Index cases from a clinically relevant cohort of 102 Spanish families with at least 3 cases of breast and/or ovarian cancer (at least 1 case diagnosed before age 50) in the same lineage were screened for germline mutations in the entire coding sequence and intron boundaries of the breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the prevalence of mutations was 43% in female breast/ovarian cancer families, 15% in female breast cancer families and 100% in male breast cancer families. Three recurrent mutations (185delAG, 589delCT and A1708E) explained 63% of BRCA1-related families. Early age at diagnosis of breast cancer, ovarian cancer, bilateral breast cancer, concomitant breast/ovarian cancer in a single patient and prostate cancer but not unilateral breast cancer were associated with BRCA1 and BRCA2 mutations. Male breast cancer was associated with BRCA2 mutations. The presence of male breast cancer was the only cancer phenotype that distinguished BRCA2-from BRCA1-related families. We have developed a logistic regression model for predicting the probability of harbouring a mutation in either BRCA1 or BRCA2 as a function of the cancer phenotype present in the family. The predictive positive and negative values of this model were 77.4% and 79%, respectively (probability cutoff of 30%). The findings of our work may be a useful tool for increasing the cost-effectiveness of genetic testing in familial cancer clinics. © 2002 Wiley-Liss, Inc. Key words: BRCA1; BRCA2; logistic regression modelCancer of the breast is the most common malignancy among women in Western countries. In 5-10% of these patients, the disease can be attributed to an inherited predisposition. 1 A linkagebased study estimated that the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 account, respectively, for 52% and 32% of all hereditary breast and/or ovarian cancer families with at least 4 breast cancer cases. [2][3][4] Mutation-based studies indicated that defects in the 2 breast/ovarian cancer susceptibility genes account for a varying fraction of breast cancer families in different populations. 5 The risk of breast and ovarian cancer associated with mutations in these 2 genes has been estimated, 4 and other cancer types to which mutation carriers are predisposed have been identified. 6 -9 Today, many families with a moderate number of breast and/or ovarian cancer cases seek genetic testing in familial cancer clinics. Unfortunately, current laboratory methods are costly and timeconsuming due to the fact that BRCA1 and BRCA2 mutations are apparently randomly distributed over the large coding sequence of both genes. 10 A negative result does not indicate the absence of genetic predisposition in the family because PCR-based protocols do not detect genomic rearrangements and allele-specific transcription defects. Moreover, there is also evidence of other as yet unknown predisposing genes. 4 Management of these families does not defer either without testing or with a negative testing result. Ideally, one would prefer to t...

Psoriasis is a chronic inflammatory skin disease whose clinical characteristics vary from patient to patient. We aimed to analyze how comorbidities and quality of life (QoL, as per the Dermatology Life Quality Index [DLQI]) may be affected by a family history of psoriasis and by age. The ARIZONA study was a multicenter, cross-sectional study in 1022 adult patients diagnosed with moderate to severe psoriasis at least 6 months prior to inclusion. The severity of psoriasis and the proportion of patients with comorbidities were not affected by the presence of a family history. The regression analysis revealed that the presence of a family history of psoriasis was associated with the effect on the patient's QoL (P = 0.002), regardless of disease severity. The mean DLQI total score varied significantly across age groups (5.1 ± 5.3 for the 18-30-year group, 5.7 ± 6.5 for the 31-60-year group and 3.8 ± 5.1 for the >60-year group; P = 0.001). In conclusion, the presence of a family history of psoriasis appears to disrupt QoL in patients with moderate to severe psoriasis, but it hardly affected the prevalence of comorbid conditions. The effect of age on QoL was particularly noticeable in younger patients, highlighting its negative impact. As expected, older patients appeared to be burdened with a higher number of comorbidities than their younger counterparts.

Background Post-marketing data are required to confirm the durability and the long-term benefit and safety of UST in CD in clinical practice. Our aims were: (1) to evaluate the retention rate of UST in CD patients and to identify predictive factors of UST discontinuation; (2) to assess UST short-term effectiveness; (3) to analyse the durability of the response to UST in the long-term; and (4) to evaluate the safety of UST in clinical practice. Methods Retrospective, multicentre study (>60 centres). Patients with active CD [(Harvey–Bradshaw (HBI) >4)] that received at least one dose of UST intravenously before July 2018 were included. Clinical activity plus biochemical parameters were assessed at every UST administration. Clinical remission was defined as HBI score ≤4, and clinical response as a decrease in HBI ≥3 points. Loss of efficacy was defined as reappearance of symptoms that led to intensify the treatment dose, add another medication to control CD, switching or surgery in patients with short-term remission. The retention rate of UST treatment and the cumulative incidence of loss of efficacy were evaluated by survival curves, and predictive factors were assessed by Cox-regression. The short-term response was evaluated at week 8 and after the induction (week 16). Factors associated with short-term remission were assessed by multivariate analysis. Adverse events were recorded. Data quality was assured by remote monitoring. Results 331 CD patients have been included up to date (Table 1). The incidence rate of UST discontinuation was 15% per patient-year of follow-up: 8%, 13% and 20% at 6, 12 and 18 months (Figure 1). Previous surgery was the only factor associated with a higher risk of UST discontinuation [Hazard ratio (HR) = 2.03, 95% confidence interval (CI) = 1.1–3.6]. Short-term efficacy is shown in Figure 2. Previous surgery (OR = 0.3, 95% CI = 0.2–0.6) and higher HBI score at baseline (OR = 0.8, 95% CI=0.8–0.9) were associated with an impaired response to UST at week 16. The cumulative incidence of loss of response was 32% per-patient-year of follow-up (Figure 3); A higher HBI score at baseline was associated with a higher risk of losing response (HR = 1.2, 95% CI = 1.1–1.3). Neither the concomitant treatment with immunosuppressants nor the number of previous biologics were associated with UST short- and long-term benefit. Thirty adverse events were reported in 25 (7%) patients (Table 2). Conclusion Sustain is the largest real clinical practice study of UST to treat CD patients with the longest follow-up reported to date. UST was demonstrated to be effective in real-world use in the short and long run. Safety was consistent with the known profile of UST.

Background Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice.

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We have observed that the frequency of D17S855 short alleles (139 bp and 141 bp) in individuals carrying BRCA1 germline mutations is higher than in controls (54% vs. 31%, p ‫؍‬ 0.0004). By unambiguously establishing mutation/ D17S855 phase in 18 BRCA1-positive families, we find that most (11 of 15 different mutations) BRCA1 defects are linked to chromosomes with short alleles (OR ‫؍‬ 8.21, 95% CI 1.97-39.32, p ‫؍‬ 0.0007). We suggest that BRCA1 mutations are not randomly distributed but clustered in a subset of BRCA1 alleles that can be identified by D17S855 genotyping. Further analysis involving a larger set of mutations and different populations are needed to clarify the relevance of this unexpected finding. © 2002 Wiley-Liss, Inc. Key words: BRCA1; D17S855; OR; CI; genetic testing; Spain BRCA1 was the first breast and ovarian cancer susceptibility gene to be identified. 1 Since then, more than 500 different cancerrelated mutations scattered all over the coding sequence and intron/exon boundaries have been identified, 2 suggesting that many independent, and randomly distributed mutational events have occurred in this gene, making genetic testing difficult, costly and time consuming. Interestingly, here we present data suggesting that mutations detected in breast/ovarian families are not randomly distributed but clustered in a subset of BRCA1 alleles.We have genotyped D17S855 (a highly informative BRCA1 intragenic marker, calculated heterozygosity of 0.8220 in Europeans 3 ) in index cases from 140 breast/ovarian Spanish families. Index cases (the youngest breast and/or ovarian cancer case available in each family) have been previously screened for BRCA1 germline mutations. 4 -7 Breast/ovarian families have been ascertained in several different areas from Spain: They have 3 or more cases of breast/ovarian cancer diagnosed in two generations (same lineage), one of them diagnosed before age 50. Families carrying BRCA1 mutations do not show any geographical clustering. More data concerning BRCA1 genetic testing is available upon request.D17S855 genotyping was performed in an Abby Prism 310 Genetic Analyzer (Applied Biosystems, Foster City, CA). Allele calling ranged from 139 bp to 151 bp in all cases. For statistical analyses we used the 2 test. Interestingly, we observed an overrepresentation of D17S855 short alleles (18% vs. 10% for the 139 alleles and 36% vs. 20% for the 141 alleles) in index cases carrying BRCA1 germline mutations (positive index cases through this text), when compared to index cases that were not demonstrated to carry a mutation (negative index cases). Observed frequency increases were equivalent in both cases (roughly 80%), and we did not detect a similar increase for any other D17S855 allele frequency (data not shown). We decided, therefore, to pool data from both 139 and 141 alleles (short alleles through this text) in all statistical analysis.As shown in Figure 1, D17S855 short alleles are overrepresented in positive index cases (54% vs. 31%, OR ϭ 2.57, 95% CI 1.46 -4.56, p ϭ 0.0004). I...

Background Treatment persistence is becoming a useful measure to evaluate long‐term effectiveness and safety of biological therapies in real‐world settings. Objective The main objective of this study was to explore the scientific opinion of a panel of dermatologists and hospital pharmacists to reach a consensus about the impact, causes, and best strategies and interventions that might be associated with improved drug persistence in patients with psoriasis in Spain. Methods This research was conducted using a modified Delphi method organized in two rounds and involving a panel of 90 dermatologists and 34 hospital pharmacists. A questionnaire of 70 items was developed. The items proposed to reach a consensus included topics such as definitions and measures in the treatment of psoriasis, analysis of treatment persistence, factors that may influence treatment persistence, impact of treatment persistence and economic cost of treatment. Results Dermatologists reached a consensus on 77.1% of the items proposed, and hospital pharmacists reached a consensus on 71.4%. Both groups agreed that it is important to use standardized measures in the evaluation of treatment maintenance over time. Dermatologists agreed that treatment survival, persistence and retention are synonymous, but hospital pharmacists considered only treatment persistence as a valid term. In addition, panelists agreed that drug persistence is an indicator of success in the treatment of psoriasis that may be influenced by a drug's effectiveness and safety profile, as well as by patient satisfaction. They agreed that the different causes of treatment discontinuation should be considered in Kaplan–Meier analysis of treatment persistence. Moreover, treatment persistence was agreed to decrease the cost of therapy. Conclusion This Delphi consensus highlights the different perspectives of dermatologists and hospital pharmacists regarding the interpretation of treatment persistence, and the challenge of harmonizing the results obtained.

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