Citations

Background Renovascular hypertension ( RVH ) impairs cardiac structure and left ventricular ( LV ) function, but whether mitochondrial injury is implicated in RVH ‐induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury. Methods and Results After 12 weeks of hypercholesterolemic ( HC )‐ RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial‐targeted peptide ( MTP ), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner‐membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector‐computed tomography and oxygenation by blood‐oxygen‐level–dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic‐reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert‐butyl hydroperoxide ( tBHP ) untreated or treated with MTP . Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin‐sensitive sarcoplasmic reticulum Ca 2+ ‐ ATP ase activity that declined in HC ‐ RVH normalized in MTP ‐treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP ‐treated pigs. In tBHP ‐treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics. Conclusions Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC ‐ RVH , suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy.

Abstract Background: African immigrants in the US have substantially higher prevalences of viral hepatitis and hepatocellular carcinoma than the general population. In Minnesota, which has the third largest state population of African immigrants in the US, the incidence and mortality for hepatocellular carcinoma among Blacks is 3 times higher than Caucasians (The 2012 Minnesota Department of Health Cancer Report). Most African immigrants are unaware of their risk for hepatocellular carcinoma which contributes to substantial liver health disparities. Limited research exists on the burden of viral hepatitis and hepatocellular carcinoma among African immigrants. Thus, we conducted a pilot study to evaluate the knowledge, attitudes, and behaviors (KAB) of African immigrants related to liver disease. Methods: The study used a community-engaged research framework. The research team consisted of stakeholders from an academic medical center and Ethiopian, Liberian, and Kenyan community-based organizations and faith-based centers. A semi-structured focus group guide was developed using a KAB approach with open-ended questions. Content analysis was used to thematically code the transcribed data. Qualitative analysis software (ATLAS.TI) was used to organize codes and highlight major themes contributing to liver health disparities. Results: We enrolled 63 participants and conducted 9 focus groups (1 in Amharic, 2 in Oromo, and 6 in English) in Rochester and Minneapolis, Minnesota. The mean age was 47±19; 32 participants (51%) were male; the median years lived in the US was 12 years. General knowledge of the modes of transmission of viral hepatitis and of the prevention and development of liver cancer was minimal. Themes related to barriers to viral hepatitis screening and vaccination included perceived cultural stigma and use of traditional remedies. Common sources of general health information included internet, pamphlets, friends, family, spiritual leaders and healthcare professionals. Healthcare professionals are the source for information on screening, prevention, transmission and treatment of viral hepatitis and liver cancer. Most participants sought healthcare at reputable medical institutions. Media sources and community-based events at faith-centers were preferred modes of information dissemination on viral hepatitis and liver cancer screening and prevention. Conclusions: Participants identified several factors contributing to the increased burden of hepatocellular carcinoma in Minnesota including lack of knowledge of disease transmission and progression, cultural stigma/taboos, and lack of preventive care. Culturally and linguistically appropriate interventions are needed to increase awareness, prevention, early detection, and treatment of viral hepatitis and liver cancer among African immigrants in Minnesota. Citation Format: Essa A. Mohamed, Nasra H. Giama, Hassan M. Shaleh, Linda M. Kerandi, Abdul M. Oseini, Hager F. Ahmed Mohammed, Henry M. Kerandi, Dekermue Togbah, Abdiwahab O. Ali, Ibrahim A. Waaeys, Hamdi A. Ali, Safra A. Mohamed, Hawa M. Ali, Joyce E. Balls-Berry, Lewis R. Roberts. Evaluating knowledge, attitudes, and behaviors about viral hepatitis and hepatocellular carcinoma among recent African immigrants in Minnesota: A community-engaged qualitative study. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C01.

Abstract Background: The rising incidence of hepatocellular carcinoma in the US is partly due to increased immigration from sub-Saharan Africa. Viral hepatitis is prevalent in sub-Saharan Africa, resulting in ~20% of all hepatocellular carcinoma cases worldwide. Community-based education and screening efforts aimed at identifying viral hepatitis cases among African immigrants will likely reduce the burden of hepatocellular carcinoma. Aim: To determine the knowledge, attitudes and behaviors (KAB) of Liberian and Kenyan immigrants residing in Minnesota about hepatitis B virus and hepatitis C virus screening, vaccination, acquisition, and disease management. Methods: A community-engaged research framework was used for the development of this cross-sectional study. The team created a survey using validated items designed to assess the KAB of viral hepatitis measured on a 1 to 20 scale with 1 being low and 20 being high. Using community-engaged methodology, participants who were ≥18 years of age and self-identified either as Liberian and Kenyan were recruited from churches, community centers, and community events. The survey was administered between June 2014 and February 2015. Spearman's rho correlation was used to identify associations among scores while the Mann-Whitney U-test was used for comparisons between Liberians and Kenyans. Results: Of 80 distributed surveys, 73 were returned, achieving a response rate of 91%. Respondents were 50 (64%) Liberians and 23 (29%) Kenyans; 42 (54%) were female; the mean age was 42 years (range 18-90); most were college educated (57%) and had health insurance (83%). 55% reported previous screening for hepatitis B, 51% had completed hepatitis B vaccination and 38% reported being screened for hepatitis C. Mean scores ± SD were 4.6±2.8 for knowledge, 4.7±1.0 for attitude, and 4.2±1.9 for behavior, resulting in poor knowledge and adequate attitude and behavioral levels. Significant and positive linear correlation was observed between attitude and behavior (r=.385, p<.001), while there were no significant correlations between knowledge and attitude (r=-.115, p=.33) or knowledge and behavior (r=-.11, p=.36). When Liberians and Kenyans were compared, knowledge was higher in Liberians (6.2±1.9 vs1.5±1.0; p<.001); there were no significant differences observed in attitude or behavior scores (p>.05 for both). Conclusions: There is lack of awareness among African immigrants of the health risks associated with viral hepatitis which contributes to disparities in healthcare seeking behaviors. It is important to implement comprehensive education and screening programs on viral hepatitis in these communities in order to reduce the burden of viral hepatitis and hepatocellular carcinoma development. Citation Format: Hassan M. Shaleh, Nasra H. Giama, Essa A. Mohamed, Hager F. Ahmed Mohammed, Linda M. Kerandi, Abdul M. Oseini, Abdiwahab O. Ali, Ibrahim A. Waaeys, Jonggi Choi, Henry M. Kerandi, Safra A. Mohamed, Hamdi A. Ali, Hawa M. Ali, Joyce E. Balls-Berry, Lewis R. Roberts. A cross-sectional assessment of knowledge, attitudes, and behaviors about viral hepatitis and hepatocellular carcinoma among Kenyan and Liberian immigrants living in Minnesota. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A46.

Abstract Background: We have previously shown in a phase III neoadjuvant trial that early development of lapatinib-induced rash (i.e. within 6 weeks after lapatinib initiation) is independently associated with a higher chance of obtaining a pathological complete response (Azim et al; JCO 2013). In the current study, we aimed to investigate whether early lapatinib-induced rash is associated with improved survival in the context of a large phase III adjuvant trial. Methods: This analysis is based on the ALTTO trial (BIG 2-06, Alliance N063D), in which patients with HER2-positive early breast cancer were randomized to adjuvant trastuzumab, lapatinib, their sequence or their combination for a total duration of 1 year. In this sub-study, we evaluated whether the development of rash (any grade) within 6 weeks of lapatinib initiation was associated with disease-free (DFS) and overall survival (OS). All analyses were tested in a multivariate model adjusted for treatment arm, treatment completion and trial stratification factors. Results: A total of 6,098 lapatinib-treated patients were included in the current analysis; of whom 2,006 patients (32.9%) developed early lapatinib-induced rash, 1,025 (16.8%) developed rash after 6 weeks and 3,067 (50.3%) did not develop rash. No differences in patient characteristics were observed between the three groups apart from a higher frequency of younger patients (≤ 50) in the early rash group (54% vs. 47% and 44%, p<0.0001). At a median follow-up of 4.5 years, 876 (14.37%) and 377 (6.18%) patients in the lapatinib containing arms experienced a DFS and OS event, respectively. In a multivariate analysis confined to patients randomized to the lapatinib containing arms, the development of early rash was associated with improved DFS (HR: 0.80; 95%CI: 0.69-0.93, p=0.004) and OS (HR: 0.61; 95%CI: 0.48 - 0.78, p<0.001) compared to patients who did not develop early rash, with no interaction according to patient's age (p=0.9). No significant association was observed between the development of rash after 6 weeks of lapatinib initiation and survival. Compared to patients randomized to the trastuzumab alone arm (n=2,076), patients who developed early rash in the sequence (n=580) or combination (n=704) arms of trastuzumab/lapatinib had superior DFS (Sequence: HR 0.75 [95% CI: 0.58 – 0.98], p=0.034; Combination: HR 0.69 [95% CI: 0.54 – 0.89], p=0.005) and OS (Sequence: HR 0.57 [95%CI: 0.36 – 0.88], p=0.012; Combination: HR 0.59 [95% CI: 0.39 – 0.89], p=0.011). On the other hand, patients randomized to the lapatinib only arm who developed early rash (n=722) still had inferior DFS (HR 1.28 [95% CI: 1.04 – 1.59], p=0.02) with no difference in OS (HR: 0.95; 95%CI: 0.67 – 1.35, p=0.79) compared to patients randomized to the trastuzumab alone arm. Conclusions: The results support our previous findings in the neoadjuvant setting that early development of skin rash within the first 6 weeks can identify patients who derive superior benefit of lapatinib treatment. Citation Format: Azim Jr HA, Sonnenblick A, Agbor-Tarh D, Bradbury I, Daly F, Huang Y, Dueck AC, Pritchard K, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Perez E, Piccart M, de Azambuja E. The impact of early lapatinib-induced rash on disease-free and overall survival in patients treated within the ALTTO phase III randomized trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD5-07.

An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34 + stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI ( N = 167), patients treated with autologous CD34 + stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 10 5 CD34/kg body weight), and high dose (5 × 10 5 CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA ® mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III–IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency ( p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time ( p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34 + cells had significant reduction in angina frequency ( p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose ( p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively ( p = 0.08). Autologous CD34 + cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.

Objectives: The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. Materials and Methods: Eligible patients included stage II-IIIB non–small cell lung cancer, stage I central non–small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. Results: Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients’ refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. Conclusions: Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.

Objectives/HypothesisTo present an overview of the barriers to the implementation of clinical practice guidelines (CPGs) in thyroid cancer management and to introduce a computer‐based clinical support system.Data SourcesPubMed.Review Methods: A review of studies on adherence to CPGs was conducted.ResultsAwareness and adoption of CPGs is low in thyroid cancer management. Barriers to implementation include unfamiliarity with the CPGs and financial concerns. Effective interventions to improve adherence are possible, especially when they are readily accessible at the point of care delivery. Computerized clinical support systems show particular promise. The authors introduce the clinical decision making modules (CDMMs) of the Thyroid Cancer Care Collaborative, a thyroid cancer‐specific electronic health record. These computer‐based modules can assist clinicians with implementation of these recommendations in clinical practice.ConclusionComputer‐based support systems can help clinicians understand and adopt the thyroid cancer CPGs. By integrating patient characteristics and guidelines at the point of care delivery, the CDMMs can improve adherence to the guidelines and help clinicians provide high‐quality, evidence‐based, and individualized patient care in the management of differentiated thyroid cancer. Laryngoscope, 126:2640–2645, 2016