Autophagy Governs Protumorigenic Effects of Mitotic Slippage-induced Senescence.

The most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and "slip" into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment.Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. Mol Cancer Res; 16(11); 1625-40. ©2018 AACR.

Mucin extravasation in breast core biopsies--clinical significance and outcome correlation.

AIMS: To document the spectrum of lesions associated with mucin extravasation (ME) in breast core biopsy specimens, and to correlate with open surgical excisions. METHODS AND RESULTS: Thirty-nine lesions in 37 women with ME on core biopsies constituted the study group. Fibrocystic change (FC), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) were found in 21 (53.8%), 13 (33.3%) and four (10.3%) core biopsy specimens, respectively, with one (2.6%) consisting only of mucin pools. Except for the latter, all disclosed mucocoele-like lesions (MLL) accompanying ME. Columnar cell lesions (CCL) were frequently observed (84.6%). On open biopsy, three cases underdiagnosed on core biopsy included FC that later disclosed ADH; one ADH lesion on core later upgraded to DCIS; and a case of mucin pools that revealed mucinous carcinoma on excision. The extent of CCL on core biopsy appeared to predict sinister lesions on open excision. For calcified lesions that were completely removed on core biopsy, there were no malignant lesions discovered on open excision that had not already been diagnosed preoperatively. CONCLUSIONS: ME and MLL on core biopsy warrant close radiological-pathological correlation. When the entire radiological abnormality has been removed with large core mammotome biopsy specimens, surgery may potentially be avoided in histologically benign lesions, although such an approach requires further validation.

Early detection of breast cancer through population-based mammographic screening in Asian women: a comparison study between screen-detected and symptomatic breast cancers.

The first nation-wide mammographic screening program in Asia, BreastScreen Singapore (BSS), was launched in Singapore in January 2002. This study compared the presentation and results of screen-detected breast cancers with symptomatic breast cancers in two affiliated high-volume institutions, one of which was an assessment centre for BSS. The medical records of patients diagnosed with primary breast cancer at the Department of General Surgery, Singapore General Hospital and the Department of Surgical Oncology, National Cancer Centre, Singapore, during the period January 2002 to December 2003 were reviewed. Clinical and pathological comparisons were made between screen-detected lesions and symptomatic lesions. Of a total of 767 cases, 640 (83.4%) were invasive carcinomas and 127 (16.6%) were ductal carcinoma in-situ (DCIS) lesions. Only 13.4% of them were screen-detected. Compared to symptomatic cancers, screen-detected lesions were of smaller size (median size 18 versus 23 mm), a lower stage (stages 0-2, 95 versus 83.2%) and histologic grade (grade 1-2, 71 versus 60%), with a higher incidence of DCIS (31.0 versus 14.3%) and had higher rates of breast conservation (45.6 versus 28.2%) (all p-values <0.05). By multivariate analysis, tumor palpability, tumor size >20 mm, nodal involvement, cerbB2 overexpression, and advanced disease stage were independent poor prognostic factors for disease-free survival, whereas nodal involvement, advanced disease, and recurrence predicted poor cancer-specific survival. However, there was no statistically significant difference in disease-free survival or cancer-specific survival between the two groups at a median follow-up of 38 months. Screening mammography has allowed the detection of smaller and hence oncologically more favorable lesions in Asian women. Although no significant survival benefit was demonstrated in our study, a longer period of follow-up is essential before the benefit of mortality reduction, as a result of mammography screening becomes evident in our population.

Independent component analysis of dynamic contrast-enhanced magnetic resonance images of breast carcinoma: a feasibility study.

PURPOSE: To study the possibility of using independent component analysis (ICA) to identify breast lesions as separate hemodynamic sources on dynamic contrast-enhanced (DCE) MR images, as depicted by the passage of contrast medium. MATERIALS AND METHODS: Six patients who were histopathologically confirmed with breast carcinoma underwent DCE MRI with 5 precontrast and 60 postcontrast scans at a time-resolution of 8 s. A spatial ICA algorithm was applied on the DCE MRI data set to extract spatial component maps corresponding to source locations with different signal time-intensity patterns. To verify the present hypothesis of the ability of ICA to reveal tumor voxels as a separate hemodynamic phase, tumor margins were outlined by an experienced radiologist who was blinded from the ICA results, and the manual outlines were compared with the ICA maps. RESULTS: Consistently for each of the six patient study cases, it was found that ICA yields a tumor component map associated with typical tumor enhancement patterns of rapid enhancement with washout or plateau. Tumor outlines manually drawn by the radiologist were in good agreement with the tumor locations depicted in the tumor component maps. CONCLUSION: ICA may provide an objective method for identifying the outlines of enhancing breast tumors on DCE MR images and to automatically extract the tumor signal intensity-time curve for subsequent tracer kinetics analysis.

Local experience of endorectal magnetic resonance imaging of prostate with correlation to radical prostatectomy specimens.

INTRODUCTION: We evaluated the accuracy of endorectal magnetic resonance imaging (MRI) in the staging of prostate cancer. MATERIALS AND METHODS: We retrospectively reviewed 32 patients who underwent endorectal MR prostate prior to radical prostatectomy. The tumour stage based on MR imaging was compared with the pathologic stage. The sensitivity and specificity of endorectal MR prostate in the evaluation of extracapsular extension (ECE) of the tumour were then determined. RESULTS: MR correctly diagnosed 17 cases of organ-confined prostate carcinoma and 2 cases of locally advanced disease. In the evaluation of ECE, endorectal MR achieved a high specificity of 94.4%, low sensitivity of 14.3% and moderate accuracy of 59.4%. CONCLUSION: Endorectal MR prostate has high specificity for the detection of ECE. It is useful in the local staging of prostate cancer in patients with intermediate risk as this helps to ensure that few patients will be deprived of potentially curative surgery.