Thalidomide for managing cancer cachexia [review paper]

Cancer cachexia is a multidimensional syndrome characterised by wasting, loss of weight, loss of appetite, metabolic alterations, fatigue and reduced performance status. A significant number of patients with advanced cancer develop cachexia before death. There is no identified optimum treatment for cancer cachexia. While the exact mechanism of the action of thalidomide is unclear, it is known to have immunomodulatory and anti-inflammatory properties, which are thought to help reduce the weight loss associated with cachexia. Preliminary studies of thalidomide have demonstrated encouraging results. This review aimed to (1) evaluate the effectiveness of thalidomide, and (2) identify and assess adverse effects from thalidomide for cancer cachexia. Electronic searches were undertaken in CENTRAL, MEDLINE, EMBASE, Web of Science and CINAHL (from inception to April 2011). Reference lists from reviewed articles, trial registers, relevant conference documents and thalidomide manufacturers identified additional literature. This review included randomised controlled trials (RCTs) and non-RCTs. Participants were adults diagnosed with advanced or incurable cancer and weight loss or a clinical diagnosis of cachexia who were administered thalidomide. All titles and abstracts retrieved by electronic searching were downloaded to a reference management database. Duplicates were removed and the remaining citations were read by two review authors and checked for eligibility. Studies that were deemed ineligible for inclusion had clear reasons for exclusion documented. Data were extracted independently by two review authors for all eligible studies. While a meta-analysis was planned for this review, this was not possible due to the small number of studies included and high heterogeneity among them. Thus a narrative synthesis of the findings is presented. The literature search revealed a dearth of large, well conducted trials in this area. This has hindered the review authors' ability to make an informed decision about thalidomide for the management of cancer cachexia. At present, there is insufficient evidence to refute or support the use of thalidomide for the management of cachexia in advanced cancer patients. The review authors cannot confirm or refute previous literature on the use of thalidomide for patients with advanced cancer who have cachexia and there is inadequate evidence to recommend it for clinical practice. Additional, well conducted, large RCTs are needed to test thalidomide both singularly and in combination with other treatment modalities to ascertain its true benefit, if any, for this population. Furthermore, one study (out of the three reviewed) highlighted that thalidomide was poorly tolerated and its use needs to be explored further in light of the frailty of this population

Folate and vitamin B-12: friendly or enemy nutrients for the elderly

In the UK vitamin B-12, deficiency occurs in approximately 20% of adults aged >65 years. This incidence is significantly higher than that among the general population. The reported incidence invariably depends on the criteria of deficiency used, and in fact estimates rise to 24% and 46% among free-living and institutionalised elderly respectively when methylmalonic acid is used as a marker of vitamin B-12 status. The incidence of, and the criteria for diagnosis of, deficiency have drawn much attention recently in the wake of the implementation of folic acid fortification of flour in the USA. This fortification strategy has proved to be extremely successful in increasing folic acid intakes pre-conceptually and thereby reducing the incidence of neural-tube defects among babies born in the USA since 1998. However, in successfully delivering additional folic acid to pregnant women fortification also increases the consumption of folic acid of everyone who consumes products containing flour, including the elderly. It is argued that consuming additional folic acid (as 'synthetic' pteroylglutamic acid) from fortified foods increases the risk of 'masking' megaloblastic anaemia caused by vitamin B-12 deficiency. Thus, a number of issues arise for discussion. Are clinicians forced to rely on megaloblastic anaemia as the only sign of possible vitamin B-12 deficiency? Is serum vitamin B-12 alone adequate to confirm vitamin B-12 deficiency or should other diagnostic markers be used routinely in clinical practice? Is the level of intake of folic acid among the elderly (post-fortification) likely to be so high as to cure or 'mask' the anaemia associated with vitamin B-12 deficiency?.

Hydrogels as drug-delivery platforms:Physicochemical barriers and solutions

The properties of hydrogels, in particular their high biocompatibility and water sorption uptake, make hydrogels very attractive in drug delivery and biomedical devices. These favorable features of hydrogels are compromised by certain structural limitations such as those associated with their low mechanical strength in the swollen state. This review highlights the most important challenges that may seriously affect the practical implementation of hydrogels in clinical practice and the solutions that may be applied to overcome these limitations. © 2012 Future Science Ltd.

Help needed in medication self-management for people with visual impairment: case-control study

Background: Visual impairment (VI) is rising in prevalence and contributing to increasing morbidity, particularly among older people. Understanding patients' problems is fundamental to achieving optimal health outcomes but little is known about how VI impacts on self-management of medication.

Aim: To compare issues relating to medication self-management between older people with and without VI.

Design and setting: Case-control study with participants aged =65 years, prescribed at least two long-term oral medications daily, living within the community.

Method: The study recruited 156 patients with VI (best corrected visual acuity [BCVA] 6/18 to 3/60) at low-vision clinics; community optometrists identified 158 controls (BCVA 6/9 or better). Researchers visited participants in their homes, administered two validated questionnaires to assess medication adherence (Morisky; Medication Adherence Report Scale [MARS]), and asked questions about medication self-management, beliefs, and support.

Results: Approximately half of the participants in both groups reported perfect adherence on both questionnaires (52.5% Morisky; 43.3%, MARS). Despite using optical aids, few (3%) with VI could read medication information clearly; 24% had difficulty distinguishing different tablets. More people with VI (29%) than controls (13%) (odds ratio [OR] = 2.8; 95% confidence interval [CI] = 1.6 to 5.0) needed help managing their medication, from friends (19% versus 10%) or pharmacists (10% versus 2.5%; OR = 4.4, 95% CI = 1.4 to 13.5); more received social service support (OR = 7.1; 95% CI = 3.9 to 12.9).

Conclusion: Compared to their peers without VI, older people with VI are more than twice as likely to need help in managing medication. In clinical practice in primary care, patients' needs for practical support in taking prescribed treatment must be recognised. Strategies for effective medication self-management should be explored.

A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease

This 12-week, multinational study compared the tolerability and cognitive effects of donepezil (up to 10 mg once daily) and rivastigmine (up to 6 mg twice daily) in 111 patients with mild to moderate Alzheimer's disease. Both medications were administered open label according to recommended dosing regimens from the respective product labelling available during the conduct of the study. More patients in the donepezil group (89.3%) completed the study compared with the rivastigmine group (69.1%; p=0.009), and 10.7% of the donepezil group and 21.8% of the rivastigmine group discontinued due to adverse events (AEs); 87.5% of donepezil-treated patients and 47.3% of rivastigmine-treated patients remained on the maximum approved dose of each drug at the last study visit. Both groups showed comparable improvements on the ADAS-cog administered by raters blind to study medication at weeks 4 and 12. Thus, using the recommended dosing schedules, donepezil was better tolerated with fewer discontinuations due to AEs, and both agents improved cognition to a similar extent.

The Evaluation of an Interdisciplinary Pain Protocol in Long Term Care

Objectives: To evaluate the effectiveness of (1) dissemination strategies to improve clinical practice behaviors (eg, frequency and documentation of pain assessments, use of pain medication) among health care team members, and (2) the implementation of the pain protocol in reducing pain in long term care (LTC) residents. Design: A controlled before-after design was used to evaluate the effectiveness of the pain protocol, whereas qualitative interviews and focus groups were used to obtain additional context-driven data. Setting: Four LTC facilities in southern Ontario, Canada; 2 for the intervention group and 2 for the control group. Participants: Data were collected from 200 LTC residents; 99 for the intervention and 101 for the control group. Intervention: Implementation of a pain protocol using a multifaceted approach, including a site working group or Pain Team, pain education and skills training, and other quality improvement activities. Measurements: Resident pain was measured using 3 assessment tools: the Pain Assessment Checklist for Seniors with Limited Ability to Communicate, the Pain Assessment in the Communicatively Impaired Elderly, and the Present Pain Intensity Scale. Clinical practice behaviors were measured using a number of process indicators; for example, use of pain assessment tools, documentation about pain management, and use of pain medications. A semistructured interview guide was used to collect qualitative data via focus groups and interviews. Results: Pain increased significantly more for the control group than the intervention group over the 1-year intervention period. There were significantly more positive changes over the intervention period in the intervention group compared with the control group for the following indicators: the use of a standardized pain assessment tool and completed admission/initial pain assessment. Qualitative findings highlight the importance of reminding staff to think about pain as a priority in caring for residents and to be mindful of it during daily activities. Using onsite champions, in this case advanced practice nurses and a Pain Team, were key to successfully implementing the pain protocol. Conclusions: These study findings indicate that the implementation of a pain protocol intervention improved the way pain was managed and provided pain relief for LTC residents.

The UK Renal Registry Advanced CKD Study: frequency of incorrect reporting of date of start of RRT

Background: A preliminary review of the UK Renal Registry (UKRR) pre-RRT study data revealed results suggesting that, for some patients, the date of start of renal replacement therapy (RRT), as reported to the UKRR, was incorrect and often significantly later than the true date of start. A more detailed study then aimed to validate a set of criteria to identify patients with an incorrect start date. Methods: Pre-RRT laboratory data were electronically extracted from 8,810 incident RRT patients from 9 UK renal centres. Any patient with a low urea (<15 mmol/L) at the start of RRT or with a substantial improvement in kidney function (either a fall in urea >10 mmol/L or rise in eGFR >2 ml/min/1.73 m) within the two months prior to RRT were considered to potentially have an incorrect date of start. In 4
selected centres, the electronic patient records of all patients flagged were reviewed to validate these criteria.
Results: Of 8,810 patients, 1,616 (18.3%) were flagged by the identification criteria as having a potentially incorrect date of start of RRT, although a single centre accounted for 41% of the total flagged cohort. Of these flagged patients, 61.7% had been assigned an incorrect date of start of haemodialysis (HD), 5.7% had evidence of acute RRT being given before the reported date of start of HD
and 9.2% had evidence of starting peritoneal dialysis exchanges prior to the reported date of start. Of
those flagged, 10.7% had a correct date of start of RRT.
Conclusions: Accurate reporting of RRT episodes is vital for the analysis of time dependent studies such as survival or time to transplantation. A proportion of patients starting RRT were assigned an incorrect start date. In order to improve the accuracy of this reporting the UK Renal Registry
must work with renal centres and clinical staff on improving data input for the start of RRT.

Comorbidities and current smoking status amongst patients starting renal replacement therapy in England, Wales and Northern Ireland from 2003 to 2008: national and centre-specific analyses

Introduction: The prevalence of comorbidities in incident renal replacement therapy (RRT) patients changes with age and varies between ethnic groups. This study describes these associations and the independent effect of comorbidities on outcomes. Methods: Adult patients starting RRT between 2003 and 2008 in centres reporting to the UK Renal Registry (UKRR) with data on comorbidity (n ¼ 14,909) were included. The UKRR studied the association of comorbidity with patient demographics, treatment modality, haemoglobin, renal function at start of RRT and subsequent listing for kidney transplantation. The relationship between comorbidities and mortality at 90 days and one year after 90 days from start of RRT was explored using Cox regression. Results: Completeness of comorbidity data was 40.0% compared with 54.3% in 2003. Of patients with data, 53.8% had one or more comorbidities. Diabetes mellitus and ischaemic heart disease were the most common conditions seen in 30.1% and 22.7% of patients respectively. Current smoking was recorded for 14.5% of incident RRT patients in the 6-year period. Comorbidities became more common with increasing age in all ethnic groups although the difference between the 65–74 and 75+ age groups was not significant. Within each age group, South Asians and Blacks had lower rates of comorbidity, despite higher rates of diabetes mellitus. In multivariate survival analysis, malignancy and ischaemic/neuropathic ulcers were the strongest independent predictors of poor survival at 1 year after 90 days from the start of RRT. Conclusion: Differences in prevalence of comorbid illnesses in incident RRT patients may reflect variation in access to health care or competing risk prior to commencing treatment. At the same time, smoking rates remained high in this ‘at risk’ population. Further work on this and ways to improve comorbidity reporting should be priorities for 2010–11.

Comorbidities and current smoking status amongst patients starting renal replacement therapy in England, Wales and Northern Ireland: national and centre-specific analyses

Introduction: The prevalence of 13 comorbid conditions and smoking status at the time of starting renal replacement therapy (RRT) in England, Wales and Northern Ireland are described. Methods: Adult patients starting RRT between 2002 and 2007 in centres reporting to the UK Renal Registry (UKRR) and with data on comorbidity (n¼13,293) were included. The association of comorbidity with patient demographics, treatment modality, haemoglobin, renal function at start of RRT and subsequent listing for kidney transplantation were studied. Association between comorbidities and mortality at 90 days and one year after 90 days from start of RRT was explored using Cox regression. Results: Completeness of data on comorbidity returned to the UKRR remained poor. Of patients with data, 52% had one or more comorbidities. Diabetes mellitus and ischaemic heart disease were the most common conditions seen in 28.9% and 22.5% of patients respectively. Comorbidities became more common with increasing age (up to the 65–74 age group), were more common amongst Whites and were associated with a lower likelihood of pre-emptive transplantation, a greater likelihood of starting on haemodialysis (rather than peritoneal dialysis) and a lower likelihood of being listed for kidney transplantation. In multivariable survival analysis, malignancy and ischaemic/neuropathic ulcers were the strongest predictors of poor survival at 1 year after 90 days from start of RRT. Conclusions: The majority of patients had at least one comorbid condition and comorbidity is an important predictor of early mortality on RRT.

UK RRT Incidence in 2009: national and centre-specific analyses

Introduction: This chapter describes the characteristics of
adult patients on renal replacement therapy (RRT) in the
UK in 2009. The prevalence rates per million population
(pmp) were calculated for Primary Care Trusts in England,
Health and Social Care Areas in Northern Ireland, Local
Health Boards in Wales and Health Boards in Scotland.
These areas will be referred to in this report as ‘PCT/HBs’.
Methods: Data were electronically collected from all 72
renal centres within the UK. A series of cross-sectional and
longitudinal analyses were performed to describe the
demographics of prevalent RRT patients in 2009 at centre
and national level. Age and gender standardised ratios for
prevalence rates in PCT/HBs were calculated. Results:
There were 49,080 adult patients receiving RRT in the UK
on 31st December 2009, equating to a UK prevalence of
794 pmp. This represented an annual increase in prevalent
numbers of approximately 3.2% although there was significant
variation between centres and PCT/HB areas. The
growth rate from 2008 to 2009 for prevalent patients by
treatment modality in the UK was 4.2% for haemodialysis
(HD), a fall of 7.2% for peritoneal dialysis (PD) and a
growth of 4.4% with a functioning transplant. There has
been a slow but steady decline in the proportion of PD
patients from 2000 onwards. Median RRT vintage was 5.4
years. The median age of prevalent patients was 57.7
years (HD 65.9 years, PD 61.2 years and transplant 50.8
years). For all ages, prevalence rates in males exceeded
those in females: peaks for males were in the 75–79 years
age group at 2,632 pmp and for females in the 70–74
years age group at 1,445 pmp. The most common identifiable
renal diagnosis was biopsy-proven glomerulonephritis
(16.0%), followed by diabetes (14.7%). Transplantation was
the most common treatment modality (48%), HD in 44%
and PD 8%. However, HD was increasingly common with
increasing age and transplantation less common. Conclusions:
The HD and transplant population continued to
expand whilst the PD population contracted. There were
national, regional and dialysis centre level variations in
prevalence rates. This has implications for service planning
and ensuring equity of care for RRT patients.

Standardization of diagnostic biomarker concentrations in urine; the hematuria caveat

Sensitive and specific urinary biomarkers can improve patient outcomes in many diseases through informing early diagnosis. Unfortunately, to date, the accuracy and translation of diagnostic urinary biomarkers into clinical practice has been disappointing. We believe this may be due to inappropriate standardization of diagnostic urinary biomarkers. Our objective was therefore to characterize the effects of standardizing urinary levels of IL-6, IL-8, and VEGF using the commonly applied standards namely urinary creatinine, osmolarity and protein. First, we report results based on the biomarker levels measured in 120 hematuric patients, 80 with pathologically confirmed bladder cancer, 27 with confounding pathologies and 13 in whom no underlying cause for their hematuria was identified, designated “no diagnosis”. Protein levels were related to final diagnostic categories (p = 0.022, ANOVA). Osmolarity (mean = 529 mOsm; median = 528 mOsm) was normally distributed, while creatinine (mean = 10163 µmol/l, median = 9350 µmol/l) and protein (0.3297, 0.1155 mg/ml) distributions were not. When we compared AUROCs for IL-6, IL-8 and VEGF levels, we found that protein standardized levels consistently resulted in the lowest AUROCs. The latter suggests that protein standardization attenuates the “true” differences in biomarker levels across controls and bladder cancer samples. Second, in 72 hematuric patients; 48 bladder cancer and 24 controls, in whom urine samples had been collected on recruitment and at follow-up (median = 11 (1 to 20 months)), we demonstrate that protein levels were approximately 24% lower at follow-up (Bland Altman plots). There was an association between differences in individual biomarkers and differences in protein levels over time, particularly in control patients.

Patterns of family adaptation to childhood asthma

This study examined patterns in adaptation among parents with a child who had moderate to severe persistent asthma. Specifically, we were interested in examining the differences in adaptation between mothers and fathers in which it was hypothesized that gender effects would be obtained in patterns of coping. Eighty-four parents participated in the study, representing 37 intact families in which both parents were present and 13 single-parent families. Within intact families, mothers exhibited greater efforts than fathers in coping patterns including strategies to acquire social support outside the family, enhance self-worth, and decrease psychological tensions. When compared to mothers in single-parent families, mothers within intact families had a greater tendency to use coping patterns related to family integration and cooperation. Such findings demonstrate a need for additional support for mothers in their role in caring for the chronically ill child. The implications of these findings for clinical practice are discussed. Copyright 2002, Elsevier Science (USA). All rights reserved.

Protocolized versus non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients (Review)

BACKGROUND: Reducing weaning time is desirable in minimizing potential complications from mechanical ventilation. Standardized weaning protocols are purported to reduce time spent on mechanical ventilation. However, evidence supporting their use in clinical practice is inconsistent.

OBJECTIVES: To assess the effects of protocolized weaning from mechanical ventilation on the total duration of mechanical ventilation for critically ill adults; ascertain differences between protocolized and non-protocolized weaning in terms of mortality, adverse events, quality of life, weaning duration, intensive care unit (ICU) and hospital length of stay (LOS); and explore variation in outcomes by type of ICU, type of protocol and approach to delivering the protocol.

SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2010), MEDLINE (1950 to 2010), EMBASE (1988 to 2010), CINAHL (1937 to 2010), LILACS (1982 to 2010), ISI Web of Science and ISI Conference Proceedings (1970 to 2010), Cambridge Scientific Abstracts (inception to 2010) and reference lists of articles. We did not apply language restrictions.

SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials of protocolized weaning versus non-protocolized weaning from mechanical ventilation in critically ill adults.

DATA COLLECTION AND ANALYSIS: Three authors independently assessed trial quality and extracted data. A priori subgroup and sensitivity analyses were performed. We contacted study authors for additional information.

MAIN RESULTS: Eleven trials that included 1971 patients met the inclusion criteria. The total duration of mechanical ventilation geometric mean in the protocolized weaning group was on average reduced by 25% compared with the usual care group (N = 10 trials, 95% CI 9% to 39%, P = 0.006); weaning duration was reduced by 78% (N = 6 trials, 95% CI 31% to 93%, P = 0.009); and ICU LOS by 10% (N = 8 trials, 95% CI 2% to 19%, P = 0.02). There was significant heterogeneity among studies for total duration of mechanical ventilation (I(2) = 76%, P <0.01) and weaning duration (I(2) = 97%, P <0.01), which could not be explained by subgroup analyses based on type of unit or type of approach.

AUTHORS' CONCLUSIONS: There is some evidence of a reduction in the duration of mechanical ventilation, weaning duration and ICU LOS with use of standardized protocols, but there is significant heterogeneity among studies and an insufficient number of studies to investigate the source of this heterogeneity. Although some study authors suggest that organizational context may influence outcomes, these factors were not considered in all included studies and therefore could not be evaluated.

A comparative analysis of the health and wellbeing of cancer survivors to the general population

Background
The population of people surviving cancer is continually increasing and currently cancer survivors represent approximately 3.7% of the American population and 3% of the UK population. There is limited and inconclusive empirical evidence regarding the long-term health and well-being of cancer survivors.

Methods
Two hundred eighty-nine cancer survivors and 262 matched-age and sex patients from the same group of General (primary care) Practices completed postal questionnaires measuring health and well-being, health service utilisation and satisfaction and health care needs.

Main Results
Cancer survivors reported poorer health and well-being and health service utilisation than the general population. Despite this poorer health, the majority of cancer survivors reported satisfaction with services and almost two-thirds of the survivors did not report any needs.

Conclusions
The majority of cancer survivors do not appear to require additional support services. There is, however, a subgroup of survivors who warrant specialist support, particularly survivors who are older, experience late effects and have had adjuvant treatments. Future research should focus on developing methods that could be used in routine clinical practice to identify ‘at risk’ or vulnerable patients and to provide appropriate and timely support.