Background The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has identified a need for biomarkers to predict which patients (pts) with psoriatic arthritis (PsA) are most likely to respond to a specific therapy. Failure to identify effective treatments early on results in sub-optimal PsA disease management. Tofacitinib is an oral JAK inhibitor for the treatment of PsA. The efficacy and safety of tofacitinib 5 and 10 mg twice daily (BID) in pts with PsA have been demonstrated. 1,2 Objectives To identify protein biomarker candidates, which may identify responders (R) vs non-responders (NR) to treatment of PsA, using mass spectrometry-based proteomics. Methods Baseline (BL) serum samples from pts with PsA receiving tofacitinib 5 or 10 mg BID, adalimumab or placebo in OPAL Broaden ( NCT01877668 ) 1 were analysed. Pts were identified as R and NR based on the Psoriatic Arthritis Disease Activity Score (PASDAS) at Month 3; pts with lowest PASDAS ≤3.2 were defined as R, those with highest PASDAS >3.2 as NR. Two proteomic strategies were employed for analysis of BL serum samples: (1) targeted mass spectrometric multiple reaction monitoring analysis of an in-house panel (‘PAPRICA’) comprising of 206 proteins, originally developed to distinguish between different arthropathies, and (2) unbiased discovery liquid chromatography-tandem mass spectrometry (LC-MS/MS). PAPRICA data were normalised using two methods: normalisation to stable isotopically labelled peptide spike-ins (SIL; corrects for fluctuations in sample injections/mass spectrometry loading amounts), and normalisation to an endogenous peptide panel representing total serum protein abundance (TSPA; corrects for different amounts of total serum protein across samples). Univariate analyses (Student’s t-test) and multivariate machine learning Random Forest (RF) modelling 3 were performed. Univariate analysis of the PAPRICA panel of proteins was performed on R vs NR, and within each treatment arm, with no adjustment for multiplicity. Results 96 pts were identified as 47 R and 49 NR based on PASDAS scores. Of pts receiving tofacitinib 5 or 10 mg BID (data pooled), adalimumab or placebo, there were 26 R vs 26 NR, 13 R vs 13 NR and 8 R vs 10 NR, respectively. Results from univariate analysis identified 110 differentially expressed PAPRICA peptides between R vs NR (p≤0.05). RF multivariate analysis of all data (n=96) revealed a set of PAPRICA peptide signatures with the ability to differentiate between R and NR. Two RF models generated from the PAPRICA peptide data had training area under curves (AUCs) 0.956 [95% CI 0.93, 0.99] (TSPA) and 0.959 [95% CI 0.94, 0.98] (SIL). In total, 115 PAPRICA peptides representing 87 proteins were identified as potential biomarkers for predicting treatment response. Using unbiased discovery LC-MS/MS, univariate analysis of all data revealed one candidate peptide biomarker (p≤0.05). RF modelling revealed peptides that contributed to two prediction models with training AUCs of 0.903 [95% CI 0.86, 0.96] and 0.928 [95% CI 0.89, 0.96]. In total, from unbiased discovery LC-MS/MS, 66 peptides representing 39 proteins that may act as potential peptide biomarkers were identified in univariate and multivariate analyses. Conclusion Using two complementary proteomic approaches and a combination of univariate and machine learning models, a total of 181 candidate biomarker peptides corresponding to 106 proteins have been identified that may act as potential biomarkers for predicting response to treatment of PsA. Further study is required to verify and evaluate these candidate biomarkers, and we will report how these proteins map to biological processes, pathways and networks. References [1]Mease et al. N Engl J Med 2017; 377: 1537-1550. [2]Gladman et al. N Engl J Med 2017; 377: 1525-1536. [3]Breiman. Machine Learning 2001; 45: 5-32. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by Lauren Hogarth, CMC Connect, and funded by Pfizer Inc. Disclosure of Interests James Waddington Employee of: Atturos, Ruoyi Zhou Employee of: Atturos, Orla Coleman Employee of: Atturos, Bruna Wundervald Employee of: Atturos, Andrew Parnell: None declared, Philip J Mease Speakers bureau: AbbVie, Amgen, Janssen, Novartis, Pfizer Inc and UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, CorEvitas, Eli Lilly, Galapagos, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer Inc, Sun Pharma and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, Sun Pharma and UCB, Vinod Chandran Consultant of: AbbVie, Amgen, BMS, Eli Lilly, Janssen, Novartis, Pfizer Inc and UCB, Grant/research support from: AbbVie, Amgen, Eli Lilly, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Douglass Chapman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Remy Pollock Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Shibing Deng Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Oliver FitzGerald Shareholder of: Atturos, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc and UCB, Employee of: University College Dublin, Stephen Pennington Shareholder of: Atturos, Employee of: University College Dublin

Background Tofacitinib is an oral JAK inhibitor for the treatment of RA. A novel automated quantification method for RA MRI-detected pathology using statistical shape modelling technology (RAMRIQ) provides a tool that may be even more responsive than the sensitive RAMRIS semi-quantitative standard.1 Objectives To determine if early changes in RAMRIQ were predictive of subsequent MRI and radiographic damage progression in a study of tofacitinib for the treatment of early RA in methotrexate-naïve patients with minimal radiographic progression. Methods We used data from an exploratory, Phase 2 randomised controlled trial comparing tofacitinib, methotrexate and the combination (n=109) in methotrexate-naïve patients with early active RA.1 All patients met ACR classification criteria for active RA. MRI was performed at baseline and at 1, 3, 6 and 12 months. A single centralised reader read all MRI data; data for each patient were randomised by time point and read in the same sitting. We examined changes in synovitis, osteitis and erosions for RAMRIQ and RAMRIS at 1 and 3 months and performed univariate analyses on their relationship to RAMRIS, RAMRIQ and radiographic progression (modified Total Sharp Score [mTSS]) at 12 months. Results Reduction in RAMRIQ synovitis and osteitis at 1 and 3 months were significantly associated with reduction in RAMRIS erosion progression at 12 months (Table). Improvement in RAMRIQ synovitis and osteitis at 1 and 3 months were also associated with reduction in radiographic progression at 12 months, while RAMRIQ erosions at 1 and 3 months were not significantly associated with radiographic progression (Table). Early changes in RAMRIS erosion at 1 and 3 months were associated with radiographic progression at 12 months (Table). Treatment with tofacitinib alone or in combination with methotrexate was also associated with reduced progression in RAMRIS erosions (p=0.017 and p=0.007, respectively). Conclusions In this study, sensitive automated detection demonstrated that change in synovitis and osteitis predict subsequent RAMRIS erosion and radiographic progression. Treatment with tofacitinib as monotherapy or in combination with methotrexate was also highly predictive of no progression of erosive damage. Because of its enhanced sensitivity, novel quantitative imaging analysis has the potential to change RA clinical trial design where assessing structural damage is an objective. References Conaghan PG et al. Ann Rheum Dis 2016; 75: 1024–1033. Acknowledgements Previously presented at ACR 2016 and reproduced with permission. This study was sponsored by Pfizer Inc. Editorial support was provided by S Morgan of CMC and was funded by Pfizer Inc. Disclosure of Interest P. G. Conaghan Consultant for: AbbVie, Eli Lilly, Flexion, Novartis, Pfizer Inc, Roche, Speakers bureau: AbbVie, Novartis, Roche, M. A. Bowes Employee of: Imorphics Ltd, M. Østergaard Grant/research support from: AbbVie, Centocor, Merck, Consultant for: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Eli Lilly, GSK; Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer Inc, Regeneron, Roche, Schering-Plough, Takeda, UCB, Wyeth, Speakers bureau: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Eli Lilly, GSK; Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer Inc, Regeneron, Roche, Schering-Plough, Takeda, UCB, Wyeth, G. Guillard Employee of: Stryker Co, D. Chapman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Stein Employee of: Quintiles, J. Andrews Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Z. Xie Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Koenig Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, B. Wilkinson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Tofacitinib is anoral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives This post hoc analysis aims to explore the efficacy of tofacitinib in patients (pts) with RA based on their baseline (BL) body mass index (BMI). Methods Data were analysed from six Phase 3 studies for pts who were methotrexate-naïve (NCT01039688) or had an inadequate response to DMARDs (NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385) and received ≥1 dose of tofacitinib 5 or 10 mg twice daily (BID) or placebo (PBO). Pts were stratified by BL BMI (<25, 25 to <30, ≥30). Efficacy endpoints (American College of Rheumatology [ACR]20/50/70 response rates at Month [M]6; changes from baseline [Δ] in Health Assessment Questionnaire-Disability Index [HAQ-DI], Disease Activity Score in 28 joints based on Erythrocyte Sedimentation Rate [DAS28-4(ESR)], DAS28 based on C-reactive protein [DAS28-4(CRP)] and Clinical Disease Activity Index [CDAI] at M3 and M6) were assessed. Non-responder imputation was used for the binary endpoints. No imputation was used for continuous endpoints. No multiplicity adjustment was performed in this post hoc analysis. Results Overall, 1589, 1611 and 681 pts received tofacitinib 5 and 10 mg BID and PBO, respectively, with 1690, 1173 and 1017 pts in the BMI <25, 25 to <30 and ≥30 categories, respectively. BL demographics were generally similar between BMI categories with the exception of higher rates of diabetes (12.9-14.2% vs 3.5-9.8%), hypertension (53.2-58.9% vs 22.0-39.8%), and use of prior TNFi (23.7-46.8% vs 15.0-26.9%), and numerically higher tender (28.8-29.9 vs 23.5-26.9) and swollen joint counts (16.5-17.1 vs 14.5-16.3) and HAQ-DI scores (1.6 vs 1.4-1.5) in the BMI ≥30 group vs BMI <25 or 25 to <30. ACR response rates were significantly higher (p<0.05) in the tofacitinib vs PBO groups, regardless of BMI category(figure 1). In general, there appeared to be a trend towards lower ACR20/50/70 response rates with increasing BMI at M6 in tofacitinib- and PBO-treated pts; however, confidence intervals (CI) overlapped. At M6, ΔHAQ-DI was numerically smaller for pts receiving tofacitinib 5 mg BID with BMI ≥30 vs lower BMIcategories, with overlapping CI. The ΔDAS28-4(ESR), ΔDAS28-4(CRP) and ΔCDAIscores were similar within each treatment group regardless of BL BMI. Generallysimilar trends were observed when stratified by weight. Conclusions Results of this post hoc analysis suggest that tofacitinib is associated with improvements in RA outcomes compared with PBO regardless of BL BMI category. In both tofacitinib and PBO groups, similar trends in improvements were seen in most endpoints regardless of BMI category, implying that the effect of BL BMI is not specific to tofacitinib. Further investigation is needed to assess the degree of impactof BMI on tofacitinib efficacy. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by C Viegelmann of CMC and funded by Pfizer Inc. Disclosure of Interest: A. DikranianGrant/research support from: AbbVie, Mallinckrodt, Pfizer Inc, Speakers bureau:AbbVie, Amgen, Celgene, Mallinckrodt, Pfizer Inc, M. Gonzalez-Gay Consultant for: Pfizer Inc, F. Wellborne Grant/research support from: AbbVie, BMS, EliLilly, Novartis, Pfizer Inc, Sanofi/Genzyme/Regeneron, Consultant for: AbbVie,BMS, Novartis, Pfizer Inc, Sanofi/Genzyme/Regeneron, Speakers bureau: AbbVie,BMS, Eli Lilly, Novartis, Pfizer Inc, Sanofi/Genzyme/Regeneron, J.Alvaro-Gracia Consultant for: Abbvie, BMS, Eli Lilly, MSD, Novartis, PfizerInc, Roche, Sanofi/Genzyme/Regeneron, Speakers bureau: Abbvie, BMS, Eli Lilly,MSD, Novartis, Pfizer Inc, Roche, Sanofi/Genzyme/Regeneron, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Chapman Shareholder of: Pfizer Inc,Employee of: Pfizer Inc, S. Tatulych Shareholder of: Pfizer Inc, Employee of:Pfizer Inc, P. Dahl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J.Curtis Grant/research support from: Amgen, Corrona, Crescendo Bio, Pfizer Inc, Consultant for: AbbVie, Amgen, BMS, Corrona, Eli Lilly, Janssen, Myriad, Roche/Genentech,UCB

We characterized maraviroc susceptibility of dual/mixed tropic viruses from subjects enrolled onto phase IIb study A4001029. Maraviroc baseline plasma samples from 13 multidrug-experienced subjects were sequenced and the HIV-1-env gene cloned into pNL4.3Δenv to obtain recombinant viruses. The V3 region was sequenced by the Sanger method and ultradeep sequencing. By analysing subjects having a weighted optimized background therapy susceptibility (wOBT) score of <1, 3/7 subjects were characterized by good in vivo and in vitro response to maraviroc therapy. Molecular docking simulations allowed us to rationalize the maraviroc susceptibility of dual/mixed tropic viruses. A subset of subjects with dual/mixed tropic viruses responded to maraviroc. Further investigations are warranted of CCR5 antagonists in subjects carrying dual/mixed tropic virus that explore the feasible use of maraviroc in subjects that is potentially larger than those infected with a pure R5 virus.

Safety was evaluated for collagenase Clostridium histolyticum (CCH) based on 11 clinical trials ( N = 1082) and compared with fasciectomy data in a structured literature review of 48 European studies ( N = 7727) for treatment of Dupuytren’s contracture. Incidence of adverse events was numerically lower with CCH vs. equivalent complications from fasciectomy (median [range] incidence), including nerve injury (0% vs. 3.8% [0%−50+%]), neurapraxia (4.4% vs. 9.4% [0%−51.3%]), complex regional pain syndrome (0.1% vs. 4.5% [1.3%−18.5%]) and arterial injury (0% vs. 5.5% [0.8%−16.5%]). Tendon injury (0.3% vs. 0.1% [0%−0.2%]), skin injury (16.2% vs. 2.8% [0%−25.9%]) and haematoma (77.7% vs. 2.0% [0%−25%]) occurred at a numerically higher incidence with CCH than surgery. Adverse events in CCH trials not reported after fasciectomy included peripheral oedema; extremity pain; injection site pain, haemorrhage and swelling; tenderness; pruritus and lymphadenopathy. CCH-related adverse events were reported as predominantly injection-related and transient. These results may support clinical decision-making for treatment of Dupuytren’s contracture.

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

BACKGROUND Serotonin reuptake inhibitors (SRIs) have demonstrated consistent efficacy in the treatment of obsessive-compulsive disorder (OCD), while agents that are primarily norepinephrine reuptake inhibitors have not. Comparable efficacy has been demonstrated for SRI and non-SRI antidepressants in uncomplicated major depressive disorder (MDD). This multicenter trial is the first comparison of an SRI (sertraline) and a non-SRI antidepressant (desipramine) in the treatment of OCD with concurrent MDD. METHODS One hundred sixty-six patients diagnosed using structured clinical interviews and recruited from 16 treatment sites were randomly assigned to double-blind treatment with either sertraline (up to 200 mg/d) or desipramine (up to 300 mg/d) over 12 weeks. Measures of severity of OCD and MDD symptoms, as well as adverse effects of the medications, were monitored over the course of the treatment period. RESULTS Patients assigned to sertraline responded significantly better at end point on measures of OCD and MDD symptoms compared with patients assigned to desipramine. Sertraline was also associated with a significantly greater number of patients who achieved a "robust" improvement in OCD symptoms (> or =40% reduction) compared with desipramine. More patients receiving desipramine than sertraline discontinued treatment because of adverse events. CONCLUSIONS The SRI sertraline was more effective in reducing MDD and OCD symptoms than the primarily norepinephrine reuptake inhibitor desipramine for patients with concurrent OCD and MDD.

BACKGROUND, The management of pediatric oncology patients with fever and neutropenia assumes that all patients are at risk for bacteremia, and therefore generally involves hospitalization and broad-spectrum parenteral antibiotics for all patients. The determination of which patients are at low risk for having positive blood cultures and for developing complications related to bacteremia is of potential benefit.METHODS, The records of 161 pediatric patients with neoplastic disease hospitalized for 509 episodes of fever and neutropenia between January 1990 and June 1992 were retrospectively reviewed. Clinical features at initial presentation, clinical and microbiologic documentation of infection, and outcome were analyzed.RESULTS. The only presenting clinical features that correlated with an increased likelihood of having positive blood cultures were chills, hypotension, the requirement for fluid resuscitation (P < 0.001), or a diagnosis of leukemia or lymphoma (P < 0.041). Leukemia patients with relapse admitted for fever and neutropenia were no more likely to have positive blood cultures than those patients in remission. There were ten episodes of fever and neutropenia in which patients were transferred to the intensive care unit (ICU), and two sepsis related deaths. Nine episodes involving ICU management and both deaths were in patients who had persistent fever and an absolute neutrophil count (ANC) of less than 100 after 48 hours of hospitalization (n = 177). Patients with an ANC of less than 100 after 48 hours were twice as likely to have antibiotic changes, 15 times more likely to receive amphotericin B, and were hospitalized twice as long as patients with an ANC of 100 or higher after 48 hours.CONCLUSIONS. Children hospitalized for fever and neutropenia who have persistent fever and an ANC of less than 100 after 48 hours are at high risk for morbidity and are more likely to require antibiotic changes and antifungal therapy. Children who initially lack signs of sepsis, are afebrile, and have an ANC of 100 or higher after 48 hours are at low risk for complications and could be selectively discharged on antimicrobials after a 48-hour period of inpatient hospitalization. (C) 1996 American Cancer Society.

Background. We studied three new dose schedules of hepatic arterial infusion of floxuridine (FUDR) and leucovorin and update survival analysis of a previously reported trial using these drugs by hepatic arterial infusion for patients with hepatic metastases from colorectal carcinoma.Methods. Untreated patients with hepatic metastases from colorectal cancer were treated with three dose schedules: Group D, FUDR (0.3 mg/kg/day) and leucovorin (30 mg/m(2)/day) as a 14-day continuous infusion through an implantable hepatic arterial pump alternating with a 4-week rest period; Group E, a lower dose of FUDR (0.25 mg/kg/day) and leucovorin (30 mg/m(2)/day) as a 14-day infusion alternating with 2 weeks of saline; and Group F, FUDR (0.3 mg/kg/day) with a lower leucovorin dose (15 mg/m(2)/day) for 2 weeks followed by a 2-week rest.Results. In 42 patients with unresectable hepatic metastases, the complete-plus-partial response rate was 56%, with a median survival of 24.2 months. Complete-plus-partial response rates for groups D, E, and F were 30%, 54%, and 75%, respectively. Twelve percent of the 42 patients developed biliary sclerosis; the percentages of patients per group were 17%, 15%, and 6%, respectively. Updated median survival of the original 24 patients treated with FUDR and leucovorin by hepatic arterial infusion and these 42 new patients (66 total) was 28.8 months. One-, two-, three-, four-, and five-year survival rates were 86%, 62%, 31%, 15%, and 7%, respectively.Conclusions. Hepatic arterial chemotherapy with FUDR and leucovorin for patients with hepatic metastases from colorectal carcinoma yields a high response rate and 1- and 2-year survivals of 86% and 62%, respectively. Although a lower dose of leucovorin (15 mg/m(2)) with FUDR produces a high response rate with less toxicity, before larger scale trials are initiated, further investigation is needed to reduce toxicity. A study of hepatic arterial dexamethasone with FUDR and leucovorin has been initiated for this purpose.

Seventy-seven patients with endometrial cancer with cervical involvement were treated at Memorial Sloan-Kettering Cancer Center from 1968 to 1982. Fractional curettage specimens showed that 25 patients (32%) had involvement of cervical stroma and 52 (68%) had only detached fragments of carcinoma present in endocervical curettings. Six patients treated for palliation only are excluded from analysis of treatment and survival. Our preferred treatment during the time interval studied consisted of preoperative whole pelvic radiotherapy followed by modified radical hysterectomy and bilateral salpingo-oophorectomy with post-operative intravaginal brachytherapy. This regimen was well tolerated by the 37 patients so treated. The remaining patients were treated with a variety of regimens, most commonly radiotherapy and simple hysterectomy (25 patients). With a mean follow-up among survivors of 97 months, disease-free survival is 72%. Mean time to relapse was 19 months, with 90% of relapses occurring within 40 months. Initial sites of relapse included abdomen, 9 (12.6%); lungs, 8 (11.3%); brain, 2 (2.8%); lateral pelvis, 2 (2.8%); and bone, 1 (1.4%). Clinicopathologic variables significantly related to risk of relapse included presence of extrauterine disease at surgery (P = 0.0001), extent of cervical involvement as determined prior to hysterectomy (P = 0.001), depth of myometrial invasion (P = 0.005), and papillary serous histology (P = 0.0002). Treatment of endometrial cancer with cervical involvement with combinations of radiotherapy and surgery is well tolerated and results in an excellent long-term disease-free survival and a low rate of pelvic relapse.

Improved results in the adjuvant and therapeutic treatment of colon cancer has led to renewed interest in the role of adjuvant chemotherapy following liver resection for colorectal hepatic metastases. However, little is known about the most effective method or timing of delivery of adjuvant chemotherapy. Sixty-nine BD-IX rats underwent a right hepatic lobectomy following tumour inoculation via a splenic injection of 10(7) K12/TRb colon cancer cells. The rats were then randomized to receive systemic FUdR (1 mg kg-1 d-1 for 7 d) or regional (hepatic artery or portal vein) FUdR (2 mg kg-1 d-1 for 7 d) immediately or 72 h following tumour injection. On Day 28, a laprotomy was performed, and tumour nodules in the liver were counted. The animals were followed to death, and at autopsy the cause of death from hepatic or extrahepatic metastases was determined. All methods of FUdR infusion were superior to no treatment. Immediate portal vein (PV) FUdR infusion delayed the appearance of hepatic tumour (P = 0.003), changed the cause of death from hepatic to extrahepatic disease (P = 0.019), and prolonged survival (P < 0.05). Infusion of FUdR via the PV 72 h later did not delay the appearance of hepatic tumours nor prolong survival. In contrast, delayed HA FUdR infusion controlled hepatic metastases (P = 0.04) and improved survival (P < 0.05).