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Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

Objective.We analyzed the characteristics of patients with psoriatic arthritis (PsA) with and without axial involvement in the US-based Corrona Psoriatic Arthritis/Spondyloarthritis Registry.Methods.All patients were included who had PsA and data on axial involvement, defined as physician-reported presence of spinal involvement at enrollment, and/or radiograph or magnetic resonance imaging showing sacroiliitis. Demographics, clinical measures, patient-reported outcomes, and treatment characteristics were assessed at enrollment.Results.Of 1530 patients with PsA, 192 (12.5%) had axial involvement and 1338 (87.5%) did not. Subgroups were similar in sex, race, body mass index, disease duration, presence of dactylitis, and prevalence of most comorbidities. However, patients with axial involvement were younger and more likely to have enthesitis, a history of depression, and more frequently used biologics at enrollment. They were also more likely to have moderate/severe psoriasis (body surface area ≥ 3%, 42.5% vs 31.5%) and significantly worse disease as measured by a lower prevalence of minimal disease activity (30.1% vs 46.2%) and higher nail psoriasis scores [visual analog scale (VAS) 11.4 vs 6.5], enthesitis counts (5.1 vs 3.4), Bath Ankylosing Spondylitis Disease Activity Index (4.7 vs 3.5) scores, Bath Ankylosing Spondylitis Functional Index (3.8 vs 2.5) scores, C-reactive protein levels (4.1 vs 2.4 mg/l), and scores for physical function (Health Assessment Questionnaire, 0.9 vs 0.6), pain (VAS, 47.7 vs 36.2), and fatigue (VAS, 50.2 vs 38.6).Conclusion.Presence of axial involvement was associated with a higher likelihood of moderate/severe psoriasis, with higher disease activity and greater effect on quality of life. These findings highlight the importance of monitoring patients with PsA for signs of axial symptoms or spinal involvement.

Objective To describe the characteristics of patients with ankylosing spondylitis (AS) and patients with nonradiographic axial spondyloarthritis (SpA) in the US. Methods Demographics, clinical characteristics, patient-reported outcomes, and treatment characteristics of patients with AS and those with nonradiographic axial SpA were assessed at the time of enrollment in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry. Patients with AS were defined as those who fulfilled the 1984 modified New York criteria for AS; patients with nonradiographic axial SpA were defined as all other patients with axial SpA who did not fulfill the radiology criterion. Results Of the 407 patients with a diagnosis of axial SpA who were included in this study, 310 had AS, and 97 had nonradiographic axial SpA. Although patients with nonradiographic axial SpA were younger and showed a trend toward a shorter symptom duration, the nonradiographic axial SpA and AS groups shared a similar disease burden, as reflected by comparisons of disease activity and function, quality of life, pain, fatigue, job absenteeism, and loss of work productivity (all P > 0.05). The proportions of patients with nonradiographic axial SpA and patients with AS who received prior biologic disease-modifying drugs (DMARDs) (74.2% and 64.8%, respectively) or were currently receiving biologic DMARDs (63.9% and 61.3%, respectively) were also similar (P > 0.05). Conclusion This was the first nationwide study to characterize patients with AS and nonradiographic axial SpA in the US. Consistent with studies published outside of the US, this study showed that patients with nonradiographic axial SpA and patients with AS shared a comparable degree of disease burden and had similar treatment patterns in clinical practice.

Background Achievement of minimal disease activity (MDA) may represent an objective target for treatment for patients with psoriatic arthritis (PsA). 1 A patient is considered to have achieved MDA when 5 of the following 7 criteria are met: tender joint count (TJC) ≤1, swollen joint count (SJC) ≤1, affected body surface area (BSA) ≤3%, patient pain VAS ≤15, patient global activity VAS ≤20, HAQ score ≤0.5 and tender entheseal points ≤1. 1 Objectives To retrospectively report the MDA and patient-reported outcomes (PROs) over time (baseline vs first follow-up [FU] visit vs second FU visit) that may contribute to achievement of MDA in responders versus non-responders to biologic treatment. Methods This analysis included all patients with PsA in the Corrona registry aged ≥18 years between March 2013 and March 2016 who received biologics (index biologics) at enrollment (baseline) and had ≥2 FU visits (at ≈ 6-month intervals, mean [SD] 2nd FU visit: 15.7 [3.7] months). Responders were defined as patients who achieved MDA at the second FU visit and remained on their index biologic. Demographics, clinical characteristics, PROs and treatment history were collected at enrollment and at both FU visits. Trend tests of MDA over time were performed using the Wilcoxon rank-sum nonparametric test for responders and non-responders separately. Results Of 148 patients who met the inclusion criteria (mean [SD] age, 54.7 [11.0] years; mean [SD] disease duration, 11.8 [10.1] years), 34 patients (23%) were classified as responders and 114 patients (77%) were non-responders at the second FU visit. The core components of MDA in these patients are shown in Table 1. Among responders, there were significant improvements in clinical characteristics and PROs such as mean TJC (3.4 vs 2.1 vs 0.6; P =0.004), SJC (2.5 vs 0.8 vs 0.5; P P =0.03), patient pain (34.7 vs 26.1 vs 21.9; P =0.007) and HAQ scores (0.6 vs 0.4 vs 0.3; P =0.04); however, there were no significant changes over time for patient global assessment or enthesitis counts ( P >0.05). Non-responders failed to have a significant improvement from baseline to the first and second FU visits in TJC, SJC, enthesitis, pain, patient global assessment and percentage of affected BSA (all P >0.05). Conclusions Only 23% of patients achieved MDA on their index biologic at the second FU visit and were considered responders. Over time, responders showed significant improvements in TJC and SJC, percentage of affected BSA, patient pain and HAQ scores; these most likely contributed to achievement of MDA response. A treat-to-target approach may be considered given the low number of patients in MDA. References Coates, LC et al. Ann Rheum Dis. 2010;69(1):48–53. Acknowledgements Corrona, LLC, has been supported through contracted subscriptions in the last 2 years by AbbVie, Amgen, BMS, Crescendo, Eli Lilly and Company, GSK, Horizon Pharma USA, Janssen, Momenta Pharmaceuticals, Novartis, Pfizer, Roche and UCB. Disclosure of Interest P. Mease Grant/research support from: Celgene, Novartis, AbbVie, Amgen, BMS, Lilly, Pfizer, UCB, Consultant for: Celgene, Corrona, Novartis, AbbVie, Amgen, BMS, Crescendo, Genentech, Janssen, Lilly, Merck, Pfizer, UCB, C. Karki Employee of: Corrona, LLC, M. Liu Employee of: Corrona, LLC, A. Kavanaugh Grant/research support from: Amgen, AbbVie, Janssen, Pfizer, Novartis, C. Ritchlin Grant/research support from: Amgen, Janssen, UCB, Consultant for: AbbVie, Amgen, Janssen, Regeneron, UCB, D. Hunyh Speakers bureau: AbbVie, BMS, R. Pandurengan Employee of: Corrona, LLC, J. Palmer Employee of: Novartis, J. Greenberg Shareholder of: Corrona, LLC, Consultant for: Lilly, Genentech, Janssen, Novartis, Pfizer, Employee of: Corrona, LLC

Background Axial spondyloarthritis (axSpA) is a chronic inflammatory disease affecting the sacroiliac joints and spine. Treatment primarily consists of first-line nonsteroidal anti-inflammatory drugs (NSAIDs) and/or biologic therapy when disease activity persists despite NSAID therapy. Although many studies have evaluated the efficacy of these treatments, there are few studies that have characterized NSAIDs and/or biologic therapy among patients with axSpA in the United States. Objectives To characterize patients with axSpA treated with NSAIDs only, biologics only, or both NSAIDs and biologics at the time of enrollment in the US-based Corrona PsA/SpA Registry. Methods This study included all patients with axSpA diagnosed by the rheumatologist aged ≥18 years enrolled in the Corrona Registry between March 2013 and September 2016 who were treated with NSAIDs only, biologics only, or both NSAIDs and biologics at the time of enrollment (baseline). Patients fulfilled the Assessment of SpondyloArthritis international Society classification criteria. 1 Demographics, clinical characteristics, disease activity measures and treatment history were collected at enrollment and described for each group. Results As of September 2016, 359 patients with axSpA met the study inclusion criteria; at baseline, 224 patients (62.4%) were receiving NSAIDs (92 [25.6%] with NSAIDs only and 132 [36.8%] with both NSAIDs and biologics) and 135 patients (37.6%) were receiving biologics only. Baseline characteristics were similar across all treatment subgroups with regards to age, race and body mass index. Fewer females were treated with biologics (with/without NSAIDs) compared to the NSAIDs only group. At baseline, patients treated with NSAIDs or both NSAIDs and biologics were older, had longer duration of disease with worse disease activity (measured by ASDAS and BASDAI), functional impairment (BASFI and HAQ-DI) and had worse pain and fatigue compared to those treated with biologics only (Table 1). 88–96% of patients receiving biologics (with or without NSAIDs) had prior biologic use compared to only 25% of NSAIDs only group. Patients treated with biologics only reported decreased percentage of impairment while working, overall work impairment and activity impairment at baseline compared with patients treated with NSAIDs only and both NSAIDs and biologics. Conclusions About two-thirds of patients with axSpA were treated with NSAIDs (with or without biologics) and about three-fourths of patients were treated with biologics (with or without NSAIDs) at enrollment. Patients that were already treated with biologics without NSAIDs at enrollment showed better measures of disease activity and PROs compared with the other treatment groups. Future research will assess changes in clinical and disease characteristics over time by treatment subgroup. References Rudwaleit M, et al. Ann Rheum Dis. 2009;68(6):777–783. Acknowledgements Corrona, LLC, has been supported through contracted subscriptions in the last 2 years by AbbVie, Amgen, BMS, Crescendo, Eli Lilly and Company, GSK, Horizon Pharma USA, Janssen, Momenta Pharmaceuticals, Novartis, Pfizer, Roche and UCB. Disclosure of Interest P. Mease Grant/research support from: Celgene, Novartis, AbbVie, Amgen, BMS, Lilly, Pfizer, UCB, Consultant for: Celgene, Corrona, Novartis, AbbVie, Amgen, BMS, Crescendo, Genentech, Janssen, Lilly, Merck, Pfizer, UCB, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi Aventis and UCB, Employee of: Imaging Rheumatology BV, C. Karki Employee of: Corrona, LLC, M. Liu Employee of: Corrona, LLC, R. Pandurengan Employee of: Corrona, LLC, Y. Park Employee of: Novartis, J. Greenberg Shareholder of: Corrona, LLC, Consultant for: Lilly, Genentech, Janssen, Novartis, Pfizer, Employee of: Corrona, LLC

Background: Enrollment into acute ischemic stroke (AIS) trials is usually limited to weekday working hours. At our center, the majority of patients (64%) that receive tPA arrive after-hours. As a result, a large portion of eligible patients do not receive the opportunity to participate in these trials, hence enrollment rate suffers. Objectives: Demonstrate ongoing experience regarding feasibility and implementation of a 24/7 enrollment plan for an international AIS trial. Compare differences in patients’ characteristics enrolled during working hours ( WH - Mon-Fri 07:00-17:00) vs. after hours+weekend ( AH ). Methods: Data obtained from an on-going, multi-center, randomized, time-sensitive, tPA-adjunctive clinical trial (ARTSS-2; NCT01464788) Centers capable of doing so, implemented an on-call system for coordinators to respond AH. AH enrollment includes a coordinated effort to reduce time and meet the time challenges of screening, consent, randomization and starting study drug before the end of tPA infusion. The coordinator arrives at the ED to assist in-house physician with study procedures. We conducted descriptive analyses that explore differences between WH vs. AH . Results: As of 08/14, a total of 240 patients were eligible of which 75 were enrolled. Of these, 32 (43%) were enrolled AH at a total of 6 sites. 15 of 32 AH patients were enrolled at non-coordinating centers. AH patients were younger and more likely to be male (Table 1). Compared to WH, AH enrollment did not delay tPA initiation, time to website randomization, or initiation of study drug. No signal of increased harm or trial protocol deviations was evident between the two groups. Conclusion: 24/7 clinical trial enrollment is safe and feasible in a multicenter, international thrombolysis trial. We increased recruitment by 75% with no delays in randomization or initiation of study treatment. Efforts to provide 24/7 coverage should be implemented to improve trial recruitment rates.

Objective: The purpose of this study was to assess the incidence of deterioration, fluctuation, and associated risk of poor outcome in patients with subcortical stroke (SCS). Methods: We conducted a prospective observational study, enrolling patients admitted with SCS based on their clinical examination and imaging studies. An NIH Stroke Scale evaluation was performed daily and whenever deterioration in examination was detected. Neurologic deterioration was defined as a motor score increase of at least 1 on the NIH Stroke Scale. Modified Rankin Scale scores at discharge were used to assess outcome. Results: Among 90 enrolled patients, 37 (41%) deteriorated, 75% of them in the first 24 hours after enrollment. Administration of tissue plasminogen activator was significantly associated with deterioration (hazard ratio 2.25; 95% confidence interval [CI]: 1.13–4.49) even after controlling for the association of deterioration with the early poststroke period. Deterioration conferred an increased risk of poor outcome (modified Rankin Scale scores 3–6) at discharge (relative risk: 1.80; 95% CI: 1.71–1.93). Reversion back to predeterioration deficits occurred in 38% of patients, and was associated with reduced risk of poor outcome at discharge (relative risk: 0.12; 95% CI: 0.02–0.83). Treatment with tissue plasminogen activator conferred better chances of spontaneous recovery to predeterioration deficits after initial deterioration (hazard ratio: 4.36; 95% CI: 1.36–14.01). Conclusion: More than 40% of patients with SCS deteriorate neurologically. Deterioration tends to occur early after stroke, spontaneously reverses in approximately one-third of cases, and poses an increased risk of poor outcome. Therapies are needed to prevent, arrest, or reverse deterioration in patients with SCS.

BACKGROUND MRI DWI abnormalities have been reported in 22-35% of patients with intracerebral hemorrhage (ICH). The mechanism underlying these changes is unknown. The timing of development of DWI changes has not been well described. We evaluated the time at which DWI changes occurred in a prospective database of patients with spontaneous ICH in the Safety of Pioglitazone for Hematoma Resolution In Intracerebral Hemorrhage trial (SHRINC). We also sought to examine if clinical features might predict the time at which DWI changes occurred. METHODS SHRINC is an ongoing prospective, randomized study evaluating the safety of pioglitazone versus placebo in patients with ICH. Patients undergo serial MRI on Day (D)1, D2, D7/14, D28, and D42. We captured the occurrence of DWI lesions on MRI and categorized patients into 4 groups according to the time of onset of DWI lesions: observed on admission (hyperacute), D2 (acute), D7 or 14 (subacute) or >28 days (chronic). Patients were excluded if they did not have an MRI for comparison on the selected days. Baseline characteristics were collected prospectively on admission and compared between groups. RESULTS: Thirty patients had complete imaging; 17 (56.67%) had DWI abnormalities in total. Characteristics are included in Table 1. Seven patients (23.33%) had DWI abnormalities remote from the ICH. There were no differences in the baseline characteristics between the groups except INR was significantly lower in the hyperacute group compared to the chronic group (p CONCLUSION: Our data demonstrate that DWI lesions are more frequently seen at the time of initial ICH. The occurrence of DWI lesions at later time points suggests there may be different mechanisms accounting for these changes. Our study is limited by the small sample size and blinded nature of treatment allocation. Further study is needed to understand the underlying mechanisms of these DWI changes and their clinical relevance.

Objective: Patients with progressive strokes during hospitalization have increased morbidity and mortality as well as worsened functional outcome compared with those who remain stable. While the reported rate of fluctuations in subcortical stroke patients has ranged between 20 to 70%, there are no prospective “natural history” data regarding in-hospital deterioration, neurofluctuation, and reversion back to baseline. The purpose of this prospective study was to capture the incidence of fluctuations and their outcome in subcortical stroke patients receiving standard of care (antiplatelet drugs, intravenous fluids, and bed rest). Methods: We conducted a prospective study of all patients with subcortical strokes identified based on their clinical exam and routine imaging studies. Informed consent was obtained and demographics collected. An NIH stroke scale (NIHSS) was performed daily and whenever symptoms worsened (defined as a motor score increase of at least 1 on the NIHSS). Modified Rankin scales (mRS) were obtained at 90 days. Results: 90 patients were prospectively enrolled. Analysis is shown in the corresponding tables. Thirty eight percent (34/90) of patients deteriorated; 41% of those patients fully recovered back to their admission NIHSS and 32% experienced partial recovery. There were no differences in age, gender, admission NIHSS, or ethnicity between those who deteriorated and those who remained stable. Deteriorating patients were more likely to have received tPA, have a higher discharge NIHSS, and a higher 90 day mRS. Three quarters of the patients had deterioration within 24 hours of symptom onset. Of the deteriorating patients who initially received tPA, all worsened within 24 hours. Patients who deteriorated had a significantly higher incidence of mRS 3-6 compared to patients who remained stable. There were no associations between age, gender, or ethnicity with neurological recovery back to admission NIHSS in those patients who initially deteriorated. Conclusion: This is the first prospective study to characterize the natural history of subcortical stroke fluctuation during hospitalization. Nearly 40% of all subcortical strokes patients deteriorated neurologically, but nearly 40% of those patients who deteriorated returned to their pre-deterioration status. Deterioration was associated with worse functional outcome at 90 days. Our study establishes a natural history template for designing future studies and identifies a subpopulation of patients for which new in-hospital therapies are needed to treat neurological deterioration in subcortical stroke.

Background and Purpose— Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion. Methods— During standard-dose intravenous tPA, a 100-μg/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75× baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography. Results— Sixty-five patients were enrolled (45% men, mean age 63±14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38–60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2–7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7–15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9–12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%). Conclusions— The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted. Clinical Trial Registration— URL: www.clinicaltrials.gov . Unique identifier: NCT00268762.

Background and Purpose— The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients. Methods— ICARO was a case-control multicenter study on prospectively collected data. Patients with acute ischemic stroke and ICA occlusion treated with intravenous recombinant tissue-type plasminogen activator within 4.5 hours from symptom onset (cases) were compared to matched patients with acute stroke and ICA occlusion not treated with recombinant tissue-type plasminogen activator (controls). Cases and controls were matched for age, gender, and stroke severity. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale, dichotomized as favorable (score of 0–2) or unfavorable (score of 3–6). Safety outcomes were death and any intracranial bleeding. Results— Included in the analysis were 253 cases and 253 controls. Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%; adjusted odds ratio (OR), 1.80; 95% confidence interval [CI], 1.03–3.15; P =0.037). A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%; adjusted OR, 2.28; 95% CI, 1.36–3.22; P =0.001). There were more fatal bleedings (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87–58.71; P =0.068) in the cases than in the controls. Conclusions— In patients with stroke attributable to ICA occlusion, thrombolytic therapy results in a significant reduction in the proportion of patients dependent in activities of daily living. Increases in death and any intracranial bleeding were the trade-offs for this clinical benefit.