Overexpression of the NEK9-EG5 axis is a novel metastatic marker in pathologic stage T3 colon cancer.

NEK9 is a key player in the NEK9-EG5 axis for microtubule polymerization, chromosome alignment, and mitosis. In present study, we investigated the altered expression of the NEK9, EG5 and acetyl-α-tubulin as well as common epithelial-mesenchymal transition (EMT) markers (E-cadherin, vimentin, claudin-1, and ß-catenin) through the immunohistochemistry analysis of 138 patients with pathologic T3 (pT3) stage colon cancers, and evaluated their metastatic potential. NEK9 expression showed an association with distant metastasis (P = 0.032) and was an independent predictive factor for distant metastasis (HR = 3.365, P < 0.001) by multivariate analysis, which was more significant than either the regional nodal metastasis (HR = 2.496, P = 0.007) or lymphovascular invasion (HR = 2.090, P = 0.153). Positive correlations were observed between NEK9 and EG5 or acetyl-α-tubulin (r = 0.236 and P = 0.007; r = 0.181 and P = 0.038, respectively) and concordant overexpression of the NEK9-EG5 axis was further confirmed in colon cancer cell lines. These findings collectively suggest that the overexpression of the NEK9-EG5 axis is present and associated with distant metastasis in colon cancer. These biomarkers might be useful for predicting metastatic potential among the patients with pT3 colon cancers.

EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7.

EML4-ALK is an oncogenic fusion present in ∼5% of non-small cell lung cancers. However, alternative breakpoints in the EML4 gene lead to distinct variants of EML4-ALK with different patient outcomes. Here, we show that, in cell models, EML4-ALK variant 3 (V3), which is linked to accelerated metastatic spread, causes microtubule stabilization, formation of extended cytoplasmic protrusions and increased cell migration. EML4-ALK V3 also recruits the NEK9 and NEK7 kinases to microtubules via the N-terminal EML4 microtubule-binding region. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates migration in a microtubule-dependent manner that requires the downstream kinase NEK7 but does not require ALK activity. Strikingly, elevated NEK9 expression is associated with reduced progression-free survival in EML4-ALK patients. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through NEK9 and NEK7, leading to increased cell migration. This represents a novel actionable pathway that could drive metastatic disease progression in EML4-ALK lung cancer.

Characterization of Hepatocellular Carcinoma Patients with FGF19 Amplification Assessed by Fluorescence in situ Hybridization: A Large Cohort Study.

BACKGROUND: FGF19 amplification is a relatively novel type of genetic aberration that has been proposed to be a driver of hepatocarcinogenesis. Selective inhibitors of FGFR4, a receptor of FGF19, have been developed as targeted therapies for hepatocellular carcinoma (HCC). Despite the role of FGF19 in mediating HCC progression, the clinicopathological characterization of patients exhibiting FGF19 amplification remains unclear. Immunohistochemical staining is the simplest and most widely used method of identifying aberrations in the FGF19 gene, although its specificity is very low. METHODS: This study investigated the prognostic significance of FGF19 amplification in a large cohort of 989 HCC patients using fluorescence in situ hybridization (FISH), which has a high degree of specificity. In addition, FISH data from formalin-fixed, paraffin-embedded sections were compared with copy number variation (CNV) data obtained from fresh frozen sections to validate the use of FISH as a diagnostic tool. RESULTS: FGF19 amplifications were detected by FISH in 51 (5.15%) of the 989 patients, and were independently associated with poor survival and a higher risk of tumor recurrence, as well as with poor prognostic factors such as a high α-fetoprotein level, hepatitis B or C virus infection, a large tumor size, microvascular invasion, and necrosis. In addition, FGF19 amplification was associated with TP53 mutation, and was mutually exclusive with CTNNB1 mutation. The results of the FISH and CNV analyses exhibited a significant concordance rate of 96% (κ = 0.618, p < 0.001). CONCLUSIONS: These data indicate that FGF19 amplification represents a unique molecular subtype associated with poor prognostic characteristics, which supports the hypothesis that the FGF19-FGFR4 signaling pathway plays an important role in hepatocarcinogenesis. We have also demonstrated that FISH is a viable alternative to CNV analysis, offering a number of advantages in the clinical setting.

Poor prognosis in Epstein-Barr virus-negative gastric cancer with lymphoid stroma is associated with immune phenotype.

BACKGROUND: Gastric cancer with lymphoid stroma (GCLS) is pathologically characterized by poorly developed tubular structures with a prominent lymphocytic infiltration. Its clinical and prognostic features differ in patients positive and negative for Epstein-Barr virus (EBV) infection. This study analyzed the expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and the density of tumor-infiltrating lymphocytes (TILs) including CD3+ and CD8+ T cells, as well as their prognostic significance in patients with GCLS. METHODS: The study included 58 patients with GCLS (29 EBV+ and 29 EBV-) who underwent curative resection. Expression of CD3, CD8, PD-1, and PD-L1 in tumor cells and TILs was analyzed using a quantitative multispectral imaging system (Opal™), with these results validated by immuno-histochemical assays for PD-L1 on whole slide sections. RESULTS: The proportion of tumors overexpressing PD-L1 (31.0 vs. 0%, P = 0.002), TIL density (4548 vs. 2631/mm2, P < 0.001), and intra-tumoral CD8+ T-cell density (2650 vs. 1060/mm2, P < 0.001) were significantly higher in EBV+ than in EBV- GCLS. In addition, CD8+/CD3+ T-cell ratio was higher in EBV+ than in EBV- GCLS (55.3 vs. 35.8%, P < 0.001). Lower TIL density, defined as < 1350/mm2, was a significant negative factor of survival. CONCLUSIONS: Despite histopathological similarity, quantitative multispectral imaging revealed differences in the tumor immune micro-environment between EBV+ and EBV- GCLS, indicating that the underlying pathogenesis differs in these two disease entities. TIL density may be a prognostic marker in patients with GCLS.

Hepatocellular Carcinoma Arising in a Huge Hepatocellular Adenoma with Bone Marrow Metaplasia.

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 ß-catenin nuclear positivity and bone marrow metaplasia that contained hematopoietic cells. This case was unique because malignant transformation, inflammatory type HCA, ß-catenin nuclear staining, and bone marrow metaplasia were simultaneously observed. Additionally, it should be noted that a large HCA with ß-catenin activation can undergo malignant transformation and should be surgically resected in a timely manner.

Protein Phosphatase Magnesium-Dependent 1δ (PPM1D) Expression as a Prognostic Marker in Adult Supratentorial Diffuse Astrocytic and Oligodendroglial Tumors.

BACKGROUND: Protein phosphatase magnesium-dependent 1δ (PPM1D) is a p53-induced serine/threonine phosphatase, which is overexpressed in various human cancers. A recent study reported that a mutation in the PPM1D gene is associated with poor prognosis in brainstem gliomas. In this study, we evaluated the utility of PPM1D as a prognostic biomarker of adult supratentorial diffuse astrocytic and oligodendroglial tumors. METHODS: To investigate PPM1D protein expression, mRNA expression, and copy number changes, immunohistochemistry, RNAscope in situ hybridization, and fluorescence in situ hybridization were performed in 84 adult supratentorial diffuse gliomas. We further analyzed clinical characteristics and overall survival (OS) according to PPM1D protein expression, and examined its correlation with other glioma biomarkers such as isocitrate dehydrogenase (IDH) mutation, and p53 expression. RESULTS: Forty-six cases (54.8%) were PPM1D-positive. PPM1D expression levels were significantly correlated with PPM1D transcript levels (p= .035), but marginally with PPM1D gene amplification (p=.079). Patients with high-grade gliomas showed a higher frequency of PPM1D expression than those with low-grade gliomas (p <.001). Multivariate analysis demonstrated that PPM1D expression (hazard ratio [HR], 2.58; p=.032), age over 60 years (HR, 2.55; p=.018), and IDH1 mutation (HR, 0.18; p=.002) were significantly independent prognostic factors; p53 expression had no prognostic significance (p=.986). The patients with tumor expressing PPM1D showed a shorter OS (p=.003). Moreover, patients with tumor harboring wild-type IDH1 and PPM1D expression had the worst OS (p<.001). CONCLUSIONS: Our data suggest that a subset of gliomas express PPM1D; PPM1D expression is a significant marker of poor prognosis in adult supratentorial diffuse astrocytic and oligodendroglial tumors.

Low-Grade Papillary Schneiderian Carcinoma: A Case Report.

The nasal cavity and paranasal sinuses are covered with ciliated respiratory mucosa of ectodermal origin, known as Schneiderian epithelium, which can give rise to different types of sinonasal carcinomas. A 42-year-old woman with a history of nasal polypectomy 3 years previously presented with nasal obstruction and rhinorrhea. She was found to have a papillary mass involving the left nasal cavity, and the left maxillary and ethmoidal sinuses by radiologic examination. She underwent endonasal resection under the diagnosis of oncocytic papilloma. The resected specimen showed exuberant invasive growth of papillary or inverted architectures of epithelial cells. The neoplastic cells were very bland, showing a round to polygonal shape, low nuclear-to-cytoplasmic ratio, abundant oncocytic cytoplasm, uniform nuclei, indistinct nucleoli, and scarce mitosis. The overall features were identical to those of a recent report of a low-grade papillary Schneiderian carcinoma. The main differential diagnosis is Schneiderian papilloma, and awareness of this novel entity is important for its proper treatment.

Diverse Immunoprofile of Ductal Adenocarcinoma of the Prostate with an Emphasis on the Prognostic Factors.

BACKGROUND: Ductal adenocarcinoma (DAC) of the prostate is an uncommon histologic subtype whose prognostic factors and immunoprofile have not been fully defined. METHODS: To define its prognostic factors and immunoprofile, the clinicopathological features, including biochemical recurrence (BCR), of 61 cases of DAC were analyzed. Immunohistochemistry was performed on tissue microarray constructs to assess the expression of prostate cancer-related and mammalian target of rapamycin (mTOR) signaling-related proteins. RESULTS: During the median follow-up period of 19.3 months, BCR occurred in 26 cases (42.6%). DAC demonstrated a wide expression range of prostate cancer-related proteins, including nine cases (14.8%) that were totally negative for pan-cytokeratin (PanCK) immunostaining. The mTOR signaling-related proteins also showed diverse expression. On univariate analysis, BCR was associated with high preoperative serum levels of prostate-specific antigen (PSA), large tumor volume, predominant ductal component, high Gleason score (GS), comedo-necrosis, high tumor stage (pT), lymphovascular invasion, and positive surgical margin. High expressions of phospho-mTOR (p-mTOR) as well as low expressions of PSA, phospho-S6 ribosomal protein (pS6) and PanCK were associated with BCR. On multivariable analysis, GS, pT, and immunohistochemical expressions of PanCK and p-mTOR remained independent prognostic factors for BCR. CONCLUSIONS: These results suggest GS, pT, and immunohistochemical expressions of PanCK and p-mTOR as independent prognostic factors for BCR in DAC. Since DAC showed diverse expression of prostate cancer-related proteins, this should be recognized in interpreting the immunoprofile of DAC. The diverse expression of mTOR-related proteins implicates their potential utility as predictive markers for mTOR targeted therapy.

Acute myocardial infarction caused by coronary embolism from Aspergillus endocarditis.

Although the primary cause of acute coronary syndrome is atherosclerotic disease, it is important to include other causes of acute myocardial infarction. This report describes the case of a 53-year-old man with acute myeloid leukemia, who was referred to our cardiology department for treatment of acute myocardial infarction with ST segment elevation on an electrocardiogram. Portable echocardiography showed large areas of vegetation on the anterior mitral leaflet, while coronary angiography demonstrated the total occlusion of the left anterior descending artery. A histologic examination of the embolectomy specimen confirmed the presence of Aspergillus fungal thrombi. This report highlights a rare case of fatal Aspergillus endocarditis with myocardial infarction due to embolism in an immunosuppressed patient.