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Backgroud. To evaluate improvement of arsenic trioxide-loaded PLGA nanoparticles (As2O3-PLGA-NPs) to Human Vascular Smooth Muscle Cells (HUVSMCs) in vitro. Methods. As2O3-PLGA-NPs were synthesized and characterized by transmission electron microscopy (TEM), scanning electron microscope (SEM), and energy dispersive spectrometry (EDS), and the cumulative release rates of As2O3-PLGA-NPs were measured in vitro; HUVSMCs were treated with As2O3-PLGA-NPs in vitro. MTT assay and flow cytometry assay (FCM) were performed to examine the inhibitory effect of As2O3-PLGA-NPs on HUVSMCs and compared with As2O3 solution at various concentrations. Optical microscope was used to observe the morphological change of HUVSMCs treated with As2O3-PLGA-NPs. The expression of Bcl-2, Bax, and MMP-9 in HUVSMCs was detected by RT-PCR and Western blot (WB). Results. EDS confirmed that prepared nanoparticles contained elements of arsenic. The surface coating of the eluting stent of As2O3-PLGA-NPs has the same characteristics with our self-prepared As2O3-PLGA-NPs, and it also has a drug sustained-release character. Compared with the control group, cell proliferation and migration cell were significantly suppressed with concentration-dependent ( P < 0.05 , respectively). Meanwhile, in concentration-dependent, As2O3-PLGA-NPs depressed mRNA and protein expression of Bcl-2 and MMP-9 and increased mRNA and protein expression of Bax. Conclusion. As2O3-PLGA-NPs had an inhibitory effect on HUVSMCs’ proliferation and migration, and it may work via regulating Bax, Bcl-2, and MMP-9 expression in vitro.

Purpose To assess the performance of combining computed tomography (CT) texture analysis with machine learning for discriminating different histopathological grades of pancreatic ductal adenocarcinoma (PDAC). Methods From July 2012 to August 2017, this retrospective study comprised 56 patients with confirmed histopathological PDAC (32 men, 24 women, mean age 64.04±7.82 years) who had undergone preoperative contrast-enhanced CT imaging within 1 month before surgery. Two radiologists blinded to the histopathological outcome independently segmented lesions for quantitative texture analysis. Histogram features, co-occurrence, and run-length texture were calculated. A support-vector machine was constructed to predict the pathological grade of PDAC based on preoperative texture features. Results Pathological analysis confirmed 37 low-grade PDAC (five well-differentiated/grade I and 32 moderately differentiated/grade II) and 19 high-grade PDAC (19 poorly differentiated/grade III) tumors. There were no significant differences in clinical or biological characteristics between patients with high-grade and low-grade tumors (P>0.05). There were significant differences between low-grade PDAC and high-grade PDAC on nine histogram features, seven run-length features, and two co-occurrence features. Cluster shade was the most important predictor (sensitivity 0.315). Using these texture features, the support-vector machine achieved 86% accuracy, 78% sensitivity, 95% and specificity. Conclusion Machine learning-based CT texture analysis accurately predicted histopathological differentiation grade of PDAC based on preoperative texture features, leading to maximization patient survival and achievement of personalized precision treatment.

The Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021 (2021 guidelines) was recently released. The guidelines summarized the evidences from literatures up to July 2019, and composed by 6 parts as "screening and early treatment", "infection", "hemodynamic management", "ventilation", "additional therapies" and "long-term outcomes and goals of care" with a total of 93 items and 99 recommendations. Compared with the 2016 guidelines (96 recommendations), although the total number of recommendations in the 2021 guidelines is similar, the number of "strong recommendations (recommend)" in 2021 guidelines has dropped significantly, as the number of "weak recommendations (suggest)" has increased significantly, and the level of the quality of evidence on which the recommendations are based has been significantly lowered. Furthermore, 2021 guidelines have also markedly deleted or simplified the recommendations regarding infection prevention, acute respiratory distress syndrome (ARDS) treatment, nutritional support and so on. While, the most obvious improvement appears in the segment of "long-term outcomes and goals of care", in which the patients and their families could get help in term of determining their physical rehabilitation and discharge follow-up plans and formulating exact goals of care. 2021 guidelines did not adopt new and emerging therapies or treatments, such as metagenomic next-generation sequencing (mNGS), diaphragm protective ventilation, timing of initiating renal replacement therapy for acute kidney injury, early mobility, endotoxin adsorption, tranexamic acid, E-medicine and telemedicine, big data and artificial intelligence and other new therapies. Collectively, it may suggest the 2021 guidelines tend to be conservative and simplified rather than fairly optimized and logicalized, which may arouse controversy in the future and affect clinician compliance.

Compared with early gastric intramucosal carcinoma, submucosal carcinoma is known to have a higher risk for lymph node metastasis (LMN), but risk factors in submucosal carcinoma remain elusive. In this multicenter study with 621 radical gastrectomies for submucosal early gastric carcinoma, we investigated tumor budding and other risk factors of LMN that were identified in 172 cases (27.7%). Overall, independent high-risk factors for LMN included lymphovascular invasion (odds ratio, 3.9; 95% confidence interval, 2.5-6.1), tumor budding (odds ratio, 3.3; 95% confidence interval, 1.9-5.9), mixed tubular/papillary adenocarcinoma with poorly cohesive carcinoma (odds ratio, 2.1; 95% confidence interval, 1.0-4.3), and female sex (odds ratio, 1.6; 95% confidence interval, 1.0-2.6), whereas gastric cardiac submucosal carcinomas had a significantly lower risk for LMN (odds ratio, 0.5; 95% confidence interval, 0.3-0.9). In 276 well/moderately differentiated tubular or papillary submucosal early gastric carcinomas, independent risk factors were tumor budding (odds ratio, 3.7; 95% confidence interval, 1.6-8.7), deep submucosal (SM2) invasion (odds ratio, 3.1; 95% confidence interval, 1.3-7.6), and lymphovascular invasion (odds ratio, 2.7; 95% confidence interval, 1.3-5.6). In 174 cases without tumor budding and lymphovascular invasion, no LMN was identified in 47 cardiac tumors, and 15 tumors1.0 cm in size. In conclusion, tumor budding, lymphovascular invasion, mixed tubular/papillary adenocarcinoma with poorly cohesive carcinoma, and female gender were found to be significant high-risk factors for LMN in submucosal early gastric carcinoma, while submucosal gastric cardiac carcinoma had a significantly lower risk for nodal metastasis.

Chemoresistance remains the major obstacle to achieve optimal prognosis in gastric cancer patients, and the underlying molecular mechanisms of cancer-associated fibroblasts (CAFs) in gastric cancer chemoresistance remain poorly understood. We identified the high pretherapeutical serum IL-8 level in gastric cancer patients was associated with poor response to platinum-based therapy, and it increased gradually during neoadjuvant chemotherapy and it decreased after radical surgery. Immunohistochemistry assays showed that IL-8 was highly expressed in gastric cancer tissues in chemoresistant patients, and located in CAFs. Primary CAFs produced more IL-8 than the corresponding normal fibroblasts, and human stomach fibroblast line Hs738 secreted more IL-8 after co-cultured with conditioned media from AGS or MGC-803 cells. IL-8 increased the IC50 of cisplatin (CDDP) in AGS or MGC-803 in vitro. Simultaneously, IL-8 treatment enhanced the expression of PI3K, phosphorylated-AKT (p-AKT), phosphorylated-IKb (p-IKb), phosphorylated-p65 (p-p65) and ABCB1, and ABCB1 and p-p65 were overexpressed in tumor tissues of chemoresistant patients. Collectively, CAFs derived IL-8 promotes chemoresistance in human gastric cancer via NF-κB activation and ABCB1 up-regulation. Our study provides a novel strategy to improve the chemotherapeutical efficacy and the prognosis of gastric cancer.

Background Germline BRCA1/2 prevalence is relatively low in sporadic triple-negative breast cancer (TNBC). We hypothesized that non-BRCA genes may also have significant germline contribution to Chinese sporadic TNBC, and the somatic mutational landscape of TNBC may vary between ethnic groups. We therefore conducted this study to investigate germline and somatic mutations in 43 cancer susceptibility genes in Chinese sporadic TNBC. Patients and methods Sixty-six Chinese sporadic TNBC patients were enrolled in this study. Germline and tumor DNA of each patient were subjected to capture-based next-generation sequencing using a 43-gene panel. Standard bioinformatic analysis and variant classification were performed to identify deleterious/likely deleterious germline mutations and somatic mutations. Mutational analysis was conducted to identify significantly mutated genes. Results Deleterious/likely deleterious germline mutations were identified in 27 (27/66, 40.9%) patients. Among the 27 patients, 9 (9/66, 13.6%) were TP53 carriers, 5 (5/66, 7.6%) were MSH6 carriers, and 5 (5/66, 7.6%) were BRCA1 carriers. Somatic mutations were identified in 64 (64/66, 97.0%) patients. TP53 somatic mutations occurred in most of the patients (45/66, 68.2%) and with highest mean allele frequency (28.1%), while NF1 and POLE were detected to have the highest mutation counts. Conclusions Our results supported our hypotheses and suggested great potentials of TP53 and MSH6 as novel candidates for TNBC predisposition genes. The high frequency of somatic NF1 and POLE mutations in this study showed possibilities for clinical benefits from androgen-blockade therapies and immunotherapies in Chinese TNBC patients. Our study indicated necessity of multi-gene testing for TNBC prevention and treatment. Electronic supplementary material The online version of this article (10.1186/s40246-018-0186-y) contains supplementary material, which is available to authorized users.

Wenli Qiu,1 Rong Chen,2 Xiao Chen,3 Huifeng Zhang,1 Lina Song,3 Wenjing Cui,3 Jingjing Zhang,1 Dandan Ye,1 Yifen Zhang,4 Zhongqiu Wang3 1The First Clinical Medical School, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; 3Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 4Department of Pathology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China Purpose: Early diagnosis and therapy are critical to improve the prognosis of patients with pancreatic cancer. However, conventional imaging does not significantly increase the capability to detect early stage disease. In this study, we developed a multifunctional theranostic nanoplatform for accurate diagnosis and effective treatment of pancreatic cancer.Methods: We developed a theranostic nanoparticle (NP) based on gold nanocages (AuNCs) modified with hyaluronic acid (HA) and conjugated with anti-Glypican-1 (anti-GPC1) antibody, oridonin (ORI), gadolinium (Gd), and Cy7 dye. We assessed the characteristics of GPC1-Gd-ORI@HAuNCs-Cy7 NPs (ORI-GPC1-NPs) including morphology, hydrodynamic size, stability, and surface chemicals. We measured the drug loading and release efficiency in vitro. Near-infrared fluorescence (NIRF)/magnetic resonance imaging (MRI) and therapeutic capabilities were tested in vitro and in vivo.Results: ORI-GPC1-NPs demonstrated long-time stability and fluorescent/MRI properties. Bio-transmission electron microscopy (bio-TEM) imaging showed that ORI-GPC1-NPs were endocytosed into PANC-1 and BXPC-3 (overexpression GPC1) but not in 293 T cells (GPC1-negative). Compared with ORI and ORI-NPs, ORI-GPC1-NPs significantly inhibited the viability and enhanced the apoptosis of pancreatic cancer cells in vitro. Moreover, blood tests suggested that ORI-GPC1-NPs showed negligible toxicity. In vivo studies showed that ORI-GPC1-NPs enabled multimodal imaging and targeted therapy in pancreatic tumor xenografted mice.Conclusion: ORI-GPC1-NP is a promising theranostic platform for the simultaneous diagnosis and effective treatment of pancreatic cancer. Keywords: pancreatic cancer, GPC1, ORI, theranostic

The consensus of endoscopic therapy for early gastric cancer (EGC) mainly depends on its clinicopathological features. However, the roles of tumor-associated neutrophils (TANs) in EGC remain uncertain. Here, we explored its predictive role for lymph node metastasis (LNM) in EGC. Three hundred twenty-two patients who underwent radical gastrectomy for EGC were enrolled. Preoperative peripheral blood was used to analyze the neutrophil-to-lymphocyte ratio (NLR), and the different status of TANs was determined by hematoxylin-and-eosin staining (H&E) and immunohistochemistry (IHC). TANs, rather than NLR, were positively associated with tumor size, Lauren classification, lymphovascular invasion (LVI), and LNM. Univariate analysis revealed that TANs were associated with LNM as well as tumor size, depth of invasion, Lauren classification, histological classification, LVI, and perineural invasion. In addition to histological classification and LVI, TANs were found to be an independent risk factor for LNM in EGC (P = 0.013). Stratification analysis by depth of invasion showed LVI in SM1 tumor, and both LVI and TANs (P = 0.042) in SM2 tumor were independent risk factors for LNM. In conclusion, TANs in EGC can predict LNM, and TANs may help to estimate LNM precisely in addition to the current criteria.

Summary Purpose This study aims to analyze sensitivities and polymorphisms of the Bethesda panel markers (BAT25, BAT26, D2S123, D5S346 and D17S250) for microsatellite instability testing in Chinese from Jiangsu Province and their clinical implication. Methods MSI, sensitivity and polymorphism analysis in 541 colorectal cancer (CRC) patients were detected by fragment analysis. Results Five hundred and twenty-five tissue samples and 541 blood samples of the 541 sample pairs were successfully amplified. Thirty-four (6.5%) cases were MSI-high (MSI-H) while 33 (6.3%) and 458 (87.2%) were MSI-low (MSI-L) and microsatellite stable (MSS), respectively. BAT26 (85.3%) exhibited the highest instability followed by BAT25 (82.4%), D2S123 (67.6%), D17S250 (64.7%) and D5S346 (50.0%) in MSI-H cases. The median ages of CRC patients with LS, MSI-H, MSI-L and MSS status were 38–43, 48, 60 and 63, respectively. 75.0%, 44.1%, 12.1% and 7.0% CRC cases were mucinous carcinomas in LS, MSI-H, MSI-L and MSS group, respectively. For D2S123, D17S250 and D5S346, heterozygosity was 80.8%, 74.1% and 57.7% and sizes of polymorphic variation range (PVR) were 207 bp to 234 bp, 140 bp to 169 bp and 109 bp to 137 bp, respectively. For D2S123 and D5S346, there was a bimodal distribution distinguishing the D17S250 from an indistinct trimodal or tetramodal distribution. Conclusion MSI-H cases showed earlier onset and higher proportion of mucinous carcinomas. Mononucleotide BAT26 and BAT25 exhibited higher sensitivity than dinucleotides D2S123, D17S250 and D5S346 in the Chinese population. The dinucleotide markers were highly polymorphic with high percent of heterozygosity, great variation in repeat length and non-normal distribution in Chinese population from Jiangsu Province.

Perineural invasion (PNI) after radical prostatectomy (RP) is a common feature of prostate cancer (PCa) and has been associated with unfavorable tumor characteristics. However, its prognostic relevance is controversial. In this study, we evaluated the impact of both PNI status (PNI+ versus PNI-) and quantified number of PNI focus on the long-term prognosis of biochemical recurrence (BCR) after RP. After reevaluating PNI of a total of 721 patients with localized PCa who underwent RP at our institution between 2000 and 2002, we examined associations between PNI status or PNI focus number and clinicopathological factors including tumor stage, Gleason score, margin status, tumor location, preoperative prostate specific antigen, age, prostate weight as well as BCR outcome. PNI was present in 530 of 721 cases (73.5%) of the RP specimens and was associated with more aggressive disease. BCR occurred in 19.4% of all patients within a median follow-up period of 8.5 years. PNI+ status was associated with poor BCR prognosis in univariate analysis but lost in multivariate analysis. Based on the number of PNI focus, PNI was further divided into 2 distinct group: PNI+ a (≤3) and PNI+ b (>3). In a multivariate Cox regression model, PNI+ b (>3) was identified as an independent BCR prognostic factor. Quantification of PNI focus number beside the dichotomized status recording will not only provide more detailed information but also be a novel prognostic indicator for risk stratification. Further external validation will be needed for an optimal cut-off value of the PNI focus number. Our findings will help further research on the relevance of PNI in the pretreatment setting and support ongoing efforts to understand its role of cancer progression.

Background Biomarker-targeted molecular imaging holds promise for early detection of pancreatic cancer. The aim of this study was to design and evaluate a plectin-1 targeted multi-functional nanoparticle probe for pancreatic cancer imaging. Methods 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-amino(polyethylene glycol) (DSPE-PEG-NH2)-modified superparamagnetic iron oxide (Fe3O4) nanoparticles (SPION) were conjugated with plectin-1 antibody and/or Cy7 to create the multi-functional targeted nanoparticle targeted probe (Plectin-SPION-Cy7) or non-targeted probe (SPION-Cy7). Pancreatic carcinoma cell lines expressing plectin-1 were cultured with the targeted or control probes and then were imaged using confocal laser scanning microscopy and magnetic resonance imaging (MRI). Accumulations of the nanoparticles in pancreatic tumor xenografted mice were determined by MRI and fluorescence imaging. Results In vitro optical imaging and MRI showed that the targeted nanoparticles were highly accumulated in MIAPaCa2 and XPA-1 carcinoma cells but not in non-carcinoma MIN6 cells, which was further confirmed by Prussian blue staining. In vivo MRI showed a significant T2 signal reduction. Prussian blue staining further confirmed that the plectin-1 targeted nanoparticles were highly accumulated in the tumor mass but not in normal pancreatic tissues, or in the liver and kidney, and few nanoparticles were observed in the tumors of mice injected with SPION-Cy7. Conclusions Our data demonstrate that plectin-1 targeted fluorescence and MR dual-functional nanoparticle can visualize pancreatic cancer, and it has great potential to be used with various imaging devices for pancreatic cancer detection., Highlights • We designed a plectin-1 targeted dual-modality nanoparticle (Plectin-SPION-Cy7). • The targeted nanoparticles were highly accumulated in carcinoma cells but not in non-carcinoma cells. • Plectin-1 targeted dual-functional nanoparticle has great potential in pancreatic cancer detection. Molecular-based radiographic tests hold the promise to help precisely identifying pancreatic malignant lesions and their precursors at early stages. Previous studies showed that plectin-1 highly expressed in pancreatic ductal adenocarcinoma but not in non-carcinoma tissues. In the current study, we designed a plectin-1 targeted dual-modality nanoparticle (Plectin-SPION-Cy7). In vitro and in vivo data both indicated that plectin-1 targeted nanoparticles were highly accumulated in carcinoma cells/tissues but not in non-carcinoma cells/tissues. These results show that plectin-1 targeted fluorescence and MR dual-functional nanoparticle is useful for pancreatic cancer detection.

Although Internet games have been proven to be addictive, only a few game players develop online gaming addiction. A large number of players play online games recreationally without being addicted to it. These individuals are defined as recreational Internet gaming users (RGU). So far, no research has investigated decision-making and impulse control in RGU. In the current study, we used delay discounting (DD) task and probabilistic discounting (PD) task to examine decision-making and impulse control in 20 healthy controls, 20 subjects with Internet gaming disorder (IGD) and 23 RGU during fMRI scanning. At the behavioral level, RGU showed lower DD rate and higher PD rate than subjects with IGD and there was no significant difference between RGU and healthy controls on the DD and PD rates. At the neural level, RGU showed increased neural response in the parahippocampal gyrus, the anterior cingulate cortex, the medial frontal gyrus and the inferior frontal gyrus as compared with subjects with IGD. These brain regions may play an important role in preventing RGU from developing addiction. The results suggest that the RGU are capable of inhibiting impulse due to additional cognitive endeavor and the subjects with IGD have deficit in decision-making and impulsive control, which are associated with brain dysfunction.

Heterotopic pancreas (HP) is often an incidental finding during operative or endoscopic procedures and described in case reports and small series in the literature. Large clinicopathological studies with a systematic analysis remain lacking. Herein, we identified 184 (0.18%; 184/99 544) consecutive histology-proven HP cases of 89 770 surgical resections and 9774 upper endoscopic biopsies carried out at a single medical center in China. Each case was diagnosed by unequivocal identification of pancreatic acini at a location outside the pancreas. The patients' median age was 49 years (range, 14-82) with a slight female predominance (male/female ratio, 0.94). Clinical presentation at diagnosis was nonspecific. Preoperatively, most (54.9%; 101/184) HP lesions were misdiagnosed. Only 26 HP lesions (14.1%) were correctly diagnosed, all in the stomach except for 1 in the duodenum; 57 (31%) were detected during operative procedures for other conditions. The most frequent location of HP was, in descending order, the stomach (97; 52.7%), small intestine (48; 26%), lesser and greater curvature omentum (18; 10%), spleen and hilar region (5; 2.7%), porta hepatis (2; 1%), gallbladder (1; 0.5%), peridistal esophageal tissue (4; 2.2%), and mesentery (7; 3.8%). The size of HP varied from smaller than 0.5 cm (35.3%), 0.6 to 1 cm (34.8%), to larger than 1.1 cm (29.9%). Because of difficulty in preoperative diagnosis, careful workup for upper gastrointestinal diseases with HP as a differential diagnosis may increase the chance of accurate diagnosis and appropriate patient management.

This study utilized independent component analysis to explore the abnormal functional connectivity (FC) in male participants with Internet gaming disorder (IGD). Functional magnetic resonance imaging and behavioral data were collected from 21 healthy controls (HC) and 18 IGD patients when they were performing a delay discounting task. Behavioral results revealed that the IGD patients showed higher delay discounting rates than HC. Two networks were found to be associated with IGD: (1) the executive control network containing the anterior cingulate cortex and the medial and superior frontal gyrus, and (2) the basal ganglia network containing the lentiform nucleus. Comparing to HC, IGD exhibited stronger FC when selecting small and now options. In addition, the delay discounting rates were positively correlated with the modulation of the two networks and the reaction time. The results suggested that the IGD patients have enhanced sensitivity to reward and decreased ability to control their impulsivity effectively, which leads to myopic decision making.

Although numerous neuroimaging studies have detected structural and functional abnormality in specific brain regions and connections in subjects with Internet gaming disorder (IGD), the topological organization of the whole-brain network in IGD remain unclear. In this study, we applied graph theoretical analysis to explore the intrinsic topological properties of brain networks in Internet gaming disorder (IGD). 37 IGD subjects and 35 matched healthy control (HC) subjects underwent a resting-state functional magnetic resonance imaging scan. The functional networks were constructed by thresholding partial correlation matrices of 90 brain regions. Then we applied graph-based approaches to analysis their topological attributes, including small-worldness, nodal metrics, and efficiency. Both IGD and HC subjects show efficient and economic brain network, and small-world topology. Although there was no significant group difference in global topology metrics, the IGD subjects showed reduced regional centralities in the prefrontal cortex, left posterior cingulate cortex, right amygdala, and bilateral lingual gyrus, and increased functional connectivity in sensory-motor-related brain networks compared to the HC subjects. These results imply that people with IGD may be associated with functional network dysfunction, including impaired executive control and emotional management, but enhanced coordination among visual, sensorimotor, auditory and visuospatial systems.

Clinicopathology and risk factors of lymph node metastasis (LNM) in micropapillary early (pT1) gastric carcinoma (MEGC) remain elusive because of the extreme rarity. In this multicenter study, we investigated 1890 consecutive radical resections of early gastric carcinoma diagnosed with the World Health Organization criteria and identified 29 (1.5%) MEGC cases with a small (≥5%) micropapillary component. MEGC showed a male predominance (male-to-female ratio, 21:8). Most (93.1%; 27/29) tumors invaded submucosa. Lymphovascular invasion was detected in 14 (48.3%) of 29 cases. LNM was found in 13 cases (44.8%; 11 identified with a routine hematoxylin-eosin stain and 2 additional cases with a positive pancytokeratin immunostain). Overall, independent risk factors for LNM in early gastric carcinoma included patient age of 62 years or less, female sex, noncardiac location, ulcerative pattern, tumor size of greater than 2 cm, submucosal invasion, Lauren diffuse type, lymphovascular invasion, and MEGC. In MEGC, advanced pathologic stages were demonstrated in 6 (20.7%) of 29 cases. The 5-year overall survival rate of MEGC patients was 58.6%. Submucosal invasion, lymphovascular invasion, and LNM were significantly more frequent in the MEGC group than in the non-MEGC groups. Advanced pathologic stages were significantly more common in MEGC than in nonmicropapillary Lauren intestinal- but not diffuse-type early gastric carcinomas. In conclusion, MEGC demonstrated a high propensity for lymphovascular invasion, LNM with advanced stages, and dismal prognosis.

The microphthalmia (MiT) subfamily of transcription factors includes TFE3, TFEB, TFEC, and MITF. In the 2016 World Health Organization classification, MiT family translocation renal cell carcinoma (tRCC) including Xp11 tRCC and t(6;11) RCC, was newly defined as an RCC subtype. Xp11 and t(6;11) RCC are characterized by the rearrangement of the MiT transcription factors TFE3 and TFEB, respectively. Recent studies identified the fusion partner-dependent clinicopathological and immunohistochemical features in TFE3-rearranged RCC. Furthermore, RCC with TFEB amplification, melanotic MiT family translocation neoplasms, was identified may as a unique subtype of MiT family associated renal neoplasms, along with MITF associated RCC. In this review, we will collect available literature of these newly-described RCCs, analyze their clinicopathological and immunohistochemical features, and summarize their molecular and genetic evidences. We expect this review would be beneficial for the understanding of these rare subtypes of RCCs, and eventually promote clinical management strategies. Keywords: Microphthalmia, TFE3, TFEB, MITF, Kidney, Renal cell carcinoma, Translocation

The relationship between autophagy and tumour is well studied, but tumour cell morphological changes associated with autophagy defects are rarely reported, especially in renal cell carcinoma (RCC). We collected 10 renal tumour samples with characteristic eosinophilic cytoplasmic inclusions (ECIs) and found that the ECIs were majorly composed of sequestosome 1/P62, neighbor of BRCA1 gene 1 (NBR1), PEX14, and CATALASE1 (CAT1). Further, transmission electron microscopy analysis revealed that ECIs were aggregates of proteinaceous material and peroxisomes. These results confirmed that ECIs in RCCs were the products of autophagy defects. The presence of ECIs was correlated with high Fuhrman grade components of RCCs. Whole-exome sequencing (WES) and Sanger sequencing confirmed that tumours with ECIs showed somatic mutations or high frequency of genetic variations in autophagy-related (ATG) genes, such as ATG7, ATG5, and ATG10. These results indicate that nucleotide changes in ATG genes are associated with autophagy defect, ECI formation, and even tumour grade in RCCs.

Aims: This study aimed to compare the clinicopathological features, incidence, and prognosis between type II ovarian carcinoma (OC) and fallopian tube carcinoma (FTC) in Chinese women and to analyze the origin of high-grade serous carcinoma (HGSC). Methods: Three hundreds and seventy-four OC cases and 45 FTC cases were retrospectively studied with histomorphology, tissue microarray, and immunohistochemistry. Results: Our data showed that the characteristics of OC and FTC in Chinese women were younger at diagnosis with worse prognosis. There was no significant difference between type II OC and FTC in the clinicopathological information and survival. Serous tubal intraepithelial carcinoma (STIC) were found in 41.7% (43/103) of ovarian high-grade serous carcinoma (HGSC) and 52.4% (22/42) cases of tubal HGSC, and 26 patients were found with only fallopian tube (FT) mucosal invasive carcinoma. Seventy-eight of 87 cases of ovarian HGSC with tubal lesions (STIC and/or FT mucosal invasive carcinoma) was in advanced stage. There was no significant difference between newly assigned FTC (ovarian HGSC with tubal lesions and FTC) and type II OC without tubal lesions in many clinicopathological parameters, expression of immunohistochemical indicators and survival, but type I OC was quite much different from the former two. Conclusions: Our data suggested that OC of type II and FTC might be originated from the same organ, and strongly supported the dualistic model of epithelial ovarian cancer. Moreover, this study provided a further clinical basis for the prophylactic salpingectomy to reduce the risk of OC.

Background and Aims: Attentional bias for drug-related stimuli is a key characteristic for drug addiction. Characterizing the relationship between attentional bias and brain reactivity to Internet gaming-related stimuli may help in identifying the neural substrates that critical to Internet gaming disorder (IGD). Methods: 19 IGD and 21 healthy control (HC) subjects were scanned with functional magnetic resonance imaging while they were performing an addiction Stroop task. Results: Compared with HC group, IGD subjects showed higher activations when facing Internet gaming-related stimuli in regions including the inferior parietal lobule, the middle occipital gyrus and the dorsolateral prefrontal cortex. These brain areas were thought to be involved in selective attention, visual processing, working memory and cognitive control. Discussion and Conclusions: The results demonstrated that compared with HC group, IGD subjects show impairment in both visual and cognitive control ability while dealing with gaming-related words. This finding might be helpful in understanding the underlying neural basis of IGD.

Down-regulation of ECD may associate with infiltrative tumor growth and result in poor prognosis. However, ECD expression is not significantly associated with tumor metastasis.To investigate the prognostic role of E-cadherin (ECD) expression in laryngeal cancer.In a clinical study, a total of 79 laryngeal cancer patients who received surgery were included in this study. The expression of ECD in laryngeal cancer tissue was detected by immumohistochemical staining. In an in vitro study, ECD up-regulated cells (Ad-ECD) and ECD down-regulated cells (sh-ECD) were cultured, along with interference by siRNA. Cell apoptosis was detected by flow cytometry. In an in vivo study, nude mice were injected with Ad-ECD, sh-ECD, and Hep-2 cells. The ECD expression and tumor metastasis in the brain, liver, and lung tissues were detected.Clinical data showed that expression of ECD was statistically correlated with survival rate (p 0.05), but not with other clinical characteristics, such as age, gender, lymphatic metastasis, and TNM staging. ECD was down-regulated in sh-ECD cells and the down-regulation significantly reduced apoptosis of Hep-2 cells. Tumor growth was significantly inhibited in the Ad-ECD group. Except the tumor tissue, no positive ECD expression or significant tumor cells were found in the brain, liver, and lung tissues.

Although Internet games have been proven to be addictive, only a few game players develop online gaming addiction. A large number of players play online games recreationally without being addicted to it. These individuals are defined as recreational Internet gaming users (RGU). So far, no research has investigated decision-making and impulse control in RGU. In the current study, we used delay discounting (DD) task and probabilistic discounting (PD) task to examine decision-making and impulse control in 20 healthy controls, 20 subjects with Internet gaming disorder (IGD) and 23 RGU during fMRI scanning. At the behavioral level, RGU showed lower DD rate and higher PD rate than subjects with IGD and there was no significant difference between RGU and healthy controls on the DD and PD rates. At the neural level, RGU showed increased neural response in the parahippocampal gyrus, the anterior cingulate cortex, the medial frontal gyrus and the inferior frontal gyrus as compared with subjects with IGD. These brain regions may play an important role in preventing RGU from developing addiction. The results suggest that the RGU are capable of inhibiting impulse due to additional cognitive endeavor and the subjects with IGD have deficit in decision-making and impulsive control, which are associated with brain dysfunction.

Gliomatosis peritonei, a rare condition often associated with immature ovarian teratoma, is characterized by the presence of mature glial tissue in the peritoneum. We retrospectively evaluated 21 patients with gliomatosis peritonei and studied their clinicopathologic features and immunophenotype. The patients’ ages ranged from 5 to 42 years (median, 19 years). Their primary ovarian tumors consisted of immature teratoma (n = 14), mixed germ cell tumors (n = 6), and mature teratoma with a carcinoid tumor (n = 1). Gliomatosis peritonei was diagnosed at the same time as primary ovarian neoplasm in 16 patients and secondary surgery in 5 patients. Also, 11 of 21 patients had metastatic immature teratoma (n = 4), metastatic mature teratoma (n = 2), or both (n = 5). One patient developed glioma arising from gliomatosis peritonei. Seventeen patients had follow-up information and were alive with no evidence of disease (n = 13), alive with disease (n = 3), or alive with an unknown disease status (n = 1). The follow-up durations ranged from 1 to 229 months (mean, 49 months; median, 23 months). Immunohistochemistry results demonstrated that SOX2 was expressed in all cases of gliomatosis peritonei and glioma with tissue available (9 of 9 cases), whereas OCT4 and NANOG were negative in all cases with available tissue (8 of 8 cases). In conclusion, both gliomatosis peritonei and glioma arising from it show a SOX2+/OCT4−/NANOG− immunophenotype. These findings demonstrated that gliomatosis peritonei is associated with favorable prognosis, although it is important to rule out potentially associated immature teratoma and maligant transformation. SOX2 may play an important role in the development of gliomatosis peritonei.

To explore the clinicopathological implications of single positive core prostate cancer.A total of 45 patients with transrectal ultrasound (TRUS)-guided prostate biopsy were diagnosed with single positive core prostate cancer and subsequently underwent radical prostatectomy (RP). Their clinicopathological parameters were examined to identify the factors for disease upgrading or upstaging.On final pathology, only 31.1% patients had unilateral prostate cancer. And 37.8% patients experienced Gleason score upgrading, 66.7% patients had upstaging and 31.1% were found positive surgical margins. On multivariable analyses, the percentage of positive cores was an independent predictor of stage upgrading and perineural invasion at RP pathology. Age, prostate volume and preoperative prostate-specific antigen/prostate-specific antigen density (PSA/PSAD) had no significant effect on underestimated tumor burden.Most single positive core prostate cancer diagnosed by 12-core biopsy may be underestimated. The percentage of positive cores is an independent predictor of underestimated prostate cancer. Currently we have no instruments for accurately identifying microfocal or unilateral prostate cancer.

The current study presents a case of Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) in a 30-year-old female. The patient was referred to The Affiliated Drum Tower Hospital of the Medical College of Nanjing University (Nanjing, Jiangsu, China) due to a right renal tumor without evident symptoms, which was found by a routine physical examination. A computed tomography (CT) scan indicated that the mass exhibited cystic and solid components. The patient underwent laparoscopic radiofrequency ablation-assisted enucleation. Immunohistochemistry revealed intense nuclear staining for transcription factor E3 protein in the cancer cells. The patient was diagnosed with Xp11.2 RCC. The urological and radiological outcomes remained satisfactory after >2.5 years of follow-up.

Supraglottic adenoid cystic carcinoma (ACC) is extremely rare and may be misdiagnosed as laryngeal amyloidosis. The present report describes a case of supraglottic ACC, which went unrecognized until histopathological examination of the neoplasm 18 months after the first presentation. The present patient presented with progressive hoarseness for half a year and initially required partial resection. Following quick regional recurrence, the patient received a total laryngectomy while refusing radiotherapy. Adjuvant post-operational traditional Chinese medicine was accepted. Over 3 years’ follow-up, there was no evidence of regional relapse or distant metastases. The present case is compared with a second case of supraglottic submucosal mass in which the signs, symptoms and examinations were similar to the first case, but that was diagnosed as laryngeal amyloidosis. Attention should be paid to submucosal masses in the larynx to prevent underlying malignancy and subsequent disease progression. Immunocytochemistry, such as p63 staining, is mandatory for making an early differential diagnosis of supraglottic ACC. Traditional Chinese medicine may be a useful adjuvant therapy for this rare disease.

Tat-interacting protein 30 (TIP30), a transcriptional repressor for ERalpha-mediated transcription, possesses several characteristics of a tumor suppressor in certain human and mouse cells. It is reported that deletion of TIP30 gene preferentially increases tumorigenesis in the female knockout mice. Here, we analyzed TIP30 gene expression in the databases of several DNA microarray studies of human prostate cancer and show that TIP30 is specifically overexpressed in metastatic prostate cancers. We demonstrate that TIP30 nuclear expression is associated with prostate cancer progression and metastasis by immunohistochemical analysis in primary and metastatic prostate cancers. Consistent with these data, we also show that knockdown of TIP30 expression, through use of a short hairpin RNA-expressing plasmid, suppresses the cellular growth of PC3 and LNCaP prostate cancer cells. Ectopic overexpression of TIP30 stimulates metastatic potential of prostate cancer cells in an in vitro invasion assay, whereas knockdown of TIP30 inhibits the prostate cancer cells invasion. Finally, we demonstrate that ectopic overexpression of TIP30 enhances androgen receptor mediated transcription, whereas knockdown of TIP30 results in a decreased transcription activity. These data provide evidence that TIP30 plays a role in prostate cancer progression and that TIP30 overexpression may promote prostate cancer cell growth and metastasis.

Early gastric carcinoma (EGC) in Chinese patients remains poorly understood and endoscopic therapy has not been well established. Here, we compared endoscopic and clinicopathologic features between early proximal gastric carcinoma (PGC, n = 131) and distal gastric carcinoma (DGC, n = 307) in consecutive 438 EGCs diagnosed with the WHO criteria. By endoscopy, PGCs showed protruding and elevated patterns in 61.9%, while depressed and excavated patterns in 33.6%, which were significantly different from those (32.6% and 64.5%) in DGCs. PGCs were significantly smaller (1.9 cm in average, versus 2.2 cm in DGCs), invaded deeper (22.9% into SM2, versus 13% in DGCs), but had fewer (2.9%, versus 16.7% in DGCs) lymph node metastases. Papillary adenocarcinoma was significantly more frequent (32.1%, versus 12.1% in DGCs), as were mucinous and neuroendocrine carcinomas, carcinoma with lymphoid stroma (6.9%, versus 1.6% in DGCs); but poorly cohesive carcinoma was significantly less frequent (5.3%, versus 35.8% in DGCs). The overall 5-year survival rate was 92.9% in EGCs and PGC patients showed shorter (42.4 months, versus 48.3 in DGCs) survival. Papillary and micropapillary adenocarcinomas and nodal metastasis were independent risk factors for worse survival in EGCs. EGCs in Chinese were heterogeneous with significant differences in endoscopy and clinicopathology between PGC and DGC.

Gastric-type mucinous adenocarcinoma, an uncommon subtype of cervical carcinoma, is characterized by a distinct morphology and immunophenotype. Herein, we report a case of a 71-year-old woman who received neoadjuvant radiotherapy and chemotherapy after cervical biopsy revealed moderately differentiated invasive endocervical adenocarcinoma. Subsequently, the outside patient underwent radical hysterectomy with bilateral salpingo-oophorectomy. The post-neoadjuvant therapy hysterectomy specimen showed tumor cells with clear cytoplasm, hyperchromatic nuclei with irregular contours, which mimicked clear cell carcinoma. However, immunohistochemical staining showed that these tumor cells were positive for carcinoembryonic antigen, cytokeratin 7 (diffuse), and cytokeratin 20 (patchy), After review of the pretreatment cervical biopsy specimen, the tumor was favored to represent a gastric-type mucinous adenocarcinoma of the cervix. Pathologists should be aware of this rare tumor and its post-neoadjuvant therapy morphologic changes, which can make diagnosis more challenging.

The Internet search engines, which have powerful search/sort functions and ease of use features, have become an indispensable tool for many individuals. The current study is to test whether the short-term Internet search training can make people more dependent on it. Thirty-one subjects out of forty subjects completed the search training study which included a pre-test, a six-day's training of Internet search, and a post-test. During the pre- and post- tests, subjects were asked to search online the answers to 40 unusual questions, remember the answers and recall them in the scanner. Un-learned questions were randomly presented at the recalling stage in order to elicited search impulse. Comparing to the pre-test, subjects in the post-test reported higher impulse to use search engines to answer un-learned questions. Consistently, subjects showed higher brain activations in dorsolateral prefrontal cortex and anterior cingulate cortex in the post-test than in the pre-test. In addition, there were significant positive correlations self-reported search impulse and brain responses in the frontal areas. The results suggest that a simple six-day's Internet search training can make people dependent on the search tools when facing unknown issues. People are easily dependent on the Internet search engines. published

To study the potential factors in influencing the performance of immunohistochemical testing for HER2 protein in gastric cancers.The HER2 protein expression status of 1 471 surgically resected archival gastric cancer cases in Drum Tower Hospital collected during two different periods was retrospectively analyzed. The materials included 957 cases tested during the period from 2007 to 2009 (group 1) and 514 cases from 2012 to 2013 (group 2). The test procedures and results observed during these two periods were compared.The percentages of score 3 HER2 protein expression (14.4%, 74/514 versus 9.5%, 91/957) and score 2 or score 3 HER2 protein expression (27.2%, 140/514 versus 21.7%, 208/957) were both higher in group 2 than in group 1 (P0.05). In group 1, the cancer tissue was fixed in 10% formalin, stained manually with HER2 antibody A0485 (Dako) and assessed by different pathologists.In group 2, the tissue was fixed in 10% neutral buffered formalin (pH 7.2), stained using automated immunostaining system (Roche Benchmark XT) with HER2 antibody 4B5 (Ventana) and assessed by a specialized team of pathologists.The results of HER2 immunostaining in gastric cancer are influenced by a number of factors including type of fixative, clone number of primary antibody, staining methods and experience of pathologists.

To explore the pathological features and prognosis of appendiceal mucinous neoplasms (AMN) based on WHO classification 2010.Seventy consecutive cases of AMN were classified into 5 groups according to WHO classification of digestive system tumors in 2010 including mucinous adenomas/cystadenoma (MA), low grade appendiceal mucinous neoplasms (LAMN), low grade pseudomyxoma peritoneum originated from appendix (PMP-L), invasive mucinous adenocarcinomas (MAC) and high grade pseudomyxoma peritoneum originated from appendix (PMP-H). Clinicopathological features, classification, treatment and prognosis of AMN were investigated retrospectively.There were 11 cases of MA with neoplastic epithelium and mucin being defined in lumen and mucosa but without invasive lesions, and no relapse or death was found. In 41 LAMN cases, mucin was found in submucosa, muscularis proparis, or serosa of appendix, no or only scant mucinous epithelium with low grade dysplasia presented in mucinous pools in most cases (39/41). Among 41 LAMN cases, 3 developed relapse or PMP-L, and no death was observed. In 7 PMP-L cases, low grade dysplastic mucinous epithelium in mucinous pools could be found easily in 3 cases and was very scanty in 4 cases, with 1 relapse and 1 death. Eleven invasive carcinomas were found, including 7 MAC cases and 4 PMP-H cases, with local high grade dysplastic epithelium at least. In these invasive lesions, 4 cases recurred and 3 case died (including 2 recurred cases above). MA and LAMN were both non-invasive neoplasms histologically, however, PMP-L, MAC and PMP-H were regarded as adenocarcinomas according to their biological behavior.AMN displays a relatively homogeneous group of neoplasms that pursues a predictable clinical course based on their nature, so it is necessary to diagnose and administrative accurately with consistently standards for these neoplastic entities.

To evaluate tissue regeneration, body reaction, and biological safety of xenogeneous bladder acellular matrix (BAM) that can be used to repair rabbit bladder.Porcine BAM was prepared through physical, chemical, and enzymatic methods, and the effects of acellularization and the structure were observed with HE staining and scanning electron microscope (SEM). Eighteen New Zealand white rabbits (weighing, 2.5-3.0 kg) undergoing partial cystectomy were randomly divided into 2 groups. After partial (about 30%) cystectomy, the porcine BAM was used to replace partial rabbit bladder in the experimental group (n=12), and the incision was directly sutured as control group (n = 6). The survival condition of animals was observed after operation. At 15 days, 1, 2, 3, and 6 months after operation, the blood routine, renal function, and electrolyte were tested by collecting the blood samples. At 1, 2, 3, and 6 months after operation, maximum bladder capacity, bladder leak point pressure, and bladder compliance were measured through urodynamic studies. Then gross observation was performed for regeneration of bladder, and the specimens of the bladder were harvested for HE staining and immunohistochemical staining. The surrounding organs and local lymphoid tissues were harvested for gross observation and HE staining.Cell components were completely removed in the porcine BAM, showing three-dimensional porous structure under SEM. All the animals survived during the experiment. At 15 days after operation, white blood cell count increased, and then returned to normal level in 2 groups, showing no significant difference between 2 groups (P0.05). The tests of renal function and electrolyte suggested no significant difference between 2 groups (P0.05). The level of serum creatinine showed a tendency of increase, but it remained within normal range at 6 months after operation. The maximum bladder capacity and compliance in experimental group were significantly higher than those in control group at 3 and 6 months after operation (P0.05), but no significant difference in bladder leak point pressure at each time point between 2 groups (P0.05). The urothelial regeneration, smooth muscle regeneration, and blood vessel regeneration were seen by histological observation in 2 groups. In the 2 groups, chronic inflammatory cells infiltration could be observed at 1 month postoperatively, and then chronic inflammatory cells decreased significantly (P0.05), until complete disappearance. There was no significant difference in score of chronic inflammatory cell infiltration between 2 groups at 3 and 6 months after operation (P0.05). The alpha-smooth muscle actin expression was significantly increased with time passing in 2 groups (P0.05), and it was significantly higher in control group than in experimental group at each time point (P0.05). In addition, gross and HE staining observations showed no abnormalities in surrounding organs and local lymphoid tissues.No immune rejection response occurs when porcine BAM is used for xenotransplantation. It is indicated that porcine BAM is relative safety for xenotransplantation.

Background: To investigate the immunohistochemical expression profiles of mismatch repair (MMR) genes (MLH1, PMS2, MSH2, and MSH6) and explore their relationships with clinicopathological features and the expressions of P-glycoprotein (Pgp), glutathione-S-transferase (GSTπ), DNA topoisomerase II (Topo II), and cell proliferation antigen Ki-67 in patients with colorectal cancer. Methods: The clinicopathological data of 93 patients with colorectal cancer who had been treated in our hospital from February 2014 to May 2015 were retrospectively analyzed. The expressions of MMR genes (MLH1, PMS2, MSH2, and MSH6), Pgp, GSTπ, Topo II, and Ki-67 in cancer tissues were determined by immunohistochemical staining. Then we used multiple sample rate (or constituent ratio) comparisons (i.e., χ 2 test with R×C table) to analyze the relationships of the expressions of MMR genes (MLH1, PMS2, MSH2, and MSH6) with clinopathology and the expressions of Pgp, GSTπ, Topo II, and Ki-67 in colorectal cancer. Pearson correlation analyses were used to analyze the correlation of the expressions between MMR genes (MLH1, PMS2, MSH2, and MSH6) and Ki-67. Results: The missing expression rate of MMR genes MLH1, PMS2, MSH2, and MSH6 were 14.0%, 17.2%, 10.8%, and 11.8%, respectively. The expression rates of Pgp(−), Pgp (+), Pgp (++), and Pgp (+++) were 3.2%, 25.8%, and 51.6%, 19.3%. The expression rates of GSTπ (−), GSTπ (+), GSTπ (++), and GSTπ (+++) were 3.3%, 16.7%, 56.7%, and 23.3%. Topo II had no negative or level IV expression, and its level I, II and III expressions accounted for 19.3%, 77.4%, and 3.2%. The expression rates of Ki-67 50% (+) accounted for 1.3%, 25%, and 50%, respectively. The missing expressions of MMR genes (MLH1, PMS2, MSH2, and MSH6) showed no significant correlation with gender, age, histological differentiation, and TNM staging (all P>0.05). There was also no significant correlation (P>0.05) between MSH2 missing expression and the lesion location (P>0.05). However, the missing expressions of MLH1, PMS2, and MSH6 showed significant correlation with the lesion location (P 0.05). However, the missing expressions of MLH1, PMS2, MSH2, and MSH6 were significantly correlated with the Ki-67 expression (P 50% (+) were 6.1%, 4.1%, 8.2%, and 6.1%, respectively. MLH1, PMS2, MSH2, and MSH6 missing expressions were negatively correlated with Ki-67 expression (correlation coefficient r=−0.969, r=−0.464, r=−0.143, r=−0.344, respectively; all P Conclusions: The missing expressions of MMR genes (MLH1, PMS2, MSH2, MSH6) are more likely to occur in right colon, followed by left colon and rectum. The missing expressions of these MMR genes are negatively correlated with Ki-67 expression.

Congenital cystic adenomatoid malformation (CCAM), also named congenital pulmonary airway malformation (CPAM), is a congenital abnormality of lung which is uncommon in adults. Here we present 2 adult cases of CCAM with unusual clinical and pathologic findings. One case was complicated with aspergillosis which was seldom reported. The other case was suffered bilateral lesions and the patient's mother had been previously radiographically discovered bilateral cystic lesions that CCAM could not be ruled out. A review of currently published related literatures has also been provided. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6406766736634578.