CRY1 Variations Impacts on the Depressive Relapse Rate in a Sample of Bipolar Patients

Objective

A relevant part of the social and personal burden caused by Bipolar Disorder (BD) is related to depressive phases. Authors investigated the genetic impact of a set of variations located in CRY1, a gene involved in the control of the circadian rhythms, towards depressive episodes in a sample of bipolar patients from the STEP-BD sample. As a secondary analysis, CYR1 variations were analyzed as predictors of sleep disruption.

Methods

654 bipolar patients were included in the analysis. Data were available genome-wide. The part of the genome coding for the CRY1 was imputed and pruned according to standards in the field. 7 SNPs were available for the analysis. A correction for multitesting was applied and we had sufficient power (0.80) to detect a small-medium effect size (0.22) between two allelic frequencies each one represented by at least 300 subjects.

Results

Intronic rs10861688 was associated with the number of depressive events corrected for the times patients were assessed during the period of observation. In particular, AA subjects (n=21) had 4.46±3.15 events, AG (n=141) had 3.08±3.17 and GG (n=342) 2.65±2.97 (p=0.0048, beta=-0.22). No other significant associations were reported.

Conclusion

We bring further evidence that genes involved in the regulation of circadian rhythms may be relevant to depressive bipolar phases. Independent confirmation analyses are mandatory.     

Salvage image-guided intensity modulated or stereotactic body reirradiation of local recurrence of prostate cancer

Objective:

To retrospectively evaluate external beam reirradiation (re-EBRT) delivered to the prostate/prostatic bed for local recurrence, after radical or adjuvant/salvage radiotherapy (RT).

Methods:

32 patients received re-EBRT between February 2008 and October 2013. All patients had clinical/radiological local relapse in the prostate or prostatic bed and no distant metastasis. re-EBRT was delivered with selective RT technologies [stereotactic RT including CyberKnife^TM (Accuray, Sunnyvale, CA); image-guidance and intensity-modulated RT etc.]. Toxicity was evaluated using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Biochemical control was assessed according to the Phoenix definition (NADIR + 2 ng ml⁻¹).

Results:

Acute urinary toxicity: G0, 24 patients; G1, 6 patients; G2, 2 patients. Acute rectal toxicity: G0, 28 patients; G1, 2 patients; and G2, 1 patient. Late urinary toxicity (evaluated in 30 cases): G0, 23 patients; G1, 6 patients; G2, 1 patient. Late renal toxicity: G0, 25 patients; G1, 5 patients. A mean follow-up of 21.3 months after re-EBRT showed that 13 patients were free of cancer, 3 were alive with biochemical relapse and 12 patients were alive with clinically evident disease. Four patients had died: two of disease progression and two of other causes.

Conclusion:

re-EBRT using modern technology is a feasible approach for local prostate cancer recurrence offering 2-year tumour control in about half of the patients. Toxicity of re-EBRT is low. Future studies are needed to identify the patients who would benefit most from this treatment.

Advances in knowledge:

Our series, based on experience in one hospital alone, shows that re-EBRT for local relapse of prostate cancer is feasible and offers a 2-year cure in about half of the patients.Modern external beam irradiation (EBRT) is considered a cornerstone of the radical treatment of localized prostate cancer. Technological advances have been progressively introduced, using highly conformed techniques and dose escalation. In spite of this, the rate of biochemical failure ranges between 33% and 69%.^1–4 New imaging modalities such as ¹¹C-choline positron emission tomography/CT (PET/CT) or multiparametric MRI (mpMRI) are now able to detect clinically evident disease with a rate up to 75% for ¹¹C-choline-PET/CT at a prostate specific antigen (PSA) value >3 ng ml⁻¹.⁵ In up to 50% of patients with PET/CT-positive scans, isolated local relapse is diagnosed.⁵In the case of solid tumours, the approach to isolated local relapse is local treatment [surgery, radiotherapy (RT) etc.], whenever possible, and systemic therapy is rarely used. Paradoxically, in the case of prostate cancer local relapse, systemic androgen deprivation therapy (ADT) is the standard-of-care approach [National Comprehensive Cancer Network (NCCN) guidelines].⁶ Such treatment has a mainly palliative intent and is continued life long, giving rise to numerous side effects, deterioration in the quality of life and high social costs.According to the NCCN guidelines, a local approach including surgery, cryotherapy or brachytherapy should be considered for patients candidated for local salvage treatment: patients with documented recurrent local disease of limited aggressiveness (low Gleason score, stage and initial PSA), a long time interval between primary EBRT and recurrence and a slow PSA evolution. Indeed, in this clinical scenario, effective local therapy appears a more convenient strategy for controlling local disease, and it reduces the burden of systemic therapy. Radical salvage surgery is rarely used in this situation although recent studies suggest that it is more effective than other salvage treatment modalities, such as cryotherapy, high-intensity focus ultrasound (HIFU) or brachytherapy, in terms of biochemical control.⁷ The disadvantage of salvage surgery includes the risk of severe perioperative and post-operative complications owing to previous therapies and the advanced age of the patients (comorbidities). Brachytherapy might be an option for some patients, however low-dose-rate (LDR) brachytherapy requires general anaesthesia and hospitalization. It is important to note that modern technologies with image-guided intensity-modulated RT (IG-IMRT) or stereotactic body RT (SBRT) allow for the precise delivery of high radiation doses. Several dosimetric planning studies confirm that the target dose distribution might be similar between high-dose-rate brachytherapy and non-invasive EBRT, such as CyberKnife^TM (Accuray, Sunnyvale, CA).^8,9 Ablative hypofractionation regimens are commonly chosen for high-precision RT, which may increase the chance of killing prostate cancer cells, owing to their low alpha/beta ratio. Recently, several reports on stereotactic prostate reirradiation have been published: Vavassori et al¹⁰ reported the preliminary results on six patients treated with Cyberknife SBRT (30 Gy in five fractions over five consecutive days). This study was later updated by Jereczek-Fossa et al:¹¹ complete response was obtained in six out of nine patients (without any systemic therapy) with a low toxicity profile (no rectal toxicity and few urinary events). The pattern of failure was predominantly out of field (four out of five events). The authors concluded that CyberKnife reirradiation is a feasible and safe approach and offers excellent in-field tumour control.On this basis, we present a retrospective analysis of the series of patients who underwent salvage re-EBRT using highly selective modalities (IG-IMRT or SBRT) for local recurrence after radical or post-prostatectomy/salvage RT.     

Clinical,neuroradiological and genetic findings in a cohort of patients with multiple Cerebral Cavernous Malformations

Metabolic Brain Disease - Cerebral cavernous malformations (CCM) consist of clusters of irregular dilated capillaries and represent the second most common type of vascular malformation affecting...     

Employment of the mouse median nerve model for the experimental assessment of peripheral nerve regeneration

The experimental investigation of nerve regeneration after microsurgical repair is usually carried out in rats, rather than mice, because of the larger sized peripheral nerves. Today however, the availability of genetically modified mice makes the use of this laboratory animal very intriguing for investigating nerve regeneration at a molecular level. In this study we aimed to provide a standardization of the experimental model based on microsurgical direct repair, by 12/0 suture, of the left median nerve in adult male mice. Postoperative recovery was regularly assessed by the grasping test. At day-75 postoperative, regenerated median nerve fibers were analyzed by design-based quantitative morphology and electron microscopy. Yet, sections were immuno-labelled using two axonal antibodies commonly employed for rat nerve fibers. Results indicated that functional recovery begun at day-15 and progressively increased reaching values not significantly different from normal by day-50. Quantitative morphology showed that, at day-75, the number of regenerated nerve fibers was not significantly different in comparison to controls. In contrast, differences were detected in fiber density, mean axon and fiber diameter and myelin thickness which were all significantly lower than controls. Immunohistochemistry showed that axonal markers commonly used for rat nerves studies are effective also for mouse nerves. Similar to the rat, the mouse median nerve model is superior to sciatic nerve model for the minimal impact on animal well-being and the effectiveness of the grasping test for motor function evaluation. The main limitation is the small nerve size which requires advanced microsurgical skills for performing 12/0 epineurial suturing.     

Novel Twinkle (PEO1) gene mutations in mendelian progressive external ophthalmoplegia

Multiple deletions of mitochondrial DNA (mtDNA) are associated with different mitochondrial disorders inherited as autosomal dominant and recessive traits. Causative mutations have been found in five genes, mainly involved in mtDNA replication and stability. They include POLG1, the gene encoding the catalytic subunit of mtDNA polymerase (pol gamma), POLG2 encoding its accessory subunit, ANT1 coding the adenine nucleotide translocator and PEO1 which codes for Twinkle, the mitochondrial helicase. Finally OPA1 missense mutations are involved in phenotypes presenting optic atrophy as a major feature.To define the relative contribution of POLG1, POLG2, ANT1 and PEO1 genes to the mtDNA multiple deletion syndromes, we analysed them in a cohort of 67 probands showing accumulation of multiple mtDNA deletions in muscle. The patients were predominantly affected with a mitochondrial myopathy with or without progressive external ophthalmoplegia (PEO). Genetic analysis revealed that 1) PEO1 has a major role in determining familial PEO, since it accounts for 26.8% of familial cases, followed by ANT1 (14.6%) and POLG1 (9.8%); 2) no mutations in any of the known genes were found in 53.7% of probands of this series. Six novel missense mutations contributing to the mutational load of PEO1 gene (p.R334P, p.W315S, p. S426N, p.W474S, p.F478I, p.E479K) were associated with an adult onset PEO phenotype.     

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

The serotonin transporter gene promoter polymorphism (5-HTTLPR) has been repeatedly associated with antidepressant response in mood disorder patients, but findings are not consistent across studies. A meta-analysis was performed on 15 studies including data of 1435 subjects. We tested three phenotypes: remission rate, response rate and response rate within 4 weeks using the cochrane review manager. We observed a significant association of the s/s variant of 5-HTTLPR with remission rate (P<0.0001) and both s/s and s/l variants with response rate (P=0.0002). Response rate within 4 weeks was associated in both models (P=0.003-P<0.00001). This effect is quite robust to ethnic differences although a significant heterogeneity is present in Asian samples.     

Prevalence and severity of dementia among northern Italian centenarians.

Using diagnostic criteria from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, dementia was clinically diagnosed in 57 (62%) of 92 centenarians living in two northern Italian provinces. The condition was severely disabling in approximately 70% of the demented patients. Although clinically diagnosed AD accounted for 79% of dementia cases, almost one third of patients with AD had risk factors for vascular dementia, suggesting that the aging brain may be susceptible to multiple additive factors that impair cognition.