Unusual hypocalcaemia in breast cancer relapse with multiple bone metastasis

Severe hypocalcaemia in breast cancer with bone metastasis is a rare finding usually associated with an advanced stage of the disease. We report a case of a 45-year-old woman with a history of local ductal carcinoma in situ (DCIS) of the breast, who presented with muscle tremors and general weakness. Hypocalcaemia was evident, with a positive Chvostek sign and a serum calcium level of 5.9 mg/dL (1.47 mmol/L), phosphorus 5.9 mg/dL (normal range: 2.3–4.7 mg/dL) with normal levels of albumin, magnesium and parathyroid hormone. High oral doses of alpha calcitriol and calcium with i.v. infusion of high calcium doses were instituted, altogether sufficient to maintain only mild hypocalcaemia. A whole-body CT revealed bone lesions along the axial skeleton. A biopsy from a bone lesion revealed a metastasis of breast carcinoma. With this pathological finding, leuprolide (GNRH analogue) and chlorambucil (alkylating agent) were initiated, followed by prompt tapering of infused calcium down to full discontinuation. Serum calcium was kept stable close to the low normal range by high doses of oral alpha calcitriol and calcium. This course raises suspicion that breast metastases to the skeleton caused tumour-induced hypocalcaemia by a unique mechanism. We assume that hypocalcaemia in this case was promoted by a combination of hypoparathyroidism and bone metastasis. Learning points Severe hypocalcaemia can a presenting symptom for breast cancer relapse.

DysPIA: A Novel Dysregulated Pathway Identification Analysis Method

Differential co-expression-based pathway analysis is still limited and not widely used. In most current methods, the pathways were considered as gene sets, but the gene regulation relationships were not considered, and the computational speed was slow. In this article, we proposed a novel Dysregulated Pathway Identification Analysis (DysPIA) method to overcome these shortcomings. We adopted the idea of Correlation by Individual Level Product into analysis and performed a fast enrichment analysis. We constructed a combined gene-pair background which was much more sufficient than the background used in Edge Set Enrichment Analysis. In simulation study, DysPIA was able to identify the causal pathways with high AUC (0.9584 to 0.9896). In p53 mutation data, DysPIA obtained better performance than other methods. It obtained more potential dysregulated pathways that could be literature verified, and it ran much faster (∼1,700–8,000 times faster than other methods when 10,000 permutations). DysPIA was also applied to breast cancer relapse dataset and breast cancer subtype dataset. The results show that DysPIA is effective and has a great biological significance. R packages “DysPIA” and “DysPIAData” are constructed and freely available on R CRAN (https://cran.r-project.org/web/packages/DysPIA/index.html and https://cran.r-project.org/web/packages/DysPIAData/index.html), and on GitHub (https://github.com/lemonwang2020).

Breast Cancer Stem Cell Active Copper(II) Complexes with Naphthol Schiff Base and Polypyridyl Ligands

Breast cancer stem cells (CSCs) are a sub-population of tumour cells that can promote breast cancer relapse and metastasis. Current treatments are unable to completely remove breast CSCs, therefore it is essential to develop new chemotherapeutics that can remove breast CSCs at clinically compatible doses. Here we present the synthesis, characterisation, and anti-breast CSC properties of copper(II) complexes, [Cu(L2)(1,10-phenanthroline)]PF6 (2) and [Cu(L3)(1,10-phenanthroline)]PF6 (3) comprising of a tridentate (O,N,S) coordinated naphthol Schiff base ligand (L2 = (E)-1-(((2-(methylthio)ethyl)imino)methyl)naphthalen-2-ol or L3 = (E)-1-(((2-(ethylthio)ethyl)imino)methyl)naphthalen-2-ol and 1,10-phenanthroline. The copper(II) complexes (2 and 3) kill breast CSCs, cultured in monolayer and three-dimensional systems, in the micromolar range. Notably, 2 and 3 are more potent towards breast CSC mammospheres than salinomycin (up to 4.5-fold), an established anti-breast CSC agent. Further, cell-based studies indicate that 2 and 3 are readily taken up by breast CSCs and elevate intracellular reactive oxygen species (ROS) levels upon short exposure times (0.5–1 h). The latter is likely to be the underlying mechanism by which 2 and 3 induces breast CSC death.

Bioinformatic Study of Involved Mechanisms in Relapse and Drug Resistance of Tamoxifen-Treated Breast Cancer

Background: Breast cancer is currently among the most common cause of mortality in women. Estrogen and its subsequent signaling pathways play an important role in the occurrence of breast cancer relapse. Tamoxifen is the most common breast cancer treatment option in ER+ patients, which acts as an adjuvant endocrinotherapy with X-ray and surgery. This approach is recommended as the first line treatment and has increased the survival rate of breast cancer patients and reduced the relapse cases. However, we can observe resistance to tamoxifen and relapse cases in one-third of patients treated with this drug, which has become a major concern. Objective: The precise mechanisms of relapse and resistance to tamoxifen have not yet been identified and were explored in this study. Methods: Microarray profiles of relapse and relapse-free patients were investigated to explain the processes leading to relapse and possibly to tamoxifen resistance. Results: According to the preliminary analysis, 1460 genes showed increased expression and 1132 genes showed decreased expression. According to our default for inclusion (-2LogFC≥ + 2), 36 genes had increased expression (upregulated) and 33 genes had decreased expression (down-regulated). Conclusion: It seems that the mechanisms of resistance and relapse are multifactorial, and tumor cells induce relapse and resistance to tamoxifen through mechanisms of cell proliferation, survival, invasion, angiogenesis, extracellular matrix secretion, pump and membrane changes and immune evasion.

Pre-surgical level of von Willebrand factor as an evident indicator of breast cancer recurrence

BACKGROUND: Endothelial and platelet activation as well as a disruption of haemostatic balance are crucial in cancer-dependent venous thromboembolism development. OBJECTIVE: The aim of this study was to investigate the influence of von Willebrand factor (VWF), sE-selectin, sP-selectin as well as VWF/sE-selectin and sP-selectin/sE-selectin ratios on the probability of disease relapse in invasive breast carcinoma (IBrC) cases. METHODS: Eighty-four patients with IA-IIB stage of IBrC who passed a comprehensive clinicopathologic evaluation were included in the study. Follow-up was completed in all patients with a 15.48 % recurrence rate. An immunoassay of VWF antigen, sE-selectin, sP-selectin, as well as an immunohistochemistry of oestrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki67 was performed in all cases. RESULTS: The VWF/sE-selectin ratio was significantly higher in patients with poorly differentiated tumours than in those with high-differentiated tumours. A positive correlation between VWF concentration and tumour grade was noted. Eleven of 13 events happened in patients with VWF value below 600 mU/mL with recurrence rate of 25%, but only two events occurred in subject with VWF values above the 600 mU/mL (5%; P= 0.0028). CONCLUSIONS: Our study show that VWF could be considered as a suitable biomarker of breast cancer relapse.

Mycobacterium szulgai Lung Disease or Breast Cancer Relapse—Case Report

Cancers are one of the risk factors of non-tuberculous mycobacterial (NTM) lung disease. The majority of data in this group of patients concern infections caused by Mycobacterium avium—the most prevalent NTM species worldwide. In contrast, limited information can be found regarding the uncommon NTM such as Mycobacterium szulgai. We present the case of M. szulgai lung disease in a patient with a history of breast cancer. Coexistence of NTM lung disease and breast cancer lung metastasis as well as primary lung cancer was suspected. Finally, neoplastic disease was ruled out based on negative results of endobronchial biopsy and negative tumor markers for lung and breast cancer. M. szulgai lung disease was successfully treated with rifampicin, ethambutol and clarithromycin.