CALIPSO: A Randomized Controlled Trial of Calfactant for Acute Lung Injury in Pediatric Stem Cell and Oncology Patients

To assess if calfactant reduces mortality among children with leukemia/lymphoma or after hematopoietic cell transplantation (HCT) with pediatric acute respiratory distress syndrome (PARDS), we conducted a multicenter, randomized, placebo-controlled, double-blinded trial in 17 pediatric intensive care units (PICUs) of tertiary care children's hospitals. Patients ages 18 months to 25 years with leukemia/lymphoma or having undergone HCT who required invasive mechanical ventilation for bilateral lung disease with an oxygenation index (OI) > 10 and <37 were studied. Interventions used were intratracheal instillation of either calfactant or air placebo (1 or 2 doses). Forty-three subjects were enrolled between November 2010 and June 2015: 26 assigned to calfactant and 17 to placebo. There were no significant differences in the primary outcome, which was survival to PICU discharge (adjusted hazard ratio of mortality for calfactant versus placebo, 1.78; 95% confidence interval, .53 to 6.05; P?=?.35), OI, functional outcomes, or ventilator-free days, adjusting for risk strata and Pediatric Risk of Mortality (PRISM) score. Despite the risk-stratified randomization, more allogeneic HCT patients received calfactant (76% and 39%, respectively) due to low recruitment at various sites. This imbalance is important because independent of treatment arm and while adjusting for PRISM score, those with allogeneic HCT had a nonsignificant higher likelihood of death at PICU discharge (adjusted odds ratio, 3.02; 95% confidence interval, .76 to 12.06; P?=?.12). Overall, 86% of the patients who survived to PICU discharge also were successfully discharged from the hospital. These data do not support the use of calfactant among this high mortality group of pediatric leukemia/lymphoma and/or HCT patients with PARDS to increase survival. In spite of poor enrollment, allogeneic HCT patients with PARDS appeared to be characterized by higher mortality than even other high-risk immunosuppressed groups. Conducting research among these children is challenging but necessary, because survival to PICU discharge usually results in successful discharge to home.     

The impact of a phase-change cooling vest on heat strain and the effect of different cooling pack melting temperatures

Cooling vests (CV) are often used to reduce heat strain. CVs have traditionally used ice as the coolant, although other phase-change materials (PCM) that melt at warmer temperatures have been used in an attempt to enhance cooling by avoiding vasoconstriction, which supposedly occurs when ice CVs are used. This study assessed the effectiveness of four CVs that melted at 0, 10, 20 and 30 °C (CV₀, CV₁₀, CV₂₀, and CV₃₀) when worn by 10 male volunteers exercising and then recovering in 40 °C air whilst wearing fire-fighting clothing. When compared with a non-cooling control condition (CON), only the CV₀ and CV₁₀ vests provided cooling during exercise (40 and 29 W, respectively), whereas all CVs provided cooling during resting recovery (CV₀ 69 W, CV₁₀ 66 W, CV₂₀ 55 W and CV₃₀ 29 W) (P < 0.05). In all conditions, skin blood flow increased when exercising and reduced during recovery, but was lower in the CV₀ and CV₁₀ conditions compared with control during exercise (observed power 0.709) (P < 0.05), but not during resting recovery (observed power only 0.55). The participants preferred the CV₁₀ to the CV₀, which caused temporary erythema to underlying skin, although this resolved overnight after each occurrence. Consequently, a cooling vest melting at 10 °C would seem to be the most appropriate choice for cooling during combined work and rest periods, although possibly an ice-vest (CV₀) may also be appropriate if more insulation was worn between the cooling packs and the skin than used in this study.     

Does prophylactic antidepressant treatment boost interferon-alpha treatment completion in HCV?

Depression is often a side effect of interferon-alpha treatment for hepatitis C, and is recognized as a cause for treatment discontinuation. When detected, antidepressant treatment begins promptly. In contrast to this rescue approach, prophylactic antidepressant treatment has been considered as a superior approach. While studies indicate that depression is lower with prophylaxis, no study has prospectively evaluated the degree that treatment completion might be boosted by the prophylactic strategy. A structured literature search was conducted to discover all trials of antidepressant prophylaxis for patients undergoing antiviral treatment for chronic hepatitis C. Selection criteria included: antidepressant prophylaxis study; report of depression treatment outcome; report of numbers discontinuing and reason for discontinuation (including any of the following: discontinuation data for medical side effects (i.e., thrombocytopenia); discontinuation due to lack of antiviral response; discontinuation due to lack of antidepressant effect; discontinuation due to antidepressant side effects; discontinuation due to patient preference; discontinuation due to loss to follow-up; or unspecified discontinuation). Across the studies, total enrollees were determined for the prophylaxis arms and the rescue arms, and then, again across studies, those discontinuing for reasons other than lack of antiviral response or medical side effect were summed for each of these two arms. Twelve studies were discovered. One was a retrospective chart review, one was an uncontrolled trial, and ten were controlled trials. Discontinuation of antiviral therapy was not less common in the prophylaxis arms: of the 396 patients treated by the prophylaxis strategy, 47 (11.9%) discontinued; of the 380 patients in the rescue strategy, 45 (11.8%) discontinued. While the prophylaxis strategy seems to manage depression symptoms, it does not seem to boost treatment completion. Rescue was a very successful strategy when indicated. While antidepressant prophylaxis has benefit in antiviral treatment, it should not generally be valued for boosting the likelihood of treatment completion.     

The use of defenses and physician health care costs: are physician health care costs lower in persons with more adaptive defense profiles?

BACKGROUND: The objective of the present study was to determine if persons who use more adaptive defenses have lower physician health care costs compared to those who use less adaptive defenses. METHODS: We randomly selected 667 persons from the 1995 population-based Nova Scotia Health Survey who completed a videotaped structured interview. Each interview was rated for typical defense use by the Defense-Q. We obtained physician health care costs for 3 months before and after the interview, as well as medical diagnoses and measures of psychological functioning. RESULTS: A more adaptive defense profile significantly predicted lower future physician health care costs. These results were found when controlling for other psychosocial variables, before and after controlling for previous physician health care costs, and when testing only within a physically healthy subsample. Results of secondary analyses showed that a more adaptive defense profile was positively related to a number of psychosocial variables, such as nurse's rating of competence, lack of depressive symptoms, and days at work. CONCLUSIONS: The adaptiveness of a person's defense use in managing affect is important in predicting physician health care costs as well as psychosocial functioning.     

Association of complex lipids containing gangliosides with cognitive development of 6-month-old infants

Background

Human breastmilk contains gangliosides which may play an important role in infant neurodevelopment.

Aim

A pilot study was conducted to assess the impact of infant formula supplemented with gangliosides from complex milk lipid on cognitive functions of normal healthy infants.

Study design

The study was a double-blind, randomized, controlled, parallel group clinical trial in which infants received the treatment or control product from 2 to 8 weeks of age until 24 weeks of age. The control group (n = 30) received standard infant formula and the treatment group (n = 29) received the same formula supplemented with complex milk lipid to increase the ganglioside content to approximately 11 to 12 μg/ml. A reference group (n = 32) consisted of normal healthy exclusively breast-fed infants.

Outcome measures

Cognitive development using the Griffith Scales and serum gangliosides was measured before (2–8 weeks of age) and after intervention (24 weeks of age).

Results

Ganglioside supplementation using complex milk lipids significantly increased ganglioside serum levels (control group vs treatment group, P = 0.002) and resulted in increased scores for Hand and Eye coordination IQ (P < 0.006), Performance IQ (P < 0.001) and General IQ (P = 0.041). Cognitive development scores and serum ganglioside levels for the treatment group did not differ from the reference group.

Conclusions

Supplementation of infant formula with complex milk lipid to enhance ganglioside content appears to have beneficial effects on cognitive development in healthy infants aged 0–6 months, which may be related to increased serum ganglioside levels.     

High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

Genetic variation in alcohol dehydrogenase is associated with neurocognition in men with HIV and history of alcohol use disorder: preliminary findings

The co-occurrence of HIV and alcohol use disorder (AUD) amplifies risk for neural injury and neurocognitive deficits. However, the substantial neurocognitive heterogeneity across HIV+/AUD+ individuals suggests inter-individual differences in vulnerability to the neurotoxicity of comorbid HIV/AUD. Genetic variation in alcohol dehydrogenase (ADH), which metabolizes ethanol, may contribute to inter-individual neurocognitive variability. We evaluated associations between five ADH single-nucleotide polymorphisms (SNPs) and neurocognition in men stratified by HIV and lifetime AUD status. Neurobehavioral assessments were administered to 153 men. Three-way ANOVAs examined the interaction of HIV, AUD, and ADH SNPs on global and domain-specific demographically corrected T scores. Follow-up ANCOVAs adjusted for age, estimated verbal IQ, depression, and remote non-alcohol substance use disorders. HIV/AUD groups differed globally and for verbal fluency, working memory, executive function, and processing speed T scores specifically, with HIV+/AUD+ exhibiting the poorest performance. ADH4 (rs1126671) was associated with large effects on working memory (d?=???1.16, p?=?.001) and executive function (d?=???0.77, p?=?.028) selectively in HIV+/AUD+, which remained significant in ANCOVA models. ADH1A (rs3819197) moderated the deleterious effects of HIV+/AUD+ on processing speed such that HIV+/AUD+ related to slower information processing in A allele carriers but not GG homozygotes (ps?<?0.03). Preliminary findings suggest genetic variation in the ADH pathway moderates the deleterious neurocognitive effects of comorbid HIV/AUD. Differential metabolism of heavy ethanol exposure may compromise neurocognition under conditions of neurobiological stress, such as in HIV infection. The functional effects on ethanol metabolism of ADH SNPs examined in this study remain poorly understood, warranting further examination of pharmacokinetic mechanisms mediating ADH gene-neurobehavior relationships in HIV.

     

Endothelial cell transformation in primary biliary cirrhosis: a morphological and biochemical study

There is increasing interest in the changes of the endothelial lining of the hepatic sinusoids during the development of chronic liver disease. In this study we looked for evidence of hepatic sinusoidal endothelial cell transformation and basement membrane production in patients with primary biliary cirrhosis. Morphological transformation to vascular-type endothelial cells, as evidenced by the development VIII-related antigen, was seen at the interface between portal tracts or fibrous septae and hepatic parenchyma; the most marked changes were observed in patients with established cirrhosis. Increased immunohistochemical staining for the basement membrane components type IV collagen and laminin was also found in a similar distribution. Raised serum levels of hyaluronic acid, a glycosaminoglycan metabolized by normal hepatic endothelial cells, were found in most patients and correlated strongly with advancing histological stage. Furthermore, significant positive correlations were found between serum hyaluronic acid and serum levels of laminin and type IV collagen. The unique structure of the normal endothelial lining of the hepatic sinusoids is important in the maintenance of hepatic function. Our data show that significant changes in endothelial cell structure and function occur in primary biliary cirrhosis and appear to be a contributing factor to the progression of the disease. Further studies are needed to determine the extent and importance of these changes in other forms of chronic liver disease.     

Flash visual evoked responses in the early encephalopathy of chronic liver disease

In recent years many variants of EEG sensory evoked responses have been studied as potential diagnostic aids in the detection and quantification of hepatic encephalopathy (HE). This study assesses the value of the flash visual evoked response (VER). Twenty-six controls and 21 non-encephalopathic and 12 encephalopathic (grade 1/2), biopsy-proven, cirrhotic patients were assessed clinically, psychometrically, and electrophysiologically. Flash VER from three different leads were obtained from each patient. Data from the fronto-occipital leads gave the best differentiation between the subjects. The P2 and N3 peak latencies were significantly increased in the two liver groups and correlated with the mental state and psychometric results. The N3 latency had a 92% specificity and a 50% sensitivity in the detection of grade 1/2 HE. This study suggests that the N3 latency changes may be a good marker of early clinical HE and useful in the longitudinal assessment of individual patients.     

1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study

Background

There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma?>?1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma?>?1 mm in BT.

Methods

This phase III, multicentre trial [NCT02385214] administered by the Australia & New Zealand Medical Trials Group (ANZMTG 03.12) randomised patients with a primary cutaneous melanoma?>?1 mm in BT to a 1 versus 2-cm wide excision margin to be performed with sentinel lymph node biopsy. Surgical closure technique was at the discretion of the treating surgeon. Patients’ QoL was measured (FACT-M questionnaire) at baseline, 3, 6, and 12 months after randomisation.

Results

Between January 2015 and June 2016, 400 patients were randomised from 17 centres in 5 countries. A total of 377 patients were available for analysis. Primary melanomas were located on the trunk (56.9%), extremities (35.6%), and head and neck (7.4%). More patients in the 2-cm margin group required reconstruction (34.9 vs. 13.6%; p?<?0.0001). There was an increased wound necrosis rate in the 2-cm arm (0.5 vs. 3.6%; p?=?0.036). After 12 months’ follow-up, no differences were noted in QoL between groups.

Discussion

This pilot study demonstrates the feasibility of a large international RCT to provide a definitive answer to the optimal excision margin for patients with intermediate- to high-risk primary cutaneous melanoma.