Behavior and Outcomes of Pregnancy Associated Breast Cancer

Introduction: Pregnancy Associated Breast cancer (PABC) is associated with poor prognosis and a decreased overallsurvival. A retrospective review was conducted to review the experience and outcome in a tertiary care hospital, and tocompare those seen in a matched group for year of diagnosis. Materials and Methods: This is a retrospective reviewof a prospectively collected breast cancer registry. The study was conducted in a tertiary care hospital in Riyadh, SaudiArabia from January to Decamber 2014 . Female patients with PABC were identified and matched with similar cohortof non-pregnant breast cancer patients that were diagnosed between 2001-2010. Clinical data including age, tumorbiology, clinical stage, follow up and outcomes (disease free survival, DFS) were analyzed and compared between thetwo groups using SAS 9.3 and R-2.14.1 Results: A total of 110 patients in Group 1 and 114 patients in Group II wereanalyzed. In both groups, the patient age ranged was between 20 to 45 years; the median follow up was 34 months inPABC and 54 months in non-pregnant cohort. PABC were statistically more likely to be triple negative (p value-0.05) anddiagnosed at advanced stage (stage 3 and 4) (p value-0.02). There was no difference in the occurrence of Her-2 positivedisease. In pregnant patients there was a 5-year survival rate of 65% compared to non-pregnant cohort of 82% with pvalue of 0.002 and DFS was also 47.5% versus 65.4% with a p value .002 which is statistically significant. Conclusion:Pregnancy associated breast cancer (PABC) is diagnosed at a more advanced stage and tends to be triple negative andthey are associated with a worse DFS and overall survival. Early detection during pregnancy may improve outcome.     

Accuracy of routinely collected comorbidity data in patients undergoing colectomy: a retrospective study

Objectives

This paper aimed to determine the baseline accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of routinely collected comorbidity data in patients undergoing any types of colectomy.

Methods

All patients aged >18 who underwent right hemicolectomy, left hemicolectomy, sigmoid colectomy, subtotal colectomy, or total colectomy between 1 January 2015 and 1 November 2016 were identified. The following comorbidities were considered: hypertension, ischemic heart disease (IHD), diabetes, asthma, chronic obstructive pulmonary disease (COPD), cerebrovascular disease (CVD), chronic kidney disease (CKD), and hypercholesterolemia. The comorbidity data from clinical notes were compared with corresponding data in hospital episode statistics (HES) database in order to calculate accuracy, sensitivity, specificity, PPV, and NPV of HES codes for comorbidities. In order to assess the agreement between clinical notes and HES data, we also calculated Cohen’s kappa index value as a more robust measure of agreement.

Results

Overall, 267 patients comprising 2136 comorbidity codes were included. Overall, HES codes for comorbidities in patients undergoing colectomy had substandard accuracy 94% (kappa 0.542), sensitivity (39%), and NPV (89%). The HES codes were 100% specific with PPV of 100%. The results were consistent when individual comorbidities were analyzed separately.

Conclusions

Our results demonstrated that HES comorbidity codes in patients undergoing colectomy are specific with good positive predictive value; however, they have substandard accuracy, sensitivity, and negative predictive value. Better documentation of comorbidities in admission clerking proforma may help to improve the quality of source documents for coders, which in turn may improve the accuracy of coding.

     

Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells

Cervical cancer is caused by human papilloma virus (HPV) expressing E6 and E7 oncoproteins, which are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Repression of HPV oncoproteins would therefore result in reactivation of tumor suppressor pathways and cause apoptosis in cancer cells. Withaferin A (WA), the active component of the medicinal plant Withania Somnifera, has exhibited inhibitory effects against several different cancers. We examined the activity of WA on human cervical cancer cells in vitro and in vivo. WA potently inhibited proliferation of the cervical cancer cells, CaSki (IC(50) 0.45 ± 0.05 μM). Mechanistically, WA was found to (i) downregulate expression of HPV E6 and E7 oncoproteins, (ii) induce accumulation of p53, (iii) increase levels of p21(cip1/waf1) and its interaction with proliferating cell nuclear antigen (PCNA), (iv) cause G(2)/M cell cycle arrest, associated with modulation of cyclin B1, p34(cdc2) and PCNA levels, (v) decrease the levels of STAT3 and its phosphorylation at Tyr(705) and Ser(727) and (vi) alter expression levels of p53-mediated apoptotic markers-Bcl2, Bax, caspase-3 and cleaved PARP. In vivo, WA resulted in reduction of nearly 70% of the tumor volume in athymic nude mice with essentially similar trend in the modulation of molecular markers as in vitro. This is the first demonstration indicating that WA significantly downregulates expression of HPV E6/E7 oncogenes and restores the p53 pathway, resulting in apoptosis of cervical cancer cells. Together, our data suggest that WA can be exploited as a potent therapeutic agent for the treatment and prevention of cervical cancer without deleterious effects.     

Edible oil adulterants, argemone oil and butter yellow, as aetiological factors for gall bladder cancer

Carcinogenic potential of argemone oil (AO) and butter yellow (BY), the adulterants encountered in edible oil, in gall bladder of Swiss albino mice was undertaken to investigate the potential aetiological factors of gall bladder carcinoma (GBC) in the Indo-Gangetic basin. Twice weekly intraperitoneal (ip) administration of AO (5 ml/kg body wt) and BY (25 mg/kg body wt) to Swiss albino male and female mice for 30 and 60 days indicated that females were more vulnerable to these adulterants in terms of responses to inflammatory markers. Subsequent experiments with dietary exposure of AO (1%) and BY (0.06%) for 6 months in female mice showed symptoms related to cachexia, jaundice and anaemia. High levels of total cholesterol, low density lipoprotein (LDL), TG, bilirubin and low level of high density lipoprotein (HDL) as well as gallstone formation was shown by AO exposure only, leading to the development of adenocarcinoma. BY exposure resulted in adenoma and hyperplasia without stone formation. The cyclooxygenase (COX-2) overexpression was found to be related to prostaglandin E2 (PGE2) production in AO treated mice but not in BY exposed animals, thereby indicating a differential pathway specific carcinogenicity. PGE2 stimulates the secretion of secreted mucins (MUC5AC), which is involved in stone formation following AO exposure. Enhanced secretion of membrane bound mucins (MUC4) in BY and AO exposed mice resulted in the activation of ErbB2 and downstream signalling such as p-AKT, p-ERK and p-JNK, which ultimately affects the target proteins, p53 and p21 leading to adenoma and adenocarcinoma, respectively. The study suggests that AO and BY are responsible for producing GBC in mice along with stone formation in the AO exposed animals.     

Berry anthocyanidins synergistically suppress growth and invasive potential of human non-small-cell lung cancer cells

P-glycoprotein-mediated multidrug resistance (MDR) is a major limiting factor in the efficacy of most microtubule-targeting agents. Here, we investigated the novel, synthetic, and small-molecule microtubule-destabilizing agent, 2-(2-amino-5-(1-ethyl-1H-indol-5-yl) pyrimidin-4-yl) phenol (YHHU0895), for its anti-tumor activity and potential for overcoming P-glycoprotein-mediated MDR. YHHU0895 inhibited purified tubulin polymerization through binding to tubulin at the colchicine-binding site and significantly inhibited human tumor cell proliferation. Notably, P-glycoprotein-overexpressing KBV200 and K562/ADR cells, which are strongly resistant to colchicine, vinorelbine and paclitaxel, were sensitive to YHHU0895 both in vitro and in vivo. These findings indicate that YHHU0895 is a novel type of microtubule-destabilizing agent that has the potential for the treatment of patients with drug resistance mediated by P-glycoprotein.     

Cucurbitacin B potently suppresses non-small-cell lung cancer growth: Identification of intracellular thiols as critical targets

Cucurbitacin B (CuB), has recently emerged as a potent anticancer agent; however, its efficacy in non-small-cell lung cancer (NSCLC) and the mechanism(s) initiating its biological effects remain largely unclear. In this study, CuB potently suppressed the growth of four NSCLC cells (H1299, A549, HCC-827 and H661) in vitro and the highly aggressive H1299 xenograft in vivo. CuB significantly altered the actin cytoskeletal assembly, induced G2/M cell-cycle arrest and mitochondrial apoptosis through the modulation of several key molecular targets mediating the aforementioned processes. Interestingly, all cellular effects of CuB were completely attenuated only by the thiol antioxidant N-acetylcysteine (NAC). Furthermore, pretreatment with glutathione synthesis inhibitor butithione-sulfoxime (BSO), significantly exacerbated CuB’s cytotoxic effects. To this end, cells treated with CuB revealed a rapid and significant decrease in the levels of protein thiols and GSH/GSSG ratio, suggesting disruption of cellular redox balance as the primary event in CuB’s cytotoxic arsenal. Using UV and FTICR mass spectrometry we also demonstrate for the first time a physical interaction of CuB with NAC and GSH in a cell-free system suggesting that CuB interacts with and modulates cellular thiols to mediate its anti-cancer effects. Collectively, our data sheds new light on the working mechanisms of CuB and demonstrate its therapeutic potential against NSCLC.