarray (TMA) technique with antibodies to e-cadherin, β-catenin, PAX8, bcl-2, EMA, and MIB-1. Keratin AE1/AE3 and p63 were used for quality control. A significant finding was strong and consistent positivity for bcl-2 in type A (90%) and type AB (88.8%) thymoma, while 100% of B1, B2, and B3 were negative. The distribution of e-cadherin and β-catenin was not useful for differential diagnosis. E-cadherin and β-catenin were expressed in a high proportion of all the tumors (92-100%), except for B2 thymoma which showed only 45% expression. A significant increase in the expression of the MIB-1 proliferation marker (mean: 12.8% nuclear positivity) was also observed in B3 thymoma compared with the other histologic types. Statistical significance was confirmed using Kruskal's non-parameterized test for distribution. EMA was generally negative except for spindle cells in the fibrous septa in types A and AB thymoma. PAX8 showed less consistent nuclear staining than p63 and was only widely expressed in 55.7% of cases. Bcl-2 may serve as a useful marker to separate spindle cell thymomas (Type A and AB) from the other types, and the MIB1 proliferation index may be of use to differentiate type B2 from type B3 thymoma.

Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection. SCC has various stages, and local recurrence is common. The purpose of this study was to investigate thrombospondin-1 expression and its association with prognosis. In this retrospective study, a gene expression array along with immunohistochemistry were performed for the evaluation of thrombospondin-1 expression, localization, as well as Ki67 labeling cell indices in carcinoma in situ (Tis) and advanced conjunctival SCC (Tadv). The presence or absence and intensity of cytoplasmic and nuclear staining in tumor cells were also divided into groups with a score of 0–3 and semi-quantitatively analyzed to investigate intracellular staining patterns. The association between thrombospondin-1 expression and tumor progression in a series of 31 conjunctival SCCs was further investigated. All 31 patients in the cohort (100%) were East Asian. A simple comparison between Tis and Tadv demonstrated significant differences in expressions of 45 genes, including thrombospondin-1 (p

Background Gastrointestinal neuroendocrine tumor (GI-NET) is a group of neoplasia consisting of amine and acid producing cells with different hormonal profiles. Although the entire GIS accounts for about 2% of tumors, recent research reveals that the incidence rate has increased. Given the increasing incidence in GI-NETs, more and more extensive research is needed on this subject. In this regard, the demographic and clinicopathological features of the patients diagnosed with GI-NET and their relationship with survival were investigated in the present study. Methods Thirty-four patients diagnosed with GI-NETs between January 2009 and December 2019 at the Department of Gastroenterology, Inonu University Faculty of Medicine were analyzed retrospectively. Gender, age, tumor localization, metastasis status, tumor number, tumor diameter, tumor grade, Ki-67 index, and the relationships of these factors with overall survival were examined. Results Of the patients, 61.8% included in the study were male and 38.2% were female. The average age of the patients was 60.74 years. The most common tumor location was in the stomach (26.5%) and liver (26.5%). Apart from this, 17.6% of NETs were seen in the pancreas, 11.8% in the colon, 8.8% in the rectum, 5.9% in the small intestine, and 2.9% in the appendix. No significant relationship was observed between tumor location and gender (p = .326) and age (p = .641). The tumor diameter ranged from 0.2 cm to 13.91 cm, but the average tumor diameter was 3.84 cm. Solitary tumor was found in 51.5% of cases and multiple tumors in 48.5% of cases. The most common grade was Grade 1 with 41.2% of occurrence. The average of Ki-67 index was 18.36%. There was metastasis in 52.9% of cases. The rate of medical treatment was 48.5%. The median overall survival time of the patients was 23.1 months. In addition, 1-year overall survival was 74.9%, 2-year overall survival was 44.6%, and 5-year overall survival was 35.7%. A statistically significant difference was found between tumor grade and the presence of metastasis, and the overall survival (p = .003 and p = .005). Conclusions The tumor grade and the presence of metastasis in gastrointestinal neuroendocrine tumors were found to be the most important prognostic factors affecting overall survival.

BACKGROUND The purpose of this study is to investigate the correlation between cytokeratin 7 (CK7) and marker of proliferation Ki67 protein expression and clinical characteristics and prognosis of patients with cervical adenocarcinoma after surgery. METHODS A total of 126 patients with cervical adenocarcinoma treated by surgery in our hospital from June 2011 to September 2015 were enrolled in this study. Immunohistochemistry (IHC) was used to detect the expression of CK7 and Ki67 in 126 cases of cervical adenocarcinoma tissues. The chi-square (χ2) test was used to compare the relationship between the positive expression rate of CK7 or Ki67 and clinicopathological features. Kaplan-Meier method was used to analyze the survival of different protein expression groups and Cox proportional hazards regression model was used to analyze the risk factors affecting the prognosis. RESULTS The positive rate of CK7 was correlated with muscle invasion, vascular invasion, differentiation, and lymph node metastasis (all P

Background The development of efficient strategies for managing high-risk human papillomavirus (HR-HPV)-positive women is a major challenge when human papillomavirus-based primary screening is being performed. The objectives of this study were to evaluate the comparative effectiveness of HR-HPV testing based on self-collection (SC) and HR-HPV testing based on collection by a health professional (HP) and to assess the potential usefulness of HR-HPV testing combined with testing with the biomarkers p16/Ki-67, α-mannosidase, and superoxide dismutase 2 (SOD2). Methods This was a cross-sectional study of 232 women admitted for colposcopy because of an abnormal Papanicolaou smear. The collected material underwent liquid-based cytology, HR-HPV detection, and immunocytochemical testing (p16/Ki-67, α-mannosidase, and SOD2). The gold standard was the histopathological result; the positive reference was CIN2+. Results The overall accuracy of HR-HPV testing was 76.6%; the results for the SC group (78.1%) and the HP group (75.2%) were similar. The positive predictive values (HP, 76.5%; SC, 80.0%), the negative predictive values (HP, 66.7%; SC, 64.3%), the positive likelihood values (HP, 1.35; SC, 1.36), and the negative likelihood values (HP, 0.21; SC, 0.19) were also similar. p16/Ki-67 showed higher sensitivity than the other 2 biomarkers: 78.1% versus 45.8% for α-mannosidase and 44.5% for SOD2. The specificities of the biomarkers were equivalent: 71.4% for p16/Ki-67, 77.8% for α-mannosidase, and 71.2% for SOD2. In the HP group, accuracy also leaned more heavily toward the final score (using α-mannosidase and SOD2) without statistical significance (80.8% vs 77.9%). The contrast with the SC group yielded the same level of accuracy. Conclusions SC, when associated with testing with biomarkers, is as accurate as collection by HPs in the detection of women at risk for cervical cancer.

The diagnosis of histological transformation of follicular lymphoma can be challenging and ambiguous. We investigated the distribution of the Ki-67 labeling index of histological transformation of follicular lymphoma and determined its cutoff value to predict poor outcomes. The diagnostic criteria for histological transformation were a diffuse pattern of proliferation and a proportion of large lymphoma cells ≥20%. Of the 1121 patients with follicular lymphoma, 171 (15%) showed histological transformation to diffuse large B-cell lymphoma. Of these, 76 patients, whose biopsies were obtained from the sites with the highest maximum standardized uptake values, according to the positron emission tomography findings, were included. The Ki-67 index ranged from 16.8% to 98.4% (median, 60.6%). In patients with histological transformation, the most significant differences were found in progression-free survival (p = 0.087, 58% vs. 87% at 2 years) and overall survival (p = 0.024, 53% vs. 85% at 5 years) when a 70% cutoff was used. Additionally, overall survival was significantly shorter in patients with histological transformation with maximum standardized uptake values of ≥20 (p < 0.0001) and absence of a follicular lymphoma component (p = 0.004). A Ki-67 index of ≥70% was a significant adverse factor for overall survival in patients with histological transformation of follicular lymphoma and may predict poor outcomes.

BACKGROUND/AIM Muscle invasive bladder cancer (MIBC) is an aggressive disease with high rates of local recurrence following radical cystectomy (RC). Currently, there are no clinically validated biomarkers to predict local only recurrence (LOR) and guide adjuvant treatment decisions. This pilot study evaluated the role of Ki-67, MRE11 and PD-L1 as predictive biomarkers for recurrence patterns in patients undergoing RC for MIBC. PATIENTS AND METHODS Our institutional cystectomy database containing cases from 1992-2014 was queried for patients with local only recurrence (LOR), and case-matched to patients with distant recurrence (DR) and no recurrence (NR). Clinicopathological data were collected and a tissue microarray was analyzed for presence of Ki-67, MRE11, and PD-L1 using immunofluorescence and immunohistochemistry. RESULTS Pathologic specimens from 42 patients (18 NR, 16 LOR, and 8 DR) were reviewed. Compared to normal bladder tissue, tumors had increased expression of Ki-67 (p

Aim Gallium-68-labelled inhibitors of the fibroblast activation protein (FAPi) enable positron emission tomography/computed tomography (PET/CT) imaging of fibroblast activation. We evaluated if [68Ga]Ga-DATA5m.SA.FAPi PET/CT is related to Ki-67 as a marker of tumour aggressiveness in patients with liver metastases of NET. Methods Thirteen patients with liver metastases of a histologically confirmed NET who underwent PET/CT with [68Ga]Ga-DATA5m.SA.FAPi, [18F]FDG and [68Ga]Ga-DOTA-TOC were retrospectively analyzed. PET-positive liver tumour volumes were segmented for calculation of volume, SUVmax and PET-positive tumour fraction (TF). PET parameters were correlated with Ki-67. Results FDGSUVmax correlated positively (rho = 0.543, p < 0.05) and DOTATOCSUVmax correlated negatively (rho = –0.618, p < 0.05) with Ki-67, the correlation coefficients were in the moderate range. There was no significant correlation between FAPiSUVmax and Ki-67 (rho = 0.382, p > 0.05). FAPiTF correlated positively (rho = 0.770, p < 0.01) and DOTATOCTF correlated negatively (rho = –0.828, p < 0.01) with Ki-67, both significantly with high correlation coefficients. FDGTF also correlated significantly with Ki-67, with a moderate correlation coefficient (rho = 0.524, p < 0.05). The ratio FAPiVOL:DOTATOCVOL showed a significant and strong correlation with Ki-67 (rho = 0.808, p < 0.01). Conclusion The ratio FAPiVOL:DOTATOCVOL might serve as a clinical parameter for the assessment of dedifferentiation and aggressiveness of liver metastases in patients with NET. [68Ga]Ga-DATA5m.SA.FAPi might hold potential for identification of high-risk patients. Further studies are warranted to evaluate its prognostic significance in comparison to [18F]FDG in patients with NET.

AimsThis study was aimed to investigate the clinicopathological significance of immunohistochemical (IHC) Wilm’s tumour 1 (WT1) expression in invasive breast carcinoma with >90% mucinous components.MethodsOne hundred specimens of invasive breast carcinoma with >90% mucinous component were collected. All H&E-stained slides were reviewed, and the clinicopathological data, including sex, age, tumour size, nuclear grade, histological grade, growth pattern and lymph node (LN) status, were collected. IHC staining of WT1, oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 was performed. Fluorescence in situ hybridisation was used to verify the amplification of the HER2 gene. The relationship between WT1 expression and clinicopathological features was analysed statistically.ResultsWT1 expression was detected in 67% (67/100) of invasive breast carcinoma with >90% mucinous components. WT1 expression was significantly associated with low-to-intermediate nuclear grade/histological grade, ER and PR positivity, HER2 negativity, Ki-67 proliferation index ConclusionsWT1 expression was significantly related with low-intermediate nuclear/histological grade, ER positivity, HER2 negativity, a lower Ki-67 proliferation index and no LN metastasis in invasive breast carcinoma with >90% mucinous component. The micropapillary growth pattern in this type of tumour did not show a specific relationship with WT1 expression.

BACKGROUND The aim of this study was to compare the differential Ki-67 and p27 staining properties of acquired cholesteatoma in adult patients for prognostic analysis. METHODS Forty-two adult patients with acquired cholesteatoma were enrolled. The cholesteatoma and matched meatal skin tissues of the patients were immunostained with Ki-67 and p27 antibodies. Canal wall down mastoidectomy was performed in all patients. The differential staining properties--positive staining in the cholesteatoma and negative staining in the skin tissue (C+S-), negative staining in the cholesteatoma and positive staining in the skin tissue(C-S+)--were compared for bone erosion scores (BES), stage, and recurrence rates. RESULTS Isolated findings in the cholesteatoma tissues, without matching with the skin tissues, demonstrated that stage and recurrence rates were not related to findings in the cholesteatoma tissues (P > .05). However, C+S- for Ki-67 and C-S+ for p27 are risk factors for worse prognosis including advanced stage (P < .001 for Ki-67 and P = .008 for p27), BES values (P < .001 for Ki-67 and P = .001 for p27), and recurrence rates (P < .001 for Ki-67 and P = .037 for p27). CONCLUSION This is the first paper assessing the cholesteatoma prognosis according to the differential Ki-67 and p27 staining properties of cholesteatoma and healthy skin tissues. Cellular proliferation rate in the cholesteatoma is important but insufficient by itself for predicting the prognosis of cholesteatoma patients. Patients having lower basal levels of cellular proliferation rate and higher cellular activity in the cholesteatoma tissue are prone to worse prognosis with increased stage, recurrence rates, and degree of bone erosion.

Objectives This study aimed to identify the tumor mutation burden (TMB) value in Egyptian breast cancer (BC) patients. Moreover, to find the best TMB prediction model based on the expression of estrogen (ER), progesterone (PR), human epidermal growth factor receptor 2 (HER-2), and proliferation index Ki-67. Methods The Ion AmpliSeq Comprehensive Cancer Panel was used to determine TMB value of 58 Egyptian BC tumor tissues. Different machine learning models were used to select the optimal classification model for prediction of TMB level according to patient's receptor status. Results The measured TMB value was between 0 and 8.12/Mb. Positive expression of ER and PR was significantly associated with TMB ≤ 1.25 [(OR =0.35, 95% CI: 0.04-2.98), (OR = 0.17, 95% CI= 0.02-0.44)] respectively. Ki-67 expression positive was significantly associated with TMB >1.25 than those who were Ki-67 expression negative (OR = 9.33, 95% CI= 2.07-42.18). However, no significant differences were observed between HER2 positive and HER2 negative groups. The optimized logistic regression model was TMB = -27.5 -1.82 ER - 0.73 PR + 0.826 HER2 + 2.08 Ki-67. Conclusion Our findings revealed that TMB value can be predicted based on the expression level of ER, PR, HER-2, and Ki-67.

Ki67, a nuclear proliferation-related protein, is heavily used in anatomic pathology but has not become a companion diagnostic or a standard-of-care biomarker due to analytic variability in both assay protocols and interpretation. The International Ki67 Working Group in breast cancer has published and has ongoing efforts in the standardization of the interpretation of Ki67, but they have not yet assessed technical issues of assay production representing multiple sources of variation, including antibody clones, antibody formats, staining platforms, and operators. The goal of this work is to address these issues with a new standardization tool. We have developed a cell line microarray system in which mixes of human Karpas 299 or Jurkat cells (Ki67(+)) with Sf9 (Spodoptera frugiperda) (Ki67(−)) cells are present in incremental standardized ratios. To validate the tool, six different antibodies, including both ready-to-use and concentrate formats from six vendors, were used to measure Ki67 proliferation indices using IHC protocols for manual (bench-top) and automated platforms. The assays were performed by three different laboratories at Yale and analysed using two image analysis software packages, including QuPath and Visiopharm. Results showed statistically significant differences in Ki67 reactivity between each antibody clone. However, subsets of Ki67 assays using three clones performed in three different labs show no significant differences. This work shows the need for analytic standardization of the Ki67 assay and provides a new tool to do so. We show here how a cell line standardization system can be used to normalize the staining variability in proliferation indices between different antibody clones in a triple negative breast cancer cohort. We believe that this cell line standardization array has the potential to improve reproducibility among Ki67 assays and laboratories, which is critical for establishing Ki67 as a standard-of-care assay.

Objective: The aim of the study is to analyse the Immuno-histochemical expression of Ki-67 and P16INK4a in CIN and cervical cancer cases and their utility to determine the accuracy of histological diagnosis and prediction of biological behavior of cervical lesion. Methodology: A retrospective cross-sectional study was carried in 110 numbers of cervical biopsy that included 25 CIN1, 21 CIN2, 12 CIN3, 26 SCC and 01 adenocarcinoma and 25 non neoplastic lesion. The tissue sections were stained with Ki-67 and P16INK4a. Results: Ki-67 expression was seen in 55.5% (61/110) cases of cervical lesion., out of which 3.6% (4/110; cervicitis -2/110 and metaplasia-2/110) cases were non dysplaia, 51.8% (57/110) cases were dysplasia /CIN of varying grade including invasive cancer. P16INK4a expression was noted 51.8% (57/110). There was an increasing trend of the intensity of Ki-67 and P16INK4a from focal positivity in low grade lesion to diffuse intensity in higher grade lesion and is statistically significant. There was strong association between the two variables Ki-67 and P16INK4a positive cases with their histologic grade. Conclusion: Though histopathology remains the ‘‘gold standard’’ for the diagnosis of CIN, both low and high-grade, biomarkers like Ki-67 and P16INK4a have emerged as helpful adjuncts. Their combined use may assist in the histopathologic classification of preinvasive lesions and facilitate the distinction from nondysplasia.

The aim and objective of the study were to evaluate the immunohistochemical expression of proliferative markers, Ki67, and MCM2 in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), to compare the relationship of their staining patterns, and to look for correlation between them, if any.Thirty archival paraffin-embedded tissue blocks of previously diagnosed cases of OED, OSCC each, and 10 normal oral mucosa were used in the study. Immunohistochemical staining for MCM2 and Ki67 markers was done and the slides were individually evaluated for MCM2 and Ki67 expression, with immunopositivity determined on the basis of dark brown staining of the nucleus. The number of positively stained nuclei was counted in 10 representative areas and the data were charted and statistically analyzed.The overall mean expression of both the proteins increased progressively from normal mucosa to OED to OSCC. In normal mucosa, all positively stained nuclei were seen in the basal compartment of the epithelium, while in dysplastic cases, expression was seen toward the surface of squamous epithelium. In OSCC, the frequency of expression of MCM2 and Ki-67 proteins showed an inverse correlation with the degree of tumor differentiation. In well-differentiated cases, the positivity of either marker was restricted to the outermost layer of the tumor cells. In moderately differentiated cases, an expression of Ki-67 was more diffuse in inner layers, whereas the MCM2 antigen was found to be more intense and diffuse in both the inner and outer layers. Whereas in poorly differentiated SCC, positive expression was seen in most of the tumor cells, the mean expression of MCM2 was found to be higher than that of Ki67 in all cases.MCM2, as a proliferation marker, is superior to Ki67 as it indicates the capacity of proliferation and the ability of DNA replication of a cell.

Retroperitoneal leiomyoma is a very rare disease, with little reported information on its origin. Herein, we report a case of a large retroperitoneal leiomyoma that developed from the pelvic floor. A 44-year-old woman had a large mass protruding outside the body from the right hip. Imaging revealed a large tumor developing from the pelvic floor to the buttocks. It was difficult to identify the place of origin. Upon preoperative biopsy, the patient was diagnosed with retroperitoneal leiomyoma. Tumor removal with abdominoperineal and partial vaginal resection was performed. Based on the histological findings of the surgical specimens, she was diagnosed with a retroperitoneal leiomyoma (gynecologic type) via immunohistochemistry, the tumor cells were positive for αSMA, desmin, estrogen receptor(ER), and progesterone receptor(PgR), but negative for myoglobin, S-100, CD34, and MIB-1.This is a case of a large retroperitoneal leiomyoma that was successfully removed via abdominoperineal and partial vaginal resection.

Background We analysed the reproducibility of Ki67 labelling index (LI) between two scorers using the International Ki67 Working Group (IKWG) global methods on an Android application (APP), correlated the APP and eyeball estimate (EBE) with digital image analysis (DIA) scores and determined the prognostic significance of Ki67LI. Methods Global weighted (GW) and global unweighted (GUW)) Ki67 app scores of hormone receptor positive and HER2 (human epidermal growth factor receptor 2) negative breast cancer patients were obtained. Reproducibility of Ki67LI between 2 scorers and correlation of APP and EBE scores with DIA scores was performed. The prognostic significance of APP scores and its correlation with other clinico-pathologic variables were evaluated. Results The intra-class correlation coefficient (ICC) between 2 scorers showed excellent reliability with both GW and GUW methods. ICC between DIA and APP scores was significantly greater than DIA versus EBE. The 3 categories of APP scores based on median value and cut points of 10%, 18% and 38% were significantly associated with poor DFS. On multivariate analysis, significant association between Ki67LI, tumour size, nodal involvement and DFS was noted. Conclusion Our study shows that the visual Ki67 scoring app is effective in bringing consistency to KI67LI and APP scores showed significant correlation with DFS.

Congenital biliary dilatation (CBD), defined as pancreaticobiliary maljunction (PBM) with biliary dilatation, is a high risk factor for biliary tract cancer (BTC). KRAS and p53 mutations reportedly affect this process, but the mechanisms are unclear, as is the likelihood of BTC later in life in children with CBD. We investigated potential carcinogenetic pathways in children with CBD compared with adults. The subjects of this study were nine children with CBD and 13 adults with PBM (10 dilated, 3 non-dilated) without BTC who underwent extrahepatic bile duct resections, as well as four control patients who underwent pancreaticoduodenectomy for non-biliary cancer. We evaluated expressions of Ki-67, KRAS, p53, histone deacetylase (HDAC) and activation-induced cytidine deaminase (AID) in the biliary tract epithelium immunohistochemically. The Ki-67 labeling index (LI) and expressions of KRAS, p53, HDAC, and AID in the gallbladder epithelium were significantly higher or tended to be higher in both the children with CBD and the adults with PBM than in the controls. BTC may develop later in children with CBD and in adults with PBM, via HDAC and AID expression and through epigenetic and genetic regulation.

AIMS Tumour grade and RET mutation status, especially the presence of high-risk exon 15 and 16 RET mutations, have been reported to be prognostic in patients with sporadic medullary thyroid carcinoma (MTC). The aims of our study were to evaluate the performance of two recently proposed grading systems and to assess the association between grade and genotype in a cohort of sporadic MTCs. METHODS AND RESULTS We identified 44 sporadic MTCs. All available tumour slides were examined, and cases were assigned a grade on the basis of either mitotic count and tumour necrosis, or mitotic count, tumour necrosis, and Ki-67 proliferative index, as described in two recent studies. Additional clinicopathological features and outcome information were obtained from the pathology reports and electronic medical records. The presence of RET and RAS mutations was determined either with direct sequencing or with massively parallel sequencing. Both grading systems were prognostic for progression-free survival and disease-specific survival on univariate analysis. There was no correlation between grade and mutation status. Specifically, neither RET nor high-risk RET mutations were enriched in high-grade tumours, as assessed by either grading scheme. CONCLUSION Our findings suggest that grade is not correlated with RET/RAS mutation status, indicating that grade and genotype may give independent prognostic information.

Background Malignant peritoneal mesothelioma is the most common primary peritoneal neoplasm. The only universally recognised pathological prognostic factor is histopathological subtype. Prognostic markers based on patient features and clinical stages have been disappointing. Aims To assess the prognostic role of several clinicopathological features in a retrospective cohort of 60 patients diagnosed with peritoneal mesothelioma. Methods Sixty patients were centrally collected and were immunohistochemically analysed for the expression of osteopontin (OPN), GLUT1 and Ki‐67. Labelling was assessed by two pathologists. Complete clinical information and follow‐up were obtained from patients' records. Results OPN expression was identified in 52 (86.6%) of 60 specimens, and GLUT1 in 39 (65%) of 60 specimens. Univariate Cox regression analysis showed that a lower peritoneal carcinomatosis index (PCI), tumour‐directed treatment (chemotherapy or surgery alone or in any combination), lower Ki‐67, GLUT1 and lower OPN expression had a statistically significant positive effect on overall survival (OS). PCI (hazard ratio (HR) = 1.032 (95% confidence interval (CI): 1.000–1.067); P = 0.054) and tumour‐directed treatment (HR = 0.211 (95% CI: 0.104–0.430); P

Background Nuclear protein Ki-67 indicates the status of cell proliferation and has been regarded as an attractive biomarker for the prognosis of HCC. The aim of this study is to investigate which radiomics model derived from different sequences and phases of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI was superior to predict Ki-67 expression in hepatocellular carcinoma (HCC), then further to validate the optimal model for preoperative prediction of Ki-67 expression in HCC. Methods This retrospective study included 151 (training cohort: n = 103; validation cohort: n = 48) pathologically confirmed HCC patients. Radiomics features were extracted from the artery phase (AP), portal venous phase (PVP), hepatobiliary phase (HBP), and T2-weighted (T2W) images. A logistic regression with the least absolute shrinkage and selection operator (LASSO) regularization was used to select features to build a radiomics score (Rad-score). A final combined model including the optimal Rad-score and clinical risk factors was established. Receiver operating characteristic (ROC) curve analysis, Delong test and calibration curve were used to assess the predictive performance of the combined model. Decision cure analysis (DCA) was used to evaluate the clinical utility. Results The AP radiomics model with higher decision curve indicating added more net benefit, gave a better predictive performance than the HBP and T2W radiomic models. The combined model (AUC = 0.922 vs. 0.863) including AP Rad-score and serum AFP levels improved the predictive performance more than the AP radiomics model (AUC = 0.873 vs. 0.813) in the training and validation cohort. Calibration curve of the combined model showed a good agreement between the predicted and the actual probability. DCA of the validation cohort revealed that at a range threshold probability of 30–60%, the combined model added more net benefit compared with the AP radiomics model. Conclusions A combined model including AP Rad-score and serum AFP levels based on enhanced MRI can preoperatively predict Ki-67 expression in HCC.

The solid variant of odontogenic keratocyst (SOKC) is an extremely rare odontogenic lesion, which remains poorly defined even in the 2017 World Health Organization odontogenic tumour classification. It is difficult to distinguish between SOKC and so called keratoameloblastoma (KAB), both rare lesions that have similarities in clinical, histological and biological characteristics. Here, we report clinicopathological data and results of molecular analysis of nine cases with a literature review. First, they were compared to previously reported cases of SOKC and/or KAB, and many overlaps were found in clinical and pathological characteristics. Second, we performed PCR analysis for BRAF V600E mutation. Although ameloblastoma-like epithelia were often encountered, none exhibited BRAF V600E mutation, which has been reported to occur frequently in ameloblastomas but not in odontogenic keratocysts (OKCs). One of two cases of SOKC in the present series from which fresh frozen tissue specimens were available was found to harbour PTCH1 mutations, indicating that these were more likely to be a subtype of OKC. Moreover, we also examined the differences between SOKC and primary intraosseous carcinoma (PIOC) with regard to the expression of cytokeratins (pan-CK, CK5/6, CK7, CK8/18, CK10, CK14 and CK19), p53 and Ki-67. The proportions of p53-and Ki-67-positive cells were significantly higher in PIOC than in SOKC. These findings suggest that immunostaining for p53 and Ki-67 would be useful to differentiate between SOKC and PIOC. We also conducted a review of SOKC and KAB cases reported in the English language literature.

Aims: One of the major drivers of the adoption of digital pathology in clinical practice is the possibility of introducing digital image analysis (DIA) to assist with diagnostic tasks. This offers potential increases in accuracy, reproducibility, and efficiency. Whereas stand-alone DIA has great potential benefit for research, little is known about the effect of DIA assistance in clinical use. The aim of this study was to investigate the clinical use characteristics of a DIA application for Ki67 proliferation assessment. Specifically, the human-in-the-loop interplay between DIA and pathologists was studied. Methods and results: We retrospectively investigated breast cancer Ki67 areas assessed with human-in-the-loop DIA and compared them with visual and automatic approaches. The results, expressed as standard deviation of the error in the Ki67 index, showed that visual estimation (eyeballing) (14.9 percentage points) performed significantly worse (P < 0.05) than DIA alone (7.2 percentage points) and DIA with human-in-the-loop corrections (6.9 percentage points). At the overall level, no improvement resulting from the addition of human-in-the-loop corrections to the automatic DIA results could be seen. For individual cases, however, human-in-the-loop corrections could address major DIA errors in terms of poor thresholding of faint staining and incorrect tumour-stroma separation. Conclusion: The findings indicate that the primary value of human-in-the-loop corrections is to address major weaknesses of a DIA application, rather than fine-tuning the DIA quantifications. Funding Agencies|ALF grant from Region Ostergotland

Owing to an increased number of colonoscopy screenings, the incidence of diagnosed rectal neuroendocrine tumors (NETs) has also increased. Tumor size is one of the most frequently regarded factors when selecting treatment; however, it may not be the determinant prognostic variable. We aimed to evaluate oncological outcomes according to the treatment modality based on the size of rectal NETs. A retrospective analysis was performed on patients who were treated for rectal NETs between March 2000 and January 2016 at the Asan Medical Center, Seoul, Korea. Patients who underwent endoscopic removal, local surgical excision, and radical resection were included. The primary outcome was recurrence-free survival (RFS). Data were specified and analyzed following the 2019 World Health Organization classification (WHO). A total of 644 patients were categorized under three groups according to the treatment modality used: endoscopic removal (n = 567), surgical local excision (n = 56), and radical resection (n = 21). Of a total of 35 recurrences, 27 were local, whereas eight were distant. The RFS rate did not differ significantly between the treatment groups in the same tumor-size group ( $$\le$$ 1 cm group: P = .636, 1–2 cm group: P = .160). For T1 tumors, RFS rate was not different between local excision and radical resection ( $$\le$$ 1 cm group: P = .452, 1–2 cm group: P = .700). Depth of invasion, a high Ki-67 index, and margin involvement were confirmed as independent risk factors for recurrence. Among patients treated with endoscopic removal, endoscopic biopsy was a significant factor for worse RFS (P

BACKGROUND: Proliferative abnormalities are believed to represent an early phase of colorectal carcinogenesis. Narrow band imaging (NBI) colonoscopy allows visual assessment of the mucosal vascular pattern (MVP) without dyeing. The aim of this study was to investigate the predictive value of MVP for mucosal proliferation in ulcerative colitis (UC). METHODS: A total of 119 colorectal lesions were analyzed from 42 patients with UC who underwent NBI colonoscopy. Both the MVP and the Mayo endoscopic score (MES) were assessed. The mucosal inflammation was histologically graded using a colitis score. The proliferation marker Ki-67 was assessed by immunohistochemical staining. RESULTS: The results showed that MVP correlated well with the MES (r = 0.796, P < .001). There was moderate correlation between the distribution of Ki-67 staining and MVP (r = 0.492, P < .001), and the Ki-67 labeling index increased with the orderly patterns of MVP (P < .001). An expansion of Ki-67 staining upward from the crypt base may be caused by active inflammation. CONCLUSION: MVP based on NBI colonoscopy can predict mucosal proliferation which is associated with inflammation in patients with UC.

Background Some patients with glioblastoma multiforme (GBM) survive 3–5 years (or longer) after diagnosis. The goal of this study was to identify differences between the long-term survivors (LTS) and those who had a shorter overall survival (non-LTS groups). Methods This study was a retrospective analysis of prospectively maintained surgical databases. All patients who underwent safe maximal resection for GBM were included. Demographic, clinical, radiologic, and pathologic data were obtained from electronic medical records. Values of the biomarkers of systemic inflammation were computed from the preoperative hemogram reports. Patients with an overall survival (OS) ≥36 months were defined as the LTS group and were compared with the non-LTS groups (OS Results Patients in the LTS group were younger, had a better baseline performance status, and were more likely to have undergone near- or gross-total resection. LTS was associated with lower Ki67 labeling, MGMT methylation, IDH mutation, and lack of p53 overexpression. Several novel findings were generated by this study. A longer pretreatment duration of symptoms was associated with a longer OS. Higher pretreatment levels of the absolute neutrophil count, neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio, derived neutrophil-lymphocyte ratio and systemic index of inflammation, and lower levels of the absolute eosinophil count and eosinophil-lymphocyte ratio all correlated with a shorter OS. Conclusions Several differences were identified between the LTS and non-LTS groups. These differences will likely be incorporated into future prognostic models. They may also aid in differentiation between recurrent disease and treatment-related changes.

Objective To investigate the clinical characteristics and factors affecting the prognosis of myxopapillary ependymoma (MPE). Methods We retrospectively analyzed the clinical data of 24 patients diagnosed with MPE who were surgically treated from January 2010 to January 2020 in the Department of Neurosurgery at Tongji Hospital (Tongji Medical School, Huazhong University of Science and Technology). Results Among the 24 included patients, there were 13 male and 11 female patients. The ages of the included patients ranged from 15 to 59 years old, with an average age of 35.2 years old. The Preoperative McCormick grade included 20 cases (83.3%) that were grade II and 4 cases (16.7%) that were grade III. The follow-up times ranged from 6 months to 10 years, with an average of 50.9 months. The Postoperative McCormick grade included 7 cases (29.2%) that were grade I, 4 cases (16.7%) that were grade II, 12 cases (50%) that were grade III and 1 case (4.2%) that was grade IV. The 1-year, 2-year, and 10-year recurrence rate was 8.3%, 29.2%, 41.7%, respectively. The 1-year, 2-year, and 10-year survival rate was 100%, 100%, 95.8% respectively. χ2 test revealed a significant difference between the degree of surgical resection (P = 0.012 Conclusions Our findings suggest that the degree of surgical resection was a key factor that affected the prognosis and neurologic function of the included patients with MPE.

OBJECTIVE We aimed to determine the predictive significance of Ki-67 and platelet lymphocyte ratio (PLR) in patients with gastric cancer (GC), who received fluorouracil, leucovorin, oxaliplatin, docetaxel (FLOT) as neoadjuvant chemotherapy (NAC). STUDY DESIGN Descriptive study. PLACE AND DURATION OF STUDY Department of Medical Oncology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey from March 2016 to January 2020. METHODOLOGY Seventy-five patients with GC, who received FLOT treatment as NAC were included in the study. Ki-67 and PLR, which were examined pre-NAC and aft-NAC, were recorded. Associations between clinical-histopathological parameters with disease-free survival (DFS) and overall survival (OS) were analysed using Kaplan-Meier curves. Cox-regression analysis was used to assess their prognostic values. RESULTS There was a statistically significant difference between pre-NAC and aft-NAC Ki-67, and aft-NAC PLR values between groups with complete response, partial response, and stable disease aft-NAC (p: 0.023, p

Background Chronic wounds constitute a significant medical and social problem. Chronic wound treatment may be supported by various techniques, such as negative pressure therapy, phototherapy or stem cells therapy, yet most of those supporting therapies need more evidence to be used for standard wound care. Current study covers the use of sonicated Antlerogenic Stem Cells (ASC) extract on chronic wounds. Methods Study was performed on 20 dermatological patients with venous leg ulcers, divided into two groups – treated with and without ASC extract respectively. The area and circumference of the wounds during the follow-up visits were measured on the wound imprint. Dynamics of wound healing was determined and compared between control and study group; statistics includes changes in absolute values (wound area, circumference), as well as relative (percentage of wound decrease, circumference/area ratio) and their change in time. For the purpose of Ki-67 immunohistochemical staining, sections were sampled from the wound edge at distinct check-points during therapy. Results of both groups were compared with Student test or Mann-Whitney test, depending on results distribution. Results Besides Ki-67 expression, all tested wound healing parameters (including relative and absolute wound decrease and changes in circumference/area ratio) were statistically significant more favorable in experimental group. Conclusion ASC extract significantly supported standard chronic wound treatment. Due to small population of study the results should be considered preliminary, yet promising for further research.

Background/aim The histopathological variability of each type of pituitary adenoma (PA) that causes growth hormone (GH) excess influences the phenotype, radiological characteristics and therapy response of acromegaly patients. We correlated the immunohistochemical (IHC) features of GH-secreting PAs with their clinical, laboratory and imaging data. Patients and methods We included 32 patients with documented acromegaly; tumour specimens were histologically and IHC examined: anterior pituitary hormones, pituitary-specific transcription factor-1 (PIT-1), Ki-67 labelling index were evaluated. Results Macroadenomas represented 93.75%. Post-surgery disease control negatively correlated with the maximum initial tumour diameter (p=0.04). Ki-67 did not predict remission. No correlation was found between GH serum levels and IHC expression (p=0.45). PIT-1 was positive in all specimens, two had a weak expression. Four were considered PIT-1 positive plurihormonal adenomas and several had unusual IHC combinations. Conclusion PIT-1 accurately classifies GH-secreting PAs. The IHC classification as well as radiological dimensions and extent influence disease control, probably being the best prognosis factors.

Progressive vision loss, caused by retinal degenerative (RD) diseases such as age-related macular degeneration, retinitis pigmentosa, and Leber congenital amaurosis, severely impacts quality of life and affects millions of people. Finding efficient treatment for blinding diseases is among the greatest unmet clinical needs. The evagination of optic vesicles from developing pluripotent stem cell-derived neuroepithelium and self-organization, lamination, and differentiation of retinal tissue in a dish generated considerable optimism for developing innovative approaches for treating RD diseases, which previously were not feasible. Retinal organoids may be a limitless source of multipotential retinal progenitors, photoreceptors (PRs), and the whole retinal tissue, which are productive approaches for developing RD disease therapies. In this study we compared the distribution and expression level of molecular markers (genetic and epigenetic) in human fetal retina (age 8-16 weeks) and human embryonic stem cell (hESC)-derived retinal tissue (organoids) by immunohistochemistry, RNA-seq, flow cytometry, and mass-spectrometry (to measure methylated and hydroxymethylated cytosine level), with a focus on PRs to evaluate the clinical application of hESC-retinal tissue for vision restoration. Our results revealed high correlation in gene expression profiles and histological profiles between human fetal retina (age 8-13 weeks) and hESC-derived retinal tissue (10-12 weeks). The transcriptome signature of hESC-derived retinal tissue from retinal organoids maintained for 24 weeks in culture resembled the transcriptome of human fetal retina of more advanced developmental stages. The histological profiles of 24 week-old hESC-derived retinal tissue displayed mature PR immunophenotypes and presence of developing inner and outer segments. Collectively, our work highlights the similarity of hESC-derived retinal tissue at early stages of development (10 weeks), and human fetal retina (age 8-13 weeks) and it supports the development of regenerative medicine therapies aimed at using tissue from hESC-derived retinal organoids (hESC-retinal implants) for mitigating vision loss.