Somatic and germline aberrations in homologous recombination repair genes among Chinese high-risk breast cancer patients by multi-gene next-generation sequencing.

INTRODUCTION: Recently, genes involved in homologous recombination repair (HRR) pathway have been extensively studied. However, the landscapes of HRR gene mutations remain poorly defined in Chinese high-risk breast cancer (BC) patients. Our study aims to identify the status of germline and somatic HRR gene mutations and their association with clinicopathological features in these patients. MATERIALS AND METHODS: A total of 100 high-risk BC patients from our institution who underwent paired peripheral blood germline and BC tissues somatic 26 genes next-generation sequencing (NGS) from January 2018 to July 2023 were enrolled for retrospective analysis. RESULTS: Out of 100 high-risk BC patients, 55 (55%) had at least one germline or somatic mutation in HRR genes. Among them, 22% carried germline pathogenic variants (19 BRCA1/2 and 3 non-BRCA genes), 9% harbored somatic pathogenic mutations (3 BRCA1/2 and 6 non-BRCA genes). Among high-risk factors, family history and early onset BC showed a correlation with HRR gene mutations (p < 0.05). BRCA1 germline and HRR gene somatic mutations showed a correlation with TNBC, but BRCA2 germline mutations were associated with Luminal B/HER2-negative BC (p < 0.05). Patients with HRR gene somatic pathogenic variant more likely had a lympho-vascular invasion and distant metastasis (p < 0.05). CONCLUSION: The prevalence of HRR gene germline and somatic mutations were higher in Chinese BC patients with high risk factors. We strongly recommend that these high-risk BC patients receive comprehensive gene mutation testing, especially HRR genes, which are not only related to genetic consultation for BC patients and provide a theoretical basis for necessary prevention and individualized treatment.

Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer.

In gastric cancer, lymph node metastasis (LNM) is the major metastasis route, and lymphatic invasion is the precursor of LNM. Tumor-associated neutrophils (TANs) promote LNM. However, the molecular mechanisms underlying TANs-mediated lymphatic invasion and/or LNM remain unclear. Herein, we revealed that high level of TANs was the independent risk factor for lymphatic invasion and LNM respectively, and lymphatic tumor cell-neutrophil clusters were positively correlated with LNM. Crosstalk between neutrophils and tumor cells was required for enhanced tumor cell invasiveness, endowing neutrophils to boost epithelial-to-mesenchymal transition (EMT) of tumor cells and in turn promoting LNM. Mechanically, tumor cells educated neutrophils via TGFß1 to produce more FAM3C through Smad2/3 signaling activation, and FAM3C promoted tumor cell EMT through JNK-ZEB1/Snail signaling pathway. The crosstalk enhanced the affinity of neutrophils with tumor cells through interaction of integrins α6ß1 and α6ß4 with CD151. Furthermore, studies using tumor-bearing mice demonstrated that neutrophils were the important driver for gastric cancer tumorigenesis and invasiveness. The study clearly identifies the functional roles of TANs in promoting tumor invasion, and facilitates a better understanding of novel mechanisms responsible for LNM of gastric cancer, which provides potential targets for developing new strategies to prevent or treat LNM in gastric cancer.

Naringin Interferes Doxorubicin-Induced Myocardial Injury by Promoting the Expression of ECHS1.

Doxorubicin (DOX) leads to myocardial cell damage and irreversible heart failure, which limits the clinical application of DOX. Naringin has biological functions of inhibiting inflammation, oxidative stress and apoptosis. Our aim was to investigate whether Naringin could prevent DOX-related cardiotoxicity in mice. Naringin was administered by gavage and mice were intraperitoneally injected with doxorubicin (1 mg/kg/day) for 15 days. H&E, Masson, TUNEL and others experiments were examined. NRVMs and H9C2 cells were treated with Naringin and DOX in vitro. Using IF, ELISA and Western Blot to detect the effect of Naringin and ECHS1 on cells. The results showed that Naringin could prevent DOX related cardiac injury, inhibit cardiac oxidative stress, inflammation and apoptosis in vivo and in vitro. Inhibition of ECHS1 could interfere the effect of Naringin on DOX-induced myocardial injury. Naringin may provide a new cardiac protective tool for preventing the cardiotoxicity of anthracycline drugs.

[Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021, interpretation and expectation].

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.

Prediction of BRCA Gene Mutation in Breast Cancer Based on Deep Learning and Histopathology Images.

BACKGROUND: Breast cancer is one of the most common cancers and the leading cause of death from cancer among women worldwide. The genetic predisposition to breast cancer may be associated with a mutation in particular genes such as gene BRCA1/2. Patients who carry a germline pathogenic mutation in BRCA1/2 genes have a significantly increased risk of developing breast cancer and might benefit from targeted therapy. However, genetic testing is time consuming and costly. This study aims to predict the risk of gBRCA mutation by using the whole-slide pathology features of breast cancer H&E stains and the patients' gBRCA mutation status. METHODS: In this study, we trained a deep convolutional neural network (CNN) of ResNet on whole-slide images (WSIs) to predict the gBRCA mutation in breast cancer. Since the dimensions are too large for slide-based training, we divided WSI into smaller tiles with the original resolution. The tile-based classification was then combined by adding the positive classification result to generate the combined slide-based accuracy. Models were trained based on the annotated tumor location and gBRCA mutation status labeled by a designated breast cancer pathologist. Four models were trained on tiles cropped at 5×, 10×, 20×, and 40× magnification, assuming that low magnification and high magnification may provide different levels of information for classification. RESULTS: A trained model was validated through an external dataset that contains 17 mutants and 47 wilds. In the external validation dataset, AUCs (95% CI) of DL models that used 40×, 20×, 10×, and 5× magnification tiles among all cases were 0.766 (0.763-0.769), 0.763 (0.758-0.769), 0.750 (0.738-0.761), and 0.551 (0.526-0.575), respectively, while the corresponding magnification slides among all cases were 0.774 (0.642-0.905), 0.804 (0.676-0.931), 0.828 (0.691-0.966), and 0.635 (0.471-0.798), respectively. The study also identified the influence of histological grade to the accuracy of the prediction. CONCLUSION: In this paper, the combination of pathology and molecular omics was used to establish the gBRCA mutation risk prediction model, revealing the correlation between the whole-slide histopathological images and gRCA mutation risk. The results indicated that the prediction accuracy is likely to improve as the training data expand. The findings demonstrated that deep CNNs could be used to assist pathologists in the detection of gene mutation in breast cancer.

Systematic Analysis of mRNAs and ncRNAs in BMSCs of Senile Osteoporosis Patients.

Senile osteoporosis (SOP) is a worldwide age-related disease characterized by the loss of bone mass and decrease in bone strength. Bone mesenchymal stem cells (BMSCs) play an important role in the pathology of senile osteoporosis. Abnormal expression and regulation of non-coding RNA (ncRNA) are involved in a variety of human diseases. In the present study, we aimed to identify differentially expressed mRNAs and ncRNAs in senile osteoporosis patient-derived BMSCs via high-throughput transcriptome sequencing in combination with bioinformatics analysis. As a result, 415 mRNAs, 30 lncRNAs, 6 circRNAs and 27 miRNAs were found to be significantly changed in the senile osteoporosis group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to analyze the function of differentially expressed mRNAs and ncRNAs. The circRNA-miRNA-mRNA regulatory network was constructed using the cytoHubba plugin based on the Cytoscape software. Interestingly, circRNA008876-miR-150-5p-mRNA was the sole predicted circRNA-miRNA-mRNA network. The differential expression profile of this ceRNA network was further verified by qRT-PCR. The biological function of this network was validated by overexpression and knockdown experiments. In conclusion, circRNA008876-miR-150-5p-mRNA could be an important ceRNA network involved in senile osteoporosis, which provides potential biomarkers and therapeutic targets for senile osteoporosis.

Molecular screening and clinicopathologic characteristics of Lynch-like syndrome in a Chinese colorectal cancer cohort.

Colorectal cancers (CRC) with microsatellite instability (MSI) or mismatch repair-deficiency (dMMR), but without detectable MMR germline mutations are termed Lynch-like syndrome (LLS). We assess the clinicopathologic and molecular characteristics of LLS tumors and the proportion in LLS, which remain poorly investigated in China. We enrolled 404 CRC patients with surgery in our institution from 2014 to 2018. LLS tumors were detected by a molecular stratification based on MMR protein expression, MLH1 methylation and MMR gene mutation. LLS tumors were profiled for germline mutations in 425 cancer-relevant genes. Among 42 MMR-deficient tumors, 7 (16.7%) were attributable to MLH1 methylation and 7 (16.7%) to germline mutations, leaving 28 LLS cases (66.6%). LLS tumors were diagnosed at a mean age of 60.7 years, had an almost equivalent ratio among rectum, left colon and right colon, and had high rates of lymph node metastases (50%, 4/28 N2). Most MMR gene mutations (88.2%, 15/17) in LLS tumors were variants of unknown significance (VUS). Two novel frameshift mutations were detected in ATM and ARID1A, which are emerging as candidate responsible genes for LLS. In this study, 28 (66.6%) MMRd tumors were classified as LLS, which were significantly higher than reports of western countries. LLS tumors were more likely to carry lymph node metastases. However, it's hard to differentiated LLS tumors from LS through family history, tumor location, histological type of tumors, immunohistochemistry (IHC) for MMR proteins and MSI analysis.

Tumor-Associated Neutrophils Can Predict Lymph Node Metastasis in Early Gastric Cancer.

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.

Distinct clinicopathological differences between early gastric cardiac and non-cardiac carcinomas: a single-center retrospective study of 329 radical resection cases.

BACKGROUND: Early gastric carcinoma is heterogeneous and can be divided into early gastric cardiac carcinoma (EGCC) and early gastric non-cardiac carcinoma (EGNCC) groups. At present, differences in clinicopathology remains obscure between EGCC and EGNCC fundus-corpus and antrum-angularis-pylorus subgroups, especially between EGCC with and without oesophageal invasion. METHODS: In this study, we studied 329 consecutive early gastric carcinoma radical gastrectomies with 70 EGCCs and 259 EGNCCs. RESULTS: Compared to the EGNCC antrum-angularis-pylorus (n = 181), but not fundus-corpus (n = 78), sub-group, EGCC showed significantly older age, lower prevalence of the grossly depressed pattern, better tumor differentiation, higher percentage of tubular/papillary adenocarcinoma, but lower frequency of mixed poorly cohesive carcinoma with tubular/papillary adenocarcinoma, and absence of lymph node metastasis (LNM) in tumors with invasion up to superficial submucosa (SM1). In contrast, pure poorly cohesive carcinoma was less frequently seen in EGCCs than in EGNCCs, but mixed poorly cohesive carcinoma with tubular/papillary adenocarcinomas was significantly more common in the EGNCC antrum-angularis-pylorus sub-group than in any other group. No significant differences were found between EGCC and EGNCC sub-groups in gender, tumor size, H. pylori infection rate, and lymphovascular/perineural invasion. EGCC with oesophageal invasion (n = 22), compared to EGCC without (n = 48), showed no significant differences in the H. pylori infection rate and oesophageal columnar, intestinal, or pancreatic metaplasia, except for a higher percentage of the former in size > 2 cm and tubular differentiation. CONCLUSIONS: There exist distinct clinicopathologic differences between EGCC and EGNCC sub-groups; EGCC was indeed of gastric origin. Further investigations with larger samples are needed to validate these findings.

Sensitivity and polymorphism of Bethesda panel markers in Chinese population.

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 207bp to 234bp, 140bp to 169bp and 109bp to 137bp, 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.

Superficial esophageal lymphoepithelioma-like carcinoma treated with endoscopic submucosal dissection: a case report.

Lymphoepithelioma-like carcinoma (LELC) of esophagus is an extremely rare tumor only a few cases were successfully treated with endoscopic submucosal dissection (ESD). We herein report one case of superficial esophageal LELC with adjacent squamous intraepithelial neoplasia successfully treated by ESD, and the status of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) were detected simultaneously. A 71-year-old woman presented with complaints of substernal discomfort. Under endoscopy, a dome-shaped bulge of 1.2 cm × 0.8 cm was located at the mucosal lamina propria in the left lateral wall of the middle esophagus, and the mucosa covering the bulge was smooth and normal-appearing. A brownish lesion was found adjacent to the bulge. Microscopically, the tumor was well demarcated, and nests of syncytial epithelioid cells were identified in the lamina propria of the mucosa, with a large number of inflammatory cells. The squamous epithelium covering the surface of the infiltrating tumor and the second brownish lesion demonstrated low grade squamous intraepithelial neoplasia. Tumor tissue showed CK5/6, p63, and p40 positive staining, was EBV negative, and had microsatellite stability. After treatment with ESD, this patient received no further treatment, and had no recurrence or metastasis at 25-month follow-up.

Quantification of perineural invasion focus after radical prostatectomy could improve predictive power of recurrence.

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.

Pancreatic Ductal Adenocarcinoma: Machine Learning-Based Quantitative Computed Tomography Texture Analysis For Prediction Of Histopathological Grade.

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.

Microphthalmia family of transcription factors associated renal cell carcinoma.

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.

Tumor Budding and Other Risk Factors of Lymph Node Metastasis in Submucosal Early Gastric Carcinoma: A Multicenter Clinicopathologic Study in 621 Radical Gastrectomies of Chinese Patients.

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 tumors <1.0 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.

Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer.

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.

Germline TP53 and MSH6 mutations implicated in sporadic triple-negative breast cancer (TNBC): a preliminary study.

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.

Micropapillary early gastric carcinoma with distinct clinicopathological features, high risk for lymph node metastasis, and dismal prognosis: a multicenter clinicopathological study of 29 cases identified in 1890 early gastric carcinoma radical gastrectomies.

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.

Oridonin-loaded and GPC1-targeted gold nanoparticles for multimodal imaging and therapy in pancreatic cancer.

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.