Salvatore Terrazzino

Voltage‐gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin‐induced peripheral neurotoxicity: Results from a prospective multicenter study

The current prospective, multicenter study sought to identify single nucleotide polymorphisms of voltage‐gated sodium channels (SCNAs) genes that might confer susceptibility to an increased incidence and severity of oxaliplatin‐induced peripheral neuropathy (OXAIPN) in patients treated with either leucovorin, 5‐fluorouracil, and oxaliplatin (FOLFOX) or oxaliplatin plus capecitabine (XELOX) for colorectal cancer (CRC).

Common Variants of GSTP1, GSTA1, and TGFβ1 are Associated With the Risk of Radiation-Induced Fibrosis in Breast Cancer Patients

PURPOSE To provide new insights into the genetic basis of normal tissue radiosensitivity, we evaluated the association between eight polymorphic variants located in six genes related to DNA repair mechanisms, oxidative stress, and fibroblast proliferation (XRCC1 Arg399Gln, XRCC1 Arg194Trp, TP53 Arg72Pro, GSTP1 Ile105Val, GSTA1 C-69T, eNOS G894T, TGFβ1 C-509T, and TGFβ1 T869C) and the risk of subcutaneous fibrosis in a retrospective series of patients who received radiotherapy after breast-conserving surgery. METHODS AND MATERIALS Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue--Subjective Objective Management Analytical scale in 257 breast cancer patients who underwent surgery plus adjuvant radiotherapy. Genotyping was conducted by polymerase chain reaction--restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. The association between genetic variants and the risk of moderate to severe fibrosis was evaluated by binary logistic regression analysis. RESULTS Two hundred thirty-seven patients were available for the analysis. Among them, 41 patients (17.3%) developed moderate to severe fibrosis (Grade 2-3), and 196 (82.7%) patients displayed no or minimal fibrotic reactions (Grade 0-1). After adjustment of confounding factors, GSTP1 Ile105Val (odds ratio [OR] 2.756; 95% CI, 1.188-6.393; p = 0.018), GSTA1 C-69T (OR 3.223; 95% CI, 1.176-8.826; p = 0.022), and TGFβ1 T869C (OR 0.295; 95% CI, 0.090-0.964; p = 0.043) polymorphisms were found to be significantly associated with the risk of Grade 2-3 radiation-induced fibrosis. In the combined analysis, carriers of three risk genotypes were found to be at higher odds for the development of Grade 2-3 fibrosis than were patients with two risk genotypes (OR 4.415; 95% CI, 1.553-12.551, p = 0.005) or with no or one risk genotype (OR 8.563; 95% CI, 2.671-27.447; p = 0.0003). CONCLUSIONS These results suggest that functional variations in genes involved in oxidative stress response and fibroblast proliferation may modulate the development of radiation-induced fibrosis in breast cancer patients. The results of the combined analysis support the notion that approaches based on the combination of different genetic markers have the potential to predict normal tissue responses.

The serotonin transporter gene polymorphism STin2 VNTR confers an increased risk of inconsistent response to triptans in migraine patients.

The aim of the present observational study was to assess the value of the C825T polymorphism of the beta-3 subunit of G proteins (GNB3) as well as of variants in the SLC6A4 gene (5HTTLPR and STin2 VNTR) and DRD2 gene (TaqI A and NcoI) as predictive markers for consistency in headache response to triptans in migraine patients. Consistent responders to triptans were defined as the migraineurs who experienced a > or =2 point reduction in a 4-point scale intensity of pain from 3 (severe) to 0 (absent) 2h after triptan administration, in at least two attacks out of the three. Genotyping was performed by PCR and PCR-RFLP on genomic DNA extracted from peripheral blood. The impact of clinical and biological variables on consistency status of headache response to triptans was evaluated by using a binary logistic regression model with stepwise selection. Forty-three (33%) of the 130 migraine patients included in the study did not consistently respond to triptan administration. In a binary logistic regression model, STin 2.12/12 genotype (OR=3.363, 95% CI: 1.262-8.966, P=0.005) and non-use of migraine prophylactic medications (OR=2.848, 95% CI: 1.019-7.959, P=0.010) were found as significant factors increasing the odds of achieving inconsistent response to triptans. The analysis of classificatory power of the model showed moderate values of sensitivity (0.56), high specificity (0.87), and an overall prediction correctness (0.77). These results support the role of STin2 VNTR polymorphism of serotonin transporter gene as a relevant genetic factor conferring a higher risk of inconsistent response to triptans in migraine patients.

Migraine aura symptoms: Duration, succession and temporal relationship to headache

Background As there are no biological markers, a detailed description of symptoms, particularly temporal characteristics, is crucial when diagnosing migraine aura. Hitherto these temporal aspects have not been studied in detail. Methods We conducted a prospective diary-aided study of the duration and the succession of aura symptoms and their temporal relationship with headache. Results Fifty-four patients completed the study recording in a diary the characteristics of three consecutive auras (n = 162 auras). The median duration of visual, sensory and dysphasic symptoms were 30, 20 and 20 minutes, respectively. Visual symptoms lasted for more than one hour in 14% of auras (n = 158), sensory symptoms in 21% of auras (n = 52), and dysphasic symptoms in 17% of auras (n = 18). Twenty-six percent of patients had at least one aura out of three with one symptom lasting for more than one hour. In aura with multiple symptoms the subsequent symptom, second versus first one or third versus second, might either start simultaneously (34 and 18%), during (37 and 55%), with the end (5 and 9%), or after (24 and 18%) the previous aura symptom. The headache phase started before the aura (9%), simultaneously with the onset of aura (14%), during the aura (26%), simultaneously with the end of aura (15%) or after the end of aura (36%). Conclusion We provide data to suggest that symptoms may last longer than one hour in a relevant proportion of auras or migraine with aura patients, and that there is a high variability of scenarios in terms of time relationship among aura symptoms and between aura and headache.

Triptan nonresponders: Do they exist and who are they?

Background: Triptans represent the best treatment option for most migraine attacks, although this is not as well studied as it might be in controlled trials. Their efficacy and tolerability vary, both between agents, and from patient to patient, with about 30%–40% of patients not responding adequately to therapy. As yet unexplained, the failure of one triptan does not predict failure with another, and therefore triptan nonresponders cannot be defined as individuals who have failed a single triptan. Five clinical studies provide evidence that switching from a triptan that is ineffective to a second one can result in effective treatment in a proportion of patients. Systematic studies investigating whether there are patients who do not respond to all triptans in all formulations are lacking. Methods: Here we discuss the importance of identifying triptan nonresponders, the literature supporting their existence, and the issues to be resolved to design trials to investigate this. Conclusion: So far, no scientific data about the presence of a triptan nonresponder population are available. We propose a pragmatic study design to assess the existence of this subpopulation, recognizing the complexity of the question and the likelihood that more than one issue is at play in nonresponders.

Genetic determinants of chronic oxaliplatin-induced peripheral neurotoxicity: a genome-wide study replication and meta-analysis

We aimed at validating the role of genetic variants identified by a recent genome‐wide association study (GWAS) as determinants of chronic oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin‐based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI‐CTC criteria and the clinical version of the Total Neuropathy Score© (TNSc©). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI‐CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc© scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10–0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI‐CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI‐CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40–5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P‐value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta‐analysis for validation of GWAS findings.

Clinical features of migraine aura: Results from a prospective diary-aided study

Background A detailed evaluation of migraine aura symptoms is crucial for classification issues and pathophysiological discussion. Few studies have focused on the detailed clinical aspects of migraine aura. Methods We conducted a prospective diary-based study of migraine aura features including presence, quality, laterality, duration of each aura symptom, their temporal succession; presence of headache and its temporal succession with aura. Results Seventy-two patients completed the study recording the characteristics of three consecutive auras (n = 216 auras). Visual symptoms occurred in 212 (98%), sensory symptoms in 77 (36%) and dysphasic symptoms in 22 (10%). Most auras had more than one visual symptom (median 2, IQR 1–3, range 1–4). The majority of patients (56%) did not report a stereotyped aura on the three attacks with respect to visual features, the combination and/or temporal succession of the three aura symptoms. Fifty-seven percent of patients also reported a different scenario of temporal succession between aura and headache in the three attacks. Five per cent of aura symptoms were longer than four hours. Conclusion These findings show a high inter- and intravariability of migraine with aura attacks. Furthermore, they provide reliable data to enrich and clarify the spectrum of the aura phenotype.

O011. Patients with “prolonged aura” do not show clinical or demographic differences from the patients with “typical aura”

Background A recent systematic review of the duration of migraine aura reported that aura symptoms may last longer than one hour in a significant proportion of patients [1]. Here we investigated in a prospective diary-aided study whether patients with a “prolonged aura” (PA an aura in which there is at least one symptom lasting for more than one hour) are different from the patients with a “typical aura” (TA).

Impact of SLC22A1 and CYP3A5 genotypes on imatinib response in chronic myeloid leukemia: A systematic review and meta-analysis

Graphical abstract Figure. No caption available. ABSTRACT Contrasting results have been reported on the role of rs628031 and rs683369 polymorphisms of SLC22A1 and rs776746 of CYP3A5 on imatinib treatment response in patients with chronic myeloid leukemia (CML). In the present study, we conducted a systematic review and meta‐analysis of published studies to estimate the impact of the above‐mentioned gene variants on major molecular response (MMR) or complete cytogenetic response (CCyR) in imatinib‐treated CML patients. We performed a comprehensive search through PubMed, Web of Knowledge, and Cochrane databases up to September 2017. The pooled analyses showed association between carriers of SLC22A1 rs628031A allele (GA + AA vs GG, OR: 0.58, 95% CI: 0.38–0.88, P = 0.011) or rs683369G allele (CG + GG vs CC, OR: 0.64, 95% CI: 0.42–0.96, P = 0.032) and a lower MMR rate. The combined analyses also revealed a correlation between the dominant (GG + AG vs AA, OR: 2.43, 95%CI: 1.12–5.27, P = 0.024) or the allelic model (G vs A, OR: 1.72, 95% CI: 1.09–2.72, P = 0.020) of CYP3A5 rs776746 with higher CCyR rates. The subsequent sensitivity analysis confirmed the statistical significance of CYP3A5 rs776746 among Asian CML patients (dominant model OR: 3.90; 95%CI: 2.47–6.14, P < 0.001; allelic model OR: 2.08; 95% CI: 1.47–2.95, P < 0.001). In conclusion, the present meta‐analysis supports the association of SLC22A1 and CYP3A5 genotypes with clinical imatinib response rates of CML patients, nevertheless further large studies, particularly in Caucasians, are still warranted to provide conclusive evidences.