Pooled Rate of Pseudoprogression, Patterns of Response, and Tumor Burden Analysis in Patients Undergoing Immunotherapy Oncologic Trials for Different Malignancies.

AIMS: Assess rates of true pseudoprogression in unconfirmed progressive disease (iUPD) in a pool of immunotherapy clinical trials for different cancers, analyze tumor characteristics that drive iUPD classification, and investigate potentials predictors of pseudoprogression. MATERIALS AND METHODS: Retrospective interpretation of prospectively acquired data. Patients from 18 immunotherapy clinical trials with two arms (RECIST 1.1, iRECIST), of 10 cancer types were selected. Pooled rate of true pseudoprogression among iUPD was estimated using a common effect meta-analysis. Target, Non-target, and new lesions as the trigger of confirmed-vs pseudo-progression were compared using Chi-Square and Fisher exact tests. Conditional logistic regression was used to investigate the association between age, sex, tumor burden at baseline, and number of follow ups and pseudoprogression. RESULTS: 60/287 (21%) patients (17 women) were classified as iUPD with at least one subsequent confirmatory timepoint. The overall pooled estimate of pseudoprogression was 15% (95%CI: 8%--26%). Nontarget lesions were significantly more frequent the cause of iUPD than change in Target lesions size (p< 0.001). Most observations of true pseudoprogression occurred in the first follow-up (77%), whereas confirmed progression occurred in later time points during the trial. Pseudoprogression was not significantly associated with age, sex, tumor burden at baseline, or number of timepoints. CONCLUSION: In a pool of immunotherapy trials, the rate of true pseudoprogression was 15%, most often in the first timepoint after baseline than later in treatment. iUPD categorization was mostly driven by changes in NT lesions rather than objective changes in measurements of target lesions.

Predicting fruit and vegetable consumption in long-haul heavy goods vehicle drivers: Application of a multi-theory, dual-phase model and the contribution of past behaviour.

Fruit and vegetable intake is insufficient in industrialized nations and long-haul heavy goods vehicle (HGV) drivers are considered a particularly at-risk group. The aim of the current study was to test the effectiveness of a multi-theory, dual-phase model to predict fruit and vegetable consumption in Australian long-haul HGV drivers. A secondary aim was to examine the effect of past fruit and vegetable consumption on model paths. A prospective design with two waves of data collection spaced one week apart was adopted. Long-haul HGV drivers (N = 212) completed an initial survey containing theory-based measures of motivation (autonomous motivation, intention), social cognition (attitudes, subjective norms, perceived behavioural control), and volition (action planning, coping planning) for fruit and vegetable consumption. One week later, participants (n = 84) completed a self-report measure of fruit and vegetable intake over the previous week. A structural equation model revealed that autonomous motivation predicted intentions, mediated through attitudes and perceived behavioural control. It further revealed that perceived behavioural control, action planning, and intentions predicted fruit and vegetable intake, whereby the intention-behaviour relationship was moderated by coping planning. Inclusion of past behaviour attenuated the effects of these variables. The model identified the relative contribution of motivation, social cognition, and volitional components in predicting fruit and vegetable intake of HGV drivers. Consistent with previous research, inclusion of past fruit and vegetable consumption led to an attenuation of model effects, particularly the intention-behaviour relationship. Further investigation is needed to determine which elements of past behaviour exert most influence on future action.

Group B streptococcal PCR testing in comparison to culture for diagnosis of late onset bacteraemia and meningitis in infants aged 7-90 days: a multi-centre diagnostic accuracy study.

The aim of this study was to compare an in-house real-time PCR assay, with bacterial culture as the reference, for the diagnosis of late onset group B Streptococcal (GBS) disease. This was a retrospective review. All children aged 7-90 days presenting to four paediatric centres that had a blood or CSF sample tested by GBS PCR were included. Of 7,686 blood and 2,495 cerebrospinal fluid (CSF) samples from patients of all ages received for PCR testing, 893 and 859 samples were eligible for the study, respectively. When compared to culture, the sensitivity of blood PCR was 65% (13/20) in comparison to the CSF PCR test which was 100% (5/5). Ten of 23 PCR-positive blood samples and 17 of 22 PCR-positive CSF samples were culture negative. The median threshold Ct values for culture-positive/PCR-positive CSF samples was lower than that of culture-negative/PCR-positive CSF samples (p = 0.08). Clinical details of 17 available cases that were culture negative/PCR positive were reviewed; seven were deemed to be definite cases, eight were probable and two were possible. The results showed that detection of GBS by PCR is useful for CSF samples from infants aged 7-90 days with suspected meningitis; however, analysis of blood samples by PCR is of limited value as a routine screening test for late onset GBS sepsis and should not replace bacterial culture.

Paediatric tracheostomy-An 11 year experience at a Scottish paediatric tertiary referral centre.

AIMS: The aim of this paper was to review the indications, complications and outcomes for tracheostomy at a Scottish paediatric tertiary referral hospital. METHODS: All patients undergoing tracheostomy between January 2001 and September 2012 were identified. A retrospective case note analysis was performed. RESULTS: 111 tracheostomies were done in the study period. The mean number per year was 11 (3-12). Full data was available for 95 patients. There were 56 (59%) males and 39 (41%) females. Age at time of tracheostomy ranged from one day to 15 years, the mean age of tracheostomy insertion was 69 weeks. The majority of patients, 75 (79%), were under one year old when they had their tracheostomy. The most common indication was long-term ventilation (20%), followed by craniofacial abnormality causing airway obstruction (18%), followed by subglottic stenosis (14%). 37% of patients were decannulated. CONCLUSIONS: This series reflects current trends in the indications for paediatric tracheostomy, with chronic lung disease of prematurity being the most common indication.

A phase I study of cabozantinib (XL184) in patients with renal cell cancer.

BACKGROUND: Cabozantinib targets tyrosine kinases including the hepatocyte growth factor receptor (MET) and vascular endothelial growth factor (VEGF) receptor 2, which are important drug targets in renal cell carcinoma (RCC). PATIENTS AND METHODS: This single-arm open-label phase I trial evaluated the safety and tolerability of cabozantinib in heavily pretreated patients with metastatic clear cell RCC. RESULTS: The study enrolled 25 RCC patients for whom standard therapy had failed. Patients received a median of two prior systemic agents, and most patients had previously received at least one VEGF pathway inhibiting therapy (22 patients [88%]). Common adverse events included fatigue, diarrhea, nausea, proteinuria, appetite decreased, palmar-plantar erythrodysesthesia, and vomiting. Partial response was reported in seven patients (28%). Median progression-free survival was 12.9 months, and median overall survival was 15.0 months. CONCLUSION: Cabozantinib demonstrates preliminary anti-tumor activity and a safety profile similar to that seen with other multitargeted VEGFR tyrosine kinase inhibitors in advanced RCC patients. Further evaluation of cabozantinib in RCC is warranted. ClinicalTrials.gov identifier: NCT01100619.

Positive predispositions, quality of life and chronic illness.

This study assessed the extent to which being predisposed towards engaging in acts of gratitude and forgiveness is associated with enhanced quality of life (QoL), and whether these associations are mediated by positive and negative affective states. The study sample comprised 327 people with one of three chronic illnesses (arthritis, chronic obstructive pulmonary disease and diabetes). Participants completed self-report measures of two positive predispositions (the tendencies towards gratitude and forgiveness), two affective states (positive and negative) and three indices of QoL (physical, psychological and satisfaction with life). As hypothesised, gratitude, and to a lesser extent forgiveness, predicted enhanced QoL, with most effects mediated via increased positive affect. Findings support the view that predispositions towards interpersonal gratitude, and possibly interpersonal forgiveness, may bolster the QoL of people living with chronic physical illness. Consistent with contemporary theories of positive emotion, gratitude appears to have its effects via enhancing positive affect. The study adds to the emerging evidence that a predisposition towards gratitude benefits QoL and extends past findings by identifying a mechanism that is important in people with chronic illnesses.

Global variability in diabetes mellitus and its association with body weight and primary healthcare support in 49 low- and middle-income developing countries.

AIMS: In the absence of any previous global comparison, we examined the variability in prevalence of diabetes mellitus across 49 developing countries, and the associations of diabetes with body weight and primary healthcare support using data from the World Health Survey. METHODS: Diabetes mellitus was defined by individuals' self-report of a physician diagnosis of diabetes. BMI is the weight (kg)/the square of the height (m). Healthcare support was assessed using clinical treatment status and whether patients with diabetes followed prescribed behaviour changes to control diabetes. Associations of diabetes with BMI and diabetes treatment status were analysed cross-sectionally. RESULTS: A total of 215898 participants were included in the analysis. Age-adjusted prevalence of diabetes ranged from 0.27% (Mali) to 15.54% (Mauritius). Participants who were underweight (BMI <18.5 kg/m(2) ), overweight (BMI 25-29.9 kg/m(2) ) and obese (BMI ≥ 30 kg/m(2) ) were significantly associated with odds of having diabetes as compared with those who were of normal weight (BMI 18.5-24.9 k/m(2) ), with corresponding values of multivariate adjusted odds ratios (95% CI) of 1.15 (1.07-1.24), 1.56 (1.44-1.68) and 2.35 (2.17-2.61), respectively. The overall untreated rate of those with diabetes mellitus was 9.6% in the total sample. Patients with underweight had the highest diabetes untreated rate, followed by those with normal weight, overweight and obesity. CONCLUSION: There are significant variations in prevalence of diabetes and primary healthcare support for diabetes across low- and middle-income countries. Aggressively preventing abnormal body weight and improving healthcare support may play a pivotal role in ameliorating the unfavourable epidemic of diabetes in developing countries.

Use of risk stratification to guide ambulatory management of neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee.

Utilization of risk-stratification tools in the setting of neutropenic fever is currently limited by inadequate knowledge and lack of awareness. Within this context, the approach to management of low-risk patients with neutropenic fever is inconsistent with the available evidence across many Australian treating centres. These clinical guidelines define and clarify an accepted standard of care for this patient group given the current evidence base. The Multinational Association for Supportive Care in Cancer risk index is presented as the preferred risk assessment tool for determining patient risk. Suitability of ambulatory care within specific patient populations is discussed, with defined eligibility criteria provided to guide clinical decision-making. Detailed recommendations for implementing appropriate ambulatory strategies, such as early discharge and outpatient antibiotic therapy, are also provided. Due consideration is given to infrastructural requirements and other supportive measures at a resourcing and operational level. An analysis of the relevant health economics is also presented.

A survey of owners' perceptions of fear of fireworks in a sample of dogs and cats in New Zealand.

AIMS: To establish reliable information regarding the behavioural responses of dogs and cats to fireworks in New Zealand; record interventions used by owners, and their perceived efficacies; and establish the prevalence of firework-related injury, and quantify owners' attitudes towards fireworks. METHODS: A questionnaire targeting dog and cat ownerswas distributed via the Auckland Society for the Prevention of Cruelty to Animals (SPCA) Animals Voice magazine and 25 veterinary clinics. The questionnaire covered demographics of animals, fear of fireworks, severity of the fear, and behaviours exhibited. Also included were treatments tried, source and perceived efficacy, prevalence of injury, and owners' attitudes towards the sale of fireworks for private use. RESULTS: From a total of 8,966 questionnaires distributed, 1,007 valid questionnaires were returned, representing 3,527 animals. Of these 1,635 (46%) animals displayed a level of fear of fireworks recognisable to their owners. Owners of dogs identified a significantly higher fear response than owners of cats but the duration of these fear responses did not differ between species. Fear of fireworks frequently resulted in dogs exhibiting active fear behaviours, whereas cats were more likely to exhibit hiding and cowering behaviours. A significantly increased severity and duration of fear response over time in dogs and cats was associated with owners who comforted them when they displayed a fearful response. Only 141/890 (15.8%) of owners sought professional treatment from a veterinarian, animal behaviourist or animal trainer for their animals, with variable efficacy. Six percent (51/923) of animals had received physical injuries from fireworks. The majority (837/1,007; 83%) of respondents, regardless of whether they owned a fearful animal or not, supported a ban on the sale of fireworks for private use. CONCLUSIONS: The results provide valuable information that is, as yet, unsubstantiated in New Zealand, although potential biases exist due to the non-random selection of respondents. Differences between dogs and cats were likely due to differing responses to fear-provoking stimuli between the species. Owner-reported increase in fearful response over time for comforted animals may indicate a negative impact on the longer-term psychological welfare of their animal. CLINICAL RELEVANCE: The greater the awareness of effective treatment plans for animals that suffer from a fear of fireworks, the greater the possibility that this fear can be reduced. Wider dissemination of effective owner behaviour and treatment programmes for firework fears is needed to improve levels of professional treatment for dogs and cats.

Developmental PCB exposure induces hypothyroxinemia and sex-specific effects on cerebellum glial protein levels in rats.

Polychlorinated biphenyls (PCBs) are persistent lipophilic environmental contaminants which are found in fatty tissues of humans and wild-life alike. Maternal transfer of PCBs to offspring is easily achieved across the placenta and via lactation. In male rats, perinatal PCB exposure induces behavioral abnormalities, in addition to hypothyroxinemia and white matter changes. There are sex differences in white matter volume synthesis and density in adult and aged rodents. Yet whether PCB exposure effects on white matter are sex-specific is unclear, because the previous studies were conducted in male offspring. Furthermore, although hypothyroxinemia induced by PCB exposure is thought to trigger white matter changes, PCBs also affect interleukin-6 (IL-6) expression, and IL-6 regulates white matter growth. We hypothesized that perinatal PCB exposure would have sex-specific effects on white matter development associated with altered IL-6 levels. We found that female offspring had higher levels of myelin basic protein (MBP) than males did, at postnatal day (PND) 7, 18 and 21. PCB exposure induced hypothyroxinemia in males and females at PND7, 14, 21, and 42. PCB exposure also increased MBP and reduced glial fibrillary acidic protein (GFAP) levels in males at PND21, but had the opposite effect in females. In addition, at PND14 and 21, PCB exposure elevated IL-6 levels in male offspring only. The induction of sex-specific changes in white matter proteins, in the absence of sex differences in thyroxine levels after PCB exposure, suggests that serum thyroxine levels do not directly contribute to the white matter alterations. Instead, IL-6 may contribute to increased MBP levels in males, whereas in females estromimetic and thyromimetic PCB metabolites may affect white matter development. This data adds to an increasing body of literature showing that perinatal insults induce sex-specific effects in offspring.

MRI as an outcome in multiple sclerosis clinical trials.

INTRODUCTION: T2-weighted and gadolinium enhanced T1-weighted MRI scans measure plaque burden and breakdown of the blood-brain barrier, respectively, in multiple sclerosis (MS) lesions. These have become widely used outcome measures for monitoring disease activity in clinical trials and clinical practice. However, their use as surrogates or biomarkers for disability and relapses, key clinical outcome measures, has remained incompletely validated. METHODS: In a clinical trial database comprised of 31 relapsing-remitting and secondary progressive MS trial placebo groups, we assessed relationships between 1) T2 lesion load (TLL) change and disability change and 2) gadolinium enhancement of MS lesions and on-study relapses with univariate and multivariate analyses. RESULTS: In relapsing-remitting MS, TLL change (n = 223) made no independent contribution to predicting change in disability from baseline to trials' end. Similarly, inclusion of gadolinium enhancing lesions (n = 170) into multivariate models did not independently contribute to the predictive value for on-trial relapses. In secondary progressive MS, a small effect of TLL was found for disability change (n = 355) but in multivariate analysis this accounted for less than 5% of the variance in end-of-trial disability. Results were replicated in independent datasets, more than doubling effective sample sizes. CONCLUSIONS: MRI measures widely used in trials of relapsing-remitting and progressive multiple sclerosis add little if anything independently to the clinically relevant relapse and disability outcomes. These results reemphasize the importance of validating potential surrogate markers against clinical measures and highlight the need for better MRI markers of disease activity and progression.

Long-term survival of patients with multiple sclerosis in West France.

In France no data have been published about comparing survival in multiple sclerosis (MS) patients with the general French population. We estimated survival probabilities in MS patients from a major centre for MS in West France. We also compared MS survival with the general population and assessed prognostic parameters. All patients with MS onset after January 1976 and classified as dead or alive on 1 January 2004 were included. One thousand eight-hundred and seventy-nine patients (sex ratio W: M 2.3; relapsing/progressive onset 77.4%/22.6%) fulfilled these criteria, disease duration ranged from one to 28 years. By 2004, 68 patients died (51 due to MS) and the 15 and 25-year survival probabilities were 96% and 88%. Male gender, progressive course (either primary or secondary), polysymptomatic onset, and increased annual relapse rate during the first two years of MS were related to a worse prognosis. After a mean follow-up duration of 12.7 years since clinical onset, MS increased the number of deaths compared with the general population. However taking into account disability status, we found that less disabled MS patients had a better survival and highly disabled patients a worse survival (eight-fold increase of mortality) compared with the French population.

Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial.

OBJECTIVE: To evaluate the effects of mitoxantrone (Mx) in progressive multiple sclerosis (MS) on MRI. METHODS: A total of 194 patients with worsening relapsing-remitting or secondary progressive MS were treated with Mx 12 mg/m2 (n = 34), Mx 5 mg/m2 (n = 40), or placebo (n = 36) at 3-month intervals IV over a 2-year period. In preselected MRI centers unenhanced and Gd-enhanced MRI scans were performed at month (M) 0, 12, and 24 in a non-randomized subset of 110 patients and non-selected for MRI criteria. The primary MRI outcome measure was the total number of MRI scans with positive Gd enhancement per group. RESULTS: Twelve mg/m2 Mx failed to reach a significant difference from placebo as measured by the primary MRI outcome at month 12 (p = 0.431) and 24 (p = 0.065). Secondary MRI outcome measures: 5 mg/m2 Mx influenced favorably the number of Gd-enhancing lesions only at month 24 (p = 0.004), but not at month 12 (p = 0.095). Twelve mg/m2 Mx reduced the number of T2-weighted lesions at month 24 (p = 0.027) and showed a positive trend at month 12 (p = 0.069), but not 5 mg/m2 Mx. The number of active MR lesions showed a strong trend toward reduction in the 12 mg/m2 Mx group only at month 24 (p = 0.054). All comparisons are vs placebo, and unadjusted for baseline incidence. CONCLUSIONS: In the MIMS trial 12 mg/m2 Mx does not reduce the number of MRI scans with positive Gd enhancement at month 12 and 24 vs placebo. Results of secondary MRI outcome measures are suggestive of a positive impact of 12 and 5 mg/m2 Mx on some of the Gd enhanced and unenhanced MRI measures as expected from other Mx MRI studies in the past.

Mitoxantrone in the treatment of multiple sclerosis.

Mitoxantrone is useful for the treatment of cancer and MS and, as with other chemotherapeutic agents, many studies have examined its tolerability. The suitability of mitoxantrone in MS is particularly interesting because of its role in treating various stages of the disease. Evidence shows that mitoxantrone could be a first-line treatment for malignant forms of MS, and a second-line drug in relapsing-remitting or secondary progressive MS that is unresponsive to interferon beta-1a, -1b or glatiramer acetate. Mitoxantrone should, however, be restricted to patients with demonstrable inflammatory disease activity, and should only be prescribed by neurologists with previous experience in both MS and mitoxantrone therapy. This review examines the properties of mitoxantrone, its tolerability, and discusses its suitability for treating various forms of MS, referring to several important studies.

Predictive parameters of mitoxantrone effectiveness in the treatment of multiple sclerosis.

INTRODUCTION: In a number of controlled trials it was established that mitoxantrone has a beneficial effect on disease progression in multiple sclerosis (MS) patients with a worsening disease course. The aim of this study was to investigate the use of mitoxantrone in clinical practice, and especially to describe predictive parameters of its effectiveness under these conditions. OBJECTIVES AND METHODS: In a retrospective, open-label mitoxantrone study we analysed 94 MS patients (49% relapsing remitting MS (RRMS), 41% secondary progressive MS and 10% primary progressive MS) who received monthly 20 mg i.v. mitoxantrone and 1 g i.v. methylprednisolone for six months, and selected as a criterion of effectiveness the percentage of patients with an Expanded Disability Status Scale (EDSS) improvement of at least one point (confirmed after one year) after stopping the treatment. A multivariate analysis was undertaken to assess the predictive value of five parameters on mitoxantrone effectiveness: (1) total number of relapses since disease onset and before treatment, (2) number of relapses within the past 24 months before treatment, (3) number of relapses in separate areas within the past 24 months before treatment, (4) active MRI scans (including Gd-enhanced lesions), and (5) clinical course of MS. RESULTS: During the observation period from 1 January 1997 to 30 May 2000 more than 44% of the patients improved by one point or more on the EDSS (confirmed after one year), 39% remained stable and 17% deteriorated. In patients with a RRMS course three or more relapses within the past 24 months preceding treatment, and at least one Gd-enhancing lesion resulted in a strong relative benefit (i.e., relative risk) of mitoxantrone effectiveness. In contrast, total number of relapses since disease onset had no impact on disease evolution and disability progression. Multivariate analysis revealed the number of relapses in separate areas within the past 24 months before treatment as the strongest predictive parameter (P < 0.001). CONCLUSION: Mitoxantrone is effective in improving and stabilizing patients with a worsening MS course in routine clinical practice. Several strong predictive parameters of mitoxantrone effectiveness were investigated among which the number of relapses in separate areas within the past 24 months before treatment was found to be the strongest parameter to predict clinical improvement.

Subcutaneous emphysema secondary to foreign-body aspiration.

Pneumomediastinum is uncommon in pediatric medical practice, outside the neonatal period. While asthma or respiratory infections are the most frequent underlying causes, it is important not to forget the possibility of foreign body aspiration, particularly after the clinical presentation.

Rhythmic feet movements while falling asleep.

During the wake-sleep transition and sleep, diverse motor phenomena such as hypnagogic foot tremor may occur in the lower extremities. We investigated the relevance of this phenomenon in 375 consecutive subjects examined polysomnographically in a sleep disorders center. Rhythmic feet movements while falling asleep (RFM) were found in 28 subjects (7.5%). RFM occurred mostly as single, short series with a duration of between 10 and 15 seconds. They had a high night-to-night variability and were detected as rhythmic, oscillating movements of the whole foot or toes. Surface electromyographic (EMG) recordings displayed series of repetitive phasic bursts with a periodicity mostly between 1 and 2 per second. Single EMG burst duration varied between 300 and 700 msec. RFM at highest intensity occurred during presleep wakefulness, and usually persisted in sleep stages 1 and 2. RFM did not have a major sleep-disturbing effect in any of the affected subjects. Due to its high prevalence and the lack of a major sleep-disturbing effect, short series of RFM could be considered a quasiphysiological phenomenon. However, in more severe forms of RFM with evidence of a sleep-disturbing effect, RFM should be considered abnormal.

Renal effects of recombinant prolactin in anaesthetized rats.

OBJECTIVE: To re-examine the controversial possibility that prolactin exerts renal effects, using recombinant mouse prolactin (rmP), in the presence and absence of circulating vasopressin. DESIGN: In experiment 1, the renal effects of rmP were examined in anaesthetized Brattleboro rats with hereditary hypothalamic diabetes insipidus (BDI) lacking circulating vasopressin and normal animals of the parent Long Evans (LE) strain. In experiment 2, salt and water excretion were studied in fluid-loaded normal Sprague-Dawley (SD) rats, some of which received rmP. METHODS: In experiment 1, BDI and LE rats maintained in fluid balance were infused i.v. with each of three concentrations of rmP (10, 20 and 40 microg/ml per h) or maintained on 150 mmol/l NaCl vehicle (controls). In experiment 2, the SD rats were infused with 75 mmol/l NaCl in order to induce a state of diuresis comparable to that of BDI rats, some of them then receiving the rmP i.v. RESULTS: A profound rmP-induced dose-dependent decrease in urine excretion (P<0.005) and a lesser decrease in sodium excretion in the BDI rats was in marked contrast with the small but significant increase in urine excretion in the LE rats compared with controls (P<0.025). The rmP-infused fluid-loaded SD rats also demonstrated a significant (P<0.05) dose-related antidiuresis compared with the control animals, in addition to a decrease in sodium excretion. CONCLUSIONS: These results show that prolactin has a profound antidiuretic effect in the absence of circulating vasopressin. In contrast, when vasopressin is present in the circulation rmP has a small, but opposite, diuretic effect. Thus the use of a recombinant prolactin has provided evidence for renal effects of this hormone which are modified in the presence of the circulating neurohypophysial hormone vasopressin.