Cannabis Use in Young Adult Cancer Patients.

Background: The use of cannabis by young adult (YA) cancer patients is likely to increase as medical cannabis becomes more available. Clinically relevant data on cannabis use are needed to establish benchmarks for use, to identify patients who are more likely to use cannabis, and to assess outcomes associated with use. Objective: The current study sought to determine the rate of cannabis use in YA cancer patients ages 18 to 39, identify demographic and clinical correlates of use, and examine differences in moderate-to-severe symptoms between users and nonusers. Methods: We conducted a retrospective review of objectively measured tetrahydrocannabinol (THC), self-reported cannabis use, and cancer-related symptomatology in YA cancer patients in active treatment referred for comprehensive supportive care. Results: Approximately 30% of YA cancer patients tested positive for THC on urine drug testing. At the univariate level, cannabis users were more likely to be male, to have a lifetime history of smoking at least 100 cigarettes, and to be more recently diagnosed. Cannabis use was associated with moderate-to-severe symptomatology, including pain, nausea, lack of appetite, constipation, difficulty sleeping, and poorer overall well-being. Conclusions: YAs referred for comprehensive supportive care may be managing their cancer-related symptoms with cannabis. Further research is needed to better understand patients' perceptions of cannabis's therapeutic and adverse effects, in patients who used cannabis before diagnosis, and in patients who commenced use in response to a cancer diagnosis.

Relationship of Cannabis Use to Patient-Reported Symptoms in Cancer Patients Seeking Supportive/Palliative Care.

Background: The use of cannabis by cancer patients has become increasingly common. With expanding access to medical cannabis, unsanctioned cannabis use is likely to increase. Despite this, the extent to which patients seeking specialized palliative or supportive care for cancer-related symptoms are actively using cannabis has not been well established. Objective: We sought to determine the extent to which patients seeking specialized symptom management were using cannabis and to compare the severity of cancer-related symptoms between users and nonusers. Methods: We conducted a retrospective review of objectively measured tetrahydrocannabinol (THC) and subjectively reported cannabis use, its demographic and clinical correlates, and patient-reported symptoms in 816 cancer patients in active treatment referred to a supportive/palliative care outpatient clinic for specialized symptom management between January 2014 and May 2017. Results: Nearly one-fifth (19.12%) tested positive for THC on urine drug testing. Users were younger, more likely to be men, single, and to have a history of cigarette smoking. Users also were likely to be more recently diagnosed and to have received radiotherapy. Certain moderate-to-severe symptoms, such as lack of appetite, shortness of breath, tiredness, difficulty sleeping, anxiety, and depression, were associated with use after accounting for sociodemographic and clinical differences between cannabis users and nonusers. Conclusions: Findings suggest patients seeking specialized symptom management are self-treating with cannabis, despite the lack of high-quality evidence for its use in palliative care. Unsanctioned use is likely to increase in cancer patients. Accurate information is urgently needed to help manage patient expectations for its use and increase understanding of risks and benefits.

Fludrocortisone-a treatment for tubulopathy post-paediatric renal transplantation: A national paediatric nephrology unit experience.

Calcineurin inhibitors post-renal transplantation are recognized to cause tubulopathies in the form of hyponatremia, hyperkalemia, and acidosis. Sodium supplementation may be required, increasing medication burden and potentially resulting in poor compliance. Fludrocortisone has been beneficial in addressing tubulopathies in adult studies, with limited paediatric data available. A retrospective review of data from an electronic renal database from December 2014 to January 2016 was carried out. Forty-seven post-transplant patients were reviewed with 23 (49%) patients on sodium chloride or bicarbonate. Nine patients, aged 8.3 years (range 4.9-16.4), commenced fludrocortisone 22 months (range 1-80) after transplant and were followed up for 9 months (range 2-20). All patients stopped sodium bicarbonate; all had a reduction or no increase in total daily doses of sodium chloride. Potassium levels were significantly lower on fludrocortisone, 5.2 vs 4.5 mmol/L, P = .04. No difference was noted in renal function (eGFR 77.8 vs 81.7 mL/min/1.73 m2 , P = .45) and no significant increase in systolic blood pressure (z-scores 0.99 vs 0.85, P = .92). No side effects secondary to treatment with fludrocortisone were reported. A significant proportion of renal transplant patients were on sodium supplementation and fludrocortisone reduced sodium supplementation without significant effects on renal function or blood pressure. Fludrocortisone appears to be safe and effective for tubulopathies in children post-transplantation.

Single Institute Experience With Methylphenidate and American Ginseng in Cancer-Related Fatigue.

BACKGROUND: Single therapy with methylphenidate or American ginseng contributes to the reduction in cancer-related fatigue (CRF) with different pharmacologic mechanisms and is relatively safe. However, the safety and efficacy of treating CRF with methylphenidate and AG combination therapy is unknown. AIM: The primary objective was to assess the clinical safety and the change in fatigue with numerical rating scale (NRS) on the Edmonton Symptom Assessment Scale (ESAS) after intervention with methylphenidate and AG combination therapy. METHODS: We reviewed the electronic medical records of 857 patients seen in our Palliative Medicine outpatient clinic between February 1, 2015, and December 31, 2015. Fatigue was assessed by NRS on ESAS. Toxicity was reviewed on clinician's documents. RESULTS: We identified 28 patients who were prescribed a combination of methylphenidate (10-40 mg/d) and AG (2000 mg/d). Ten patients did not comply with the combination therapy. Three patients had stage 2 adverse effects. Fifteen patients completed prescribed combination therapy per instructions. The mean time interval between pre- and postintervention follow-up was 30.5 days (standard deviation [SD]: 7.78). There was a significant reduction in the fatigue score (mean score 6.93-4.13) from the pre- to postscore records (mean: -2.8; SD: 1.61; P < .0002* [*refers to statistically significant]). Sixty percent of patients reported significant reduction in fatigue (cutoff value: ≥3; reduction in fatigue score from baseline: 80% ≥2, 60% ≥3, and 46.7% ≥4). CONCLUSION: In our retrospective medical record review, the combination treatment of methylphenidate and AG had no discernible associated toxicities and showed potential clinical benefit in CRF.

Cycled enteral antibiotics reduce sepsis rates in paediatric patients on long-term parenteral nutrition for intestinal failure.

BACKGROUND: Long-term parenteral nutrition has transformed the prognosis for children suffering from intestinal failure. However, parenteral nutrition itself is associated with considerable morbidity and mortality including that caused by sepsis. AIM: To examine a strategy of cycled enteral antibiotics in reducing the incidence of sepsis in paediatric intestinal failure patients. METHODS: Retrospective analysis of the incidence of sepsis rates of patients on long-term parenteral nutrition, at a tertiary paediatric hospital. Patients were separated into those who received cycled enteral antibiotics and a control group. Sepsis rates before and during cycled enteral antibiotics were compared with comparable timeframes between the cycled enteral antibiotics and control groups. Central venous catheter removal rates were also compared. RESULTS: Fifteen patients (eight cycled enteral antibiotics, & seven controls) received 9512 parenteral nutrition days, with a total of 132 sepsis episodes. All eight patients of the treatment group demonstrated a decrease in the frequency of episodes of sepsis following the introduction of cycled enteral antibiotics. The cycled enteral antibiotics group had a significant reduction in infection rate during the treatment period (from 2.14 to 1.06 per 100 parenteral nutrition days, P = 0.014: median effect size -1.04 CI 95%-1.93, -0.22), whereas the controls had no significant change (1.91 - 2.36 per 100 parenteral nutrition days P = 0.402: median effect size 0.92 CI 95%-1.96, 4.17). The central venous catheter survival rates increased in the cycled enteral antibiotics group from 0.44 central venous catheter removals per 100 parenteral nutrition days to 0.27 central venous catheter removals per 100 parenteral nutrition days, although this was not statistically significant. CONCLUSIONS: Cycled enteral antibiotics significantly reduced the rate of sepsis in a small group of paediatric intestinal failure patients. Larger well-designed prospective studies are warranted to further explore this finding.

Rosiglitazone and pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase.

The effects of rosiglitazone or pioglitazone (thiazolidinediones, TZDs) on estrogen production and aromatase activity in human ovarian cells were examined. Human granulosa cells were incubated in the tissue culture medium supplemented with androstenedione or testosterone, with or without insulin, TZDs, or type 1 17ß-hydroxysteroid-dehydrogenase (17ß-HSD) inhibitor. Estrogen concentrations in the conditioned medium, aromatase mRNA and protein expression in the cells and androgen substrate binding to aromatase were measured. With androstenedione as substrate, rosiglitazone or pioglitazone inhibited estrone production by up to 22% (p<0.012) while type 1 17ß-HSD inhibitor enhanced this effect of rosiglitazone or pioglitazone by 37% (p<0.001) and by 67% (p<0.001), respectively. With testosterone as substrate, rosiglitazone or pioglitazone inhibited estradiol production by 32% (p<0.001). With (3)H-testosterone as substrate, rosiglitazone or pioglitazone inhibited the (3)H-tritiated water release by the cultured cells by 45% and 35%, respectively, thus directly demonstrating inhibition of aromatase. Rosiglitazone or pioglitazone, however, had no significant effect on aromatase mRNA or protein expression. Rosiglitazone or pioglitazone inhibited (125)I-androstenedione and (125)I-testosterone binding to aromatase by 38% (p<0.001). It was concluded that rosiglitazone or pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase.

Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells.

Vitamin D Receptor (VDR) is expressed in both animal and human ovarian tissue, however, the role of vitamin D in human ovarian steroidogenesis is unknown. Cultured human ovarian cells were incubated in tissue culture medium supplemented with appropriate substrates, with or without 50 pM-150 pM or 50 nM-150 nM of 1,25-(OH)2D3, and in the presence or absence of insulin. Progesterone, testosterone, estrone, estradiol, and IGFBP-1 concentrations in conditioned tissue culture medium were measured. Vitamin D receptor was present in human ovarian cells. 1,25-(OH)2D3 stimulated progesterone production by 13% (p<0.001), estradiol production by 9% (p<0.02), and estrone production by 21% (p<0.002). Insulin and 1,25-(OH)2D3 acted synergistically to increase estradiol production by 60% (p<0.005). 1,25-(OH)2D3 alone stimulated IGFBP-1 production by 24% (p<0.001), however, in the presence of insulin, 1,25-(OH)2D3 enhanced insulin-induced inhibition of IGFBP-1 production by 13% (p<0.009). Vitamin D stimulates ovarian steroidogenesis and IGFBP-1 production in human ovarian cells likely acting via vitamin D receptor. Insulin and vitamin D synergistically stimulate estradiol production. Vitamin D also enhances inhibitory effect of insulin on IGFBP-1 production.

Neuroimaging of meditation's effect on brain reactivity to pain.

Some meditation techniques reduce pain, but there have been no studies on how meditation affects the brain's response to pain. Functional magnetic resonance imaging of the response to thermally induced pain applied outside the meditation period found that long-term practitioners of the Transcendental Meditation technique showed 40-50% fewer voxels responding to pain in the thalamus and total brain than in healthy matched controls interested in learning the technique. After the controls learned the technique and practiced it for 5 months, their response decreased by 40-50% in the thalamus, prefrontal cortex, total brain, and marginally in the anterior cingulate cortex. The results suggest that the Transcendental Meditation technique longitudinally reduces the affective/motivational dimension of the brain's response to pain.

An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of managing critically ill patients in adult, general intensive care with or without pulmonary artery catheters (PACs). DESIGN: An open, multi-centre, randomised controlled trial with economic evaluation (cost-utility and cost-effectiveness analysis). SETTING: The setting was general (mixed medical/surgical) intensive care units (ICUs) in the UK admitting adults. PARTICIPANTS: Adult patients in participating ICUs deemed by the responsible treating clinician to require management with a PAC. INTERVENTIONS: These were insertion of a PAC and subsequent clinical management, at the discretion of the responsible treating clinicians, using data derived from the PAC. The control group were managed without a PAC but with the option of using alternative cardiac output monitoring devices. MAIN OUTCOME MEASURES: The main outcome measure was hospital mortality. Secondary outcome measures were length of stay in the ICU, length of stay in an acute hospital and organ-days of support in the ICU. For the economic evaluation, the main outcome measure was quality-adjusted life-years (QALYs) and the secondary outcome measure was hospital mortality. RESULTS: Sixty-five ICUs in the UK participated. Of these, 43 (66%) used alternative cardiac output monitoring devices in control group patients. A total of 1263 patients were identified as being eligible for the trial. Of these, 1041 (82.4%) were randomised and allocated to management with (n = 519) or without (n = 522) a PAC. There were no losses to follow-up. However, 27 patients (13 in the PAC group and 14 in the control group) were withdrawn from the trial because either the patient withdrew consent on recovering mental competency or the relatives withdrew agreement following randomisation. Data on 1014 patients were included in the analysis. Participants in the two groups had similar baseline characteristics. There was no difference in hospital mortality for patients managed with (68.4%) or without (65.7%) a PAC. The adjusted hazard ratio (PAC versus no PAC) was 1.09 [95% confidence interval (CI) 0.94 to 1.27]. There was no difference in the median length of stay in ICU, the median length of stay in an acute hospital or mean organ-days of support in ICU between the two groups. The economic evaluation found that the expected cost per QALY gained from the withdrawal of PAC was 2985 pounds. The expected cost per life gained from the withdrawal of PAC was 22,038 pounds. CONCLUSIONS: Clinical management of critically ill patients with a PAC, as currently practised in the UK, neither improves hospital survival for adult, general intensive care patients nor reduces length of stay in hospital. The lack of demonstrable benefit from a device previously believed to be beneficial could be explained by statistical chance, by misinterpretation of PAC-derived data, by ineffective treatment strategies based on data correctly interpreted using the current paradigm or by subsequent inaction following insertion of the device. It is also possible that detailed data on haemodynamics, however used, cannot modify the disease process sufficiently to influence disease outcome. The economic evaluation, using decision analysis techniques rather than conventional hypothesis testing, suggests that the withdrawal of the PAC from routine clinical practice in the NHS would be considered cost-effective in the current decision-making climate, and might result in lives or life-years being saved at modest cost. With the declining use of PACs in the UK and the findings of this report indicating no overall benefit from management with a PAC, it should now be possible to examine protocolised management with a PAC in selected groups of critically ill patients against appropriate controls, something that was difficult while PACs were the considered standard of care.

Individual and area factors associated with general practitioner integration in Australia: a multilevel analysis.

The further integration of primary care within the wider health system is an imperative for reform in all countries. The aim of this paper is to determine the factors associated with general practitioner (GP) integration using the GP Integration Index which has been recently developed and is demonstrating good reliability. The analysis is based on a database derived from an Australia-wide mail questionnaire survey of 1874 GPs drawn from a 20% stratified random sample of 123 Divisions of General Practice (47.8% adjusted response rate). The GP Integration Index measures the level of GPs' integration with the health care system based upon a description of their own behaviour. It consists of nine GP integration factors, and their two associated higher-order factors-Primary Care Management (PCM) and Community Health Role (CHR)-as well as five GP integration enabling factors. A multivariate multilevel analysis was undertaken. An explanatory model for both PCM and CHR was tested based on the GP integration factors as well as general practice, GP and regional characteristics. CHR and PCM were most strongly associated with GP integration enabling factors (mainly at the individual-level) and, for CHR only, with urban-rural location (mainly at the area-level). The most important single explanatory variable for both PCM and CHR was the GP integration enabling factor, "Knowledge of local resources." The important explanatory variables were those reflecting the way GPs work, rather than their broad 'classification' within individual or GP-setting groupings. Based on these results, some revision to the proposed model was necessary. We conclude that processes of care factors (as compared to structure of care factors) are more important in relation to GP integration than previously recognised. Future policy initiatives to promote GP integration should focus on programs to improve GP's knowledge of local resources.

Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone.

BACKGROUND AND AIMS: Clinical adrenal insufficiency has been reported with doses of inhaled fluticasone proprionate (FP) > 400 microg/day, the maximum dose licensed for use in children with asthma. Following two cases of serious adrenal insufficiency (one fatal) attributed to FP, adrenal function was evaluated in children receiving FP outwith the licensed dose. METHODS: Children recorded as prescribed FP > or = 500 microg/day were invited to attend for assessment. Adrenal function was measured using the low dose Synacthen test (500 ng/1.73 m2 intravenously) and was categorised as: biochemically normal (peak cortisol response > 500 nmol/l); impaired (peak cortisol < or = 500 nmol/l); or flat (peak cortisol < or = 500 nmol/l with increment of < 200 nmol/l and basal morning cortisol < 200 nmol/l). RESULTS: A total of 422 children had been receiving FP alone or in combination with salmeterol; 202 were not investigated (137 FP within license; 24 FP discontinued); 220 attended and 217 (age 2.6-19.3 years) were successfully tested. Of 194 receiving FP > or = 500 microg/day, six had flat responses, 82 impaired responses, 104 were normal, and in 2 the LDST was unsuccessful. Apart from the index child, the other five with flat responses were asymptomatic; a further child with impairment (peak cortisol 296 nmol/l) had encephalopathic symptoms with borderline hypoglycaemia during an intercurrent illness. The six with flat responses and the symptomatic child were all receiving FP doses of > or = 1000 microg/day. CONCLUSION: Overall, flat adrenal responses in association with FP occurred in 2.8% of children tested, all receiving > or = 1000 microg/day, while impaired responses were seen in 39.6%. Children on above licence FP doses should have adrenal function monitoring as well as a written plan for emergency steroid replacement.

Tetrahydrobenzothiophene inhibitors of hepatitis C virus NS5B polymerase.

A novel series of selective HCV NS5B RNA dependent RNA polymerase inhibitors has been disclosed. These compounds contain an appropriately substituted tetrahydrobenzothiophene scaffold. This communication will detail the SAR and activities of this series.

BMS-201620: a selective beta 3 agonist.

A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human beta3 adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent beta3 full agonist (Ki = 93 nM, 93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.

Angiogenesis and antiangiogenic therapy of colon cancer liver metastasis.

The fact that tumor growth and metastatic spread relies on angiogenesis has been widely proven and accepted. The understanding of cancer biology and metastasis formation has led to the development of new therapeutic approaches that target tumor biology. The survival and establishment of metastatic lesions depend on a shift in the normal balance of proangiogenic and antiangiogenic factors that favor angiogenesis. Colorectal cancer is one of the leading cancer deaths worldwide. Angiogenesis has been associated with colon cancer progression and metastatic spread, thereby significantly affecting patient survival. New experimental approaches that inhibit angiogenic processes have demonstrated promising antineoplastic effects on metastatic colorectal cancer and are partially being investigated in clinical trials. This review focuses on angiogenesis in colorectal cancer metastasis formation as a target for antiangiogenic therapy, describing the experience from experimental studies and current clinical trials.

Construction of a GP integration model.

There are frequent calls to improve integration of health services, within and between primary and secondary care sectors. In Australia, general medical practitioners (GPs) are central to these endeavours. This paper aims to better conceptualise GP integration and to develop a model and index based on this. A conceptualisation of integration is proposed based on integration fundamentally as an activity or process not structure. Integration process is the frequency and quality of episodes of information exchange involving the GP and another practitioner or patient and aimed at fulfilling the objectives of the health care system with regard to patient care. These are both direct responses to structural forces and emergent GP capacities and dispositions. The content of this typology was studied using Concept Mapping in 11 groups of GPs, consumers and other practitioners. Clusters of related statements within thematic domains were used as the basis for a provisional model. This was tested using confirmatory factor analysis in a data set derived from a national probability sample of 501 GPs. Some re-specification of the model was necessary, with three integration process factors needing to be subdivided. One factor congeneric model assumptions were used to identify the constituent items for these factors. The result was a model in which 50 items measured nine integration process factors and 20 items measured five enabling factors. Two distinct but correlated higher order factors, relating to individual patient care and public (or community) health--in contrast to a single higher order factor for integration--were identified. The re-specified model was tested with a new sample of 151 GPs and exhibited strong psychometric properties. Reliability and validity were acceptable to this stage of the indices' development. Further testing of the index is necessary to demonstrate factor invariance of the indices in other contexts as well as their utility in cross-structural analysis. That said, the indices have immediate uses.

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

BMS-196085: a potent and selective full agonist of the human beta(3) adrenergic receptor.

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

Evaluating the quality of clinical practice guidelines.

OBJECTIVE: To review and identify established methods for evaluating the quality of practice guidelines and to use a selected assessment tool to assess 2 chiropractic practice guideline documents. METHODS: A search of the medical literature was performed to identify current methods and procedures for practice guideline evaluation. Two chiropractic practice guideline documents, Vertebral Subluxation in Chiropractic Practice (CCP) and Guidelines for Chiropractic Quality Assurance and Practice Parameters (Mercy) were then independently evaluated for validity by 10 appraisers using the identified appraisal tool. The appraisal scores were tabulated, and consensus appraisals were generated for the CCP and Mercy guideline documents. RESULTS: The "Appraisal Instrument for Clinical Guidelines" (Cluzeau instrument) was identified as a reliable and valid method of guideline evaluation. The result of the application of this appraisal tool in the assessment of the CCP and Mercy guideline documents was that the former scored notably lower than the latter. On the basis of the results of the guideline appraisals, the CCP document is not recommended, and its guidelines are not considered suitable for application in chiropractic practice. The Mercy guidelines are recommended for application in chiropractic practice, with the proviso that new scientific data should be considered. CONCLUSIONS: The literature reviewed suggests that professional organizations or groups should undertake a critical review of guidelines using available critical guideline appraisal tools. Guideline validity appraisal should be done before acceptance by the chiropractic profession. To avoid unwarranted utilization of poorly constructed guidelines, it is strongly recommended that all future guidelines be reviewed for validity and scientific accuracy with the findings published in a medically indexed journal before they are adopted by the chiropractic community.

Integration from the Australian GP's perspective.

OBJECTIVE: To report on what general practitioners' perceptions are about their role in relation to activities that support integration and what they are doing. METHOD: General practitioner perceived integrative behaviour was measured using a survey containing 114 statements about, 'what constitutes a well integrated GP'. Four hundred and forty-eight GPs were randomly sampled from the Health Insurance Commission (HIC) Medicare billing database in 1996. A response rate of 47% was obtained, yielding 208 surveys for analysis. RESULTS: General practitioners reported integrative activities such as being accessible to patients and working within a multidisciplinary team as currently occurring optimally. Not occurring optimally were: hospital and community involvement; participation in local projects; student education; and payment for working with others. Rural practitioners reported significantly more hospital and community involvement compared with metropolitan practitioners. Less than one-third of GPs reported that they were linked to other services by computer and used a computer for storage/communication of patient information. DISCUSSION: There are many obstacles preventing integrative activities in daily general practice. Policy and attitudinal changes as well as financial incentives are required to enable GPs to practise in an integrated manner. Infrastructure support to encourage GP education, training and information technology are essential to improve GP integration. Many such initiatives are currently in progress, and will require future evaluation. Findings from this 1996 survey will provide some useful baseline information assisting with future evaluation studies.