Τρίτη 3 Νοεμβρίου 2020

Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma

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Objective

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with limited treatment options. Cabozantinib, an orally bioavailable multikinase inhibitor is now approved by Food and Drug Administration (FDA) for HCC patients. We evaluated the therapeutic efficacy of cabozantinib, either alone or in combination, in vitro and in vivo.

Design

Human HCC cell lines and HCC mouse models were used to assess the therapeutic efficacy and targeted molecular pathways of cabozantinib, either alone or in combination with the pan-mTOR inhibitor MLN0128 or the checkpoint inhibitor anti-PD-L1 antibody.

Results

Cabozantinib treatment led to stable disease in c-Met/β-catenin and Akt/c-Met mouse HCC while possessing limited efficacy on Akt/Ras and c-Myc liver tumours. Importantly, cabozantinib effectively inhibited c-MET and ERK activity, leading to decreased PKM2 and increased p21 expression in HCC cells and in c-Met/β-catenin and Akt/c-Met HCC. However, cabozantinib was ineffective in inhibiting the Akt/mTOR cascade. Intriguingly, a strong inhibition of angiogenesis by cabozantinib occurred regardless of the oncogenic drivers. However, cabozantinib had limited impact on other tumour microenvironment parameters, including tumour infiltrating T cells, and did not induce programmed death-ligand 1 (PD-L1) expression. Combining cabozantinib with MLN0128 led to tumour regression in c-Met/β-catenin mice. In contrast, combined treatment with cabozantinib and the checkpoint inhibitor anti-PD-L1 antibody did not provide any additional therapeutic benefit in the four mouse HCC models tested.

Conclusion

c-MET/ERK/p21/PKM2 cascade and VEGFR2-induced angiogenesis are the primary targets of cabozantinib in HCC treatment. Combination therapies with cabozantinib and mTOR inhibitors may be effective against human HCC.

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Sleep and the athlete: narrative review and 2021 expert consensus recommendations

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Elite athletes are particularly susceptible to sleep inadequacies, characterised by habitual short sleep (<7 hours/night) and poor sleep quality (eg, sleep fragmentation). Athletic performance is reduced by a night or more without sleep, but the influence on performance of partial sleep restriction over 1–3 nights, a more real-world scenario, remains unclear. Studies investigating sleep in athletes often suffer from inadequate experimental control, a lack of females and questions concerning the validity of the chosen sleep assessment tools. Research only scratches the surface on how sleep influences athlete health. Studies in the wider population show that habitually sleeping <7 hours/night increases susceptibility to respiratory infection. Fortunately, much is known about the salient risk factors for sleep inadequacy in athletes, enabling targeted interventions. For example, athlete sleep is influenced by sport-specific factors (relating to training, travel and competition) and non-sport factors (eg, female gender, stress and anxiety). This expert consensus culminates with a sleep toolbox for practitioners (eg, covering sleep education and screening) to mitigate these risk factors and optimise athlete sleep. A one-size-fits-all approach to athlete sleep recommendations (eg, 7–9 hours/night) is unlikely ideal for health and performance. We recommend an individualised approach that should consider the athlete's perceived sleep needs. Research is needed into the benefits of napping a nd sleep extension (eg, banking sleep).

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Injury characteristics in male youth athletics: a five-season prospective study in a full-time sports academy

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Objectives

To describe the injury characteristics of male youth athletes exposed to year-round athletics programmes.

Methods

Injury surveillance data were prospectively collected by medical staff in a cohort of youth athletics athletes participating in a full-time sports academy from 2014–2015 to 2018–2019. Time-loss injuries (>1 day) were recorded following consensus procedures for athletics. Athletes were clustered into five event groups (sprints, jumps, endurance, throws and non-specialised) and the nu mber of completed training and competition sessions (athletics exposures (AE)) were calculated for each athlete per completed season (one athlete season). Injury characteristics were reported overall and by event groups as injury incidence (injuries per 1000 AE) and injury burden (days lost per 1000 AE).

Results

One-hundred and seventy-eight boys (14.9±1.8 years old) completed 391 athlete seasons, sustaining 290 injuries. The overall incidence was 4.0 injuries per 1000 AE and the overall burden was 79.1 days lost per 1000 AE. The thigh was the most common injury location (19%). Muscle strains (0.7 injuries per 1000 AE) and bone stress injuries (0.5 injuries per 1000 AE) presented the highest incidence and stress fractures the highest burden (17.6 days lost per 1000 AE). The most burdensome injury types by event group were: bone stress injuries for endurance, hamstring strains for sprints, stress fractures for jumps, lesion of meniscus/cartilage for throws and growth plate inju ries for non-specialised athletes.

Conclusion

Acute muscle strains, stress fractures and bone stress injuries were identified as the main injury concerns in this cohort of young male athletics athletes. The injury characteristics differed between event groups.

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Neuroendocrine Involvement in Immune-Mediated Rheumatic Diseases

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Abstract

In the present chapter, the evidences showing how neuro-endocrine-immune network integrates human organism functions in healthy and disease status will be summarized. Central and peripheral nervous systems in fact were demonstrated to present receptors for immune system products, like pro-inflammatory cytokines and growth factors. At the same time, immune system cells and peripheral tissues show receptors and are able produce and catabolize neurotransmitters and hormones. Consequently, in the main immune-mediated rheumatic diseases, several alterations of the interactions between nervous, endocrine, and immune systems have been described. At the same time, disease-modifying and biologic drugs have shown in several cases to determine the restoration of hormonal and nervous system activity while performing their main immune-modulating effect.

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Impact of Endocrine Disorders on Autoimmune Diseases

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Abstract

Endocrine diseases are a heterogeneous group of disorders which can affect nearly any body system including the musculoskeletal system. Rheumatic manifestations of endocrine disorders may present as a definite rheumatic disease (such as pseudogout in hyperparathyroidism), as rheumatic symptoms such as arthralgia and myalgia, as positive immune serology, or may mimic rheumatic diseases (e.g., skeletal abnormalities in hypoparathyroidism can mimic ankylosing spondylitis). The rheumatic manifestations may result from a direct effect of the hormones, the occurrence of several autoimmune phenomena in the same person (due to genetic or environmental influences), secondary to endocrine disease complications or effects of advanced glycation end products in the case of diabetes. Rheumatic manifestations of diabetes, thyroid, pituitary, parathyroid, and adrenal disorders will be discussed.

Rheumatic diseases are associated with endocrine disorders which may have an impact on the clinical aspects of those diseases. The impact of endocrine disorders on rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) is reviewed. Rheumatoid arthritis is the most common coexisting autoimmune disorder in patients with Grave's disease and Hashimoto thyroiditis. RA patients are more likely to have thyroid-related antibodies, and some studies indicate an increased prevalence of thyroid diseases in RA. Hypothyroidism contributes to the increased risk for cardiovascular diseases and metabolic syndrome in RA patients and may be correlated with RA disease activity and response to treatment. In most studies, thyroid diseases (mainly hypothyroidism) are more common in SLE patients. Their impact on disease activity is controversial. Pregnant SLE patients are more prone to develop thyroid diseases and pospartum thyroitidis, and in case they suffer from thyroid disease, they have an increased prevalence of preterm delivery. Polyautoimmunity is reported in a high percentage of SS patients. The most frequent coexisting disease is autoimmune thyroid disease (AITD) which may be partially explained by the higher prevalence of thyroid dysfunction in middle-aged women rather than a true association. The prevalence of SS among patients with autoimmune thyroiditis is increased by two- to tenfold.

Patients with RA have an increased risk of insulin resistance (IR) and diabetes (DM) secondary to genetic, inflammatory components or to comorbidities and treatment. The impact of diabetes on disease activity is yet to be fully elucidated. Some of the therapies for RA have a positive impact on DM. Although poly-autoimmunity is frequently described in SLE, the association with type 1 DM is uncommon. An association between SLE and insulin resistance and DM type II is described. Glucocorticoids might have an impact on development of DM, while hydroxycholoroquine treatment is protective. DM does not appear to be a major contributor to damage accrual in SLE.

Addison's disease is mainly related to endocrine autoimmunities, and the association with connective tissue diseases is rare. Cushing syndrome in the rheumatic diseases is mainly secondary to glucocorticoid treatment.

Prolactinoma is associated with an increased risk for autoimmune diseases. Autoimmune thyroid disease is the most common, while rheumatic diseases are rare. Data concerning prolactin and RA are conflicting. Hyperprolactinemia has been described in 20–30% of patients with SLE, but the exact origin of the increased prolactin in SLE patients is unknown. Prolactin might be an independent factor related to SLE activity and disease damage. Elevated prolactin during pregnancy in SLE patients is associated with lupus activity and poor outcome. Bromocriptine (a dopaminergic drug) reduced SLE flares in non-pregnant patients and prevented flares and improved fetal and maternal outcome during pregnancy.

Clinical bone disease secondary to primary hyperparathyroidism is rare today thanks to early detection. Chondrocalcinosis may appear in hyperparathyroid patients. Hyperparathyroidism is probably not increased in RA and SLE.

The association between hypoparathyroidism and rheumatoid arthritis is rare. Hypoparathyroidism was found to be increased in SLE patients and may be secondary to anti-parathyroid antibodies.

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One Anastomosis Gastric Bypass for the Treatment of Type 2 Diabetes: Long-Term Results and Recurrence

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Abstract

Background

Bariatric/metabolic surgery has been incorporated into the therapeutic treatment of type 2 diabetes mellitus (T2DM). Among many bariatric/metabolic procedures, one anastomosis gastric bypass (OAGB) is one of the most effective procedures but long-term data about T2DM recurrence after OAGB are lacking.

Methods

Outcomes of 134 patients who had undergone OAGB for the treatment of T2DM with long-term (5 years) follow-up were assessed in a retrospective cohort study. The remission of T2DM after OAGB surgery was evaluated in different groups using a scoring system composed of the age, BMI, C-peptide level, duration of T2DM (ABCD score), and percent of total weight loss (%TWL).

Results

The %TWL and percent of excess weight loss (%EWL) of the OAGB patients at 5 years after surgery were 29.2 (10.6) and 72.1(27.5), respectively. The mean BMI decreased from 39.5(7.9) to 27.6(5.3) kg/m2 and mean glycated hemoglobin A1C (HbA1c) decreased from 8.9 to 5.9% in OAGB patients at 5 years after OAGB. The complete T2DM remission rate of OAGB was 76.1% at 1 year and 64.2% at 5 years after surgery. Forty-one (57.8%) out of 71 patients who completed a 10-year follow-up remained in complete T2DM remission. The T2DM recurrence rate of OAGB patients was 15.7% at 5 years after surgery.

Conclusions

OAGB is highly effective in inducing T2DM remission but a significant number of patients will still have T2DM recurrence. To select patient with an ABCD score > 5 and maintaining a weight loss greater than 30% is important for durable T2DM remission after OAGB.

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Changes in Bone Mineral Density After Weight Loss Due to Metabolic Surgery or Lifestyle Intervention in Obese Patients

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Abstract

Purpose

Metabolic surgery and lifestyle intervention are two common methods used to treat obesity, but the effects of weight loss on bone mineral density (BMD) remain controversial. Our aim was to evaluate changes in BMD of the total hip, femoral neck, and lumbar spine after weight loss caused by metabolic surgery or lifestyle intervention.

Materials and Methods

We searched PubMed, Web of Science, and the Cochrane Library to identify relevant studies published before 5 August 2020. The primary outcomes, including the BMD of the total hip, femoral neck, and lumbar spine before and 12 months after metabolic surgery or lifestyle intervention, were extracted.

Results

A total of 19 studies with 1095 participants with obesity were included. Among them, 603 participants with obesity accepted metabolic surgery, while 492 accepted lifestyle intervention. At 12 months after weight loss, the BMD of the total hip decreased significantly in obese patients (mean difference [MD] = 0.06 g/cm2; 95% confidence interval [CI] 0.03 to 0.08; I2 = 67%; P < 0.001), while the BMD of the lumbar spine did not significantly change (P > 0.05). In the subgroup analysis, the BMD of the femoral neck decreased significantly at 12 months in obese patients who underwent metabolic surgery (MD = 0.08 g/cm2; 95% CI 0.04 to 0.13; I2 = 84%; P < 0.001), while it did not significantly change in obese patients who underwent lifestyle treatment (P > 0.05).

Conclusion

Regardless of whether the patients underwent metabolic surgery or lifestyle treatment, the BMD of the total hip significantly decreased in obese patients after weight loss. Different methods used to lose weight may have different effects on the BMD of the femoral neck. Prospective studies, preferably randomized controlled trials (RCTs), are still required to investigate whether the effects of the two treatments on bone metabolism are truly different.

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Lenalidomide with Rituximab for Previously Treated Follicular Lymphoma and Marginal Zone Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

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Abstract

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of lenalidomide (Revlimid®), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of lenalidomide in combination with rituximab (MabThera®), together referred to as R2, for the treatment of adults with treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The CS included one relevant study, for the compa rison of R2 versus rituximab monotherapy (R-mono): the AUGMENT trial. In addition, the company performed an unanchored indirect comparison of R2 versus rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and rituximab combined with cyclophosphamide, vincristine, and prednisolone (R-CVP), using data for R2 from the AUGMENT trial and pooled data for R-CHOP/R-CVP from the Haematological Malignancy Research Network (HMRN) database. During the STA process, the company provided an addendum containing evidence on only the FL population, in line with the marketing authorisation obtained at that time, which did not include MZL. The probabilistic incremental cost-effectiveness ratios (ICERs) presented by the company were £27,768 per quality-adjusted life year (QALY) gained for R2 versus R-CHOP, £41,602 per QALY gained for R2 versus R-CVP, and £23,412 per QALY gained for R2 versus R-mono. The ERG's concerns included the validity of the unanchored comparison, the unavailability of a state transition model to verify the outcomes of the partitioned survival model, substantial uncertainty in survival curves, and potential over-estimation of utility values. The revised ERG base case resulted in ICERs ranging from £16,874 to £44,888 per QALY gained for R2 versus R-CHOP, from £23,135 to £59,810 per QALY gained for R2 versus R-CVP, and from £18,779 to £27,156 per QALY gained for R2 versus R-mono. Substantial uncertainty remained around these ranges. NICE recommended R2 within its marketing authorisation, as an option for previously treated FL (grade 1–3A) in adults, contingent on the company providing lenalidomide according to the commercial arrangement.

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'Supportive and Palliative Care Indicators Tool (SPICT) improves renal nurses confidence in recognising patients approaching end of life

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Background

Identification of people with deteriorating health is essential for quality patient-centred care and optimal management. The Supportive and Palliative Care Indicators Tool (SPICT) is a guide to identifying people with deteriorating health for care planning without incorporating a prognostic time frame.

Objectives

To improve renal nursing staff confidence in identifying patients approaching end-of-life and advocate for appropriate multidisciplinary care planning.

Design

This pilot feasibility pro spective cohort study conducted in the renal ward of a major metropolitan health service during 2019 included a preintervention/postintervention survey questionnaire. A programme of education was implemented training staff to recognise end-of-life and facilitate appropriate care planning.

Results

Several domains in the postintervention survey demonstrated a statistically significant improvement in renal nurses' perception of confidence in their ability to recognise end of life. Of the 210 patients admitted during the study period, 16% were recognised as SPICT positive triggering renal physicians to initiate discussions about end-of-life care planning with patients and their families and to document a plan. Six months poststudy, 72% of those patients recognised as SPICT positive had died with a documented plan of care in place.

Conclusion

The use of SPICT for hospital admissions and the application of education in topics related to end-of-life care resulted in a significa nt improvement in nurses' confidence in recognising deteriorating and frail patients approaching their end of life. The use of this tool also increased the number of deteriorating patients approaching end of life with goals of care documented.

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Ethical decision making when demand for intensive care exceeds available resources. The need for public discussion.

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By Tim Cook, Kim J Gupta, Robin Fackrell, Sarah Wexler, Bernie Marden

Early in the COVID-19 pandemic the first author of this blog wrote a Guardian article which was titled "ICU doctors now face the toughest decisions they will ever have to make." It referred to the possibility – then expected to be a reality – that the UK's intensive care resources would be insufficient to cope with the demands of the pandemic, and that doctors would be confronted with the need to make 'triage' decisions (a term from the battlefield) about which patients to treat in ICU when not all could be. At that time, it was common to hear it said that "doctors make these decisions all the time". In reality this is not true. In normal circumstances, as stated in the Guardian article, "doctors wrestle with decisions about what is right for the patient in front of them…but when resource-based triage occurs, the decisions become about what is in the "greater good" and "doing the best for the most."

In the Royal United Hospitals in Bath, as in other hospitals in the UK and beyond, we prepared for the mass influx of patients. We expanded our intensive care capacity, built up supplies, and retrained and redeployed staff. However, expectations and models still suggested that at the height of the pandemic demand would exceed resource significantly: specifically that there would be insufficient intensive care capacity in terms of beds, ventilators or staff to care for all patients who could benefit from it.

In this situation of national crisis, we hoped for clear national guidance on the principles that should be applied if medical demand exceeded medical resource. Several documents were produced but these were either treatises on the ethics of the matter or policy documents that tended to emphasise universal access and failed to directly address what actions to take when resources are inadequate. To be explicit, those decisions might include deciding which of two patients would be placed on a ventilator when two needed it and both would benefit but only one ventilator was available, or whether it would ever be acceptable to remove one patient from a ventilator to enable it to be used for another patient who had a better chance of survival. These are invidious situations – almost incomprehensible to talk or write about – but they were prominent in our thoughts in March. In the absence of national guidance, we needed either to develop a plan that could be enacted locally or simply let individual doctors use whatever personal mental and ethical resource they could summon when confronted with this dreadful situation. We chose the former.

A multidisciplinary group of individuals was brought together with medical, nursing, legal, lay and ethical experience. Together we pondered, discussed, and occasionally argued about what such a document should contain. Over a few weeks it took form and after reconsideration, consultation and revision, a working document was finalised. We hope we developed a document that enables structured, explicit, transparent decision-making in a situation we all hoped to avoid.

In the United Kingdom, during the first wave of the pandemic, the anticipated volume of patients requiring intensive care was ultimately mitigated by a three-fold approach. This involved a widespread, rapid expansion of intensive care capacity, a reduction of healthcare demand from non-COVID-19 sources by temporarily pausing much of normal healthcare delivery and by reduced demand through governmental and societal responses that included national lockdown. Service overload and the need for triage was thus narrowly avoided. But make no mistake, the system was severely stretched, and in some locations pushed close to breaking point.

Our triage document has fortunately not been required during the pandemic so far, and the document did not become hospital policy. However, it is not inconceivable that the document may yet be required. As winter approaches the NHS comes under the strain of 'normal winter pressures', compounded by an emerging second wave of COVID-19 activity, and a strong strategic desire to maintain normal NHS activity for as long as possible. National lockdown is also unlikely: schools, universities and many town centres will remain open. Winter, COVID-19 and routine services will all require and compete for the limited intensive care services. Preparations for national responses to manage increase ICU demand are well established, but it is not unthinkable that over this winter demand for services will overwhelm capacity and 'triage' documents yet may be needed at the bedside.

In an article in the Journal of Medical Ethics we have described how our document was created and we present the document itself. It is our strongly held position that creation of a document such as this is too important to be left to a few doctors and nurses in a single hospital. As part of the development process it was viewed and commented on by our local ethics advisory group – and greatly modified as a result. But we wanted to go further. The article in The Guardian stated "… we can't do this alone. If it becomes necessary, a framework to inform these decisions should be shared with the rest of society. In this urgent crisis we need a public discussion to help guide these difficult decisions, and clear advice from our medical, philosophical and political leaders." We have published the article and the document to be transparent and as a starting-point for stakeholder feedback and discussion. We welcome all comments and feedback, from ethicists and professio nals and anyone who is interested but especially from patients and the wider public.

Lastly, our paper has become particularly topical as several media outlets have raised claims and concerns that the elderly or chronically ill had reduced access to ICU admission in the first pandemic surge. Those concerns have included clams of extensive use of triage tools to control who might be considered for ICU admission. It is important not to conflate triage when ICU capacity still exists with its use in situations where there is insufficient resource, and such decisions are unavoidable. Our paper, and the triage tool it includes, relates only to the latter situation but we believe the discussion is none the less timely.

 

Paper title: Development of a structured process for fair allocation of critical care resources in the setting of insufficient capacity: a discussion paper. (Forthcoming)

Authors: Tim Cook, Kim Gupta, Christopher Dyer, Robin Fackrell, Sarah Wexler, Heather Boyes, Ben Colleypriest, Richard Graham, Helen Meehan, Sarah Merritt, Derek Robinson, Bernie Marden

Affiliations: Royal United Hospitals Bath NHS Foundation Trust, Combe Park, Bath

Competing interests: None

Social media accounts of post author: @doctimcook

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