Characteristics of human parainfluenza virus type 4 infection in hospitalized children in Korea.

BACKGROUND: The characteristics of human parainfluenza virus type 4 (hPIV4) infection are not thoroughly understood. We therefore clarified the characteristics of hPIV4 in Korea. METHOD: From January 2013 to December 2017, children admitted with respiratory tract infection at the Department of Pediatrics in Chung-Ang University Hospital were enrolled in the study. Nasopharyngeal aspirate specimens were obtained from patients and tested for hPIV types by multiplex reverse transcription polymerase chain reaction. We retrospectively reviewed subject medical records, focusing on epidemiological and clinical characteristics. RESULTS: Of the 12 423 NPA specimens, 8,406 were positive by multiplex reverse transcription polymerase chain reaction for nine respiratory viruses, and 1,018 were positive for one of the four types of hPIV: 1,018 specimens led to the detection of 1,029 hPIVs; 3ss (31.3%) were positive for hPIV1, 120 (11.7%) were positive for hPIV2, 356 (34.6%) were positive for hPIV3, and 231 (22.4%) were positive for hPIV4. Of the hPIV-positive patients, the mean age was 2.3 years (range, 0.1-12.7 years), 225 (97.4%) had no underlying disease, and 178 (77.1%) had a fever with a duration of 4.1 ± 2.3 days and a peak temperature of 39.0 ± 0.7 ℃. The most common diagnosis in hPIV4 infection was pneumonia (44.2%), followed by bronchiolitis (26.0%) and upper respiratory tract infection (24.3%). Only 2.2% of patients were diagnosed with croup. Although the most prevalent overall type of hPIV was hPIV3, hPIV4 generally caused acute respiratory tract infection in summer and early fall in an irregular annual pattern. CONCLUSIONS: Human parainfluenza virus type 4 is an important common pathogen of respiratory tract infections in pediatric patients in Korea.

Voxel-Based Dosimetry of Iron Oxide Nanoparticle-Conjugated 177Lu-Labeled Folic Acid Using SPECT/CT Imaging of Mice.

Several radiolabeled folic acid conjugates have been developed for targeted imaging and therapy. However, the therapeutic concept with radiolabeled folate conjugates has not yet been applied to clinical applications owing to the high renal absorbed dose. The effectiveness of targeted radionuclide therapy (TRT) depends primarily on the absorbed dose rate and on the total absorbed dose delivered to the tumor and to normal tissue. Owing to various limitations associated with organ level dosimetry, voxel-based dosimetry has become essential for the assessment of a more  accurate absorbed dose during TRT. In this study, we synthesized iron oxide nanoparticle (IONP)-conjugated radiolabeled folate (177Lu-IONP-Folate) and performed voxel-based dosimetry using SPECT/CT images of normal mice through direct Geant4 application for emission tomography (GATE) Monte Carlo (MC) simulation. We also prepared 177Lu-Folate and 177Lu-IONPs for the comparison of absorbed doses with that of 177Lu-IONP-Folate. In addition, we calculated the mean absorbed dose at the organ-level using the medical internal radiation dose (MIRD) schema. The radioactivities of all three radiotracers were mainly accumulated in the liver and kidneys immediately after injection. For the kidneys, the voxel-based absorbed doses obtained with 177Lu-IONP-Folate, 177Lu-Folate, and 177Lu-IONPs were 1.01 ± 0.17, 2.46 ± 0.50, and 0.52 ± 0.08 Gy/MBq, respectively. The renal absorbed dose decreased significantly (∼half) when 177Lu-IONP-Folate was used compared with when the 177Lu-Folate only was used. The mean absorbed dose values obtained at organ-level using the MIRD schema were comparable to voxel-based absorbed doses estimated with GATE MC. The voxel-based absorbed dose values obtained in this study of individualized activity show that the renal absorbed dose could be reduced to almost half with 177Lu-IONP-Folate. Therefore, 177Lu-IONP-Folate could be clinically applicable in the TRT of folate receptor-positive cancers in a personalized manner when using the voxel-based dosimetry method.

Complete Histologic Regression of Endometrioid Adenocarcinoma on Endometrial Biopsy After Progestin Treatment Does Not Guarantee the Regression of an Invasive Carcinoma Within the Myometrium.

Currently, the indications for progestin therapy are limited to endometrioid adenocarcinoma that are International Federation of Gynecology and Obstetrics (FIGO) grade 1, FIGO stage IA, and confined to the endometrium. However, there have been attempts to broaden the indications of progestin therapy to patients with higher FIGO grades and/or with superficial myometrial invasion. We experienced a case with myoinvasive endometrioid adenocarcinoma treated with oral progestin, whose follow-up endometrial curettage specimen showed an apparent complete histologic regression; however, the final hysterectomy specimen disclosed myoinvasive endometrioid adenocarcinoma within the superficial myometrium, with absence of residual tumor in the endometrium. We describe this case to demonstrate that complete histologic regression of the endometrial lesion in a follow-up curettage specimen after progestin treatment does not guarantee histologic regression of the carcinoma within the myometrium. Our case indicates that current indications for progestin treatment should not be broadened to patients with superficial myometrial invasion.

Dishevelled segment polarity protein 3 (DVL3): a novel and easily applicable recurrence predictor in localised prostate adenocarcinoma.

OBJECTIVE: To identify new biomarkers for biochemical recurrence (BCR) of prostate adenocarcinoma. PATIENTS AND METHODS: Clinical information of 500 patients with prostate adenocarcinoma and their 152 RNA-sequencing and protein-array data from The Cancer Genome Atlas (TCGA) were separated into a discovery set and a validation set. Each dataset was analysed according to the Gleason grade groups reflecting BCR. The results obtained from the analysis using TCGA dataset were confirmed by immunohistochemistry analyses of a confirmation cohort composed of 395 patients with localised prostate adenocarcinoma. RESULTS: TCGA discovery set was subgrouped into lower- and higher-risk groups for recurrence-free survival (RFS) (P < 0.001). Cyclin B1 (CCNB1), dishevelled segment polarity protein 3 (DVL3), paxillin (PXN), RAF1, transferrin, X-ray repair cross complementing 5 (XRCC5) and BIM had lower expression in the lower-risk group than that in the higher-risk group (all, P < 0.05). In TCGA validation set, CCNB1, DVL3, transferrin, XRCC5 and BIM were also differently expressed between the two groups. Immunohistochemically, DVL3 positivity was associated with high prostate-specific antigen (PSA) levels, resection margin involvement, and BCR (all, P < 0.05). A high Gleason score indicated a marginal relationship (P = 0.055). BIM positivity was related to high PSA levels, lymphovascular invasion, and BCR (all, P < 0.05). Both DVL3 positivity (P = 0.010) and BIM positivity (P = 0.024) were associated with shorter RFS, but statistical significance was lost when the multivariate Cox regression model included all patients. In the lower-risk group, the multivariate Cox model confirmed that DVL3 was an independent predictor for poor RFS (hazard ratio 1.80, P = 0.040), and the concordance index (C-index) was 0.805. CONCLUSIONS: DVL3 and BIM were expressed in patients with a higher risk of BCR. DVL3 may be a novel and easily applicable recurrence predictor of localised prostate adenocarcinoma.

Association between Morphological Patterns of Myometrial Invasion and Cancer Stem Cell Markers in Endometrial Endometrioid Carcinoma.

In endometrial endometrioid adenocarcinoma (EEC), the depth of myometrial invasion (MI) is an important parameter for determining whether additional treatment is warranted. The present study investigated the association between MI patterns, cancer stem cell (CSC) phenotypes, and their clinicopathological significance in EEC. A total of 73 cases of EEC with MI were examined in this study. Haematoxylin and eosin-stained tissue specimens were analysed for MI pattern, which was categorised as infiltrating; expansile; adenomyosis (AM)-like; or microcystic, elongated, and fragmented (MELF)-type. The expression of CSC markers such as cluster of differentiation (CD)44, CD133, and Nanog1, as well as oestrogen receptor (ER) and progesterone receptor (PR) was examined by immunohistochemistry. Clinicopathological features including age, DOI, MI pattern, LVI, lymph node (LN) metastasis, disease progression, and survival outcome were recorded. Most examined cases (45/73) were International Federation of Gynecology and Obstetrics (FIGO) stage I. MI showed infiltrating (49.3%), AM-like (26.3%), MELF (15.1%), and expansile (9.6%) patterns. Tumours with the infiltrating pattern were associated with high FIGO grade (P = 0.002), reduced ER and PR, and CD44 expression (P = 0.014, 0.026, and 0.030, respectively); those with a MELF pattern showed LN metastasis (P < 0.001), lymphovascular invasion (P = 0.011), and reduced ER, CD44, and CD133 expression (P = 0.036, 0.006, and 0.016, respectively). EEC with infiltrating/MELF patterns of MI is associated with worse prognosis. These results suggest that CSC expression profiles are an unfavourable indicator of EEC.

Tumor Budding is a Valuable Diagnostic Parameter in Prediction of Disease Progression of Endometrial Endometrioid Carcinoma.

Recently, tumor budding (TB) found at the invasive margin has been related to lymph node involvement (LNI), local recurrence, and poor prognosis in various cancers. We assessed the presence of TB in endometrial endometrioid carcinoma (EEC), and examined the immunohistochemical (IHC) profiles to define its clinicopathological significance. Ninety-six EECs were obtained from 2008 to 2013. During the follow-up, ten patients experienced disease progression; of these, three patients succumbed to the disease. All hematoxylin and eosin-stained slides were scrutinized for the presence of TB. IHC stainings for estrogen receptor (ER), progesterone receptor (PR), ß-catenin, and E-cadherin were performed. All cases were grouped as FIGO grade (G) 1 (47.9%), G2 (29.2%), and G3 (22.9%). The distribution for depth of invasion (DOI) was 68.5% with a DOI of less than half and 31.5% with a DOI of more than half. Myometrial invasion was characterized as infiltrating pattern (52.1%), adenomyosis-like (20.8%), microcystic, elongated, and fragmented (17.7%), or expansile (9.4%). TB was identified in 63 cases (65.6%). Lymphovascular invasion (LVI) and LNI were identified in 47 and 37 cases, respectively. TB was associated with deep DOI (p = 0.001), higher FIGO grade (p = 0.006), LVI (p < 0.0001), and LNI (p < 0.0001). TB showed loss of ER (p < 0.0001) and PR (p < 0.0001), reduced E-cadherin (p < 0.0001) expression, and aberrant ß-catenin expression (p = 0.042). In EECs, TB was associated with deep DOI, less-differentiated histology, frequent LVI, and LNI; furthermore, TB was closely related to epithelial-mesenchymal transition phenotype and downregulation of hormonal receptors. Therefore, TB might be a determinant histologic clue for prediction of disease progression in EECs.

Development of Response Classifier for Vascular Endothelial Growth Factor Receptor (VEGFR)-Tyrosine Kinase Inhibitor (TKI) in Metastatic Renal Cell Carcinoma.

Vascular endothelial growth factor receptor (VEGFR)-targeted therapy improved the outcome of metastatic renal cell carcinoma (mRCC) patients. However, a prediction of the response to VEGFR-tyrosine kinase inhibitor (TKI) remains to be elucidated. We aimed to develop a classifier for VEGFR-TKI responsiveness in mRCC patients. Among 101 mRCC patients, ones with complete response, partial response, or ≥24 weeks stable disease in response to VEGFR-TKI treatment were defined as clinical benefit group, whereas patients with <24 weeks stable disease or progressive disease were classified as clinical non-benefit group. Clinicolaboratory-histopathological data, 41 gene mutations, 20 protein expression levels and 1733 miRNA expression levels were compared between clinical benefit and non-benefit groups. The classifier was built using support vector machine (SVM). Seventy-three patients were clinical benefit group, and 28 patients were clinical non-benefit group. Significantly different features between the groups were as follows: age, time from diagnosis to TKI initiation, thrombocytosis, tumor size, pT stage, ISUP grade, sarcomatoid change, necrosis, lymph node metastasis and expression of pAKT, PD-L1, PD-L2, FGFR2, pS6, PDGFRß, HIF-1α, IL-8, CA9 and miR-421 (all, P < 0.05). A classifier including necrosis, sarcomatoid component and HIF-1α was built with 0.87 accuracy using SVM. When the classifier was checked against all patients, the apparent accuracy was 0.875 (95% CI, 0.782-0.938). The classifier can be presented as a simple decision tree for clinical use. We developed a VEGFR-TKI response classifier based on comprehensive inclusion of clinicolaboratory-histopathological, immunohistochemical, mutation and miRNA features that may help to guide appropriate treatment in mRCC patients.

Nonsteroidal anti-inflammatory drugs induced diaphragm disease: a report of 3 cases and literature review.

Multiple strictures of small bowel induced by nonsteroidal anti-inflammatory drugs (NSAIDs), were known as diaphragm disease. The purpose of these case reports is to present 3 cases of diaphragm disease of small bowel and summarize the clinical features of this disease entity. A 34-year-old man, a 63-year-old man, and a 66-year-old woman were admitted to Daegu Catholic University Medical Center because of recurrent intestinal obstructions. Two of these patients had taken heavy NSAIDs use. Capsule endoscopy was performed in all cases and the all capsules were retained by circumferential strictures of the ileum. Segmental resection of the strictures was performed in 2 patients and 1 underwent just enterotomy and capsule removal. In conclusion, clinicians should be aware that diaphragm disease might be a cause of small bowel obstruction especially in patients receiving long term NSAIDs therapy.

Significance of microcystic, elongated, and fragmented glandular-like features in intraductal papillary mucinous neoplasm of the pancreas.

Microcystic, elongated, and fragmented (MELF) glandular features are associated with epithelial-mesenchymal transition, invasion, and progression in endometrioid adenocarcinoma of the uterus. Similar histological features are also observed at the periphery of pancreatic intraductal papillary mucinous neoplasms (IPMNs). However, the clinicopathological significance of MELF-like features-particularly whether they represent regenerative or truly neoplastic conditions-in IPMNs remains unclear. We assessed a total of 152 surgically resected IPMNs. Fifty cases exhibited MELF-like features, including 26 cases of IPMNs with accompanying adenocarcinomas and 24 cases of IPMNs without accompanying adenocarcinomas. MELF-like features were more frequently observed in IPMN cases with accompanying adenocarcinomas, larger tumors, main-duct type, and non-gastric histologic subtype. A positive correlation between the presence of MELF-like features and high-grade dysplasia was observed in IPMNs without accompanying adenocarcinomas. Moreover, DPC4 loss and p53 overexpression in MELF-like glands were more commonly observed in IPMNs with high-grade dysplasia. IPMN patients with MELF-like features had worse overall and disease-specific survival by univariate analyses. Our observations suggest that MELF-like features in some IPMNs with high-grade dysplasia could be related to stromal invasion. Hence, when MELF-like features are observed in IPMNs, pathologists should carefully evaluate the results of microscopic examinations to identify the invasive components; and, immunohistochemical staining for DPC4 and p53 could help clarify its clinicopathological significance.

A Rare Case of Intramural Müllerian Adenosarcoma Arising from Adenomyosis of the Uterus.

Müllerian adenosarcomas usually arise as polypoid masses in the endometrium of post-menopausal women. Occasionally, these tumors arise in the cervix, vagina, broad and round ligaments, ovaries and rarely in extragenital sites; these cases are generally associated with endometriosis. We experienced a rare case of extraendometrial, intramural adenosarcoma arising in a patient with adenomyosis. A 40-year-old woman presented with sudden-onset suprapubic pain. The imaging findings suggested leiomyoma with cystic degeneration in the uterine fundus. An ill-defined ovoid tumor with hemorrhagic degeneration, measuring 7.5 cm in diameter, was detected. The microscopic findings showed glandular cells without atypia and a sarcomatous component with pleomorphism and high mitotic rates. There was no evidence of endometrial origin. To recognize that adenosarcoma can, although rarely, arise from adenomyosis is important to avoid overstaging and inappropriate treatment.

Overexpression of Aquaporin-1 is a Prognostic Factor for Biochemical Recurrence in Prostate Adenocarcinoma.

Aquaporins (AQP) are transmembrane proteins that provide channels for water and solutes, and some are involved in tumor progression and invasion. We evaluated the expression of AQP-1, AQP-3, and AQP-5 and their clinicopathological significance in prostate adenocarcinomas (PCA). Prostatectomy specimens (n = 99) were retrieved from the surgical pathology archives and clinicopathological data were obtained from the medical database at Kyungpook National University Hospital. Immunohistochemical staining for AQP-1, AQP-3, and AQP-5 was performed on tissue microarrays comprising paired malignant and benign prostatic tissues. Seventeen PCA cases (17.2 %) showed AQP-1 overexpression, specifically 7 tumors (9.7 %) with lower Gleason scores (GS) and 10 tumors (37.0 %) with higher GS, with statistical significance (P = 0.001). AQP-1 overexpression was significantly associated with higher GS (P = 0.001), higher pathologic T (pT) stages (P = 0.024), and biochemical recurrence (BR) (P = 0.002). The difference in AQP-3 and AQP-5 expression between neoplastic and non-neoplastic tissues was not established and there were no correlations with clinicopathological parameters. AQP-1 overexpression was evident in tumors with higher GS, it was less evident in tumors with lower GS, and it was associated with BR and a higher pT stage. AQP-1 overexpression is associated with prostate cancer progression.

Prophylactic extended-field irradiation with concurrent chemotherapy for pelvic lymph node-positive cervical cancer.

PURPOSE: This study aimed to evaluate whether prophylactic extended-field pelvic radiotherapy (EF-PRT) yields better results than standard whole pelvic radiotherapy (WPRT) in patients with pelvic lymph node-positive cervical cancer treated with concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: A total of 126 cases of stage IB-IVA cervical cancer that had pelvic lymph node involvement in magnetic resonance imaging and were treated with CCRT between 2000 and 2016 were reviewed. None of the patients had paraaortic lymph node (PALN) metastases. The patients were classified to two groups, namely, those treated with EF-PRT, including prophylactic para-aortic radiotherapy, and those treated only with WPRT. The median dose to the PALN area in patients treated with EF-PRT was 45 Gy. All patients received concurrent cisplatin-based chemotherapy. RESULTS: Overall, 52 and 74 patients underwent EF-PRT and WPRT, respectively. Patient characteristics and irradiated dose were not significantly different, except the dose to the para-aortic area, between the two groups. The median follow-up period was 75.5 months (range, 5 to 195 months). The 10-year cumulative recurrence rate of PALN for EF-PRT vs. WPRT was 6.9% and 10.1% (p = 0.421), respectively. The 10-year disease-free survival and overall survival for EF-PRT vs. WPRT were 69.7% vs. 66.1% (p = 0.748) and 71.7% vs. 72.3% (p = 0.845), respectively. Acute gastrointestinal complications were significantly higher in EF-PRT (n = 21; 40.4%) than WPRT (n = 26; 35.1%) (p = 0.046). Late toxicities were not significantly different in both groups. CONCLUSION: In this study, prophylactic radiotherapy for PALN does not have an additional benefit in patients with pelvic lymph node-positive cervical cancer treated with CCRT.

Pellino 1 inactivates mitotic spindle checkpoint by targeting BubR1 for ubiquitinational degradation.

Aberrant constitutive activation of receptor-mediated downstream signalling plays an active role in the deregulation of cell cycle control. The mitotic spindle checkpoint is important in preventing abnormal mitotic cell cycle with chromosome missegregation from achieving neoplastic aneuploidy. However, mechanisms coupling receptor-mediated signalling to mitotic spindle checkpoint regulation remain unclear. Pellino 1 is a receptor signal-responsive E3 ubiquitin ligase, and the application of certain receptor-mediated signalling regulates the expression and activity of Pellino 1. In the present study, Pellino 1 expression induced extensive chromosome aneuploidy and allowed abnormal mitotic cells to adapt and become aneuploid in vitro and in vivo. Pellino 1 directly interacted with BubR1, a key component of mitotic spindle checkpoint, in a mitotic cell-cycle dependent manner, and down-regulated the stability of BubR1 by ubiquitination-mediated degradation and induced mitotic dysfunction. In summary, Pellino 1 expression acts as an inhibitory signal of the homeostatic regulation of mitotic cell cycle and checkpoint, and thus contributes to the initiation and progression of neoplastic chromosome aneuploidy.

Apamin inhibits TNF-α- and IFN-γ-induced inflammatory cytokines and chemokines via suppressions of NF-κB signaling pathway and STAT in human keratinocytes.

BACKGROUND: Atopic dermatitis (AD) is identified by an increase in infiltrations of several inflammatory cells including type 2 helper (Th2) lymphocytes. Th2-related chemokines such as thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), and pro-inflammatory cytokines including interleukin (IL)-1ß and IL-6 are considered to play a crucial role in AD. Tumor necrosis factor (TNF)-α- and interferon (IFN)-γ induce the inflammatory condition through production of TARC, MDC, IL-1ß and IL-6, and activations of related transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT) in keratinocytes. Apamin, a peptide component of bee venom, has been reported its beneficial activities in various diseases. However, anti-inflammatory effects of apamin on inflammatory condition in keratinocytes have not been explored. Therefore, the present study aimed to demonstrate the anti-inflammatory effect of apamin on TNF-α- and IFN-γ-induced inflammatory condition in keratinocytes. METHODS: HaCaT was used as human keratinocytes cell line. Cell Counting Kit-8 was performed to measure a cytotoxicity of apamin. The effects of apamin on TNF-α-/IFN-γ-induced inflammatory condition were determined by real-time PCR and Western blot analysis. Further, NF-κB signaling pathways, STAT1, and STAT3 were analyzed by Western blot and immunofluorescence. RESULTS: Apamin ameliorated the inflammatory condition through suppression of Th2-related chemokines and pro-inflammatory cytokines. Further, apamin down-regulated the activations of NF-κB signaling pathways and STATs in HaCaT cells. CONCLUSIONS: These results suggest that apamin has therapeutic effect on AD through improvement of inflammatory condition.

Molecular Testing for Gastrointestinal Cancer.

With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2-4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus-positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

Adult granulosa cell tumor presenting with massive ascites, elevated CA-125 level, and low (18)F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography.

Adult granulosa cell tumors (AGCTs) presenting with massive ascites and elevated serum CA-125 levels have rarely been described in the literature. An ovarian mass, massive ascites, and elevated serum CA-125 levels in postmenopausal women generally suggest a malignant ovarian tumor, particularly advanced epithelial ovarian cancer. AGCT has low (18)F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography due to its low metabolic activity. In the present report, we describe a case of an AGCT with massive ascites, elevated serum CA-125 level, and low (18)F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography.

Prognostic significance of neuroendocrine components in gastric carcinomas.

BACKGROUND: Gastric neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs) are aggressive tumours but the prognostic significance of a neuroendocrine component in <30% of the tumour remains unclear. Here, the implication of neuroendocrine components in gastric carcinomas was assessed according to proportion. METHODS: Surgically resected primary gastric carcinomas with neuroendocrine morphology (NEM; n=88) from 2000 to 2012 at Asan Medical Center were retrospectively reviewed. Neuroendocrine differentiation (NED) was defined as immunopositivity for one of three neuroendocrine markers (synaptophysin, chromogranin or CD56) within the NEM area. To validate the prognostic significance of NED, these cases were compared with 650 randomly selected gastric adenocarcinomas without NEM from the same time period. RESULTS: Gastric carcinomas with NEM were reclassified as NEC (⩾70% NED, n=47), MANEC (30-70% NED, n=10), gastric carcinoma with 10-30% NED (GCNED, n=8) and carcinoma with <10% NED (n=23). The survival rates of patients with ⩾10% NED were significantly poorer than those with <10% NED but no survival difference was observed between NEC and MANEC. In univariate analyses, older age (⩾60years), larger tumour size (⩾4cm), advanced stage group, ⩾10% NED and lymphovascular or perineural invasion were indicative of a poor prognosis. Stage group and ⩾10% NED remained as independent prognostic factors by multivariate analysis. CONCLUSIONS: A minor proportion (10-30%) of NED should not be overlooked in gastric carcinomas with NEM. NED should be carefully evaluated to predict patient outcomes and plan optimal additional therapies.