Mesenchymal stem cell therapy for the treatment of myocardial infarction

Mesenchymal stem cells (MSCs) are currently under investigation as repair agents in the preservation of cardiac function following myocardial infarction (MI). However concerns have emerged regarding the safety of acute intracoronary (IC) MSC delivery specifically related to mortality, micro-infarction and microvascular flow restriction post cell therapy in animal models. This thesis aimed to firstly identify an optimal dose of MSC that could be tolerated when delivered via the coronary artery in a porcine model of acute MI (AMI). Initial dosing studies identified 25x106 MSC to be a safe MSC cell dose, however, angiographic observations from these studies recognised that on delivery of MSC there was a significant adverse decrease in distal blood flow within the artery. This observation along with additional supportive data in the literature (published during the course of this thesis) suggested MSC may be contributing to such adverse events through the propagation of thrombosis. Therefore further studies aimed to investigate the innate prothrombotic activity of MSC. Expression of the initiator of the coagulation cascade initiator tissue factor (TF) on MSC was detected in high levels on the surface of these cells. MSC-derived TF antigen was catalytically active, capable of supporting thrombin generation in vitro and enhancing platelet-driven thrombus deposition on collagen under flow. Infusion of MSC via IC route was associated with a decreased coronary flow reserve when delivered but not when coadministered with an antithrombin agent heparin. Heparin also reduced MSC-associated in situ thrombosis incorporating platelets and VWF in the microvasculature. Heparin-assisted MSC delivery reduced acute apoptosis and significantly improved infarct size, left ventricular ejection fraction, LV volumes, wall motion and scar formation at 6 weeks post AMI. In addition, this thesis investigated the paracrine factors secreted by MSC, in particular focusing on the effect on cardiac repair of a novel MSC-paracrine factor SPARCL1. In summary this work provides new insight into the mechanism by which MSC may be deleterious when delivered by an IC route and a means of abrogating this effect. Moreover we present new data on the MSC secretome with elucidation of the challenges encountered using a single paracrine factor cardiac repair strategy.

The defining characteristics of alternative food initiatives in Ireland: a social movement battling for an alternative food future?

Alternative food initiatives (AFIs) have been described as an attempt to change and improve aspects of how the food system operates. They are focused around more traditional, local and sustainable food production and circulation. AFIs such as farmers’ markets, allotments and community gardens, share a desire to reduce the number of steps food goes through from production to plate. The role of these initiatives in the food system, and their potential to impact real change, has however been questioned. Working to better understand this issue is a central concern of this research. To do this a two tier analysis has been deployed. The first tier involves identifying the characteristics and general dynamics of AFIs. Bourdieu’s theory of practice, and the theories of field and capital, are the concepts applied. The research then uses these findings in the second tier of analysis concerned with relating AFI characteristics and dynamics back to their key traits, positive and negative, as well as arguments made about AFI’s role identified from previous research. Another part of this second tier of analysis is exploring if AFIs, the producers, consumers, organisations and groups that make up this phenomenon, can be considered a social movement. AFIs can be referred to collectively as a social movement, but are not often explored theoretically from this perspective. AFIs in Ireland provide the empirical context for this research. A series of qualitative interviews in four areas of Ireland, as well as evidence from primary and secondary sources are analysed. The research finds that AFIs can be understood as the potential beginnings of a lifestyle social movement. Leaders are of central importance to its development. It is also found that an important role of AFIs is revitalising, supporting and contributing to food culture.

Effectiveness of rescue antiretroviral therapy including intravenously administered zidovudine and foscarnet in a child with HIV-1 enteropathy.

Case Reports

Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over.

PURPOSE: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival ¿PFS) and to explore the degree of cross-resistance between the two agents. PATIENTS AND METHODS: Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m(2), 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m(2), intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. RESULTS: Objective response in first-line therapy was significantly better (P =.003) for doxorubicin (response rate ¿RR, 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P <.001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P =.38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. CONCLUSION: At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting.

Adjuvant therapy in elderly patients with breast cancer.

The elderly population has been neglected by the traditional approach to clinical breast cancer research. Elderly women have been underrepresented in breast cancer clinical trials, with the majority of studies being restricted to patients aged < 70 years. Elderly patients frequently have comorbidities and/or impaired organ function. These facts may often lead to death from causes other than cancer, thus nullifying any possible benefit of adjuvant treatment; furthermore, they render extrapolation of standard treatment recommendations to the elderly potentially hazardous, particularly with respect to chemotherapy. Therefore, specific clinical trials are needed to investigate adjuvant treatments tailored for the heterogeneous older population.

Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer.

BACKGROUND: Women with hormone-responsive metastatic breast cancer (MBC) may respond to or have stable disease with a number of hormone therapies. We explored the efficacy and safety of the steroidal aromatase inactivator exemestane as first-line hormonal therapy in MBC in postmenopausal women. PATIENTS AND METHODS: Patients with measurable disease were eligible if they had received no prior hormone therapy for metastatic disease and had hormone receptor positive disease or hormone receptor unknown disease with a long disease-free interval from adjuvant therapy. They were randomized to tamoxifen 20 mg/day or exemestane 25 mg/day in this open-label study. RESULTS: Blinded independently reviewed response rates for exemestane and tamoxifen were 41% and 17%, respectively. Fifty-seven per cent of exemestane- and 42% of tamoxifen-treated patients experienced clinical benefit, defined as complete or partial response, or disease stabilization lasting at least 6 months. There was a low incidence of severe flushing, sweating, nausea and edema in women who received exemestane. One exemestane-treated patient had a pulmonary embolism with grade 4 dyspnea. CONCLUSIONS: Exemestane is well tolerated and active in the first-line treatment of hormone-responsive MBC. An ongoing EORTC phase III trial is comparing the efficacy, measuring time-to-disease progression, of exemestane and tamoxifen.

A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer

BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of metastatic breast cancer. We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease, aged < or = 70 years, received one of the following regimens: a) sequential A-->T-->CMF: doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x 3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T-->CMF: A and T were administered at the same doses q 2 weeks; c) combination therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF x 4. When indicated, radiotherapy was administered during or after CMF, and tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been treated. Median age was 48 years. A 30% rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy (23% during A-->T), due principally to severe skin toxicity. Median relative dose-intensity was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c: 48%. After a median follow-up of 18 months, no late toxicity has been reported. CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity. The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy.

3-year results of docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer: a pilot study.

BACKGROUND: Docetaxel has proven efficacy in metastatic breast cancer. In this pilot study, we explored the efficacy/feasibility of docetaxel-based sequential and combination regimens as adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: From March 1996 till March 1998, four consecutive groups of patients with stages II and III breast cancer, aged < or = 70 years, received one of the following regimens: a) sequential Doxorubicin (A) --> Docetaxel (T) --> CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil): A 75 mg/m q 3 wks x 3, followed by T100 mg/m2 q 3 wks x 3, followed by i.v. CMF Days 1+8 q 4 wks x 3; b) sequential accelerated A --> T --> CMF: A and T administered at the same doses q 2 wks with Lenograstin support; c) combination therapy: A 50 mg/m2 + T 75 mg/m2 q 3 wks x 4, followed by CMF x 4; d) sequential T --> A --> CMF: T and A, administered as in group a), with the reverse sequence. When indicated, radiotherapy was administered during or after CMF, and Tamoxifen after CMF. RESULTS: Ninety-three patients were treated. The median age was 48 years (29-66) and the median number of positive axillary nodes was 6 (1-25). Tumors were operable in 94% and locally advanced in 6% of cases. Pathological tumor size was >2 cm in 72% of cases. There were 21 relapses, (18 systemic, 3 locoregional) and 11 patients (12%) have died from disease progression. At median follow-up of 39 months (6-57), overall survival (OS) was 87% (95% CI, 79-94%) and disease-free survival (DFS) was 76% (95% CI, 67%-85%). CONCLUSION: The efficacy of these docetaxel-based regimens, in terms of OS and DFS, appears to be at least as good as standard anthracycline-based adjuvant chemotherapy (CT), in similar high-risk patient populations.

Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer.

PURPOSE: Taxanes (paclitaxel or docetaxel) have been sequenced or combined with anthracyclines (doxorubicin or epirubicin) for the first-line treatment of advanced breast cancer. This meta-analysis uses data from all relevant trials to detect any advantages of taxanes in terms of tumor response, progression-free survival (PFS), and survival. PATIENTS AND METHODS: Individual patient data were collected on eight randomized combination trials comparing anthracyclines + taxanes (+ cyclophosphamide in one trial) with anthracyclines + cyclophosphamide (+ fluorouracil in four trials), and on three single-agent trials comparing taxanes with anthracyclines. Combination trials included 3,034 patients; single-agent trials included 919 patients. RESULTS: Median follow-up of living patients was 43 months, median survival was 19.3 months, and median PFS was 7.1 months. In single-agent trials, response rates were similar in the taxanes (38%) and in the anthracyclines (33%) arms (P = .08). The hazard ratios for taxanes compared with anthracyclines were 1.19 (95% CI, 1.04 to 1.36; P = .011) for PFS and 1.01 (95% CI, 0.88 to 1.16; P = .90) for survival. In combination trials, response rates were 57% (10% complete) in taxane-based combinations and 46% (6% complete) in control arms (P < .001). The hazard ratios for taxane-based combinations compared with control arms were 0.92 (95% CI, 0.85 to 0.99; P = .031) for PFS and 0.95 (95% CI, 0.88 to 1.03; P = .24) for survival. CONCLUSION: Taxanes were significantly worse than single-agent anthracyclines in terms of PFS, but not in terms of response rates or survival. Taxane-based combinations were significantly better than anthracycline-based combinations in terms of response rates and PFS, but not in terms of survival.

E12. Progress in systemic therapy for breast cancer

SCOPUS: ar.j

Fertility preservation: Successful transplantation of cryopreserved ovarian tissue in a young patient previously treated for Hodgkin's disease

Cryopreservation of ovarian tissue is now offered as an experimental procedure to preserve the fertility of young patients with a high risk for premature ovarian failure resulting from cancer therapy. This is the only available option to preserve the fertility of prepubertal patients treated with gonadotoxic chemotherapy. At present, thousands of patients all over the world have undergone this procedure with the hope of later restoring their fertility. Although the efficiency of the transplantation of cryopreserved ovarian tissue to restore ovarian function has been established, reports of pregnancy are still very scarce. Here, we describe the second published full-term spontaneous pregnancy after an orthotopic and heterotopic transplantation of cryopreserved ovarian tissue in a 31-year-old woman previously treated by conditioning therapy for bone marrow transplantation for Hodgkin's disease. This birth gives compelling evidence for the graft origin of the gamete and confirms the efficacy of ovarian tissue transplantation in restoring human natural fertility after oncological treatment. This case report stresses the importance of proposing the ovarian tissue cryopreservation procedure to all young patients who require potentially sterilizing treatment, with all alternative options to preserve fertility being duly taken into consideration.

The ranking of alternative tariff and quota policies in the presence of domestic monopoly

Bhagwati demonstrated the nonequivalence between tariffs and quotas in the presence of monopoly. This paper also assumes domestic production to be monopolized and shows that giving import licenses or tariff revenues to the domestic producer may raise or lower the welfare cost of protection and the price paid by consumers from the price under other tariff and quota arrangements which maintain the same market share for the domestic producer. However, if the monopolist realizes that commercial policy is an instrument used to maximize the policymaker's welfare function, instead of being a goal in itself, the equivalence of tariffs and quotas re-emerges. © 1977.

Patient-based outcome assessment instruments in acupuncture research.

BACKGROUND: Outcome assessment can support the therapeutic process by providing a way to track symptoms and functionality over time, providing insights to clinicians and patients, as well as offering a common language to discuss patient behavior/functioning. OBJECTIVES: In this article, we examine the patient-based outcome assessment (PBOA) instruments that have been used to determine outcomes in acupuncture clinical research and highlight measures that are feasible, practical, economical, reliable, valid, and responsive to clinical change. The aims of this review were to assess and identify the commonly available PBOA measures, describe a framework for identifying appropriate sets of measures, and address the challenges associated with these measures and acupuncture. Instruments were evaluated in terms of feasibility, practicality, economy, reliability, validity, and responsiveness to clinical change. METHODS: This study was a systematic review. A total of 582 abstracts were reviewed using PubMed (from inception through April 2009). RESULTS: A total of 582 citations were identified. After screening of title/abstract, 212 articles were excluded. From the remaining 370 citations, 258 manuscripts identified explicit PBOA; 112 abstracts did not include any PBOA. The five most common PBOA instruments identified were the Visual Analog Scale, Symptom Diary, Numerical Pain Rating Scales, SF-36, and depression scales such as the Beck Depression Inventory. CONCLUSIONS: The way a questionnaire or scale is administered can have an effect on the outcome. Also, developing and validating outcome measures can be costly and difficult. Therefore, reviewing the literature on existing measures before creating or modifying PBOA instruments can significantly reduce the burden of developing a new measure.

Prostate biopsy in selecting candidates for hemiablative focal therapy.

Focal therapy (FT) for the management of clinically localized prostate cancer (PCa) is growing from a concept to reality because of increased interest of both patients and physicians. Selection protocols, however, are yet to be established. We discuss the role of prostate biopsy in candidate selection for FT and highlight the different strategies and technical aspects of the use of prostate biopsy in this setting. In our opinion, prostate biopsy plays a major role in the selection process and tailoring appropriate treatment strategy to the patient. FT necessitates dedicated biopsy schemes that would reliably predict the extent, nature, and location of PCa in selected patients. Currently, there is insufficient scientific evidence to propose a specific biopsy scheme that could fit every candidate, providing accurate characterization of the disease in the individual patient. Further research is necessary to establish solid selection protocols that would reliably identify appropriate candidates for FT of PCa.

Genetic engineering of mesenchymal stem cells and its application in human disease therapy.

The use of stem cells for tissue regeneration and repair is advancing both at the bench and bedside. Stem cells isolated from bone marrow are currently being tested for their therapeutic potential in a variety of clinical conditions including cardiovascular injury, kidney failure, cancer, and neurological and bone disorders. Despite the advantages, stem cell therapy is still limited by low survival, engraftment, and homing to damage area as well as inefficiencies in differentiating into fully functional tissues. Genetic engineering of mesenchymal stem cells is being explored as a means to circumvent some of these problems. This review presents the current understanding of the use of genetically engineered mesenchymal stem cells in human disease therapy with emphasis on genetic modifications aimed to improve survival, homing, angiogenesis, and heart function after myocardial infarction. Advancements in other disease areas are also discussed.