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Background: Although mood disorders have been well characterized by immune-mediated inflammatory diseases, physical function and satisfaction with social roles have not yet been defined as independent domains. Objective: The study aims to assess satisfaction with social roles and physical function alterations in a population with immune-mediated inflammatory diseases and identify associated characteris-tics. Methods: Physical function and social role satisfaction were evaluated through the Patient-reported Outcomes Measurement System. Besides comparison between groups, univariate and multivariable logistic regression analyses were performed to identify independent predictors. Results: Two hundred sixty-five patients with immune-mediated inflammatory diseases and 206 controls were recruited. Compared to controls, patients with inflammatory bowel diseases had impaired physical function (p Conclusion: Immune-mediated inflammatory diseases determine alterations in physical function and social life satisfaction. Gender and treatment are independently associated factors. Patient-reported outcomes should be considered in clinical management to define patients’ real needs.

Fatigue is a main symptom of chronic diseases, including immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease (IBD) and inflammatory arthritis (IA); however, the pathophysiological mechanisms are not completely understood. The aim of this study was to assess the prevalence of fatigue and the associated factors in an IMIDs population. A control group, IBD, and IA patients, were enrolled. The PROMIS® fatigue questionnaire was used to evaluate the symptoms. Information on demographics, anthropometrics, disease characteristics, and medications was collected for each participant. A total of 471 subjects (137 with IBD, 103 with IA, and 206 controls) were enrolled. IBD and IA patients reported greater fatigue than controls (p < 0.001, each). In univariate regression, patients with anxiety and depression were more likely to report fatigue (p = 1.40 × 10−9 and p = 3.80 × 10−11, respectively). Males, holding a high school diploma, and being employed were inversely correlated to the domain (p = 1.3 × 10−5; p = 0.003 and p = 0.005, respectively). The use of steroids and disease activity determined increased fatigue (p = 0.014 and p = 0.019; respectively). In the multivariate analysis, anxiety and depression remained associated (p = 0.002 and p = 1.3 × 10−5, respectively). IMIDs patients present increased fatigue compared with healthy subjects. Anxiety and depression are the main associated factors, suggesting a psychological component of the symptom; thus, a holistic management should be established.

Aspirin is the most commonly used medication worldwide. Beside its well-known anti-inflammatory effects, a role has emerged in the prevention of cardiovascular events. However, a significant benefit has been demonstrated in secondary cardiovascular prevention only, while there is limited evidence supporting a role in primary prevention. This discrepancy might depend on the that so far, the high-risk populations that will achieve the greatest benefits yet experiencing minimal harmful side effects have not been identified. Patients with autoimmune systemic rheumatic diseases have an increased risk of cardiovascular complications compared with the general population, which makes aspirin of potential value in these subjects. Moving from general aspects of aspirin pharmacology and specific issues in general population, the aim of this study is to review the evidence about the role of low-dose aspirin in primary cardiovascular prevention in autoimmune systemic rheumatic diseases.

In the last few years, immunotherapy has become part of everyday clinical practice for the treatment of many solid tumors including metastatic non-small-cell lung cancer. These drugs, however, can yield a specific toxicity profile that consists of immune-related adverse events (irAEs). Hepatotoxicity is one of irAEs and occurs in about 1-3% of cases and may be manifested by the presence of increate levels of liver enzymes (aspartate aminotransferase, alanine aminotransferase) and/or biliary stasis evidence; in these cases, a differential diagnosis with other hepatic diseases must be considered. We present the case of a 73-year-old man who presented with an alteration in liver function during treatment with pembrolizumab (anti-programmed death 1 monoclonal antibody) for a stage IV nonsquamous non-small-cell lung cancer, which was initially mistaken for drug-induced irAEs hepatic toxicity.

Central studies carried out on vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-COV2) excluded patients receiving immunosuppressive therapy and those diagnosed with an immunosuppressive condition. Moreover, there are no data on vaccine efficacy regarding older patients with cancer. Objectives The primary objective was to evaluate the seroprevalence of the SARS-CoV2 IgG in older patients (aged ≥80 years) diagnosed with solid or hematological malignancies, one month after administering the second dose of the BNT162b2 vaccine. Materials and methods We screened 74 older patients with cancer, 45 of them accepted to receive the vaccination and collected serum samples from 36 patients; a group of medical doctors and nurses from our hospital was used as a control in a 1:2 ratio. Results The median age was 82 years (range 80–89). Median serum IgG were 2396,10 AU/ml (range 0–32,763,00) in patients with cancer and 8737,49 AU/ml (398.90–976,280,00) in the control group, p < 0.0001. Additional subgroup analyses were performed comparing males and females, patients treated with chemotherapy versus other therapies (immunotherapy, targeted therapy), solid tumors versus hematological malignancies, early (I-II) versus advanced (III-IV) stage of disease, continuative corticosteroid use or not. None of them reached statistical significance. Conclusion Our study shows for the first time that patients with cancer aged ≥80 years can have a serological response to the BNT162b2 COVID-19 vaccine one month after vaccination and consequently support the vaccination campaign currently underway in this frail population.

Objectives To assess the efficacy of the novel anti-IL-23 monoclonal antibody guselkumab in a real-life observational cohort of patients with early PsA. Methods We conducted an observational study on patients with early PsA followed by the joint dermatology-rheumatology clinics of two Italian centres starting therapy with guselkumab for severe skin involvement. Each patient was evaluated at baseline and every 24 weeks for one year, recording Disease Activity Index for PsA (DAPSA), PASI, VAS Pain, VAS Prutitus, Patient's Global Assessment (PtGA) and assessing DAPSA response. Results Twenty-four patients were recruited (16 women). The mean duration of skin disease was 12.5 years (CI 8; 17), but all patients had a shorter articular disease duration, 21.29 months (CI 15.9; 26.68). At baseline, all patients displayed a moderate cutaneous disease with a mean PASI of 15.2 (CI 11.7–18.6) and high disease activity, characterized by mean DAPSA of 26.84 (CI 22.49–31.19). An inflammatory low back pain was reported by five patients (20%) with a mean BASDAI 5.1 (CI 4,38–5,85) at baseline. The majority of guselkumab-treated patients (n = 18; 75%) reached DAPSA remission or DAPSA low disease activity after six months. Seventeen out of 24 patients completed 12 months of treatment, 11 of them (65%) in low disease activity, six (35%) in remission. All patients with axial disease reported improvement of inflammatory low back pain at week 24 with a mean BASDAI 2.98 (CI 2,18– 3,77). No significant side effects were reported. Conclusions Real-life data on a cohort of early PsA patients confirm the efficacy and safety of guselkumab on peripheral and axial manifestations.

Background Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown aetiology usually affecting young adults. Interestingly, recent evidence from the juvenile counterpart of AOSD suggested the emergent high fatality rate of lung disease (LD) in these patients. In this work, we aimed to characterise LD in AOSD, to identify associated clinical features and predictive factors, and to describe long-term outcomes of the disease comparing patients with LD and those without. Methods A retrospective assessment of prospectively followed patients, from January 2001 to December 2019, was provided to describe the rate of LD in AOSD, associated clinical features and predictive factors, and long-term outcomes. Patients with AOSD, who were included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort, were assessed. Results Out of 147 patients included in GIRRCS cohort, 18 (12.25%) patients were reported to be affected by LD, at the time of diagnosis of AOSD, who were characterised by older age, a higher prevalence of myalgia, of lymph node involvement, of pleuritis, and abdominal pain. Furthermore, patients with LD showed higher values of systemic score and ferritin. Among those clinical variables, older age and systemic score were also independently predictors of LD. Chest CT scans were also obtained, and the most common finding was the peripheral consolidations in 8 (44.4%) patients. Finally, a higher mortality rate, of 38.9%, was registered in patients with LD than others, since it was associated with a significant decreased survival rate. Conclusions The presence of LD could suggest an emergent cause of mortality in AOSD, as observed in juvenile counterpart recognising a further marker of severity and poor prognosis to be careful evaluated. Patients with LD were also characterised by some clinical features, higher values of systemic score and ferritin than the others, identifying a subset of patients mostly burdened by systemic signs and symptoms. Although specific designed future studies are needed to fully elucidate the significance of LD in AOSD, a more accurate evaluation and management of this feature could improve the long-term outcomes of these patients.

Objective.Macrophage activation syndrome (MAS) is a reactive form of hemophagocytic lymphohistiocytosis, which can complicate adult-onset Still disease (AOSD). We investigated AOSD clinical features at the time of diagnosis, to assess predictors of MAS occurrence. Further, we analyzed the outcomes of patients with AOSD who experience MAS.Methods.Patients with AOSD admitted to any Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale center were retrospectively analyzed for features typical of AOSD, MAS occurrence, and their survival rate.Results.Of 119 patients with AOSD, 17 experienced MAS (12 at admission and 5 during followup). Twelve patients with MAS at first admission differed from the remaining 107 in prevalence of lymphadenopathy and liver involvement at the time of diagnosis. In addition, serum ferritin levels and systemic score values were significantly higher in the patients presenting with MAS. At the time of diagnosis, the 5 patients who developed MAS differed from the remaining 102 in the prevalence of abdominal pain, and they showed increased systemic score values. In the multivariate analysis, lymphadenopathy (OR 7.22, 95% CI 1.49–34.97, p = 0.014) and abdominal pain (OR 4.36, 95% CI 1.24–15.39, p = 0.022) were predictive of MAS occurrence. Finally, MAS occurrence significantly reduced the survival rate of patients with AOSD (p < 0.0001).Conclusion.MAS occurrence significantly reduced the survival rate in patients with AOSD. Patients with MAS at baseline presented an increased prevalence of lymphadenopathy and liver involvement, as well as high serum ferritin levels and systemic score values. The presence of lymphadenopathy and abdominal pain was associated with MAS occurrence.

Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is efficacious as first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Dosage reduction is recommended in patients with intolerable adverse events; however, data regarding the efficacy of low-dose afatinib are limited. We report the case of a 71-year-old female patient who was diagnosed with advanced EGFR-mutated NSCLC and started treatment with oral afatinib 40 mg daily. The patient achieved partial tumor response on computed tomography imaging, but developed unacceptable skin-related toxicities requiring dosage reduction to 20 mg daily. The patient subsequently achieved complete tumor response and showed improvements in performance status. These observations suggest that low-dose afatinib is effective in patients with EGFR-mutated NSCLC who require dosage reduction for intolerable adverse events.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Fifty percent of the cases are metastatic at diagnosis and about 20% develop brain metastasis. The brain involvement represents a negative prognostic factor. However, some patients could benefit from locoregional treatments of metastatic foci and experience an unexpected long survival or healing. In the previous years some classifications were proposed to identify patients’ prognostic category, according to stage of the primary tumor, the timing of metastases occurrence (synchronous or metachronous) and the number of metastatic sites. Several data show a benefit in patients receiving resection of both the primary tumor and brain metastases. Whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) are the selected options in most cases. Overall, literature data showed highly variable outcome, with an overall survival (OS) ranging from 5.9 to 68 months. No data from randomized and homogeneous trials are currently available. Therefore, a growing interest in this field is observed. Different trials investigating the effectiveness of local treatments and studies analyzing biological mechanisms are ongoing. In this report we analyze literature data and we explore the current field of study. Furthermore, we show a single institutional experience of multimodal management of stage IV NSCLC with brain metastases, experiencing an unexpected long survival. We conclude that a better knowledge of this subpopulation of patients and new studies in this field can lead to distinguish the patients who can benefit from local treatment from those with poor prognosis.

The discovery of tyrosine kinase inhibitors (TKI) has remarkably improved the clinical course of patients with non-small cell lung cancer driven by Epidermal Growth Factor Receptor (EGFR) mutations. However, virtually in all cases, the disease resurfaces in a TKI-resistant form that is mainly linked to an acquired EGFR-T790M mutation, a MET amplification, or small cell lung cancer (SCLC) transformation. Third-generation TKIs are able to block tumor growth through an irreversible binding to the T790M-mutated receptor. Such new treatments require the diagnostic analysis of new pathologic tissue or a liquid biopsy to detect the presence of the T790M mutation.Pre-TKI and post-TKI biopsies from 27 patients with an activating EGFR mutation were collected and analyzed for EGFR-T790M mutation, MET amplification, and SCLC transformation.The T790M mutation was found in 16 patients (59%) whereas MET gene amplification was found in 2 (10.5%) of 19 evaluated cases. The histologic transformation from adenocarcinoma (ADC) to SCLC was identified in 3 patients (11%). In one of them reversal from SCLC back to adenocarcinoma was observed. One patient had the T790M mutation concordantly detected in 2 synchronous lesions whereas another patient showed T790M positivity only in one of 2 specimens. In 4 patients longitudinal biopsies revealed T790M gains and losses not always according to biological expectations.Intrapatient molecular or histologic heterogeneity may be frequently found during routine treatment of non-small cell lung cancer patients. This biological aspect may have profound repercussions on subsequent therapeutic decisions, and therefore requires in-depth investigation.

Introduction: The recent introduction of checkpoint inhibitor–based immunotherapy has revolutionized the treatment of advanced lung cancers, becoming standard of care in both first- and second-line treatment. New types of toxicity are emerging with the increasingly widespread use of these inhibitors. Case presentation: We describe a case of aplastic anemia in a patient with stage IV non-small cell lung cancer after a single administration of nivolumab. Conclusions: Several similar case reports reported in literature show an increasing rate of toxicities from immunotherapy in this setting. These real-world data provide an insight into patient outcomes and treatment decisions being made in clinical practice.

Background The systemic inflammatory process and the “traditional” cardiovascular (CV) risk factors could synergize the enhancement of CV burden in rheumatoid arthritis (RA) [1]. Objectives To assess the occurrence and the predictive factors of subclinical and clinical atherosclerosis in patients with RA. Methods During 2015, consecutive patients, admitted to Italian Rheumatology Units, were assessed in GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) cohort [2]. After that, patients were followed-up in a 3-year, prospective, observational study, assessing the occurrence of subclinical (carotid and/or peripheral arteries atherosclerotic lesions detected by ultrasound imaging) and clinical atherosclerosis (myocardial infarction and/or congestive heart failure and/or cerebrovascular accidents) and possible predictive factors. McNemar test was employed to assess the changes in subclinical and clinical atherosclerosis and regression analyses exploited the ORs for the occurrence of those comorbidities. Results After 3 years of prospective follow-up, 797 patients (82.7% female, median age of 60 years, range 21-89) were assessed. We also observed a median RA duration of 8.35 years (range 0.1-35), 70.9% of patients showed rheumatoid factor and 55.7% ACPA. Among “traditional” CV risk factors, we observed that BMI was 27.21 ± 4.05, 33% of patients reported smoking habit, 49.3% were affected by high blood pressure (HBP) and 12.3% by type 2 diabetes (T2D). Corticosteroids were administered in 75.5% of patients (low dosage 66.8%), methotrexate in 86.8%, hydroxychloroquine in 28.1% and biologic DMARDs in 60.7%. The remission was reached and maintained in 42.6% of patients, during the follow-up. We recorded an increased rate of subclinical atherosclerosis (70 vs 130 patients p Conclusion The maintenance of remission was strongly associated with a reduced risk of clinical and subclinical atherosclerosis in 3-year prospective follow-up. Among “traditional” CV risk factors, T2D was significantly associated with both clinical and subclinical atherosclerosis. References [1] Nurmohamed MT, et al. Nat Rev Rheumatol. 201511:693-704 [2] Ruscitti P, et al. Medicine (Baltimore). 2017;96:e8180. Disclosure of Interests Piero Ruscitti Grant/research support from: PFIZER INNOVARE 2018, Speakers bureau: MSD, BMS, SOBI, LILLY, PFIZER, Paola Cipriani Grant/research support from: ACTELION, Speakers bureau: ACTELION, Vasiliki Liakouli Grant/research support from: PFIZER, Speakers bureau: SANOFI, Daniela Iacono Speakers bureau: PFIZER, Ilenia Pantano: None declared, Giulia Maria Destro Castaniti: None declared, Nicola Maruotti Speakers bureau: N Maruotti has received speaker honoraria from Pfizer outside this work, Domenico Paolo Emanuele Margiotta: None declared, Licia Picciariello: None declared, Francesco Caso: None declared, Rosa Daniela Grembiale Grant/research support from: BMS, Consultant for: JANSSEN, CELGENE, Speakers bureau: PFIZER, JANSSEN, BMS, NOVARTIS, Fabiola Atzeni: None declared, Raffaele Scarpa Speakers bureau: ABBVIE, MSD, PFIZER, LILLY, JANSEEN, CELGENE, Federico Perosa Speakers bureau: OCCASIONALLY, Antonella Afeltra Grant/research support from: MSD, PFIZER, ABBVIE, ROCHE, UCB, Speakers bureau: MSD, PFIZER, BMS, ROCHE, SANOFI, Francesco Paolo Cantatore Speakers bureau: PFIZER, ROCHE, Giuliana Guggino Grant/research support from: Laborest, Pfizer, Consultant for: Novartis, Abbvie, Speakers bureau: Sandoz, Francesco Ciccia Grant/research support from: CELGENE, PFIZER, Consultant for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, Paid instructor for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, Speakers bureau: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, ROCHE, AMGEN, Roberto Giacomelli Grant/research support from: Pfizer, Actelion, Speakers bureau: Actelion, Bristol-Myers Squibb, Merck Sharp & Dohme, Abbvie, Pfizer, Sobi, Roche

Background: Pathogenesis of Granulomatosis with polyangiitis (GPA) is still unknown. However, it has been observed a skewing of circulating CD4+ T cells toward the Th17 and Th2 phenotype. The pro-inflammatory cytokine interleukin 25 (IL-25) is a member of IL-17 cytokine family associated to the Th2 immune phenotype. Through the receptor IL17RB, IL-25 further sustains the Th2-type immune response and elicits the expansion of the type 2 innate lymphoid cells (ILC2) and M2 macrophages. A pathogenic role of the innate lymphoid cells in GPA has been recently demonstrated; however, the relevance of IL-25 in this condition remains unexplored. Objectives: Aim of the study was to evaluate the expression of IL-25/IL-25R axis and its functional relevance in patients with granulomatosis with polyangiitis (GPA). Methods: Thirty patients with a diagnosis of GPA fulfilling the Chapel Hill Consensus Conference and ACR classification criteria, and 20 age-matched healthy controls (HC) were included in this study: age range 30-66 years, 40% female in GPA group and 32-63 years, 20% female in HC. IL-25 and IL-33 serum levels were measured by ELISA at the diagnosis and after Rituximab (RTX) therapy (n=15). Immunohistochemical staining for IL-25, IL-33, IL-17B was performed on sections of renal biopsies obtained from GPA patients (n=10). Kidney ILC2 infiltration was assessed by confocal microscopy. Frequencies ILC1, ILC2 and ILC3 were evaluated by flow cytometry analysis by CD45, Lyn, CRTH2, GATA3, Tbet, CD56, NKp44, IL-22, IL-23R, RORc. Expression levels of IL-5 and IL-13 in kidney were quantified by quantitative real-time PCR (qRT-PCR). Results: Increased pre-RTX serum levels of IL-25 and IL-33 at baseline were observed in GPA compared to HC (p Conclusion: Our data confirm the increases in IL-33 levels previously reported by other authors. The increased circulating and tissue levels of IL-25 and IL-25 receptor-expressing cells, including ILC2, suggests a role for the IL-25/IL-17RB axis in GPA pathogenesis. Treatment with anti-CD20 Rituximab may lead to modulation of IL-25/IL-17RB axis and reduction in ILC2. Disclosure of Interests: Daniele Mauro: None declared, Giuliana Guggino Grant/research support from: Laborest, Pfizer, Consultant for: Novartis, Abbvie, Speakers bureau: Sandoz, Angelo Ferrante: None declared, cristiano alessandri: None declared, SERENA FASANO: None declared, Daniela Iacono Speakers bureau: PFIZER, Marianna Lo Pizzo: None declared, Riccardo Alessandro: None declared, Aroldo Rizzo: None declared, Francesco Ciccia Grant/research support from: CELGENE, PFIZER, Consultant for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, Paid instructor for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, Speakers bureau: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, ROCHE, AMGEN

Background Current recommendations on the treatment of Rheumatoid Arthritis (RA) are based on a treat to target approach, nevertheless which biologic drug should be used in an unresponsive patient is not clarified (1). Such a strategy is essentially justified by the fact that no biotechnological drug has proved to be superior to any other (2). Recent studies have reported some disease or patient features that are associated with a greater or lesser likelihood of response (3). Nevertheless, an adapted therapy to the single patient and based on physiopathological mechanisms has not been acquired yet. Objectives Aim of this study was to evaluate if the choice of a tailored therapy, based on patient and disease features, would be an effective strategy. Methods From April 1st 2017, at our Department of Rheumatology of the University of Campania, each patient with RA has been characterized, at enrolment, for demographic and disease features, and started a biological Disease-modifying antirheumatic drug based on an established algorithm (Figure 1). Attainment of the targeted end point i.e. remission (R) as assessed by Simplified Disease Activity Index (SDAI) Results Forty-nine patients were admitted to our centre from April 1st2017 to December 31st2018. Out of them, 36 patients have been followed up at least for 3 months and were included in the study (algorithm+ patients). Out of them, 26 (72.2%) reached 6 months of treatment, while 16 (44.4%) 12 months of treatment. Among the 26 patients evaluated at 6 months, 23(88.5%) achieved the targeted end point. At 12 months, 16/16 patients (100%) preserved a status of remission or at least low disease activity. We compared our results to those registered, from January 2015 to September 2016, in a RA cohort of 79 patients (RA general cohort). We found a significant difference in regard to attainment of the target at 6 months (23/26 patients, 88.5% algorithm+ vs 45/67 patients, 67.2% RA general cohort; p=0.04) and at 12 months (16/16 patients, 100% algorithm+ vs 40/57 patients, 70.2% RA general cohort; p=0.01) (Table 1). Notably, 32 out of the 79 patients had undergone a biological drug which didn’t follow the predefined algorithm. These patients (algorithm- patients) presented a further lower incidence of response with regard to those enrolled according to the algorithm: 22/32 patients (68.7%) at 3 months; p=0.4; 17/29 (58.6%) at 6 months; p=0.001; 17/24 (70.8%) at 12 months; p=0.03). Conclusion The choice of a personalized approach toward treatment of RA might be an effective strategy to achieve the targeted end point of remission or at least low disease activity in every patient. References [1] Smolen JS et al. Ann Rheum Dis 2017;76:960–77 [2] Pierreisnard A et al. Joint Bone Spine. 2013;80:386-92. [3] Daien CI et al. Mediators of Inflammation 2014;2014:386148 Disclosure of Interests DANIELA IACONO Speakers bureau: PFIZER company, Ilenia Pantano: None declared, SERENA FASANO: None declared, GIUSEPPE SCALISE: None declared, Francesco Ciccia Grant/research support from: CELGENE, PFIZER, Consultant for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, Paid instructor for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, Speakers bureau: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, MSD, ROCHE, AMGEN

e16240 Background: Germline pathogenetic mutations in BRCA1/2 genes are described in pancreatic cancer patients (PCP) in about 5–9% of cases. The purpose of this study was to determine their relevance in an unselected consecutive cohort of PCP describing family and clinical history. Methods: Patients (pts) were recruited at a single cancer center from September 2019 to October 2020. Participants provided blood for DNA analysis; cancer family history and treatment records were reviewed; DNA was analyzed by Next Generation Sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1/2 Results: 69 pts were included, 61 (88,4%) with locally advanced and metastatic pancreatic cancer received first line chemotherapy and 38 (62%) were full eligible for BRCA analysis; 8 out of 69 pts were BRCA screened even if in adjuvant setting, 10 patients are still under evaluation. Out of the 38 first line screened PCP germline BRCA mutations were found in 9 (19%): 4 pts (8,7%) with pathogenetic BRCA-2 variants (subgroup 1 – S1) and 5 pts (10,8%) with variants of unknown significances (VUSs), i.e. c.5339T>C and c.5096G>A in BRCA1 (subgroup 2 – S2). Samples from 29 pts were established as BRCA wild-type (subgroup 3 – S3). Pathogenetic BRCA-2 variants were observed in 2 male and 2 female (median age, 61.5 years, range 48-69), 3 out 4 without family history of breast, ovarian and pancreatic cancer, one patient (pt) had ovarian cancer family history. All pts had a negative personal history of others cancers. All S1 pts received FOLFIRINOX regimen achieving one complete response, 2 partials responses and 1 disease progression with RECIST criteria. The S2 included 2 male and 3 female (median age, 61 years, range 45-70) 2 with family history of pancreatic cancer, no pt had personal history of others cancers; 2 pts had stable disease and 3 disease progression receiving platinum-based regimen (4 pts) and gemcitabine/nabpaclitaxel (1 pt), respectively. Platinum responders were observed only in the well known pathogenetic BRCA-2 variants group with twice a median progression-free survival (PFS, months -ms-) as compared to the one observed in VUSs group. (>6 C.I. 95% 2- >12 ms; vs 3 ms, 95% C.I. 3-12 ms). S3 included 9 male and 20 female, (median age, 66 years, range 42-78); 5 pts had family history of pancreatic or breast cancer, 5 pts had a personal history of other cancers (breast and thyroid). In this group,16 pts received a platinum based regimen and 12 pts have been treated without platinum based regimen. Conclusions: Our results suggest that: 1) BRCA pathogenetic mutations rate (8,7%) is in line with literature data and seems not to be related with family or personal history, and to be associated with a better outcome; 2) No BRCA mutations were detected in patients over 70 years. 3) VUSs subgroup do not seem to benefit from platinum-regimen.

Background:The new coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) is a source of concern for the management of patients suffering from rheumatic and musculoskeletal diseases (RMDs) treated with immunomodulatory therapies (1).Objectives:We aimed to analyze the prevalence of SARS-CoV-2 infection in patients with RMDs living in Italy.Methods:During the first wave (March-May 2020) and during the second wave (October-December 2020) of COVID-19, we conducted a survey to investigate the incidence of SARS-CoV-2 infection in patients with RMDs followed at the Rheumatology Unit of the University of Campania, Italy. The demographic data, medication use, the frequency of respiratory symptoms and the incidence of COVID-19 confirmed by nasopharyngeal swab were collected with questionnaires administered by phone. The prevalence of COVID-19 of our cohort was compared to that of the general population (2).Results:During the first wave, we collected data from 900 patients with RMDs (Table 1): 320 patients with rheumatoid arthritis (RA), 295 patients with spondyloarthropathies (SpA), 283 patients with systemic lupus erythematosus (SLE), 2 patients with vasculitis. 546 (60%) were treated with bDMARD/tsDMARDs. Overall, a total of 11/900 (1%) cases were tested for COVID-19 due to compatible symptoms. 2 (0.2%) adult patients treated with bDMARDs were registered as swab test positive by PCR for COVID-19. 2 patients without confirmed COVID-19 developed pneumonia that required admission to hospital. No deaths occurred among the patients with confirmed COVID-19.During the second wave, data were collected from 470 patients who accepted to take part of the study (Table 1). 49 presented with symptoms that were compatible with COVID-19. 139 patients were tested whereas 30 patients (6%) had a swab confirmation of SARS-CoV-2 infection. Among them, 16 (53%) were treated with bDMARDs and a patient was treated with tofacitinib. we found no increase in COVID-19 prevalence in patients treated with bDMARD/tsDMARDs (p>0.05). A patient with SLE developed pneumonia that required admission to hospital and died.Lacking distinct prevalence data between first and second waves, we found no differences in total COVID-19 prevalence between general population living in Campania (215.752/5.802.000; 3.7%) and patients with RMDs (32/900; 3.5%). However, we had a significant increase in COVID-19 prevalence in our cohort during the second wave compared to the first. Nevertheless, no increase in mortality or hospitalization was recorded, confirming the safety of immunomodulatory therapies in patients with RMDs.Conclusion:In this cohort of patients with RMDs in a geographical region with a high prevalence of COVID-19, the risk of SARS-CoV-2 infection does not appear different from that observed in the general population.References:[1]Wang L., Wang Y., Ye D. Int J Antimicrob Agents. 2020:105948.[2]http://www.protezionecivile.gov.it/ (accessed 28.01.21)Table 1.Demographics and clinical characteristics of 900 patients with rheumatic diseases during the COVID-19 Pandemic.First waveSecond waveWomen, n 660 (73 %) 366(77%)Age, years, median (range)56 (54-57)53 (51-55)Rheumatoid Arthritis320 (35.5%)143 (30%)Spondyloarthritis295 (32%)110 (23%)Systemic Lupus Erythematosus283 (31%)217 (46 %)Vasculitis2 (0.2%)1 (0.2%)Prior ILD56 (6%)22 (4.6%)Smokers220 (24%)118 (25%)Hydroxychloroquine215 (23%)155 (32%)Steroids337 (37%)194 (41%)Prednisone equivalent dose, median (range)5 (0-75)5 (0-50)bDMARD/tsDMARDs546 (60%)247 (52%)csDMARDS387 (43%)185 (39%)Angiotensin-converting enzyme (ACE) inhibitors178 (19.8%)101 (21%)Angiotensin II receptor blockers(ARBs)153 (17%)61 (13%)Fever64 (7%)30 (6.3%)Cough83 (9%)36 (7%)Shortness of breath34 (3%)15 (3%)Sore throat32 (3%)11 (2.3%)Rhinorrhoea36 (3%)11 (2.3%)Headache5 (0.5%)2 (0.4%)Anosmia10 (1%)24 (5%)Myalgia2 (0.2%)1 (0.2%)Gastrointestinal symptoms24 (2.6%)3 (0.6%)Pneumonia2 (0.2%)2 (0.4%)Admission to hospital2 (0.2%)9 (1.9%)Swab confirmation of SARS-CoV-2 infection230Disclosure of Interests:None declared.

Background:Psoriatic arthritis (PsA) is a chronic inflammatory arthritis burdened by a series of metabolic comorbidities. Among them, obesity is very common in PsA, with a prevalence of 27%, as confirmed by a recent Spanish work (1). Obesity in PsA has been associated with higher disease activity and a worse effectiveness of biologic treatment in PsA. This has been certainly proven for anti-TNF-α as demonstrated by different studies reporting, in obese patients, a reduced treatment response and adherence. In particular, results coming from DAN-BIO and ICE-BIO registries, (2) point out that obesity is a risk factor for anti-TNF withdrawal due to poor response. Although a recent multi-centric, retrospective study in Spain has shown that obese subjects with psoriasis have a poor therapeutic response to secukinumab, (3) no data are currently available for secukinumab in PsA obese patients.Objectives:Our studies focused on the relationship between BMI and clinical response to secukinumab in PsA.Methods:We, retrospectively, analysed clinical data of 100 patients with PsA (57% female, median age 53 (49.2-55 years)) satisfying CASPAR criteria (4) for PsA, afferent to our clinic, who were treated with secukinumab. Patients were divided into 2 groups based on BMI (BMIResults:In the normal weight group 75% were female, median age was 50.5 (41-54.6), median BMI was 22 (20.2-23.3) and median DAPSA was 19.19 (15.6-24.2). The features of the overweight/obese patients were similar to the normal weight group (48% were female, median age 54 (50-59), median BMI 29 (27.4-30.1) and median DAPSA 21.2 (19-24.4)). Clinical response to therapy, evaluated as the achievement of low disease activity or remission according to DAPSA, was recorded 6 months after starting treatment. After 6 months of treatment, the variation of the DAPSA was inversely related to BMI: overweight/obese patients had in fact a better response to secukinumab compared to normal weight patients. By using a correlation coefficient (SPSS), to analyze the degree of association between BMI and DAPSA, we observed that BMI and DAPSA are inversely related in our PsA patients (p=0.05). Interestingly, analysis of serum levels of IL-17 in 20 obese patients compared to 20 non-obese patients, showed significantly higher serum levels of IL-17 in the former (Figure 1), indicating IL-17 as a key cytokine driving inflammation in PsA obese patients.Conclusion:These are the first data about clinical response to secukinumab in obese PsA patients. Our results support the relevance of IL-17 in driving systemic inflammation in obese PsA patients, also providing evidence that obese patients may have a better response to secukinumab compared to non-obese patients. Interestingly, this effect was notReferences:[1]Rubén Queiro, Lorenzo A, Tejón P et al. Obesity in psoriatic arthritis. Comparative prevalence and associated factors. Medicine 2019 Jul;98(28):e16400[2]Pil Højgaard, Glintborg B, Kristensen LE et al. The influence of obesity on response to tumour necrosis factor-a inhibitors in psoriatic arthritis:results from the DANBIO and ICEBIO registries. Rheumatology (Oxford). 2016 Dec;55(12):2191-2199[3]Jaime Notario, Deza G, Vilarrasa E et al. Treatment of patients with plaque psoriasis with secukinumab in a real-life setting: a 52-weeks, multicenter, retrospective study in Spain. Journ of Derm Treat 2019 Aug;30(5):424-429[4]Taylor W, Gladman D, Helliwell P et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006 Aug;54(8):2665-73.[5]Lluís Puig. Cardiometabolic Comorbidities in Psoriasis and Psoriatic Arthritis. Int J Mol Sci. 2017 Dec 25;19(1).Disclosure of Interests:Ilenia Pantano: None declared, DANIELA IACONO Speakers bureau: PFIZER, BRISTOL MAYERS SQUIBB, SANOFI, ENNIO GIULIO FAVALLI: None declared, GIUSEPPE SCALISE: None declared, Luisa Costa: None declared, Francesco Caso: None declared, Giuliana Guggino Grant/research support from: Pfizer, Celgene, Speakers bureau: Celgene, Sandoz, Pfizer, Raffaele Scarpa: None declared, francesco ciccia Grant/research support from: pfizer, novartis, roche, Consultant of: pfizer, novartis, lilly, abbvie, Speakers bureau: pfizer, novartis, lilly, abbvie

Background Rheumatoid Arthritis (RA) is a chronic systemic inflammatory disorder associated with increased mortality, in particular from cardiovascular (CV) disease, infections and cancer. We recently demonstrate a incidence mortality rate (IMR) in 654 RA patients enrolled over a 6 year period in a South-Italian tertiary Rheumatology Centre lower than that reported in the Norfolk Arthritis Registry. 1 Objectives The present study is devoted to investigate differences in IMR between our series and other European tertiary centre cohorts. Furthermore we evaluated the role, if any, of Anticarbamylated protein antibodies (anti-CarP Ab) in modulating the low IMR detected in our patients. Methods Clinical charts of patients consecutively admitted to our centre, from January 1st, 2008 to December 31st, 2014 were reviewed. IMRs and causes of death as assessed at December 31st 2015, were registered. Sera collected at the time of admission to our centre in 61 patients representative of our RA cohort were investigated for the presence and the level of anti-CarP Ab. Demographic and clinical features, mortality rates and prevalence of anti-CarP Ab detected in our series were compared with those reported in the Better Anti-rheumatic Farmaco-therapy (BARFOT) cohort, the Leiden Early Arthritis Clinic cohort (Leiden EAC) and a Spanish cohort. 2 3 Results Six hundred and eight patients were observed for a median of 3.51 years. All causes and cause-specific IMRs were significantly lower in our cohort with respect to the BARFOT and the Spanish cohort, while only all causes and CV IMRs were significantly lower in our series with respect to the Leiden EAC. These discrepancies might depend on demographic and clinical differences among the various cohorts. Nevertheless, we failed to find putative differences with respect to each North European cohort, but we detected a significantly lower prevalence of anti-CarP Ab in our series with respect to that reported in the other European cohorts considered (table 1). Conclusions In conclusion, we confirm that the mortality rate in our South Italian RA cohort is lower than that detected in patients from both North and South European countries. We detected a very low prevalence of anti-CarP Ab in our sample representative of the entire cohort. Whether this is the aspect underpinning the low mortality rate detected in our series, awaits to be furtherly investigated. References [1] Iacono D, et al. Mortality in Italian patients with rheumatoid arthritis: evidence for a low mortality rate from cancer and infections in patients followed up at a tertiary center. Open Access Rheumatol2017. [2] Ajeganova S, et al. Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts. Ann Rheum Dis2016. [3] Vidal-Bralo L, et al. Anti-carbamylated protein autoantibodies associated with mortality in Spanish rheumatoid arthritis patients. PLoS One2017. Disclosure of Interest None declared

Background Cardiovascular (CV) morbidity and mortality are significantly greater in Rheumatoid Arthritis (RA) patients than in the general population. Acetylsalicylic acid (ASA) is known to be associated with a significant decrease in the incidence of CV events in patients at high CV risk, as we have recently demonstrated in patients with Systemic Lupus Erythematosus, but its effectiveness as primary prophylaxis in RA patients has not yet been addressed. Objectives To investigate the role of ASA in reducing the incidence of CV events in an Italian multicentre RA cohort from the GIRRCS ( Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale ). Methods The clinical charts of RA patients consecutively admitted to 4 GIRRCS centres for their 1 st visit from November 1 st 2000 to December 31 st 2015, who, at admission, satisfied 2010 ACR/EULAR criteria for RA and had not experienced any CV event, were analysed. The incidence of CV events during follow-up was recorded at December 2016. Kaplan Meier curve and log-rank test were used to investigate differences in event-free survival. Cox regression analysis served to identify factors associated with CV event occurrence. Results Seven hundred and forty-six consecutive RA patients were enrolled and followed up for a median of 5.6 years (range 2.9–8.9 years). The incidence rate (IR) of CV events was 7.8/1000 person-years (pys) in the overall cohort. Patients were subdivided into two groups, namely ASA- (242 patients) and non-ASA-treated (504 patients). The IR of CV events was significantly lower in the ASA-treated with respect to the non ASA-treated group (IR 1.7 vs 11.5/1000 pys;p=0.0002). Furthermore, the CV event-free rate was longer in ASA-treated than in non-ASA-treated patients (log-rank test 12.3;p=0.0004). Figure 1. At multivariate analysis hypertension and metabolic syndrome (HR 5.6, 95% CI:1.2–26.3;p 0.03 and HR 3.7, 95% CI:1.3–9.8;p 0.009) resulted to be the only positive predictors; ASA treatment (HR 0.04, 95% CI:0.06–0.33;p 0.02) the only negative one. Conclusions The incidence rate of CV events in our italian multicentric cohort was lower than that reported in other European and non European cohorts. Low-dose ASA may have a role in the primary prophylaxis of CV events in RA patients. References [1] del Rincon ID, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum2001;44(12):2737–45. [2] Fasano S, et al. Longterm Hydroxychloroquine Therapy and Low-dose Aspirin May Have an Additive Effectiveness in the Primary Prevention of Cardiovascular Events in Patients with Systemic Lupus Erythematosus. J Rheumatol2017;44(7):1032–1038. [3] Meek IL, et al. Cardiovascular case fatality in rheumatoid arthritis is decreasing; first prospective analysis of a current low disease activity rheumatoid arthritis cohort and review of the literature. BMC Musculoskelet Disord2014;15:142. Disclosure of Interest None declared

Background Cardiovascular (CV) disease is the leading cause of premature death among Systemic Lupus Erythematosus (SLE) patients1. Several studies have analysed the incidence of CV events in SLE patients. However, the majority of them have been conducted in American and North European countries 2–7. At the best of our knowledge, no studies in Italy have considered cumulative incidence and incidence rate of CV events in Italy. Objectives The present study is devoted to estimate the incidence of a first ever CV event in Italian lupus patients from five rheumatologic tertiary units from North, Centre and South Italy and to search for features associated with and potentially causative of the detected differences. Methods Clinical charts of SLE patients consecutively admitted to five Italian rheumatologic centres from November 1 st 2000 and December 31 st 2016 were retrospectively studied. Patients selected were free of CV events at baseline. CV cumulative incidence was evaluated as the proportion of patients who experienced a new CV event over the follow up period. CV incidence rate was expressed as the number of events in the cohort divided by the total number of years at risk. Our incidence was compared with that detected in the Italian general population and those reported in SLE cohorts from other countries. Results The median duration of follow-up was 6 years (IQR=3–11). During the observational period, 39(cumulative incidence=7.6%) of the 511 patients had a first CV event with an incidence rate of 10.4/1000 person-years i.e. 12 times higher than in the general population. The CV cumulative incidence detected in our Italian cohort was similar to that reported in the Spanish cohort, but lower than those from North European and American cohorts. The Italian cohort differed from other SLE cohorts in some traditional risk factors (smoke, hypertension, dyslipidemia) and treatment with aspirin and hydroxychloroquine.(table1) Conclusions Our study confirmed the increased CV risk in SLE compared with the general population. However, the incidence of CV events in our SLE series was lower than that detected in North European and American lupus cohorts. These disparities could be ascribed to the differences in the prevalences of traditional CV risk factors among the distinct cohorts. Nevertheless, our CV cumulative incidence was very similar to that detected in the Spanish cohort, despite their higher frequency of traditional risk factors. For this evidence, the geographic (Mediterranean) origin deserve to be considered. On the other hand, the slight difference detected between our series and Baltimore cohort2(where patients were examined every 3 months) underlines the need of a strict follow-up of the SLE patient. References [1] Cervera R, et al. Medicine (Baltimore)2003. [2] Magder LS, Petri M. Am J Epidemiol2012. [3] Bertoli AM, et al. Lupus2009. [4] Bartels CM, et al. J Rheumatol2014. [5] Gustafsson J, et al. Arthritis Res Ther2009. [6] Hermansen M-L, et al. Rheumatol Oxf Engl2017. [7] Fernandez-Nebro A, et al. Medicine (Baltimore)2015. Disclosure of Interest None declared

Recent advances in the understanding of non-small cell lung cancer (NSCLC) biology have revealed a number of 'targetable' genetic alterations that underlie cancer growth and survival in specific patients subgroups. The anaplastic lymphoma kinase (ALK) gene rearrangement identifies a population of NSCLCs in whom dysregulation of ALK-tyrosine kinase (-TK) leads to uncontrolled proliferation of cancer cells, thus providing the basis for the therapeutic use of ALK-TK inhibitors (-TKIs) in ALK-rearranged (-positive) disease. Crizotinib was the first ALK-TKI to undergo clinical development in ALK-positive advanced NSCLC, in which it has been shown to greatly outperform the best available chemotherapy regimen in either second- or first-line setting. More recently, the novel second-generation ALK-TKI ceritinib has been shown to be highly active in either crizotinib-pretreated or -naïve population. Nevertheless, as mechanisms of resistance to crizotinib and ALK-TKIs in general are being progressively elucidated, the treatment landscape of ALK-positive NSCLC is expected to evolve rapidly. In the present review we will briefly discuss the current knowledge of ALK-positive advanced non-small cell lung cancer. Also, we will touch upon new developments on drugs/combination regimens aimed at inhibiting the ALK-TK, in an attempt to delineate how treatment of ALK-positive disease may change in the next future.

Daniela Iacono, Serena Fasano, Virginia D’Abrosca, Ilenia Pantano, Gabriele Valentini Department of Clinical and Experimental Medicine, Rheumatology Section, University of Campania “Luigi Vanvitelli,” Naples, Italy Objectives: Mortality in patients with rheumatoid arthritis (RA) has never been investigated in Italy. This study is devoted to investigating all the distinct causes of mortality in Italian RA patients.Methods: Clinical charts of patients consecutively admitted to an Italian tertiary center, from January 1, 2008 to December 31, 2014, were reviewed. Mortality rates (incidence mortality rate [IMR] and standardized mortality rate [SMR]) and causes of death as assessed at December 31, 2015, were registered. Mortality rates detected in our series were compared to those reported in other European cohorts and in the general Italian population.Results: Six hundred and eight patients were observed for a median of 3.51 years. Overall IMR was 0.79 deaths/100 person-years. No significant difference between our IMR and that reported in Italian population by the National Institute of Statistics was observed. All-cause and neoplasm IMRs in our series were found to be significantly lower than that reported in the Norfolk Arthritis Registry, while no difference was detected in cardiovascular (CV) mortality. On the other hand, all causes and CV SMRs in our series were found to be higher than that reported in the general Italian population, while cancer and infectious SMRs were found to be lower.Conclusion: In our series, RA patients had an increased all-cause mortality, and in particular an increased death rate due to CV. However, a lower death rate due to cancer and infections was observed. This figure might be due to the careful follow-up of RA patients in tertiary centers, and the results underlines the need to improve the management of CV risk. Keywords: rheumatoid arthritis, mortality, cancer, infections, cardiovascular deaths

Background Cardiovascular events (CV) i.e. acute myocardial infarction and stroke are recognized as a leading cause of mortality in patients with Rheumatoid Arthritis (RA) [1,2]. Acetylsalicylic acid (ASA) is known to be associated with a significant decrease in the incidence of CV events in patients at high risk for atherosclerosis like patients with diabetes [3] and has been recently reported to play a primary prophylactic role of CV events in Systemic Lupus Erythematosus by our team [4]. Objectives To investigate the so far unexplored role of ASA in reducing CV morbidity in RA. Methods We analysed patients admitted to our Outpatient clinic from January to December 2015. Out of 199, 155 patients, who had been followed from January 2000 and had not experienced any CV event at the first visit, were enrolled. The incidence of CV morbidity was recorded at December 2016. Results The 155 patients had been followed-up for a median of 8 years (range 1–15 years). Out of them, 111 patients had been treated with ASA, that we currently administer to patients undergoing steroid treatment. During the 15-years of follow up, 5 CV events (2 cerebrovascular, 3 acute myocardial infarction) had occurred (Incidence rate 3.93/1000 person/year). Interestingly, only 1 CV event had occurred in ASA treated patients (Incidence rate 1.12/1000 person/year) with respect to 4 in the non-ASA group (44 patients) (Incidence rate 10.48/1000 person/year) (p=0.0146). Conclusions Our study has several limitations including the low number of patients and CV events. Nevertheless, it might suggest a primary prophylactic role of ASA in RA, that awaits to be investigated in large controlled prospective studies. References Arthritis Rheum. 2001 Dec;44(12):2737–45. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditionalcardiac risk factors. del Rincόn ID, Williams K, Stern MP, Freeman GL, Escalante A. BMC Musculoskelet Disord. 2014 Apr 29;15:142. Cardiovascular case fatality in rheumatoid arthritis is decreasing; first prospective analysis of a current low disease activity rheumatoid arthritis cohort and review of the literature. Meek IL, Vonkeman HE, van de Laar MA. Diabetes Res Clin Pract. 2016 Oct;120:31–9. Aspirin for primary prevention of cardiovascular disease in patients with diabetes: A meta-analysis. Kokoska LA, Wilhelm SM, Garwood CL, Berlie HD. Rheumatology (Oxford). 2016 Sep;55(9):1623–30. Low-dose aspirin as primary prophylaxis for cardiovascular events in systemic lupus erythematosus: a long-term retrospective cohort study. Iudici M, Fasano S, Gabriele Falcone L, Pantano I, La Montagna G, Migliaresi S, Valentini G. Disclosure of Interest None declared

Background: Adult-onset Still's disease (AOSD) is rare inflammatory disease of unknown etiology that usually affects young adults. The more common clinical manifestations are spiking fevers, arthritis, evanescent rash, elevated liver enzymes, lymphadenopathy, hepatosplenomegaly, and serositis. The multi-visceral involvement of the disease and the different complications, such as macrophage activation syndrome, may strongly decrease the life expectancy of AOSD patients. Methods: This study aimed to identify the positive and negative features correlated with the outcome of patients. A retrospective analysis of AOSD patients prospectively admitted to three rheumatologic centers was performed to identify the clinical features present at the time of diagnosis and to predict the possible outcome. Furthermore, we investigated the as yet to be validated prognostic value of the systemic score previously proposed. Results: One hundred consecutive AOSD patients were enrolled. The mean systemic score showed that the majority of patients had a multi-organ involvement. Sixteen patients showed different complications, mainly the macrophage activation syndrome. A strong increase of inflammatory markers was observed. All patients received steroids at different dosages, 55 patients in association with immunosuppressive drugs and 32 in association with biologic agents. Sixteen patients died during the follow-up. Regression analysis showed that the higher values of the systemic score and the presence of AOSD-related complications, assessed at the time of diagnosis, were significantly correlated with patient mortality. A prognostic impact of the systemic score of ≥ 7.0 was reported. Conclusions: Our study showed that a higher systemic score and the presence of AOSD-related complications at the time of diagnosis were significantly associated with mortality. Of note, a cut-off at 7.0 of the systemic score showed a strong prognostic impact in identifying patients at risk of AOSD-related death.

Background The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis). Methods and findings This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: −0.85, p < 0.001, 95% CI −1.28 to −0.42) and 6 months (β: −1.05, p < 0.001, 95% CI −1.50 to −0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: −1.04, p < 0.001, 95% CI −1.52 to −0.55) and 6 months (β: −1.24, p < 0.001, 95% CI −1.75 to −0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs. Conclusions In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. Trial registration The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481., Roberto Giacomelli and co-authors study treatment of comorbid rheumatoid arthritis and type 2 diabetes via interleukin-1 blockade., Author summary Why was this study done? A growing body of evidence suggests the inflammatory contribution to type 2 diabetes (T2D) as observed in rheumatoid arthritis (RA). Interleukin-1 (IL-1) would be a common pathogenic mediator in T2D and RA, suggesting a possible common therapeutic target. We investigated whether IL-1 inhibition with anakinra, a human IL-1-receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis). What did the researchers do and find? In a multicentre, open-label, randomised controlled trial, 39 participants with RA and T2D (age 62.72 ± 9.97 years, 74.4% female sex) were randomised to anakinra or to TNFi in order to evaluate the efficacy of these drugs in controlling the metabolic alterations of T2D. Anakinra showed a significant improvement of metabolic alteration (reduction of percentage of glycated haemoglobin [HbA1c%]) after both 3 months and 6 months of therapy (crude difference of 0.93 HbA1c% between groups), whereas TNFi did not show any significant improvement on these features. No severe adverse events, hypoglycaemic episodes, or deaths were observed. What do these findings mean? Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. Managing the inflammatory disease and the metabolic comorbidity by an agent inhibiting IL-1 may lead to a consequent beneficial impact on participants’ compliance, their overall cardiovascular (CV) risk, and the burden of healthcare costs. Our study has some limitations, mainly due to open-label design, and future studies are necessary to fully clarify this topic.

2559 Background: In the preliminary analysis of the FAMI-L1 study, we found a significant association between family history of cancer (FHC) and better clinical outcomes with anti-PD1/PD-L1 inhibitors. Methods: We retrospectively evaluated advanced cancer patients treated with single agents PD1/PD-L1 inhibitors. Patients were categorized as follow: FHC-high (in case of at least one cancer diagnoses in both straight and collateral family line), FHC-low (in case of a cancer diagnoses in only one family line) and FHC-negative. FHC was collected till the second degree of relatedness. Results: Between September 2013 and May 2018, 772 consecutive patients were evaluated. Median age was 68 years; male/female ratio was 521/251. Primary tumors were: NSCLC (58.3%), melanoma (22.1%), renal cell carcinoma (16.6%) and others (3%). 114 patients (14.9%) had ECOG-PS ≥ 2. 341 patients (44.3) were FHC-positive: 268 of them (34.75) were FHC-low while 74 (9.6%) were FHC-high. FHC-high patients had a significantly higher incidence of irAEs compared to FHC-negative (55.4% vs 35.6%; p = 0.0012) and to FHC-low (41.4%; p = 0.0323). No significant differences were found in terms of ORR among subgroups (data not shown). At median follow-up of 15.8 months, median PFS was 9.1 months (95%CI: 8.1-10.4; 452 events) and median OS was 19.7 months (95%CI: 15.7-24.4; 436 censored). No significant differences were found regarding PFS (data not shown). Median OS of FHC-high patients was 31.6 months (95%CI: 26.2-31.6; 50 censored patients), which was significantly longer than 18.2 months (95%CI: 14.7-21.3; 229 censored patients) of FHC-negative patients (HR = 0.60 [95%CI: 0.39–0.92), p = 0.0213). No significant differences in terms of OS were found between FHC-high/low patients (data not shown). After adjusting for primary tumor, sex, treatment-line, number of metastatic sites and ECOG-PS, FHC-high was confirmed an independent predictor of longer OS compared to FHC-negative (HR: 0.57 [95%CI: 0.37-0.88], p = 0.0098). Conclusions: FHC-high seems to be an independent predictor for longer OS in cancer patients treated with anti-PD-1/PD-L1. DNA damage and response (DDR) genes alterations may underlie that results.

Background: Mortality is increased in RA patients, mainly due to cardiovascular (CV) disease; however, the biologic mechanisms are unknown. Increased CV risk in RA is attributed to both traditional risk factors and systemic inflammation. CV risk scores, even after modification as recommended by EULAR, underestimate risk in RA and thus there is a need to develop a better means of risk stratification. Murine collagen-induced arthritis (mCIA) is associated with vascular dysfunction, characterized by reduced vascular constriction to 5- hydroxytryptamine (5-HT). This study was undertaken to characterize the relationship between vascular cell adhesion molecule 1 (VCAM-1), which is induced in pro-atherosclerotic conditions in the general population and vascular dysfunction in mCIA and CV risk in RA patients. Methods: mCIA was induced in DBA/1 mice. The severity of arthritis was assessed by the arthritis index score. Constriction responses to 5- HT were used to assess vascular function in isolated sections of thoracic aorta. Serum VCAM-1 was measured with ELISA. Serum VCAM-1, IL-6, ESR and CRP were measured with ELISA in RA patients [182 patients, 4 female:1 male, mean age 60 years (range 21–89), mean disease duration 11.4 years (S.D. 11)]. CV risk was calculated using the Framingham risk calculator and the QRISK2 algorithm. The latter includes RA as an independent CV risk factor. Results: In mCIA, VCAM-1 levels [mean 1500 mg/ml range (929–2528)] correlated with the arthritis index score (r¼0.43, P¼0.03) and negatively correlated with maximal aortic contraction (r¼�0.35, P10% over 10 years [1200 ng/ ml (S.D. 547)] compared with those with

Background CXCL4 (platelet factor4, PF4) is a pleiotropic α-granules chemokine, produced by platelets, dendritic cells, macrophages and neutrophils. Recently, CXCL4 levels have been found to increase under treatment with infliximab, in unresponsive Rheumatoid Arthritis (RA) patients [1]. At present, the influence of non TNFalfa blockers biological DMARDs (Abatacept and Tocilizumab) on CXCL4 serum levels not have been investigated in RA. Objectives To investigate CXCL4 serum levels in RA patients naive for biological disease-modifying anti-rheumatic drugs (bDMARDs) at baseline and after 1-year treatment and look for associations with disease features at baseline and distinct biological therapy overtime. Methods Fifty-six RA were enrolled in the study at the time of initiating a treatment with a biological DMARD. CXCL4 serum levels were investigated by a multiplex suspension immunoassay at baseline and after 1 year and compared with those detected in 30 healthy controls. Epidemiological, clinical and serological features of RA patients at baseline are showed in table 1. Results Out 56 RA patients, 39 (70%) were assigned to an anti-TNF-α treatment (3 patients to Infliximab, 12 to Etanercept, 24 to Adalimumab); 10 to Abatacept and 7 to Tocilizumab. At baseline, CXCL4 serum levels were found to be increased in RA patients as compared to controls but the difference was not significant (1,538 ng/ml vs 1.26 ng/ml, p=0.082). Moreover, CXCL4 levels were not found to be related to any disease feature. At baseline, 6 (10%) RA patients presented serum CXCL4 levels exceeding the 95th percentile of the values detected in controls (4.569 ng/ml). These patients did not differed from the remaining RA patients in any feature. After 1 year of treatment, CXCL4 levels increased with respect to basal values in the whole series (3.280 ng/ml vs 1.538 ng/ml, p Conclusions Similarly to previous studies (1) we found an increase in CXCL4 serum levels in patients undergoing an antiTNFa agent, but we failed to find differences between responsive and unresponsive patients. Moreover, we found that treatment with Abatacept and Tocilizumab did not modify CXCL4 serum level. Finally, we failed to detect any correlation between CXCL4 levels and any disease feature both at baseline and during follow-up. References Trocme C., et al. Ann Rheum Dis. Aug 2009; 68(8): 1328–1333 Disclosure of Interest None declared

Screening for active tuberculosis (TB) and latent TB infection (LTBI) is mandatory to the initiation of biological therapy in patients with rheumatic diseases. To determine the prevalence of LTBI in patients with rheumatoid arthritis before treatment with biological therapy (anti-TNF, abatacept, and tocilizumab) and the rate of TB conversion during treatment in rheumatoid arthritis (RA) patients, we evaluated the file of 275 patients with RA treated with biological agents. We considered patients with negative baseline TB screening (tuberculin skin test (TST); quantiferon TB gold in tube (QFT-GIT); chest x-ray) and with rescreening for a TB assay every year. Twenty-six patients (10.6%) resulted positive to TB screening at baseline. Two hundred and forty-nine patients (mean age 55.3 ± 11.9; median 55.8 years, range 16–81.9; 210 female) with TB screening negative at baseline were enrolled. One hundred and sixty-eight (67.5%) patients were treated with anti-TNF, 37 (14.9%) patients with abatacept, and 44 (17.7%) patients with tocilizumab. After a period of 12–120 months (median 24), 34 (13.6%) patients displayed conversion of at least one screening assay. Out of the 34 patients with conversion, 6 (16.2%) were treated with abatacept, 7 (15.9%) with tocilizumab, and 21 (12.5%) with anti-TNF. During the follow-up period, no patients developed active TB. Our study shows that a proportion of patients (13.6%) converts at least one TB screening assay during biological therapy. This study underscores the American College of Rheumatology advice for annual screening in some or all biologically treated patients.

To investigate prevalence and age-distribution of ALK- or ROS1-translocated adenocarcinomas in patients ≤50 years of age.Paraffin sections of pulmonary adenocarcinoma were analyzed for ALK (637 cases) and ROS1 (376 cases) translocations using FISH, and for EGFR mutations (789 cases) using mutant-specific Real-Time PCR.ALK or ROS1 fusions were detected in 55 of 637 cases (8.6%). When patients were stratified for age, it was found that six of six cases (100%) of lung adenocarcinoma diagnosed in patients30 years of age were translocated for ALK (4 cases) or ROS1 (2 cases). With the increase of age, there was a gradual decrease in the percentage of positive cases. In fact, ALK-translocated or ROS1-translocated cases were 5 of 17 cases (29%) in the 31-40 years age-group, 6 of 46 cases (13%) in the 41-50 years age-group, and 38 of 568 cases (7.0%) in patients older than 50 years. The six patients30 years of age (5F/1M), including two pediatric patients (≤18 years old), presented with stage IV disease, were never or light smoker, and had no family history of pulmonary tumours. Four of the six patients, were treated with crizotinib and had an objective response.Our findings provide evidence that ALK or ROS1 translocations are crucial events in tumourigenesis of pulmonary adenocarcinoma of very young patients, including pediatric patients.

Background:Specific mutations of the epidermal growth factor receptor (EGFR) gene are predictive for favorable response to tyrosine kinase inhibitors (TKIs) and are associated with a good prognosis. In contrast, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation has been shown to predict poor response to such therapy. Nevertheless, tumor that initially responds to EGFR-TKIs almost inevitably becomes resistant later. Other mechanisms of resistance to EGFR inhibitors could involve activating mutations of the other main EGFR effector pathway, i.e., the phosphoinositide-3-kinase/phosphate and tensin homologue deleted from chromosome 10 (PTEN)/alpha serine/threonine protein kinase (AKT) pathway. The aim of this study was to investigate the role of phosphoinositide-3-kinase catalytic alpha (PIK3CA), EGFR, and KRAS gene mutations in predicting response and survival in patients with non-small cell lung cancer (NSCLC) treated with EGFR-TKIs.Patients and Methods:A total of 166 patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. PIK3CA, EGFR, and KRAS mutations were analyzed using polymerase chain reaction-based sequencing.Results:EGFR mutation was detected in 25.3% of patients, PIK3CA mutation in 4.1%, and KRAS mutation in 6.7%. PIK3CA mutation correlated with shorter median time to progression (TTP) (p = 0.01) and worse overall survival (OS) (p < 0.001). EGFR mutation (p < 0.0001) correlated with favorable response to TKIs treatment and longer TTP (p < 0.0001). KRAS mutation correlated with progressive disease (p = 0.05) and shorter median TTP (p = 0.003) but not with OS. Cox multivariate analysis including histology and performance status showed that PIK3CA mutation was an independent factor to predict worse OS (p = 0.0001) and shorter TTP (p = 0.03), while KRAS mutation to predict shorter TTP (p = 0.01).Conclusion:PIK3CA and KRAS mutations seem to be indicators of resistance and poor survival in patients with NSCLC treated with EGFR-TKIs.

Introduction. Angiosarcoma is a rare cancer of the inner lining of blood vessels and can arise anywhere in the body, most commonly presenting as cutaneous disease in elderly patient, involving head and neck (H&N), especially the scalp. Pegylated liposomal doxorubicin (PLD) is one of the available treatments in patients with advanced or metastatic disease. Common toxicities are myelosuppression, palmar-plantar erythrodysesthesia, nausea, and stomatitis. Regarding PLD-related pulmonary fibrosis in an uncommon toxicity, there are few cases reported in literature. None of these occurred in angiosarcoma.Methods. This is a case report describing an elderly patient treated with PLD for advanced H&N cutaneous angiosarcoma who developed G5 pulmonary toxicity after the second PLD administration.Results. According to our data and patient clinical outcome, we believe that she passed away from fatal PLD-induced pulmonary fibrosis. This is the first case of fatal interstitial pneumonitis in a 77-year-old woman treated with PLD for angiosarcoma. The case has been reported for its rarity.Conclusions. Pathophysiology of this phenomenon is still unclear and more studies are necessary to understand the true incidence of pulmonary toxicities in patients in treatments with PLD and its mechanism.

Glucocorticoids (GC) represent a mainstay in the therapeutical strategies of many autoimmune diseases, but their role in systemic sclerosis (SSc) is controversial. The main objective of this review is to assess the extent of and the factors associated with GC use in SSc patients, taking into account data from cohort studies and registries. We performed a search in MEDLINE databases updated to April 2013. The pooled prevalence and factors associated with GC utilization in both SSc patients collectively considered and in any of the two subsets of the disease were calculated. The pooled prevalence was 0.36 (95 % confidence interval (CI) 0.28-0.43) for overall sample. In six studies, data about the GC prescription in the two different subsets of the disease were available. The pooled prevalence was 0.52 (95 % CI 0.49-0.55) in diffuse and 0.33 (95 % CI 0.31-0.35) in limited cutaneous disease patients. Five papers reporting data about the dose of GC prescribed showed a pooled prevalence of 0.89 (95 % CI 0.87-0.91) for a daily dose of 75 %). No significant correlation was detected between the extent of GC utilization and either the percentage of concomitant immunosuppressants intake (p = 0.347), diffuse subset (p = 0.720) or female sex (p = 0.913). Despite the limited evidence for their effectiveness, GC are frequently prescribed in SSc patients, mostly in those with the diffuse subset. The variability in the extent of their utilization in different centres is considerable and suggests the need to develop treatment recommendations.

Background Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder associated with increased mortality (1), (standardized mortality ratio for all causes–SMR, being 1.47 in the last 50 years) (2). Objectives To investigate the mortality rate and predictive factors as assessed at admission in a cohort of RA patients followed at a South Italy tertiary centre. Methods RA patients admitted to the outpatient Clinic of a tertiary centre from 01/01/2008 to 31/12/2015 were investigated. Table 1 shows patients features (age, sex, disease duration, Simplified Disease Activity Index-SDAI index, Health Assessment Questionnaire-Disability Index-HAQ-DI, Rheumatoid Factor-RF and/or Anti-Citrullinated Cyclic Peptides Antibody-ACPA, concomitant comorbidity) as detected at baseline, and treatment during follow-up. RA patients mortality incidence rate (event/100person year) was calculated, baseline predictors of mortality were analyzed by univariate and multivariate cox-regression analysis. Results A total of 608 RA patients were included (497 women), median age 56.8 years, range 15–89.5. On December 31 2015, 589 out of patient were alive, 19 were known to have died and 7,3% had been lost to follow up. Mortality Incidence rate (MIR) in our cohort was 0.79 deaths/100 person-year, SMR with respect to Italian population was 0.79 (MIR in Italy 1/100 person-year). This feature might depend on the low prevalence of RF/ACPA positivity (69.13%) in our series. Cox regression analysis (univariate analysis) pointed out age at first visit (HR 1.14; p≤0.0001), diabetes (HR 4.395; p=0.004) and a HAQ value>1 (HR 6.02; p=0.02) as independent predictors of mortality. On the contrary, female sex resulted to have a protective role (HR 0.349, p=0.027). At multivariate analysis, the only baseline independent predictor of mortality was age at admission (HR 1.17, 95% CI 1.01–1.35, p=0.026). Conclusions The present study points out a South Italian RA SMR lower than that in general Italian population and significantly lower than that reported in RA patients from other countries (2). This result can depend on the lower percentage of RF/ACPA positive patients in our cohort in respect to general population. Epidemiological studies on the sierological profile of South Italian RA patients are needed. References Sokka T et al. ClinExpRheumatol. 2008;26(Suppl):S35–61. Dadoun S et al. Joint Bone Spine. 2013;80:29–33. Disclosure of Interest None declared

Background Adult onset Still9s disease (AOSD) is rare inflammatory disease [1]. Three different patterns of AOSD have been identified: i. monocyclic pattern, characterized by a systemic single episode; ii. polycyclic pattern, associated with multiple flares, separated by remissions; iii. chronic pattern, related to a persistently active disease with associated polyarthritis [2]. Until now, the treatment of AOSD remains largely empirical, lacking controlled clinical trials [1]. Objectives We aimed to investigate clinical data of AOSD patients and any possible correlation among these features and the outcome of patients. Methods Clinical data of 100 AOSD patients were recorded. All patients fulfilled the Yamaguchi AOSD diagnostic [3]. Gender, age, clinical features, disease activity Pouchot9s score [4], complications, serum ferritin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), treatments, comorbidities, patterns and AOSD-associated death, were reported. Furthermore, we evaluated any possible correlation among these clinical features and the outcome of patients, by using linear regression analysis. Results One hundred consecutive AOSD patients (66 men, 34 women), whose age at diagnosis was 45.35±16.23 (mean±SD), were enrolled. All patients experienced fever, 86 patients showed joints involvement, 79 patients showed splenomegaly, skin rash was present in 78 patients, 62 patients showed hepatic involvement, 57 patients showed enlargement of lymph nodes. The Pouchot9s score, 6.11±2.02 (mean±SD), confirmed the activity of the disease. Sixteen patients experienced different complications, mainly the macrophage activation syndrome. A strong increase of inflammatory markers (mean±SD) was observed: serum ferritin was 2560.07±3726.64 ng/mL, ESR was 67.28±26.65 mm/hr, CRP was 78.35±72.76. All the patients received steroids at different dosages, and 55 patients were treated with steroids and immunosuppressive drugs, mainly methotrexate and ciclosporin. Thirty-two patients were treated with biologic agents: 5 with anakinra, 8 with tocilizumab, and 19 with TNF inhibitors. Twenty-nine patients showed the monocyclic pattern, 22 patients showed the polycyclic pattern, 33 patients showed the chronic pattern. AOSD-associated death occurred in 16 patients. Regression analysis showed that Pouchot9s score (p=0.011), the presence of any complication (p Conclusions This study provides information on the clinical, laboratory, therapeutic, and prognostic features in a large cohort of AOSD patients. The Pouchot9s score, the presence of complications and comorbidities were significantly associated with the AOSD-associated death. References Gerfaud-Valentin M, et al. Adult-onset Still9s disease, Autoimmun Rev 2014;13,708–722. Cush JJ, et al. Adult-onset Still9s disease. Clinical course and outcome. Arthritis Rheum 1987;30:186–9425. Yamaguchi M, et al. Preliminary criteria for classification of adult Still9s disease. J Rheumatol 1992;19:424–30. Pouchot J, et al. Adult Still9s disease: manifestations, disease course, and outcome in 62 patients. Medicine (Baltimore) 1991;70:118–36. Disclosure of Interest None declared

Aims and Background HER-3 signaling might contribute to resistance to trastuzumab. To clarify the role of HER-3 in HER-2-positive breast cancer, it is important to evaluate the level of HER-3 and its correlations with clinical outcome in metastatic breast cancer patients treated with trastuzumab. Methods HER-3 status by immunohistochemistry was evaluated in HER-2-positive metastatic breast cancer patients treated with trastuzumab-based therapy at our institution. Two scorings were utilized for interpreting staining for HER-3, and the correlation between HER-3 status and clinical outcome was evaluated. Results We evaluated HER-3 status in 61 of 76 HER-2-positive metastatic breast cancers treated with trastuzumab-based therapy at our institution from 4/1999 to 3/2006. We observed 55.2% objective responses; median time to progression and overall survival from start of trastuzumab therapy were 9.6 months (0.921–78.87) and 29.1 months (1.4–129.5+), respectively. With a cutoff of 50% staining tumor cells, we found 30 HER-3-negative and 31 HER-3-positive tumors. HER-3 status was not significantly associated with clinical outcome, but a shorter time to progression and overall survival were observed in patients with HER-3-positive tumors. Conclusions HER-3 status by immunohistochemistry was not significantly associated with clinical outcome in HER-2-positive metastatic breast cancer patients. Further studies are necessary to evaluate the prognostic and predictive role of HER-3.

Aim: ALK and ROS1 gene rearrangements are the “oncogenic drivers” of two subsets of LA that have been shown to be sensitive to the ALK inhibitor crizotinib (Criz). We present an observational analysis of the outcome of the ALK and ROS1-positive (pos) patients (pts) treated at our institution. Methods: We identified 39 ALK-pos LA by analyzing for a 3-gene panel (ALK, KRAS, EGFR) 705 samples. 147 triple-neg samples were studied by FISH for ROS1. Results: Between September 2011 and April 2014, 46 (39 ALK-pos and 7 ROS1-pos) stage IIIB and IV pts received Criz [n = 47 (100%)] at the dose of 250 mg B.I.D. At progression, 13 pts (28.2%) received ceritinib (Cer) at dose of 750 mg once daily. Criz was administered as 1st line in 2 pts (4.3%), as 2nd-3rd in 34 pts (74.5%) and in subsequent lines in 10 pts (21.3% ). Cer was administered as 3rd line in 5 pts (38.5%), as subsequent lines in 8 pts (61.6%). Patients' characteristics prior to Criz were: 19 (40.4%) males and 28 (59.6%) females. Median age 48 years (range:24-71). 8 pts (17.3%) were current or former smokers while 38 pts (80.9%) never smokers. 40 (85.1%) pts were stage IV and 10 (22.7%) had brain metastases. At start of Criz ECOG PS was 0-1 in 39 (84.7%) pts and 2-3 in 7 (14.9%) while at start of Cer PS ECOG was 0 for 10 (76.9%) pts and 1 for 3 (23.1%). 100% of pts were evaluable for the activity of both Criz (46/46) and Cer (13/13). The overall response rate (ORR) to Criz was 27/38 (71 %) in ALK-pos and 6/7 (85.7%) in ROS1-pos pts. The responses to Criz were: one (2.2%) complete response (CR) in a ROS1-pos pt, 32 (69.6%) partial responses (PR), 7 (15.2%) stable diseases (SD) and 6 (13.0%) progressive diseases (PD) with a median time to response of 2 months. Median progression-free survival (PFS) for Criz was 16.9 months (95% C.I.: 3.6-30.3). While median overall survival (OS) has not been reached, 1- and 2-years OS were of 77% and 72%, respectively. In ALK-pos pts 1- and 2-years OS for Criz were of 74.1% and 69.7%, respectively while in ROS1-pos pts OS was 100% both at 1 and at 2-years. As for Cer, responses were: 10 (76.9%) PR, 2 (15.4%) SD and 1 (7.7%) PD with a median time to response of 1.9 months. Median PFS for Cer was 8.6 months (95% C.I.: 6.3-11.0) and 1- and 2-years OS was 92%. Conclusions: These data are consistent with those previously reported. In our experience Cer following Criz was associated with a shorter PFS but similar antitumor activity to that seen with Criz. Disclosure: All authors have declared no conflicts of interest.

Aim: NSCLC in NS often harbors proto-oncogene aberrations, showing enrichment for targetable alterations compared to unselected populations. Objectives of this study were to define the proportions of the driver gene alterations and to examine survival in genotype-specific subsets of NS NSCLC. Methods: We identified 243 NS NSCLC pts treated at our Institution from October 2003 to January 2014. Pts with tissue available for biological analysis were as follows: 207 pts (85.1%) assessable for EGFR/KRAS mutation, 77 (31.6%) for ALK rearrangement, 37 (15.2%) for ROS1 rearrangement, 33 (13.5%) and 32 (13.1%) for RET fusion and HER2 mutation. The cohort comprised 58% women, median age 62, 86% advanced adenocarcinomas (10% brain metastases at diagnosis). Results: Out of 207 tumors, frequency of EGFR and KRAS mutation was 42.5% (88 pts) and 7.7% (16), respectively. Among pts screened for ALK, ROS1, RET, HER2, the proportion of individual testing, were 25.9% (20), 13.5% (5), 9% (3), 0%. 228 pts were evaluable for treatment and outcomes.158 pts (69%) received at least one line of an EGFR tyrosine kinase inhibitor (TKI), of which 42 (27%) as first line. 16 pts (7%) received an ALK/ROS1 inhibitor, and 8 pts (4%) had both treatments, 50 pts (21%) received exclusively chemotherapy. Median progression-free survival (PFS) after treatment with first line EGFR TKI was 13.2 months (mo) vs 5.3 mo for chemotherapy (p Conclusions: The study confirmed the clinical and outcome features which make lung cancer in NS a distinct disease. Of particular note is the marked increase in OS with EGFR TKI therapy when evaluating this subset in contrast to previous studies not specifically focusing on NS. Disclosure: All authors have declared no conflicts of interest.