Comparing how significantly the pharmacological treatment of genitourinary cancer in a non-curative setting affects endpoints of survival or response

Prevalence of advanced genitourinary cancer is high considering approximately 70,000 patients die annually of prostate, bladder and kidney cancer in the United States. Treatment is non-curative but along with the aim of relieving symptoms and improving quality of life, patients and doctors are driven by the goal of prolonging life. In modern urological practice, with the ever increasing number of novel therapies, clinical benefit to patients has to be measured by evaluating the trial endpoints of response and survival against adverse events. This is especially true as the population with advanced cancer is increasingly older and co-morbid. Currently, we are in a time of exponential drug development, innumerable registered trials and a vast amount of expenditure on pharmacological cancer treatment. In this era of financial uncertainty, it is even more important for clinicians to objectively assess the benefit of these expensive, moderately effective treatments that still have associated adverse sequelae. We aim to highlight the pivotal data available and put into context the survival benefit we can currently achieve with the pharmacological treatment of advanced genitourinary cancer, allowing us to critically judge whether a potentially toxic systemic treatment is worthwhile or whether it is better to defer to best supportive care. The figures presented are from the key publications that form the basis of international guideline recommendations and are the standard that newly developed treatments must emulate.     

Is porcine endogenous retrovirus (PERV) transmission still relevant?

Xenotransplantation using porcine cells or organs may be associated with the risk of transmission of zoonotic microorganisms. Porcine endogenous retroviruses (PERVs) pose a potentially high risk because they are integrated into the genome of all pigs and PERV-A and PERV-B at least, which are present in all pigs, can infect human cells. However, PERV transmission could not be demonstrated in the first recipients of clinical xenotransplantation or after numerous experimental pig-to-non-human primate transplantations. In addition, inoculation of immunosuppressed small animals and non-human primates failed to result in demonstrable PERV infection. Nevertheless, strategies to reduce the possible danger of PERV transmission to humans, however low, could be of benefit for the large-scale clinical use of porcine xenotransplants. One strategy is to select pigs free of PERV-C, thereby preventing recombination with PERV-A. A second strategy involves the selection of animals that express only very low levels of PERV-A and PERV-B. To this end, sensitive and specific methods have been developed to allow the distribution and expression of PERV to be analyzed. A third strategy is to develop a vaccine capable of protecting against PERV transmission. Finally, a fourth strategy is based on the inhibition of PERV expression by RNA interference. Using PERV-specific short hairpin RNA (shRNA) and retroviral vectors, inhibition of PERV expression in primary pig cells was demonstrated and transgenic pigs were generated that show reduced PERV expression in all tissues analyzed. Intensive work is required to improve and to combine these strategies to further decrease the putative risk of PERV transmission following xenotransplantation.     

Use of symptom questionnaires in the assessment and follow-up of men with benign prostatic disease

The assessment of lower urinary tract symptoms is an essential component of the evaluation of men with benign prostatic disease in clinical practice and research. Symptom evaluation is necessary for the formal evaluation of the effectiveness of treatments in randomized controlled trials and in the assessment of outcome in individuals, and can also be useful in determining the numbers of individuals in the community who might potentially require or benefit most from treatment. Increasingly, symptom assessments are being undertaken using a small number of questionnaires that are self-completed by patients and have been tested for validity and reliability.     

Clinical application of the cardioprotective effects of volatile anaesthetics: PRO--get an extra benefit from a proven anaesthetic free of charge

Volatile anaesthetic agents have been used in millions of patients around the world and have proved to be both well tolerated and efficient. In recent years, cardioprotective properties of these drugs have been demonstrated unequivocally in numerous experimental investigations, but the beneficial effects of volatile anaesthetics in daily clinical practice are still under debate. In order to elucidate their cardioprotective properties in an unbiased way, the STAIR (Stroke Therapy Academic Industry Roundtable Preclinical Recommendation) criteria proposed as a framework for researchers in the field of neuroprotection can be applied to research conducted in the field of cardioprotection by volatile anaesthetics. All STAIR criteria have already been clearly fulfilled when all experimental and clinical studies are considered. Specifically, a dose-response pattern has been found with a minimal alveolar concentration value and a ceiling effect; volatile anaesthetics show two distinct therapeutic windows after application; important outcome measures such as hospital length of stay have been addressed; and multiple species have been studied by different independent groups of researchers who were largely able to reproduce their findings. Given the numerous confounding factors capable of attenuating or even abolishing the cardioprotective properties of volatile anaesthetics in laboratory investigations, the positive effects found in the majority of clinical trials point to the fact that the cardioprotective effects exerted by volatile anaesthetics are robust and triggered by interactions with several distinct cellular and subcellular targets, thereby providing multiplication and reiteration. The available evidence indicates that volatile anaesthetic agents should be used routinely in clinical practice in order to claim an extra benefit for our patients 'free of charge'.     

Fungus and chronic rhinosinusitis: Weighing the evidence

The hypothesis that fungus causes most, if not all, cases of chronic rhinosinusitis (CRS) has been debated for over a decade. Many opinions and interpretations have been rendered, but it is the objective data that speaks the loudest. The debate simply boils down to a core tenet of the scientific method: Can the data be independently replicated? If so, our patients benefit as new treatments are developed. If not, then the hypothesis must be discarded and new lines of research pursued.Initial clinical trials supporting the fungal hypothesis have not been replicated in recent years by independent investigators. An attempt to independently replicate the basic science foundation of this hypothesis has also failed in a more heterogeneous group of CRS patients. The data can be dissected, reanalyzed, and reinterpreted and myriad arguments can be put forth. But an unbiased review of the data demonstrates that nearly every researcher outside of the original proponents of the fungal hypothesis has failed to replicate their work. The weight of the evidence is increasingly tipping the scales away from this theory.     

Dialysis adequacy reconsidered: The person comes first

Although many nephrologists see value in maximizing clearance and time on dialysis, clinical trials have failed to show a clear and consistent benefit of increasing clearance above the minimum threshold level recommended in clinical practice guidelines or of increasing dialysis session length or frequency. Available evidence suggests that patients and clinicians do not necessarily agree on what matters most when it comes to dialysis care, and that what patients consider to be an adequate dialysis session is highly individual and has little to do with solute clearance. Qualitative studies suggest that patients value spending less time on dialysis, having the dialysis procedure go smoothly, and being treated like an individual by staff members. Because many patients feel that they have little choice but to show up for their dialysis sessions, failing to involve them in decisions about time spent on the machine can contribute to feelings of powerlessness and loss of control, erode their sense of self, and diminish the quality of therapeutic relationships. On the other hand, a flexible and shared approach to decision-making about time spent on dialysis (and other aspects of care) can help to strengthen relationships, uphold personhood, and align care with what matters most.     

Allogeneic stem cell transplantation for renal cell carcinoma

Although the prognosis for patients with metastatic kidney cancer remains poor, a number of promising immunotherapeutic approaches for the treatment of metastatic disease have been developed over the past decade. The response of some patients to cytokines such as interleukin-2 and interferon-alpha, and more recently, vaccination with dendritic cell/tumor fusions has laid the ground work for ongoing immune-based investigational approaches. Allogeneic stem cell transplantation is a potent form of immunotherapy capable of delivering potentially curative immune-mediated anti-tumor effects against a number of different hematological malignancies. Knowledge of renal cell carcinoma's unusual susceptibility to immune attack has led to the hypothesis that tumor rejection, mediated through immunocompetent donor T-cells, might be generated against this solid tumor following the transplantation of an allogeneic immune system. Although clinical trials are early and ongoing, the recent observation of metastatic disease regression following non-myeloablative stem cell transplantation has identified renal cell carcinoma as being susceptible to a graft-versus-tumor effect. Disease responses following such therapy have ranged from partial to complete and have been observed even in patients who have failed conventional cytokine based strategies. This article reviews the design, methodology and early clinical results of studies investigating the use of allogeneic stem cell transplantation in metastatic renal cell carcinoma.     

Understanding the difference between theory and practice: The extracranial-intracranial bypass trials in prevention of ischemic stroke

BackgroundPatients with atherosclerotic carotid or middle cerebral artery occlusions suffer ischemic events that might theoretically be preventable with a surgical extracranial-intracranial bypass, but theory by itself does not justify surgical interventions.MethodsWe review landmark randomized trials on EC-IC bypass surgery for the treatment of ischemic stroke in patients with atherosclerotic stenoses or occlusions.ResultsThe initial EC-IC bypass trial from 1985 did not show any clinical benefit from surgery. The carotid occlusion surgery study (COSS) performed more than 20 years later included only patients highly selected to potentially benefit from bypass by using modern perfusion studies. While EC-IC bypasses were successfully created and they did improve cerebral perfusion, the COSS study also failed to show any clinical benefit to the participating patients.ConclusionNeurosurgical interventions must not only work in theory; they must improve patient outcomes in real practice.     

Evidence for Cerebral Hemodynamic Measurement-based Therapy in Symptomatic Major Cerebral Artery Disease

In patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease, chronic reduction in cerebral perfusion pressure (chronic hemodynamic compromise) increases the risk of ischemic stroke and can be detected by directly measuring hemodynamic parameters. However, strategies for selecting treatments based on hemodynamic measurements have not been clearly established. Bypass surgery has been proven to improve hemodynamic compromise. However, the benefit of bypass surgery for reducing the stroke risk in patients with hemodynamic compromise is controversial. The results of the two randomized controlled trials were inconsistent. Hypertension is a major risk factor for stroke, and antihypertensive therapy provides general benefit to patients with symptomatic atherosclerotic major cerebral artery disease. However, the benefit of strict control of blood pressure for reducing the stroke risk in patients with hemodynamic compromise is a matter of debate. The results of the two observational studies were different. We must establish strategies for selecting treatments based on hemodynamic measurements in atherosclerotic major cerebral artery disease.     

‘Conditioning’ the heart during surgery

Coronary heart disease (CHD) is the leading cause of death worldwide. Coronary artery bypass graft (CABG) surgery remains the procedure of choice for coronary artery revascularisation in a large number of patients with severe CHD. However, the profile of patients undergoing CABG surgery is changing with increasingly higher-risk patients being operated upon, resulting in significant morbidity and mortality in this patient group. Myocardial injury sustained during cardiac surgery, most of which can be attributed to acute myocardial ischaemia–reperfusion injury, is associated with worse short-term and long-term clinical outcomes. Clearly, new treatment strategies are required to protect the heart during cardiac surgery in terms of reducing myocardial injury and preserving left ventricular systolic function, such that clinical outcomes can be improved. ‘Conditioning’ the heart to harness its endogenous cardioprotective capabilities using either brief ischaemia or pharmacological agents, provides a potentially novel approach to myocardial protection during cardiac surgery, and is the subject of this review article.     

Bilirubin,a new therapeutic for kidney transplant?

In patients with end-stage renal disease, kidney transplantation has been associated with numerous benefits, including increased daily activity, and better survival rates. However, over 20% of kidney transplants result in rejection within five years. Rejection is primarily due to a hypersensitive immune system and ischemia/reperfusion injury. Bilirubin has been shown to be a potent antioxidant that is capable of potentially reversing or preventing damage from reactive oxygen species generated from ischemia and reperfusion. Additionally, bilirubin has several immunomodulatory effects that can dampen the immune system to promote organ acceptance. Increased bilirubin has also been shown to have a positive impact on renal hemodynamics, which is critical post-transplantation. Lastly, bilirubin levels have been correlated with biomarkers of successful transplantation. In this review, we discuss a multitude of potentially beneficial effects that bilirubin has on kidney acceptance of transplantation based on numerous clinical trials and animal models. Exogenous bilirubin delivery or increasing endogenous levels pre- or post-transplantation may have therapeutic benefits.     

Management of locally advanced bladder cancer: early vs deferred chemotherapy

Locally advanced bladder cancer is associated with a high risk of local recurrence and distant metastases. Clinical and pathologic variables have been useful in predicting outcome in patients with muscle-invasive bladder cancer. Recently, a number of molecular prognostic markers have been identified that help predict tumor aggressiveness, response to chemotherapy, and survival. Transitional cell carcinoma is a chemosensitive tumor. The early use of chemotherapy to reduce the risk of recurrence and improve survival has been the focus of many randomized clinical trials. Unfortunately, the majority of studies have failed to show a survival advantage for chemotherapy-treated patients. Well-designed prospective trials that target high-risk patients, defined by clinical, pathological, and molecular features, and incorporate new more tolerable chemotherapeutic agents are needed to clarify the benefit of early chemotherapy.     

The concept of anaesthetic-induced cardioprotection: mechanisms of action

The mechanisms by which ischaemia reperfusion injury can be influenced have been the subject of extensive research in the last decades. Early restoration of arterial blood flow and surgical measures to improve the ischaemic tolerance of the tissue are the main therapeutic options currently in clinical use. In experimental settings ischaemic preconditioning has been described as protecting the heart, but the practical relevance of interventions by ischaemic preconditioning is strongly limited to these experimental situations. However, ischaemia reperfusion of the heart routinely occurs in a variety of clinical situations, such as during transplantations, coronary artery bypass grafting or vascular surgery. Moreover, ischaemia reperfusion injury occurs without any surgical intervention as a transient myocardial ischaemia during a stressful anaesthetic induction. Besides ischaemic preconditioning, another form of preconditioning was discovered over 10 years ago: the anaesthetic-induced preconditioning. There is increasing evidence that anaesthetic agents can interact with the underlying pathomechanisms of ischaemia reperfusion injury and protect the myocardium by a preconditioning mechanism. Hence, the anaesthetist himself can substantially influence the critical situation of ischaemia reperfusion during the operation by choosing the right anaesthetic. A better understanding of the underlying mechanisms of anaesthetic-induced cardioprotection not only reflects an important increase in scientific knowledge but may also offer the new perspective of using different anaesthetics for targeted intraoperative myocardial protection. There are three time windows when a substance may interact with the ischaemia reperfusion injury process: (1) during ischaemia, (2) after ischaemia (i.e. during reperfusion), and (3) before ischaemia (preconditioning).     

Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke

Opinion statement Currently, intravenous recombinant tissue plasminogen activator is the only US Food and Drug Administration-approved therapy for acute ischemic stroke. Although efficacious, its usefulness is limited, mainly because of the very limited time window for its administration. Neuroprotective treatments are therapies that block the cellular, biochemical, and metabolic elaboration of injury during or after exposure to ischemia, and have a potential role in ameliorating brain injury in patients with acute ischemic stroke. More than 50 neuroprotective agents have reached randomized human clinical trials in focal ischemic stroke, but none has been unequivocally proven efficacious, despite successful preceding animal studies. The failed neuroprotective trials of the past have greatly increased understanding of the fundamental biology of ischemic brain injury and have laid a strong foundation for future advance. Moreover, the recent favorable results of human clinical trials of hypothermia in human cardiac arrest and global brain ischemia have validated the general concept of neuroprotection for ischemic brain injury. Recent innovations in strategies of preclinical drug development and clinical trial design that rectify past defects hold great promise for neuroprotective investigation, including novel approaches to accelerating time to initiation of experimental treatment, use of outcome measures sensitive to treatment effects, and trial testing of combination therapies rather than single agents alone. Although no neuroprotective agent is of proven benefit for focal ischemic stroke, several currently available interventions have shown promising results in preliminary trials and may be considered for cautious, off-label use in acute stroke, including hypothermia, magnesium sulfate, citicoline, albumin, and erythropoietin. Overall, the prospects for safe and effective neuroprotective therapies to improve stroke outcome remain promising.     

Controversies in renal artery stenosis: a review by the American Society of Nephrology Advisory Group on Hypertension

Renovascular hypertension is a recognized secondary potentially curable cause of hypertension since the work of Harry Goldblatt. Operative treatments for renal artery stenosis (RAS) have been offered for decades and percutaneous interventions have been widely available for 20 years. Stenting has largely obviated recurrence and modern techniques have contributed greatly to the safety of the procedure. Nevertheless, controversy abounds and prospective randomized trials have not successfully documented the value of intervention in patients with atherosclerotic RAS. The patient population has also changed remarkably. Whereas earlier patients with RAS were identified on clinical grounds, RAS is now commonly found serendipitously during angiography for other reasons. Whether or not these patients benefit from 'drive by' stenting is unknown. The practice may be hazardous and should be critically examined. A dialog and closer cooperation between cardiologists and nephrologists is warranted and organized programs should be formulated to address this problem.     

Role of targeted therapy in combination with surgery in renal cell carcinoma

Surgical complete resection is the only curative treatment of renal cell carcinoma including patients with locally advanced disease and those with limited metastatic disease. Patients at high risk of recurrence after complete resection might theoretically benefit from adjuvant and neoadjuvant systemic treatment strategies to prolong disease‐free survival and ultimately overall survival. Another rationale for using targeted therapy includes downsizing/downstaging of surgically complex locally advanced renal cell carcinoma to facilitate complete resection or primary tumors to allow for nephron‐sparing strategies. Unfortunately, a considerable percentage of patients are diagnosed with metastatic disease at first presentation. Although large population‐based studies consistently show a survival benefit after cytoreductive nephrectomy in the targeted therapy era, confounding factors preclude definite conclusions for this heterogeneous patient group until ongoing phase III trials are published. Presurgical targeted therapy has been proposed to identify patients with clinical benefit and potentially long‐term survival after cytoreductive nephrectomy. Recently, the use of targeted therapy before or after local treatment of metastases has been reported in small retrospective series. The present review revisits the current evidence base of targeted therapy in combination with surgery for the various disease stages in renal cell carcinoma.     

Ischaemic and inflammatory injury in renal graft from brain death donation: an update review

Renal transplantation remains an important therapy in treating renal failure and can be considered to be a curative treatment. The demand for renal grafts outstrips supply available each year, making it increasingly important to look at improving the treatment of both renal grafts and recipients, and thereby improving patient outcomes and increasing the pool of potential donor grafts. Important to this, however, is knowledge of the underlying mechanisms leading to damage to the graft and rejection from the recipient. This includes ischaemia and consequently the priming of the organ during storage for ischaemia reperfusion injury (IRI) on implantation and the importance of the innate immune system which can be activated via multiple pathways, often via TLR-4, and the consequent production of danger-associated molecular patterns. This makes the time period involving both explantation and storage an important therapeutic window for improving outcomes. Other windows explored include treatment of IRI and improvement in immunosuppressive therapy. The multiple windows of potential therapeutic input have spawned a large body of work exploring both the underlying mechanisms and also how to exploit these mechanisms to improve overall outcomes and to allow for more marginal organs to be used.     

Conservative strategies for the treatment of stress urinary incontinence

The conservative treatment of stress urinary incontinence for women has many facets. Each intervention may have value and patients may benefit from simple, reversible recommendations and techniques versus invasive surgery. Starting with a thorough history, lifestyle modifications may lead to decreased incontinence. Depending on the patient’s goals and clinical situation, they may benefit from a pessary or anti-incontinence device. Finally, the use of pelvic floor muscle exercises has been shown to benefit a significant number of patients. Regardless of the degree of stress urinary incontinence, conservative strategies should be considered a fundamental part of the treatment plan.     

Is Remote Ischemic Conditioning of Benefit to Patients Undergoing Kidney Transplantation?

Renal ischemia-reperfusion injury (IRI), an inevitable event during kidney transplantation procedure, can result in delayed graft function or even primary nonfunction. In addition to strategies to limit IRI such as advancements in organ allocation systems and preservation of organs, and reduction in cold and warm ischemia time, remote ischemic conditioning (RIC) has attracted much attention in recent years. With promising findings and data suggesting a potential benefit of RIC in animal kidney transplantation models, a few clinical trials have investigated the use of RIC in human kidney transplantation. Unfortunately, the findings from these investigations have been inconclusive due to a number of factors such as diverse time points of RIC, limited sample size, and complexity of kidney transplant patients. This brief commentary aims to discuss the effects of RIC on clinical outcomes and proinflammatory cytokines in patients undergoing kidney transplantation.     

Clinically isolated syndrome and multiple sclerosis: Rethinking the arsenal

Opinion statement  Until the end of the past century, a diagnosis of multiple sclerosis (MS) was often accompanied by a sense of apprehension, fueled primarily by the lack of available therapies and failed attempts with numerous agents. The modern era of MS therapeutics introduced in the past 20 years has helped to assuage the previous belief that little could be done to treat MS. The advent of disease-modifying treatments such as interferons and glatiramer acetate has had a notable impact on the course of MS. Numerous trials have demonstrated the clear benefit of initiating therapy in patients with a diagnosis of MS, but more importantly, they have shown that early initiation of treatment can delay progression to clinically definite MS in patients with clinically isolated syndrome who have concurrent changes on MRI. As newer agents become available, trials to assess their efficacy and tolerability are under way in an effort to expand the arsenal of available treatments. However, questions constantly resurface about the effect of treatments on disability, the safety of combination therapies, the role in neuroprotection, and other aspects. Moreover, recent attention regarding a radiologic and clinical dissociation, best illustrated by the anecdotally termed “radiologically isolated syndrome,” highlights the frustrations facing clinicians when they try to predict disease course and the role of medications, if any. Despite the need for clear answers to these questions, the current practice is to initiate the available treatments early in patients with relapsing-remitting multiple sclerosis, in order to reduce the severity and frequency of clinical relapses. Treatment should also be initiated early in patients with clinically isolated syndrome because they are at high risk for developing clinically definite multiple sclerosis.