A novel machine learning prediction model for metastasis in breast cancer.

BACKGROUND: Breast cancer (BC) metastasis is the common cause of high mortality. Conventional prognostic criteria cannot accurately predict the BC metastasis risk. The machine learning technologies can overcome the disadvantage of conventional models. AIM: We developed a model to predict BC metastasis using the random survival forest (RSF) method. METHODS: Based on demographic data and routine clinical data, we used RSF-recursive feature elimination to identify the predictive variables and developed a model to predict metastasis using RSF method. The area under the receiver operating characteristic curve (AUROC) and Kaplan-Meier survival (KM) analyses were plotted to validate the predictive effect when C-index was plotted to assess the discrimination and Brier scores was plotted to assess the calibration of the predictive model. RESULTS: We developed a metastasis prediction model comprising three variables (pathological stage, aspartate aminotransferase, and neutrophil count) selected by RSF-recursive feature elimination. The model was reliable and stable when assessed by the AUROC (0.932 in training set and 0.905 in validation set) and KM survival analyses (p < .0001). The C-indexes (0.959) and Brier score (0.097) also validated the good predictive ability of this model. CONCLUSIONS: This model relies on routine data and examination indicators in real-time clinical practice and exhibits an accurate prediction performance without increasing the cost for patients. Using this model, clinicians can facilitate risk communication and provide precise and efficient individualized therapy to patients with breast cancer.

The new insights into autophagy in thyroid cancer progression.

In recent decades, the incidence of thyroid cancer keeps growing at a shocking rate, which has aroused increasing concerns worldwide. Autophagy is a fundamental and ubiquitous biological event conserved in mammals including humans. Basically, autophagy is a catabolic process that cellular components including small molecules and damaged organelles are degraded for recycle to meet the energy needs, especially under the extreme conditions. The dysregulated autophagy has indicated to be involved in thyroid cancer progression. The enhancement of autophagy can lead to autophagic cell death during the degradation while the produced energies can be utilized by the rest of the cancerous tissue, thus this influence could be bidirectional, which plays either a tumor-suppressive or oncogenic role. Accordingly, autophagy can be suppressed by therapeutic agents and is thus regarded as a drug target for thyroid cancer treatments. In the present review, a brief description of autophagy and roles of autophagy in tumor context are given. We have addressed summary of the mechanisms and functions of autophagy in thyroid cancer. Some potential autophagy-targeted treatments are also summarized. The aim of the review is linking autophagy to thyroid cancer, so as to develop novel approaches to better control cancer progression.

Development and Validation of a New Multiparametric Random Survival Forest Predictive Model for Breast Cancer Recurrence with a Potential Benefit to Individual Outcomes.

Purpose: Breast cancer (BC) is a multi-factorial disease. Its individual prognosis varies; thus, individualized patient profiling is instrumental to improving BC management and individual outcomes. An economical, multiparametric, and practical model to predict BC recurrence is needed. Patients and Methods: We retrospectively investigated the clinical data of BC patients treated at the Third Affiliated Hospital of Sun Yat-sen University and Liuzhou Women and Children's Medical Center from January 2013 to December 2020. Random forest-recursive feature elimination (run by R caret package) was used to determine the best variable set, and the random survival forest method was used to develop a predictive model for BC recurrence. Results: The training and validations sets included 623 and 151 patients, respectively. We selected 14 variables, the pathological (TNM) stage, gamma-glutamyl transpeptidase, total cholesterol, Ki-67, lymphocyte count, low-density lipoprotein, age, apolipoprotein B, high-density lipoprotein, globulin, neutrophil count to lymphocyte count ratio, alanine aminotransferase, triglyceride, and albumin to globulin ratio, using random survival forest (RSF)-recursive feature elimination. We developed a recurrence prediction model using RSF. Using area under the receiver operating characteristic curve and Kaplan-Meier survival analyses, the model performance was determined to be accurate. C-indexes were 0.997 and 0.936 for the training and validation sets, respectively. Conclusion: The model could accurately predict BC recurrence. It aids clinicians in identifying high-risk patients and making treatment decisions for Breast cancer patients in China. This new multiparametric RSF model is instrumental for breast cancer recurrence prediction and potentially improves individual outcomes.

[All-trans retinoic acid effectively inhibits breast cancer stem cells growth in vitro].

OBJECTIVE: To detect the inhibitory effect of all-trans retinoic acid(ATRA) on breast cancer stem cells (CSCs). METHODS: The inhibitory effect of ATRA on MCF-7 and SK-BR-3 cell lines was analyzed using a Cell Counting Kit-8 (CCK-8). The proportion of CD44(+)CD24(-) tumor cells of the two cell lines were measured before and after the ATRA treatment, and the role of ATRA in the regulation of CSC self-renewing ability was evaluated with a tumor sphere assay. The tumor spheres were grown in an adherent culture to evaluate the ATRA-induced differentiation of breast cancer stem cells. RESULTS: ATRA effectively inhibited the unsorted cells and stem cells, but the CSCs were more sensitive to ATRA. At a concentration of 10(-6) mol/L, the inhibitory rate of MCF-7 unsorted cells and stem cells were (8.66 ± 1.06)% and (21.09 ± 3.25)%, respectively (P = 0.004). For SK-BR-3 cells, the rates were (39.19 ± 1.47)% and (51.22 ± 2.80)%, respectively (P = 0.005). The self-renewing ability of the CSCs was impaired by ATRA at a concentration of 10(-6) mol/L. The rate of MCF-7 and SK-BR-3 stem cells to form tumor sphere was 5.2% (5/96) and 13.5% (13/96), respectively. For the control group, it was 86.5% (83/96) and 93.8% (90/96), respectively (P < 0.001). ATRA also promoted the CD44(+)CD24(-) subpopulation to differentiate. SK-BR-3 stem cells were grown in an adherent culture. After using ATRA, the proportion of CD44(+)CD24(-) cells was (48.1 ± 2.5)% and that of the control group was (86.6 ± 2.5)% (P < 0.001). CONCLUSIONS: ATRA effectively inhibits breast NCSCs and CSCs, but CSCs are more sensitive to ATRA. ATRA impairs the self-renewing ability of CSCs and promotes CSCs to differentiate.

An oncolytic herpes simplex virus vector, G47Δ, synergizes with paclitaxel in the treatment of breast cancer.

Paclitaxel-containing treatment regimens are standard chemotherapy schemes for breast cancer patients. The use of oncolytic herpes simplex virus (oHSV) vectors has been shown to be a safe and effective therapeutic approach for different types of cancer. We hypothesized that paclitaxel in combination with an oHSV vector would present an enhanced killing effect when used against breast cancer cells. In the present study, we demonstrated that the combined use of the oHSV vector G47Δ and paclitaxel produced a synergistic effect against breast cancer cells both in vitro and in vivo. In vitro studies demonstrated that paclitaxel and G47Δ both caused dose-dependent cytotoxicity against the human breast cancer cell lines MCF-7 and MDA-MB-468. G47Δ and paclitaxel also demonstrated synergistic cytotoxicity when applied together, with Chou-Talalay combination indices ranging from 0.44 to 0.77 for MCF-7 cells and 0.68 to 0.83 for MDA-MB­468 cells. Paclitaxel did not enhance viral replication or viral spread among tumor cells. However, G47Δ increased the antitumor ability of paclitaxel by inducing mitotic arrest and apoptosis. In vivo studies indicated that when combined with G47Δ, the dose of paclitaxel could be reduced at least 5-fold while maintaining levels of tumor reduction similar to those achieved with the administration of paclitaxel alone. Combination therapy resulted in no morbidity in vivo. Our data demonstrated that G47Δ and paclitaxel combination therapy had synergistic effects in the treatment of breast cancer. This combination therapy may be promising for breast cancer patients.

Low expression of tyrosine-protein phosphatase nonreceptor type 12 is associated with lymph node metastasis and poor prognosis in operable triple-negative breast cancer.

BACKGROUND: Low tyrosine-protein phosphatase nonreceptor type 12 (PTPN12) expression may be associated with breast cancer growth, proliferation, and metastasis. However, the prognostic value of PTPN12 in breast cancer has not been clearly identified. PATIENTS AND METHODS: 51 triple-negative breast cancer (TNBC) patients and 83 non-TNBC patients with a histopathology diagnosis from October 2001 to September 2006 were included in this study. Immunohistochemical staining for PTPN12 on tissue microarrays was conducted. RESULTS: High PTPN12 expression was seen in 39.2% of TNBC and 60.2 % of non-TNBC cases. Low PTPN12 expression was associated with lymph node status (p = 0.002) and distant metastatic relapse (p = 0.002) in TNBC patients. Similarly, low PTPN12 expression in non-TNBC patients was significantly correlated with lymph node status (p = 0.002), stage (p = 0.002) and distant metastatic relapse (p = 0.039). The high PTPN12 expression group was associated with longer DFS and OS compared with low PTPN12 expression group only in TNBC cases (p = 0.005, p = 0.015), according to univariate Cox regression analysis. CONCLUSION: These findings provide evidence that low expression of PTPN12 is associated with worse prognosis and may be used as a potential prognostic biomarker in TNBC patients.

Anti-tumor effect of oncolytic herpes simplex virus G47delta on human nasopharyngeal carcinoma.

Oncolytic herpes simplex virus (HSV) can replicate in and kill cancer cells without harming normal tissue. G47delta is a third-generation HSV vector. In this study, the therapeutic effects of G47delta on human nasopharyngeal carcinoma (NPC) were determined in vitro and in vivo. The human NPC cell lines CNE-2 and SUNE-1, primary normal nasopharyngeal epithelial cells (NPECs), and immortalized nasopharyngeal cells NP-69 and NPEC2/Bmi1 were infected with G47delta at different multiplicities of infection (MOIs). The survival of infected cells was observed daily. Two subcutaneous models of NPC were established with CNE-2 and SUNE-1 in Balb/c nude mice. G47delta or virus buffer as control was injected into the subcutaneous tumors. Tumor size was measured twice a week, and animals were euthanized when the diameter of their tumors exceeded 18 mm or when the animals appeared moribund. For the NPC cell lines CNE-2 and SUNE-1, more than 85% and 95% of cells were killed on day 5 after G47delta infection at MOI = 0.01 and MOI = 0.1, respectively. Similar results were observed for an immortalized cell line NPEC2/Bmi-1. A moderate effect of G47delta was also found on another immortalized cell line NP-69, of which only 27.7% and 75.9% of cells were killed at MOI = 0.01 and MOI = 0.1, respectively. On the contrary, there was almost no effect observed on NPECs. The in vivo experiments showed that tumors in mice in the G47delta-treated group regressed completely, and the mice exhibited much longer survival time than those in the control groups. Our results suggest that the potential therapeutic effects of G47delta would be applicable for treatment of NPC patients in the future.

[Expression of estrogen receptor, progesterone receptor, and human epithelial growth factor receptor 2 in breast cancer and the significance thereof: analysis of 910 cases].

OBJECTIVE: To investigate the expression of estrogen receptor (ER), progesterone receptor (PR), and human epithelial growth factor receptor 2 (HER2) in breast cancer, and to explore their correlation with the age of patient, and size, clinic stage, and lymph node metastasis of the tumor. METHODS: The data of 910 breast cancer, 89.4% of invasive ductal carcinoma, 1.7% of invasive lobular carcinoma, 44 cases 5% of ductal carcinoma in situ, and 4.9% of other pathologic types, 29.9% being less than 2 cm, 45.6% being 2-5 cm, and 24.5% bigger than 5 cm in size, 54.2% without metastasis in lymph node, 25.5% with metastasis in 1-3 lymph nodes, and 20.3% with metastasis in more than 3 lymph nodes respectively, were analyzed retrospectively. Immunohistochemistry was used to detect the expression of ER, PR, and HER2. RESULTS: The ER negative expression rate was 33.0%, and PR negative expression rate was 27.4%, and HER2 overexpression rate was 20.3%. The possibility of lymph node metastasis decreased along with the increase of age (P < 0.001). Tumor size was negatively correlated with the expression of ER and PR (both P < 0.001), and positively correlated with the expression of HER2 (P < 0.001). There was no significant difference between the situation of lymph node metastasis and the expression of ER, PR and HER2 in primary tumors. CONCLUSION: As good prognostic markers of breast invasive ductal cancer, ER and PR are negatively correlated with the HER2 expression, as a worse prognostic marker. ER/PR positive or HER2 negative tumors are morel likely to be diagnosed at earlier stages.

[Selection of the initial surgery extent for differentiated thyroid cancer without metastasis].

OBJECTIVE: To discuss the selection of the initial surgery extent for differentiated thyroid cancer (DTC) without metastasis. METHODS: The clinical data of 504 cases with DTC, who accepted the surgical treatment from Jan 1995 to Dec 2004, were analyzed and studied. There were 329 cases without metastasis. The operative extents less than total thyroidectomy were performed on 93 cases (92.1%) with stage T(1), 166 cases (88.3%) with stage T(2), 22 cases (91.7%) with stage T(3) and 12 cases (75.0%) with stage T(4). The recurrence situation after the initial surgery was compared between different T-stage groups and between different surgical extents, total and less than total thyroidectomy. RESULTS: The recurrence of DTC was found in 37 cases of the follow-up cases (8.9%), including 29 cases without metastasis in the initial surgery. There was no significant difference in the recurrent rate between T(1) and T(2) groups (P>0.05). The significant difference was found in recurrent rate between T(1) and T(3) or T(4) groups, T(2) and T(3) or T(4) groups (P<0.05). No significant difference in the ratio of the initial surgical extent less than total thyroidectomy was found between stage T(1) and T(2) cases without metastasis (P>0.05). The rate of the recurrent laryngeal nerve injury was 1.2%. The transient hypoparathyroidism happened in 2% of the cases, without the permanent hypoparathyroidism. CONCLUSIONS: The surgical extent less than total thyroidectomy, especially subtotal thyroidectomy, is rational and available to stage T(1) and T(2) cases of DTC without metastasis. It can effectively remove the tumor and avoid postoperative complications. Total thyroidectomy should be performed on stage T(3) and T(4) cases of DTC.

Oncolytic herpes simplex virus vectors for the treatment of human breast cancer.

BACKGROUND: Oncolytic herpes simplex virus (HSV) vectors can be used for cancer therapy as direct cytotoxic agents, inducers of anti-tumor immune responses, and as expressers of anti-cancer genes. In this study, the efficacy of HSV vectors, G47Delta and NV1023 were examined for the treatment of the human breast cancer. METHODS: Human breast cancer MDA-MB-435 cells were cultured or implanted subcutaneously in BALB/c nude mice. The cells or tumors were inoculated with G47Delta or NV1023, and cell killing or inhibition of tumor growth determined. Both viruses contained the LacZ gene and expression in infected cells was detected with X-gal histochemistry. RESULTS: G47Delta and NV1023 were highly cytotoxic to MDA-MB-435 cells in vitro at very low multiplicities of infection. X-gal staining of infected tumor cells in vitro and in vivo illustrated the replication and spread of both viruses. G47Delta and NV1023 inoculation inhibited tumor growth and prolonged mouse survival. Both vectors behaved similarly. CONCLUSIONS: Oncolytic HSV vectors, G47Delta and NV1023, were extremely effective at killing human breast cancer cells in vitro and in tumor xenografts in vivo. This novel form of cancer therapy warrants further investigation and consideration of clinical application.