CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling.

Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab-resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti-HER2 therapies.

Multicenter retrospective analysis of the clinicopathologic features of monomorphic epitheliotropic intestinal T-cell lymphoma.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a provisional entity in the 2017 World Health Organization classifications. To further elucidate the clinicopathologic features of this new disease, we carried out a retrospective, multicenter analysis of 42 patients with MEITL. The median age of the patients was 59 years (range, 20-84 years), and 27 patients (64 %) were male. Thirty-two patients (76 %) were Ann-Arbor stages I-II and 28 (67 %) were Lugano stages I-II1&2. The most frequent site of involvement was the jejunum (N = 21). Most cases expressed CD8 (79 %) and CD56 (95 %) and did not express CD30 (5 %) or EBER (0 %). The median progression-free survival was 6.9 months (95 % CI 4.3-9.6); the median OS was 14.8 months (2.4-27.2). Thirty-two patients (76 %) underwent surgery and 37 (88 %) received chemotherapy. A complete response (CR) rate was 38 %. Sixteen patients had undergone autologous stem cell transplantation (ASCT). Relapse or progression was documented in 24 cases, most frequently in the primary site (N = 23). Four cases showed central nervous system relapse. Age over 55 years, poor performance scale, advanced Lugano stage (IIE-IV), not achieving CR, and not receiving ASCT were associated with inferior OS. While the optimal management of MEITL remains undetermined, achieving CR and consolidative ASCT seem essential. As CHOP might be insufficient for achieving CR, more efficient combinations should be investigated. Additionally, considering the frequent local failure and CNS relapse, novel therapeutic approaches are required to improve survival.

Long-Term Outcomes After Metal-on-Metal Total Hip Arthroplasty With a 28-mm Head: A 17- to 23-Year Follow-Up Study of a Previous Report.

BACKGROUND: Second-generation, metal-on-metal total hip arthroplasty (MoM THA) using a 28-mm head has shown favorable results compared with large head MoM THA. The purpose of this study is to evaluate the long-term outcomes of cementless primary MoM THA with a 28-mm head and the incidence of osteolysis using computed tomography. METHODS: A total of 92 patients (53 men and 39 women) who underwent primary cementless MoM THA (114 hips) with a 28-mm head were enrolled in this study. Their mean age was 46.2 years at the time of surgery. The mean follow-up duration was 20 years. The Harris hip score, presence of thigh or groin pain, radiographic results, presence of peri-implant osteolysis, histologic analysis, and Kaplan-Meier survival curves were evaluated. RESULTS: The mean preoperative Harris hip score of 50.5 improved to 85.1 at the final follow-up. Eight patients (8 hips) experienced groin pain, but none had thigh pain. Twelve revisions (6.2%) were performed including 10 hips for aseptic loosening with osteolysis and 2 hips for periprosthetic fracture around the stem. At 23 years, 91% of patients were free from revision of the acetabular component due to aseptic loosening and 90.1% were free from revision of both femoral and acetabular components due to any reason. Osteolysis was identified around the cup in 12 cases (10.5%) and around the stem in 7 cases (6.1%). CONCLUSION: MoM THA with a 28-mm head showed a relatively low rate of aseptic implant loosening at a mean follow-up of 20 years.

Expression Pattern of Smad4/GATA3 as a Predictor of Survival in Invasive Ductal Carcinoma of the Breast.

BACKGROUND: Smad4 and GATA3 proteins are known prognostic markers in various cancers. Smad4 is a mediator linked to both tumour suppression and progression. GATA3 is a regulator of development and morphogenesis of the mammary gland. We assessed and compared the predictive performance of Smad4 and GATA3 for clinical outcomes in patients with breast cancer. METHODS: The combined expression pattern based on Smad4+/- and GATA3+/- was evaluated by immunostaining using breast cancer tissue microarray, and the relationships between protein expression and clinicopathological variables were analysed. RESULTS: Smad4 expression was only associated with an ill-defined tumour border, whereas GATA3 was associated with several good prognostic factors. On analysis of combined markers, there was a significant difference in the expression of fascin (an important factor for cancer invasiveness) between the Smad4+/GATA3- and Smad4-/GATA3+ groups. Smad4+/GATA3- was correlated with worse clinicopathological parameters, relapse-free survival (RFS), and overall survival (OS), compared to Smad4-/GATA3+. CONCLUSION: Combined markers of Smad4/GATA3 showed a superior performance compared to single markers for predicting RFS and OS in patients with breast cancer.

Invasion Depth Measured in Millimeters is a Predictor of Survival in Patients with Distal Bile Duct Cancer: Decision Tree Approach.

BACKGROUND: AJCC staging system is unreliable for predicting survival in distal bile duct (DBD) cancer patients, due to inter-observer variation. Measured depth of invasion (DOI) is suggested to be more accurate to predict patients' clinical outcome in extra-hepatic cholangiocarcinomas, but its significance in DBD cancer and cutoff values are still debatable. This study aimed to identify the optimal cutoff value of DOI in relation to prognosis in DBD cancer patients. METHODS: Data of 179 patients with DBD adenocarcinoma treated in three institutions were investigated. Under microscopic review, DOI was measured. The relationships between the clinicopathological parameters and the groups based on DOI (≤3; 3-10; >10 mm) were evaluated, and the survival times of each group based on DOI and T classification were compared. RESULTS: Deeply invading tumors exhibited a greater tendency toward the infiltrative type, high histological grade, AJCC stage, and pancreatic, duodenal, lymphovascular and perineural invasion. The measured DOI was significantly correlated with worse relapse-free and overall survival (all p < 0.05). In multivariate analyses, the DOI remained as one of the prognostic factors (all p < 0.05), while T classification was not a significant prognostic factor. The new prognostic models (low, intermediate, and high risk) that applied DOI and nodal metastasis showed significant difference in recurrence and survival rate (all p < 0.05). CONCLUSIONS: On the basis of the proposed cutoff value, the DOI could be clear and meaningful, overcoming the vagueness of the T classification for predicting clinical outcomes in patients with DBD carcinoma.

Comparative analysis of the expression of E-cadherin, ß-catenin, and ß1 integrin in congenital and acquired cholesteatoma.

E-cadherin, ß-catenin, and ß1 integrin are important cell adhesion molecules to maintain epithelial structure and function. We investigated the expression of these cell adhesion molecules in cholesteatomas to understand the role of cell-cell and cell-extracellular matrix interaction in cholesteatomas. An immunohistochemical investigation was carried out on 35 cholesteatoma tissue samples (14 congenital, 21 acquired cholesteatomas) and 10 normal retroauricular skin (RAS) tissues which are obtained during middle ear surgery. The expression rate was measured to find out differences between retroauricular skin and cholesteatoma, as well as between congenital and acquired cholesteatoma. E-cadherin expression rate was significantly lower in the cholesteatoma (spinous layer 88.7 ± 17.9 %, granular layer 54.6 ± 22.6 %) than in the RAS (100 %, 74.4 ± 7.4 %) and in the acquired (83.3 ± 19.4 %, 48.1 ± 22.9 %) than in the congenital (96.7 ± 12.0 %, 64.4 ± 18.8 %). ß-catenin expression rate was significantly lower in the cholesteatoma (spinous layer 84.1 ± 17.2 %, granular layer 28.7 ± 30.8 %) than in the RAS (100 %, 75.9 ± 6.1 %) and in the acquired (78.1 ± 17.0 %, 17.1 ± 22.3 %) than in the congenital (93.2 ± 13.5 %, 46.1 ± 34.2 %). The expression pattern of ß-catenin is similar to that of E-cadherin. In ß1 integrin, there was no significant difference of the expression rate between RAS and cholesteatoma, as well as between congenital and acquired cholesteatoma. In conclusion, the expression of E-cadherin and ß-catenin is reduced in cholesteatoma, and the reduction is more pronounced in acquired cholesteatoma than in congenital cholesteatoma. Acquired cholesteatomas showed more aggressive characteristics than congenital cholesteatomas in terms of cell-cell adhesion.

Increased expression of forkhead box M1 is associated with aggressive phenotype and poor prognosis in estrogen receptor-positive breast cancer.

Fox transcription factors play a critical role in the regulation of a variety of biological processes. While FoxM1 behaves like the oncogenic transcription factor, FoxO3a is known as a tumor suppressor by inhibiting FoxM1. This study aimed to investigate the clinicopathological significance of FoxM1 and FoxO3a expression in breast cancer. Expression of FoxM1 and FoxO3a were analyzed by immunohistochemical staining on tissue microarray sections from 236 breast cancer patients, and correlated with various clinicopathological characteristics. Overexpression of FoxM1 correlated with adverse clinicopathological features, such as larger tumor size, lymph node metastasis, advanced tumor stage, and lymphovascular invasion. The Kaplan-Meier survival curves revealed no prognostic significance of FoxM1 expression. However, in subgroup analyses with patients of estrogen receptor (ER) positive breast cancers, FoxM1 overexpression associated with poor disease free and overall survival. No association was found between FoxO3a and FoxM1 expression. Regarding clinicopathological variables, the only association between histologic grade and FoxO3a was observed. In conclusion, FoxM1 overexpression was significantly associated with aggressive phenotypes and poor prognosis of ER-positive breast cancer. These findings suggest the possible role of FoxM1 as a prognostic biomarker and putative target of anti-cancer therapy.

Pathological Predictors for Defining a Therapeutic Strategy for Early Colon Cancer after Endoscopic Resection: Multicenter Retrospective Analysis from Surgically Resected Specimens.

BACKGROUND/AIMS: For the possibility of regional lymph node metastasis (LNM), early colon cancer (ECC) is a boundary lesion between endoscopic resection and surgery. The aim of study is to clarify risk factors for LNM and to determine therapeutic strategy after endoscopic resection in patients with ECC. METHODOLOGY: The histopathology of patients with ECC underwent surgery with LN dissection in 8 university hospitals were reviewed by experienced pathologist blinded to LN status. RESULTS: In total, 370 patients (107 with mucosal cancer, 263 with submucosal invasive colorectal carcinoma [SICC]) were enrolled. Excluding mucosal cancer, the LNM rate was 11.8% (31/263, including 15.4% [8/52] with pedunculated SICC [P-SICC] and 10.9% [23/211] with non-pedunculated SICC [NP-SICC]). Multivariate analysis showed that tumor sprouting (P < 0.001; odds ratio [OR], 8.83; 95% confidence interval [CI], 3.04-25.69), submucosal invasion depth (SM depth) > 2000 µm (P = 0.024; OR, 3.68; 95% CI, 1.19-11.37), and lymphatic invasion (P = 0.022; OR, 3.48; 95% CI, 1.19-10.13) were related to LNM. All LNMs with SM depth < 2000 µm showed tumor sprouting without lymphatic invasion. CONCLUSIONS: Significant risk factors for predicting LNM in patients with SICC were tumor sprouting, SM depth > 2000 µm, and lymphatic invasion.

Diagnostic and prognostic relevance of MMP-11 expression in the stromal fibroblast-like cells adjacent to invasive ductal carcinoma of the breast.

BACKGROUND: Matrix metalloproteinase 11 (MMP-11) is a matrix degrading enzyme known to be involved in the remodeling of extracellular matrix proteins. This enzyme recently has been reported to play a key role in tumor progression and results in poor clinical outcomes for several different types of tumors. METHODS: A total of 192 patients diagnosed with invasive ductal carcinoma between 2000 and 2005 were included in this study. MMP-11 expression in tumors and stromal fibroblast-like cells was analyzed by immunohistochemical staining on a tissue microarray. Subsequently, evaluation of the associations between MMP-11 expression and clinicopathological characteristics was performed. RESULTS: MMP-11 expression of stromal fibroblast-like cells was correlated with prognostic factors, including tumor size, metastasis, histological grade, central tumor fibrosis, p53 expression, and luminal A subtype and was linked to therapeutic markers, such as ER and HER2 (all p < 0.05). There was a significant relationship between worse overall survival and MMP-11 expression in both tumors and stromal fibroblast-like cells (all p < 0.05). In multivariate analysis, MMP-11 expression of stromal fibroblast-like cells was still significantly associated with poor prognosis (p = 0.043). CONCLUSIONS: MMP-11 expression was significantly related to clinicopathological parameters, which may be essential to the prediction of disease outcome in patients with invasive ductal carcinoma of the breast.

Expression of insulin-like growth factor 1 and insulin-like growth factor 1 receptor is associated with the favorable clinicopathologic parameters in small intestinal carcinomas.

OBJECTIVE: The insulin-like growth factor (IGF) system has been known to play a critical role in tumor development and progression in many human cancers. However, the role of the IGF system in small intestinal carcinoma (SIC) has not been studied yet. METHODS: We evaluated the expression of IGF1 and IGF1 receptor (IFG1R) in a total of 194 cases of SIC. RESULTS: IGF1 expression was associated with well/moderate differentiation, better survival, lower pT, lower stage and no lymph node metastasis. IGF1R was more diffusely and strongly expressed in tumors with lower pT and lower stage. CONCLUSIONS: IGF1 and IGF1R expression is associated with favorable clinicopathologic parameters and may involve early carcinogenesis of SICs. Target therapy for the IGF1R signaling pathway may not have a major therapeutic role in treating SIC.

Does submucosal fibrosis affect the results of endoscopic submucosal dissection of early gastric tumors?

BACKGROUND: Endoscopic submucosal dissection (ESD) is an effective treatment of early gastric tumors, but submucosal fibrosis can be an obstacle to successful ESD. OBJECTIVE: To examine the association between endoscopic and pathologic factors and submucosal fibrosis in early gastric tumors, and to measure the association between degree of submucosal fibrosis and outcomes of ESD. DESIGN: A retrospective study. SETTING: An academic medical center. PATIENTS: From November 2006 to April 2011, 161 patients with 167 early gastric tumors treated by ESD. INTERVENTION: ESD. MAIN OUTCOME MEASUREMENTS: Endoscopic and pathologic factors related to submucosal fibrosis. Procedure time, en bloc resection rate, and complications according to degree of submucosal fibrosis. RESULTS: In univariate analysis, the presence of endoscopic submucosal fibrosis was significantly related to tumor size, location, ulceration, histologic findings, and submucosal invasion. Multivariate analysis for these factors showed that endoscopic submucosal fibrosis was independently associated with lesions in tumor size greater than 30 mm, in the proximal portion of the stomach, and more common in adenocarcinomas than in adenomas. After correction for multiple testing, only the middle of the stomach as a locational risk factor retains statistical significance. Also, the more advanced the endoscopic submucosal fibrosis, the longer the time required for ESD (P < .0001). The severity of endoscopic submucosal fibrosis was associated with a lower en bloc resection rate and with abundant immediate bleeding. LIMITATIONS: Retrospective, single-center study. CONCLUSION: Submucosal fibrosis of early gastric tumors is closely related to tumor size, location, ulceration, histologic findings, and submucosal invasion. Moreover, the greater the degree of submucosal fibrosis the longer the time taken for the ESD procedure and the higher the frequency of complications such as perforation and immediate bleeding.

Is use of PPIs related to increased intraepithelial lymphocytes in the colon?

BACKGROUND: The use of proton pump inhibitors (PPIs) is thought to increase the incidence of microscopic colitis (MC), although the exact mechanisms are not fully understood. Increased infiltration of intraepithelial lymphocytes (IELs) is a pathologic finding of MC (including collagenous or lymphocytic colitis). AIMS: We investigated whether PPI use is associated with increased IEL infiltration and inflammation in the lamina propria. METHODS: We retrospectively reviewed the medical records and histological reports of 78 patients receiving PPIs who had no symptoms of diarrhea, and their age- and gender- matched controls. The levels of IELs and inflammation in the lamina propria were assessed independently by two pathologists using H&E and immunohistochemical staining for CD3 and CD8. RESULTS: The IEL count was significantly higher in the PPI group than in controls (12.92 ± 6.27 vs. 8.10 ± 4.21 per 100 epithelial cells, p < 0.001), as was the extent of inflammation (1.74 ± 0.90 vs. 0.86 ± 0.78, p < 0.001). PPI use was associated with increased IEL infiltration in a multivariate analysis (OR, 3.232; 95 % CI, 1.631-6.404, p < 0.001). Within the PPI group, however, the IEL count was not significantly associated with gender, age, type of PPI, or duration of PPI use. CONCLUSIONS: The use of PPIs has a significant association with increased IEL infiltration for subjects without symptoms of diarrhea. This finding suggests that changes such histological alterations seen in the early phage seen in MC possibly represent the stage of the disease even before the onset of symptoms.

Expression of hMLH1, hMSH2 and hMSH6 in small intestinal carcinomas.

BACKGROUND/AIMS: Although primary small intestinal carcinoma (SIC) is morphologically similar to colorectal carcinoma and shares many of the genetic changes of carcinogenesis, little is known about the role of defective mismatch repair (MMR) genes involved in the SIC. The aim of this study is to investigate the role of defective MMR genes and correlation between clinicopathological factors and loss of MMR protein in SIC. METHODOLOGY: A total of 195 SIC cases were collected from 20 institutions in Korea and tissue microarrays (TMA) were made. The loss of expression of hMLH1, hMSH2 and hMSH6 was examined by immunohistochemistry (IHC). RESULTS: The loss of expression of hMLH1, hMSH2 and hMSH6 was identified in 25/193 (13.0%), 25/193 (13%) and 29/195 (15%), respectively. The loss of hMSH2 expression was associated with retroperitoneal seeding. Patients with loss of hMSH6 expression had a tendency to invade deeply and a higher frequency of pancreas invasion. The loss of hMSH6 expression was associated less frequently with peritumoral adenoma. There was no survival difference by MMR protein expression status. CONCLUSIONS: The loss of MMR protein was associated with some distinct clinicopathological features. MMR pathway seems to be major pathway in carcinogenesis of SICs. MMR defect seems to be related with sporadic-microsatellite instability (MSI).

Carcinoid tumors of the extrahepatic biliary tract: report of four cases.

Carcinoid tumors located in the biliary tree are exceedingly rare, accounting for 0.2%-2% of all gastrointestinal carcinoids. This study describes four cases of carcinoid tumors of the extrahepatic biliary tract. Four carcinoid tumors arising in the common bile duct (Case 1, 59-year-old man), gallbladder (Case 2, 49-year-old man; Case 3, 65-year-old man), and ampulla of Vater (Case 4, 52-year-old woman) were studied. All of the cases were misdiagnosed before surgery as proximal bile duct cancer, stomach cancer with liver metastasis, gallbladder cancer, and adenocarcinoma of ampulla of Vater, respectively. The clinicopathological characteristics and clinical course were reviewed. Treatment depends on the location of the tumor and the extent of the disease. Aggressive surgical therapy with a curative intention therefore offers the only chance for cure and has to be considered whenever possible.

Increased VEGF-A in solid type of lung adenocarcinoma reduces the patients' survival.

The histological classification of lung adenocarcinoma includes 5 types: lepidic, acinar, papillary, micropapillary and solid. The complex gene interactions and anticancer immune response of these types are not well known. The aim of this study was to reveal the survival rates, genetic alterations and immune activities of the five histological types and provide treatment strategies. This study reviewed the histological findings of 517 patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database and classified them into five types. We performed gene set enrichment analysis (GSEA) and survival analysis according to the different types. We found six oncogenic gene sets that were higher in lung adenocarcinoma than in normal tissues. In the survival analysis of each type, the acinar type had a favorable prognosis, and the solid subtype had an unfavorable prognosis; however, the survival differences between the other types were not significant. Our study focused on the solid type, which had the poorest prognosis. The solid type was related to adaptive immune resistance associated with elevated CD8 T cells and high CD274 (encoding PD-L1) expression. In the pathway analyses, the solid type was significantly related to high vascular endothelial growth factor (VEGF)-A expression, reflecting tumor angiogenesis. Non-necrosis/low immune response affected by high VEGF-A was associated with worse prognosis. The solid type associated with high VEGF-A expression may contribute to the development of therapeutic strategies for lung adenocarcinoma.

Prognostic Value of LC3B and p62 Expression in Small Intestinal Adenocarcinoma.

Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we assessed the expression of autophagy markers, LC3B and p62, in 171 surgically resected primary SIACs using automated quantitative analysis. Positive LC3B, p62 nuclear (p62Nu), and p62 cytoplasmic (p62Cy) expression was observed in 23 (13.5%), 52 (30.4%), and 43 (25.1%) carcinomas, respectively. LC3B+ expression was correlated with undifferentiated carcinoma (p < 0.001) and high histologic grade (p = 0.029). The combined expression of LC3B and p62Nu (LC3+/p62Nu+) was related to the older age of patients (p = 0.017), undifferentiated carcinoma (p < 0.001), and high grade (p = 0.031). LC3B+ (p = 0.006), p62Cy+ (p = 0.041), or p62Nu+ (p = 0.006) expression were associated with worse survival. In addition, SIAC patients with either LC3B+/p62Nu+ (p = 0.001) or LC3B+/p62Cy+ (p = 0.002) expression had shorter survival times. In multivariate analysis, LC3B expression remained an independent prognostic factor (p = 0.025) for overall survival. In conclusion, autophagy may play a role in the tumorigenesis of SIACs, and LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for SIACs.

Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations.

Recent studies identified germline mutations in HAVCR2 (encoding T-cell immunoglobulin mucin 3) as a genetic factor that predisposes to subcutaneous panniculitis-like T-cell lymphoma (SPTCL). However, the differences between HAVCR2-mutated (HAVCR2MUT) and HAVCR2 wild-type (HAVCR2WT) SPTCLs remain unclear. A nationwide cohort of 53 patients with SPTCL diagnosed at 8 Korean institutions was established. Whole-exome sequencing and RNA-sequencing were performed on 8 patients in the discovery set. In the validation set, targeted gene sequencing or direct sequencing of HAVCR2 was performed. Of 49 patients with available HAVCR2 status, 25 (51.0%) were HAVCR2Y82C. HAVCR2Y82C was associated with younger age (P = .001), development of hemophagocytic lymphohistiocytosis or hemophagocytic lymphohistiocytosis-like systemic illness (P < .001), and short relapse-free survival (RFS) (P = .023). Most mutated genes in SPTCLs were involved in immune responses, epigenetic modifications, and cell signaling. Mutations in UNC13D, PIAS3, and KMT2D were more frequent in HAVCR2WT SPTCLs. At the gene expression level, HAVCR2Y82C SPTCLs were enriched in genes involved in IL6-JAK-STAT3 signaling and in tumor necrosis factor-α signaling via NF-κB. CCR4 was significantly upregulated in HAVCR2WT SPTCLs both at the messenger RNA level and at the protein level. We established a risk stratification system for SPTCL by integrating clinical and histopathological features, including age and HAVCR2 mutation status. This risk stratification system was strongly associated with RFS (P = .031). In conclusion, the HAVCR2Y82C mutation was common in Korean patients with SPTCL and was associated with unique clinicopathological and genetic features. Combining clinicopathological parameters could aid in predicting prognosis for patients with SPTCL.

NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression.

Histone methyltransferase NSD3 is frequently dysregulated in human cancers, yet the epigenetic role of NSD3 during cancer development remains elusive. Here we report that NSD3-induced methylation of H3K36 is crucial for breast tumor initiation and metastasis. In patients with breast cancer, elevated expression of NSD3 was associated with recurrence, distant metastasis, and poor survival. In vivo, NSD3 promoted malignant transformation of mammary epithelial cells, a function comparable to that of HRAS. Furthermore, NSD3 expanded breast cancer-initiating cells and promoted epithelial-mesenchymal transition to trigger tumor invasion and metastasis. Mechanistically, the long isoform (full-length transcript) of NSD3, but not its shorter isoform lacking a catalytic domain, cooperated with EZH2 and RNA polymerase II to stimulate H3K36me2/3-dependent transactivation of genes associated with NOTCH receptor cleavage, leading to nuclear accumulation of NICD and NICD-mediated transcriptional repression of E-cadherin. Furthermore, mice harboring primary and metastatic breast tumors with overexpressed NSD3 showed sensitivity to NOTCH inhibition. Together, our findings uncover the critical epigenetic role of NSD3 in the modulation of NOTCH-dependent breast tumor progression, providing a rationale for targeting the NSD3-NOTCH signaling regulatory axis in aggressive breast cancer. SIGNIFICANCE: This study demonstrates the functional significance of histone methyltransferase NSD3 in epigenetic regulation of breast cancer stemness, EMT, and metastasis, suggesting NSD3 as an actionable therapeutic target in metastatic breast cancer.

Actinomycosis of the pancreas: a case report and review of the literature.

Actinomycosis is a chronic suppurative and granulomatous disease usually caused by Actinomyces israelii. The pathogen produces a characteristic granulomatous inflammatory fibrosis and mass lesion. Abdominal actinomycosis is often difficult to diagnose before operation because of its rarity and chronic disease progression without any characteristic clinical features. In particular, pancreas is very rare location of actinomycosis. The present paper is a report of a case of 55-year-old man with pancreatic actinomycosis presenting as symptoms of pancreatitis. The patient was confirmed by pancreatoduodenectomy for impression of pancreatolith and mass-like lesion of head portion of pancreas. Treatment with operation followed by additional oral penicillin therapy for 3 months was successful. We report a case of pancreatic actinomycosis with a brief review of literature.

Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma.

The clinicopathologic and prognostic significances of tumor budding (TB) and poorly-differentiated clusters (PDC) have not been investigated in small intestinal adenocarcinomas (SIACs). In 236 surgically-resected SIACs, we counted TB (single cells or clusters ≤4 tumor cells) and PDC (clusters ≥5 tumor cells) at the peritumoral-invasive front (p) and in the intratumoral area (i) independently to classify as grade-1 (≤4), grade-2 (5-9), or grade-3 (≥10). Consequently, grades-2 and -3 were considered high-grade. High-pTB, -iTB, -pPDC, and -iPDC were observed in 174 (73.7%), 129 (54.7%), 118 (50.0%), and 85 (36.0%) cases, respectively. High-TB/PDCs were more frequently observed in tumors with high-grade, higher T- and N-categories and stage grouping, and perineural or lymphovascular invasion. Patients with high-TB/PDC had a shorter survival than those with low-TB/PDC. In a multivariate analysis, high-pTB, nonintestinal type, high N-category, retroperitoneal seeding, and microsatellite-stable were worse independent-prognostic predictors. Subgroup analysis demonstrated that patients with high-pTB showed worse survival (median: 42.5 months) than those with low-pTB (133.7 months; p = 0.007) in the lower stage (stages I-II) group. High-TB/PDC, both in peritumoral and intratumoral localizations, were associated with aggressive behaviors in SIACs. High-pTB can be used as an adverse prognostic indicator in SIAC patients, especially when patients are in early disease stages.