Serum semaphorin 4C as a diagnostic biomarker in breast cancer: A multicenter retrospective study.

BACKGROUND: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. METHODS: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan-cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre-treatment serum SEMA4C levels, measured using optimized in-house enzyme-linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post-surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. RESULTS: We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900-0.941) and 0.932 (95%CI: 0.911-0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early-stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916-0.946) and 0.879 (95%CI: 0.832-0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. CONCLUSIONS: Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.

LncRNA-HAGLR motivates triple negative breast cancer progression by regulation of WNT2 via sponging miR-335-3p.

BACKGROUND: Triple negative breast cancer (TNBC) is a group of highly heterogeneous mixed breast cancer at the level of gene expression profile. Therefore, it is of great clinical significance to explore the molecular mechanism of TNBC and find a targeted therapeutic approach from the molecular level. METHODS: Long non-coding RNA (lncRNA) HAGLR expression level was measured by and qRT-PCR in TNBC tissues and cell lines. EdU, MTT, wound healing and Transwell assays were performed to explore the role of HAGLR on the malignancy of TNBC cells. Luciferase assay was used to clarify the binding between miR-335-3p with HAGLR and WNT2. The tumor formation experiment in nude mice was used to explore the function of HAGLR in vivo. RESULTS: HAGLR was increased in TNBC tissues and cell lines. Silencing of HAGLR inhibited viability, proliferation, migration, and invasion of BT549 cells. Furthermore, HAGLR acted as a sponge of miR-335-3p and inhibited its expression. And miR-335-3p directly targeted WNT2. Functionally, forced expression of miR-335-3p or knockdown of WNT2 removed the promoted effects of lncRNA HAGLR on TNBC development. In vivo tumorigenesis experiments indicated HAGLR accelerated tumor growth via miR-335-3p/WNT2 axis. CONCLUSION: Our study revealed that HAGLR promoted the growth of TNBC, which was mediated by miR-335-3p/WNT2 axis.

Nuclear Her2 contributes to paclitaxel resistance in breast cancer cells.

Translocation of full-length Her2 receptor into nucleus was reported by some studies. Here, we tested whether nuclear Her2 contributes to paclitaxel resistance in Her2-overexpressing breast cancer cells. Breast cancer cell was transfected with plasmids containing cDNA of wild-type Her2 or mutant-type Her2 lacking the nuclear localization signal (NLS) sequence which is required for Her2 nuclear transport. Cell resistance to paclitaxel was analyzed. Paclitaxel-resistant breast cancer cell was also developed and nuclear Her2 expression was tested. Then, correlation between nuclear Her2 and resistance to paclitaxel were analyzed. Expression of importin ß1 was decreased to downregulate nuclear Her2 level and cell resistance to paclitaxel was tested. We found that Her2 overexpression increases Her2 nuclear expression and cells resistance to paclitaxel in MCF-7 cells. In the paclitaxel resistant cell (SK-BR-3/R), nuclear Her2 expression is upregulated compared with parental SK-BR-3 cells. Increased expression of nuclear Her2 after short-time (48 h) treatment of paclitaxel was also observed in SK-BR-3 cells. Further downregulation of Her2 nuclear expression through blocking expression of importin ß1 sensitizes the cells to paclitaxel. The analysis showed that the Her2 nuclear expression increases the survivin expression which leads to resistance to paclitaxel. Her2 nuclear expression decreases paclitaxel-induced apoptosis. However, co-immunoprecipitation was applied, and the physical interaction of nuclear Her2 and survivin was not detected. We show for the first time that nuclear Her2 contributes to paclitaxel resistance in breast cancer cells which suggests that nuclear Her2 as a potential target to sensitize breast cancers to paclitaxel treatment.

Chemotherapy for breast cancer progresses to liver metastases after surgery and systemic treatment.

BACKGROUND: This study aims to evaluate the effectiveness of hepatic arterial infusion chemotherapy/portal vein infusion chemotherapy (HAIC/PVIC), transcatheter hepatic arterial chemoembolization (TACE) and transcatheter arterial embolization (TAE) for unresectable breast cancer liver metastases (UBCLM). METHODS: The present study included 57 patients. These patients were randomly divided into three groups (n=19, each): HAIC/PVIC group, TACE group and TAE group. Patients in the HAIC/PVIC group were treated with the same systemic chemotherapy regimen previously received by infusion through an intra-arterial and portal vein catheter. Patients in the TACE group received cyclophosphamide, epirubicin and 5-fluorouracil, and embolization. Patients in the TAE group were only treated with embolization. RESULTS: The median number of treatments was 6 (range, 3-13) in the HAIC/PVIC group, 5 (range, 4-9) in the TACE group, and 6 (range, 4-8) in the TAE group. The 1-, 2- and 3-year survival rates for these groups were 18/19 (94.7%), 14/19 (73.7%) and 11/19 (57.9%), 14/19 (73.7%), 9/19 (47.4%) and 8/19 (42.1%), and 8/19 (42.1%), 4/19 (21.1%) and 0/19 (0%), respectively. The median overall survival from the original breast cancer diagnosis was 88 (range, 11-133), 75 (range, 9-115), and 49 (range, 10-64) months in the HAIC/PVIC, TACE and TAE groups, respectively. Grade I-II and grade III-IV bone marrow suppression was observed in 12/19 (63.2%) and 3/19 (15.8%) patients in the HAIC/PVIC group, respectively, in 17/19 (89.5%) and 5/19 (26.3%) patients in the TACE group, respectively, and in 0/19 (0%) and 0/19 (0%) patients in the TAE group, respectively. CONCLUSIONS: HAIC/PVIC with the same regional chemotherapy regimen of the original systemic treatment is feasible, and can benefit patients with UBCLM, who have progressed on prior systemic therapies.

Adjacent skin rotation flap for large defect in primary breast tumor.

BACKGROUNDS: Surgical resection of large primary breast tumor often results in large chest wall defects. The purpose of this study is to evaluate the feasibility of using adjacent skin rotation (ASR) flap in patients with giant primary breast tumor. METHODS: A total of 26 giant primary breast tumor patients treated with ASR flap were included in this study. The postoperative conditions, including operating time, blood loss, length of hospital stay, and clinical complications were observed. Meanwhile, the information on 17 breast tumor patients treated with transverse rectus abdominis myocutaneous (TRAM) flap were collected and assigned to a control group. RESULTS: The mean defect size after mastectomy was 16.7 × 13.4 cm, while the median follow-up period was 13 months after surgery. A total of 15.4% patients had developed with local complications, and one of them had more than one complication. When comparing the postoperative outcomes, statistically significant differences were found between the two groups with respect to operating time, blood loss, and length of hospital stay (P < 0.001). CONCLUSIONS: ASR flap is a reliable technique for immediate reconstruction of massive chest wall defects in patients with giant primary breast tumor.

Identification of potential core genes in triple negative breast cancer using bioinformatics analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome and limited treatment options. Lacking molecular targets, chemotherapy is the main adjuvant treatment for TNBC patients. MATERIALS AND METHODS: To explore potential therapeutic targets for TNBC, we analyzed three microarray datasets (GSE38959, GSE45827, and GSE65194) derived from the Gene Expression Omnibus (GEO) database. The GEO2R tool was used to screen out differentially expressed genes (DEGs) between TNBC and normal tissue. Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery to identify the pathways and functional annotation of DEGs. Protein-protein interaction of these DEGs was analyzed based on the Search Tool for the Retrieval of Interacting Genes database and visualized by Cytoscape software. In addition, we used the online Kaplan-Meier plotter survival analysis tool to evaluate the prognostic value of hub genes expression in breast cancer patients. RESULTS: A total of 278 upregulated DEGs and 173 downregulated DEGs were identified. Among them, ten hub genes with a high degree of connectivity were picked out. Overexpression of these hub genes was associated with unfavorable prognosis of breast cancer, especially, CCNB1 overexpression was observed and indicated poor outcome of TNBC. CONCLUSION: Our study suggests that CCNB1 was overexpressed in TNBC compared with normal breast tissue, and overexpression of CCNB1 was an unfavorable prognostic factor of TNBC patients. Further study is needed to explore the value of CCNB1 in the treatment of TNBC.

Is laparoscopic appendectomy feasible for complicated appendicitis ?A systematic review and meta-analysis.

BACKGROUND: laparoscopic appendectomy(LA) has proved to be a safe alternative to open appendectomy(OA) in uncomplicated appendicitis; however, the feasibility of LA for complicated appendicitis(CA) has not been conclusively determined. OBJECTIVES: To assess the feasibility and safety of LA for CA through a systematic review and meta-analysis. METHODS: A literature search in PubMed, Embase, Cochrane Library, and web of Science was performed for eligible studies published from the inception of the databases to January 2016. All studies comparing LA and OA for CA were reviewed. After literature selection, data extraction and quality assessment were performed by two reviewers independently, and meta-analysis was conducted using Revman software, vision 5.2. RESULTS: Two randomized controlled trials (RCTs) and 14 retrospective cohort studies(RCSs) were finally identified. Our meta-analysis showed that LA for CA could reduce the rate of surgical site infections (SSIs) (OR = 0.28; 95% CI: 0.25 to0.31, P < 0.00001), but LA did not increase the rate of postoperative intra-abdominal abscess(IAA) (OR = 0.79; 95% CI: 0.45 to 1.34, P = 0.40). The results showed that the operating time in the LA groups was much longer than that in the OA groups (WMD = 13.78, 95% CI: 8.99 to 18.57, P < 0.00001). However, the length of hospital stays in the LA groups were significantly shorter than those in the OA groups (WMD = -2.47, 95%CI: -3.75 to -1.19, P < 0.0002), and the time until oral intake(TTOI) was much earlier in the LA groups than in the OA groups (WMD = -0.88, 95% CI: -1.20 to -0.55, P < 0.00001). No significant difference was observed in the times of postoperative analgesia between the two groups(P > 0.05). CONCLUSION: LA was feasible and safe for complicated appendicitis, and it not only could shorten the hospital stays and the time until oral intake, but it could also reduce the risk of surgical site infection.

Effect of immune suppression on metastasis in a patient with hepatocellular carcinoma metastasized to the colon and stomach: A case report.

Hepatocellular carcinoma (HCC) is a highly malignant cancer, which can invade the portal vein and cause liver/long bone metastasis, although digestive tract metastatic tumor from the liver is very rare. This case report describes an unusual case of HCC (clear cell type), determined by pathology of the original liver tumor resected on March 16th, 2004. The patient returned to our hospital in February and July 2009 complaining of 'black stool' in the first instance, and 'anemia' on the second occasion. Colonoscopy and gastroscopy indicated colon cancer and stomach cancer, respectively. The right half colon and distal stomach were resected, and pathological inspection revealed liver cancer metastasis. The patient succumbed to respiratory failure due to liver cancer lung metastasis on the May 23rd, 2013. Tests for CD4+ and CD8+ T cells and the CD4+/CD8+ ratio, in addition to the expression of Fas, Fas ligand (FasL), indicated an evident difference in patient immunity during the tumor metastasis period. The disease progression in this patient suggested that immune surveillance may have been involved in the metastases. Furthermore, this case shows that clinicians should be alert to the possibility of metastases in uncommon sites that may be misdiagnosed as primary tumors. Surgical resection remains a valuable treatment for isolated digestive tract metastasis from liver cancer.

Effect of BRCA2 mutation on familial breast cancer survival: A systematic review and meta-analysis.

Reports of BRCA2 genetic mutations on the prognosis of familial breast cancer (BC) patients have been contradictory. True difference in survival, if it exists, would have important implications for genetic counseling and in treatment of hereditary BC. The purpose of this study was to compare overall survival rate (OSR) among BRCA2 mutation carriers, non-carriers and sporadic BC patients. We searched the PUBMED and EMBASE databases and retrieved 4529 articles using keywords that included breast cancer, BRCA, prognosis and survival. Nine articles were selected for systematic review and among them 6 were included in our meta-analysis. We used the fixed and random effect models to calculate the summary odds ratio (OR) and corresponding 95% confidence interval (CI). BRCA2 mutation carriers had significantly higher long-term OSR than non-carriers (OR=0.69 [95% CI=0.5-0.95]), while both short-term and long-term OSR of BRCA2 mutation carriers did not differ from those of patients with sporadic disease (OR=1.11 [95% CI=0.74-1.65]; 0.85 [95% CI=0.38-1.94], respectively). For BC-specific survival rate (BCSSR), BRCA2 mutation carriers had a similar BCSSR to the non-carriers (OR=0.61 [95% CI=0.28-1.34]). There was no significant difference in disease-free survival (DFS) between BRCA2 mutation carriers and patients with sporadic disease. Our results suggest that BRCA2 mutation increases long-term OSR in hereditary BC, which reminds us a new prospect of management of the disease.

Efficiency and prognosis of whole brain irradiation combined with precise radiotherapy on triple-negative breast cancer.

AIM: To investigate the treatment efficiency of whole brain irradiation combined with precise radiotherapy on triple-negative (TN) phenotype breast cancer patients with brain metastases and their survival times. MATERIALS AND METHODS: A total of 112 metastatic breast cancer patients treated with whole brain irradiation and intensity modulated radiotherapy (IMRT) or 3D conformal radiotherapy (3DCRT) were analyzed. Thirty-seven patients were of TN phenotype. Objective response rates were compared. Survival times were estimated by using the Kaplan-Meier method. Log-rank test was used to compare the survival time difference between the TN and non-TN groups. Potential prognostic factors were determined by using a Cox proportional hazard regression model. RESULTS: The efficiency of radiotherapy treatment on TN and non-TN phenotypes was 96.2% and 97%, respectively. TN phenotype was associated with worse survival times than non-TN phenotype after radiotherapy (6.9 months vs. 17 months) (P < 0.01). On multivariate analysis, good prognosis was associated with non-TN status, lower graded prognosis assessment class, and nonexistence of active extracranial metastases. CONCLUSION: After whole brain irradiation followed by IMRT or 3DCRT treatment, TN phenotype breast cancer patients with intracranial metastasis had high objective response rates but shorter survival time. With respect to survival in breast cancer patients with intracranial metastasis, the TN phenotype represents a significant adverse prognostic factor.

Effect of nonparallelism of guiding air-liquid layers on the reflection dip in attenuated total reflection.

The effect attributable to the nonparallelism of the guiding layer of a planar waveguide on the reflection dip of the attenuated total reflection (ATR) spectrum is investigated. It is considered that the reflected light from a nonparallel waveguide is, indeed, the superposition of a series of beams propagating in different directions. The ATR spectra are numerically calculated with various inclination values. Compared with those of the corresponding parallel ones, with the inclination of waveguides exceeding 1 microrad, the characteristics of the ATR spectra begin to differ considerably, and when the inclination reaches 10 microrad, the sensitivity of sensors based on the waveguide is reduced by 62.7% and 67.3% for the free space coupling structure and the prism coupling structure, respectively. When the inclination becomes larger than 100 microrad, the ATR phenomenon cannot be observed any longer.

Optical approach to angular displacement measurement based on attenuated total reflection.

An optical approach for angular displacement measurement (ADM) based on the attenuated total reflection technique is presented. As a laser beam is incident upon a planar optical waveguide, an m line is obtained by scanning the incident angle. Theoretical analysis shows that the m line sharply shifts with a tiny variation of the thickness of the waveguided layer. And the specific schemes for ADM, which are based on the angular interrogation and the intensity measurement, are analyzed. The calculated result of sensitivity demonstrates that the intensity measurement is more efficient than the angular interrogation. Furthermore, small incident angles indicate higher sensitivity to the angular displacement than relatively large incident angles for the intensity measurement.