Patients with advanced heart failure have improved survival rates and quality of life when treated with implanted pulsatile-flow left ventricular assist devices as compared with medical therapy. New ...continuous-flow devices are smaller and may be more durable than the pulsatile-flow devices.
In this randomized trial, we enrolled patients with advanced heart failure who were ineligible for transplantation, in a 2:1 ratio, to undergo implantation of a continuous-flow device (134 patients) or the currently approved pulsatile-flow device (66 patients). The primary composite end point was, at 2 years, survival free from disabling stroke and reoperation to repair or replace the device. Secondary end points included survival, frequency of adverse events, the quality of life, and functional capacity.
Preoperative characteristics were similar in the two treatment groups, with a median age of 64 years (range, 26 to 81), a mean left ventricular ejection fraction of 17%, and nearly 80% of patients receiving intravenous inotropic agents. The primary composite end point was achieved in more patients with continuous-flow devices than with pulsatile-flow devices (62 of 134 46% vs. 7 of 66 11%; P<0.001; hazard ratio, 0.38; 95% confidence interval, 0.27 to 0.54; P<0.001), and patients with continuous-flow devices had superior actuarial survival rates at 2 years (58% vs. 24%, P=0.008). Adverse events and device replacements were less frequent in patients with the continuous-flow device. The quality of life and functional capacity improved significantly in both groups.
Treatment with a continuous-flow left ventricular assist device in patients with advanced heart failure significantly improved the probability of survival free from stroke and device failure at 2 years as compared with a pulsatile device. Both devices significantly improved the quality of life and functional capacity. (ClinicalTrials.gov number, NCT00121485.)
The incidence of oesophageal cancer, in particular adenocarcinoma, has markedly increased over the last four decades with adenocarcinoma becoming the dominant subtype in the West, and mortality rates ...are high. Nevertheless, overall survival of patients with oesophageal cancer has doubled in the past 20 years, with earlier diagnosis and improved treatments benefiting those patients who can be treated with curative intent. Advances in endotherapy, surgical approaches, and multimodal and other combination therapies have been reported. New vistas have emerged in targeted therapies and immunotherapy, informed by new knowledge in genomics and molecular biology, which present opportunities for personalised cancer therapy and novel clinical trials. This review focuses exclusively on the curative intent treatment pathway, and highlights emerging advances.
Many cancers possess the ability to suppress the immune response to malignant cells, thus facilitating tumour growth and invasion, and this has fuelled research to reverse these mechanisms and ...re-activate the immune system with consequent important therapeutic benefit. One such approach is to use histone deacetylase inhibitors (HDACi), a novel class of targeted therapies, which manipulate the immune response to cancer through epigenetic modification. Four HDACi have recently been approved for clinical use in malignancies including multiple myeloma and T-cell lymphoma. Most research in this context has focussed on HDACi and tumour cells, however, little is known about their impact on the cells of the immune system. Additionally, HDACi have been shown to impact the mechanisms by which other anti-cancer therapies exert their effects by, for example, increasing accessibility to exposed DNA through chromatin relaxation, impairing DNA damage repair pathways and increasing immune checkpoint receptor expression. This review details the effects of HDACi on immune cells, highlights the variability in these effects depending on experimental design, and provides an overview of clinical trials investigating the combination of HDACi with chemotherapy, radiotherapy, immunotherapy and multimodal regimens.
•Histone deacetylase inhibitors have diverse immunomodulatory functions.•Immunotherapy can propagate established immune responses.•Histone deacetylase inhibitors can be used as an adjunct to conventional therapies.•Clinical trials support this review and provide evidence for their clinical use.
There is compelling epidemiological evidence linking obesity to many tumours; however, the molecular mechanisms fuelling this association are not clearly understood. Emerging evidence links changes ...in the tumour microenvironment with the obese state, and murine and human studies highlight the relevance of adipose stromal cells (ASCs), including immune cells, both at remote fat depots, such as the omentum, as well as in peritumoural tissue. These obesity-associated changes have been implicated in several hallmarks of cancer, including the chronic inflammatory state and associated cell signalling, epithelial-to-mesenchymal transition (EMT), tumour-related fibrosis, angiogenesis, and genomic instability. Here, we present a summary of developments over the past 5 years, with particular focus on the tumour microenvironment in the obese state.
The roles of microRNA in cancer and apoptosis Lynam-Lennon, Niamh; Maher, Stephen G.; Reynolds, John V.
Biological reviews of the Cambridge Philosophical Society,
February 2009, Volume:
84, Issue:
1
Journal Article
Peer reviewed
microRNAs (miRNAs) are highly conserved, non‐protein‐coding RNAs that function to regulate gene expression. In mammals this regulation is primarily carried out by repression of translation. miRNAs ...play important roles in homeostatic processes such as development, cell proliferation and cell death. Recently the dysregulation of miRNAs has been linked to cancer initiation and progression, indicating that miRNAs may play roles as tumour suppressor genes or oncogenes. The role of miRNAs in apoptosis is not fully understood, however, evidence is mounting that miRNAs are important in this process. The dysregulation of miRNAs involved in apoptosis may provide a mechanism for cancer development and resistance to cancer therapy. This review examines the biosynthesis of miRNA, the mechanisms of miRNA target regulation and the involvement of miRNAs in the initiation and progression of human cancer. It will include miRNAs involved in apoptosis, specifically those miRNAs involved in the regulation of apoptotic pathways and tumour suppressor/oncogene networks. It will also consider emerging evidence supporting a role for miRNAs in modulating sensitivity to anti‐cancer therapy.
Increasing recognition of an association between obesity and many cancer types exists, but how the myriad of local and systemic effects of obesity affect key cellular and non-cellular processes ...within the tumour microenvironment (TME) relevant to carcinogenesis, tumour progression and response to therapies remains poorly understood. The TME is a complex cellular environment in which the tumour exists along with blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, signalling molecules and the extracellular matrix. Obesity, in particular visceral obesity, might fuel the dysregulation of key pathways relevant to both the adipose microenvironment and the TME, which interact to promote carcinogenesis in at-risk epithelium. The tumour-promoting effects of obesity can occur at the local level as well as systemically via circulating inflammatory, growth factor and metabolic mediators associated with adipose tissue inflammation, as well as paracrine and autocrine effects. This Review explores key pathways linking visceral obesity and gastrointestinal cancer, including inflammation, hypoxia, altered stromal and immune cell function, energy metabolism and angiogenesis.
To critically assess centralization policies for highly specialized surgeries in Europe and North America and propose recommendations.
Most countries are increasingly forced to maintain quality ...medicine at a reasonable cost. An all-inclusive perspective, including health care providers, payers, society as a whole and patients, has ubiquitously failed, arguably for different reasons in environments. This special article follows 3 aims: first, analyze health care policies for centralization in different countries, second, analyze how centralization strategies affect patient outcome and other aspects such as medical education and cost, and third, propose recommendations for centralization, which could apply across continents.
Conflicting interests have led many countries to compromise for a health care system based on factors beyond best patient-oriented care. Centralization has been a common strategy, but modalities vary greatly among countries with no consensus on the minimal requirement for the number of procedures per center or per surgeon. Most national policies are either partially or not implemented. Data overwhelmingly indicate that concentration of complex care or procedures in specialized centers have positive impacts on quality of care and cost. Countries requiring lower threshold numbers for centralization, however, may cause inappropriate expansion of indications, as hospitals struggle to fulfill the criteria. Centralization requires adjustments in training and credentialing of general and specialized surgeons, and patient education.
There is an obvious need in most areas for effective centralization. Unrestrained, purely "market driven" approaches are deleterious to patients and society. Centralization should not be based solely on minimal number of procedures, but rather on the multidisciplinary treatment of complex diseases including well-trained specialists available around the clock. Audited prospective database with monitoring of quality of care and cost are mandatory.
Patients with cancer of the lung or oesophagus, undergoing curative treatment, usually require a thoracotomy and a complex oncological resection. These surgeries carry a risk of major morbidity and ...mortality, and risk assessment, preoperative optimisation, and enhanced recovery after surgery (ERAS) pathways are modern approaches to optimise outcomes. Pre-operative fitness is an established predictor of postoperative outcome, accordingly, targeting pre-operative fitness through exercise prehabilitation has logical appeal. Exercise prehabilitation is challenging to implement however due to the short opportunity for intervention between diagnosis and surgery. Therefore, individually prescribed, intensive exercise training protocols which convey clinically meaningful improvements in cardiopulmonary fitness over a short period need to be investigated. This project will examine the influence of exercise prehabilitation on physiological outcomes and postoperative recovery and, through evaluation of health economics, the impact of the programme on hospital costs.
The PRE-HIIT Randomised Controlled Trial (RCT) will compare a 2-week high intensity interval training (HIIT) programme to standard preoperative care in a cohort of thoracic and oesophageal patients who are > 2-weeks pre-surgery. A total of 78 participants will be recruited (39 per study arm). The primary outcome is cardiorespiratory fitness. Secondary outcomes include, measures of pulmonary and physical and quality of life. Outcomes will be measured at baseline (T0), and post-intervention (T1). Post-operative morbidity will also be captured. The impact of PRE-HIIT on well-being will be examined qualitatively with focus groups/interviews post-intervention (T1). Participant's experience of preparation for surgery on the PRE-HIIT trial will also be explored. The healthcare costs associated with the PRE-HITT programme, in particular acute hospital costs, will also be examined.
The overall aim of this RCT is to examine the effect of tailored, individually prescribed high intensity interval training aerobic exercise on pre-operative fitness and postoperative recovery for patients undergoing complex surgical resections, and the impact on use of health services.
The study is registered with Clinical Trials.Gov (NCT03978325). Registered on 7th June 2019.
The aim of this article was to study the prevalence and significance of sarcopenia in the multimodal management of locally advanced esophageal cancer (LAEC), and to assess its independent impact on ...operative and oncologic outcomes.
Sarcopenia in cancer may confer negative outcomes, but its prevalence and impact on modern multimodal regimens for LAEC have not been systematically studied.
Two hundred fifty-two consecutive patients were studied. Lean body mass (LBM), skeletal muscle index (SMI), and fat mass (FM) were determined pre-treatment, preoperatively, and 1 year postoperatively. Sarcopenia was defined by computed tomography (CT) at L3 as SMI < 52.4 cm/m for males and SMI < 38.5 cm/m for females. All complications were recorded prospectively, including comprehensive complications index (CCI), Clavien-Dindo complication (CDC), and pulmonary complications (PPCs). Multivariable linear, logistic, and Cox regression analysis was performed.
In-hospital mortality was 1%, and CCI was 21 ± 19. Sarcopenia increased (P = 0.02) from 16% at diagnosis to 31% post-neoadjuvant therapy, with loss of LBM (-3.0 ± 5.4 kg, P < 0.0001), but not FM (-0.3 ± 2.7 kg, P= 0.31) during treatment. On multivariable analysis, preoperative sarcopenia was associated with CCI (P = 0.043), and CDC ≥IIIb (P = 0.003). PPCs occurred in 36% nonsarcopenic versus 55% sarcopenic patients (P = 0.01). Sarcopenia did not impact disease-specific (P = 0.14) or overall survival (P = 0.11) after resection. At 1 year, 35% had sarcopenia, significantly associated with pre-treatment BMI (P = 0.013) but not complications (P = 0.20).
Sarcopenia increases through multimodal therapy, is associated with an increased risk of major postoperative complications, and is prevalent in survivorship. These data highlight a potentially modifiable marker of risk that should be assessed and targeted in modern multimodal care pathways.
Summary
Esophagectomy is an exemplar of complex oncological surgery and is associated with a relatively high risk of major morbidity and mortality. In the modern era, where specific complications are ...targeted in prevention and treatment pathways, and where the principles of enhanced recovery after surgery are espoused, optimum outcomes are targeted via a number of approaches. These include comprehensive clinical and physiological risk assessment, specialist perioperative care by a high-volume team, and multimodal inputs throughout the patient journey that aim to preserve or restore nutritional deficits, muscle mass and function.
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