Effect of protracted treatment with rosiglitazone, a PPARgamma agonist, in patients with Cushing's disease

OBJECTIVE: Cushing's disease, hypercortisolism due to a pituitary ACTH-secreting tumour, is a highly morbid illness as yet without effective medical therapy. Recent studies have demonstrated that peroxisome proliferator-activated receptor gamma (PPARgamma) agonists effectively suppress ACTH secretion in a murine tumoral corticotroph cell line, but the few studies conducted so far in patients with ACTH-secreting pituitary adenomas have yielded variable results. DESIGN: Ten patients with Cushing's disease were treated with 4-16 mg rosiglitazone p.o. daily for 1-8 months (median 3 months) and plasma ACTH and cortisol, urinary free cortisol (UFC), as well as parameters of insulin sensitivity, were recorded. An acute challenge with 8 mg rosiglitazone for 2 days preceded long-term rosiglitazone administration. RESULTS: The acute challenge with rosiglitazone did not significantly modify plasma ACTH and cortisol levels. During protracted treatment with rosiglitazone, four patients showed a persistent reduction in UFC levels (up to 24% of pretreatment values), achieving normalization in three. In the others, UFC as well as plasma ACTH and cortisol decrements were inscribed within wide, random oscillations indicating that disease activity was substantially unchanged. Insulin sensitivity was ameliorated in most patients, without relation to ACTH or cortisol secretion. Untoward effects, such as weight gain, oedema and worsening of ecchymoses, were reported in several patients. CONCLUSIONS: Although effective in a subset of patients, protracted rosiglitazone administration did not consistently restrain ACTH and cortisol secretion in patients with Cushing's disease. Further investigations are needed to fully define the therapeutic potential of PPARgamma agonists in this disorder.     

Do the limits of serum prolactin in disconnection hyperprolactinaemia need re‐definition? A study of 226 patients with histologically verified non‐functioning pituitary macroadenoma

BACKGROUND: The differentiation of a pituitary non-functioning macroadenoma from a macroprolactinoma is important for planning appropriate therapy. Serum PRL levels have been suggested as a useful diagnostic indicator. However, values between 2500 and 8000 mU/l are a grey area and are currently associated with diagnostic uncertainty. OBJECTIVE: We wished therefore, to investigate the serum PRL values in a large series of patients presenting with apparently non-functioning pituitary macroadenomas. PATIENTS AND METHODS: All patients presenting to the Department of Endocrinology in Oxford with clinically non-functioning pituitary macroadenomas (later histologically verified) between 1990 and 2005 were studied. Information documented in the notes on the medications and on the presence of conditions capable of affecting the serum PRL levels at the time of blood sampling was also collected. RESULTS: Two hundred and twenty-six patients were identified (median age at diagnosis 55 years, range 18-88 years; 146 males/80 females; 143 gonadotroph, 46 null cell, 25 plurihormonal and 12 silent ACTH adenomas). All tumours had suprasellar extension. At the time of blood sampling 41 subjects were taking medications capable of increasing serum PRL. Hyperprolactinaemia was found in 38.5% (87/226) of the patients. The median serum PRL values in the total group were 386 mU/l (range 16-3257) (males: median 299 mU/l, range 16-1560; females: median 572 mU/l, range 20-3257) and in those not taking drugs capable of increasing serum PRL 363 mU/l (range 16-2565) (males: median 299 mU/l, range 16-1560; females: median 572 mU/l, range 20-2565). Serum PRL < 2000 mU/l was found in 98.7% (223/226) of the total group and in 99.5% (184/185) of those not taking drugs. Among the three subjects with serum PRL > 2000 mU/l, two were taking oestrogen preparations. CONCLUSIONS: Based on a large series of histologically confirmed cases, serum PRL > 2000 mU/l is almost never encountered in nonfunctioning pituitary macroadenomas. Values above this limit in the presence of a macroadenoma should not be surrounded by diagnostic uncertainty (after acromegaly or Cushing's disease have been excluded); a prolactinoma is the most likely diagnosis and a dopamine agonist should be considered as the treatment of choice.     

XML-based clinical data standardisation in the National Health Service Scotland

The objective of this paper is to clarify the role that socio-economic factors played in shaping the development of XML-based clinical data standards in the National Health Service in Scotland from 2000 to 2004. The paper discusses the NHS Scotland approach to clinical data standardisation, emphasising the actors involved, their choices during the standard development process and the factors that have shaped these choices. The case suggests that the NHS Scotland approach to clinical data standardisation is shaped by strong political pressures for fast development of an integrated electronic patient care system, economic pressures for high efficiency and cost reductions, and organisational requirements for strong clinical support. Such economic, political and organisational pressures explain the informal approach to standard development, the emphasis on fast system development and strong clinical involvement. At the same time, market factors explain the low commitment of the IT vendors, which might have otherwise put significant pressure on NHS Scotland to pursue a more formalised standardisation approach within an internationally recognised standard-setting body.     

Neuroendocrine effects of citalopram infusion in anorexia nervosa

Because of the role of serotonin (5HT) in regulating food intake and mood, several studies have focused their attention on the assessment of serotonergic activity in eating disorders, and in particular in anorexia nervosa, but the results have been inconsistent. Citalopram, a highly selective 5HT reuptake inhibitor, has been recently reported as a neuroendocrine probe to assess the serotonergic function in physiological and pathological conditions. We evaluated the adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL) and growth hormone (GH) secretion during placebo or citalopram IV infusion (20 mg over 120 min), in six women with anorexia nervosa restricter type, and in six healthy women, in order to test the hypothesis that this neurotransmitter system is abnormal in this group of patients. ACTH and PRL secretion was higher during citalopram infusion compared to placebo (p<0.05) in both groups, while cortisol secretion was higher during citalopram infusion only in healthy controls (p<0.05), but not in anorexic patients. GH levels were unaffected by citalopram in both groups. These results demonstrate that serotonergic activation by citalopram affects corticotroph and lactotroph but not somatotroph secretion in anorexic as well as in normal subjects. Our preliminary findings do not support the existence of remarkable alterations in the serotonergic control of anterior pituitary function in anorexia nervosa, while there seems to be an impairment of the adrenal function in this group of patients.     

Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss

Deletions of portions of chromosomes 1p and 19q are closely associated with the oligodendroglioma histologic phenotype. In most cases, 1p and 19q are codeleted, yet the mechanism of dual loss is unexplained. We report 5 cases (World Health Organization grade III) in which metaphase cytogenetics identified a derivative chromosome consisting of what appears to be the whole arms of 1q and 19p forming a der(1;19)(q10;p10). Metaphase fluorescent in situ hybridization (FISH) confirmed the derivative chromosome was composed of 1q and 19p material in 3 cases; in 2 cases with few metaphases, FISH confirmed 19p material on the derivative chromosome. In all cases, interphase FISH showed net loss of 1p and 19q in 77% to 92% of cells, and microsatellite studies were consistent with 1p and 19q loss. We hypothesize the following: occurrence of a balanced whole-arm translocation between chromosomes 1 and 19 forming 2 derivative chromosomes, one composed of 1q and 19p, the other of 1p and 19q. Subsequent loss of the der(1;19)(p10;q10) then results in the simultaneous 1p and 19q loss observed in oligodendroglioma with retention of the der(1;19)(q10;p10) seen in these cases.     

Invasive versus non-invasive cooling after in- and out-of-hospital cardiac arrest: a randomized trial

Introduction

Mild induced hypothermia (MIH) is indicated for comatose survivors of sudden cardiac arrest (SCA) to improve clinical outcome. In this study, we compared the efficacy of two different cooling devices for temperature management in SCA survivors.

Methods

Between April 2008 and August 2009, 80 patients after survived in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) were included in this prospective, randomized, single center study. Hypothermia was induced after randomization by either invasive Coolgard^® cooling or non-invasive ArcticSun^® surface cooling at 33.0 °C core body temperature for 24 h followed by active rewarming. The primary endpoint was defined as the efficacy of both cooling systems, measured by neuron-specific enolase (NSE) levels as a surrogate parameter for brain damage. Secondary efficacy endpoints were the clinical and neurological outcome, time to start of cooling and reaching the target temperature, target temperature-maintenance and hypothermia-associated complications.

Results

NSE at 72 h did not differ significantly between the 2 groups with 16.5 ng/ml, interquartile range 11.8–46.5 in surface-cooled patients versus 19.0 ng/ml, interquartile range 11.0–42.0 in invasive-cooled patients, p = 0.99. Neurological and clinical outcome was similar in both groups. Target temperature of 33.0 °C was maintained more stable in the invasive group (33.0 versus 32.7 °C, p < 0.001). Bleeding complications were more frequent with invasive cooling (n = 17 [43.6 %] versus n = 7 [17.9 %]; p = 0.03).

Conclusion

Invasive cooling has advantages with respect to temperature management over surface cooling; however, did not result in different outcome as measured by NSE release in SCA survivors. Bleeding complications were more frequently encountered by invasive cooling.     

Healthcare resource utilization in patients with metastatic melanoma receiving first-line therapy with dabrafenib + trametinib versus nivolumab or pembrolizumab monotherapy

Objective: To compare healthcare resource utilization (HRU) between patients with metastatic melanoma (MM) initiated on first-line (1L) combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib (D?+?T; oral) and those initiated on 1?L monotherapy with the anti-PD1 monoclonal antibodies nivolumab or pembrolizumab (N/P; intravenous).

Methods: Patients with melanoma initiated on D?+?T or N/P from Q1/2014 to Q2/2016 (defined as 1?L treatment for MM) were identified in the Truven MarketScan database. Entropy balancing was used to reweight the N/P cohort in order to make it comparable to the D?+?T cohort with respect to the mean and variance of baseline covariates. HRU outcomes during 1?L therapy, reported per patient-year (PPY), were described and compared between the two cohorts post-weighting (i.e. independently of baseline covariates).

Results: Of the 445 patients included, 202 and 243 were initiated on D?+?T and N/P, respectively. After weighting, patients initiated on N/P had more outpatient visits for drug administration during 1?L therapy than those initiated on D?+?T (difference?=?18.6 visits PPY [95% CI?=?16.0–21.1]). Patients initiated on N/P also had more outpatient office visits for reasons other than drug administration (difference?=?8.1 visits PPY [95% CI?=?1.9–13.7]). No significant differences were observed for other HRU parameters (i.e. inpatient admissions, inpatient days, and emergency department visits during 1?L therapy).

Conclusions: HRU during 1?L therapy was generally similar between patients initiated on D?+?T and N/P. Nonetheless, patients initiated on N/P had more outpatient visits, including more outpatient visits for reasons unrelated to drug administration.     

I don't know how I feel,therefore I act: Alexithymia,urgency, and alcohol problems

This study examined the relationships between alexithymia, impulsivity, and alcohol use and related problems. The sample consisted of 429 undergraduate students who reported drinking alcohol at least once in the past 3 months. Negative urgency mediated the relationship between alexithymia and alcohol-related problems, whereas positive urgency mediated the relationship between alexithymia and alcohol consumption. In addition, positive urgency moderated the relationship between alexithymia and alcohol-related problems, increasing the strength of this association. These results indicate distinct relationships between alexithymia and negative urgency and positive urgency in predicting alcohol consumption and related problems. The findings of this research contribute to the body of the literature on alexithymia, self-regulation, and etiology of alcohol misuse and related consequences. Furthermore, the findings of the current study provide support for the importance of emotion identification and expression skills training in substance abuse treatment.