Citations

LBA504 Background: Limited efficacy and serious toxicities have limited uptake of tamoxifen or raloxifene as preventatives of breast cancer. Aromatase inhibitors (AIs) prevent contralateral breast cancers more than tamoxifen in adjuvant trials and have fewer serious side effects. This is the first report of an AI used in primary prevention. Methods: NCIC CTG MAP.3 is a randomized trial designed to detect a 65% reduction in annual incidence of invasive breast cancer (IBC) on exemestane (E) versus placebo (P). Eligible postmenopausal women had ≥ one of the following risk factors: Gail score >1.66%, prior ADH, ALH, LCIS or DCIS with mastectomy, age over 60. Health-related and menopause-specific quality of life (QOL) were assessed by SF-36 and MENQOL questionnaires. Results: From 2004-2010, 4,560 women were randomized: age 62.5 yrs (37-90); Gail Score 2.3 % (0.6-21); BMI 28.0 kg/m2 (15.9-65.4). Risk factors included: age >60 yrs (49%); Gail score >1.66 (40%); and prior ADH, ALH, LCIS or DCIS with mastectomy (11%). At median follow-up of 35 months there were 11 IBCs on E and 32 on P (annual incidence 0.19% vs 0.55%; HR= 0.35, 95% CI 0.18-0.70, p = 0.002); ductal (10E/27P), lobular (1E/5P). Most tumors were ER positive (7E/27P); Her2/neu negative (10E/26P); TNM stage T1 (8E/28P), N0 (7E/22P), M0 (11E/30P). E was superior in all subgroups: by Gail score, age, BMI, prior LCIS and DCIS. The annual incidence rate of IBC or DCIS was 0.35% E and 0.77% P (HR=0.47;95% CI 0.27-0.79; p = 0.004) based on 64 IBCs or DCISs (20E/44P). Clinical bone fractures, osteoporosis, hypercholesterolemia or cardiovascular events were equal in both arms. No clinically meaningful differences in QOL were detected. Conclusions: Exemestane significantly reduced invasive and pre-invasive breast cancers in postmenopausal women at increased risk for breast cancer with no serious toxicities. Exemestane should be considered a new option for primary prevention of breast cancer. Supported by the Canadian Cancer Society; Pfizer Inc. PEG supported in part by Avon Foundation.

Cardiac output (CO) assessment as a basic hemodynamic parameter has been of interest in exercise physiology, cardiology, and anesthesiology. Noninvasive techniques available are technically challenging, and thus difficult to use outside of a clinical or laboratory setting. We propose a novel method of noninvasive CO assessment using a single, upper-arm cuff. The method uses the arterial pressure pulse wave signal acquired from the brachial artery during 20-s intervals of suprasystolic occlusion. This method was evaluated in a cohort of 12 healthy individuals (age, 27.7 ± 5.4 yr, 50% men) and compared with an established method for noninvasive CO assessment, the open-circuit acetylene method (OpCirc) at rest, and during low- to moderate-intensity exercise. CO increased from rest to exercise (rest, 7.4 ± 0.8 vs. 7.2 ± 0.8; low, 9.8 ± 1.8 vs. 9.9 ± 2.0; moderate, 14.1 ± 2.8 vs. 14.8 ± 3.2 l/min) as assessed by the cuff-occlusion and OpCirc techniques, respectively. The average error of experimental technique compared with OpCirc was −0.25 ± 1.02 l/min, Pearson’s correlation coefficient of 0.96 (rest + exercise), and 0.21 ± 0.42 l/min with Pearson’s correlation coefficient of 0.87 (rest only). Bland-Altman analysis demonstrated good agreement between methods (within 95% boundaries); the reproducibility coefficient (RPC) = 0.84 l/min with R2= 0.75 at rest and RPC = 2 l/min with R2= 0.92 at rest and during exercise, respectively. In comparison with an established method to quantify CO, the cuff-occlusion method provides similar measures at rest and with light to moderate exercise. Thus, we believe this method has the potential to be used as a new, noninvasive method for assessing CO during exercise.

AbstractBackgroundAs a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient′s native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions.MethodsConsecutive experiments were carried out between 2009 and 2013. Twenty‐one genetically modified pigs (GGTA1‐knockout/hCD46/± thrombomodulin, in one caseHLA‐E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according toISregimen:In group one (n = 10), pre‐treatment started either one (anti‐CD20) or four weeks (anti‐CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti‐thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti‐CD20.In group two (n = 11), myeloablative pre‐treatment as in multiple myeloma patients (long and short regimens) was added to extended conventionalIS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600cGY) was used to further reduce antibody‐producing cells.ResultsIn the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique orISregimen.Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12–50) days and 16 (7–35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer‐lasting grafts; myocardial histology confirmed pre‐clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy.Grafts of group 2 presented with only mild‐to‐moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due toTLI.ConclusionsLonger‐term results were difficult to achieve in this model due to theISregimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.

Purpose To assist in determining barriers to an oncology career incorporating cancer prevention, the American Society of Clinical Oncology (ASCO) Cancer Prevention Workforce Pipeline Work Group sponsored surveys of training program directors and oncology fellows. Methods Separate surveys with parallel questions were administered to training program directors at their fall 2013 retreat and to oncology fellows as part of their February 2014 in-training examination survey. Forty-seven (67%) of 70 training directors and 1,306 (80%) of 1,634 oncology fellows taking the in-training examination survey answered questions. Results Training directors estimated that ≤ 10% of fellows starting an academic career or entering private practice would have a career focus in cancer prevention. Only 15% of fellows indicated they would likely be interested in cancer prevention as a career focus, although only 12% thought prevention was unimportant relative to treatment. Top fellow-listed barriers to an academic career were difficulty in obtaining funding and lower compensation. Additional barriers to an academic career with a prevention focus included unclear career model, lack of clinical mentors, lack of clinical training opportunities, and concerns about reimbursement. Conclusion Reluctance to incorporate cancer prevention into an oncology career seems to stem from lack of mentors and exposure during training, unclear career path, and uncertainty regarding reimbursement. Suggested approaches to begin to remedy this problem include: 1) more ASCO-led and other prevention educational resources for fellows, training directors, and practicing oncologists; 2) an increase in funded training and clinical research opportunities, including reintroduction of the R25T award; 3) an increase in the prevention content of accrediting examinations for clinical oncologists; and 4) interaction with policymakers to broaden the scope and depth of reimbursement for prevention counseling and intervention services.

We investigate the in vivo patterns of stem cell divisions in the human hematopoietic system throughout life. In particular, we analyze the shape of telomere length distributions underlying stem cell behavior within individuals. Our mathematical model shows that these distributions contain a fingerprint of the progressive telomere loss and the fraction of symmetric cell proliferations. Our predictions are tested against measured telomere length distributions in humans across all ages, collected from lymphocyte and granulocyte sorted telomere length data of 356 healthy individuals, including 47 cord blood and 28 bone marrow samples. We find an increasing stem cell pool during childhood and adolescence and an approximately maintained stem cell population in adults. Furthermore, our method is able to detect individual differences from a single tissue sample, i.e. a single snapshot. Prospectively, this allows us to compare cell proliferation between individuals and identify abnormal stem cell dynamics, which affects the risk of stem cell related diseases.

The gene product affected in cystic fibrosis, the cystic fibrosis transmembrane conductance regulator (CFTR), is a chloride-selective ion channel that is regulated by cAMP-dependent protein kinase-mediated phosphorylation, ATP binding and ATP hydrolysis. Mutations in the CFTR gene may result in cystic fibrosis characterized by severe pathology (e.g. recurrent pulmonary infection, male infertility and pancreatic insufficiency) involving organs expressing the CFTR. Interestingly, in the kidney, where expression of the CFTR has been reported, impaired ion transport in patients suffering from cystic fibrosis could not be observed. To understand the role of the CFTR in chloride transport in the kidney, we attempted to identify an epithelial cell line that can serve as a model. We demonstrate that the CFTR is expressed constitutively in MadineŐDarby canine kidney (MDCK) type I cells, which are thought to have originated from the distal tubule of the dog nephron. We show expression at the mRNA level, using reverse transcriptase-PCR, and at the protein level, using Western blot analysis with three different monoclonal antibodies. Iodide efflux measurements indicate that CFTR expression confers a plasma membrane anion conductance that is responsive to stimulation by cAMP. The cAMP-stimulated iodide release is sensitive to glybenclamide, diphenylamine carboxylic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid, but not to 4,4ƀ-di-isothiocyanostilbene-2,2ƀ-disulphonic acid, an inhibitor profile characteristic of the CFTR chloride channel. Finally, the polarized localization of the CFTR to the apical plasma membrane was established by iodide efflux measurements and cell-surface biotinylation on MDCK I monolayers. Interestingly, MDCK type II cells, which are thought to have originated from the proximal tubule of the kidney, lack CFTR protein expression and cAMP-stimulated chloride conductance. In conclusion, we propose that MDCK type I and II cells can serve as convenient model systems to study the physiological role and differential expression of CFTR in the distal and proximal tubule respectively.