Corticosteroids for the management of cancer-related fatigue in adults with advanced cancer.

BACKGROUND: Fatigue is the most commonly reported symptom in people with advanced cancer. Cancer-related fatigue (CRF) is pervasive and debilitating, and can greatly impact quality of life (QoL). CRF has a highly variable clinical presentation, likely due to a complex interaction of multiple factors. Corticosteroids are commonly used to improve CRF, but the benefits are unclear and there are significant adverse effects associated with long-term use. With the increasing survival of people with metastatic cancer, the long-term effects of medications are becoming increasingly relevant. Since the impact of CRF can be immensely debilitating and can negatively affect QoL, its treatment warrants further review. OBJECTIVES: To determine the benefits and harms of corticosteroids compared with placebo or an active comparator in adults with advanced cancer and CRF. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, Science Citation Index (ISI Web of Science), LILACS, and two clinical trial registries from inception to 18 July 2022.  SELECTION CRITERIA: We included randomised controlled trials in adults aged ≥18 years. We included participants with advanced cancer who were suffering from CRF. We included trials that randomised participants to corticosteroids at any dose, by any route, administered for the relief of CRF; compared to placebo or an active comparator, including supportive care or non-pharmacological treatments. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed titles identified by the search strategy; two review authors assessed risk of bias; and two extracted data. We extracted the primary outcome of participant-reported fatigue relief using validated scales and secondary outcomes of adverse events, serious adverse events and QoL. We calculated the risk ratio with 95% confidence intervals (CIs) between groups for dichotomous outcomes. We measured arithmetic mean and standard deviation, and reported the mean difference (MD) with 95% CI between groups for continuous outcomes. We used standardised mean difference (SMD) with 95% CIs when an outcome was measured with different instruments measuring the same construct. We used a random-effects model to meta-analyse the outcome data. We rated the certainty of the evidence using GRADE and created two summary of findings tables.  MAIN RESULTS: We included four studies with 297 enroled participants; data were available for only 239 participants. Three studies compared corticosteroid (equivalent ≤ 8 mg dexamethasone) to placebo. One study compared corticosteroid (dexamethasone 4 mg) to an active comparator (modafinil 100 mg). There were insufficient data to evaluate subgroups, such as dose and duration of treatment. One study had a high risk of performance and detection bias due to lack of blinding, and one study had a high risk of attrition bias. Otherwise, we assessed risks of bias as low or unclear. Comparison 1: corticosteroids compared with placebo Participant-reported fatigue relief The was no clear difference between corticosteroids and placebo (SMD -0.46, 95% CI -1.07 to 0.14; 3 RCTs, 165 participants, very low-certainty evidence) for relief of fatigue at one week of the intervention. We downgraded the certainty of the evidence three times for study limitations due to unclear risk of bias, imprecision, and inconsistency. Adverse events There was no clear difference in the occurrence of adverse events between groups, but the evidence is very uncertain (3 RCTs, 165 participants; very low-certainty evidence). Serious adverse events There was no clear difference in the occurrence of serious adverse events between groups, but the evidence is very uncertain (2 RCTs, 118 participants; very low-certainty evidence). Quality of lIfe One study reported QoL at one week using the Edmonton Symptom Assessment System (ESAS) well-being, and found no clear difference in QoL between groups (MD -0.58, 95% CI -1.93 to 0.77). Another study measured QoL using the Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs (QoL-ACD), and found no clear difference between groups. There was no clear difference between groups for either study, but the evidence is very uncertain (2 RCTs, 118 participants; very low-certainty evidence).  Comparison 2: corticosteroids compared with active comparator (modafinil) Participant-reported fatigue relief There was improvement in fatigue from baseline to two weeks in both groups (modafinil MD 10.15, 95% CI 7.43 to 12.87; dexamethasone MD 9.21, 95% CI 6.73 to 11.69), however no clear difference between the two groups (MD -0.94, 95% CI -4.49 to 2.61; 1 RCT, 73 participants, very low-certainty evidence). We downgraded the certainty of the evidence three times for very serious study limitations and imprecision. Adverse events There was no clear difference in the occurrence of adverse events between groups, but the evidence is very uncertain (1 RCT, 73 participants; very low-certainty evidence).  Serious adverse events There were no serious adverse events reported in either group (1 RCT, 73 participants; very low-certainty evidence).  Quality of lIfe One study measured QoL at two weeks, using the ESAS-well-being. There was marked improvement in QoL from baseline in both groups (modafinil MD -2.43, 95% CI -2.88 to -1.98; dexamethasone MD -2.16, 95% CI -2.68 to -1.64), however no clear difference between the two groups (MD 0.27, 95% CI -0.39 to 0.93; 1 RCT, 73 participants, very low-certainty evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of systemic corticosteroids in adults with cancer and CRF. We included four small studies that provided very low-certainty of evidence for the efficacy of corticosteroids in the management of CRF. Further high-quality randomised controlled trials with larger sample sizes are required to determine the effectiveness of corticosteroids in this setting.

Systemic corticosteroids for the management of cancer-related breathlessness (dyspnoea) in adults.

BACKGROUND: Dyspnoea is a common symptom in advanced cancer, with a prevalence of up to 70% among patients at end of life. The cause of dyspnoea is often multifactorial, and may cause considerable psychological distress and suffering. Dyspnoea is often undertreated and good symptom control is less frequently achieved in people with dyspnoea than in people with other symptoms of advanced cancer, such as pain and nausea. The exact mechanism of action of corticosteroids in managing dyspnoea is unclear, yet corticosteroids are commonly used in palliative care for a variety of non-specific indications, including pain, nausea, anorexia, fatigue and low mood, despite being associated with a wide range of adverse effects. In view of their widespread use, it is important to seek evidence of the effects of corticosteroids for the management of cancer-related dyspnoea. OBJECTIVES: To assess the effects of systemic corticosteroids for the management of cancer-related breathlessness (dyspnoea) in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, Science Citation Index Web of Science, Latin America and Caribbean Health Sciences (LILACS) and clinical trial registries, from inception to 25 January 2018. SELECTION CRITERIA: We included randomised controlled trials that included adults aged 18 years and above. We included participants with cancer-related dyspnoea when randomised to systemic corticosteroids (at any dose) administered for the relief of cancer-related dyspnoea or any other indication, compared to placebo, standard or alternative treatment. DATA COLLECTION AND ANALYSIS: Five review authors independently assessed trial quality and three extracted data. We used means and standard deviations for each outcome to report the mean difference (MD) with 95% confidence interval (CI). We assessed the risk of bias and quality of evidence using GRADE. We extracted primary outcomes of sensory-perceptual experience of dyspnoea (intensity of dyspnoea), affective distress (quality of dyspnoea) and symptom impact (burden of dyspnoea or impact on function) and secondary outcomes of serious adverse events, participant satisfaction with treatment and participant withdrawal from trial. MAIN RESULTS: Two studies met the inclusion criteria, enrolling 157 participants (37 participants in one study and 120 in the other study), of whom 114 were included in the analyses. The studies compared oral dexamethasone to placebo, followed by an open-label phase in one study. One study lasted seven days, and the duration of the other study was 15 days.We were unable to conduct many of our predetermined analyses due to different agents, dosages, comparators and outcome measures, routes of drug delivery, measurement scales and time points. Subgroup analysis according to type of cancer was not possible.Primary outcomesWe included two studies (114 participants) with data at one week in the meta-analysis for change in dyspnoea intensity/dyspnoea relief from baseline. Corticosteroid therapy with dexamethasone resulted in an MD of lower dyspnoea intensity compared to placebo at one week (MD -0.85 lower dyspnoea (scale 0-10; lower score = less breathlessness), 95% CI -1.73 to 0.03; very low-quality evidence), although we were uncertain as to whether corticosteroids had an important effect on dyspnoea as results were imprecise. We downgraded the quality of evidence by three levels from high to very low due to very serious study limitations and imprecision.One study measured affective distress (quality of dyspnoea) and results were similar between groups (29 participants; very low-quality evidence). We downgraded the quality of the evidence three times for imprecision, inconsistency, and serious study limitations.Both studies assessed symptom impact (burden of dyspnoea or impact on function) (113 participants; very low-quality evidence). In one study, it was unclear whether dexamethasone had an effect on dyspnoea as results were imprecise. The second study showed more improvement for physical well-being scores at days eight and 15 in the dexamethasone group compared with the control group, but there was no evidence of a difference for FACIT social/family, emotional or functional scales. We downgraded the quality of the evidence three times for imprecision, inconsistency, and serious study limitations.Secondary outcomesDue to the lack of homogenous outcome measures and inconsistency in reporting, we could not perform quantitative analysis for any secondary outcomes. In both studies, the frequency of adverse events was similar between groups, and corticosteroids were generally well tolerated. The withdrawal rates for the two studies were 15% and 36%. Reasons for withdrawal included lost to follow-up, participant or carer (or both) refusal, and death due to disease progression. We downgraded the quality of evidence for these secondary outcomes by three levels from high to very low due to serious study limitations, inconsistency and imprecision.Neither study examined participant satisfaction with treatment. AUTHORS' CONCLUSIONS: There are few studies assessing the effects of systemic corticosteroids on cancer-related dyspnoea in adults with cancer. We judged the evidence to be of very low quality that neither supported nor refuted corticosteroid use in this population. Further high-quality studies are needed to determine if corticosteroids are efficacious in this setting.

Castrate-resistant prostate cancer: lessons learnt from a pilot study in the palliative care research population.

BACKGROUND: Palliative care patients are inherently difficult to recruit to and retain on studies. Even when patients are recruited, it is hard to complete studies with sufficient data. There is a dearth of literature specific to men with castrate resistant prostate cancer (CRPC) and the clinical trials coordinator/research nurse's perspective in improving trial outcomes in palliative care. Objectives To describe the lessons learnt (by the nursing research team) from a prospective cohort study of men with CRPC and the practical implications for future research in this area. METHODS: A pilot feasibility cohort study that followed patients with CRPC from referral until death. The participants completed questionnaires while the researcher documented treatments, disease status and symptom burden. The recruitment methods, data quality and results were analysed. RESULTS AND DISCUSSION: Several lessons have been learnt with regard to facilitating trial recruitment and design. These lessons are: the importance of building relationships with local urology teams, including all men with the diagnosis of CRPC as documented by a medical oncologist or urologist, reducing questionnaire burden, capturing symptom scores in clinic, actively following up patients by phone, and recording all reasons for drop-out or lost to follow-up. These lessons can now be implemented to improve future studies involving this demographic.

Corticosteroids for adult patients with advanced cancer who have nausea and vomiting (not related to chemotherapy, radiotherapy, or surgery).

BACKGROUND: Nausea is a common symptom in advanced cancer, with a prevalence of up to 70%. While nausea and vomiting can be related to cancer treatments, such as chemotherapy, radiotherapy, or surgery, a significant number of people with advanced cancer also suffer from nausea unrelated to such therapies. Nausea and vomiting may also cause psychological distress, and have a negative impact on the quality of life of cancer patients; similarly to pain, nausea is often under-treated. The exact mechanism of action of corticosteroids on nausea is unclear, however, they are used to manage a number of cancer-specific complications, including spinal cord compression, raised intracranial pressure, and lymphangitis carcinomatosis. They are also commonly used in palliative care for a wide variety of non-specific indications, such as pain, nausea, anorexia, fatigue, and low mood. However, there is little objective evidence of their efficacy in symptom control, and corticosteroids have a wide range of adverse effects that are dose and time dependent. In view of their widespread use, it is important to seek evidence of their effects on nausea and vomiting not related to cancer treatment. OBJECTIVES: To assess the effects of corticosteroids on nausea and vomiting not related to chemotherapy, radiotherapy, or surgery in adult cancer patients. SEARCH METHODS: We searched CENTRAL, MEDLINE Ovid, Embase Ovid, CINAHL EBSCO, Science Citation Index Web of Science, Latin America and Caribbean Health Sciences (LILACS), Conference Proceedings Citation Index - Science Web of Science, and clinical trial registries, from inception to 23rd August 2016. SELECTION CRITERIA: Any double-blind randomised or prospective controlled trial that included adults aged 18 years and over with advanced cancer with nausea and vomiting not related to chemotherapy, radiotherapy, or surgery were eligible for the review, when using corticosteroids as antiemetic treatment. DATA COLLECTION AND ANALYSIS: All review authors independently assessed trial quality and extracted data. We used arithmetic means and standard deviations for each outcome to report the mean difference (MD) with 95% confidence interval (CI). We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Three studies met the inclusion criteria, enrolling 451 participants. The trial size varied from 51 to 280 participants. Two studies compared dexamethasone to placebo, and the third study compared a number of additional interventions in various combinations, including metoclopramide, chlorpromazine, tropisetron, and dexamethasone. The duration of the studies ranged from seven to 14 days. We included two studies (127 participants) with data at eight days in the meta-analysis for nausea intensity; no data were available that incorporated the same outcome measures for the third study. Corticosteroid therapy with dexamethasone resulted in less nausea (measured on a scale of 0 to 10, with a lower score indicating less nausea) compared to placebo at eight days (MD 0.48 lower nausea, 95% CI 1.53 lower to 0.57 higher; very low-quality evidence), although this result was not statistically significant (P = 0.37). Frequency of adverse events was not significantly different between groups, and the interventions were well tolerated. Factors limiting statistical analysis included the lack of standardised measurements of nausea, and the use of different agents, dosages, and comparisons. Subgroup analysis according to type of cancer was not possible due to insufficient data. The quality of this evidence was downgraded by three levels, from high to very low due to imprecision, likely selection bias, attrition bias, and the small number of participants in the included studies. AUTHORS' CONCLUSIONS: There are few studies assessing the effects of corticosteroids on nausea and vomiting not related to chemotherapy, radiotherapy, or surgery in adult cancer patients. This review found very low-quality evidence which neither supported nor refuted corticosteroid use in this setting. Further high quality studies are needed to determine if corticosteroids are efficacious in this setting.

Opioid addiction and misuse in adult and adolescent patients with cancer.

In the context of a therapeutic opioid epidemic, particularly in the USA, where increasingly stringent screening for 'at risk' individuals and close monitoring of opioid prescription and use is strongly recommended, the issue of misuse within the cancer population must be addressed. Most patients with advanced cancer will have pain requiring opioid therapy at some stage during their disease course. In the majority, this will provide good pain relief with no short- or longer-term adverse sequelae. A subset will present with substance misuse issues that will influence management and prescribing practice. The potential ethical issues of limiting effective analgesia on the basis of addiction risk or history must be acknowledged. Both a judgemental or 'relaxed' approach to such patients is problematic. Ignoring the situation will not be in the patient's best interest, but an undue focus on this aspect may damage therapeutic relationships with clinicians and adversely affect a holistic approach to care. Clinical practitioners must be aware of the risk factors for opioid misuse and in patients who are not under palliative care consider screening prior to commencing opioids. Clinicians must be able to manage and monitor those identified as having an opioid misuse problem.

CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects.

AIMS: Ketamine analgesia is limited by low intrinsic efficacy compounded by large interindividual variability in drug responses, possibly due to the heterogeneity in drug concentration. The CYP2B6*6 allele is associated with substantially reduced ketamine metabolism in vitro and, therefore, may affect ketamine clearance. Our aims were to examine the impact of the CYP2B6*6 allele on ketamine plasma clearance and on adverse effects in chronic pain patients. METHODS: CYP2B6 genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine (Css,k ) and norketamine (Css,nk ) were determined using HPLC. RESULTS: The median plasma clearance of ketamine after 100 mg 24 h(-1) dose was significantly lower in patients with the CYP2B6*6/*6 (21.6 l h(-1) ) and CYP2B6*1/*6 (40.6 l h(-1) ) genotypes compared with patients with the CYP2B6*1/*1 genotype (68.1 l h(-1) , P < 0.001). The ketamine : norketamine plasma metabolic ratio was significantly higher in patients with the CYP2B6*6/*6 genotype than in those with the CYP2B6*1/*6 and the CYP2B6*1/*1 genotypes (P < 0.001). Patients who experienced adverse effects had lower plasma clearance (45.6 l h(-1) ) than those who did not (52.6 l h(-1) , P = 0.04). The CYP2B6*6 genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in Css,k , respectively. Similar results were observed after higher doses. CONCLUSIONS: The CYP2B6*6 allele is associated with a substantial decrease in steady-state ketamine plasma clearance in chronic pain patients. The decreased clearance and resultant higher plasma concentrations may be associated with a higher incidence of ketamine adverse effects.

Beginning and duration of pregnancy in automated health care databases: review of estimation methods and validation results.

PURPOSE: To describe methods reported in the literature to estimate the beginning or duration of pregnancy in automated health care data, and to present results of validation exercises where available. METHODS: Papers reporting methods for determining the beginning or duration of pregnancy were identified based on Pubmed searches, by consulting investigators with expertise in the field and by reviewing conference abstracts and reference lists of relevant papers. From each paper or abstract, we extracted information to characterize the study population, data sources, and estimation algorithm. We then grouped these studies into categories reflecting their general methodological approach. RESULTS: Methods were classified into 5 categories: (i) methods that assign a uniform duration for all pregnancies, (ii) methods that assign pregnancy duration based on preterm-delivery or health care related codes, or codes for other pregnancy outcomes, (iii) methods based on the timing of prenatal care, (iv) methods based on birth weight, and (v) methods that combine elements from 2 and 3. Validation studies evaluating these methods used varied approaches, with results generally reporting on the mistiming of the start of pregnancy, incorrect estimation of the duration of pregnancy, or misclassification of drug exposure during pregnancy or early pregnancy. CONCLUSIONS: In the absence of accurate information on the beginning or duration of pregnancy, several methods of varying complexity are available to estimate them. Validation studies have been performed for many of them and can serve as a guide for method selection for a particular study.

Corticosteroids for the management of cancer-related pain in adults.

BACKGROUND: One of the most feared symptoms associated with cancer is pain. Opioids remain the mainstay of pain treatment but corticosteroids are often used concurrently as co- or adjuvant analgesics. Due to their anti-inflammatory mechanism of action, corticosteroids are said to provide effective analgesia for pain associated with inflammation and in the management of cancer-related complications such as brain metastasis and spinal cord compression. However, corticosteroids have a wide range of adverse effects that are dose and time dependent. OBJECTIVES: To evaluate the efficacy of corticosteroids in treating cancer-related pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4), MEDLINE (OVID) (1966 to 29 September 2014), EMBASE (OVID) (1970 to 29 September 2014), CINAHL (1982 to 29 September 2014), Science Citation Index (Web of Science) (1899 to 29 September 2014) and Conference Proceedings Citation Index - Science (Web of Science) (1990 to 29 September 2014). SELECTION CRITERIA: Any randomised or prospective controlled trial that included patients over 18 years with cancer-related pain were eligible for the review. Corticosteroids were compared to placebo or usual treatment and/or supportive care. DATA COLLECTION AND ANALYSIS: All review authors independently assessed trial quality and extracted data. We used arithmetic means and standard deviations for each outcome to report the mean difference (MD) with 95% confidence interval (CI). MAIN RESULTS: Fifteen studies met the inclusion criteria, enrolling 1926 participants. The trial size varied from 20 to 598 patients. Most studies compared corticosteroids, particularly dexamethasone, to standard therapy. We included six studies with data at one week in the meta-analysis for pain intensity; no data were available at that time point for the remaining studies. Corticosteroid therapy resulted in less pain (measured on a scale of 0 to 10 with a lower score indicating less pain) compared to control at one week (MD 0.84 lower pain, 95% CI 1.38 to 0.30 lower; low quality evidence). Adverse events were poorly documented. Factors limiting statistical analysis included the lack of standardised measurements of pain and the use of different agents, dosages, comparisons and routes of drug delivery. Subgroup analysis according to type of cancer was not possible. The quality of this evidence was limited by the risk of bias of the studies and small sample size. The results were also compromised by attrition, with data missing for the enrolled patients. AUTHORS' CONCLUSIONS: The evidence for the efficacy of corticosteroids for pain control in cancer patients is weak. Significant pain relief was noted in some studies, albeit only for a short period of time. This could be important for patients with poor clinical status. Further trials, with increased numbers of participants, are needed to evaluate the safety and effectiveness of corticosteroids for the management cancer pain in adults, and to establish an ideal dose, duration of therapy and route of administration.

Institute of medicine 2009 gestational weight gain guideline knowledge: survey of obstetrics/gynecology and family medicine residents of the United States.

BACKGROUND: In 2009, the Institute of Medicine revised gestational weight gain recommendations; revisions included body mass index (BMI) category cut-point changes and provision of range of gain for obese women. Our objective was to examine resident prenatal caregivers' knowledge of revised guidelines. METHODS: Anonymous electronic survey of obstetrics/gynecology and family medicine residents across the United States from January to April 2010. RESULTS: Overall, 660 completed the survey; 79 percent female and 69 percent aged between 21 and 30. When permitted to select ≥ 1 response, 87.0 percent reported using BMI to assess weight status at initial visits, 44.4 percent reported using "clinical impression based on patient appearance," and 1.4 percent reported not using any parameters. When asked the most important baseline parameter for providing recommendations, 35.8 percent correctly identified prepregnancy BMI, 2.1 percent reported "I don't provide guidelines," and 4.5 percent reported "I do not discuss gestational weight gain." Among respondents, 57.6 percent reported not being aware of new guidelines. Only 7.6 percent selected correct BMI ranges for each category, and only 5.8 percent selected correct gestational weight gain ranges. Only 2.3 percent correctly identified both BMI cutoffs and recommended gestational weight gain ranges per 2009 guidelines. CONCLUSIONS: Guideline knowledge is the foundation of accurate counseling, yet resident prenatal caregivers were minimally aware of the 2009 Institute of Medicine gestational weight gain guidelines almost a year after their publication.

Using aggregated single patient (N-of-1) trials to determine the effectiveness of psychostimulants to reduce fatigue in advanced cancer patients: a rationale and protocol.

BACKGROUND: It is estimated that 29% of deaths in Australia are caused by malignant disease each year and can be expected to increase with population ageing. In advanced cancer, the prevalence of fatigue is high at 70-90%, and can be related to the disease and/or the treatment. The negative impact of fatigue on function (physical, mental, social and spiritual) and quality of life is substantial for many palliative patients as well as their families/carers. METHOD/DESIGN: This paper describes the design of single patient trials (n-of-1 s or SPTs) of a psychostimulant, methylphenidate hydrochloride (MPH) (5 mg bd), compared to placebo as a treatment for fatigue, with a population estimate of the benefit by the aggregation of multiple SPTs. Forty patients who have advanced cancer will be enrolled through specialist palliative care services in Australia. Patients will complete up to 3 cycles of treatment. Each cycle is 6 days long and has 3 days treatment and 3 days placebo. The order of treatment and placebo is randomly allocated for each cycle. The primary outcome is a reduction in fatigue severity as measured by the Functional Assessment of Cancer Therapy-fatigue subscale (FACIT-F). Secondary outcomes include adverse events, quality of life, additional fatigue assessments, depression and Australian Karnovsky Performance Scale. DISCUSSION: This study will provide high-level evidence using a novel methodological approach about the effectiveness of psychostimulants for cancer-related fatigue. If effective, the findings will guide clinical practice in reducing this prevalent condition to improve function and quality of life. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609000794202.

Society for Birth Defects Research and Prevention 2022-2027 strategic plan.

BACKGROUND: The sixth Strategic Planning Session of the Society for Birth Defects Research and Prevention (BDRP) was held on April 24-25, 2022, in Alexandria, VA. METHODS: This effort built upon previous strategic planning sessions, conducted every 5 years. RESULTS: The overall process was designed to identify BDRP's vision, purpose, culture, and potential, as well as to communicate the value that BDRP brings to its members, volunteers, partners, and the greater community. CONCLUSIONS: The BDRP 2022-2027 Strategic Plan provides the BDRP leadership, members, and staff with a clearly articulated framework and direction to support long-term sustainability and growth of the society.

An Open-Label Pilot Study Testing the Feasibility of Assessing Total Symptom Burden in Trials of Cannabinoid Medications in Palliative Care.

Background: There is considerable interest in the use of cannabinoids for symptom control in palliative care, but there is little high-quality evidence to guide clinical practice. Objectives: Assess the feasibility of using global symptom burden measures to assess response to medicinal cannabis, to determine median tolerated doses of cannabidiol (CBD) and tetrahydrocannabinol (THC), and to document adverse events (AEs). Design: Prospective two-arm open-label pilot trial of escalating doses of CBD and THC oil. Setting/Subjects: Participants had advanced cancer and cancer-related symptoms in a palliative and supportive care service in an Australian cancer center. Measurements: The main outcome measures were the number of participants screened and randomized over the time frame, the number of participants completing days 14 and 28 and providing total symptom distress scores (TSDSs) (measured using the Edmonton Symptom Assessment Scale), and the change from baseline of the TSDS at day 14. Results: Of the 21 participants enrolled (CBD, n = 16; THC, n = 5), 18 (86%) completed the primary outcome measure at day 14 and 8 completed at day 28. The median maximum tolerated doses were CBD, 300 mg/day (range 100-600 mg); THC, 10 mg/day (range 5-30 mg). Nine of 21 patients (43%) met the definition of response (≥6 point reduction in TSDS). Drowsiness was the most common AE. Conclusions: Trials of medicinal cannabis in advanced cancer patients undergoing palliative care are feasible. The doses of THC and CBD used in this study were generally well tolerated and the outcome measure of total symptom distress is promising as a measure of overall symptom benefit. Trial registration: ACTRN12618001205224.

Prevalence of QTc Prolongation in Patients With Advanced Cancer Receiving Palliative Care-A Cause for Concern?

CONTEXT: Medications commonly used for symptom control along with other known risk factors have the potential to prolong ventricular repolarization as measured by the QT interval (the time from the start of the Q wave to the end of the T wave) on a standard electrocardiogram (ECG). OBJECTIVES: To document the prevalence of a prolonged QT interval corrected for heart rate (QTc) interval in the palliative/oncology setting, compare automatic ECG QTc measurements with manual readings and identify any correlation between QTc prolongation and the use of drugs or other risk factors. METHODS: A convenience sample of consecutive patients with cancer, admitted under or known to the palliative/supportive care teams in two metropolitan hospitals, and willing to provide an ECG recording and basic demographic information including QTc risk factors were included. Both automated and manually calculated QTc intervals were recorded. Multivariable analysis was used to determine risk factors independently associated with prolonged QTc intervals. RESULTS: Of the 389 participants, there was a significant difference in mean QTc between sites using automated but not manual calculations. Manual readings were therefore used with predetermined cutoffs of 0.44 seconds (males) and 0.46 seconds (females). Seventy-two (18.5%) of the participants had a prolonged QTc with six (1.5%) having a prolongation of >0.50 seconds. At-risk drugs were being taken by 218 participants (56.0% of total cohort). Factors shown to be associated with QTc prolongation included age, gender, performance status, and hypocalcemia. No specific medication was associated with increased risk. CONCLUSION: Although almost 20% of patients receiving palliative care had prolongation of QTc, the possibility of serious consequences appeared to be low despite the frequent occurrence of risk factors.

Long-term efficacy of the pubovaginal Mersilene mesh sling.

OBJECTIVE: The objective of the study was to determine the efficacy of the pubovaginal Mersilene mesh sling (PVMMS) for complicated urodynamic stress incontinence (USI). STUDY DESIGN: Between 1990 and 2008, patients with USI plus an at-risk diagnosis underwent a PVMMS by a single surgeon. They were followed up with urodynamics (UDE) and Pelvic Floor Distress Inventory-short form 20 (PFDI-20). Stratification was in an at-risk hierarchy: intrinsic sphincter deficiency (ISD) greater than recurrent USI (RUSI) greater than USI with chronically increased intraabdominal pressure (CI-IAP). A cough stress test determined objective cure. PFDI question 17 assessed subjective cure. RESULTS: Three hundred six patients with ISD (43.5%), RUSI (26.8%), and CI-IAP (29.7%) had objective cure rates of 89.2% in the short term, 86.7% in the intermediate term, and 91.2% in the long term. A group of 48 patients with both short- and long-term UDEs showed cures of 100% and 91.7%. Long-term objective cure rates were: ISD, 90.5% (n = 21); RUSI, 84.2%, (n = 19); CI-IAP, 100% (n = 17). The mean score of postoperative PFDI question 17 was 0.57 (n = 119). Mean symptom improvement was -2.98 (n = 52; P < .0001). CONCLUSION: We demonstrated PVMMS to be subjectively and objectively effective in long-term treatment of complicated forms of USI.

Risk of hospitalization for common neonatal morbidities in preterm and term infants: assessing the impact of one or more major congenital anomalies.

OBJECTIVE: To analyze the impact of ≥1 major congenital anomaly (CA) on risk and hospitalization for common neonatal morbidities. STUDY DESIGN: Retrospective infant cohort: 241,033 preterm and 3,446,156 term singletons in the US Premier Healthcare database (2006-2013) with up to 1-year follow-up. Discharge records were searched for ≥1 CA and neonatal morbidities. RESULTS: Five morbidities demonstrated strong increasing rates as GA decreased. RRs in preterm infants with CAs relative to those without CAs were: RDS (2.17, 95% CI 2.14-2.21), sepsis (2.42, 95% CI 2.37-2.46), apnea (2.04, 95% CI 2.01-2.07), infectious diseases (2.37, 95% CI 2.34-2.41), and hyperbilirubinemia (1.25, 95% CI 1.24-1.26). Median length of NICU stay (days) was consistently longer in infants with ≥1 CA relative to infants without CA during each GA period. CONCLUSIONS: Preterm infants with ≥1 major CA have increased risk of hospitalization for common morbidities, implying compromised neonatal health regardless of CA type.

Assessing feasibility of resources at health facilities in Uganda to diagnose pregnancy and neonatal outcomes.

BACKGROUND: Standardized case definitions for obstetric and neonatal outcomes were developed by the Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project. These definitions can facilitate comparable assessment of maternal immunization safety surveillance and research. This study assessed the capabilities of health centers (HC) in Uganda to implement these definitions in a low income country, which has not been explored. METHODS: Healthcare practitioners at 15 government-accredited health centers and one government-funded district hospital in the Iganga-Mayuge Health and Demographic Surveillance Site (IMHDSS) in Uganda were interviewed about the facility's clinical diagnostic and laboratory capabilities. Five obstetric and five neonatal case definitions were evaluated. Definitions with the highest diagnostic certainty were designated as level 1, while definitions that decreased in certainty were designated as level 2 or 4. HCs were evaluated on diagnostic and laboratory capabilities to apply the GAIA definitions. RESULTS: Higher-level facilities in the IMHDSS demonstrated the ability to diagnose more specific levels of the GAIA obstetric and neonatal outcomes than lower-level facilities. Furthermore, for the neonatal outcome assessment, there was an increased ability to diagnose outcomes moving from GAIA level 1 to level 3. CONCLUSIONS: The ability of health centers to implement globally standardized definitions is promising for implementation of standardized data collection methods for global vaccine safety surveillance and research.

Treatment of nausea and vomiting in terminally ill cancer patients.

Nausea and vomiting is a common and distressing symptom complex in patients with far-advanced cancer, affecting up to 60% of individuals at some stage of their illness. The current approach to the palliative care of patients with nausea and vomiting is based on identifying the cause, understanding its pathophysiology and knowing the pharmacology of the drugs available for its amelioration. The following six main syndromes are identified: gastric stasis, biochemical, raised intracranial pressure, vestibular, mechanical bowel obstruction and ileus. A careful history, focused physical examination and appropriate investigations are needed to elucidate the syndrome and its cause, so that therapy is rational. Drugs are the mainstay of treatment in terminal cancer, and the main classes of antiemetic agents are prokinetics, dopamine antagonists, antihistamines, anticholinergics and serotonin antagonists. Dexamethasone and octreotide are also used, especially in bowel obstruction. Non-drug measures are important in relieving the associated distress. Patients should be able to die comfortably, without tubes. Despite decades of practice affirming this approach, the evidence base is weak and well designed studies are urgently needed.