Clinical epidemiology for childhood primary central nervous system tumors

This work was conducted by the French Brain Tumor Data Bank (FBTDB) and aims to prospectively record all primary central nervous system tumors (PCNST), in France, for which histological diagnosis is available. Results concerning children are presented. This study analyzes the childhood cases (0–19 years) of newly diagnosed and histologically confirmed PCNST (during the years 2004–2006) which have been recorded by the FBTDB. All French neuropathology and neurosurgery departments participated in this program. Neurosurgeons and neuropathologists completed a data file containing socio-demographic, clinical, radiologic and anatomopathologic information. The Tumor Registry from Herault was authorized to compile the data files with personal identifiers. About 1,017 cases (533 boys and 484 girls) of newly diagnosed childhood PCNST have been recorded (gliomas: 52%, all other neuroepithelial tumors: 31%, craniopharyngioma: 5%, germ cell tumors, meningioma and neurinoma: approximately 3% each, all histological subtypes have been detailed). Tumor resections were performed in 83.3%, and biopsies in 16.7%. The distributions by histology, cryopreservation of the samples, age, sex, tumor site and surgery have been detailed. To our knowledge, this work is the first databank in Europe dedicated to PCNST that includes the collection of clinical, radiological and histological data (including cryopreservation of the specimen). The long term goals of the FBTDB are to create a national registry and a network to perform epidemiological studies, to implement clinical and basic research protocols, and to evaluate and harmonize the healthcare of children and adult patients affected by PCNST. Luc Bauchet, Valérie Rigau are equally contributed to this work.     

Excitation and desensitization of mouse rod photoreceptors in vivo following bright adapting light

Electroretinographic (ERG) methods were used to determine response properties of mouse rod photoreceptors in vivo following adapting illumination that produced a significant extent of rhodopsin bleaching. Bleaching levels prevailing at ∼10 min and ∼20 min after the adapting exposure were on average 14% and 9%, respectively, based on the analysis of visual cycle retinoids in the eye tissues. Recovery of the rod response to the adapting light was monitored by analysing the ERG a -wave response to a bright probe flash presented at varying times during dark adaptation. A paired-flash procedure, in which the probe flash was presented at defined times after a weak test flash of fixed strength, was used to determine sensitivity of the rod response to the test flash. Recovery of the response to the adapting light was 80% complete at 13.5 ± 3.0 min (mean ± s.d .; n = 7) after adapting light offset. The adapting light caused prolonged desensitization of the weak-flash response derived from paired-flash data. By comparison with results obtained in the absence of the adapting exposure, desensitization determined with a test-probe interval of 80 ms was ∼fourfold after 5 min of dark adaptation and ∼twofold after 20 min. The results indicate, for mouse rods in vivo , that the time scale for recovery of weak-flash sensitivity substantially exceeds that for the recovery of circulating current following significant rhodopsin bleaching. The lingering desensitization may reflect a reduced efficiency of signal transmission in the phototransduction cascade distinct from that due to residual excitation.     

‘Oh my God,I can't handle this!’: trainees’ emotional responses to complex situations

Context

Dealing with emotions is critical for medical trainees’ professional development. Taking a sociocultural and narrative approach to understanding emotions, we studied complex clinical situations as a specific context in which emotions are evoked and influenced by the social environment. We sought to understand how medical trainees respond to emotions that arise in those situations.

Methods

In an international constructivist grounded theory study, 29 trainees drew two rich pictures of complex clinical situations, one exciting and one frustrating. Rich pictures are visual representations that capture participants’ perceptions about the people, situations and factors that create clinical complexity. These pictures were used to guide semi‐structured, individual interviews. We analysed visual materials and interviews in an integrated way, starting with looking at the drawings, doing a ‘gallery walk’, and using the interviews to inform the aesthetic analysis.

Results

Participants’ drawings depicted a range of personal emotions in response to complexity, and disclosed unsettling feelings and behaviours that might be considered unprofessional. When trainees felt confident, they were actively participating, engaged in creative problem‐solving strategies, and emphasised their personal involvement. When trainees felt the situation was beyond their control, they described how they were running away from the situation, hiding themselves behind others or distancing themselves from patients or families.

Conclusions

A sense of control seems to be a key factor influencing trainees’ emotional and behavioural responses to complexity. This is problematic, as complex situations are by their nature emergent and dynamic, which limits possibilities for control. Following a social performative approach to emotions, we should help students understand that feeling out of control is an inherent property of participating in complex clinical situations, and, by extension, that it is not something they will ‘grow out of’ with expertise.

     

Resident hesitation in the operating room: does uncertainty equal incompetence?

Context

In postgraduate medical programmes, the progressive development of autonomy places residents in situations in which they must cope with uncertainty. We explored the phenomenon of hesitation, triggered by uncertainty, in the context of the operating room in order to understand the social behaviours surrounding supervision and progressive autonomy.

Methods

Nine surgical residents and their supervising surgeons at a Canadian medical school were selected. Each resident–supervisor pair was observed during a surgical procedure and subsequently participated in separate post‐observation, semi‐structured interviews. Constructivist grounded theory was used to guide the collection and analysis of data.

Results

Three hesitation‐related themes were identified: the principle of progress; the meaning of hesitation, and the judgement of competence. Supervisors and residents understood hesitation in the context of a core surgical principle we termed the ‘principle of progress’. This principle reflects the supervisors’ and residents’ shared norm that maintaining progress throughout a surgical procedure is of utmost importance. Resident hesitation was perceived as the first indication of a disruption to this principle and was therefore interpreted by supervisors and residents alike as a sign of incompetence. This interpretation influenced the teaching–learning process during these moments when residents were working at the edge of their abilities.

Conclusions

The principle of progress influences the meaning of hesitation which, in turn, shapes judgements of competence. This has important implications for teaching and learning in direct supervision settings such as surgery. Without efforts to change the perception that hesitation represents incompetence, these potential teaching–learning moments will not fully support progressive autonomy.

     

The impact of statin use on the efficacy of abiraterone acetate in patients with castration‐resistant prostate cancer

Background

Statins compete with DHEAS for influx through the SLCO2B1 transporter, which may prolong time to progression (TTP) on androgen deprivation therapy. Abiraterone acetate (AA) may also undergo SLCO‐mediated transport. Based on preclinical findings showing antagonism, we hypothesized that statins may compete with AA for influx via SLCO2B1 and could negatively impact drug efficacy.

Methods

We queried two institutional clinical databases (Dana‐Farber Cancer Institute [DFCI], Johns Hopkins University [JHU]) for CRPC patients treated with AA. Treatment duration was a surrogate for TTP. Associations between statin use and AA duration were estimated using the Kaplan‐Meier method. Multivariable Cox regression modeling adjusted for known prognostic factors.

Results

Of the 224 DFCI and 270 JHU patients included, the majority (96%) had metastatic disease. Nearly half (41% and 45%) were statin users. In the DFCI cohort, there was a trend toward longer AA duration in statin users: 14.2 versus 9.2 months (HR 0.79, 95%CI: 0.57‐1.09, P = 0.14). There was no association between statin use and AA duration in the JHU cohort: 8.3 versus 8.0 months (HR 0.89, 95%CI: 0.69‐1.16, P = 0.38) in the statin users versus non‐users, except for a trend in patients that had not previously received docetaxel or enzalutamide (HR 0.79; 95%CI: 0.57‐1.10).

Conclusions

Contrary to our initial hypothesis, there was a trend toward longer (rather than shorter) AA duration in statin users in the entire DFCI cohort and in the enzalutamide‐ and docetaxel‐naïve JHU patients. Together, these results do not support the hypothesis that statins interfere with AA efficacy.     

Silence, power and communication in the operating room

Title.  Silence, power and communication in the operating room.
Aim.  This paper is a report of a study conducted to explore whether a 1- to 3-minute preoperative interprofessional team briefing with a structured checklist was an effective way to support communication in the operating room.
Background.  Previous research suggests that nurses often feel constrained in their ability to communicate with physicians. Previous research on silence and power suggests that silence is not only a reflection of powerlessness or passivity, and that silence and speech are not opposites, but closely interrelated.
Methods.  We conducted a retrospective study of silences observed in communication between nurses and surgeons in a multi-site observational study of interprofessional communication in the operating room. Over 700 surgical procedures were observed from 2005–2007. Instances of communication characterized by unresolved or unarticulated issues were identified in field notes and analysed from a critical ethnography perspective.
Findings.  We identified three forms of recurring 'silences': absence of communication; not responding to queries or requests; and speaking quietly. These silences may be defensive or strategic, and they may be influenced by larger institutional and structural power dynamics as well as by the immediate situational context.
Conclusions.  There is no single answer to the question of why 'nobody said anything'. Exploring silences in relation to power suggests that there are multiple and complex ways that constrained communication is produced in the operating room, which are essential to understand in order to improve interprofessional communication and collaboration.     

Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME‐ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene‐based and pathway‐based analyses by applying the summary‐based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME‐ON and PLCO, after Bonferroni correction (p_pathway < 0.00625). The two most significant genes were NPAS2 (p_gene = 0.0062) and AANAT (p_gene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME‐ON (p_pathway = 0.021); this association was not confirmed in GECCO (p_pathway = 0.76) or the combined data (p_pathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.     

Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors.

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m(2) BID for 7 days) during the first study period, followed by 5-FU (300 mg/m(2) CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary alpha-fluoro-beta-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for > or = 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean +/- SD steady-state plasma concentration (C(P)) and area under the curve (AUC)(144-168h) for CVI 5-FU (104 +/- 45 ng/mL and 2,350 +/- 826 ng x h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 +/- 7.7 ng/mL and 722 +/- 182 ng x h/mL, respectively [P <.00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state C(P) and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.