Allyl Isothiocyanate Suppresses the Proliferation in Oral Squamous Cell Carcinoma via Mediating the KDM8/CCNA1 Axis.

The dysregulated expression of cyclin genes can lead to the uncontrolled proliferation of cancer cells. Histone demethylase Jumonji-C domain-containing protein 5 (KDM8, JMJD5) and cyclin A1 (CCNA1) are pivotal in cell cycle progression. A promising candidate for augmenting cancer treatment is Allyl isothiocyanate (AITC), a natural dietary chemotherapeutic and epigenetic modulator. This study aimed to investigate AITC's impact on the KDM8/CCNA1 axis to elucidate its role in oral squamous cell carcinoma (OSCC) tumorigenesis. The expression of KDM8 and CCNA1 was assessed using a tissue microarray (TMA) immunohistochemistry (IHC) assay. In vitro experiments with OSCC cell lines and in vivo experiments with patient-derived tumor xenograft (PDTX) and SAS subcutaneous xenograft tumor models were conducted to explore AITC's effects on their expression and cell proliferation. The results showed elevated KDM8 and CCNA1 levels in the OSCC patient samples. AITC exhibited inhibitory effects on OSCC tumor growth in vitro and in vivo. Additionally, AITC downregulated KDM8 and CCNA1 expression while inducing histone H3K36me2 expression in oral cancer cells. These findings underscore AITC's remarkable anticancer properties against oral cancer, highlighting its potential as a therapeutic option for oral cancer treatment by disrupting the cell cycle by targeting the KDM8/CCNA1 axis.

Triptolide suppresses oral cancer cell PD-L1 expression in the interferon-γ-modulated microenvironment in vitro, in vivo, and in clinical patients.

Biological and prognostic roles of programmed death ligand 1 (PD-L1) remain unclear in oral squamous cell carcinoma (OSCC). Moreover, the pivotal role of tumor microenvironmental interferon-gamma (IFN-γ) in host responses to malignant cells, oral cancer growth, and PD-L1 expression has not been adequately studied. Thus, PD-L1 expression in 130 OSCC samples was analyzed using immunohistochemistry, which was found significantly overexpressed at the tumor site (P < .01). We further analyzed the effects of IFN-γ on OSCC cell proliferation using enzyme-linked immunosorbent assays and found that IFN-γ drives PD-L1 expression in OSCC cells in a dose-dependent manner. Triptolide (TPL), a bioactive compound isolated from Tripterygium wilfordii, exhibits anti-inflammatory and antitumor activities. To investigate whether the antitumor effect of TPL involves the suppression of PD-L1 expression, we treated OSCC cells in vitro and a patient-derived tumor xenograft (PDTX) model with TPL. TPL suppressed PD-L1 expression in the PDTX model, inhibiting tumor growth, and in OSCC cells in an IFN-γ-modulated microenvironment. We concluded that TPL inhibits tumor growth in oral cancer and downregulates PD-L1 expression in oral cancer cells in vitro. Our results provide evidence for the clinical development of PD-L1-targeted therapy for OSCC.

Downregulation of Jumonji-C domain-containing protein 5 inhibits proliferation by silibinin in the oral cancer PDTX model.

Dysregulation of histone demethylase Jumonji-C domain-containing protein 5 (JMJD5) has been identified as a great effect on tumorigenesis. Silibinin is a commonly used anti-hepatotoxic drug and exhibits anticancer effect in various cancers. However, the antitumor mechanism between silibinin and JMJD5 in oral squamous cell carcinoma (OSCC) remains unclear. In this study, the clinical significance of JMJD5 on OSCC patients was assessed through tissue microarray. Furthermore, mice bearing patient-derived tumor xenografts (PDTXs) and tongue cancer cell lines were treated with silibinin and evaluated for tumor growth and JMJD5 expression. High expression of JMJD5 in oral cancer was significantly associated with tumor size (P = 0.0241), cervical node metastasis (P = 0.0001) and clinical stage (P = 0.0002), was associated with worse survival rate compared with that of the total cohort (P = 0.0002). Collectively the data indicate that JMJD5 expression may be suitable for detection of unfavorable prognosis in OSCC patients, based in part on its apparent role as a marker of metastasis. In addition, silibinin inhibits cancer growth in vitro and in PDTX models. Furthermore, metastasis-associated protein 1 (MTA1) could regulate the expression for JMJD5 and had a positive correlation with JMJD5. Moreover, silibinin could downregulate JMJD5 and MTA1 in oral cancer. Present study thus identifies that JMJD5 might be an essential prognostic indicator and therapeutic target against OSCC progression. In addition, silibinin is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating JMJD5 in OSCC, through a mechanism likely involving MTA1/JMJD5 axis.

Pretreatment body mass index as a prognostic predictor in patients with oral squamous cell carcinoma.

OBJECTIVES: To evaluate whether low body mass index (BMI) is a potential adverse prognostic factor in patients with oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: This cross-sectional study included 320 patients with OSCC who underwent therapeutic surgical treatment in Taiwan. The pretreatment BMI was measured as a common indicator of the pretreatment nutritional status to calculate the overall survival in Kaplan-Meier method. The adverse histopathological features of margin status, depth of invasion (DOI), lymphovascular invasion (LVSI), perineural invasion (PNI), and extranodal extension (ENE) were analyzed using the Cox regression model. RESULTS: Low BMI (underweight), DOI > 5 mm, and ENE were identified as detrimental prognostic factors. On multivariate Cox regression analysis, the low BMI group (odds ratio [OR] = 1.683; 95% confidence interval [95% CI] 1.116-2.539; P = 0.022), DOI > 5 mm (OR = 2.399; 95% CI 1.459-3.943; P = 0.001), and ENE (OR = 2.467; 95% CI 1.540-3.951; P = 0.000) yielded reduced survival rate. CONCLUSIONS: The lower BMI had an important and significant effect on the survival of patients with oral cancer and their surgical outcomes. In addition to the adverse histopathological features, a DOI > 5 mm and positive ENE were also identified as the most important prognostic factors. CLINICAL RELEVANCE: Underweight patients with low BMI, DOI of > 5 mm, and positive ENE should receive more intensive nutritional supplementation and postoperative adjuvant therapy.

A histopathological evaluation and potential prognostic implications of oral squamous cell carcinoma with adverse features.

OBJECTIVES: This study aimed to evaluate the adverse clinicopathologic features of oral squamous cell carcinoma (OSCC), including margin status, depth of invasion, lymphovascular invasion, perineural invasion, and extranodal extension that significantly affect survival outcomes. MATERIALS AND METHODS: This retrospective cross-sectional study included 341 patients with OSCC who underwent therapeutic surgical treatment in Taiwan. The Kaplan-Meier method was used to estimate survival outcomes. A multivariable Cox regression model was used to evaluate the associations of various clinicopathologic features with 5-year overall survival (OS) outcomes in patients with pN0 and pN+ tumors. RESULTS: Overall, the patients had 5-year OS and progression-free survival rates of 60.0 and 47.9%, respectively. In the pN0 group, the multivariate analysis identified a positive margin (odds ratio [OR] = 16.3, 95% confidence interval [95% CI]: 3.7-72.3; P = 0.001), depth of invasion >5 mm (OR = 2.1, 95% CI: 1.2-3.7; P = 0.012), presence of lymphovascular space invasion (OR = 5.4, 95% CI: 1.3-22.0; P = 0.018), and presence of perineural invasion (OR = 4.3, 95% CI: 1.7-11.1; P = 0.002) as independent and significant prognosticators of OS. In the pN+ group, only the presence of extranodal extension independently predicted OS (OR = 1.7, 95% CI: 1.1-2.7; P = 0.0026). CONCLUSIONS: When determining survival prognosis for patients with a pN0 status, we recommended including all adverse features. In contrast, extranodal extension was the most important prognostic factor for patients with a pN+ status.

Anti-oral cancer effects of triptolide by downregulation of DcR3 in vitro, in vivo, and in preclinical patient-derived tumor xenograft model.

BACKGROUND: Aberrant expression of decoy receptor 3 (DcR3) is considered to be a diagnostic and therapeutic target for human cancers. The aim of this study was to assess DcR3 as a target of the anticancer effects of triptolide (TPL) in preclinical patient-derived tumor xenograft (PDTX) models of oral squamous cell carcinoma (OSCC). METHODS: The expression of DcR3 was evaluated through immunohistochemistry, and correlations were examined using clinical variables. The effects of TPL on the expression of DcR3 and cell proliferation were investigated in OSCC cell lines and in PDTX models. RESULTS: DcR3 overexpression was associated with overall survival and tumor size. TPL significantly decreased tumor growth. Moreover, TPL inhibited the expression of metastasis-associated protein 1 (MTA1), a transcription factor for DcR3 in vivo, in vitro, and in PDTX models. CONCLUSION: TPL appeared to exert anticancer effects by repressing DcR3 and MTA1 in vitro, in vivo, and in PDTX models.

Lymph node density as a prognostic predictor in patients with betel nut-related oral squamous cell carcinoma.

OBJECTIVES: Lymph node metastasis in oral squamous cell carcinoma (OSCC) is a poor prognostic factor. The histopathologic stage (e.g., pN) is used to evaluate the severity of lymph node metastasis; however, the current staging system insufficiently predicts survival and recurrence. We investigated clinical outcomes and lymph node density (LND) in betel nut-chewing individuals. MATERIAL AND METHODS: We retrospectively analyzed 389 betel nut-exposed patients with primary OSCC who underwent surgical resection in 2002-2015. The prognostic significance of LND was evaluated by overall survival (OS) and disease-free survival (DFS) using the Kaplan-Meier method. RESULTS: Kaplan-Meier analyses showed that the 5-year OS and DFS rates in all patients were 60.9 and 48.9%, respectively. Multivariate analysis showed that variables independently prognostic for OS were aged population (hazard ratio [HR] = 1.6, 95% confidence interval [95% CI] = 1.1-2.5; P = .025), and cell differentiation classification (HR = 2.4, 95% CI = 1.4-4.2; P = .002). In pathologic N-positive patients, a receiver operating characteristic (ROC) curve for OS was used and indicated the best cutoff of 0.05, and the multivariate analysis showed that LND was an independent predictor of OS (HR = 2.2, 95% CI = 1.3-3.7; P = .004). CONCLUSIONS: Lymph node density, at a cutoff of 0.05, was an independent predictor of OS and DFS. OS and DFS underwent multiple analyses, and LND remained significant. The pathologic N stage had no influence in the OS analysis. CLINICAL RELEVANCE: LND is a more reliable predictor of survival in betel nut-chewing patients for further post operation adjuvant treatment, such as reoperation or adjuvant radiotherapy.

Danshen extract circumvents drug resistance and represses cell growth in human oral cancer cells.

BACKGROUND: Danshen is a common traditional Chinese medicine used to treat neoplastic and chronic inflammatory diseases in China. However, the effects of Danshen on human oral cancer cells remain relatively unknown. This study investigated the antiproliferative effects of a Danshen extract on human oral cancer SAS, SCC25, OEC-M1, and KB drug-resistant cell lines and elucidated the possible underlying mechanism. METHODS: We investigated the anticancer potential of the Danshen extract in human oral cancer cell lines and an in vivo oral cancer xenograft mouse model. The expression of apoptosis-related molecules was evaluated through Western blotting, and the concentration of in vivo apoptotic markers was measured using immunohistochemical staining. The antitumor effects of 5-fluorouracil and the Danshen extract were compared. RESULTS: Cell proliferation assays revealed that the Danshen extract strongly inhibited oral cancer cell proliferation. Cell morphology studies revealed that the Danshen extract inhibited the growth of SAS, SCC25, and OEC-M1 cells by inducing apoptosis. The Flow cytometric analysis indicated that the Danshen extract induced cell cycle G0/G1 arrest. Immunoblotting analysis for the expression of active caspase-3 and X-linked inhibitor of apoptosis protein indicated that Danshen extract-induced apoptosis in human oral cancer SAS cells was mediated through the caspase pathway. Moreover, the Danshen extract significantly inhibited growth in the SAS xenograft mouse model. Furthermore, the Danshen extract circumvented drug resistance in KB drug-resistant oral cancer cells. CONCLUSION: The study results suggest that the Danshen extract could be a potential anticancer agent in oral cancer treatment.

Discrimination of CD44 and Oct3/4 Expression in Pancreatic Adenocarcinoma from Benign Pancreatic Ducts in Small Biopsy Specimens.

Cluster of differentiation 44 (CD44) and octamer-binding transcription factor 3/4 (Oct3/4) are important factors influencing cancer stem cell (CSC) development, but their clinical applications on pancreatic cancer are still unknown. Here, we tested the hypothesis that expression of CD44 and Oct3/4 correlates with the clinicopathological parameters of pancreatic ductal adenocarcinomas (PDACs). Firstly, data on the mRNA expression levels in PDACs and normal pancreatic tissues were collected from Gene Expression Omnibus (GEO) repository datasets. Immunohistochemical analyses of CD44 and Oct3/4 were next performed in tissue microarrays of 80 surgical specimens derived from a Chinese population, which included 9 normal pancreatic ducts and 71 PDACs, amongst which 12 were well differentiated, 47 moderately differentiated, and 12 poorly differentiated. From the GEO results, mRNA expression levels of both CD44 and Oct3/4 were higher in PDACs than in normal pancreatic tissues. In addition, immunostaining scores of these biomarkers were higher in most PDACs than in non-neoplastic pancreatic ducts. The intensity of CD44 and Oct3/4 staining in normal pancreatic tissues was weak and limited to small areas. Although CD44 and Oct3/4 overexpression in PDACs tended to be associated with advanced histologic grades of PDACs, the correlation of CD44 and Oct3/4 expression with the American Joint Committee on Cancer (AJCC) pathological stage was not statistically significant. In conclusion, CD44 and Oct3/4 overexpression may imply malignant transformation of pancreatic ducts and could help pathologists make a more accurate diagnosis and decision on clear surgical margins.

Melatonin exerts anti-oral cancer effect via suppressing LSD1 in patient-derived tumor xenograft models.

Aberrant activation of histone lysine-specific demethylase (LSD1) increases tumorigenicity; hence, LSD1 is considered a therapeutic target for various human cancers. Although melatonin, an endogenously produced molecule, may defend against various cancers, the precise mechanism involved in its anti-oral cancer effect remains unclear. Patient-derived tumor xenograft (PDTX) models are preclinical models that can more accurately reflect human tumor biology compared with cell line xenograft models. Here, we evaluated the anticancer activity of melatonin by using LSD1-overexpressing oral cancer PDTX models. By assessing oral squamous cell carcinoma (OSCC) tissue arrays through immunohistochemistry, we examined whether aberrant LSD1 overexpression in OSCC is associated with poor prognosis. We also evaluated the action mechanism of melatonin against OSCC with lymphatic metastases by using the PDTX models. Our results indicated that melatonin, at pharmacological concentrations, significantly suppresses cell proliferation in a dose- and time-dependent manner. The observed suppression of proliferation was accompanied by the melatonin-mediated inhibition of LSD1 in oral cancer PDTXs and oral cancer cell lines. In conclusion, we determined that the beneficial effects of melatonin in reducing oral cancer cell proliferation are associated with reduced LSD1 expression in vivo and in vitro.

Triptolide represses oral cancer cell proliferation, invasion, migration, and angiogenesis in co-inoculation with U937 cells.

OBJECTIVES: Advanced oral cancer is a major public health concern because of a lack of effective prevention and treatment. Triptolide (TPL), a diterpenoid triepoxide derived from the Chinese herb Tripterygium wilfordii, has been demonstrated to possess strong anticancer properties. In this study, we investigated whether TPL exerts anticancer effects on the tumor microenvironment of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Human macrophage-like U937 cells were co-inoculated with oral cancer SAS cells in a noncontact transwell coculture system. Cytokine expression was detected using ELISA, and cell proliferation was detected using methylene blue. RNA levels were detected using qPCR. Protein levels were detected using Western blot analysis. In vivo experiments involved using xenografted NOD/SCID mice. RESULTS: Our results demonstrated that TPL inhibited the growth of SAS cells co-inoculated with U937 cells in vitro and in vivo. TPL inhibited the invasion, migration ability, and angiogenesis of SAS cells co-inoculated with U937 cells. Expression of cytokines IL-6, IL-8, and TNF-α was induced by co-inoculation, but TPL repressed their expression. CONCLUSION: TPL suppressed the expression of cytokines IL-6, IL-8, and TNF-α, as well as tumor growth, invasion, migration, and angiogenesis in the co-inoculation of human tongue cancer cells with macrophage-like U937 cells. CLINICAL RELEVANCE: TPL is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating tumor-associated macrophages in a tumor microenvironment of HNSCC.

A tissue microarray study of toll-like receptor 4, decoy receptor 3, and external signal regulated kinase 1/2 expressions in astrocytoma.

INTRODUCTION: Decoy receptor 3 (DcR3) functions as a death decoy inhibiting apoptosis mediated by the tumor necrosis factor receptor family. It is highly expressed in many tumors and its expression can be regulated by the MAPK/ERK signaling pathway and ERK is a vital member of this pathway. Toll-like receptor 4 (TLR4) is expressed on immune cells. Increased TLR4 expression has been associated with various types of cancers. MATERIAL AND METHODS: The study was conducted to investigate the expression of DcR3, ERK1/2, and TLR4 in astrocytomas and evaluate if they are validating markers for discriminating glioblastoma from anaplastic astrocytoma in limited surgical specimen. Expression of DcR3, ERK1/2, and TLR4 was determined by immunohistochemical staining of tissue microarray from 48 paraffin-embedded tissues. A binary logistic regression method was used to generate functions that discriminate between anaplastic astrocytomas and glioblastomas. RESULTS: The expression of TLR4 and DcR3 was significantly higher in glioblastomas than in anaplastic astrocytomas. DcR3 could discriminate anaplastic astrocytomas from glioblastomas with high sensitivity (93.8%), specificity (90%), and accuracy (92.3%). CONCLUSION: Our results suggest that DcR3 may be a useful marker for discriminating anaplastic astrocytomas from glioblastomas.

Effect of External Pressure and Catheter Gauge on Flow Rate, Kinetic Energy, and Endothelial Injury During Intravenous Fluid Administration in a Rabbit Model.

The effects of intravenous (IV) catheter gauge and pressurization of IV fluid (IVF) bags on fluid flow rate have been studied. However, the pressure needed to achieve a flow rate equivalent to that of a 16 gauge (G) catheter through smaller G catheters and the potential for endothelial damage from the increased kinetic energy produced by higher pressurization are unclear. Constant pressure on an IVF bag was maintained by an automatic adjustable pneumatic pressure regulator of our own design. Fluids running through 16 G, 18 G, 20 G, and 22 G catheters were assessed while using IV bag pressurization to achieve the flow rate equivalent to that of a 16 G catheter. We assessed flow rates, kinetic energy, and flow injury to rabbit inferior vena cava endothelium. By applying sufficient external constant pressure to an IVF bag, all fluids could be run through smaller (G) catheters at the flow rate in a 16 G catheter. However, the kinetic energy increased significantly as the catheter G increased. Damage to the venous endothelium was negligible or minimal/patchy cell loss. We designed a new rapid infusion system, which provides a constant pressure that compresses the fluid volume until it is free from visible residual fluid. When large-bore venous access cannot be obtained, multiple smaller catheters, external pressure, or both should be considered. However, caution should be exercised when fluid pressurized to reach a flow rate equivalent to that in a 16 G catheter is run through a smaller G catheter because of the profound increase in kinetic energy that can lead to venous endothelium injury.

False-positive finding of retropharyngeal lymph node recurrence in both fluorine (18)FDG PET and MRI in a patient with nasopharyngeal carcinoma.

BACKGROUND: Biopsy of the retropharyngeal node is not routinely accessible. The diagnosis of retropharyngeal lymph node recurrence in patients with nasopharyngeal carcinoma (NPC) is often based on an imaging study. METHODS: We reported a patient with NPC who was incorrectly diagnosed with left retropharyngeal lymph node recurrence by both MRI and positron emission tomography (PET)/CT. RESULTS: A woman who was treated for stage IVA NPC 2 years previously was found to have a nodal lesion in the left retropharyngeal space on MRI together with focal fluorodeoxyglucose (FDG) uptake on PET/CT. Locoregional recurrence was suspected, and surgery was performed. Subsequent pathology results showed reactive lymphoid hyperplasia. CONCLUSION: Although tissue biopsy for the retropharyngeal node is technically difficult, this case demonstrates that tumor recurrence cannot be diagnosed even based on both positive findings on MRI and PET/CT in patients with NPC.

Daxx and TCF4 interaction links to oral squamous cell carcinoma growth by promoting cell cycle progression via induction of cyclin D1 expression.

OBJECTIVES: Death domain-associated protein (Daxx) has been recently implicated as a positive factor in ovarian cancer and prostate cancer, but the role of Daxx in oral squamous cell carcinoma (OSCC) has never been addressed. Herein, we investigate the expression and function of Daxx in OSCC. MATERIALS AND METHODS: RT-quantitative PCR, Western blotting, and immunohistochemistry were used to evaluation of the expression of Daxx in human OSCC cell lines and clinical surgical specimens. Short hairpin RNA targeting Daxx was transduced by lentivirus infection to knockdown the expression of Daxx in SAS and SCC25 cell lines, and the influence of this knockdown was evaluated by analyzing the growth and the cell cycle in transduced cells. Immunoprecipitation and sequential chromatin immunoprecipitation-quantitative PCR were used to analyze the associations between Daxx, TCF4, and cyclin D1 promoter. Xenograft tumor model was used to evaluate the in vivo tumorigenicity of Daxx in OSCC. RESULTS: Daxx mRNA and protein expression are elevated in several OSCC cell lines and human OSCC samples in comparison to those in normal tissue. We further find that depletion of Daxx decreases OSCC cell growth activity through G1 cell cycle arrest. Daxx silencing reduces cyclin D1 expression via a Daxx-TCF4 interaction, whereas the Daxx depletion-mediated G1 arrest can be relieved by ectopic expression of cyclin D1. Moreover, we show that in OSCC clinical samples, the expression of Daxx is significantly correlated with that of cyclin D1. CONCLUSION: Our data demonstrate the importance of Daxx in regulation of cyclin D1 expression and provide the first evidence that Daxx exhibits tumor-promoting activity in OSCC. CLINICAL RELEVANCE: Daxx plays an important role in malignant transformation of OSCC and may serves as a target for cancer prevention and treatment.

Salutary Effects of Cepharanthine against Skeletal Muscle and Kidney Injuries following Limb Ischemia/Reperfusion.

Limb ischemia/reperfusion (I/R) causes oxidation and inflammation and subsequently induces muscle and kidney injuries. Cepharanthine, a natural plant alkaloid, possesses anti-inflammatory and antioxidative properties. We elucidated the salutary effects of cepharanthine against muscle and kidney injuries following limb I/R. Adult male rats were randomized to receive I/R or I/R plus cepharanthine. I/R was achieved by applying tourniquet high around each thigh for 3 hours followed by reperfusion for 24 hours. Cepharanthine (10 mg/kg, intraperitoneal) was injected immediately before reperfusion. After euthanization, degrees of tissue injury, inflammation, and oxidation were examined. Our data revealed that the I/R group had significant increases in injury biomarker concentrations of muscle (creatine kinase and lactate dehydrogenase) and kidney (creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1). Histological assays revealed moderate muscle and kidney injury characteristics in the I/R group. The I/R group also had significant increases in concentrations of inflammatory molecules (interleukin-6, macrophage inflammatory protein-2, and prostaglandin E2) and reactive nitrogen species (nitric oxide) as well as lipid peroxidation (malondialdehyde). Of note, these effects of limb I/R could be mitigated by cepharanthine. These data confirmed that cepharanthine attenuated muscle and kidney injuries induced by limb I/R. The mechanisms may involve its anti-inflammatory and antioxidative capacities.

Squamous Cell Carcinoma Arising From Massive Localized Lymphedema of Scrotum Mimicking Scrotal Smooth Muscle Hamartoma of Dartos: A Case Report.

Massive localized lymphedema (MLL) is an uncommon benign skin lesion typically presenting with prominent edema and vascular proliferation in the adipose tissue of lower limbs. When rarely occurring in scrotum, it instead is characterized by a striking proliferation of dermal smooth muscle bundles mimicking acquired smooth muscle hamartoma of dartos. The authors report a rare case of scrotal MLL. A 57-year-old obese man with a history of previous surgery for rectal adenocarcinoma, 20 years earlier, presented with progressive nodular enlargement of the scrotum for 2 years, causing discomfort, difficulty in ambulation, and cosmetic problems. The preoperative radiographic investigation revealed thickening of the scrotal wall with multiple soft-tissue nodules. The patient underwent a wide excision of the scrotal wall, perineum, and penile skin. The pathological examination showed a scrotal MLL associated with well-differentiated squamous cell carcinoma. The authors speculate that prior radiotherapy and surgery together with morbid obesity led to long-standing lymphedema that triggered the proliferation of smooth muscle cells, chronic epidermal change, and finally squamous cell carcinoma.

Nuclear overexpression of urocortin discriminates primary brain tumors from reactive gliosis.

The role of urocortin (UCN) is still ambiguous in human cancers. We tested the hypothesis that using UCN expression discriminates reactive gliosis from primary brain tumors (PBTs). Immunohistochemical analysis of UCN was performed in six reactive gliosis and 99 PBTs. The immunostain scores of UCN were calculated as the degree of intensity multiplied by the percentage of expressed tumor cells. Nuclear staining of UCN revealed weak intensity and small portion of positively stained cells in reactive gliosis. However, comparing with non-neoplastic tissues, higher immunostain scores of UCN were identified in each WHO grade of astrocytomas and meningiomas. Finally, neither WHO grade nor overall survival rate did not significantly correlate with UCN expression in astrocytomas and meningiomas. Our findings demonstrate for the first time that the application of UCN might be a novel biomarker for not only discriminating reactive gliosis from PBTs, but also deciding where the clear surgical margin was.

The interleukin-15 system suppresses T cell-mediated autoimmunity by regulating negative selection and nT(H)17 cell homeostasis in the thymus.

The interleukin-15 (IL-15) system is important for regulating both innate and adaptive immune responses, however, its role in autoimmune disease remained unclear. Here we found that Il15(-/-) and Il15ra(-/-) mice spontaneously developed late-onset autoimmune phenotypes. CD4(+) T cells of the knockout mice showed elevated autoreactivity as demonstrated by the induction of lymphocyte infiltration in the lacrimal and salivary glands when transferred into nude mice. The antigen-presenting cells in the thymic medullary regions expressed IL-15 and IL-15Rα, whose deficiency resulted in insufficient negative selection and elevated number of natural IL-17A-producing CD4(+) thymocytes. These findings reveal previously unknown functions of the IL-15 system in thymocyte development, and thus a new layer of regulation in T cell-mediated autoimmunity.

Biomarkers distinguishing mammary fibroepithelial neoplasms: a tissue microarray study.

AIM: To determine whether any markers in biopsy specimens were useful for distinguishing (1) fibroadenoma (FA) from benign phyllodes tumors (PTs); and (2) from benign borderline PTs of the breast. MATERIALS AND METHODS: Specimens of 80 breast tumors (20 FA, 38 benign, 12 borderline, and 10 malignant PTs) diagnosed at Tri-Service General Hospital from 1986 to 2006 and 10 normal breast tissue were investigated immunohistochemically for the expression of 11 biomarkers including p53, Ki-67, topoisomerase IIα, p16, retinoblastoma protein (pRb), fascin-1, estrogen receptor-ß, CD117, osteopontin, hypoxia-inducible factor-1α, and cyclooxygenase-2. The binary logistic regression method was used to generate functions that discriminate between benign and borderline PT and also between FA and benign PT. RESULTS: On the basis of the most active area of stained stromal cells, the staining intensity, and the immunoscore, the expression of Ki-67, topoisomerase IIα, p16, and pRb was significantly higher in borderline or malignant PTs than in benign PTs. Ki-67 could discriminate benign from borderline PTs singly with a high sensitivity (91.7%), specificity (100%), and accuracy (98%). In addition, expression of Ki-67, p16, and pRb was significantly higher in benign PT than in FA. Binary logistic regression identified p16 and pRb as the only marker combination capable of distinguishing FA from benign PTs with sensitivity (94.7%), specificity (75%), and accuracy (87.9%). CONCLUSION: Ki-67 may be a useful marker for discriminating benign from borderline PTs, and p16 and pRb may be a useful combination of markers for distinguishing FA from benign PTs in core biopsy specimen.