Pericyte-derived extracellular vesicle-mimetic nanovesicles ameliorate erectile dysfunction via lipocalin 2 in diabetic mice

Diabetes mellitus is one of the main causes of erectile dysfunction (ED). Men with diabetic ED do not respond well to oral phosphodiesterase-5 inhibitors owing to neurovascular dysfunction. Pericyte-derived extracellular vesicle-mimetic nanovesicles (PC-NVs) are known to promote nerve regeneration in a mouse model of cavernous nerve injury. Here, we report that administration of PC-NVs effectively promoted penile angiogenesis and neural regeneration under diabetic conditions, thereby improving erectile function. Specifically, PC-NVs induced endothelial proliferation and migration and reduced cell apoptosis under diabetic conditions. In addition, PC-NVs induced neural regeneration in STZ-induced diabetic mice in dorsal root ganglion and major pelvic ganglion explants in vivo and ex vivo under high-glucose conditions. We found that lipocalin 2 (Lcn2) is a new target of PC-NVs in this process, demonstrating that PC-NVs exert their angiogenic and nerve-regeneration effects by activating MAP kinase and PI3K/Akt and suppressing P53 signaling pathway in an Lcn2-dependent manner. Our findings provide new conclusive evidence that PC-NVs can promote neurovascular regeneration and recovery of erectile function under diabetic conditions via an Lcn2-dependent mechanism. Thus, local administration of PC-NVs may be a promising treatment strategy for the treatment of diabetic ED.     

Stem cell therapy for the treatment of Leydig cell dysfunction in primary hypogonadism

The production of testosterone occurs within the Leydig cells of the testes. When production fails at this level from either congenital, acquired, or systemic disorders,the result is primary hypogonadism. While numerous testosterone formulations have been developed, none are yet fully capable of replicating the physiological patterns of testosterone secretion. Multiple stem cell therapies to restore androgenic function of the testes are under investigation. Leydig cells derived from bone marrow, adipose tissue, umbilical cord, and the testes have shown promise for future therapy for primary hypogonadism. In particular, the discovery and utilization of a group of progenitor stem cells within the testes, known as stem Leydig cells(SLCs), has led not only to a better understanding of testicular development, but of treatment as well. When combining this with an understanding of the mechanisms that lead to Leydig cell dysfunction, researchers and physicians will be able to develop stem cell therapies that target the specific step in the steroidogenic process that is deficient. The current preclinical studies highlight the complex nature of regenerating this steroidogenic process and the problems remain unresolved. In summary, there appears to be two current directions for stem cell therapy in male primary hypogonadism. The first method involves differentiating adult Leydig cells from stem cells of various origins from bone marrow, adipose, or embryonic sources. The second method involves isolating, identifying, and transplanting stem Leydig cells into testicular tissue. Theoretically, in-vivo re-activation of SLCs in men with primary hypogonadism due to age would be another alternative method to treat hypogonadism while eliminating the need for transplantation.     

N‐acetylcysteine improves diabetic associated erectile dysfunction in streptozotocin‐induced diabetic mice by inhibiting oxidative stress

Oxidative stress appears to play a role in the pathogenesis of diabetes mellitus erectile dysfunction (DMED). This study aimed to investigate the effect of N‐acetylcysteine (NAC) on DMED in streptozotocin‐induced diabetic mice and to explore potential mechanisms. In the present study, we show that an erectile dysfunction is present in the streptozotocin‐induced mouse model of diabetes as indicated by decreases in intracavernous pressure responses to electro‐stimulation as well as from results of the apomorphine test of erectile function. After treatment of NAC, the intracavernous pressure was increased. In these DMED mice, oxidative stress and inflammatory responses were significantly reduced within the cavernous microenvironment, while activity of antioxidant enzymes in this cavernous tissue was enhanced after NAC treatment. These changes protected mitochondrial stress damage and a significant decreased in apoptosis within the cavernous tissue of DMED mice. This appears to involve activation of the nuclear factor erythroid 2‐like‐2 (Nrf2) signalling pathway, as well as suppression of the mitogen‐activated protein kinase (MAPK) p38/ NF‐κB pathway within cavernous tissue. In conclusion, NAC can improve erectile function through inhibiting oxidative stress via activating Nrf2 pathways and reducing apoptosis in streptozotocin‐induced diabetic mice. NAC might provide a promising therapeutic strategy for individuals with DMED.     

Human amniotic fluid stem cell therapy can help regain bladder function in type 2 diabetic rats

BACKGROUNDDiabetes mellitus (DM) is a serious and growing global health burden. It is estimated that 80% of diabetic patients have micturition problems such as poor emptying, urinary incontinence, urgency, and urgency incontinence. Patients with diabetic bladder dysfunction are often resistant to currently available therapies. It is necessary to develop new and effective treatment methods.AIMTo examine the therapeutic effect of human amniotic fluid stem cells (hAFSCs) therapy on bladder dysfunction in a type 2 diabetic rat model.METHODSSixty female Sprague-Dawley rats were divided into five groups: Group 1, normal-diet control (control); group 2, high-fat diet (HFD); group 3, HFD plus streptozotocin-induced DM (DM); group 4, DM plus insulin treatment (DM + insulin); group 5, DM plus hAFSCs injection via tail vein (DM + hAFSCs). Conscious cystometric studies were done at 4 and 12 wk after insulin or hAFSCs treatment to measure peak voiding pressure, voided volume, intercontraction interval, bladder capacity, and residual volume. Immunoreactivities and/or mRNA expression of muscarinic receptors, nerve growth factor (NGF), and sensory nerve markers in the bladder and insulin, MafA, and pancreatic-duodenal homeobox-1 (PDX-1) in pancreatic beta cells were studied.RESULTSCompared with DM rats, insulin but not hAFSCs treatment could reduce the bladder weight and improve the voided volume, intercontraction interval, bladder capacity, and residual volume (P < 0.05). However, both insulin and hAFSCs treatment could help to regain the blood glucose and bladder functions to the levels near controls (P > 0.05). The immunoreactivities and mRNA expression of M2- and M3-muscarinic receptors (M2 and M3) were increased mainly at 4 wk (P < 0.05), while the number of beta cells in islets and the immunoreactivities and/or mRNA of NGF, calcitonin gene-related peptide (CGRP), substance P, insulin, MafA, and PDX-1 were decreased in DM rats (P < 0.05). However, insulin and hAFSCs treatment could help to regain the expression of M2, M3, NGF, CGRP, substance P, MafA, and PDX-1 to near the levels of controls at 4 and/or 12 wk (P > 0.05).CONCLUSIONInsulin but not hAFSCs therapy can recover the bladder dysfunction caused by DM; however, hAFSCs and insulin therapy can help to regain bladder function to near the levels of control.     

Stem cell therapy: A novel approach for myocardial infarction

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Until recently, it was thought that myocardium was not able to repair itself, but studies have now shown that resident cardiac stem cells have regenerative capacity, and stem cell therapy may be a novel approach for cardiac muscle repair and regeneration. Stem cell-derived paracrine factors have been shown to regulate ventricular remodeling, inflammation, apoptosis, cardiomyocytes regeneration, and neovascularization in regions of infarcted cardiac tissue. In this review, we summarize the evidence from cellular, animal, and clinical studies supporting the potential clinical significance of stem cell therapy as a novel therapeutic approach for the treatment of MI.     

Application of mesenchymal stem cell therapy for the treatment of osteoarthritis of the knee: A concise review

Osteoarthritis(OA) refers to a chronic joint disease characterized by degenerative changes of articular cartilage and secondary bone hyperplasia. Since articular cartilage has a special structure, namely the absence of blood vessels as well as the low conversion rate of chondrocytes in the cartilage matrix, the treatment faces numerous clinical challenges. Traditional OA treatment(e.g., arthroscopic debridement, microfracture, autologous or allogeneic cartilage transplantation,chondrocyte transplantation) is primarily symptomatic treatment and pain management, which cannot contribute to regenerating degenerated cartilage or reducing joint inflammation. Also, the generated mixed fibrous cartilage tissue is not the same as natural hyaline cartilage. Mesenchymal stem cells(MSCs) have turned into the most extensively explored new therapeutic drugs in cell-based OA treatment as a result of their ability to differentiate into chondrocytes and their immunomodulatory properties. In this study, the preliminary results of preclinical(OA animal model)/clinical trials regarding the effects of MSCs on cartilage repair of knee joints are briefly summarized, which lay a solid application basis for more and deeper clinical studies on cell-based OA treatment.     

Advances in stem cell therapy for the lower urinary tract

Lower urinary tract diseases are emotionally and financially burdensome to the individual and society. Current treatments are ineffective or symptomatic. Conversely, stem cells (SCs) are regenerative and may offer long-term solutions. Among the different types of SCs, bone marrow SCs (BMSCs) and skeletal muscle-derived SCs (SkMSCs) have received the most attention in pre-clinical and clinical trial studies concerning the lower urinary tract. In particular, clinical trials with SkMSCs for stress urinary incontinence have demonstrated impressive efficacy. However, both SkMSCs and BMSCs are difficult to obtain in quantity and therefore neither is optimal for the eventual implementation of SC therapy. On the other hand, adipose tissue-derived SCs (ADSCs) can be easily and abundantly obtained from "discarded" adipose tissue. Moreover, in several head-on comparison studies, ADSCs have demonstrated equal or superior therapeutic potential compared to BMSCs. Therefore, across several different medical disciplines, including urology, ADSC research is gaining wide attention. For the regeneration of bladder tissues, possible differentiation of ADSCs into bladder smooth muscle and epithelial cells has been demonstrated. For the treatment of bladder diseases, specifically hyperlipidemia and associated overactive bladder, ADSCs have also demonstrated efficacy. For the treatment of urethral sphincter dysfunction associated with birth trauma and hormonal deficiency, ADSC therapy was also beneficial. Finally, ADSCs were able to restore erectile function in various types of erectile dysfunction (ED), including those associated with diabetes, hyperlipidemia, and nerve injuries. Thus, ADSCs have demonstrated remarkable therapeutic potentials for the lower urinary tract.     

Stem cell-based cell therapy for neuroprotection in stroke: A review

Neurological disorders, such as stroke, are triggered by a loss of neurons and glial cells. Ischemic stroke remains a substantial problem for industrialized countries. Over the previous few decades our understanding about the pathophysiology of stroke has enhanced, nevertheless, more awareness is required to advance the field of stroke recovery. Existing therapies are incapable to adequately relief the disease outcome and are not appropriate to all patients. Meanwhile, the majority of patients continue to show neurological deficits even subsequent effective thrombolysis, recuperative therapies are immediately required that stimulate brain remodeling and repair once stroke damage has happened. Cell therapy is emergent as a hopeful new modality for increasing neurological recovery in ischemic stroke. Numerous types of stem cells from various sources have been identified and their possibility and efficiency for the treatment of stroke have been investigated. Stem cell therapy in patients with stroke using adult stem cells have been first practiced in clinical trials since 15 years ago. Even though stem cells have revealed a hopeful role in ischemic stroke in investigational studies besides early clinical pilot studies, cellular therapy in human is still at a primary stage. In this review, we summarize the types of stem cells, various delivery routes, and clinical application of stem cell-based therapy for stroke treatment.     

Stem cell therapy independent of stemness

Mesenchymal stem cell (MSC) therapy is entering a new era shifting the focus from initial feasibility study to optimization of therapeutic efficacy. However, how MSC therapy facilitates tissue regeneration remains incompletely characterized. Consistent with the emerging notion that secretion of multiple growth factors/cytokines (trophic factors) by MSC provides the underlying tissue regenerative mechanism, the recent study by Bai et al demonstrated a critical therapeutic role of MSC-derived hepatocyte growth factor (HGF) in two animal models of multiple sclerosis (MS), which is a progressive autoimmune disorder caused by damage to the myelin sheath and loss of oligodendrocytes. Although current MS therapies are directed toward attenuation of the immune response, robust repair of myelin sheath likely requires a regenerative approach focusing on long-term replacement of the lost oligodendrocytes. This approach appears feasible because adult organs contain various populations of multipotent resident stem/progenitor cells that may be activated by MSC trophic factors as demonstrated by Bai et al This commentary highlights and discusses the major findings of their studies, emphasizing the anti-inflammatory function and trophic cross-talk mechanisms mediated by HGF and other MSC-derived trophic factors in sustaining the treatment benefits. Identification of multiple functionally synergistic trophic factors, such as HGF and vascular endothelial growth factor, can eventually lead to the development of efficacious cell-free therapeutic regimens targeting a broad spectrum of degenerative conditions.     

Vascular endothelial growth factor restores erectile function through modulation of the insulin-like growth factor system and sex hormone receptors in diabetic rat

Previous studies have shown that intracavernous injection of vascular endothelial growth factor (VEGF) restored erectile function in diabetic rats. However, the mechanism of VEGF in diabetes-related erectile dysfunction (ED) has not been fully investigated. We hypothesize that intracavernous injection of VEGF may reverse diabetes-related ED through modulation of the insulin-like growth factor system and sex hormone receptors. To test this hypothesis the erectile function of treated and control rats was analyzed by measurement of intracavernous pressure (ICP) following electrostimulation of the cavernous nerves. Mean ICP was significantly lower in non-treated diabetic rats compared to controls. After VEGF injection, ICP was significantly higher than in non-treated diabetic rats. IGFBP-3 mRNA and protein expression was significantly higher in non-treated diabetic rat crura than controls, while VEGF-treated animals had control levels. ER-beta and PR mRNA and protein expression was significantly lower in non-treated diabetic rat crura. After VEGF injection, ER-beta and PR mRNA and protein expression was similar to control levels. Expression of AR and ER-alpha was the same in all groups. These findings suggest that orthotopic injection of VEGF may improve the functional recovery of diabetes-related ED through modulation of the insulin-like growth factor system and sex hormone receptors. To our knowledge, this is the first study demonstrating that VEGF treatment restores erectile function through restoration of the insulin-like growth factor system and sex hormone receptor genes at the mRNA and protein levels in diabetic rat crura. These results may be important in understanding the pathogenesis of diabetes-related ED and also in providing better strategies for management of this disease.     

Stem cell therapy in intracerebral hemorrhage rat model

Intracerebral hemorrhage(ICH) is a very complex pathology, with many different not fully elucidated etiologies and prognostics. It is the most severe subtype of stroke, with high mortality and morbidity rates. Unfortunately, despite the numerous promising preclinical assays including neuroprotective, anti-hypertensive,and anti-inflammatory drugs, to this moment only symptomatic treatments are available, motivating the search for new alternatives. In this context, stem cell therapy emerged as a promising tool. However, more than a decade has passed, and there is still much to be learned not only about stem cells, but also about ICH itself, and how these two pieces come together. To date, rats have been the most widely used animal model in this research field, and there is much more to be learned from and about them. In this review, we first summarize ICH epidemiology, risk factors, and pathophysiology. We then present different methods utilized to induce ICH in rats, and examine how accurately they represent the human disease. Next, we discuss the different types of stem cells used in previous ICH studies, also taking into account the tested transplantation sites. Finally, we summarize what has been achieved in assays with stem cells in rat models of ICH, and point out some relevant issues where attention must be given in future efforts.     

Antioxidant icariside II combined with insulin restores erectile function in streptozotocin‐induced type 1 diabetic rats

Erectile dysfunction (ED) worsens in patients with diabetes mellitus (DM) despite good control of blood glucose level with insulin. Recent studies imply that diabetic vascular stresses (e.g. oxidative stress) persist in spite of glucose normalization, which is defined as metabolic memory. Studies suggest that the interaction between advanced glycation end products (AGEs) and their receptor (RAGE) mediates the development of metabolic memory. To investigate the effects of the antioxidant icariside II plus insulin on erectile function in streptozotocin (STZ)‐ induced type 1 diabetic rats. Fifty 8‐week‐old Sprague‐Dawley rats were randomly distributed into five groups: normal control, diabetic, insulin‐treated diabetic, icariside II‐treated diabetic, and insulin plus icariside II‐treated diabetic. Diabetes was induced by a single intraperitoneal injection of STZ. Eight weeks after induction of diabetes, icariside II was administered by gastric lavage once a day (5 mg/kg) for 6 weeks; and 2–6 units of intermediate‐acting insulin were given to maintain normal glycemia for 6 weeks. The main outcome measures were the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP); histology of penile endothelial cells and smooth muscle cells; neural nitric oxide synthase, AGEs and RAGE expression; malondialdehyde concentration; superoxide dismutase activity; and apoptosis index. Diabetic rats demonstrated a significantly lower ICP/MAP ratio, reduced penile endothelial cells, reduced smooth muscle cells, increased AGEs and RAGE, and increased apoptosis. Insulin and icariside II monotherapy partially restored erectile function and histological changes. However, the combination therapy group showed significantly better erectile parameters, cytological components and biochemistry, similar to those in the normal control group. These results suggest that, although insulin can effectively control glycemic levels, it does not completely alter the pathological changes in erectile tissues. Better efficacy could be expected with tight glycemic control plus the antioxidant icariside II. The proposed combination therapy might have the potential to eliminate metabolic memory by down‐regulating the AGEs‐RAGE‐oxidative stress axis.     

Stem cell therapies in cardiac diseases: Current status and future possibilities

Cardiovascular diseases represent the world’s leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.     

Stem cell therapy in stroke: designing clinical trials

Stroke is a common and disabling condition that represents a potentially attractive target for regenerative therapy. Stem cells from a wide range of origins have been investigated in studies using animal models of stroke, with evidence that neural or mesenchymal cells migrate to the site of ischemic injury after intravascular or intraparenchymal delivery, and that a proportion of cells survive and differentiate into cells with characteristics of neurons or glia. In some studies there is evidence of electrical function of transplanted cells. Some studies report improvements in neurological function with cell implantation even when undertaken up to 30 days after the stroke is induced. Few clinical trials have been undertaken to date, with two studies of a teratocarcinoma-derived cell line delivered by direct brain injection, and two of bone-marrow derived mesenchymal stem cells delivered intravascularly. Ongoing trials of other cell lines are exploring safety. There are considerable difficulties in designing future efficacy trials, some being generic to the field of regenerative treatment in stroke, and some that are specific to stem cells or their mode of delivery.     

Efficacy of a cultured conditioned medium of exfoliated deciduous dental pulp stem cells in erectile dysfunction patients

Majority of current treatment strategies against erectile dysfunction (ED) has been consisted of only a supportive care to sustain enough erection during a sexual intercourse. In this study, we investigated whether the cultured conditioned medium of human exfoliated deciduous dental pulp stem cells (SHED‐CM) had an ability to treat ED through fundamentally repairing the pathological damage of vascular endothelial cells of the corpus cavernosum. An open‐label pilot study was performed from April 2016 to October 2020. SHED‐CM was injected directly into the corpus cavernosum of penis of 38 ED patients who visited our clinic and fulfilled the inclusion criteria. Efficacy was assessed using the simplified International Index of Erectile Function (IIEF‐5) questionnaire. The average age and initial IIEF‐5 score of the patients enrolled in this study was 56 (31–79) years old and 13.1 (5–20) points, respectively. Medical history revealed 7 patients with diabetes, 7 patients with hypertension and 1 patient with priapism undergone shunt operation. Of these, 37 patients (97.4%) showed an improvement in IIEF‐5 of an average of 19.3 (7–25) points or 64.4 (10–300) % increase after three injections of SHED‐CM. Eighteen patients (47.4%) achieved more than 21 points (no ED) in IIEF‐5. No adverse events were encountered. This is the first clinical report of ED treatment in the literatures evaluating the efficacy of SHED‐CM. Treatment with SHED‐CM is expected to repair vascular damages of the corpus cavernosum, which are the main cause of ED, and to be widely spread as a fundamental clinical application for ED.     

Farnesoid X receptor activation improves erectile dysfunction in models of metabolic syndrome and diabetes

The metabolic syndrome (MetS) is an insulin-resistant state characterized by a cluster of cardiovascular risk factors, including abdominal obesity, hyperglycemia, elevated blood pressure and combined dyslipidemia. In this review, we discuss the potential of farnesoid X receptor (FXR) agonists in the treatment of erectile dysfunction (ED), a multifactorial disorder often comorbid with MetS. FXR not only regulates lipid and glucose homeostasis but also influences endothelial function and atherosclerosis, suggesting a regulatory role for this hormone nuclear receptor in the cardiovascular complications associated with the MetS, including ED. MetS induces ED via several mechanisms, and in particular through endothelial dysfunction in penile vessels. In a high-fat diet rabbit model of MetS, a 3-month treatment with the potent and selective FXR agonist INT-747 restores endothelium-dependent relaxation in isolated cavernous tissue, normalizing responsiveness to acetylcholine and to electrical field stimulation. Accordingly, eNOS expression in the penis is greatly up-regulated by INT-747 treatment. Experiments in a rat model of chemically-induced type 1 diabetes further demonstrate that INT-747 treatment preserves erectile function induced by electrical stimulation of the cavernous nerve. These results add a new facet to the pleiotropic activities mediated by FXR, and reveal novel beneficial effects of FXR activation with potential clinical relevance. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.     

Stem cell–based biological pacemakers from proof of principle to therapy: a review

Electronic pacemakers are the standard therapy for bradycardia-related symptoms but have shortcomings. Over the past 15 years, experimental evidence has demonstrated that gene and cell-based therapies can create a biological pacemaker. Recently, physiologically acceptable rates have been reported with an adenovirus-based approach. However, adenovirus-based protein expression does not last more than 4 weeks, which limits its clinical applicability. Cell-based platforms are potential candidates for longer expression. Currently there are two cell-based approaches being tested: (i) mesenchymal stem cells used as a suitcase for delivering pacemaker genes and (ii) pluripotent stem cells differentiated down a cardiac lineage with endogenous pacemaker activity. This review examines the current achievements in engineering a biological pacemaker, defines the patient population for whom this device would be useful and identifies the challenges still ahead before cell therapy can replace current electronic devices.     

Dimethyl sulfoxide-free cryopreservation for cell therapy: A review

Cell-based therapeutics promise to transform the treatment of a wide range of diseases including cancer, genetic and degenerative disorders, or severe injuries. Many of the commercial and clinical development of cell therapy products require cryopreservation and storage of cellular starting materials, intermediates and/or final products at cryogenic temperature. Dimethyl sulfoxide (Me₂SO) has been the cryoprotectant of choice in most biobanking situations due to its exceptional performance in mitigating freezing-related damages. However, there is concern over the toxicity of Me₂SO and its potential side effects after administration to patients. Therefore, there has been growing demand for robust Me₂SO-free cryopreservation methods that can improve product safety and maintain potency and efficacy. This article provides an overview of the recent advances in Me₂SO-free cryopreservation of cells having therapeutic potentials and discusses a number of key challenges and opportunities to motivate the continued innovation of cryopreservation for cell therapy.     

Prostatic irradiation-induced sexual dysfunction: A review and multidisciplinary guide to management in the radical radiotherapy era (Part III on Psychosexual Therapy and the Masculine Self-Esteem)

Psychological morbidity, sexuality, and health/system information have been identified as the highest areas of support needs in patients undergoing management of their prostate cancer (PCa). Management of a patient’s sexual function prior to, during and after PCa radiotherapy requires multidisciplinary coordination of care between radiation oncologists, urologists, dermatologists, pharmacists, and psychiatrists. The finale of this three-part review provides a framework for clinicians to better understand the role of mental healthcare providers in the management of sexual toxicities associated with prostatic radiotherapy. The authors recommend that patients be referred for psychological evaluation and possibly to individual, couples or group general or cognitive behavioral sex therapy at the time of their PCa diagnosis, for a more specialized focus on management of sexual toxicities and sexual recovery. The importance and implications of the masculine self-esteem, sexual orientation, gender identification, cultural expectations, relationship status and patient education are reviewed. Well-informed patients tend to have a better quality of life outcomes compared to patients that take on a passive role in their cancer management.