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Solitary fibrous tumor (SFT) arising from adult mesenchymal stem cells is an uncommon vascular tumor of pelvic cavity. While initially thought to be confined to the pleura, pericardium, or peritoneum, recent studies have revealed that SFTs can develop in different areas of the body. Typically, SFTs grow slowly and may not present noticeable symptoms. In this 2 case study, we describe the clinical situation of a 46-year-old female patient and 68 years old male patient who complained of persistent pelvic pain and urinary symptoms respectively. Imaging tests revealed solitary fibrous tumor in the pelvic cavity which was confirmed on histopathology, an unusual location for this type of tumor. This case reports focusses on importance of early recognition and treatment in dealing with this rare tumor.

We conducted a proteomic analysis using mass spectrometry to identify and validate protein biomarkers for accurately predicting recurrence risk in gastrointestinal stromal tumors (GIST) patients, focusing on differentially expressed proteins in metastatic versus primary GIST tissues. We selected five biomarkers—GPX4, RBM4, TPM3, PFKFB2, and PGAM5—and validated their expressions in primary tumors of recurrent and non-recurrent GIST patients via immunohistochemistry. Our analysis of the association between these biomarkers with recurrence-free survival (RFS) and overall survival (OS), along with their interrelationships, revealed that immunohistochemistry confirmed significantly higher expressions of these biomarkers in primary GIST tissues of recurrent patients. Kaplan-Meier survival analysis showed that high expressions of GPX4, RBM4, TPM3, PFKFB2, and PGAM5 correlated with lower RFS, and GPX4 and RBM4 with lower OS. All biomarker pairs showed positive associations, with high expressions correlating with increased recurrence rates, and GPX4 and RBM4 with higher mortality rates. In conclusion, the biomarkers GPX4, RBM4, TPM3, PFKFB2, and PGAM5 are clinically relevant for predicting GIST recurrence, with their high expressions in primary tumors linked to poorer RFS and OS. They serve as potential prognostic indicators, enabling early treatment and improved outcomes. The observed interrelationships among these biomarkers further validate their accuracy in predicting GIST recurrence.

Introduction: TP53 is a strong tumor suppressor gene; its deactivation contributes to carcinogenesis and influences clinical outcomes. However, the prognostic influence of p53 deactivation on early relapse in patients with surgically resected non–small cell lung cancer remains unclear. Materials and methods: A cohort of 170 patients with primary stage I through III lung adenocarcinoma (LADC) and lung squamous cell carcinoma who underwent complete resection at Tokyo Medical and Dental University was screened for TP53 mutations using panel testing, and association studies between TP53 mutations and clinical data, including histology and postoperative recurrence, were performed. The association between TP53 mutations and postoperative recurrence was validated using data from 604 patients with MSK-IMPACT from The Cancer Genome Atlas. Additional immunohistochemistry for p53 was performed on some subsets of the Tokyo Medical and Dental University population. Results: Mutations in TP53 were recurrently observed (35.9%; 61 out of 170) in the Tokyo Medical and Dental University cohort. In the histology-stratified analysis, patients with LADC histology showed TP53 mutations that were associated with poor relapse-free survival (log-rank test; P = .020), whereas patients with lung squamous cell carcinoma histology showed TP53 mutations that were not (P = .99). The poor prognosis of TP53 mutation-positive LADCs was validated in The Cancer Genome Atlas-LADC cohort (log-rank test; P = .0065). Additional immunohistochemistry for p53 in patients with LADC histology in the Tokyo Medical and Dental University cohort showed a significant correlation between TP53 mutations and abnormal IHC pattern of p53 (Cramer's correlation coefficient V = 0.67). Conclusions: TP53 mutation is a potential marker for worse prognosis in surgically resected LADC; immunohistochemistry for p53 could be a surrogate method to identify patients with LADC with a worse prognosis.

الملخص: أهداف البحث: يهدف هذا البحث إلى دراسة تأثير مستخلص زهرة الشعلة الحمراء الإيثانولي بنسبة 70% على تعبير إنزيمات الأكسدة الحلقية-2 في ظهارة اللثة لدى الجرذان المصابة بالتهاب اللثة السكري. طريقة البحث: تم تحريض الإصابة بمرض السكري والتهاب اللثة في 32 ذكرا من الجرذ النرويجي بوزن 200-300 جرام. تم حقن الستربتوزوتوسين المذاب في 1 مل من محلول السترات داخل الصفاق لتسبب ارتفاع السكر في الدم. بعد ثلاثة أيام من ظهور مرض السكري، تم قياس مستويات السكر في الدم أثناء الصيام لدى الفئران باستخدام مقياس السكر في الدم. تم التأكد من الإصابة بمرض السكري عندما تجاوزت مستويات الجلوكوز في الدم الصائم 200 ملغم / ديسيلتر. بعد تشخيص التهاب اللثة السكري، تم إعطاء حقنة يومية من مستخلص الإيثانول ''إي. إليتيور'' بنسبة 70% (العدد = 16) والمحلول الملحي (العدد = 16) داخل الصفاق لمدة سبعة أيام. تم إجراء إجراء الكيمياء المناعية للكشف عن تعبير الأكسدة الحلقية-2 في ظهارة اللثة في الأيام 1 و3 و5 و7 بعد الحقن. يتم التعبير عن عدد الخلايا الملونة بشكل إيجابي كنسبة مئوية. شوهد السيتوبلازم ذو اللون البني في ظهارة اللثة يشير إلى تعبير إيجابي لـ الأكسدة الحلقية-2، ويمتد من الطبقة القاعدية إلى الطبقة القرنية. النتائج: مقارنة بالمحلول الملحي، أدى المستخلص الإيثانولي بنسبة 70% من حقن زهرة الشعلة الحمراء إلى زيادة تعبير الأكسدة الحلقية-2 في الأيام من الأول إلى الخامس. ومع ذلك، في اليوم السابع، أظهرت مجموعة الشعلة الحمراء مستوى منخفضا بشكل كبير من تعبير الأكسدة الحلقية-2 مقارنة بالمجموعة المحقونة بالمحلول الملحي. الاستنتاجات: في التهاب اللثة الناتج عن مرض السكري، تم العثور على 70٪ من مستخلص الإيثانول زهرة الشعلة الحمراء ليكون عنصرا نشطا مفيدا في علاج تعديل المضيف. يقوم المستخلص الإيثانولي بنسبة 70٪ من زهرة الشعلة الحمراء بتعديل تعبير بشكل إيجابي كنسبة مئوية. شوهد السيتوبلازم ذو اللون البني في ظهارة اللثة يشير إلى تعبير إيجابي لـ الأكسدة الحلقية-2 في ظهارة اللثة لدى الجرذان المصابة بالتهاب اللثة السكري. Abstract: Objectives: This research was aimed at investigating the effects of 70% ethanolic Etlingera elatior flower extract on cyclooxygenase-2 (COX-2) expression in the gingival epithelium in rats with diabetic periodontitis. Methods: Diabetes and periodontitis were induced in 32 male Rattus norvegicus individuals weighing 200–300 g each. Streptozotocin dissolved in 1 mL citrate buffer was injected intraperitoneally to elicit hyperglycemia. Three days after diabetes induction, the rats' fasting blood glucose levels were measured with a GCU EasyTouch® glucometer. Diabetes was confirmed by fasting blood glucose levels exceeding 200 mg/dL. After diagnosis of diabetic periodontitis, a daily injection of 70% ethanolic E. elatior extract (n = 16) and saline (n = 16) was intraperitoneally administered for 7 days. Immunohistochemistry was used to detect COX-2 expression in the gingival epithelium on days 1, 3, 5, and 7 after injection, and the number of positively colored cells was expressed as a percentage. Brownish cytoplasm in the gingival epithelium was considered to indicate positive COX-2 expression, which extended from the basal layer to the corneum. The percentage of immunopositive cells was analyzed with two-way ANOVA followed by post-hoc LSD analysis at a 95% significance level. Results: Injection of 70% ethanolic extract of E. elatior flower, compared with saline, resulted in greater COX-2 expression on days 1–5. On day 7, however, the E. elatior group exhibited substantially lower COX-2 expression than the saline group (p

Current prognostic biomarkers fall short in stratifying Oestrogen receptor (ER)-negative breast cancer patients regarding tumour progression risk at diagnosis. The role of AIPL1 in activating its tumour suppressor client protein, NEDD8 Ultimate Buster-1 (NUB1) remains unknown in cancer. Our study demonstrated how downregulated AIPL1 results in the deactivated NUB1 protein under hypoxic conditions. We examined the AIPL1-NUB1 pathwayin vitro using cell lines i.e. MCF-7, MDA-MB-231, RCC4 etc. NUB1 expression was assessed using Oncomine, and cBioPortal was performed to assess NUB1′s prognostic significance in human cancers. In the John Radcliffe Hospital cohort (n = 122), immunohistochemistry analysis revealed downregulated AIPL1 (Log2 fold change=-0.28; p < 0.001) and upregulated NUB1 transcripts (Log2 fold change=0.59; p < 0.001) compared to adjacent normal tissues. In severe chronic hypoxia, multimerised AIPL1 localisedin the cytoplasm while NUB1 protein migrated to the nucleus, where the absence of NUB1 nuclear localisation led to cell cycle arrest. Biopsies showed that patients with lower cytoplasmic NUB1 expression (n = 57) had poorer overall survival compared to those with higher cytoplasmic expression (n = 57), HR=1.78; 95 % CI=1.01–3.35, p = 0.048. Low NUB1 protein levels in both normoxic and hypoxic conditions were associated with cell cycle arrest and upregulation ofp21 and p27 in breast cancer cell lines, correlating significantly withpoorer survival outcomes in all breast cancer and ER-negative breast cancer patients.

Background: Synovial sarcoma (SynSa) is one of the most common translocation-related soft tissue sarcomas. Patients with metastatic SynSa have limited treatment options and a very poor prognosis. Several novel experimental therapies are currently being explored in clinical trials, including T cell-based therapies targeting cancer testis antigens such as New York esophageal squamous cell carcinoma 1 (NY-ESO-1) or melanoma-associated antigen A4 (MAGE-A4), and degraders targeting bromodomain-containing protein 9 (BRD9). Preclinical studies investigate inhibitors of Yes associated protein 1 (YAP1), transcriptional co-activator with PDZ-binding motif (TAZ) and inhibitors of chemokine receptor 4 (CXCR4). Methods: We explored the immunohistochemical expression of these targets using a tissue microarray (TMA) constructed from 91 clinical SynSa samples and correlated these findings with corresponding clinicopathological data. Results: Expression of MAGE-A4 and NY-ESO-1 was found in 69 % and 56 % of the samples, respectively. NY-ESO-1 was statistically higher expressed in samples from metastatic lesions as compared to samples from primary tumors. Nuclear expression of YAP1 and TAZ was observed in 92 % and 51 % of the samples, respectively. CXCR4 was expressed in the majority of the samples (82 %). BRD9 was highly expressed in all specimens. No prognostic role could be identified for any of the investigated proteins. Conclusion: This study is a comprehensive study providing real-world data on the expression of several actionable proteins in a large proportion of SynSa samples. All evaluated markers were expressed in a clinically meaningful proportion of cases represented in our TMA, supporting the relevance of ongoing preclinical and clinical research with novel agents directed against these targets.

In this study, we present a method that enables voxel-by-voxel comparison of in vivo imaging to immunohistochemistry (IHC) biomarkers. As a proof of concept, we investigated the spatial correlation between dynamic contrast enhanced (DCE-)CT parameters and IHC biomarkers Ki-67 (proliferation), HIF-1α (hypoxia), and CD45 (immune cells). 54 whole-mount tumor slices of 15 laryngeal and hypopharyngeal carcinomas were immunohistochemically stained and digitized. Heatmaps of biomarker positivity were created and registered to DCE-CT parameter maps. The adiabatic approximation to the tissue homogeneity model was used to fit the following DCE parameters: Ktrans (transfer constant), Ve (extravascular and extracellular space), and Vi (intravascular space). Both IHC and DCE maps were downsampled to 4 × 4 × 3 mm[3] voxels. The mean values per tumor were used to calculate the between-subject correlations between parameters. For the within-subject (spatial) correlation, values of all voxels within a tumor were compared using the repeated measures correlation (rrm). No between-subject correlations were found between IHC biomarkers and DCE parameters, whereas we found multiple significant within-subject correlations: Ve and Ki-67 (rrm = -0.17, P < .001), Ve and HIF-1α (rrm = -0.12, P < .001), Ktrans and CD45 (rrm = 0.13, P < .001), Vi and CD45 (rrm = 0.16, P < .001), and Vi and Ki-67 (rrm = 0.08, P = .003). The strongest correlation was found between IHC biomarkers Ki-67 and HIF-1α (rrm = 0.35, P < .001). This study shows the technical feasibility of determining the 3 dimensional spatial correlation between histopathological biomarker heatmaps and in vivo imaging. It also shows that between-subject correlations do not reflect within-subject correlations of parameters.

Background: Evaluating multiple biomarkers including human epidermal growth factor receptor 2 (HER2), mismatch repair (MMR) status, programed death-ligand 1 (PD-L1), and claudin 18.2 (CLDN18.2) is essential for selecting appropriate first-line therapy of metastatic gastroesophageal adenocarcinoma (mGEA). However, this can be challenging if tumor tissue amount is limited and may cause delays in the initiation of chemotherapy. Therefore, we assessed the feasibility of multiple biomarkers testing in routine clinical practice. Materials and methods: We reviewed the medical records of treatment-naïve patients with mGEA who underwent prospective multiple biomarkers testing between April 2022 and October 2023 in our institution. Eight biomarker status including HER2, MMR, PD-L1, CLDN18.2, Epstein–Barr virus, fibroblast growth factor receptor 2, epidermal growth factor receptor and mesenchymal epithelial transition expressions were simultaneously examined using biopsy or surgical specimens. Results: A total of 203 patients with mGEA were analyzed. Most patients underwent gastroendoscopy and tumor biopsy shortly after referral to our institution. Biomarkers testing was successfully completed on the first attempt in 198 patients (97.5%). With additional steps including additional biopsy or asking remaining tumor samples from the referring hospital, the biomarker results were eventually available in all cases. The median turnaround time from sample collection to reporting results was 7 days. Consequently, 178 patients (87.7%) could receive first-line treatment after obtaining the biomarker status. Conclusions: Multiple biomarkers testing for patients with mGEA was feasible in clinical practice. Establishment of a testing infrastructure based on the collaboration with multiple departments is essential for implementing biomarker-driven precision treatment.

Background: The L-type amino acid transporter (LAT1) exhibits significantly increased expression within tumor cells across various neoplasms. However, the clinical significance of LAT1 expression in patients with pleural mesothelioma (PM) remains unclear. Methods: Eighty patients diagnosed with PM between June 2007 and August 2022, were eligible for this study. LAT1, alanine-serine-cysteine transporter 2 (ASCT2), Ki-67, and VEGFR2 were evaluated by immunohistochemistry. Inflammatory and nutritional indices were also correlated with different variables, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). Results: LAT1 was highly expressed in 57.5 % of patients with PM. Among the 80 patients included in this study, 65 (81.3 %) received chemotherapy, either alone or followed by surgical resection, while 15 (18.7 %) opted for best supportive care. The level of LAT1 significantly correlated with cell proliferation and ASCT2. Factors such as performance status, histology, LAT1 expression, PNI, ALI, and GPS were significant prognostic indicators for progression-free survival (PFS), while Ki-67, LAT1, NLR, SII, PNI, ALI, and GPS were identified as significant predictors for overall survival (OS). LAT1 expression emerged as an independent prognostic factor for predicting PFS and OS in all patients, as well as in the subgroup of 65 patients receiving chemotherapy. Notably, high LAT1 expression proved to be a significant predictor of outcome, particularly in the subgroup with high PLR and SII. Conclusion: LAT1 was a significant predictor of outcomes in patients with PM and was more predictive of worse outcomes in patients with high inflammatory and low nutritional status.

Ovarian cancer is the leading cause of death among gynecological cancers in most developed countries, with many patients developing chemotherapy resistance leaving them with a 5-year survival rate of

This study presents a rare case of Rosai-Dorfman disease (RDD) with nasal and nasopharyngeal involvement, illustrating the complexities in diagnosing this enigmatic histiocytic disorder. RDD, characterized by massive, painless cervical lymphadenopathy, poses diagnostic challenges due to its diverse clinical presentations. In this case, a 38-year-old woman presented with a year-long history of neck swellings, nasal congestion, headaches, and sinusitis-like symptoms. Radiological imaging and histopathological examination revealed RDD involvement in the nasopharynx and paranasal sinuses. RDD diagnosis was confirmed through immunohistochemistry. The patient's unique symptoms emphasize the importance of considering RDD in the differential diagnosis of sinonasal masses with recurrent or unusual complaints. This case underscores the need for increased awareness, multidisciplinary management, and further research to enhance understanding and treatment of RDD, especially in extranodal presentations.

Background: Synchronous endometrial and ovarian carcinomas represent up to 10% of all endometrial and ovarian tumors. These are diagnostically challenging cases to determine if they represent dual primary tumors or related metastatic tumors. Case: A 48-year-old was diagnosed with synchronous primary ovarian and endometrial malignancies on pathology based on traditional morphological parameters. However, following next generation sequencing (NGS) of tumors from both the uterus and ovary, the malignancies were unequivocally recognized as primary uterine tumor metastatic to the ovary using mismatch repair protein expression profile and tumor clonality. Conclusion: NGS using FDA-approved commercially available platforms is becoming increasingly utilized to understand the genetic landscape of tumors and select the appropriate targeted therapies for improved outcomes. Simultaneous sequencing of synchronous endometrial and ovarian carcinomas may represent the new gold standard to unequivocally demonstrate tumor clonal relationships, properly classify disease as well as guide the most appropriate adjuvant treatment in these challenging cases.

For the past 2 decades, pathologists have been accustomed to reporting the HER2 status of breast cancer as either positive or negative, based on HER2 IHC. Today, however, there is a clinical imperative to employ a 3-tier approach to interpreting HER2 IHC that can also identify tumours categorised as HER2-low. Meeting this need for a finer degree of discrimination may be challenging, and in this article, we consider the potential for the integration of computational approaches to support pathologists in achieving accurate and reproducible HER2 IHC scoring as well as outlining some of the practicalities involved.

We present a case series of seven sweat gland tumours of the hand. The rarity of these lesions and, more importantly, the great difficulty in diagnosing such lesions on clinical examination is obvious in most of the literature. Our experience is similar, with only seven sweat gland tumours diagnosed out of a total of 1073 cases of tumours of the hand over 38 years at our private hand clinic. The details of these seven cases are outlined here, out of which only one tumour was malignant. Advances in histopathological examination, particularly in immunohistochemistry, play a significant role in the diagnosis of such tumours. Level of evidence: IV.

The accurate diagnosis of papillary urothelial carcinoma (PUC) is frequently challenging due to benign mimickers. Other than morphology-based diagnostic criteria, reliable biomarkers for differentiating benign and malignant papillary urothelial neoplasms remain elusive, so we sought to discover new markers to address this challenge. We first performed tandem mass spectrometry-based quantitative proteomics using diverse papillary urothelial lesions, including PUC, urothelial papilloma (UP), inverted urothelial papilloma, and cystitis cystica. We prioritized potential diagnostic biomarkers using machine learning, and subsequently validated through immunohistochemistry (IHC) in two independent cohorts. Metabolism, transport, cell cycle, development, and immune response functions were differentially enriched between malignant and benign papillary neoplasms. RhoB and NT5DC2 were shortlisted as optimal candidate markers for PUC diagnosis. In our pilot study using IHC, NT5DC2 was subsequently selected as its expression consistently differed in PUC (p = 0.007). Further validation of NT5DC2 using 49 low-grade (LG) urothelial lesions, including 15 LG-PUCs and 17 UPs, which are the most common mimickers, concordantly revealed lower IHC expression levels in LG-PUC (p = 0.0298). Independent external validation with eight LG-PUCs and eight UPs confirmed the significant downregulation of NT5DC2 in LG-PUC (p = 0.0104). We suggest that NT5DC2 is a potential IHC biomarker for differentiating LG-PUC from its benign mimickers, especially UP.

Background: Most ovarian tumors exhibit a pure histological characteristic. Nevertheless, a combination of tumors with the same histogenetic origin but different histologic subtypes is relatively common. Additionally, co-occurrence of tumors with different histogenetic origins is very rare. Typically, these mixed tumors include mixed epithelial tumors, mixed epithelial-stromal tumors, mixed germ cell-sex cord-stromal tumors, and mixed germ cell tumors. However, mixed epithelial-sex cord stromal-lymphohematopoietic system tumors are rare. Currently, clinicians have limited knowledge of this type of tumor, and the epidemiology, diagnosis, and treatment of this disease are yet to be established. Case presentation: We report a case of a 73-year-old woman with abdominal distension and pain for three months. Imaging evaluation revealed a large pelvic mass, with ultrasound suggesting a benign ovarian cyst along with leiomyoma. Furthermore, computed tomography (CT) and magnetic resonance imaging (MRI) revealed a malignant tumor. Blood tests showed significant increases in CA125 and CA199 levels. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. During the surgery, a large multinodular cystic solid mass was observed in the right ovary, and the maximum nodular diameter was 14.2 cm. The solid areas of the mass appeared gray-white and taupe, whereas the cystic areas contained clear liquid with smooth walls 0.2 cm thick and no intracystic solid areas. The left ovary had solitary nodules, the largest being 4 cm in diameter. Microscopic examination of the right ovary revealed three different cell types. The first type of cell area was analogous, round, fusiform, and staggered mixed cells with unclear boundaries and rare nucleolus or mitosis. The second type of cell area was the cystic dilatation area. The cyst wall was covered with a single layer of flat epithelium, rich eosinophilic cytoplasm, uniform nuclear chromatin, and no papillary structures. The third type was a diffuse lymphoid region with uniform medium-sized cells, rough nuclear chromatin and evident nucleoli and mitosis. The morphology of the left ovarian cell was single, which was consistent with the first type of cell area in the right ovary. Immunohistochemistry of the right ovary indicated that the first region expressed vimentin, inhibin-α, calretinin, SF-1, WT-1 and CD56, with Ki-67 at 5 %, and no CKpan expression. The second region expressed CKpan, with Ki-67 at 1 %. The third region expressed CD20, Pax-5, Bcl-6, Bcl-2, MUM1, CD45, and C-myc, with Ki-67 at 70 %, and positive IGH clonal gene rearrangement. Lastly, the pathological diagnosis was a mixed ovarian tumor in the right ovary, comprising thecoma-fibroma, serous cystadenoma, diffuse large B-cell lymphoma, and a thecoma-fibroma in the left ovary. A follow-up examination of the patient after 15 months showed no mass or lymph node enlargement in other parts of the body, and no recurrence or metastasis was observed. Conclusions: We present a case of a postmenopausal woman with a rare combination of thecoma-fibroma, serous cystadenoma and diffuse large B-cell lymphoma in the ovary. To the best of our knowledge, this is the first reported case of such a combination. Typical pathological morphology and immunohistochemistry are crucial for the diagnosis of this disease. Owing to the limited knowledge of the disease, its pathogenesis and tissue origin are unknown. Clinicians should be careful about such patients. We believe this case report may provide some novel insights into the diagnosis and therapy of patients with this type of tumor.

Endometrial large cell neuroendocrine carcinoma (LCNEC) is a highly malignant tumor that presents with neuroendocrine function. It is difficult to diagnose at an early stage. Moreover, the diagnosis depends on the pathological and immunohistochemical findings. It is also prone to distant metastasis, but is difficult to treat and shows poor prognosis. Presently, there exists no unified treatment plan, and the prognosis of this disease is also poor. We reported here an analysis and literature review of a case of endometrial LCNEC to facilitate the comprehension of this disease and provide help toward clinical diagnosis and treatment.

Universal screening for defective mismatch repair (dMMR) in colorectal cancer utilizes immunohistochemical staining for MLH1, MSH2, MSH6 and PSM2. Additionally, BRAF V600E mutations status and MLH1 hypermethylation should be performed to distinguish germline and somatic dMMR alterations. A decade of Danish population-based registries has been analysed regarding screening uptake, detection rate and referral to genetic counselling. MMR testing was performed in 71·8% (N = 34,664) of newly diagnosed colorectal cancers with an increasing trend to 88·8% coverage in the study's final year. The likelihood of undergoing MMR testing was reduced in males with 2% (95% CI 0·4–2·7, p = 0·008), with 4·1% in patients above age 70 years (95% CI 1·5–6·6, p = 0·003) compared in patients below age 51 years, with 16·3% in rectal cancers (95% CI 15·1–17·6, p < 0·001) and 1·4% left-sided colon cancers (95% CI 0·1–1·7, p = 0·03) compared to right-sided colon cancers. Tumour stage II and III increased the likelihood of being tested, with 3·7% for stage II (95% CI 2·2–5·6, p < 0·001) and 3·3% for stage III tumours (95% CI 1·8–4·8, p < 0·001) compared to stage I tumours, whereas the likelihood for stage IV tumours is reduced by 35·7% (95% CI 34·2–37·2, p < 0·001). Test rates significantly differed between the Danish health care regions. dMMR was identified in 15·1% (95% CI 14·8–15·6, p < 0·001) cases with somatic MMR inactivation in 6·7% of the cases. 8·3% tumours showed hereditary dMMR expression patterns, and 20·0% of those were referred to genetic counselling. Despite the high uptake rates, we found disparities between patient groups and missed opportunities for genetic diagnostics.

We aimed to develop deep learning (DL) models to detect protein expression in immunohistochemically (IHC) stained tissue-sections, and to compare their accuracy and performance with manually scored clinically relevant proteins in common cancer types.Five cancer patient cohorts (colon, two prostate, breast, and endometrial) were included. We developed separate DL models for scoring IHC-stained tissue-sections with nuclear, cytoplasmic, and membranous staining patterns. For training, we used images with annotations of cells with positive and negative staining from the colon cohort stained for Ki-67 and PMS2 (nuclear model), the prostate cohort 1 stained for PTEN (cytoplasmic model) and β-catenin (membranous model). The nuclear DL model was validated for MSH6 in the colon, MSH6 and PMS2 in the endometrium, Ki-67 and CyclinB1 in prostate, and oestrogen and progesterone receptors in the breast cancer cohorts. The cytoplasmic DL model was validated for PTEN and Mapre2, and the membranous DL model for CD44 and Flotillin1, all in prostate cohorts. When comparing the results of manual and DL scores in the validation sets, using manual scores as the ground truth, we observed an average correct classification rate of 91.5 % (76.9–98.5 %) for the nuclear model, 85.6 % (73.3–96.6 %) for the cytoplasmic model, and 78.4 % (75.5–84.3 %) for the membranous model. In survival analyses, manual and DL scores showed similar prognostic impact, with similar hazard ratios and p-values for all DL models. Our findings demonstrate that DL models offer a promising alternative to manual IHC scoring, providing efficiency and reproducibility across various data sources and markers.

Myopericytoma is a rare soft tissue tumor characterized by differentiation into perivascular muscle-like cells or perimuscular cells. This tumor primarily affects adults and is uncommon in children. It is predominantly found in the subcutaneous soft tissues of the distal limbs, and cases originating in the kidney are exceedingly rare. In this report, we present a case of a patient with renal myopericytoma admitted to our hospital. We also summarize the diagnostic and therapeutic features by reviewing relevant domestic and international literature.

Introduction: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma. Methods: TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University. Results: RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%–100%) and 25.0 (range: 0–200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival. Conclusions: TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.

Background: In our study, we examined the 5-year survival of OSCC patients with HPV positive or negative status along with p16 protein expression. Method: A total of 72 biopsy tissue specimens from histologically confirmed oral squamous cell carcinoma (OSCC) patients were collected. HPV detection and genotyping were performed using HPV E6/E7 and HPV- type-specific multiplex primer for nested-PCR. Immunohistochemistry evaluation of pl6 was conducted. SPSS statistical software (ver 20) was used for data analysis. Results: High risk-HPV (hr-HPV) DNA positivity was found in 27.7% (n = 20) of OSCC patients. Stage III OSCC patients were 7.80 times more likely to survive 5 years than stage IV patients (OR-7.80 CI-95%; P-0.03). Among the hr-HPV positive OSCC patients, we found that the median survival time for the 1st year (95%), 3 years (78.5%), and 5 years (38.5%) was significantly higher than that of the hr-HPV negative [1st year (78.6%), 3 years (45.2%) and 5 years (38.5%)] OSCC patients (P-0.03 The survival of male patients with hr-HPV positive OSCC is 9.75 times greater than the survival of patients with HPV negative OSCC (OR-9.75; CI-95%; P-0.05). The p16 expression level (low to overexpression) group and negative P16 expression group of OSCC patients have not demonstrated a significant association with 5-year survival. Conclusion: We conclude that in OSCC cases of North-East India, the presence of hr-HPV in OSCC cases could be a good predictor of 5-year survival rate. Expression of p16 does not appear to have any significant association with 5-year survival.

The ridgetail white prawn, Exopalaemon carinicauda, has advantages in its rapid growth and strong environmental adaptability, and it is a good species for the biological research of crustaceans. To explore the function of the pcna gene in the ovarian development of crustaceans, we cloned the pcna (Ec-pcna) from E. carinicauda. The open reading frame of the pcna is 786 bp, and it encodes a total of 261 aa. A PCNA/RFC (replication factor C) domain exists at 208–254 aa, and according to a phylogenetic analysis, the amino acid sequence of Ec-pcna has the highest similarity with the pcna gene from Litopenaeus vannamei, and it is clustered into one branch with L. vannamei and Penaeus monodon. The results of qRT-PCR showed that the expression of pcna was highest in the ovarian tissue of E. carinicauda, and it was significantly higher than that of other tissues (p

Objective: Pancreatic neuroendocrine neoplasms (pNENs) are histologically classified as well-differentiated, poorly-differentiated, or mixed neuroendocrine-non-neuroendocrine neoplasms. There are unresectable pNENs owing to metastases or invasion in not only functional pNENs but also non-functional. However, the exact origin of pNENs has not been elucidated. This study aims to characterize the molecular biology of pNENs based on clinical information and histopathological analysis and identify prognostic biomarkers. Methods: We investigated the relationship between the biological characteristics and immunostaining of pathological tissues in 75 patients. Staining density was evaluated on a 4-point scale from 0 to 3, and the percentage of tumor cells was calculated and scored from 0 to 300 (H-score). We performed receiver operating characteristic (ROC) curve analysis of the H-score. Progression-free survival and overall survival analyses were performed based on the Kaplan–Meier curves. Results: The H-score showed that patients who died of pNEN had high Ki-67 and low somatostatin receptor (SSTR) 2 levels, and those who relapsed had high Ki-67 and low SSTR5 levels. The ROC showed that the SSTR2 H-score > 80.25 was associated with lower mortality, which was further confirmed by Kaplan–Meier curves [hazard ratio (HR): 6.039, 95 % confidence interval (CI): 1.233–29.59, P = 0.0006). SSTR5 H-score > 93.9 had less recurrence, which was confirmed using Kaplan–Meier curves (HR: 3.321, 95 % CI: 1.426–7.734, P = 0.0336). Conclusion: Ki-67 > 4.95 is associated with a significantly increased risk of death. Quantification of SSTR2 and SSTR5 immunostaining using the H-score may serve as prognostic markers.

ABSTRACT: Finding effective antibiotic alternatives is crucial to managing the re-emerging health risk of Clostridium perfringens (CP) type A/G–induced avian necrotic enteritis (NE), a disease that has regained prominence in the wake of governmental restrictions on antibiotic use in poultry. Known for its antimicrobial and immunomodulatory effects, the use of bovine lactoferrin (bLF) in chickens is yet to be fully explored. In this study, we hypothesized that bLF can accumulate in the small intestines of healthy chickens through gavage and intramuscular supplementation and serves as a potential antibiotic alternative. Immunohistochemistry located bLF in various layers of the small intestines and ELISA testing confirmed its accumulation. Surprisingly, sham-treated chickens also showed the presence of bLF, prompting a western blotting analysis that dismissed the notion of cross-reactivity between bLF and the avian protein ovotransferrin. Although the significance of the route of administration remains inconclusive, this study supports the hypothesis that bLF is a promising and safe antibiotic alternative with demonstrated resistance to the degradative environment of the chicken intestines. Further studies are needed to determine its beneficial pharmacological effects in CP-infected chickens.

Serous fluids, encompassing pleural, pericardial, and peritoneal fluids, exhibit a wide spectrum of neoplastic and non-neoplastic conditions. Malignant effusions commonly result from metastasis, particularly from adenocarcinomas, and less frequently from primary malignant mesothelioma. Cytologic assessment of serous effusions remains an invaluable tool, especially with the expanding role of ancillary techniques available to resolve diagnostically challenging cases. The recently introduced International System for Reporting Serous Fluid Cytopathology (TIS) establishes a standardized reporting system with five distinct diagnostic categories: nondiagnostic (ND), negative for malignancy (NFM), atypia of undetermined significance (AUS), suspicious for malignancy (SFM), and malignant (MAL). Understanding the distribution of malignancy in serous fluids by site of origin in effusion cytology is important, especially in patients with an unknown primary. Immunohistochemistry (IHC) combined with clinical and radiologic data plays a crucial role in confirming malignancy, establishing the primary site, determining the stage, predicting prognosis, monitoring recurrence, and influencing medical management. This review aims to provide an overview of TIS reporting system, emphasizing its malignant category. It provides updates on the distribution of malignancies in serous fluids and discusses valuable IHC panels based on differential diagnosis, addressing challenging cases within this context.

Purpose: It remains unclear whether patients with HER2-negative, low-estrogen receptor (ER-low)-positive early breast cancer (BC) benefit from Oncotype DX® (ODX) testing. Methods: We conducted a retrospective review of cases referred for ODX testing over a seven-year period from a breast biomarker testing referral center (n = 854). For each case, we recorded the ODX Recurrence Score (RS) along with percentage of ER nuclear positivity and staining intensity on immunohistochemistry. Our criteria for ER-low was defined as ≤10% cells with nuclear positivity and/or weak intensity of staining. Slides from all ER-low cases were reviewed and the reported ODX ER gene scores were recorded. We randomly selected a comparator group of 56 patients with ER > 10% positivity and non-weak staining intensity (ER-high). Results: We identified 27 cases (3.2%) that met our criteria for ER-low. Of these, 92.6% had a high RS (>25), and 7.4% had a RS of 25. All cases with ≤10% ER nuclear positivity had a high RS. Most ER-low cases (85.2%) had ODX quantitative ER gene scores in the negative range, whereas all (100%) ER-high cases had positive ER gene scores. Conclusion: ODX does not appear to add significant additional information to inform treatment decisions for most patients with ER-low BC. Incorporating weak ER staining intensity in addition to low percentage of nuclear positivity identifies about twice as many ER-low patients, although with reduced specificity for high RS. Our study supports the contention that most ER-low early BC should be regarded similarly to ER-negative BC.

Resumen: Introducción: La hepatitis autoinmune (HAI) está asociada con infiltración periportal de células plasmáticas. La detección de células plasmáticas se realiza rutinariamente por medio de tinción hematoxilina-eosina (HE). El objetivo del presente estudio fue evaluar la utilidad de CD138, un marcador inmunohistoquímico de células plasmáticas, en la evaluación de HAI. Materiales y métodos: Estudio retrospectivo; los casos compatibles con HAI se recolectaron de 2001 a 2011. Se utilizó la tinción HE para evaluación y CD138 para detectar células plasmáticas. Resultados: Se incluyeron 60 biopsias. En el grupo HE la mediana y el rango intercuartílico (RIQ) fue 6 (4-9) células plasmáticas/campo de alto poder (CAP) y de 10 (RIQ 6-20) células plasmáticas/CAP en el grupo CD138 (p

Advancements in pathology have given rise to software applications intended to minimize human error and improve efficacy of image analysis. Still, the subjectivity of image quantification performed manually and the limitations of the most ubiquitous tissue stain analysis software requiring parameters tuned by the observer, reveal the need for a highly accurate, automated nuclear quantification software specific to immunohistochemistry, with improved precision and efficiency compared with the methods currently in use. We present a method for the quantification of immunohistochemical biomarkers in keratinocyte nuclei proposed to overcome these limitations, contributing sensitive shape-focused segmentation, accurate nuclear detection, and automated device-independent color assessment, without observer-dependent analysis parameters.

To decipher the interactions between various components of the tumor microenvironment (TME) and tumor cells in a preserved spatial context, a multiparametric approach is essential. In this pursuit, imaging mass cytometry (IMC) emerges as a valuable tool, capable of concurrently analyzing up to 40 parameters at subcellular resolution. In this study, a set of antibodies was selected to spatially resolve multiple cell types and TME elements, including a comprehensive panel targeted at dissecting the heterogeneity of cancer-associated fibroblasts (CAF), a pivotal TME component. This antibody panel was standardized and optimized using formalin-fixed paraffin-embedded tissue (FFPE) samples from different organs/lesions known to express the markers of interest. The final composition of the antibody panel was determined based on the performance of conjugated antibodies in both immunohistochemistry (IHC) and IMC. Tissue images were segmented employing the Steinbock framework. Unsupervised clustering of single-cell data was carried out using a bioinformatics pipeline developed in R program. This paper provides a detailed description of the staining procedure and analysis workflow. Subsequently, the panel underwent validation on clinical FFPE samples from head and neck squamous cell carcinoma (HNSCC). The panel and bioinformatics pipeline established here proved to be robust in characterizing different TME components of HNSCC while maintaining a high degree of spatial detail. The platform we describe shows promise for understanding the clinical implications of TMA heterogeneity in large patient cohorts with FFPE tissues available in diagnostic biobanks worldwide.

The amyloid plaque is a hallmark of Alzheimer's disease. The accumulation of the amyloid precursor protein (APP) in the neuronal structure is assumed to lead to amyloid plaque formation through the excessive production of β-amyloid protein. To study the relationship between the neuronal accumulation of APP and amyloid plaque formation, we histologically analyzed their development in the different brain regions in 3xTg-AD mice, which express Swedish mutated APP (APPSWE) in the neurons. Observation throughout the brain revealed APPSWE-positive somata in the broad regions. Quantitative model analysis showed that the somatic accumulation of APPSWE developed firstly in the hippocampus from a very early age (

Bats have been reported as reservoir host of Leishmania spp. worldwide, mostly by molecular detection. However, it is still unclear whether bats act as reservoirs of Leishmania infantum to sandflies vectors. In this sense, the investigation of amastigotes forms in the target organs, and the characterization of their associated inflammation, may help to clarify the epidemiological importance of bats in endemic areas for leishmaniasis. The aim of this work was to investigate the host-parasite relationships under microscopic evaluation and predict the epidemiological role of two phyllostomid bats species naturally infected by L. infantum in an endemic area for human leishmaniasis. Fragments of skin, liver and spleen of L. infantum positive and negative bats (Artibeus planirostris and Carollia perspicillata) by qPCR, were studied by histological and immunohistochemical techniques. Both groups, positive and negative, did not show differences in the histopathological study, presenting only discrete tissue changes. Liver and skin showed mild inflammatory reactions. Findings on spleen consisted of reactivity of the lymphoid follicles, expressive presence of apoptotic cells and macrophages containing abundant phagocytic cells debris. We did not find amastigote forms in tissues by histological and IHC techniques in positive qPCR bats. Our results allow us to hypothesize that phyllostomid bats seem to have an important role in reducing the risk of transmission, possibly acting as dead-end host.

Objective: To study the histopathological staging of atrophic lesions of the gastric mucosa. Methods: Histology and immunohistochemistry were used to closely examine 2144 specimens of atrophic gastric mucosa that were taken from endoscopic biopsies. Results: When the gastric mucosa epithelium is affected by infection, chemical stimulation, immune factors, genetic factors, and other factors, it may cause an atrophy of gastric mucosa epithelium and a decrease in the number of glands, intestinal metaplasia, hyperplasia of smooth muscle fibers, and atrophy of stem cells in the proliferative zone. In this study, we characterized the above lesions as atrophic lesions of the gastric mucosa. Based on the morphological and histological characteristics of the lesion, as well as the law of cell proliferation and transformation during its occurrence and development, we propose five stages. We also noted the onset age, gender correlation, and histopathological characteristics of each stage of gastric mucosal atrophies. Conclusion: Understanding the pathological staging of gastric mucosal atrophy is essential for treating patients correctly and keeping track of changes in malignant cells. It is also very important in preventing the initiation of gastric cancer or from getting worse.

Introduction: Malignant gliomas are the most prevalent and fatal types of primary malignant brain tumors with poor prognosis. Protein phosphatase 3 catalytic subunit beta (PPP3CB) is a pivotal constituent of the Ca2+/calmodulin-dependent serine/threonine protein phosphatases and widely expressed in brain. We aimed at identifying whether PPP3CB has potential in being a novel biomarker of malignant gliomas, bringing new insights to clinical management and therapy. Methods: Transcriptomes and clinical data of Glioblastoma (GBM) and low-grade glioma (LGG) samples were downloaded from TCGA and CGGA. We first explored the expressional and survival features of tumor tissues. Then, PPP3CB-associated genes were identified and their functional pathways were explored through GSEA analyses. Western blotting was conducted to modify PPP3CB expression. Samples of glioma patients and healthy controls were collected and immunohistochemistry (IHC) staining was performed to detect protein level. Further, we carried out an immune infiltration analysis, explored the correlation between PPP3CB and immune checkpoint genes, as well as to assessed the tumor mutation burden (TMB) and tumor microenvironment score (TMEscore) of PPP3CB. Results: PPP3CB expression in malignant glioma tissues was significantly downregulated and was considered an independent prognostic factor. Several functional pathways were observed through functional pathway analyses. PPP3CB's expression was strongly related to the infiltration of various immune cells and expression of key immune checkpoint genes. PPP3CB expression in high-grade gliomas was significantly lower, affecting glioma cells' proliferation and apoptosis in vitro. Conclusion: PPP3CB was a potential biomarker for the diagnosis and prognosis of malignant gliomas.

Sclerosing epithelioid fibrosarcoma (SEF) represents a rare variant of fibrosarcoma primarily arising in the deep soft tissue of the extremities and trunk. The author reported a rare case of SEF emerged primarily in the kidney. Clinically, the patient complained of hematuria. The diagnosis was confirmed by histological examination and immunohistochemical staining of MUC4. Subsequent fluorescence in situ hybridization (FISH) analysis detected the presence of EWSR1 gene rearrangement, further confirming the histological diagnosis. The patient has been alive with 12 months follow-ups after nephrectomy. The disease should be considered in the differential diagnosis for primary renal tumors.

Background: Distinct molecular subtypes of muscle-invasive bladder cancer (MIBC) have been identified via gene expression profiling. Objective: We investigated the feasibility of a simple immunohistochemistry (IHC)-based Lund subtyping method and the association of MIBC subtypes with oncological outcomes for patients after bladder-preserving radiation-based therapy. Design, setting, and participants: Transurethral resected tumor tissues from 104 patients treated with radiation-based therapy were sampled on tissue microarray blocks. Outcome measurements and statistical analysis: The expression of KRT5, GATA3, and p16 proteins was scored via digital image analysis. Hierarchical clustering was used to classify tumors as the basal subtype or one of two luminal subtypes: genomically unstable (GU) or urothelial-like (URO). Subtypes were evaluated for association with complete response (CR), recurrence-free survival (RFS), and overall survival (OS). Results and limitations: The median OS was 43 mo (95% confidence interval 19–77) and median follow-up was 55 mo (interquartile range 39–75). Age and clinical stage had a significant impact on OS (p

Resumen: Introducción y objetivos: El cáncer colorrectal (CCR) es uno de los más prevalentes en el mundo y contribuye significativamente a las muertes relacionadas con el cáncer. La mayoría de los casos surgen de pólipos adenomatosos. Actualmente, los biomarcadores desempeñan un papel importante en la progresión tumoral. Nuestro objetivo fue identificar mastocitos perivasculares y analizar la expresión de laminina-332, MMP-9 y VEGF en casos humanos de adenoma y CCR. Materiales y métodos: Los pacientes fueron seleccionados en el servicio de coloproctología y las muestras se obtuvieron mediante biopsias. Las laminillas de adenoma y CCR se examinaron mediante inmunohistoquímica para detectar moléculas y se procesaron con azul alcián al 1% (pH 0.5) para la tinción de mastocitos. Resultados: Se observó una mayor densidad de mastocitos perivasculares en los adenomas. La expresión de laminina-332 reveló discontinuidad de la membrana basal asociada con la invasión tumoral en el CCR. Se detectó inmunotinción de MMP-9 en el adenoma en epitelios glandulares y de revestimiento en áreas cercanas a la membrana basal, mientras que en el CCR la enzima se encontró en el citoplasma de grupos invasivos. La expresión de VEGF se asoció con atipia celular en el adenoma y en áreas de desorganización de la interfaz entre el epitelio y el tejido conectivo en el CCR. Se ha detectado VEGF en células endoteliales de microvasos. Conclusiones: Demostramos los diferentes patrones de mastocitos perivasculares y expresión molecular en neoplasias colorrectales. Estos análisis favorecen el reconocimiento de la predisposición o estadio temprano de la enfermedad y tienen el potencial de definir el perfil molecular de las lesiones. Abstract: Introduction and objectives: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, and significantly contributes to cancer-related deaths. Most cases arise from adenomatous polyps. Biomarkers currently play an important role in tumor progression. Our aim was to identify perivascular mast cells and analyze the expression of laminin-332, MMP-9, and VEGF in cases of adenoma and CRC in humans. Materials and methods: Patients were selected at the Coloproctology Service and samples were obtained through biopsies. Adenoma and CRC slides were examined, utilizing immunohistochemistry to detect molecules, and were processed, using 1% Alcian Blue (pH .5) for mast cell staining. Results: Higher density of perivascular mast cells was observed in adenomas. Laminin-332 expression revealed basement membrane discontinuity associated with tumor invasion in CRC. MMP-9 immunostaining in adenoma was detected in glandular epithelium and lining epithelium, in areas close to the basement membrane, whereas in CRC, the enzyme was found in the cytoplasm of invasive clusters. VEGF expression was associated with cell atypia in adenoma and in areas of disorganization of the epithelium-connective tissue interface in CRC. VEGF has also been detected in endothelial cells from microvessels. Conclusions: We demonstrated the different patterns of perivascular mast cells and molecular expression in colorectal neoplasms. Those analyses favor the recognition of the predisposition to the disease, or its early stage, and have the potential to define the molecular profile of the lesions.

Objective: To evaluate the association between mismatch repair (MMR) protein expression and clinico-pathologic outcomes in patients with endometrioid endometrial cancer (EC). Materials and methods: A retrospective review of the clinico-pathologic outcomes was performed on patients who were diagnosed with EC and had results of MMR protein immunohistochemistry. MMR-deficient (MMR-d) was defined as absence of expression in any of the 4 MMR proteins (MLH1, MSH2, MSH6, and PMS2). Demographics, pathologic variables, and survival outcomes were compared according to the MMR status. Results: A total of 193 EC patients with available MMR expression data were included, of whom 163 patients had endometrioid type EC. Overall, 44 patients (27.0%) were classified as MMR-d. Compared with MMR-proficient (MMR-p) group, MMR-d group was associated with more frequent lymphovascular space invasion (LVSI, p = 0.001). MMR-d was also related with higher risk of lymph node (LN) metastasis in endometrioid type EC (p = 0.008), especially para-aortic LN metastasis. During the median follow-up period of 19.1 months (1–44.5), MMR-d group, especially MLH1/PMS2 subgroup, showed a tendency of reduced PFS (p = 0.036 and p = 0.008, respectively). On Cox regression analysis, however, LN metastasis remained as the only independent risk factor for PFS (p = 0.004) in endometrioid EC, and MLH1/PMS2 loss showed a marginally significant association (p = 0.054). Conclusion: Our findings of the associations between MMR deficiency and poor prognostic factors, such as LVSI and LN metastasis, may suggest the prognostic value of MMR status in EC and need further prospective validation studies.

Background: Recent clinical evidence showed that breast cancer with low HER2 expression levels responded to trastuzumab deruxtecan therapy. The HER2-low cancers comprise immunohistochemistry (IHC) score 1+ and 2+ ISH non-amplified tumours, currently classified as HER2 negative. Little data exists on the reproducibility of pathologists reporting of HER2-low cancer. Patient and methods: Sixteen expert pathologists of the UK National Coordinating Committee for Breast Pathology scored 50 digitally scanned HER2 IHC slides. The overall level of agreement, Fleiss multiple-rater kappa statistics and Cohen's Kappa were calculated. Cases with low concordance were re-scored by the same pathologists after a washout period. Results: Absolute agreement was achieved in 6% of cases, all of which scored 3+. Poor agreement was found in 5/50 (10%) of cases. This was due to heterogeneous HER2 expression, cytoplasmic staining and low expression spanning the 10% cut-off value. Highest concordance (86%) was achieved when scores were clustered as 0 versus others. Improvement in kappa of overall agreement was achieved when scores 1+ and 2+ were combined. Inter-observer agreement was moderate to substantial in the whole cohort but fair to moderate in the HER2-low group. Similarly, consensus-observer agreement was substantial to almost perfect in the whole cohort and moderate to substantial in the HER2-low group. Conclusion: HER2-low breast cancer suffers from lower concordance among expert pathologists. While most cases can reproducibly be classified, a small proportion (10%) remained challenging. Refining the criteria for reporting and consensus scoring will help select appropriate patients for targeted therapy.