Recent studies suggest that there are groups of genes that predispose simultaneously to both early-onset breast and laryngeal cancer. Studies were performed on a large series of unselected patients with laryngeal cancer diagnosed in Szczecin, Poland. Pedigrees of 683 laryngeal cancer patients were analysed for the frequency of early-onset and late-onset breast cancer among first degree relatives. The observed frequencies of breast cancer in these families were compared to those expected. In addition, common mutations/variants in the 3 genes BRCA1, NOD2 and CYP1B1, known to be associated with early-onset breast cancer, were assessed to determine their frequency in 348 unselected laryngeal cancers. The average age at diagnosis of LC among patients, who had relatives affected by BC diagnosed under the age of 50 years was 57.62. In comparison LC patients reporting a first degree relative affected by BC diagnosed above 50 years of age, had an average age of diagnosis of 66.00 years, which was significantly different (p=0.0064). Similarly, the average age of diagnosis of BC among patients with LC diagnosed under age of 50 years was 46.7 years and whereas LC patients with tumors diagnosed above 50 years had relatives diagnosed with breast cancer at an average age of 53.37 years, which was significantly different (p=0.02). From the 348 consecutive ascertained laryngeal cancer patients who had molecular studies undertaken, breast cancers among first degree relatives were found in 18 families including 8 with breast cancers diagnosed less than 50 years of age. A molecular basis was identified (the CYP1B1 355T/T genotype) in only 2 of the 8 early cases suggestive of there being additional, as yet unknown genes that are associated with an early-onset laryngeal-breast cancer phenotype.

The criteria for the diagnosis of HNPCC established by the ICG-HNPCC are very restrictive as they do not allow for the diagnosis of a large number of "suspected HNPCC" cases - these are families which do no fulfill the strict diagnostic "Amsterdam criteria", but do present with several pedigree and clinical features characteristic for HNPCC. Several series of families suspected of harboring germline mutations in DNA mismatch repair genes have been studied for germline changes in DNA mismatch repair genes and a mutation rate of somewhere between 8-60% was found. Therefore a subgroup of members of the ICG-HNPCC has been working on pedigree/clinical diagnostic criteria for suspected HNPCC. Materials and methods Part I The study was based on two series of colorectal cancer (CRC) cases: 1) HNPCC - this group comprised 190 patients affected by CRC from randomly selected families which fulfilled the Amsterdam II criteria registered in Düsseldorf, Germany (102 cases of CRC), Denmark (18 CRCs), Leiden, Holland (23 CRCs) and Szczecin, Poland (47 CRCs). 2) Consecutive CRCs - this group comprised 629 (78.0%) of 806 individuals with CRC diagnosed in 1991-1997 in the city of Szczecin (ca. 400,000 of inhabitants), Poland. Nuclear pedigrees in both groups were compared for frequency of occurrence of clinical features, that have been shown to be associated with HNPCC. Part II 52 consecutive CRC cases from Szczecin, matching the criteria recognized in part I as appropriate for diagnosis of cases "suspected of HNPCC" were studied for the occurrence of germline hMSH2/hMLH1 constitutional mutations using "exon by exon" sequencing. Results The combination of features - i.e. the occurrence of an HNPCC associated cancer (CRC or cancer of the endometrium, small bowel or urinary tract) in a 1st degree relative of a CRC patient; at least one of the patients being diagnosed under age of 50 - appeared to be strongly associated to HNPCC with an OR - 161. Constitutional mutations were identified in 18 (10 MLH1 and 8 MSH2 mutations) of 52 (34%) cases matching the above features. Conclusions The results of our studies strongly suggest that it is possible to diagnose HNPCC with a high degree of accuracy on the basis of nuclear pedigree data and clinical features.

ObjectivesThis study aimed to determine the prevalence of ultrasound-detected tendon abnormalities in healthy subjects (HS) across the age range.MethodsAdult HS (age 18–80 years) were recruited in 23 international Outcome Measures in Rheumatology ultrasound centres and were clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexors (DFs) 1–5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), tenosynovial power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of patients with rheumatoid arthritis (RA) was taken from the Birmingham Early Arthritis early arthritis inception cohort.Results939 HS and 144 patients with RA were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was a statistically significant difference in the proportion of TSH and TPD involvement between HS and subjects with RA (HS vs RA p<0.001). In HS, there was no difference in the presence of ultrasound abnormalities between age groups.ConclusionsUltrasound-detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease, especially in newly presenting RA.

Background:Tenosynovitis (TS) is a common, often clinically undetectable finding in Rheumatoid Arthritis (RA). Recent data showed TS on ultrasound (US) has a role in predicting outcome in early disease and flare in clinical remission. However data is limited on US measured TS in healthy subjects (HS), none specifically encompassing the older age range when RA commonly presents.Objectives:This OMERACT study aimed to determine prevalence of US measured tendon abnormalities in HS throughout the age range.Methods:Adult HS without: joint pain (VAS <10/100), hand osteoarthritis (ACR criteria), or inflammatory arthritis were recruited in 23 international centres from Aug 2017-Dec 2018. MCP, PIP and wrist joints were clinically examined. Bilateral digit flexor (DF) 1-5 and extensor carpi ulnaris (ECU) tendons were scanned for tenosynovial hypertrophy (TSH) and power Doppler (PD) signal and graded (OMERACT US scoring system1).A comparison cohort of DMARD-naive patients with RA (ACR-EULAR 2010 and/or 1987 criteria) at presentation was taken from the Birmingham Early Arthritis (BEACON) inception cohort, who underwent identical tendon US assessment. They were grouped into ≤12 and > 12 weeks from symptom onset.Results:Data from 899 HS and 144 RA patients were included. HS 18-39 y HS 40-59 y HS ≥60 y RA ≤12 RA > 12 5 groups p value RA ≤12 vs >12 p value n 40831118030114 Age, y (IQR) 29 (25-33)49 (44-55)68 (62-72)58 (52-69)53 (42-65)<0.0010.03 Female (%) 270 (66)270 (83)114 (62)20 (67)86 (75)<0.0010.2 DAS 28 CRP (IQR) ---5.4 (4.2-6.1)4.8 (4.1-5.7)-0.1 Tender joint* (IQR) 0 0 0 18 (10-23)17 (11-29)<0.0010.9 Swollen joint* (IQR) 0 0 0 8 (3-18)6 (3-9)<0.0010.1 DF 1-5 TSH gd ≥1 (%) 8 (0.2)9 (0.3)2 (0.1)54 (18)125 (11)<0.0010.06 DF 1-5 PD gd ≥1 (%) 3 (0.05)2 (0.06)0 49 (16)85 (8)<0.0010.02 ECU TSH gd ≥1 (%) 1 (0.1)11 (1.8)5 (1.4)13 (22)52 (23)<0.0010.8 ECU PD gd ≥1 (%) 0 0 0 12 (20)50 (22)<0.0010.7*RA had 66/68 joint countPrevalence of TSH and particularly PD abnormalities in HS was very low at all ages, and was all grade 1 except in one individual ECU tendon. ECU TSH grade≥1 was more common than DF grade≥1 in the older HS groups, and less common in the 18-39 age group (p=0.011). TSH and PD of grade ≥1 were common in RA patients, with DF PD abnormalities more common in early disease (p=0.02).Conclusion:Low prevalence of TSH or PD abnormalities in tendons of HS even in old age suggests US determined TS will be a robust tool in clinically managing RA.References:[1] Naredo E, D’Agostino MA, et al. Reliability consensus-based US score TS RA. ARD.2013;72(8):1328-34Disclosure of Interests:Jeanette Trickey: None declared, Ilfita Sahbudin: None declared, Alessandra Bortoluzzi: None declared, Annamaria Iagnocco: None declared, Carlos Pineda: None declared, Cesar Sifuentes-Cantú: None declared, Coziana Ciurtin: None declared, Cristina Reategui Sokolova: None declared, Daniela Fodor: None declared, Ellen-Margrethe Hauge: None declared, Esperanza Naredo Consultant for: Abbvie, Speakers bureau: AbbVie, Roche, Bristol-Myers Squibb, Pfizer...