European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update

Context

The European Association of Urology (EAU) Guideline Group for urothelial cell carcinoma of the upper urinary tract (UUT-UCC) has prepared new guidelines to aid clinicians in assessing the current evidence-based management of UUT-UCC and to incorporate present recommendations into daily clinical practice.

Objective

This paper provides a brief overview of the EAU guidelines on UUT-UCC as an aid to clinicians in their daily practice.

Evidence acquisition

The recommendations provided in the current guidelines are based on a thorough review of available UUT-UCC guidelines and papers identified using a systematic search of Medline. Data on urothelial malignancies and UUT-UCCs in the literature were searched using Medline with the following keywords: urinary tract cancer, urothelial carcinomas, upper urinary tract, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant treatment, neoadjuvant treatment, recurrence, risk factors, and survival. A panel of experts weighted the references.

Evidence synthesis

There is a lack of data in the current literature to provide strong recommendations due to the rarity of the disease. A number of recent multicentre studies are now available, whereas earlier publications were based only on limited populations. However, most of these studies have been retrospective analyses. The TNM classification 2009 is recommended. Recommendations are given for diagnosis as well as for radical and conservative treatment; prognostic factors are also discussed. Recommendations are provided for patient follow-up after different therapeutic options.

Conclusions

These guidelines contain information for the diagnosis and treatment of individual patients according to a current standardised approach. When determining the optimal treatment regimen, physicians must take into account each individual patient's specific clinical characteristics with regard to renal function including medical comorbidities; tumour location, grade and stage; and molecular marker status.     

EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update

Context and objective

To present the 2011 European Association of Urology (EAU) guidelines on non–muscle-invasive bladder cancer (NMIBC).

Evidence acquisition

Literature published between 2004 and 2010 on the diagnosis and treatment of NMIBC was systematically reviewed. Previous guidelines were updated, and the level of evidence (LE) and grade of recommendation (GR) were assigned.

Evidence synthesis

Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TUR is essential for the patient's prognosis. Where the initial resection is incomplete or where a high-grade or T1 tumour is detected, a second TUR should be performed within 2–6 wk.In papillary tumours, the risks of both recurrence and progression may be estimated for individual patients using the scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups—separately for recurrence and progression—is pivotal to recommending adjuvant treatment. For patients with a low risk of tumour recurrence and progression, one immediate instillation of chemotherapy is recommended. Patients with an intermediate or high risk of recurrence and an intermediate risk of progression should receive one immediate instillation of chemotherapy followed by a minimum of 1 yr of bacillus Calmette-Guérin (BCG) intravesical immunotherapy or further instillations of chemotherapy. Papillary tumours with a high risk of progression and CIS should receive intravesical BCG for 1 yr.Cystectomy may be offered to the highest risk patients, and it is at least recommended in BCG failure patients. The long version of the guidelines is available from the EAU Web site (www.uroweb.org).

Conclusions

These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice.     

Seasonal Variation in the Brain μ-Opioid Receptor Availability

Seasonal rhythms influence mood and sociability. The brain μ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported in vivo evidence. Here, we first conducted a cross-sectional study with previously acquired human [¹¹C]carfentanil PET imaging data (132 male and 72 female healthy subjects) to test whether there is seasonal variation in MOR availability. We then investigated experimentally whether seasonal variation in daylength causally influences brain MOR availability in rats. Rats (six male and three female rats) underwent daylength cycle simulating seasonal changes; control animals (two male and one female rats) were kept under constant daylength. Animals were scanned repeatedly with [¹¹C]carfentanil PET imaging. Seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability in humans. Brain regions sensitive to daylength spanned the socioemotional brain circuits, where MOR availability peaked during spring. In rats, MOR availabilities in the brain neocortex, thalamus, and striatum peaked at intermediate daylength. Varying daylength also affected the weight gain and stress hormone levels. We conclude that cerebral MOR availability in humans and rats shows significant seasonal variation, which is predominately associated with seasonal photoperiodic variation. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.SIGNIFICANCE STATEMENT Seasonal rhythms influence emotion and sociability. The central μ-opioid receptor (MOR) system modulates numerous seasonally varying socioemotional functions, but its seasonal variation remains elusive. Here we used positron emission tomography to show that MOR levels in both human and rat brains show daylength-dependent seasonal variation. The highest MOR availability was observed at intermediate daylengths. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.     

Insular dopamine D2 receptors and novelty seeking personality in Parkinson's disease.

Novelty seeking is a temperament trait characterized by impulsiveness and exploratory behavior. Dopamine has been suggested to be the primary neurotransmitter modulator of novelty seeking, and in young healthy subjects, a correlation between increased novelty seeking and decreased insular cortical dopamine D2 receptor availability has been reported. The proposed link between dopamine deficiency and reduction in novelty seeking in Parkinson's disease is controversial. The present study examined whether a link between insular D2 receptor availability and novelty seeking can be replicated in Parkinson's disease patients. [11C]FLB 457 positron emission tomography imaging was carried out in 28 patients with Parkinson's disease, and the data were analyzed using voxel-based statistical analysis. The results demonstrated a negative correlation between the novelty seeking score and the dopamine D2 availability bilaterally in the insular cortex (corrected P=0.001; r=-0.74 [right hemisphere]; r=-0.66 [left hemisphere]). The results provide further support for a relationship between novelty seeking and insular D2 receptors. They indicate that the association is cross-cultural, independent of age, and unaffected by dopaminergic degeneration.     

Mapping brain structure and personality in late adulthood

Cerebral gray matter (GM) volume decreases in normal aging with a parallel increase in intracranial cerebrospinal fluid (CSF) volume. There is considerable interindividual variation in these changes, and the consequences of age-related GM shrinkage and CSF expansion are unclear. The present study examined whether late adulthood brain structural differences are related to differences in temperament and character. Personality structures of 42 healthy aged adults (mean age 60 years) were examined together with global and regional GM, CSF, and white matter (WM) volumes calculated from structural magnetic resonance images using voxel-based morphometry (VBM). A positive relationship was seen between GM volume at the border of the temporal, parietal, and frontal cortices, and self-transcendence, a character personality trait that reflects mature creativity and spiritualism. The relationship remained significant after a conservative correction for multiple comparisons and it was seen both using uncorrected raw values and after a correction for the effects of age and sex. The results suggest that high self-transcendence, which has adaptive advantages in the later part of life, is associated with relatively greater temporal cortical GM volumes.     

Autophagy generates retrogradely transported organelles: a hypothesis

Nerve cells require trophic signals transmitted from the nerve terminal via the axon in order to survive and develop normally. As the axon may be more than a meter long, specialised mechanisms are needed to transmit these signals. This involves the retrograde axonal transport of signalling endosomes containing nerve growth factor (NGF) and other synaptically derived molecules. These are large, double membrane multivesicular bodies containing a mixture of all vesicle types seen in the nerve terminal. How this signalling endosome is formed and targeted for retrograde axonal transport, however, remains an open question. Here we show that members of the Rab family of proteins that are retrogradely transported indicate that the signalling endosome contains both early and recycling endosomes. In addition, we show that retrogradely transported labelled antibody to dopamine beta-hydroxylase, a marker for synaptic vesicles, co-localizes within the same signalling endosome as NGF. We further show that LC3, a marker for autophagosomes, is retrogradely transported and associates with retrogradely transported NGF. We propose that neurons have exploited the mechanism of autophagy to engulf a sample of the cytoplasmic contents of the nerve terminal to transport back to the cell body. This sample of cytoplasmic contents relays a reliable snapshot of the totality of signalling events occurring in the nerve terminal at that instant in time.     

Eye contact and arousal: the effects of stimulus duration

The present study investigated the effect of stimulus duration on skin conductance responses (SCRs) evoked by different gaze directions of a live person. In two separate parts of the experiment, either two fixed stimulus durations (2 s and 5 s) or a participant-controlled stimulus duration was used. The results showed that the eye contact evoked enhanced SCRs compared to averted gaze or closed eyes conditions irrespective of the presentation time. Subjective evaluations of approach-avoidance-tendencies indicated that the direct gaze elicited either approach or avoidance, depending on the participant. Participants who had evaluated a direct gaze-condition as approachable were found to be more emotionally stabile than those who had evaluated the same condition as avoidable. In the self-timing condition, averted gaze was looked at longer than direct gaze. Our results suggest that direct gaze, also when encountered only briefly like in every-day social encounterings, increases autonomic sympathetic arousal.     

Extrastriatal dopamine D<Subscript>2</Subscript> receptors in Parkinson's disease: a longitudinal study

Most antiparkinsonian drugs are known to act through central dopamine D(2) receptor agonism. A previous longitudinal positron emission tomography (PET) study has indicated that, in the striatum of Parkinson's disease (PD) patients, dopamine D(2) receptor binding declines at a relatively fast annual rate of 2-4% (compared to the rate of <1%/year in healthy individuals). In the present study, the examination of longitudinal changes in D(2) receptors was extended to extrastriatal brain regions in PD. Eight early PD patients were examined twice with PET, approximately 3 years apart, using a high-affinity extrastriatal D(2)/D(3) receptor tracer, [(11)C]FLB 457. Both the MRI-referenced region-of-interest method and the voxel-based statistical analysis method were used independently in the analysis. Regional D(2)-like availabilities (binding potentials) in the left dorsolateral prefrontal cortex, the left temporal cortex and the left and right medial thalami were significantly decreased at the second examination by 20-37% (corresponding to an annual decline of 6-11%). Thus, the annual loss of extrastriatal D(2) availability in PD is up to three times faster than the rate previously reported in the putamen. Our longitudinal study shows first evidence concerning cortical D(2) receptor loss in the progression of PD, although it is not possible to distinguish between the effects of the therapy and the disease.