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Abstract Background Accurate classification of breast cancer molecular subtypes is crucial in determining treatment strategies and predicting clinical outcomes. This classification largely depends on the assessment of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) status. However, variability in interpretation among pathologists pose challenges to the accuracy of this classification. This study evaluates the role of artificial intelligence (AI) in enhancing the consistency of these evaluations. Methods AI-powered HER2 and ER/PR analyzers, consisting of cell and tissue models, were developed using 1,259 HER2, 744 ER, and 466 PR-stained immunohistochemistry (IHC) whole-slide images of breast cancer. External validation cohort comprising HER2, ER, and PR IHCs of 201 breast cancer cases were analyzed with these AI-powered analyzers. Three board-certified pathologists independently assessed these cases without AI annotation. Then, cases with differing interpretations between pathologists and the AI analyzer were revisited with AI assistance, focusing on evaluating the influence of AI assistance on the concordance among pathologists during the revised evaluation compared to the initial assessment. Results Reevaluation was required in 61 (30.3%), 42 (20.9%), and 80 (39.8%) of HER2, in 15 (7.5%), 17 (8.5%), and 11 (5.5%) of ER, and in 26 (12.9%), 24 (11.9%), and 28 (13.9%) of PR evaluations by the pathologists, respectively. Compared to initial interpretations, the assistance of AI led to a notable increase in the agreement among three pathologists on the status of HER2 (from 49.3 to 74.1%, p

Cancer stem-like cells (CSCs) have been suggested to be responsible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE1 is a strong candidate target for anticancer therapies, its role in ovarian CSCs is yet to be elucidated. Here, we show that WEE1 plays a key role in regulating CSC properties and tumor resistance to carboplatin via a microRNA-dependent mechanism. We found that WEE1 expression is upregulated in ovarian cancer spheroids because of the decreased expression of miR-424 and miR-503, which directly target WEE1. The overexpression of miR-424/503 suppressed CSC activity by inhibiting WEE1 expression, but this effect was reversed on the restoration of WEE1 expression. Furthermore, we demonstrated that NANOG modulates the miR-424/503-WEE1 axis that regulates the properties of CSCs. We also demonstrated the pharmacological restoration of the NANOG-miR-424/503-WEE1 axis and attenuation of ovarian CSC characteristics in response to atorvastatin treatment. Lastly, miR-424/503-mediated WEE1 inhibition re-sensitized chemoresistant ovarian cancer cells to carboplatin. Additionally, combined treatment with atorvastatin and carboplatin synergistically reduced tumor growth, chemoresistance, and peritoneal seeding in the intraperitoneal mouse models of ovarian cancer. We identified a novel NANOG-miR-424/503-WEE1 pathway for regulating ovarian CSCs, which has potential therapeutic utility in ovarian cancer treatment.

Immunoglobulin G4-related disease (IgG4-RD) is a novel fibroinflammatory disorder characterized by enlargement of the involved organs, elevated IgG4 levels, and abundant infiltration of IgG4-positive plasma cells. Indeed, primary colon cancers arising from IgG4-RD are rare. This case report describes a rare occurrence of simultaneous colorectal cancer and IgG4-RD in the same lesion in a 62-year-old male patient. The patient underwent a right hemicolectomy under the suspicion of primary colon cancer. The mass was grossly well-defined and yellowish tan, and the background colon was fibrotic. Microscopically, the tumor cells showed glandular differentiation characteristic of adenocarcinoma in a background of dense lymphoplasmacytic infiltration with fibrosis and obliterative phlebitis in the pericolic fat tissue. IgG4 immunohistochemical staining showed diffuse positivity in infiltrating plasma cells. The patient was administered adjuvant chemotherapy and prednisolone therapy. The patient’s serum IgG4 levels gradually decreased, and a follow-up positron emission tomography-computed tomography scan 1 year after surgery showed no evidence of local or distant recurrence of colorectal cancer. IgG4-RD occurring concurrently with primary colon adenocarcinoma has not been reported. Increased awareness of this rare coexistence can guide clinicians in navigating diagnostic complexities and selecting optimal therapeutic strategies.

Infiltration of CD8+ T cells and their spatial contexture, represented by immunophenotype, predict the prognosis and therapeutic response in breast cancer. However, a non-surgical method using radiomics to evaluate breast cancer immunophenotype has not been explored. Here, we assessed the CD8+ T cell-based immunophenotype in patients with breast cancer undergoing upfront surgery (n = 182). We extracted radiomic features from the four phases of dynamic contrast-enhanced magnetic resonance imaging, and randomly divided the patients into training (n = 137) and validation (n = 45) cohorts. For predicting the immunophenotypes, radiomic models (RMs) that combined the four phases demonstrated superior performance to those derived from a single phase. For discriminating the inflamed tumor from the non-inflamed tumor, the feature-based combination model from the whole tumor (RM-wholeFC) showed high performance in both training (area under the receiver operating characteristic curve [AUC] = 0.973) and validation cohorts (AUC = 0.985). Similarly, the feature-based combination model from the peripheral tumor (RM-periFC) discriminated between immune-desert and excluded tumors with high performance in both training (AUC = 0.993) and validation cohorts (AUC = 0.984). Both RM-wholeFC and RM-periFC demonstrated good to excellent performance for every molecular subtype. Furthermore, in patients who underwent neoadjuvant chemotherapy (n = 64), pre-treatment images showed that tumors exhibiting complete response to neoadjuvant chemotherapy had significantly higher scores from RM-wholeFC and lower scores from RM-periFC. Our RMs predicted the immunophenotype of breast cancer based on the spatial distribution of CD8+ T cells with high accuracy. This approach can be used to stratify patients non-invasively based on the status of the tumor-immune microenvironment.

Abstract Choledochocele is a rare subtype of choledochal cyst and is associated with increased prevalence of periampullary cancers. Here, we report an unusual manifestation of infiltrative duodenal cancer arising from a choledochocele, involving superficial spreading (muscularis mucosae) of cancer cells along the duodenum causing gastric outlet obstruction, which clinically mimicked superior mesenteric artery syndrome. Histologically, wide spread of cancer cells was confirmed from periampullary region to duodenojejunal junction showing mismatch with radiologic findings, in which the cancer segment was mainly located in the distal duodenum. Clinical, radiologic, and pathologic findings are discussed with literature reviews.

Phosphaturic mesenchymal tumor (PMT) is strongly related to tumor-induced osteomalacia (TIO) which brings diverse skeletal events, such as bony deformities, gait disturbance, and multiple bone fractures. Overexpressed fibroblast growth factor 23 by the tumor induces hypophosphatemia leading to the oncogenic osteomalacia, a rare paraneoplastic syndrome. PMT occurring in the oral and maxillofacial regions is extremely rare, and this case highlights the need to understand mechanisms by which local lesions can affect systemic conditions, and the importance of a combination of physical examinations, laboratory investigations, and radiologic investigations for a decisive diagnosis.

Hepatocellular adenoma (HCA) is the most common type of benign liver tumor, and its major complication is malignant transformation to hepatocellular carcinoma (HCC). Here, we report a case of HCC arising in HCA with bone marrow metaplasia in a 24-year-old Korean woman who presented with abdominal discomfort. A huge liver mass was found on abdominal ultrasonography. She underwent surgical hepatic resection, and the resected specimen was entirely involved by a 20-cm-sized tumor. Histological review revealed a well differentiated HCC arising from inflammatory HCA with β-catenin nuclear positivity and bone marrow metaplasia that contained hematopoietic cells. This case was unique because malignant transformation, inflammatory type HCA, β-catenin nuclear staining, and bone marrow metaplasia were simultaneously observed. Additionally, it should be noted that a large HCA with β-catenin activation can undergo malignant transformation and should be surgically resected in a timely manner.

Small cell neuroendocrine carcinoma (SNEC) is a rare subset of tumors in the sinonasal sinus. Combined tumors are exceedingly rare. Here, we describe a 65-year-old male with a mixed tumor of SNEC and sarcomatoid carcinoma arising in an inverted papilloma, containing squamous cell carcinoma in situ (SqCCis) in the sinonasal sinus. We evaluated the molecular characteristics of the two separate carcinoma components using next-generation sequencing. The patient presented with a nasal obstruction. Computed tomography showed a mass infiltrating the right ethmoid and maxillary sinuses. An excisional biopsy was performed. The tumor was found to have three morphologically distinct components. The first was SqCCis arising in an inverted papilloma, which was positive for cytokeratin and P40. The second consisted of nests of densely packed small round cells representing SNEC-positive neuroendocrine markers. The third was a solid sheet of anaplastic spindle cell proliferation, which was negative for the above markers. Oncogenic mutations such as FBXW7, TP53, and EGFR were detected in both SNEC and sarcomatoid carcinoma, and MYCL amplification was observed only in the SNEC component. This case highlights an extremely rare presentation of combined SNEC and sarcomatoid carcinoma arising from an inverted papilloma in the sinonasal sinus.

Clinically significant isolated viral tracheitis is scarce in adults, and upper airway obstruction caused by viral tracheitis is even more infrequent. A 74-year-old woman, who was administered low-dose steroids for two months for chronic obstructive pulmonary disease (COPD), developed dyspnea with stridor and required mechanical ventilation for respiratory failure. Chest computed tomography showed a diffuse tracheal wall thickening with luminal narrowing and peribronchial consolidation in the right upper lobe. Bronchoscopy revealed a proximal tracheal narrowing with multiple ulcerations of the tracheal mucosa surrounded by an erythematous margin. Pathologic examinations of the tracheal mucosal tissue, including immunohistochemistry, revealed a cytomegalovirus (CMV) and herpes simplex virus (HSV) infection. Furthermore, the bronchial alveolar lavage fluid was positive on the CMV real-time polymerase chain reaction. The patient was treated with intravenous ganciclovir for 44 days. The follow-up bronchoscopy 49 days after the initiation of ganciclovir revealed improved multiple ulcerations with scars. We report a rare case of tracheitis caused by coinfection with CMV and HSV in a patient with COPD who had been taking low-dose steroids for months. The case showed that CMV and HSV are potential causes of serious tracheitis and respiratory failure.

The risk stratification of diffuse large B-cell lymphoma (DLBCL) is crucial. The International Prognostic Index, the most commonly used and the traditional risk stratification system, is composed of fixed and artificially dichotomized attributes. We aimed to develop a novel prognostic model that allows the incorporation of up-to-date attributes comprehensively without information loss. We analyzed 204 patients with primary DLBCL who were uniformly treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) from 2007 to 2012 at Asan Medical Center. Using the multivariable fractional polynomial (MFP) method and bootstrap resampling, we selected the variables of significance and the best fitted functional form in fractional polynomials. Age, serum β2-microglobulin, serum lactate dehydrogenase, and BCL2 expression were selected as significant variables in predicting overall survival (OS), while age was excluded in predicting 2-years event-free survival. The prognostic score calculated by the MFP model effectively classifies patients into four risk groups with 5-years OS of 89.91% (low risk), 81.21% (low-intermediate risk), 66.40% (high-intermediate risk), and 37.89% (high risk). We suggest a new prognostic model that is simple and flexible. By using the MFP method, we can incorporate various clinicopathologic factors into a risk stratification system without arbitrary dichotomization.

Background and Objectives: Kidney and brain protein (KIBRA) is a protein encoded by the WW and C2 domain containing 1 (WWC1) gene and is involved in the Hippo signaling pathway. Recent studies have revealed the prognostic value of KIBRA expression; however, its role in breast cancer remains unclear. The aim of this study was to examine KIBRA expression in relation to the clinical and pathological characteristics of patients with breast cancer and to disease outcomes. Materials and Methods: We analyzed the expression of KIBRA and its correlation with event-free survival (EFS) outcomes in resected samples from 486 patients with breast cancer. Results: KIBRA expression was significantly different among the molecular subgroups (low KIBRA expression: luminal A, 46.7% versus 50.0%, p = 0.641; luminal B, 32.7% versus 71.7%, p < 0.001; human epidermal growth factor receptor 2 (HER2)-enriched, 64.9% versus 45.5%. p = 0.001; triple-negative, 73.6% versus 43.8%, p < 0.001). Low KIBRA expression was also associated with high nuclear grade (60.4% versus 37.8%, p < 0.001), high histologic grade (58.7% versus 37.0%, p < 0.001), and estrogen receptor (ER) negativity (54.2% versus 23.6%, p < 0.001). Low KIBRA expression was significantly associated with poor EFS (p = 0.041; hazard ratio (HR) 1.658; 95% confidence interval (CI), 1.015–2.709). Low KIBRA expression was an independent indicator of poor prognosis (p = 0.001; HR = 3.952; 95% CI = 1.542–10.133) in triple-negative breast cancer (TNBC). Conclusion: Low KIBRA expression was associated with higher histological grade, ER negativity and poor EFS of breast cancer. In particular, our data highlight KIBRA expression status as a potential prognostic marker for TNBC.

Immunohistochemistry (IHC) is an important auxiliary method for pathologists in routine diagnostic work as well as in basic and clinical research including exploration of biomarkers, as IHC allows confirmation of target molecule expressions in the context of microenvironment. Although there has been a considerable progress in automation and standardization of IHC, there are still many things to be considered in proper optimization and appropriate interpretation. In this review, we aim to provide possible pitfalls and useful tips for practicing pathologists and residents in pathology training. First, general procedure of IHC is summarized, followed by pitfalls and tips in each step and a summary of troubleshooting. Second, ways to an accurate interpretation of IHC are discussed, with introduction to general quantification and analysis methods. This review is not intended to provide complete information on IHC, but to be used as a basic reference for practice and publication.

In the spring of 2011, a cluster of lung injuries caused by humidifier disinfectant (HD) usage were reported in Korea. Many patients required mechanical ventilation, extracorporeal membrane oxygenation, and even lung transplantation (LTPL). However, the long-term course of HD-associated lung injury remains unclear because the majority of survivors recovered normal lung function. Here we report a 33-year-old woman who underwent LTPL approximately four years after severe HD-associated lung injury. The patient was initially admitted to the intensive care unit and was supported by a high-flow nasal cannula. Although she had been discharged, she was recurrently admitted to our hospital due to progressive lung fibrosis and a persistent decline in lung function. Finally, sequential double LTPL was successfully performed, and the patient’s clinical and radiological findings showed significant improvement. Therefore, we conclude that LTPL can be a therapeutic option for patients with chronic inhalation injury.

Objective: Pigs are used in various biomedical research fields because of their anatomical and physiological similarities to humans. While farm pigs are raised outdoors for several months, minipigs are typically raised in indoor barrier facilities for several years. Although numerous studies have investigated the prevalence of major pathogens, including porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2), in farm pigs, similar studies targeting minipigs are lacking. Materials and Methods: We imported 57 minipigs to our institution from three experimental animal production facilities and immediately assessed the serological and antigenic prevalence of PRRSV and PCV2. Results: PRRSV and PCV2 had seroprevalences of 80.7% and 94.7%, respectively, with 0% antigen positivity rates for PRRSV types 1 and 2 and high-pathogenic PRRSV and PCV2. Two factors could account for the high seroprevalence rates: the majority of individuals may have been vaccinated despite official claims from the origin facilities or exposed to PRRSV and PCV2. Preventing microbial infections is crucial for obtaining accurate and reproducible results. Conclusion: As the first investigation of microbial prevalence in minipigs, our findings indicate that minipigs raised in barrier facilities are not necessarily free from vaccines or infections. These results will significantly enhance the credibility of future biomedical research. [ABSTRACT FROM AUTHOR]