MicroRNAs involved in drug resistance of breast cancer by regulating autophagy.

Autophagy is a conserved catabolic process characterized by degradation and recycling of cytosolic components or organelles through a lysosome-dependent pathway. It has a complex and close relationship to drug resistance in breast cancer. MicroRNAs (miRNAs) are small noncoding molecules that can influence numerous cellular processes including autophagy, through the posttranscriptional regulation of gene expression. Autophagy is regulated by many proteins and pathways, some of which in turn have been found to be regulated by miRNAs. These miRNAs may affect the drug resistance of breast cancer. Drug resistance is the main cause of distant recurrence, metastasis and death in breast cancer patients. In this review, we summarize the causative relationship between autophagy and drug resistance of breast cancer. The roles of autophagy-related proteins and pathways and their associated miRNAs in drug resistance of breast cancer are also discussed.

Corrigendum: Sperm Protein Antigen 17 Expression Correlates With Lymph Node Metastasis and Worse Overall Survival in Patients With Breast Cancer.

[This corrects the article DOI: 10.3389/fonc.2019.00710.].

Sperm Protein Antigen 17 Expression Correlates With Lymph Node Metastasis and Worse Overall Survival in Patients With Breast Cancer.

Purpose: The expression and role of sperm protein antigen 17 (SPA17), which has been confirmed to be immunogenic, in breast cancer remain unclear. We examined the expression of SPA17 in breast cancer and assessed its effect on patient prognosis and its function in breast cancer development. Methods: SPA17 expression was evaluated by immunohistochemistry and Q-RT-PCR in 120 breast tissue samples. Correlation of SPA17 expression with the patients' clinicopathological parameters and overall survival was assessed. The function of SPA17 was also explored. Results: By reviewing Gene Expression Omnibus datasets, we found that SPA17 expression in ductal breast carcinoma in situ (log2[fold change] = 1.14, p-value = 0.004) and invasive ductal breast cancer (log2[fold change] = 1.03, p-value = 0.016) tissues was 2.20 and 2.05 times higher, respectively, than that in normal breast tissues. Our result also showed that 27% (27/100) of breast cancer samples expressed SPA17 but none of the normal breast (0/20) samples did. Lymph node metastasis (p < 0.001) and molecular subtyping (p = 0.002) were independent factors associated with SPA17 expression. Most importantly, SPA17 expression resulted in poor prognosis. In addition, cell function assay validated that SPA17 increased the migration (p < 0.001) and invasion (p = 0.007) of breast cancer cells, but not affected the proliferation of breast cancer cells. Conclusion: Our results demonstrated the vital role of SPA17 in the development and metastasis of breast cancer and that SPA17 may be a new therapeutic target in improving breast cancer prognosis.

Retrospective observational study about reducing the false negative rate of the sentinel lymph node biopsy: Never underestimate the effect of subjective factors.

Reducing the false negative rate of sentinel lymph node biopsy (SLNB) for breast cancer patients has always been a focus of clinical research. We aimed to map the sentinel lymph nodes (SLNs) in detail, and analyze the factors related to SLNs located at locations that are often ignored by surgeons, to reduce the rate of false negatives from SLNB. A retrospective analysis involving 545 breast cancer patients who underwent SLNB in west China hospital between August 2010 and February 2016 was performed. Blue dye, radioisotope, or combined methods were used for tracing SLNs. Using blue dye, radioisotope, and a combination of blue dye and radioisotope successfully traced SLNs in 479, 507, and 525 patients, the detection rate was 88.2%, 93.9%, and 97.4%, respectively. Among the 1559 detected SLNs, 139 (9.6%) were located at the latissimus dorsi lateral margin, and 108 (6.9%) were located at level 2. Subcutaneous injection of radioisotope (P = .004) and intradermal injection of blue dye (P = .002) were independent factors associated with SLNs distributed at level 2 and the latissimus dorsi lateral margin, respectively. It was noteworthy that 2 of 7 patients had skipping metastasis in level 2, so subcutaneous injection of the isotope is strongly recommended for tracing SLNs distributed in level 2 because of the possibility of skipping metastasis. Though intradermal injection of blue dye was superior methods for tracing SLNs located at the latissimus dorsi lateral margin, we surprisingly found those patients with metastasis to the latissimus dorsi lateral margin nodes also could have metastasis to level 1 (expect for the latissimus dorsi lateral margin) nodes, it seemed that maybe there is no need to excise SLNs at the latissimus dorsi lateral margin in SLNB, whether such nodes should be regarded as useful for SLNB still needs to be determined by further large, multicenter clinical studies.

Clinicopathologic study of invasive micropapillary carcinoma of the breast.

Invasive micropapillary carcinoma (IMPC) is a rare subtype of breast carcinoma. It is presumed to be more aggressive than invasive ductal carcinoma (IDC), though it is uncertain whether the prognoses of IMPC and IDC differ. In this retrospective study, we compared the clinicopathologic characteristics and survival between 170 female patients with IMPC (pure or mixed with IDC) and 728 with pure IDC. The IMPC patients had higher clinical stages and histologic grades, higher incidences of lymphovascular invasion and axillary lymph node extracapsular extension, and a higher degree of lymph node involvement than IDC patients. Moreover, IMPC was associated with increases in estrogen receptor (ER) and progesterone receptor (PR) positivity and HER-2 overexpression. Although locoregional recurrence-free survival (LRRFS) and recurrence-free survival (RFS) were poorer in IMPC patients than IDC patients, overall survival and distant metastasis survival did not differ between the two groups. Multivariate analysis revealed that IMPC was an independent prognostic factor for LRRFS in breast cancer, and IMPC patients had poorer clinicopathologic characteristics and poorer RFS and LRRFS than IDC patients. We therefore suggest that to improve treatment decisions, patients with breast carcinoma be tested for the presence of this specific subtype.

Prediction of ovarian function in premenopausal breast cancer patients with amenorrhoea after chemotherapy: a simple clinical score.

We evaluated a non-invasive method for predicting the ovarian function of premenopausal breast cancer patients with amenorrhoea after chemotherapy. A total of 34 patients had ovarian function, whereas 56 had no ovarian function. Logistic regression analysis indicated that age (P = 0.034; hazards ratio [HR], 0.29; confidence interval [CI], 0.091-0.910), follicle-stimulating hormone (P = 0.032; HR 0.97; CI 0.944-0.997) and oestradiol (P = 0.047; HR 1.01; CI 1.000-1.015) were independent influencing factors that determine ovarian function. The ovarian function score (OFS) (P < 0.001; HR 48.00; CI 10.174-226.452) was obtained through a comprehensive analysis of these three variables, and it could more effectively predict ovarian function. According to receiver operating characteristic curve analysis, the OFS had the highest values compared with the other three variables (sensitivity, 94.6 %; specificity, 79.3 %). The OFS is simple and easy to use; thus, it is expected to become a new method for determining drug-induced amenorrhoea in women with breast cancer. Ovarian function likely still exists if the OFS is ≤1.

Mesohepatectomy versus extended hemihepatectomy for centrally located hepatocellular carcinoma.

BACKGROUND: Extended hemihepatectomy is usually recommended to treat large centrally located hepatocellular carcinoma (HCC). However, the morbidity and mortality are high because of the postoperative liver failure. Mesohepatectomy is seldom used because of its technical complexity. This study aimed to evaluate the short-term and long-term curative effect of mesohepatectomy. METHODS: From January 2002 to September 2008, a total of 198 consecutive patients with centrally located HCC underwent hepatectomy in our department. According to the surgical procedures, they were divided into mesohepatectomy (group M, n=118), extended right hemihepatectomy (group RE, n=47) and extended left hemihepatectomy (group LE, n=33) groups. The surgical techniques, clinical pathological characteristics and outcomes were compared between group M, group RE and group LE. RESULTS: The operative time of group M was significantly longer than that of the other two groups (P<0.05); however the total bilirubin on postoperative day 3 in group M was the lowest among the three groups (P<0.01). In group M, the number of the patients whose resection margin achieving 1 cm was significantly lower than that of the other two groups (P<0.05). The mortality rates in groups M, RE and LE were 2.5%, 8.5% and 3.0%, respectively (P>0.05). The morbidity rate in group M was significantly lower than that in group RE (37.3% vs 55.3%, P=0.034), but not in group LE (37.3% vs 24.2%, P=0.163). The biliary leakage tended to be more common in group M (10.2%, P>0.05). The incidence of postoperative liver failure in group M was significantly lower than that in group RE (1.7% vs 10.6%, P=0.032), but not in group LE (1.7% vs 6.1%, P=0.208). The 1-, 3- and 5-year tumor-free survival rates and the overall survival rates after mesohepatectomy were 53.4%, 30.5% and 16.9% and 67.8%, 45.5% and 28.9%, respectively. CONCLUSIONS: Mesohepatectomy is a safe and effective technique for centrally located HCC patients. Compared with extended right hemihepatectomy, mesohepatectomy can retain residual liver volume to the maximum limit and reduce postoperative liver failure rate. But no significant advantage was found compared mesohepatectomy to extended left hemihepatectomy.

Risk factors associated with early and late recurrence after curative resection of hepatocellular carcinoma: a single institution's experience with 398 consecutive patients.

BACKGROUND: Surgical resection is an important curative treatment for hepatocellular carcinoma (HCC); however, some patients experience an unexpected recurrence even after hepatectomy. The present study aimed to investigate risk factors and predictive criteria for early and late recurrence of HCC after resection. METHODS: A retrospective analysis of 398 Chinese patients who received curative resection for HCC was conducted. Patients were divided into three groups: without recurrence, early recurrence, and late recurrence. Prognostic factors and predictive criteria for early and late recurrence were statistically analyzed. RESULTS: The cumulative recurrence-free survival rates at 1, 2, 3, 4, and 5 years were 75.5%, 58.2%, 54.1%, 40.5%, and 28.7%, respectively. The distribution of the time to recurrence suggested that recurrence could be divided into early phase (before 2 years; n=164) and late phase (after 2 years; n=83). Cox's multivariate proportional hazard model analysis revealed that multiplicity of tumors (P=0.004) and venous infiltration (P=0.002) were independent risk factors associated with early recurrence. In contrast, indocyanine green retention rate at 15 minutes (P=0.007), serum albumin level (P=0.045), and HBeAg status (P=0.028) proved to be significant independent adverse prognostic factors for late recurrence. Patients with at least 1 of the 2 early recurrence risk factors (multiplicity of tumors ≥ 2 and venous infiltration) or with 2 or more late recurrence risk factors are often susceptible to recurrence (P=1.36e-4 and 1.0e-6, respectively). CONCLUSIONS: Early and late recurrences correlate with different risk factors and predictive criteria. Early recurrence primarily results from intrahepatic metastases, while late recurrence may be multicentric in origin.

An accurate predictor of liver failure and death after hepatectomy: a single institution's experience with 478 consecutive cases.

AIM: To establish a reliable definition of postoperative liver failure (PLF) and allow the prediction of outcomes after hepatectomy. METHODS: The clinical data of 478 consecutive patients who underwent hepatectomy were retrospectively analyzed. The examined prognostic factors included the ratio of total bilirubin (TBIL) on postoperative day (POD) X to TBIL on POD 1 (TBIL-r1) and the ratio of the international normalized ratio (INR) on POD X to the INR on POD 1 (INR-r1) for PODs 3, 5 and 7. Student's t test, the χ(2) test, logistic regression, survival analysis and receiver operating curve analysis were used to evaluate risk factors and establish the definition of postoperative liver failure (PLF). RESULTS: Fourteen patients (2.9%) died of liver failure within 3 mo of surgery. Significant differences were found between patients who died of liver failure and the remaining patients in terms of TBIL-r1 and INR-r1 on PODs 3, 5 and 7. The combination of TBIL-r1 and INR-r1 on POD 5 showed strong predictive power for liver failure-related death (sensitivity 92.9% and specificity 90.1%). The hepatic damage score (HDs), which was derived from TBIL-r1 and INR-r1, was used to define the degree of metabolic functional impairment after resection as mild (HDs = 0), reversible hepatic "dysfunction" (HDs = 1) or fatal hepatic failure (HDs = 2). Furthermore, the indocyanine green retention rate at 15 min (ICG-R15) and the number of resected segments (RSs) were identified as independent predictors of the HDs. A linear relationship was found between ICG-R15 and RSs in the HDs = 2 group. The regression equation was: RSs = -0.168 × ICG-R15 + 5.625 (r (2) = 0.613, F = 14.257, P = 0.004). CONCLUSION: PLF can be defined by the HDs, which accurately predicts liver failure-related death after liver resection. Furthermore, the ICG-R15 and RSs can be used as selection criteria for hepatectomy.

A new scoring system for assessment of liver function after successful hepatectomy in patients with hepatocellular carcinoma.

BACKGROUND: Whether a major liver resection is safe has been judged mainly from the patient's hepatic reserve. However, a safe limit for liver resection does not exist yet. This study aimed to construct a new scoring system as a guide to determine a safe limit for liver resection and avoid liver dysfunction after hepatectomy. METHODS: Eighty-six patients with hepatocellular carcinoma who had undergone hepatectomy in West China Hospital from March 2007 to June 2010 were reviewed. The patients were classified according to the levels of total bilirubin after hepatectomy and the parameters in the perioperative period were compared. Receiver operating characteristic (ROC) analysis was made to assess the liver function compensatory (LFC) value to predict liver dysfunction of the patients after hepatectomy. LFC value is defined as the preoperative K(ICG) value x 22.487 + standard remnant liver volume (SRLV) x 0.020. RESULTS: Patients were classified into group I (normal group, n=69) and group II (with total bilirubin >85.5 µmol/L for 7 days after hepatectomy, n=17) based on the levels of total bilirubin after hepatectomy. Group II was further divided into two subgroups: recovered subgroup (n=14) and fatal subgroup (n=3). There were no significant differences in preoperative data or intraoperative findings except the indocyanine green test parameters (K(ICG) and ICG R15) and SRLV. ROC analysis showed that the sensitivity and specificity of an LFC value ≤13.01 were 94.1% and 82.6% respectively for predicting liver dysfunction of the patients after hepatectomy. CONCLUSIONS: The LFC value appears to be a good predictor of postoperative liver dysfunction in patients who undergo hepatectomy for HCC. An expected LFC value of 13.01 seems to be a safe limit for liver resection.

[Combined indocyanine green test and standard remnant liver volume to predict post-hepatectomy hepatic insufficiency for the patients with hepatocellular carcinoma].

OBJECTIVE: To discuss the safety line to avoid the post-hepatectomy hepatic insufficiency by combining indocyanine green test by pulse dye-densitometry (PDD-ICG) and standard remnant liver volume (SRLV). METHODS: Seventy-five hepatic cancer patients undergone hepatectomy from March 2007 to February 2008 were included. According to the liver function decompensatory grades after operation, the relationship between ICG retention rate at 15 min (ICGR15) and standard remnant liver volume by linear regression were analyzed. RESULTS: There were 60 cases with slight hepatic insufficiency, 12 cases with moderate hepatic insufficiency, and 3 cases with severe hepatic insufficiency. There were no difference in age [(50 +/- 13) years old and (53 +/- 9) years old], prothrombin time [(13.6 +/- 1.0) s and (13.5 +/- 1.0) s], international normalized ratio (1.09 +/- 0.10 and 1.06 +/- 0.10) between slight hepatic insufficiency group and moderate and severe hepatic insufficiency group (P > 0.05). And there were difference in K value (0.20 +/- 0.04 and 0.17 +/- 0.03), ICGR15 (6 +/- 4 and 9 +/- 4), SRLV [(545 +/- 93) ml and (398 +/- 82) ml] between two groups (P < 0.05). Compared ICG test and standard remnant liver volume of the patients with moderate hepatic insufficiency after operation, the liner relationship was found (R = 0.640, P = 0.025), and the regression equation was: standard remnant liver volume (ml/m(2)) = 1594.6 x ICGR15 + 265. CONCLUSIONS: PDD-ICG test and standard remnant liver volume are effective to estimate hepatic function reserve of patient undergone hepatectomy.