Emicrania cronica refrattaria: efficacia e tollerabilita di OnabotuilinumtoxinA nell'esperienza clinica

Lo studio ha avuto l’obiettivo di valutare l’efficacia e la tollerabilità di OnabotulinumtoxinA nel trattamento profilattico dell’emicrania cronica refrattaria (cefalea che si presenta per almeno 15 giorni/mese con mancata risposta ad almeno due classi di farmaci profilattici di nota efficacia, da soli o in combinazione, somministrati a dosi sufficienti e per un periodo di tempo adeguato). Da maggio 2015 a maggio 2016 sono stati reclutati pazienti rispondenti ai criteri diagnostici per emicrania cronica refrattaria. I pazienti sono stati trattati ogni tre mesi in accordo con le procedure standard (155-195 unità). Al T0 e dopo sei mesi, prima della terza somministrazione (T1), è stato somministrato un questionario strutturato, comprendente: a) fattori riguardati l’emicrania [frequenza (numero di giorni di cefalea per mese), gravità del dolore (Verbal Numeric Scale, VNS), numero di assunzioni di farmaci sintomatici per mese, disabilità (Headache Impact Test, HIT-6), allodinia cutanea (Allodynia Symptoms Check-list 12, ASC-12); b) sintomi associati (fatica (Fatigue Severity Scale, FSS), sintomi d’ansia (Generalized Anxiety Disorder, GAD-7), sintomi depressivi (Patient Health Questionnaire, PHQ-9)]. I valori delle variabili riscontrati al T0 e al T1 sono stati confrontati con il test di Wilcoxon. Sono stati arruolati trentuno pazienti (M/F 7/24; età: Me=50.5 IQR=30). Solo uno ha abbandonato lo studio dopo la prima somministrazione a causa di effetti collaterali (ptosi palpebrale bilaterale). Trenta pazienti, invece, sono stati valutati al T1, riportando questi cambiamenti sulle caratteristiche dell’emicrania: frequenza al T0 Me=30 IQR=14, frequenza al T1 Me=14 IQR=26; T0 VNS Me=8.25 IQR=5, T1 VNS Me=8 IQR=7; uso di sintomatici/mese al T0 Me=20 IQR=30, uso di sintomatici/mese al T1 Me=10 IQR=30; T0 HIT-6 Me=65.5 IQR=24, T1 HIT-6 Me=63 IQR=26; T0 ASC-12 Me=7 IQR=13, T1 ASC-12 Me=6 IQR=16. I sintomi associati hanno subito la seguente variazione: T0 FSS Me=47 IQR=54, T1 FSS Me=36 IQR=54; T0 GAD-7 Me=10 IQR=18, T1 GAD-7 Me=8 IQR=17; T0 PHQ-9 Me=9 IQR=20, T1 PHQ-9 Me=7 IQR=19. Dopo due cicli di iniezioni con OnabotulinumtoxinA, la riduzione si è mostrata statisticamente significativa per le seguenti variabili: a) frequenza (P .000; r .50); b) uso di sintomatici/mese (P .000; r .51); c) FSS (P .009; r .34). La tossina botulinica di tipo A è risultata ben tollerata ed efficace nel ridurre la frequenza degli attacchi, l’uso di sintomatici e alcuni sintomi associati all’emicrania (fatica) negli emicranici cronici refrattaria. I nostri risultati supportano l’uso di OnabotulinumtoxinA come terapia profilattica laddove altri farmaci hanno fallito

Characterization of BRCA Deficiency in Ovarian Cancer

BRCA testing is recommended in all Ovarian Cancer (OC) patients, but the optimal approach is debated. The landscape of BRCA alterations was explored in 30 consecutive OC patients: 6 (20.0%) carried germline pathogenic variants, 1 (3.3%) a somatic mutation of BRCA2, 2 (6.7%) unclassified germline variants in BRCA1, and 5 (16.7%) hypermethylation of the BRCA1 promoter. Overall, 12 patients (40.0%) showed BRCA deficit (BD), due to inactivation of both alleles of either BRCA1 or BRCA2, while 18 (60.0%) had undetected/unclear BRCA deficit (BU). Regarding sequence changes, analysis performed on Formalin-Fixed-Paraffin-Embedded tissue through a validated diagnostic protocol showed 100% accuracy, compared with 96.3% for Snap-Frozen tissue and 77.8% for the pre-diagnostic Formalin-Fixed-Paraffin-Embedded protocol. BD tumors, compared to BU, showed a significantly higher rate of small genomic rearrangements. After a median follow-up of 60.3 months, the mean PFS was 54.9 ± 27.2 months in BD patients and 34.6 ± 26.7 months in BU patients (p = 0.055). The analysis of other cancer genes in BU patients identified a carrier of a pathogenic germline variant in RAD51C. Thus, BRCA sequencing alone may miss tumors potentially responsive to specific treatments (due to BRCA1 promoter methylation or mutations in other genes) while unvalidated FFPE approaches may yield false-positive results

Landscape of Constitutional <i>SOX4</i> Variation in Human Disorders

SOX proteins are transcription factors which play a role in regulating the development of progenitor cells and tissue differentiation. Twenty members are known, clustered in eight groups named A through H and sharing a common DNA-binding domain called the HMG (high-mobility-group) box. Eleven of the SOX genes have been associated with genetic disorders so far, covering a broad spectrum of developmental diseases. SOX4 is a single-exon gene and belongs to the SOXC group, together with SOX11 and SOX12. SOX4 variants have been recently described to cause a highly penetrant but heterogeneous disorder, with a phenotypic spectrum ranging from mild developmental delays and learning difficulties to intellectual disabilities with congenital anomalies. Nineteen pathogenic variants have been reported to date, generally de novo, heterozygous, and inactivating, either stop–gain or missense, the latter ones primarily targeting the HMG domain. Further, a bi-allelic variant was reported in a single consanguineous family. Copy number variants leading to whole gene deletion or duplication are rare and not clearly associated with any neurodevelopmental disorder. Many open questions remain regarding the definition of variants of unknown significance, a possible role of missense variants outside the HMG domain, genotype–phenotype correlation, the range of phenotypic spectrum and modifying factors, and treatment options

Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help?

Background: Detection of variants of uncertain significance (VUSs) in BRCA1 and BRCA2 genes poses relevant challenges for counseling and managing patients. VUS carriers should be managed similarly to probands with no BRCA1/2 variants detected, and predictive genetic testing in relatives is discouraged. However, miscomprehension of VUSs is common and can lead to inaccurate risk perception and biased decisions about prophylactic surgery. Therefore, efforts are needed to improve VUS evaluation and communication at an individual level.Aims: We aimed at investigating whether cosegregation analysis, integrated with a careful review of available functional data and in silico predictions, may improve VUSs interpretation and counseling in individual families.Methods: Patients with Breast Cancer (BC) and/or Ovarian Cancer (OC) fulfilling established criteria were offered genetic counseling and BRCA1/2 testing; VUSs identified in index cases were checked in other relatives affected by BC/OC whenever possible. As an alternative, if BC/OC clustered only in one branch of the family, the parental origin of the VUS was investigated. Public prediction tools and databases were used to collect additional information on the variants analyzed.Results: Out of 1045 patients undergoing BRCA1/2 testing in the period October 2011–April 2018, 66 (6.3%) carried class 3 VUSs. Cosegregation analysis was performed for 13 VUSs in 11 kindreds. Seven VUSs (53.8%) did not cosegregate with breast/ovarian cancer in the family, which provided evidence against their role in cancer clustering in those families. Among the 6 cosegregating VUSs, for two (BRCA1 c.5152+2T&gt;G and BRCA2 c.7975A&gt;G) additional evidence exists from databases and in silico tools supporting their pathogenicity, which reinforces the hypothesis they may have had a predisposing effect in respective families. For the remaining four VUSs (31%), cosegregation analysis failed to provide relevant information.Conclusion: Our findings suggest that cosegregation analysis in a clinical context may be helpful to improve test result interpretation in the specific family and, therefore, should be offered whenever possible. Besides, obtaining and sharing cosegregation data helps gathering evidence that may eventually contribute to VUS classification