Mobilization of Endogenous CD34+/CD133+ Endothelial Progenitor Cells by Enhanced External Counter Pulsation for Treatment of Refractory Angina.

Adult stem cell therapy via intramyocardial injection of autologous CD34+ stem cells has been shown to improve exercise capacity and reduce angina frequency and mortality in patients with refractory angina (RA). However, the cost of such therapy is a limitation to its adoption in clinical practice. Our goal was to determine whether the less costly, less invasive, and widely accessible, FDA-approved alternative treatment for RA patients, known as enhanced external counterpulsation (EECP), mobilizes endogenous CD34+ stem cells and whether such mobilization is associated with the clinical benefits seen with intramyocardial injection. We monitored changes in circulating levels of CD34+/CD133+ and CD34+/KDR+ cells in RA patients undergoing EECP therapy and in a comparator cohort of RA patients undergoing an exercise regimen known as cardiac rehabilitation. Changes in exercise capacity in both cohorts were monitored by measuring treadmill times (TT), double product (DP) scores, and Canadian Cardiovascular Society (CCS) angina scores between pre- and post-treatment treadmill stress tests. Circulating levels of CD34+/CD133+ cells increased in patients undergoing EECP and were significant (ß = -2.38, p = 0.012) predictors of improved exercise capacity in these patients. CD34+/CD133+ cells isolated from RA patients could differentiate into endothelial cells, and their numbers increased during EECP therapy. Our results support the hypothesis that mobilized CD34+/CD133+ cells repair vascular damage and increase collateral circulation in RA patients. They further support clinical interventions that can mobilize adult CD34+ stem cells as therapy for patients with RA and other vascular diseases.

Expanding the Use of Continuous Sedation Until Death and Physician-Assisted Suicide.

The controversy over the equivalence of continuous sedation until death (CSD) and physician-assisted suicide/euthanasia (PAS/E) provides an opportunity to focus on a significant extended use of CSD. This extension, suggested by the equivalence of PAS/E and CSD, is designed to promote additional patient autonomy at the end-of-life. Samuel LiPuma, in his article, "Continuous Sedation Until Death as Physician-Assisted Suicide/Euthanasia: A Conceptual Analysis" claims equivalence between CSD and death; his paper is seminal in the equivalency debate. Critics contend that sedation follows proportionality protocols for which LiPuma's thesis does not adequately account. Furthermore, sedation may not eliminate consciousness, and as such LiPuma's contention that CSD is equivalent to neocortical death is suspect. We not only defend the equivalence thesis, but also expand it to include additional moral considerations. First, we explain the equivalence thesis. This is followed by a defense of the thesis against five criticisms. The third section critiques the current use of CSD. Finally, we offer two proposals that, if adopted, would broaden the use of PAS/E and CSD and thereby expand options at the end-of-life.

Ofatumumab plus HyperCVAD/HD-MA induction leads to high rates of minimal residual disease negativity in patients with newly diagnosed mantle cell lymphoma: Results of a phase 2 study.

BACKGROUND: Ofatumumab is a humanized type 1 anti-CD20 monoclonal antibody. Preclinical studies show improved complement-mediated cytotoxicity (CMC) compared to rituximab in mantle cell lymphoma (MCL). This study evaluates the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL. METHODS: In this single-arm phase 2 study, 37 patients were treated with the combination of O-HyperCVAD for 4 or 6 cycles, followed by high dose chemotherapy and autologous stem cell transplant. Primary objectives were overall response rate (ORR) and complete response (CR) rate at the end of therapy. Secondary objectives included minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall survival (OS). RESULTS: Median age was 60 years; ORR was 86% and 73% achieved a CR by modified Cheson criteria. The MRD negativity rate was 78% after 2 cycles of therapy, increasing to 96% at the end of induction; median PFS and OS were 45.5 months and 56 months, respectively. Achieving a post-induction CR by both imaging and flow cytometry was associated with improved PFS and OS. Early MRD negativity (post-2 cycles) was also associated with an improved PFS but not OS. There were 3 deaths while on therapy, and grades 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients. CONCLUSION: The addition of ofatumumab to HyperCVAD/HD-MA led to high rates of MRD negativity by flow cytometry in patients with newly diagnosed MCL. Achieving a CR post-induction by both imaging and flow cytometry is associated with improved overall survival.

Dementia, Advance Directives, and Discontinuity of Personality.

We argue that an advance directive (AD) is not invalidated by personality changes in dementia, as is claimed by Rebecca Dresser. The claim is that a new person results under such personality changes, and that the former person cannot write an AD for the new person. After stating the argument against ADs in cases of dementia, we provide a detailed examination of empirical studies of personality changes in dementia. This evidence, though not strong due mainly to low sample sizes and different notions of personal identity, does not support Dresser's position. Given the weakness in the empirical evidence, we turn to a philosophical defense of ADs based on a social contract view supporting the current interests of those writing ADs. Additionally, we argue that personality change is not equivalent to change in personal identity, as would be required by the argument against ADs in cases of dementia.

Expanding the Use of Continuous Sedation Until Death: Moving Beyond the Last Resort for the Terminally Ill.

As currently practiced, the use of continuous sedation until death (CSD) is controlled by clinicians in a way that may deny patients a key choice in controlling their dying process. Ethical guidelines from the American Medical Association and the American Academy of Pain Medicine describe CSD as a "last resort," and a position statement from the American Academy of Hospice and Palliative Medicine describe it as "an intervention reserved for extreme situations." Accordingly, patients must progress to unremitting pain and suffering and reach a last-resort stage before the option to pursue CSD is considered. Alternatively, we present and defend a new guideline in which decisionally capable, terminally ill patients who have a life expectancy of less than six months may request CSD before being subjected to the refractory suffering of a treatment of "last resort."

Is there an ethical obligation to disclose controversial risk? A question from the ACCORD Trial.

Researchers designing a clinical trial may be aware of disputed evidence of serious risks from previous studies. These researchers must decide whether and how to describe these risks in their model informed consent document. They have an ethical obligation to provide fully informed consent, but does this obligation include notice of controversial evidence? With ACCORD as an example, we describe a framework and criteria that make clear the conditions requiring inclusion of important controversial risks. The ACCORD model consent document did not include notice of prior trials with excess death. We develop and explain a new standard labeled risk in equipoise. We argue that our approach provides an optimal level of integrity to protect the informational needs of the reasonable volunteers who agree to participate in clinical trials. We suggest language to be used in a model consent document and the informed consent discussion when such controversial evidence exists.

Carfilzomib combined with rituximab, ifosfamide, carboplatin, and etoposide for relapsed or refractory DLBCL.

The CORAL study highlighted the need to develop novel salvage regimens in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) previously treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Carfilzomib (CFZ) can overcome rituximab chemotherapy resistance in lymphoma preclinical models by targeting the ubiquitin-proteasome system. We conducted an investigator initiated, single-center, open-label, prospective phase 1 study evaluating the safety and efficacy of CFZ in combination with rituximab, ifosfamide, carboplatin, and etoposide (C-R-ICE) in high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) eligible patients with R/R DLBCL (NCT01959698). In the dose-escalation phase, 18 patients were enrolled at 6 dose levels with no dose-limiting toxicities noted. CFZ 45 mg/m2 was selected as the recommended dose for expansion. Eleven additional patients were enrolled in the dose-expansion phase. Overall response rate (ORR) was 66% (48% CR; 17% PR); 52% patients underwent HDC-ASCT. An ORR of 85% was observed in patients with nongerminal center B-cell-like (non-GCB) DLBCL compared with only 13% in those with GCB DLBCL. Median progression-free survival (PFS) was 15.2 months (5.1 months, not reached [NR]), and median overall survival (OS) was 22.6 months (6.8 months, NR). Patients with non-GCB subtype had a significantly longer PFS (NR vs 6.6 months; P = .0001) and OS (NR vs 6.6 months; P = .001) than those with GCB subtype. C-R-ICE is well tolerated in patients with R/R DLBCL with toxicities comparable to rituximab, ifosfamide, carboplatin, and etoposide therapy. Our data show that patients with non-GCB DLBCL benefit significantly from incorporating CFZ into second-line therapy and HDC-ASCT.

Rational noncompliance with prescribed medical treatment.

Despite the attention that patient noncompliance has received from medical researchers, patient noncompliance remains poorly understood and difficult to alter. With a better theory of patient noncompliance, both greater success in achieving compliance and greater respect for patient decision making are likely. The theory presented, which uses a microeconomic approach, bridges a gap in the extant literature that has so far ignored the contributions of this classic perspective on decision making involving the tradeoff of costs and benefits. The model also generates a surprising conclusion: that patients are typically acting rationally when they refuse to comply with certain treatments. However, compliance is predicted to rise with increased benefits and reduced costs. The prediction that noncompliance is rational is especially true in chronic conditions at the point that treatment begins to move closer to the medically ideal treatment level. Although the details of this theory have not been tested empirically, it is well supported by existing prospective and retrospective studies.

Deep brain stimulation and the ethics of protection and caring for the patient with Parkinson's dementia.

Deep brain stimulation (DBS) is an effective neurosurgical treatment for patients with advanced Parkinson's disease (PD) suffering from motor complications that are refractory to further medication management. DBS requires an invasive procedure of implanting brain electrodes while awake, followed by implantation of neurostimulators under general anesthesia. The neurostimulator requires battery monitoring and replacement approximately every 3 to 5 years. These two elements of the technology provide numerous decision points about continuing therapies that can involve ethical choices. Although motor function can be improved with subthalamic nucleus (STN) DBS, the long-term risks of living with implanted hardware should be carefully evaluated for patients with diminishing cognitive capacity. We describe two cases where ethical dilemmas occurred postoperatively as a result of cognitive decline and describe salient ethical dimensions that illustrate the need for a proactive postoperative plan for supervision as a prerequisite for surgery to include neuropsychological testing to predict the likelihood of net benefit to the patient and family beyond just motor improvement.

Power and control in gay strip clubs.

The gay strip club is a place in which more than displays of male beauty take place. The mix of customers, performers, liquor, and nudity results in fascinating dynamics. Of interest in this article are the power relationships and issues of control played out both among and between strippers and customers. Based on extensive participant observation conducted in eight cities and numerous bars/clubs and including more than 150 in-depth interviews, this article concerns just one aspect of the world of male strippers who perform for men.

Palliative Care and Patient Autonomy: Moving Beyond Prohibitions Against Hastening Death.

The National Hospice and Palliative Care Organization (NHPCO) upholds policies prohibiting practices that deliberately hasten death. We find these policies overly restrictive and unreasonable. We argue that under specified circumstances it is both reasonable and morally sound to allow for treatments that may deliberately hasten death; these treatments should be part of the NHPCO guidelines. Broadening such policies would be more consistent with the gold standard of bioethical principles, ie, respecting the autonomy of competent adults.

An economic theory of patient decision-making.

Patient autonomy, as exercised in the informed consent process, is a central concern in bioethics. The typical bioethicist's analysis of autonomy centers on decisional capacity--finding the line between autonomy and its absence. This approach leaves unexplored the structure of reasoning behind patient treatment decisions. To counter that approach, we present a microeconomic theory of patient decision-making regarding the acceptable level of medical treatment from the patient's perspective. We show that a rational patient's desired treatment level typically departs from the level yielding an absence of symptoms, the level we call ideal. This microeconomic theory demonstrates why patients have good reason not to pursue treatment to the point of absence of physical symptoms. We defend our view against possible objections that it is unrealistic and that it fails to adequately consider harm a patient may suffer by curtailing treatment. Our analysis is fruitful in various ways. It shows why decisions often considered unreasonable might be fully reasonable. It offers a theoretical account of how physician misinformation may adversely affect a patient's decision. It shows how billing costs influence patient decision-making. It indicates that health care professionals' beliefs about the 'unreasonable' attitudes of patients might often be wrong. It provides a better understanding of patient rationality that should help to ensure fuller information as well as increased respect for patient decision-making.

Clarifying an Expanded Use of Continuous Sedation Until Death: A Reply to the Commentary by McCammon and Piemonte.

Susan D. McCammon and Nicole M. Piemonte offer a thoughtful and thorough commentary on our manuscript entitled "Expanding the use of Continuous Sedation Until Death." In this reply we attempt to clarify and further defend our position. We show how continuous sedation until death is not a "first resort" but rather a legitimate option among many that should available to terminally ill patients whose life expectancy is less than six months. We also attempt to show that we do not equivocate the meaning of palliative care as the commentators suggested. We argue that the traditional notion of palliative care should move beyond relief of "experienced suffering" to relief of potential suffering for those whose life expectancy is less than six months. Lastly, we challenge the commentator's position that the realm of ordinary medicine" should be the guide to care, by showing how the notion of ordinary medicine has been successfully challenged in both bioethical scholarship and the courts in a way that shows ordinary medicine to be an evolving concept rather than a static, universal guide.