Pathologically Confirmed Subcutaneous Fat and Lymphovascular Invasion of a Hypopigmented Area in Extramammary Paget Disease.

Extramammary Paget disease (EMPD) is a rare adenocarcinoma that usually occurs in areas of the body that are rich in apocrine sweat glands. Great depth of tumor invasion is a well-known risk factor for worse prognosis. Paget cells usually are limited to the epidermis, whereas invasive EMPD, which infiltrates the dermis, is relatively rare. It is even rarer for the tumor to spread beyond the dermis. Only 3.1% of patients with EMPD of the penis and scrotum have exhibited infiltration of the subcutaneous fat layer. We report a case of a 62-year-old male with EMPD that invaded the subcutaneous fat layer. He presented with a several-year history of a slowly expanding erythematous plaque with the hypopigmented area on the left penoscrotum. One month before presentation, the patient had undergone punch biopsy at another hospital and diagnosed with EMPD. He had no personal history of urogenital cancers. The patient was treated with Mohs micrographic surgery, and negative margins were achieved after four stages. The histopathologic findings revealed Paget cells scattered throughout the epidermis. At the hypopigmented area, Paget cells extended to the subcutaneous fat layer with lymphovascular invasion. There was no evidence of recurrence at seven months postoperatively. Herein, we describe a case of hypopigmented EMPD that infiltrated the subcutaneous layer, which rarely has been reported in Korea.

Clinicopathological Factors Influencing Resection Margin Involvement During Mohs Micrographic Surgery for Skin Tumors.

BACKGROUND/AIM: Mohs micrographic surgery (MMS) is a specialized procedure for removing skin tumors. Intraoperative assessment of the resection margin (RM) status using frozen section examination is a crucial component of MMS. This study aimed to identify significant clinicopathological characteristics that could help surgeons determine the optimal surgical extent. PATIENTS AND METHODS: One hundred and fifty-one patients with primary skin tumors were included. The relationship between RM involvement and the clinico-pathological characteristics was analyzed for each histological type. RESULTS: Basal cell carcinoma (BCC) was significantly more likely to exhibit positive RMs and required additional excision during MMS compared to squamous cell carcinoma. In addition, the probability of RM involvement was significantly higher in high-risk BCC subtypes. CONCLUSION: When planning MMS, considering the histological type and presence of high-risk morphology may help surgeons perform more effective procedures.

Assessing nocturnal scratch with actigraphy in atopic dermatitis patients.

Nocturnal scratch is one major factor leading to impaired quality of life in atopic dermatitis (AD) patients. Therefore, objectively quantifying nocturnal scratch events aids in assessing the disease state, treatment effect, and AD patients' quality of life. In this paper, we describe the use of actigraphy, highly predictive topological features, and a model-ensembling approach to develop an assessment of nocturnal scratch events by measuring scratch duration and intensity. Our assessment is tested in a clinical setting against the ground truth obtained from video recordings. The new approach addresses unmet challenges in existing studies, such as the lack of generalizability to real-world applications, the failure to capture finger scratches, and the limitations in the evaluation due to imbalanced data in the current literature. Furthermore, the performance evaluation shows agreement between derived digital endpoints and the video annotation ground truth, as well as patient-reported outcomes, which demonstrated the validity of the new assessment of nocturnal scratch.

Mutant pattern of p53 predicts local recurrence and poor survival rate in gastric cancer.

BACKGROUND: TP53 mutation is a poor prognostic factor for various organ malignancies such as colorectal cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, lung adenocarcinoma and clinical pathologists previously evaluated it using immunohistochemistry for p53. The clinicopathologic significance of p53 expression in gastric cancer remains unclear due to inconsistent classification methods. METHODS: Immunohistochemistry for p53 protein was performed using tissue microarray blocks generated from 725 cases of gastric cancer, and p53 expression was divided into three staining patterns using a semi-quantitative ternary classifier: heterogeneous (wild type), overexpression, and absence (mutant pattern). RESULTS: Mutant pattern of p53 expression had a male predominance, greater frequency in cardia/fundus, higher pT stage, frequent lymph node metastasis, local recurrence clinically, and more differentiated histology microscopically compared with wild type. In survival analysis, p53 mutant pattern was associated with worse recurrent-free survival and overall survival rates, and significance was maintained in subgroup analysis of early versus advanced gastric cancers. In Cox regression analysis, p53 mutant pattern was a significant predicting factor for local recurrence (relative risk (RR=4.882, p<0.001)) and overall survival (RR=2.040, p=0.007). The p53 mutant pattern remained significant for local recurrence (RR=2.934, p=0.018) in multivariate analyses. CONCLUSIONS: Mutant p53 pattern on immunohistochemistry was a significant prognostic factor for local recurrence and poor overall survival in gastric cancer.

Anti-adhesion agent to prevent of post-operative adhesion and fibrosis after vasectomy: a study using a rat model.

Background: Post-vasectomy pain syndrome (PVPS) is difficult to treat. Direct damage to the vas deferens, inflammation, compression of nerves through fibrotic adhesions, and congestion of the epididymis are known to cause PVPS. The purpose of this study was to evaluate whether the application of anti-adhesion agents after vasectomy can reduce the degree of adhesion and fibrosis in a rat model. Methods: In the study, 11 Sprague-Dawley rats (22 vas deferens) from each group were evaluated. In the experimental group, surgery was terminated after applying the anti-adhesion agent; this was not applied in the control group. After 14 days of vasectomy, the scrotum was dissected to evaluate the degree of gross adhesion at the vasectomy site. Histological examination of the surrounding tissues, including the vas deferens and the spermatic cord, was also performed. Results: Adhesions were not observed in 72.73% (16/22) rats from the experimental group, in which the anti-adhesion agent was applied; in contrast, the incidence of adhesions in the control group was 100%. There was a statistically significant relationship between the distribution of grades for adhesion and anti-adhesion agent (chi-square, P<0.001). On classification of fibrosis and inflammation, application of the anti-adhesion agent was significantly associated with lower grade inflammation and fibrosis compared to that of the control group (chi-square, P=0.001). The rate of intact muscle structure was 90.91% (20/22) in the experimental group, and 36.36% (8/22) in the control group, and the application of the anti-adhesion agent demonstrated significant association with preservation of intact muscle structure (chi-square, P<0.001). Conclusions: The application of an anti-adhesion agent after vasectomy prevented the development of adhesion, fibrosis, and inflammation reaction and further reduced structural destruction.

High Receptor-interacting Serine/Threonine-protein Kinase 3 (RIP3) Expression Serves as an Independent Poor Prognostic Factor for Triple-negative Breast Carcinoma.

BACKGROUND/AIM: Receptor-interacting serine/threonine-protein kinase 3 (RIP3) is a key component related to tumor necrosis factor-dependent necroptosis. RIP3 has been known to be a predictive biomarker in many types of carcinomas. We aimed to investigate whether RIP3 expression is correlated with clinicopathological characteristics and the outcomes of patients with breast carcinoma. PATIENTS AND METHODS: We performed immunostaining for RIP3 and analyzed the association of RIP3 expression status with the clinicopathological characteristics and survival of 203 patients with invasive ductal carcinoma of the breast. RESULTS: High RIP3 expression was significantly correlated with lymph node metastasis and human epidermal growth factor receptor 2 positivity. In patients with triple-negative breast carcinoma (TNBC), high RIP3 expression was an independent prognostic factor for disease-free survival (DFS). RIP3-high TNBC showed the lowest DFS rate. CONCLUSION: High RIP3 expression is associated with aggressive clinical behavior of breast carcinoma. Our data suggest that RIP3 serves as an independent prognostic factor in TNBC.

A multi-parameter persistence framework for mathematical morphology.

The field of mathematical morphology offers well-studied techniques for image processing and is applicable for studies ranging from materials science to ecological pattern formation. In this work, we view morphological operations through the lens of persistent homology, a tool at the heart of the field of topological data analysis. We demonstrate that morphological operations naturally form a multiparameter filtration and that persistent homology can then be used to extract information about both topology and geometry in the images as well as to automate methods for optimizing the study and rendering of structure in images. For illustration, we develop an automated approach that utilizes this framework to denoise binary, grayscale, and color images with salt and pepper and larger spatial scale noise. We measure our example unsupervised denoising approach to state-of-the-art supervised, deep learning methods to show that our results are comparable.

High BMI1 Expression with Low CD8+ and CD4+ T Cell Activity Could Promote Breast Cancer Cell Survival: A Machine Learning Approach.

BMI1 is known to play a key role in the regulation of stem cell self-renewal in both endogenous and cancer stem cells. High BMI1 expression has been associated with poor prognosis in a variety of human tumors. The aim of this study was to reveal the correlations of BMI1 with survival rates, genetic alterations, and immune activities, and to validate the results using machine learning. We investigated the survival rates according to BMI1 expression in 389 and 789 breast cancer patients from Kangbuk Samsung Medical Center (KBSMC) and The Cancer Genome Atlas, respectively. We performed gene set enrichment analysis (GSEA) with pathway-based network analysis, investigated the immune response, and performed in vitro drug screening assays. The survival prediction model was evaluated through a gradient boosting machine (GBM) approach incorporating BMI1. High BMI1 expression was correlated with poor survival in patients with breast cancer. In GSEA and in in silico flow cytometry, high BMI1 expression was associated with factors indicating a weak immune response, such as decreased CD8+ T cell and CD4+ T cell counts. In pathway-based network analysis, BMI1 was directly linked to transcriptional regulation and indirectly linked to inflammatory response pathways, etc. The GBM model incorporating BMI1 showed improved prognostic performance compared with the model without BMI1. We identified telomerase inhibitor IX, a drug with potent activity against breast cancer cell lines with high BMI1 expression. We suggest that high BMI1 expression could be a therapeutic target in breast cancer. These results could contribute to the design of future experimental research and drug development programs for breast cancer.

A Persistent Homology Approach to Heart Rate Variability Analysis With an Application to Sleep-Wake Classification.

Persistent homology is a recently developed theory in the field of algebraic topology to study shapes of datasets. It is an effective data analysis tool that is robust to noise and has been widely applied. We demonstrate a general pipeline to apply persistent homology to study time series, particularly the instantaneous heart rate time series for the heart rate variability (HRV) analysis. The first step is capturing the shapes of time series from two different aspects-the persistent homologies and hence persistence diagrams of its sub-level set and Taken's lag map. Second, we propose a systematic and computationally efficient approach to summarize persistence diagrams, which we coined persistence statistics. To demonstrate our proposed method, we apply these tools to the HRV analysis and the sleep-wake, REM-NREM (rapid eyeball movement and non rapid eyeball movement) and sleep-REM-NREM classification problems. The proposed algorithm is evaluated on three different datasets via the cross-database validation scheme. The performance of our approach is better than the state-of-the-art algorithms, and the result is consistent throughout different datasets.

Nuclear Expression Loss of SSBP2 Is Associated with Poor Prognostic Factors in Colorectal Adenocarcinoma.

Single-stranded DNA binding protein 2 (SSBP2) is involved in DNA damage response and may induce growth arrest in cancer cells, having a potent tumor suppressor role. SSBP2 is ubiquitously expressed and the loss of its expression has been reported in various tumor types. However, the correlation between SSBP2 expression and colorectal cancer (CRC) prognosis remains unclear. SSBP2 nuclear expression was evaluated immunohistochemically in 48 normal colonic mucosae, 47 adenomas, 391 primary adenocarcinomas, and 131 metastatic carcinoma tissue samples. The clinicopathological factors, overall survival (OS), and recurrence-free survival were evaluated, and associations with the clinicopathological parameters were analyzed in 391 colorectal adenocarcinoma patients. A diffuse nuclear SSBP2 expression was detected in all normal colonic mucosa and adenoma samples. SSBP2 expression loss was observed in 131 (34.3%) primary adenocarcinoma and 100 (76.3%) metastatic carcinoma samples. SSBP2 expression was significantly associated with poor prognostic factors, such as vascular invasion (p = 0.005), high pT category (p = 0.045), and shorter OS (p = 0.038), using univariate survival analysis. Nuclear SSBP2 expression loss was significantly observed in colorectal carcinoma and metastatic carcinoma tissues, being associated with poor prognostic factors. SSBP2 acts as a tumor suppressor and may be used as a CRC prognostic biomarker.

Mesothelin expression and its prognostic role according to microsatellite instability status in colorectal adenocarcinoma.

The cell-surface glycoprotein, mesothelin, is normally present on mesothelial cells. Overexpression of mesothelin has been reported in many tumors and is correlated with poor outcome. We investigated the clinicopathologic significance of mesothelin expression in colorectal adenocarcinoma with microsatellites instability (MSI) status.Mesothelin expression was evaluated immunohistochemically in tissue microarray blocks from 390 colorectal adenocarcinoma samples. Mesothelin expression was interpreted according to the intensity and extent. A score of 2 was considered high expression. We analyzed the correlation between mesothelin expression and clinicopathologic characteristics.High mesothelin expression was observed in 177 (45.4%) out of 390 colorectal adenocarcinoma samples and was significantly associated with high histologic grade (P = .037), lymphatic invasion (P = .028), lymph node metastasis (P = .028), and high AJCC stage (P = .026). Kaplan-Meier survival curves revealed no significant difference between patients with high mesothelin expression and patients with low mesothelin expression in both recurrence-free survival (RFS) and cancer-specific survival (P = .609 and P = .167, respectively). In subgroup survival analyses, high mesothelin expression was associated with poor RFS in the MSI-High group of colorectal adenocarcinoma (P = .004).High mesothelin expression was significantly associated with aggressive phenotypes and poor patient outcome in MSI-High colorectal adenocarcinoma.

Single-stranded DNA binding protein 2 expression is associated with patient survival in hepatocellular carcinoma.

BACKGROUND: SSBP2, single-stranded DNA binding protein 2, is a subunit of the ssDNA-binding complex that is involved in the maintenance of genome stability. The majority of previous studies have suggested a tumor-suppressive role of SSBP2, which is silenced by promoter hypermethylation in several human malignancies, such as hematologic malignancies, prostate cancer, esophageal squamous cell carcinoma, ovarian cancer, and gallbladder cancer. However, an oncogenic role of SSBP2 has been suggested in glioblastoma patients. We investigated the clinicopathologic significance of SSBP2 expression in hepatocellular carcinoma. METHODS: We constructed tissue microarrays consisting of 21 normal liver parenchyma and 213 hepatocellular carcinoma tissues with corresponding adjacent non-neoplastic tissues. SSBP2 expression was investigated by immunohistochemistry, and positive expression was defined as more than 10% of the tumor cells to show nuclear staining. We then analyzed the correlations between SSBP2 expression and various clinicopathologic characteristics, and further studied the role of SSBP2 in cell growth and migration. RESULTS: Hepatocytes were negative for SSBP2 immunohistochemistry in all normal liver samples, whereas the nuclei of normal bile duct epithelium and sinusoidal endothelium were immunoreactive. Positive immunoreactivity was found in one (0.6%) out of 180 non-neoplastic liver tissue samples adjacent to the tumor and in 16 (8.5%) out of 189 hepatocellular carcinomas. Positive SSBP2 expression was significantly correlated with tumor multifocality (P = 0.027, chi-square test), high histologic grade (P = 0.003, chi-square test), and frequent vascular invasion (P = 0.001, chi-square test). Kaplan-Meier survival curves revealed that patients with SSBP2 expression had poor prognosis in both disease-free and overall survival (P = 0.004 and P = 0.026, respectively, log-rank test). SSBP2-positive tumors also had a higher Ki-67 proliferation index (P <  0.001, t-test). Furthermore, downregulation of SSBP2 in the Huh7 cell line inhibited cell migration (P = 0.022, t-test) with altered expression of epithelial-mesenchymal transition markers. CONCLUSIONS: The minority of hepatocellular carcinomas expressed SSBP2 by immunohistochemistry, whereas normal hepatocytes were negative. SSBP2-positive hepatocellular carcinomas were significantly associated with aggressive phenotypes and poor clinical outcome.

The Smad4/PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma.

BACKGROUND: Smad4 and PTEN are prognostic indicators for various tumor types. Smad4 regulates tumor suppression, whereas PTEN inhibits cell proliferation. We analyzed and compared the performance of Smad4 and PTEN for predicting the prognosis of patients with colorectal adenocarcinoma. METHODS: Combined expression patterns based on Smad4+/- and PTEN+/- status were evaluated by immunostaining using a tissue microarray of colorectal adenocarcinoma. The relationships between the protein expression and clinicopathological variables were analyzed. RESULTS: Smad4-/PTEN- status was most frequently observed in metastatic adenocarcinoma, followed by primary adenocarcinoma and tubular adenoma (p<.001). When Smad4-/PTEN- and Smad4+/PTEN+ groups were compared, Smad4-/PTEN- status was associated with high N stage (p=.018) and defective mismatch repair proteins (p=.006). Significant differences in diseasefree survival and overall survival were observed among the three groups (Smad4+/PTEN+, Smad4-/PTEN+ or Smad4+/PTEN-, and Smad4-/PTEN-) (all p<.05). CONCLUSIONS: Concurrent loss of Smad4 and PTEN may lead to more aggressive disease and poor prognosis in patients with colorectal adenocarcinoma compared to the loss of Smad4 or PTEN alone.

Clinicopathologic Correlations of E-cadherin and Prrx-1 Expression Loss in Hepatocellular Carcinoma.

BACKGROUND: Developing predictive markers for hepatocellular carcinoma (HCC) is important, because many patients experience recurrence and metastasis. Epithelial to mesenchymal transition (EMT) is a developmental process that plays an important role during embryogenesis and also during cancer metastasis. Paired-related homeobox protein 1 (Prrx-1) is an EMT inducer that has recently been introduced, and its prognostic significance in HCC is largely unknown. METHODS: Tissue microarray was constructed using surgically resected primary HCCs from 244 cases. Immunohistochemical staining of E-cadherin and Prrx-1 was performed. The correlation between E-cadherin loss and Prrx-1 expression, as well as other clinicopathologic factors, was evaluated. RESULTS: E-cadherin expression was decreased in 96 cases (39.4%). Loss of E-cadherin correlated with a higher recurrence rate (p < .001) but was not correlated with patient's survival. Thirty-two cases (13.3%) showed at least focal nuclear Prrx-1 immunoreactivity while all non-neoplastic livers (n = 22) were negative. Prrx-1 expression was not associated with E-cadherin loss, survival or recurrence rates, pathologic factors, or the Ki-67 labeling index. Twenty tumors that were positive for E-cadherin and Prrx-1 had significantly higher nuclear grades than the rest of the cohort (p = .037). In Cox proportional hazard models, E-cadherin loss and large vessel invasion were independent prognostic factors for shorter disease-free survival. Cirrhosis and high Ki-67 index (> 40%) were independent prognostic factors for shorter overall survival. CONCLUSIONS: Prrx-1 was expressed in small portions of HCCs but not in normal livers. Additional studies with a large number of Prrx-1-positive cases are required to confirm the results of this study.

Clinicopathologic Significance of Extranodal Tumor Extension in Colorectal Adenocarcinoma with Regional Lymph Node Metastasis.

Background. This study investigated the clinicopathologic significance of extranodal tumor extension in colorectal adenocarcinoma with lymph node metastasis. Method. Included were 419 patients who underwent curative resection for primary colorectal adenocarcinoma. Results. Extranodal tumor extension was observed more frequently in tumors with ulceroinfiltrative gross type (p = 0.026), higher histologic grade (p = 0.012), high grade tumor budding (p = 0.003), vascular invasion (p < 0.001), perineural invasion (p = 0.015), tumor deposit (p < 0.001), high ratio of metastatic/total lymph nodes (p < 0.001), and high pN stage (p < 0.001). Overall survival was significantly different between an extranodal tumor extension (-) group and an extranodal tumor extension (+) group for both N1 (p = 0.022) and N2 homogeneous staging (p = 0.007). Both overall (p = 0.002) and disease-free survival (p = 0.001) were significantly different between the two groups in an N1a homogeneous group and overall survival was significantly different (p = 0.016) in an N2b homogeneous group. Conclusion. Our study demonstrated that extranodal tumor extension was a useful prognostic factor for colorectal adenocarcinoma with lymph node metastasis, especially in homogeneous pN staging groups.

Clinicopathological significance of dual-specificity protein phosphatase 4 expression in invasive ductal carcinoma of the breast.

PURPOSE: Dual-specificity protein phosphatase 4 (DUSP4), also known as mitogen-activated protein kinase phosphatase (MKP) 2 is a member of the inducible nuclear MKP group. The role of DUSP4 in cancer development and progression appears to vary with the type of malignancy. The purpose of this study was to investigate DUSP4 expression in a case series of invasive ductal carcinoma of the breast. METHODS: We constructed tissue microarrays consisting of 16, 14, 47, and 266 cases of normal breast tissue, usual ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma, respectively. DUSP4 expression was investigated by immunohistochemistry. RESULTS: Cytoplasmic DUSP4 expression was observed. DUSP4 was more frequently expressed in malignant than in benign cases (p=0.024). The mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (p=0.019). DUSP4 expression was significantly correlated with a larger tumor size (>2 cm, p=0.015). There was no significant correlation between overall survival or disease-free survival and DUSP4 expression in all 266 patients. We evaluated the impact of DUSP4 expression on the survival of 120 patients with T1-stage tumors. Interestingly, Kaplan-Meier survival curves revealed that DUSP4 expression had a significant effect on both overall patient survival (p=0.034, log-rank test) and disease-free survival (p=0.045, log-rank test). In early T-stage breast cancer, DUSP4 expression was associated with a worse prognosis. CONCLUSION: DUSP4 is frequently upregulated in breast malignancy, and may play an important role in cancer development and progression. In addition, it may be a marker of adverse prognosis, especially in patients with early T1-stage cancer.

Immunohistochemical expression of dual-specificity protein phosphatase 4 in patients with colorectal adenocarcinoma.

The role of dual-specificity protein phosphatase 4 (DUSP4) appears to vary with the type of malignant tumors and is still controversial. The purpose of our study was to clarify the exact role of DUSP4 expression in colorectal adenocarcinoma. We constructed tissue microarrays and investigated DUSP4 expression by immunohistochemistry. DUSP4 was more frequently expressed in adenocarcinomas and lymph node/distant metastases compared to that in normal colorectal tissues and tubular adenomas (P < 0.001). Mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (P < 0.001). DUSP4 expression was significantly correlated with older age (P = 0.017), male gender (P = 0.036), larger tumor size (P = 0.014), nonmucinous tumor type (P = 0.023), and higher T stage (P = 0.040). Kaplan-Meier survival curves revealed a significant effect of DUSP4 expression on both overall survival and disease-free survival in AJCC stage I (P = 0.008 and P = 0.003, resp., log-rank test) and male gender (P = 0.017 and P = 0.049, resp., log-rank test). DUSP4 protein is frequently upregulated in colorectal adenocarcinoma and may play an important role in carcinogenesis and cancer progression and may be a marker of adverse prognosis.

High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer.

PURPOSE: Deregulation of microRNA-370 (miR-370) has been reported in various cancers, in which it can act as either an oncogene or a tumor suppressor gene. However, the clinicopathologic significance of miR-370 expression in breast cancer has not been studied. METHODS: The expression of miR-370 was determined with quantitative real-time polymerase chain reaction in 60 formalin-fixed, paraffin-embedded primary breast cancer tissues. Additionally, the protein expression levels of previously known targets of miR-370, such as FOXM1, FOXO1, and FOXO3a, were detected using immunohistochemistry. Finally, we analyzed its correlation with target protein expression, clinicopathologic features, and clinical outcome. RESULTS: High levels of miR-370 expression correlated with lymph node metastasis (p=0.009), advanced stage (p=0.002), and frequent perineural invasion (p=0.042). Moreover, patients with high miR-370 expression had poor disease-free survival compared with the low-expression group. However, no correlation was observed between miR-370 and its target protein expression. CONCLUSION: Our results indicate that upregulation of miR-370 in breast cancer is correlated with breast cancer progression and that it might be a potential biomarker for predicting clinical outcomes.