Nutrition and prostate cancer.

Nutrition is apparently a major risk factor for the development and progression of prostate cancer. Based on experimental studies and epidemiologic data mainly from case-control studies or cohort studies, there is strong evidence that reduction of the total energy consumption, a diet comprising less than 30% fat, and increased intake of phytoestrogens, vitamins D and E and selenium could yield a decreased prostate cancer incidence. Furthermore, some of these measures appear to have antitumoral capacity even in the presence of the disease. These observations have provided a rationale to forward large prospective trials on dietary interventions to prove the efficacy of the concept and further delineate the correlation between nutritional compounds and prostate cancer risk. These chemoprevention trials are either aiming a reduction prostate cancer incidence or a decrease in tumor progression. Depending on the study design, large numbers of individuals need to be enrolled and long follow-up intervals are required thus making such trials highly complex and cost-intensive. However, regarding the potential relevance of chemoprevention on public health, further efforts to identify nutritional factors affecting prostate cancer growth are warranted.     

Breast cancer: weighing up the dietary evidence

Evidence from migrant studies suggests the importance of environmental determinants in the aetiology of breast cancer. Of all dietary factors, fat intake has been the subject of the most intense debate over the past few decades, but the potential optimism from ecological studies has not been confirmed from prospective studies. Indeed, few if any strong correlations have been confirmed between dietary constituents and breast cancer. However, minor constituents of plant foods, like phytoestrogens, may potentially prove important in terms of breast cancer prevention. In this review the available evidence for dietary fat, antioxidant micronutrients, phytoestrogens, indole-3-carbinol and alcohol are addressed. A potentially protective role for plant foods requires further investigation and the results of prospective studies should clarify the relationships between dietary factors and breast cancer. Of critical importance in future research is further carefully controlled dietary intervention trials to examine in vivo the effects of minor dietary constituents on hormonal status and cell proliferation. A tentative recommendation would be to increase intakes of plant foods, and future research should lead to firmer conclusions to explain the striking international variability in breast cancer incidence rates.     

Pharmacologic adjunctive to insulin therapies in type 1 diabetes:The journey has just begun

Treatment of type 1 diabetes(T1 D) is currently based exclusively on insulin replacement therapy. However, there is a need for better glycemic control, lower hypoglycemia rates, more effective weight management, and further reduction of cardiovascular risk in people with T1 D. In this context, agents from the pharmaceutical quiver of type 2 diabetes are being tested in clinical trials, as adjunctive to insulin therapies for T1 D patients. Despite the limited amount of relevant evidence and the inter-class variability, it can be said that these agents have a role in optimizing metabolic control, assisting weight management and reducing glycemic variability in people with T1 D. Specific safety issues, including the increased risk of hypoglycemia and diabetic ketoacidosis, as well as the effects of these treatments on major cardiovascular outcomes should be further assessed by future studies, before these therapeutic choices become widely available for T1 D management.     

Evidence based review of type 2 diabetes prevention and management in low and middle income countries

AIM:To identify the newest approaches to type 2diabetes(T2DM)prevention and control in the developingworld context.METHODS:We conducted a systematic review of published studies of diabetes prevention and control programs in low and middle-income countries,as defined by the World Bank.We searched Pub Med using Medical Subject Headings terms.Studies needed to satisfy four criteria:(1)Must be experimental;(2)Must include patients with T2DM or focusing on prevention of T2DM;(3)Must have a lifestyle intervention component;(4)Must be written in English;and(5)Must have measurable outcomes related to diabetes.RESULTS:A total of 66 studies from 20 developing countries were gathered with publication dates through September 2014.India contributed the largest number of trials(11/66).Of the total 66 studies reviewed,all but 3 studies reported evidence of favorable outcomes in the prevention and control of type 2 diabetes.The overwhelming majority of studies reported on diabetes management(56/66),and among these more than half were structured lifestyle education programs.The evidence suggests that lifestyle education led by allied health professionals(nurses,pharmacists)were as effective as those led by physicians or a team of clinicians.The remaining diabetes management interventions focused on diet or exercise,but the evidence to recommend one approach over another was weak.CONCLUSION:Large experimental diabetes prevention/control studies of dietary and exercise interventions are lacking particularly those that consider quality rather than quantity of carbohydrates and alternative exercise.     

Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress

Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D). Beyond the detrimental effects of insulin resistance, inflammation and oxidative stress have emerged as critical features of T2D that define β-cell dysfunction. Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D. Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D. Such effects illustrate a pathological relationship between an abnormal inflammatory response and generation of oxidative stress during the progression of T2D. The current review explores preclinical and clinical research on the patho-logical implications of inflammation and oxidative stress during the development of β-cell dysfunction in T2D. Moreover, important molecular mechanisms and relevant biomarkers involved in this process are discussed to divulge a pathological link between inflammation and oxidative stress during β-cell failure in T2D. Underpinning the clinical relevance of the review, a systematic analysis of evidence from randomized controlled trials is covered, on the potential therapeutic effects of some commonly used antidiabetic agents in modulating inflammatory makers to improve β-cell function.     

Non-pharmacological aspects of blood pressure management: what are the data?

Hypertension affects 29% of US adults and is a significant risk factor for cardiovascular morbidity and mortality. Epidemiological data support contribution of several dietary and other lifestyle-related factors to the development of high blood pressure (BP). Several clinical trials investigated the efficacy of non-pharmacological interventions and lifestyle modifications to reduce BP. Best evidence from randomized controlled trials supports BP-lowering effects of weight loss, the Dietary Approaches to Stop Hypertension (DASH) diet, and dietary sodium (Na(+)) reduction in those with prehypertension, with more pronounced effects in those with hypertension. In hypertensive participants, the effects on BP of DASH combined with low Na(+) alone or with the addition of weight loss were greater than or equal to those of single-drug therapy. Trials where food was provided to participants were more successful in showing a BP-lowering effect. However, clinical studies with long-term follow-up revealed that lifestyle modifications were difficult to maintain. Findings from controlled trials of increased potassium, calcium, or magnesium intake, or reduction in alcohol intake revealed modest BP-lowering effects and are less conclusive. The reported effects of exercise independent of weight loss on BP are inconsistent.     

Is High Dose Vitamin D Harmful?

With the potential to minimize the risk of many chronic diseases and the apparent biochemical safety of ingesting doses of oral vitamin D several-fold higher than the current recommended intakes, recent research has focussed on supplementing individuals with intermittent, high-dose vitamin D. However, two recent randomized controlled trials (RCTs) both using annual high-dose vitamin D reported an increase, rather than a decrease, in the primary outcome of fractures. This review summarises the results from studies that have used intermittent, high doses of vitamin D, with particular attention to those finding evidence of adverse effects. Results from observational, population-based studies with evidence of a U- or J-shaped curve are also presented as these findings suggest an increased risk in those with the highest serum 25D levels. Speculative mechanisms are discussed and biochemical results from studies using high-dose vitamin D are also presented. Emerging evidence from both observational studies and RCTs suggests there should be a degree of caution about recommending high serum 25D concentrations for the entire population. Furthermore, benefit of the higher doses commonly used in clinical practice on falls risk reduction needs to be demonstrated. The safety of loading doses of vitamin D should be demonstrated before these regimens become recommended as routine clinical practice. The current dilemma of defining vitamin D insufficiency and identifying safe and efficacious repletion regimens needs to be resolved.     

Effects of glucose-lowering agents on cardiorespiratory fitness

Exercise therapy is essential for the management of type 2 diabetes (T2D). However, patients with T2D show lower physical activity and reduced cardiorespiratory fitness than healthy individuals. It would be ideal for clinicians to co-prescribe glucose-lowering agents that improve cardiorespiratory fitness or exercise capacity in conjunction with exercise therapy. Metformin does not improve cardiorespiratory fitness and may attenuate any beneficial effect of exercise in patients with T2D. In contrast, thiazolidinediones appear to improve cardiorespiratory fitness in patients with T2D. Although evidence is limited, sodium–glucose cotransporter 2 (SGLT2) inhibitors may improve cardiorespiratory fitness in patients with heart failure, and the effect of glucagon-like peptide-1 (GLP-1) receptor agonists on cardiorespiratory fitness is controversial. Recent clinical trials have shown that both SGLT2 inhibitors and GLP-1 receptor agonists exert a favorable effect on cardiovascular disease. It becomes more important to choose drugs that have beneficial effects on the cardiovascular system beyond glucose-lowering effects. Further studies are warranted to determine an ideal glucose-lowering agent combined with exercise therapy for the treatment of T2D.     

Insulin Resistance as a Physiological Defense Against Metabolic Stress: Implications for the Management of Subsets of Type 2 Diabetes

Stratifying the management of type 2 diabetes (T2D) has to take into account marked variability in patient phenotype due to heterogeneity in its pathophysiology, different stages of the disease process, and multiple other patient factors including comorbidities. The focus here is on the very challenging subgroup of patients with T2D who are overweight or obese with insulin resistance (IR) and the most refractory hyperglycemia due to an inability to change lifestyle to reverse positive energy balance. For this subgroup of patients with T2D, we question the dogma that IR is primarily harmful to the body and should be counteracted at any cost. Instead we propose that IR, particularly in this high-risk subgroup, is a defense mechanism that protects critical tissues of the cardiovascular system from nutrient-induced injury. Overriding IR in an effort to lower plasma glucose levels, particularly with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of “IR as an adaptive defense mechanism” and “insulin-induced metabolic stress” may provide explanation for some of the unexpected outcomes of recent major clinical trials in T2D. Potential molecular mechanisms underlying these concepts; their clinical implications for stratification of T2D management, particularly in overweight and obese patients with difficult glycemic control; and future research requirements are discussed.     

Metabolic surgery: A paradigm shift in type 2 diabetes management

Obesity and type 2 diabetes mellitus (T2DM) are major public health issues globally over the past few decades. Despite dietary interventions, lifestyle modifications and the availability of several pharmaceutical agents, management of T2DM with obesity is a major challenge to clinicians. Metabolic surgery is emerging as a promising treatment option for the management of T2DM in the obese population in recent years. Several observational studies and a few randomised controlled trials have shown clear benefits of various bariatric procedures in obese individuals in terms of improvement or remission of T2DM and multiple other health benefits such as improvement of hypertension, obstructive sleep apnoea, osteoarthritis and non-alcoholic fatty liver disease. Uncertainties about the long-term implications of metabolic surgery such as relapse of T2DM after initial remission, nutritional and psychosocial complications and the optimal body mass index for different ethnic groups exist. The article discusses the major paradigm shift in recent years in the management of T2DM after the introduction of metabolic surgery.     

Key observations from the NHLBI Asthma Clinical Research Network

The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/studies/). This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting ?-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma.     

Perioperative management of blood glucose during open heart surgery in infants and children

The perioperative management of blood glucose has been controversial since clinical associations between hyperglycemia and adverse outcomes were first reported more than two decades ago. Despite some early evidence supporting a causal relationship between hyperglycemia and adverse outcomes, prospective trials of tight glycemic control have been inconclusive, except in selected populations, like adult diabetics. These trials have consistently reported dramatic increases in the incidence and severity of hypoglycemia, which may also have associated adverse outcomes. Bedside glucose monitors typically used to manage glucose have increasingly been found to introduce systematic inaccuracies. Relevant studies of infants and children undergoing cardiac surgery are considerably fewer in number, requiring clinicians to extrapolate from other clinical conditions and patient populations.     

Antioxidants: a possible role in kidney protection

Oxidative stress contributes to the pathophysiology of kidney injury. Beneficial renal effects of some medications, such as angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor antagonists, calcium channel blockers, beta-blockers and lipid lowering agents depend at least partially on the ability to alleviate oxidative stress. The administration of various natural or synthetic antioxidants has been shown to be of benefit in prevention and attenuation of renal scaring in numerous animal models of kidney diseases. These include vitamins, N-acetylcysteine, alpha-lipoic acid, melatonin, dietary flavonoids and phytoestrogens, and many others. Human studies are limited in this regard. Under certain conditions, surprisingly, the antioxidant supplements may exhibit pro-oxidant properties and even worsen renal damage. To date, the evidence is insufficient to recommend antioxidant supplements in patients with kidney disease. Prospective, controlled clinical trials on safety and effectiveness of different therapeutic antioxidant strategies are indispensable.     

High-Dose Chemotherapy with Autologous Stem Cell Rescue as a Treatment Modality for Breast Cancer

▪ Abstract: Retrospective analyses of clinical trials as well as several prospective randomized clinical trials designed to evaluate dose intensity have emphasized the importance of intensive chemotherapy in determining outcomes in breast cancer treatment. One strategy that can deliver a large increment in dose intensity is high-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT), since it overcomes myelosuppression, a major dose-limiting toxicity of most chemotherapy regimens. Phase II data from HDC-ASCT trials have indicated improved complete remission rates and longer remission duration when compared to historical conventional-dose chemotherapy regimens. With declining treatment-related mortality (TRM) through improvements in supportive care and innovations in stem cell collection procedures, exploration of HDC-ASCT in prospective randomized trials has been made possible. Several prospective randomized trials have completed accrual and early results are now available, while other studies are still ongoing. Unfortunately the trial designs are quite varied, the characteristics of patients differ from study to study, the early data provide conflicting results, and the follow-up is quite short, making firm conclusions impossible at present. Of note, the comparison arms in several of the studies are performing better than historical nontransplant treatments, perhaps a result of an intermediate dose intensity employed in the nontransplant arm of these trials. These data suggest that dose intensity, whether supported by stem cells or hematopoietic growth factors, may be quite important in optimizing treatment outcomes, affirming earlier concepts of the importance of dose intensity. Further follow-up of the current clinical trials and analyses of ongoing studies not yet reported are necessary before firm conclusions are possible as to the optimal strategy of using dose intensity in the management of breast cancer. ▪     

γδ T-cell immunotherapy for lung cancer

Lung cancer is the leading cause of cancer death worldwide, yet there are still no satisfactory protocols available for treating this disease, emphasizing the urgency for more effective therapies. Recent clinical trials have provided encouraging evidence of the benefits of certain forms of immunotherapy. Here, we summarize recent developments in the area of γδ T-cell therapy for lung cancer in our center. γδ T cells constitute 2%–10% of T lymphocytes in human blood and play a role in immune surveillance against microbial pathogens and, possibly, cancer. These T cells recognize phosphoantigens via polymorphic γδ T-cell antigen receptors (TCR), as well as the major histocompatibility complex (MHC) class I chain-related molecules, A and B (MICA and MICB), via nonpolymorphic NKG2D receptors in an MHC-unrestricted manner. This implies that γδ T cells could retain antitumor effects despite reduced expression of MHC and tumor antigens on cancer cells. Thus, clinical trials have been conducted to evaluate the safety and efficacy of γδ T-cell-based immunotherapies for non-Hodgkin lymphoma, multiple myeloma, and solid tumors. This review focuses on the current status of γδ T-cell-based immunotherapy for lung cancer.     

A Review of Clinical Trials of Therapies for Osteoporosis Using Fracture as an End Point

As the population ages, fragility fractures grow in importance as a public health problem. The principal goal of osteoporosis therapy is primary and secondary fracture prevention. A growing choice of therapies is now available for the treatment of osteoporosis. In this article, we review their efficacy using fracture prevention as an end point. The considerable heterogeneity among studies with regard to patient age, past fracture history, fracture site, and analytical methods precludes the possibility of performing a meaningful meta-analysis. Fracture outcomes have been reported in clinical trials with calcium supplementation, vitamin D supplementation, estrogen replacement therapy (ERT), calcitonin, etidronate, alendronate, sodium fluoride (NaF), parathyroid hormone (PTH), and raloxifene. Compelling evidence for fracture prevention has been provided for calcium and vitamin D supplementation and alendronate treatment. Evidence of fracture prevention exists for ERT, raloxifene, calcitonin, etidronate, and PTH. Data on NaF are inconsistent. Across agents, there is a trend toward greater efficacy for patients at greatest risk of fracture.     

Benefits of intensified reductions in blood glucose and in blood pressure for patients with type 2 diabetes

Adequate blood glucose and blood pressure control is paramount for the prevention of microvascular and macrovascular complications in patients with type 2 diabetes (T2D). This review article summarises the important advances in blood glucose and blood pressure lowering from the last three decades, with a focus on the evidence from large scale randomized clinical trials and meta-analyses. This paper focuses on evidence supporting specific blood glucose and blood pressure targets, and the importance of long-term sustained risk factor control. Novel therapies including the glucagon-like peptide-1 receptor agonists (GLP1-RA) and the sodium glucose co-transporter 2 inhibitors (SGLT2i) have revolutionized the treatment of type 2 diabetes and highlighted the importance of approaches that deliver benefits beyond glucose or blood pressure lowering. This article provides an overview of contemporary management of T2D with an emphasis on tailoring treatment plans to the individual.     

Update on pharmaceutical trials in acute spinal cord injury

OBJECTIVE: To review the major pharmacological trials in acute spinal cord injury (SCI) that have been conducted over the past 25 years. METHODS: Review article. RESULTS: The publication of the first National Acute Spinal Cord Injury (NASCIS) trial in 1984 ushered in the era of pharmacological trials of therapies intended to improve neurologic outcome in acute SCI. Subsequent trials of methylprednisolone sodium succinate (MPSS) and GM-1 have added to the evidence basis that informs the current management practices for acute SCI. CONCLUSION: The last 50 years have seen a conceptual shift from the pessimism of the past to a cautious optimism that the meager prognosis for neurologic recovery in acute SCI will yield to the progress of medical science. Major advances in the understanding of primary and secondary injury mechanisms have led to the preclinical study of many promising pharmacological therapies, all with the goal of improving neurologic outcome. A few of these drugs have stood the test of animal model experiments and have made it to the forum of human clinical trials. The NASCIS trials of methylprednisolone have been acknowledged widely as the first human studies to claim improved neurologic outcome. Although the results of these trials remain controversial, the MPSS therapy that they reported has been adopted widely by clinicians around the world as the best currently available, even if not a consensus "standard of care." Clearly, the challenge for medical science remains. The search for effective treatment has only begun.     

Evidence-Based Management of Patients with Osteoporosis

Evidence-based medicine (EBM) offers an approach to solving clinical problems that places a high value on systematic clinical investigation. Evidence-based clinicians look to the highest rung on a hierarchy of evidence to guide their patient management. When considering therapeutic decisions, randomized control trials examining impact on outcomes that patients feel are important are at the top of the hierarchy of individual studies. Systematic reviews of such trials provide the best evidence for patient care decisions. Systematic reviews include explicit eligibility criteria for studies they include, a comprehensive search, an explicit rating of the methodological quality of the individual trials, and explicit strategies for pooling data. Inferences are weakened if study design is weak (trials are not blinded or we have only observational studies on which to rely), if results are inconsistent across studies, or if studies rely on substitute end points (bone density rather than long-bone fractures). Evidence-based clinicians consider not only the strength of evidence, but the patients' risk of adverse target outcomes and the magnitude of treatment effects in making their therapeutic decisions. EBM encourages quantitative approaches to trading off benefits and risks. For example, in deciding whether to recommend hormone replacement therapy to a 50-yr-old, an evidence-based clinician would consider that the woman has a 15% lifetime risk of fracturing her hip and the median age of the fracture is 79. Observational studies suggest that long-term estrogen therapy will reduce this risk by 25%, and we must therefore treat 25 women for 30 yr to prevent a single fracture. Evidence-based clinicians are also aware that evidence never provides an adequate guide for treatment decisions when considered on its own. Each therapeutic decision involves a trade-off between benefits and risks, and value judgments are invariably involved in making that trade-off.