Advancement in Opioid Abuse-deterrent Formulation Technologies and Regulatory Expectation.

Chronic pain is a byproduct of many diseases and conditions. Along with long-term opioid medication use in chronic pain management, misuse of this vital medication has been a topic of much debate over the last two decades. Abuse-deterrent formulations play a critical role in comprehensive opioid risk management strategies, limiting the attractiveness and drug-liking qualities of an opioid drug by limiting their bioavailability, making abuse of the tampered opioid medication less appealing or rewarding, or impeding the extraction of the opioid drug and thus impeding the administration of the opioid formulation via alternative routes. The present article covers various regulatory actions, expectations in abuse-deterrent formulation approval, and emerging opioid abuse-deterrent formulation strategies, such as incorporating physical barriers, chemical barriers, aversion agents, pH modulating release properties, novel delivery systems, agonist/antagonist combinations, and prodrugs, as potential approaches to encountering the crisis of the opioid abuse epidemic. Looking at the severity of the opioid crisis across the globe now is the right time for various regulatory agencies to come under one roof to save society from the opioid epidemic, define the policy on how and when to prescribe opioid formulations to patients, perform abuse risk assessments, and make more efforts to approve only abusedeterrent opioid medication.

Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study.

BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I−III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I−III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10−4.55) p = 0.0269) of the patient's gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.

Transcatheter Closure of Left Ventricular Outflow Tract-to-Left Atrium Fistula.

Surgical and rarely transcatheter aortic valve replacement can be complicated by intracardiac fistula. Transcatheter closure of those shunts has been previously reported with favorable results. We describe a case of percutaneous closure of left ventricular outflow tract-to-left atrium fistula after surgical aortic valve replacement using an Amplatzer Vascular Plug II. (Level of Difficulty: Advanced.).

Design of a novel rapid immunoassay for simultaneous detection of hepatitis C virus core antigen and antibodies.

HCV is a potential cause of viral hepatitis, which leads to blood-borne chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Anti-HCV antibody detection assays detect HCV infection after approximately 70 days. HCV core antigen can be detected much earlier than anti-HCV antibodies. However, it disappears soon after the appearance of anti-HCV antibodies. Thus, there is a need for a rapid assay for simultaneous detection of HCV core antigen and anti-HCV antibodies for early diagnosis of HCV infection. A rapid diagnostic assay (HCV Ag-Ab Combo) for simultaneous detection of HCV core antigen and anti-HCV antibodies for early diagnosis of HCV infection was developed. HCV Ag-Ab Combo was evaluated in order to determine its potential for detection of HCV infection earlier than anti-HCV antibody detection assays. We compared the sensitivity of the newly developed assay with anti-HCV antibody detection assays (ELISA [HCV Ab ELISA] and rapid test [HCV Ab Rapid]) and HCV core antigen/anti-HCV antibody detection ELISA (HCV Ag-Ab ELISA). This study included 11 samples that were found positive in HCV RNA detection and HCV Ag-Ab ELISA but negative in HCV antibody detection assays (HCV Ab ELISA and rapid), 10 samples that were found positive in HCV Ag-Ab ELISA and HCV Ab ELISA but negative in HCV Ab Rapid, 69 samples that were found positive in HCV Ag-Ab ELISA, HCV Ab ELISA, and HCV Ab Rapid, and 509 samples that were found negative in HCV Ag-Ab ELISA, HCV Ab ELISA, and HCV Ab Rapid. Three seroconversion panels, PHV 913, PHV 911 (M) and PHV904-00-1.0, and a HCV RNA genotype qualification panel (2400-0182) acquired from Seracare Life Sciences (USA) were also tested. HCV Ag-Ab Combo showed a combined sensitivity and specificity of 100% when tested with 90 samples that were positive for HCV by HCV Ag-Ab ELISA and 509 HCV-negative samples. Its positive predictive value (PPV) and negative predictive value (NPV) were found to be 100%. It detected HCV infection approximately 7 to 12 days earlier than the HCV Ab detection assays, and its performance was not affected when testing different genotypes of HCV. HCV Ag-Ab Combo did not detect HCV infection as early as HCV RNA or HCV Ag-Ab ELISA. HCV Ag-Ab Combo provided a significant improvement for the early detection of HCV infection during the preseroconversion phase when compared with anti-HCV antibody detection assays. It could be a useful screening assay, and an alternative to HCV RNA detection or HCV Ag-Ab ELISA when nucleic acid technologies cannot be implemented.

The Tendyne transcatheter mitral valve replacement system for the treatment of mitral regurgitation.

Mitral valve regurgitation (MR) is the most prevalent valvular disorder among the growing elderly population, occurring in over 6% of those aged >65. Unfortunately, many individuals with severe MR (particularly those with systolic dysfunction or secondary MR) will not be candidates for surgical valve repair or replacement due to high or prohibitive operative risk. For such patients, transcatheter mitral valve replacement represents a viable option. The TendyneTM valve (Abbott Vascular, CA, USA) is one of the most well-studied system to date, with a good safety and efficacy profile.

Percutaneous Retrieval of a Watchman Device from the Left Ventricle Using a Transarterial Approach.

Left atrial appendage closure device embolization is a rare yet serious complication. The location of the embolized device is a major determinant of the retrieval approach, percutaneous or surgical. This paper presents the case of Watchman device embolization in the left ventricle, which was retrieved percutaneously by using a transarterial approach. (Level of Difficulty: Intermediate.).

Coronary Artery Disease and Transcatheter Aortic Valve Replacement: When to Intervene.

"In patients with coronary artery disease undergoing transcatheter aortic valve replacement (TAVR), the decision of whether to revascularize, which lesions to revascularize, and the optimal timing of revascularization remains controversial. The sequence of revascularization should be made on a case-by-case basis. Pre-TAVR revascularization (staged or simultaneous with TAVR) is preferred due to unobstructed access to coronary ostia and is important to consider especially in cases in which long self-expanding valves are used. In patients who are hemodynamically compromised, the valve should be addressed first, as the most important cause of mortality is heart/multiorgan failure."

Analysis of readmissions after transoral robotic surgery for oropharyngeal squamous cell carcinoma.

BACKGROUND: As transoral robotic surgery (TORS) is being increasingly used to treat patients with oropharyngeal squamous cell carcinoma (OPSCC), there is an interest in determining contributors to readmission. METHODS: We conducted this retrospective multivariate analysis modeling 30-day readmission using the Nationwide Readmissions Database (2012-2014). RESULTS: Of 950 patients, 117 (12.3%) were readmitted. Hemorrhage and diet/aspiration accounted for 32.5% and 19.7% of readmissions, respectively. Of those readmitted, 23.1% required operative bleeding control, 11.1% required transfusion, 1.7% required tracheostomy, and 18.8% required gastrostomies. Those readmitted were older (mean 63.2 years, SD 9.5 vs 60.9 mean years, SD 10.3) and had longer hospitalizations (mean 5.7 days, SD 6.8 vs mean 4.3 days, SD 4.1) and higher rates of aspiration/pneumonia (9.4% vs 2.4%, P < .01) on index admission. Multivariate analysis demonstrated that aspiration/pneumonia on index admission was independently associated with readmission (OR 3.128, 95% CI 1.178-8.302). CONCLUSIONS: Of the patients 12.3% were readmitted within 30 days with hemorrhage and diet complications as significant contributors.

Optimizing hemodynamics of transcatheter aortic valve-in-valve implantation in 19-mm surgical aortic prostheses.

OBJECTIVE: To demonstrate the feasibility of achieving good hemodynamic results with valve-in-valve transcatheter aortic valve replacement (ViV TAVR) for degenerated 19 mm surgical bioprosthetic valves. BACKGROUND: Considerable controversy exists regarding ViV TAVR within 19mm surgical prostheses due to concerns of elevated valve gradients and mortality. METHODS: Among all patient undergoing ViV TAVR between 7/2016 and 4/2017 for symptomatic severe bioprosthetic aortic stenosis (AS), five had a 19 mm surgical valve in place and were included in this publication. None of the patients had patient-prosthesis mismatch. Aggressive post-dilation was performed in four out of five cases using a special technique we describe below. RESULTS: In all cases, mean aortic valve (AV) gradients significantly improved post-ViV TAVR, particularly after post-dilation. Interestingly, high pressure post-dilation of the ViV resulted in an increase in the diameter of surgical valve stent frame dimensions in nearly all patients who underwent post-dilation. CONCLUSIONS: Good hemodynamic outcome is possible with aggressive post-dilation in patients with 19 mm failed surgical bioprostheses. High-risk patients with 19 mm failed surgical prostheses who do not otherwise have viable surgical options should be considered for ViV TAVR.

Access Options for Transcatheter Aortic Valve Replacement in Patients with Unfavorable Aortoiliofemoral Anatomy.

In the current era, 10-15 % of transcatheter aortic valve replacement (TAVR)-eligible high and prohibitive risk patients with severe symptomatic aortic stenosis are not candidates for transfemoral arterial access. Knowledge of the various alternative access options can enable TAVR teams to provide improved quality of life and potentially life-saving treatment for a group of patients who otherwise have no viable options. In this article, we review approach to patients with unfavorable femoral arterial anatomy and provide an in-depth discussion on the various alternative routes for TAVR.

Clinical significance of inflammatory mediators in the pathogenesis of oral cancer.

Oral cancer has become a grave problem in many parts of the globe with two.thirds of the cases occurring in developing countries. Chronic inflammation plays a prominent role in the development of oral cancer. The rationale for molecular targeted prevention of oral cancer is promising. Therefore, there are continued improvements to our understanding of the molecular connections between inflammation and oral cancer. The inflammatory mediators including nuclear factor kappa B, vascular endothelial growth factor, inflammatory cytokines, prostaglandin pathways, p53, reactive oxygen and nitrogen species, and microRNAs are major key players in the pathogenesis of oral cancer. Currently, visual cytology.based techniques and biopsy are used to detect dysplasia and early stage of oral squamous cell carcinoma. These approaches are limited in their ability to judge the severities of oral lesions and are useful only after the appearance of visual changes. Thus, traditional cytological and biopsy assays combined with testing of inflammatory biomarkers would be beneficial for the efficient early detection of oral dysplastic lesions and early stages of oral squamous cell carcinoma.

Impact of intravascular ultrasound on the long-term clinical outcomes in the treatment of coronary ostial lesions.

OBJECTIVES: To evaluate the long-term outcomes of patients with ostial lesions who underwent percutaneous coronary intervention (PCI) with and without the use of intravascular ultrasound (IVUS). BACKGROUND: A higher rate of adverse cardiac events is associated with PCI of ostial lesions as compared with nonostial disease. METHODS: From 7/2002 to 8/2010, 225 patients with 233 coronary ostial lesions underwent PCI with (n = 82) and without (n = 143) IVUS guidance. Ostial lesions included both native aorto-ostial or major coronary vessel (left anterior descending, left circumflex, and ramus intermedius) lesions. Clinical outcomes [cardiovascular death, myocardial infarction (MI), and target lesion revascularization (TLR)] at a mean follow-up of 4.2 ± 2.5 years were compared between patients undergoing PCI of an ostial lesion with and without use of IVUS using univariate and propensity score adjusted analyses. RESULTS: Aorto-ostial lesions (n = 109) comprised 47% of lesions, whereas the remaining lesions (53%) involved major coronary vessels. After propensity score adjustment, IVUS use was associated with lower rates of the composite of cardiovascular death, MI, or TLR (HR 0.54, 95% CI 0.29-0.99; P = 0.04), composite MI or TLR (HR 0.39, 95% CI 0.18-0.83; P = 0.01), and MI (HR 0.31, 95% CI 0.11-0.85; P = 0.02) as compared with no IVUS. The use of IVUS was also associated with a trend towards a lower rate of TLR (HR 0.42, 95% CI 0.17-1.02; P = 0.06). CONCLUSIONS: PCI of coronary ostial lesions with the use of IVUS was associated with significantly lower rates of adverse cardiac events.

Transcatheter Advances in the Treatment of Adult and Congenital Valvular Heart Disease.

OPINION STATEMENT: Transcatheter valve therapies represent the newest frontier in interventional cardiology. At present, transcatheter aortic valve replacement and mitral valve edge-to-edge repair are currently approved by the US FDA in appropriately selected patients. These transcatheter therapies are typically employed in patients of advanced age with comorbid conditions. However, many younger adults with congenital heart disease are of comparable surgical risk due to multiple previous open heart surgeries. An array of percutaneous options currently exists for either temporizing or treating such patients (e.g., balloon septostomy, valvuloplasty, coiling of patent ductus arteriosus), but evidence-based treatment options for degenerative valve disease in this population are currently lacking. The most significant advance in this area to date has been the development and validation of transcatheter pulmonic valve implantation. Similarly, catheter-based approaches for the treatment of other valve lesions in patients with congenital valve disease are gaining interest, based in large part on promising evidence from studies of patients with acquired adult valvular heart disease.

Association of Lower Fractional Flow Reserve Values With Higher Risk of Adverse Cardiac Events for Lesions Deferred Revascularization Among Patients With Acute Coronary Syndrome.

BACKGROUND: The safety of deferring revascularization based on fractional flow reserve (FFR) during acute coronary syndrome (ACS) is unclear. We evaluated the association of FFR and adverse cardiac events among patients with coronary lesions deferred revascularization based on FFR in the setting of ACS versus non-ACS. METHODS AND RESULTS: The study population (674 patients; 816 lesions) was divided into ACS (n=334) and non-ACS (n=340) groups based on the diagnosis when revascularization was deferred based on FFR values >0.80 between October 2002 and July 2010. The association and interaction between FFR and clinical outcomes was evaluated using Cox proportional hazards models within each group (mean follow-up of 4.5±2.1 years). Subsequent revascularization of a deferred lesion was classified as a deferred lesion intervention (DLI), whereas the composite of DLI or myocardial infarction (MI) attributed to a deferred lesion was designated as deferred lesion failure (DLF). In the non-ACS group, lower FFR values were not associated with any increase in adverse cardiac events. In the ACS group, every 0.01 decrease in FFR was associated with a significantly higher rate of cardiovascular death, MI, or DLI (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.03 to 1.12), MI or DLI (HR, 1.09; 95% CI: 1.04 to 1.14), DLF (HR, 1.12; 95% CI, 1.06 to 1.18), MI (HR, 1.07; 95% CI, 1.00 to 1.14), and DLI (HR, 1.12; 95% CI, 1.06 to 1.18). CONCLUSION: Lower FFR values among ACS patients with coronary lesions deferred revascularization based on FFR are associated with a significantly higher rate of adverse cardiac events. This association was not observed in non-ACS patients.

Clinical outcomes with use of erythropoiesis stimulating agents in patients with the HeartMate II left ventricular assist device.

OBJECTIVES: This study evaluated clinical outcomes associated with erythropoiesis stimulating agent (ESA) use in left ventricular assist devices (LVAD)-supported patients. BACKGROUND: Use of ESAs in patients with LVADs may minimize blood transfusions and decrease allosensitization. ESAs increase thrombotic events, which is concerning because LVADs are sensitive to pump thrombosis (PT). METHODS: We retrospectively reviewed 221 patients at our center who received a HeartMate II (Thoratec Corp., Pleasanton, California) LVAD between January 1, 2009 and June 6, 2013. Patients were divided into those who received ESAs during index admission (n = 121) and those who did not (n = 100). Suspected PT was defined as evidence of thrombus in the LVAD or severe hemolysis (lactate dehydrogenase >1,000 mg/dl or plasma-free hemoglobin >40 mg/dl). Outcomes were compared between cohorts using inverse probability-weighted analyses. RESULTS: During a mean follow-up of 14.2 ± 11.9 months, suspected PT occurred in 37 patients (ESA 23%, no ESA 12%; p =0.03). The ESA cohort received ESAs 13.9 ± 60.9 days after LVAD implantation. At 180 days, event-free rates for suspected PT were ESA 78.6% versus no ESA 94.5% (p < 0.001). ESA use had higher rates of suspected PT (hazard ratio [HR]: 2.35; 95% confidence interval [CI]: 1.38 to 4.00; p = 0.002). For every 100-unit increase in cumulative ESA dosage, the hazard of suspected PT increased by 10% (HR: 1.10; 95% CI: 1.04 to 1.16; p < 0.001). After inverse probability weighting, ESA use was associated with a significantly higher rate of all-cause mortality (HR: 1.62; 95% CI: 1.12 to 2.33; p = 0.01). CONCLUSIONS: ESA use in LVAD patients is associated with higher rates of suspected PT.

Risk model for estimating the 1-year risk of deferred lesion intervention following deferred revascularization after fractional flow reserve assessment.

AIMS: Although lesions deferred revascularization following fractional flow reserve (FFR) assessment have a low risk of adverse cardiac events, variability in risk for deferred lesion intervention (DLI) has not been previously evaluated. The aim of this study was to develop a prediction model to estimate 1-year risk of DLI for coronary lesions where revascularization was not performed following FFR assessment. METHODS AND RESULTS: A prediction model for DLI was developed from a cohort of 721 patients with 882 coronary lesions where revascularization was deferred based on FFR between 10/2002 and 7/2010. Deferred lesion intervention was defined as any revascularization of a lesion previously deferred following FFR. The final DLI model was developed using stepwise Cox regression and validated using bootstrapping techniques. An algorithm was constructed to predict the 1-year risk of DLI. During a mean (±SD) follow-up period of 4.0 ± 2.3 years, 18% of lesions deferred after FFR underwent DLI; the 1-year incidence of DLI was 5.3%, while the predicted risk of DLI varied from 1 to 40%. The final Cox model included the FFR value, age, current or former smoking, history of coronary artery disease (CAD) or prior percutaneous coronary intervention, multi-vessel CAD, and serum creatinine. The c statistic for the DLI prediction model was 0.66 (95% confidence interval, CI: 0.61-0.70). CONCLUSION: Patients deferred revascularization based on FFR have variation in their risk for DLI. A clinical prediction model consisting of five clinical variables and the FFR value can help predict the risk of DLI in the first year following FFR assessment.

Outcomes of coronary stenoses deferred revascularization for borderline versus nonborderline fractional flow reserve values.

Current evidence supports deferral of revascularization for lesions with fractional flow reserve (FFR) values >0.80. The natural history after deferral of revascularization of lesions with borderline FFR values is unknown. This study evaluated the outcomes of patients after deferred revascularization of coronary stenoses based on a borderline FFR value. We retrospectively studied 720 patients with 881 intermediate-severity coronary stenoses who underwent FFR assessment from October 2002 to July 2010 and were deferred revascularization. Patients were divided into gray zone (0.75 to 0.80), borderline (0.81 to 0.85), and nonborderline (>0.85) FFR groups. Any subsequent percutaneous coronary intervention or coronary artery bypass grafting of a deferred stenosis during follow-up was classified as a deferred lesion intervention (DLI). Patient and/or lesion characteristics and clinical outcomes were compared between the FFR groups using univariate and propensity score-adjusted inverse probability of weighting Cox proportional hazards analyses. During a mean follow-up of 4.5 ± 2.1 years, 157 deferred lesions (18%) underwent DLI by percutaneous coronary intervention (n = 117) or coronary artery bypass grafting (n = 40). No statistically significant differences were observed in clinical outcomes between the gray zone and borderline FFR groups. Lesions with a borderline FFR were associated with a significantly higher risk of DLI compared with lesions with nonborderline FFR values (hazard ratio 1.63, 95% confidence interval 1.14 to 2.33, p = 0.007). Lesions deferred revascularization because of a borderline FFR (0.81 to 0.85) were associated with a higher risk of DLI compared with lesions with a nonborderline FFR (>0.85). Further study is needed to determine the optimal management of coronary stenoses with a borderline FFR value.

Long-term clinical outcomes with the use of a modified provisional jailed-balloon stenting technique for the treatment of nonleft main coronary bifurcation lesions.

OBJECTIVES: To assess the long-term clinical outcomes associated with treatment of nonleft main coronary bifurcation lesions using a modified provisional jailed-balloon technique (JBT). BACKGROUND: Percutaneous coronary intervention (PCI) of bifurcation lesions is associated with a higher risk of adverse events, including the risk of side branch (SB) loss during main branch (MB) stenting. METHODS: From 4/2003 to 8/2010, 406 patients with 424 nonleft main coronary bifurcation lesions underwent PCI with (n = 95) and without (n = 311) the use of JBT. Rates of SB loss and long term clinical outcomes [death, myocardial infarction (MI), and target lesion revascularization (TLR)] were compared between patients undergoing PCI with and without JBT using univariate and propensity score adjusted and matched analyses. RESULTS: The majority of patients presented with acute coronary syndrome (63%) and 90% of lesions were Medina class 1,1,1. Patients were followed for a mean of 2.7 ± 2.1 years. After propensity score matching (n = 81 in each group), JBT was associated with a significantly lower composite rate of death, MI, or TLR (HR 0.22, 95% CI 0.06-0.76; P = 0.02) and TLR (HR 0.20, 95% 0.04-0.92; P = 0.04) compared with no JBT. Permanent SB loss was significantly lower in the JBT group compared with no JBT group (OR 0.22, 95% CI 0.10-0.49; P = 0.0001). CONCLUSIONS: The use of JBT for the treatment of nonleft main coronary bifurcation lesions was associated with significantly lower rates of SB loss and major adverse cardiac events at late follow-up.

Evaluation of plasma non-enzymatic antioxidants in breast cancer etiology.

OBJECTIVE: Oxidative stress has emerged as a major etiological factor for breast cancer. Diet derived antioxidants play an important role against oxidative stress and the aim of the present study was to examine roles of non-enzymatic antioxidants in breast cancer in India. METHODS: Plasma non-enzymatic antioxidants; beta-carotene, vitamin A, vitamin E and vitamin C were analyzed spectrophotometrically from 70 healthy female controls, 30 patients with benign breast diseases (BBD) and 125 untreated breast cancer patients (BCPT). RESULTS: Plasma vitamin C levels were significantly lower in patients with BBD as compared to the controls (p= 0.043). Plasma beta-carotene, vitamin E and vitamin C levels were significantly lower in BCPT as compared to the controls (p= 0.0001, p= 0.040 and p= 0.0001, respectively). Plasma vitamin A levels were significantly higher in patients with BBD and BCPT as compared to the controls (p= 0.0001 and p= 0.0001; respectively) and in BCPT as compared to patients with BBD (p= 0.030). ROC curve analysis revealed that plasma beta-carotene and vitamin A could significantly discriminate between controls and patients with BBD (p= 0.016 and p= 0.000; respectively). Plasma beta-carotene, vitamin A, vitamin E and vitamin C could significantly discriminate between controls and BCPT (p= 0.000, p= 0.000, p= 0.001and p= 0.001, respectively). Plasma vitamin E levels could significantly discriminate between patients with BBD and BCPT (p= 0.055). Odds ratio analysis revealed that, increasing levels of plasma beta-carotene, vitamin E and vitamin C were significantly associated with decreased risk of breast cancer (p= 0.0001, p= 0.003, and p= 0.0001; respectively), whereas, increased risk was linked to plasma vitamin A (p= 0.001). CONCLUSIONS: The trends of the current study provide interesting clues to the etiology of breast cancer and suggest significance of interplay of non-enzymatic antioxidants in breast cancer. Further in-depth study is warranted to elucidate role of these antioxidants as a preventive measure.