ACSL4 upregulates IFI44 and IFI44L expression and promotes the proliferation and invasiveness of head and neck squamous cell carcinoma cells.

Reprogramming of cellular energy metabolism, including deregulated lipid metabolism, is a hallmark of head and neck squamous cell carcinoma (HNSCC). However, the underlying molecular mechanisms remain unclear. Long-chain acyl-CoA synthetase 4 (ACSL4), which catalyzes fatty acids to form fatty acyl-CoAs, is critical for synthesizing phospholipids or triglycerides. Despite the differing roles of ACSL4 in cancers, our data showed that ACSL4 was highly expressed in HNSCC tissues, positively correlating with poor survival rates in patients. Knockdown of ACSL4 in HNSCC cells led to reduced cell proliferation and invasiveness. RNA sequencing analyses identified interferon-induced protein 44 (IFI44) and interferon-induced protein 44-like (IFI44L), encoded by two interferon-stimulated genes, as potential effectors of ACSL4. Silencing IFI44 or IFI44L expression in HNSCC cells decreased cell proliferation and invasiveness. Manipulating ACSL4 expression or activity modulated the expression levels of JAK1, tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 1 (STAT1), interferon α (IFNα), IFNß, and interferon regulatory factor 1 (IRF1), which regulate IFI44 and IFI44L expression. Knockdown of IRF1 reduced the expression of JAK1, TYK2, IFNα, IFNß, IFI44, or IFI44L and diminished cell proliferation and invasiveness. Our results suggest that ACSL4 upregulates interferon signaling, enhancing IFI44 and IFI44L expression and promoting HNSCC cell proliferation and invasiveness. Thus, ACSL4 could serve as a novel therapeutic target for HNSCC.

Serpin peptidase inhibitor, clade E, member 2 is associated with malignant progression and clinical prognosis in oral squamous cell carcinoma.

Background/purpose: The serpin peptidase inhibitor, clade E, member 2 (SERPINE2), is upregulated in breast cancer, prostate cancer, and urothelial carcinoma; however, limited information exists regarding its expression in oral cancer. Therefore, this study aimed to analyze the association between SERPINE2 expression and oral squamous cell carcinoma (OSCC) outcomes. Materials and methods: SERPINE2 mRNA and protein expression in patients with head and neck squamous cell carcinoma and OSCC were investigated using online databases and tissue-array analysis. Its relationship with clinicopathological characteristics, OSCC prognosis and its biological function in OSCC cells were explored. Results: Analysis using online databases revealed higher SERPINE2 expression in tumor tissues and its role as a prognostic factor. High SERPINE2 protein levels were significantly correlated with adverse pathological parameters, including advanced clinical stage and tumor status (P < 0.001), lymph nodes (P = 0.014), and distant metastases (P = 0.013). High SERPINE2 expression was associated with worse overall survival (P < 0.001) and was identified as an independent prognostic factor for OSCC. In vitro studies revealed that SERPINE2 knockdown significantly reduced cell proliferation, migration, and invasion in OSCC cell lines. Conclusion: This study suggests that SERPINE2 may serve as a prognostic biomarker and potential therapeutic target for oral cancer.

TGFB1I1 promotes cell proliferation and migration in urothelial carcinoma.

Urothelial carcinoma (UC) is common cancer worldwide with a high prevalence in Taiwan, especially in the upper urinary tract, including the renal pelvis and ureter, also classifying as upper urinary tract urothelial carcinoma. Here, we aim to find a representative prognostic marker that strongly correlates to this type of carcinoma. Transforming growth factor beta-1-induced transcript 1 (TGFB1I1) is a cofactor of cellular TGF-ß1 and interacts with various nuclear receptors. The previous study showed that TGFB1I1 promotes focal adhesion formation, contributing to the epithelial-mesenchymal transition (EMT) with actin cytoskeleton and vimentin through TGFB1I1 regulation. We aim to reveal the role of TGFB1I1 in the tumorigenesis of UC. In silico and clinicopathological data of upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC) were accessed and analyzed for IHC staining regarding tumor characteristics, including survival outcome. Finally, an in vitro study was performed to demonstrate the biological changes of UC cells. In UTUC, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage, papillary configuration, and frequent mitosis. Meanwhile, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage and histological grade in UBUC. Moreover, the in vitro study shows that TGFB1I1 affects cell proliferation, viability, migration and wound healing. The EMT markers also decreased upon TGFB1I1 knockdown. In this study, we identified that TGFB1I1 regulates UC cell proliferation and viability and induces the EMT to facilitate cell migration in vitro, leading to its essential role in promoting tumor aggressiveness in both UTUC and UBUC.

Detection of extraprostatic extension by transperineal multiparametric magnetic resonance imaging-ultrasound fusion targeted combined with systemic template prostate biopsy.

BACKGROUND: Extraprostatic extension (EPE) of prostate cancer (PCa) on transrectal (TR) needle core biopsy (Bx) is a rare histopathological finding that can help in clinical decision-making. The detection efficiency of the transperineal (TP) approach is yet to be explored. METHODS: We retrospectively reviewed 2848 PCa cases using concomitant systemic template biopsy (SBx) and multiparametric magnetic resonance imaging (MRI)-ultrasound fusion-targeted biopsy (TBx) using the TR (n = 1917) or TP (n = 931) approach at our institution between January 2015 and July 2022. We assessed and compared clinical, MRI, and biopsy characteristics using different approaches (TP and TR) and methods (SBx and TBx). RESULTS: In total, 40 EPE cases were identified (40/2848, 1.4%). TP showed a significantly higher EPE detection rate compared to TR in SBx (TR:0.7% vs. TP:1.6%; p = 0.028) and TBx (TR:0.5% vs. TP:1.2%; p = 0.033), as well as the combined methods (2.1% vs. 1.1%, p = 0.019). A significantly higher incidence of EPEs was found at non-base sites in TP than in TR (76.7% vs. 50%, p = 0.038). SBx showed a higher EPE detection rate than TBx; however, the difference was not statistically significant. TP showed higher prostate-specific antigen density (0.35 vs. 0.17, p = 0.005), higher frequency of GG4-5 in the cores with EPE (65.0% vs. 50.0%, p = 0.020), and more PCa-positive SBx cores (10 vs. 8, p = 0.023) compared to the TR. CONCLUSIONS: TP may improve EPE detection compared with TR and should be applied to patients with adverse pre-biopsy features.

Learning more from the inter-rater reliability of interstitial fibrosis assessment beyond just a statistic.

Interstitial fibrosis assessment by renal pathologists lacks good agreement, and we aimed to investigate its hidden properties and infer possible clinical impact. Fifty kidney biopsies were assessed by 9 renal pathologists and evaluated by intraclass correlation coefficients (ICCs) and kappa statistics. Probabilities of pathologists' assessments that would deviate far from true values were derived from quadratic regression and multilayer perceptron nonlinear regression. Likely causes of variation in interstitial fibrosis assessment were investigated. Possible misclassification rates were inferred on reported large cohorts. We found inter-rater reliabilities ranged from poor to good (ICCs 0.48 to 0.90), and pathologists' assessments had the worst agreements when the extent of interstitial fibrosis was moderate. 33.5% of pathologists' assessments were expected to deviate far from the true values. Variation in interstitial fibrosis assessment was found to be correlated with variation in interstitial inflammation assessment (r2 = 32.1%). Taking IgA nephropathy as an example, the Oxford T scores for interstitial fibrosis were expected to be misclassified in 21.9% of patients. This study demonstrated the complexity of the inter-rater reliability of interstitial fibrosis assessment, and our proposed approaches discovered previously unknown properties in pathologists' practice and inferred a possible clinical impact on patients.

Unsatisfactory reproducibility of interstitial inflammation scoring in allograft kidney biopsy.

Interstitial inflammation scoring is incorporated into the Banff Classification of Renal Allograft Pathology and is essential for the diagnosis of T-cell mediated rejection. However, its reproducibility, including inter-rater and intra-rater reliabilities, has not been carefully investigated. In this study, eight renal pathologists from different hospitals independently scored 45 kidney allograft biopsies with varying extents of interstitial inflammation. Inter-rater reliabilities and intra-rater reliabilities were investigated by kappa statistics and conditional agreement probabilities. Individual pathologists' scoring patterns were examined by chi-squared tests and proportions tests. The mean pairwise kappa values for inter-rater reliability were 0.27, 0.30, and 0.26 for the Banff i score, ti score, and i-IFTA, respectively. No rater pair performed consistently better or worse than others on all three scorings. After dichotomizing the scores into two groups (none/mild and moderate/severe inflammation), the averaged conditional agreements ranged from 47.1% to 50.0%. The distributions of the scores differed, but some pathologists persistently scored higher or lower than others. Given the important role of interstitial inflammation scoring in the diagnosis of T-cell mediated rejection, transplant practitioners should be aware of the possible clinical implications of the far-from-optimal reproducibility.

Reciprocal regulation of CIP2A and AR expression in prostate cancer cells.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein overexpressed in human malignancies, including prostate cancer (PCa). In this study, we aimed to explore the oncogenic function of CIP2A in PCa cells and its underlying mechanism. We showed that 63.3% (38/60 cases) of PCa tissues exhibited a high CIP2A immunostaining, compared to 25% (3/12 cases) of BPH samples (p = 0.023). Furthermore, the protein level of CIP2A was positively correlated with patients' short survival time and nuclear AR levels in PCa tissues. Compared to PZ-HPV-7, an immortalized prostate cell line, androgen-sensitive LNCaP C-33, androgen-independent LNCaP C-81, or 22Rv1 cells exhibited a high CIP2A level, associated with high protein and phosphorylation levels of AR. While AR expression and activity modulated CIP2A expression, manipulating CIP2A expression in PCa cells regulated their AR protein levels and proliferation. The reduction of CIP2A expression also enhanced the sensitivity of PCa cells toward Enzalutamide treatment. Our data further showed that depletion of polo-kinase 1 (PLK1) expression or activity in C-81 or 22Rv1 cells caused reduced protein levels of c-Myc and AR. Notably, inhibition of PLK1 activity could abolish CIP2A-promoted expressions in c-Myc, AR, and prostate-specific antigen (PSA) in C-33 cells under an androgen-deprived condition, suggesting the role of PLK1 activity in CIP2A-promoted AR expression. In summary, our data showed the existence of a novel regulation between CIP2A and AR protein levels, which is critical for promoting PCa malignancy. Thus, CIP2A could serve as a therapeutic target for PCa.

Mucinous adenocarcinoma of the prostatic urethra after brachytherapy for prostatic adenocarcinoma: a case series.

Mucinous adenocarcinoma of the urethra is extremely rare, even more so in a setting of postradiation therapy, with only 3 cases reported up to date including the first case published by our group in 2011. In the present study, we included the long-term follow-up on our previously reported case and report 3 additional cases. This is the first case series to date of this rare disease entity. The aim of this study is to review the clinicopathologic features of mucinous adenocarcinoma of the prostatic urethra in patients after receiving brachytherapy for prostatic adenocarcinoma. We identified 4 patients with a mean age of 72 years, and a mean interval of 14.8 years from brachytherapy for prostate carcinoma (grade group 1). Patients presented with hematuria or urinary retention. A colonoscopy was performed in three-fourth of patients and was within normal limits. Three patients underwent cystoprostatectomy and 1 had a transurethral resection of the prostate. On gross examination, only tumor formed a 3.5 cm tan-gray, ulcerated, friable, and necrotic mass and 2 displayed either irregular red granular or thickened areas within the prostatic urethra. Abundant extracellular mucin pools dissecting the prostatic stroma were present in all tumors, with clusters of tumor cells floating in the mucin. The mucin pools were lined by pleomorphic pseudostratified columnar mucinous epithelium. Tumors were diffusely positive for CK20, CDX2 (4/4), and AMACR (2/2); they focally expressed CK7 (2/4), and lacked nuclear ß-catenin expression (3/3). PSA, PSAP, NKX3.1, p63, and GATA3 were negative in the tumors tested. Among the 3 patients who underwent radical surgery, 2 had stage 2 tumors (confined to the prostatic urethra and prostate), and 1 had a stage 3 tumor, with seminal vesicle involvement. All 4 patients were alive without disease with a mean follow-up of 4.9 years. In conclusion, brachytherapy-associated mucinous adenocarcinoma of the prostatic urethra displays intestinal-type features as its non-radiation-related counterpart. It appears to lack a villous adenoma component, displays a different immunohistochemical profile with diffuse CK20 and CDX2 positivity, and is associated with lower stage and less aggressive behavior.

Immunohistochemistry Helps to Distinguish Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features/Noninvasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma with Other Follicular Thyroid Lesions.

Background and Objectives: We aimed to assess the diagnostic value of various immunohistochemical (IHC) markers and panels for differentiation among benign follicular nodules (BFNs), noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), noninvasive encapsulated follicular variants of papillary thyroid carcinoma (NEFVPTCs), and infiltrative FVPTC (IFVPTC). Materials and Methods: Sixty-three cases were classified as BFNs, NIFTPs, NEFVPTCs, or IFVPTCs and were evaluated using the following markers: CK19, CD56, galectin-3, CITED1, HBME-1, VE1, and TROP-2. Results: The IHC results for NIFTP and NEFVPTC exhibited no statistically significant differences. In differentiating IFVPTCs from BFNs and NIFTPs/NEFVPTCs, galectin-3 and TROP-2 were the markers with the highest sensitivity plus high specificity, respectively. In various combinations, panel co-expression of two markers, including galectin-3 and/or HBME-1 and/or TROP-2, and the combination of galectin-3 and TROP-2 co-expression could achieve 100% in all aspects. In terms of discrimination of BFNs from NIFTP/NEFVPTC, CK19 was the single most sensitive marker (81.3%), while CD56 was the most specific (100%). The panel consisting of CK19 and/or HBME-1 exhibited the greatest sensitivity (96.9%), but the panel with CD56 and/or HBME-1 exhibited the greatest specificity (90.5%). Conclusions: Our results broaden the use of IHC markers for differential diagnoses among the four groups of follicular-based lesions. In addition, the similar IHC profiles of NIFTP and NEFVPTC also suggest the original criterion of <1% papillae within tumors, providing a reliable NIFTP diagnosis. Their close relationship may represent a spectrum of progressing neoplasia.

Current Development and Application of Anaerobic Glycolytic Enzymes in Urothelial Cancer.

Urothelial cancer is a malignant tumor with metastatic ability and high mortality. Malignant tumors of the urinary system include upper tract urothelial cancer and bladder cancer. In addition to typical genetic alterations and epigenetic modifications, metabolism-related events also occur in urothelial cancer. This metabolic reprogramming includes aberrant expression levels of genes, metabolites, and associated networks and pathways. In this review, we summarize the dysfunctions of glycolytic enzymes in urothelial cancer and discuss the relevant phenotype and signal transduction. Moreover, we describe potential prognostic factors and risks to the survival of clinical cancer patients. More importantly, based on several available databases, we explore relationships between glycolytic enzymes and genetic changes or drug responses in urothelial cancer cells. Current advances in glycolysis-based inhibitors and their combinations are also discussed. Combining all of the evidence, we indicate their potential value for further research in basic science and clinical applications.

SERPINE2 Overexpression Is Associated with Poor Prognosis of Urothelial Carcinoma.

Recent studies have reported that SERPINE2 contributes to the development of various cancers. However, its association with urothelial carcinoma (UC) remains unclear. In this study, data on urinary bladder UC (UBUC) cases from The Cancer Genome Atlas (TCGA) database were used to investigate the prognostic value of SERPINE2 mRNA expression. Then, SERPINE2 expression was analyzed with tissue microarrays constructed from 117 upper tract UC (UTUC) and 84 UBUC tissue specimens using immunohistochemical staining. Results were compared to clinicopathologic data by multivariate analysis. In the TCGA database, high SERPINE2 mRNA expression indicated a poor prognosis in patients with UBUC. Furthermore, Mann-Whitney U test showed that high SERPINE2 immunoexpression was significantly associated with adverse pathologic parameters including invasion, high grade, coexistence of UC in situ, and advanced pT stage (all p < 0.05, except for a marginal association with high-grade UBUC, p = 0.066). Kaplan-Meier analysis revealed that high SERPINE2 expression was associated with worse overall survival (OS; UTUC, p = 0.003; UBUC, p = 0.014) and disease-free survival (UTUC, p = 0.031; UBUC, p = 0.033). Moreover, multivariate analysis identified high SERPINE2 expression as an independent prognostic factor for OS (UTUC, p = 0.002; UBUC, p = 0.024). Taken together, our findings demonstrated that increased SERPINE2 expression is associated with adverse pathologic features and may serve as a prognostic biomarker for UC.

Mycobacterium abscessus Osteomyelitis of the Calcaneus Presenting as Tumor-Mimicking Lesions: A Case Report.

CASE: We present the case of a 51-year-old immunocompetent man with refractory heel pain who initially had been treated for plantar fasciitis. However, the pain was proven to be caused by a Mycobacterium abscessus infection of the calcaneus. The process of diagnosis and treatment is described. CONCLUSION: Although rare, chronic heel pain can be caused by an atypical mycobacterial infection of the calcaneus. Because of its indolent clinical course, misdiagnosis is not uncommon with calcaneal osteomyelitis. Physicians should note that this rare infection should be considered in patients with refractory heel pain.

Nasopharyngeal actinomycosis on 18F-fluorodeoxyglucose positron emission tomography/computed tomography: A case report.

Actinomycosis is a chronic disease characterized by slow progression, abscess formation, tissue fibrosis and draining sinuses. Occurrence originating from the nasopharynx is extremely low. The present study described the case of a 46-year-old otherwise healthy female, with no remarkable history of mucosal injury or teeth rottenness, who presented with an asymptomatic nasopharyngeal mass that was detected incidentally by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. A nasopharyngoscopy revealed an unclear demarcated granular mass. The patient then underwent a biopsy. Based on the obtained clinical images, microbiological results and histological findings, a diagnosis of actinomycosis was established. The patient experienced an uneventful eradication of the disease after two months of oral antibiotic treatment with amoxicillin. In conclusion, these findings indicate that actinomycosis should be included in the differential diagnosis of nasopharyngeal neoplasms.

Small bowel cavernous hemangioma complicated with intussusception: report of an extremely rare case and review of literature.

Cavernous hemangioma of the small intestine is a rare disease in adult patients. Intussusception caused by small bowel hemangioma is extremely rare. We report a 20-year-old female presenting with lower abdominal pain and post-prandial bloating. Laboratory studies showed leukocytosis with left shifting and prominent anemia. Computed tomography of the abdomen revealed small bowel intussusception with bowel ischemia. Segmental resection of the intussuscepted jejunum was performed, and the diagnosis of cavernous hemangioma causing intussusception and anemia simultaneously was made.

Ciliated muconodular papillary tumor of the lung: a newly defined peripheral pulmonary tumor with conspicuous mucin pool mimicking colloid adenocarcinoma: a case report and review of literature.

We report the case of a 68-year-old man with a newly defined rare entity of a peripheral pulmonary tumor, consisting of a nodular papillary lesion with papillary structures containing ciliated columnar and goblet cells, as well as floating tumor cells in the mucin pool. The conspicuous mucin pool was observed to be mimicking colloid adenocarcinoma in a low-power view, particularly in a frozen section slide. We originally reported it as an adenocarcinoma during intraoperative consultation. Immunohistochemically, the tumor cells exhibited a similar immunophenotype to pulmonary adenocarcinoma, except for the presence of focal ciliated and basaloid cells, which we found using CK5/6 and P63 immunostaining. No KRAS or EGFR mutation was found. We revised the diagnosis to that of a ciliated muconodular papillary tumor (CMPT). Four years after a wedge resection, the patient remained free of tumors. Although the malignant potential of CMPT cannot be ignored, a wedge resection with a safe margin might be a treatment option for CMPT patients.