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Purpose:Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses.Experimental Design:Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology–related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set.Results:Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression.Conclusions:Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.

Supplementary Figure from Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception

Supplementary Data from Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception

Background Study of the geographic distribution of cellular populations and their interaction with malignant cells in non-small cell lung cancer (NSCLC) is essential to understand the roles of cellular populations and potentially design new therapeutic approaches. Material and Methods We studied 225 formalin-fixed, paraffin-embedded tumor tissue samples from patients with stage I-III NSCLC—142 adenocarcinomas and 83 squamous cell carcinomas—placed in tissue microarrays. Twenty-three markers were used, including T-cell, B-cell, immune checkpoint, and myeloid cell markers, placed in five multiplex immunofluorescence panels. We used dimensional data reduction and cellular spatial distribution to identify cell phenotypes and their cellular distribution across panels. In addition, we analyzed associations between cellular spatial distribution patterns and clinicopathologic variables, tumor mutational status, and outcomes. Results Overall, we observed two patterns of cellular distribution—unmixed and mixed—related to T-cells, B-cells, granulocytic cells, and macrophages, and we detected various cellular interactions between malignant and immunosuppressive cells and various associations between cell distribution and clinicopathologic characteristics. Cellular distribution patterns and the distance from various cell phenotypes to malignant cells were associated with recurrence-free survival and overall survival in univariate and multivariable analysis. Conclusions Diverse populations of tumor cells and tumor-associated immune cell phenotypes can be present in NSCLC samples. Spatial distribution is a new tool to better understand the tumor microenvironment and help select therapeutic interventions.

Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses. Experimental Design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology–related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set. Results: Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression. Conclusions: Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.

Triple-negative breast cancer (TNBC) with high tumour-infiltrating lymphocytes (TILs) has been associated with a promising prognosis. To better understand the prognostic value of immune cell subtypes in TNBC, we characterised TILs and the interaction between tumour cells and immune cell subtypes. A total of 145 breast cancer tissues were stained by multiplex immunofluorescence (mIF), including panel 1 (PD-L1, PD-1, CD3, CD8, CD68 and CK) and panel 2 (Foxp3, Granzyme B, CD45RO, CD3, CD8 and CK). Phenotypes were analysed and quantified by pathologists using InForm software. We found that in the ER-negative (ER1% and HER2-negative) group and the ER/PR-low positive (ER 1-9% and HER2-negative) group, 11.2% and 7.1% of patients were PD-L1

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 We describe innovations in the study design and the efficient data coordination of a randomized multicenter trial of Argatroban in Combination with Recombinant Tissue Plasminogen Activator for Acute Stroke (ARTSS-2). Methods ARTSS-2 is a 3-arm, multisite/multiregional randomized controlled trials (RCTs) of two doses of Argatroban injection (low, high) in combination with recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke patients and rt-PA alone. We developed a covariate adaptive randomization program that balanced the study arms with respect to study site as well as hemorrhage after thrombolysis (HAT) score and presence of distal internal carotid artery occlusion (DICAO). We used simulation studies to validate performance of the randomization program before making any adaptations during the trial. For the first 90 patients enrolled in ARTSS-2, we evaluated performance of our randomization program using chi-square tests of homogeneity or extended Fisher's exact test. We also designed a four-step partly Bayesian safety stopping rule for low and high dose Argatroban arms. Results Homogeneity of the study arms was confirmed with respect to distribution of study site (UK sites vs. US sites, P = 0.98), HAT score (0–2 vs. 3–5, P = 1.0), and DICAO (N/A vs. No vs. Yes, P = 0.97). Our stopping thresholds for safety of low and high dose Argatroban were not crossed. Despite challenges, data quality was assured. Conclusions We recommend adaptive designs for randomization and Bayesian safety stopping rules for multisite Phase I/II RCTs for maintaining additional flexibility. Efficient data coordination could lead to improved data quality.

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: Patients with intracerebral hemorrhage (ICH) frequently present with elevated blood pressure (BP) requiring treatment. We conducted an exploratory analysis to examine BP management during the acute phase of ICH. We hypothesized that BP management and time to achieve goal BP would be variable. Our aim was to identify areas for improvement in BP management. Methods: We performed a retrospective chart review on consecutive patients with spontaneous ICH admitted to our neurosurgical intensive care unit (NSICU) from February-March 2015. Exclusions included secondary causes of ICH or comfort care orders placed within 72 hours of arrival. Demographic and clinical characteristics were collected as well as times for BP treatment order placement, IV treatment initiation and discontinuation. We recorded hourly BPs for the first 72 hours of hospitalization. Primary outcome measure was the time to achieve institutional guideline recommended BP control defined as SBP 6 hours. Secondary outcome included the proportion of patients who achieved SBP target >85% of the time. Results: We screened 37 patients and 29 met criteria. Baseline information is summarized in Table 1. Documented BP goals for 25 of 29 patients targeted a SBP goal 85% of the time. Conclusions: In our population, there is variability in the time it takes to achieve and maintain goal SBP with less than half of patients maintaining BP control. We identified targeted areas for improvement. Our data is limited by its retrospective nature and small size. Since aggressive BP management limits hematoma growth and may improve outcomes, we propose development of benchmarks to guide BP management in ICH patients.

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.

Background: Per American Heart Association guidelines, blood pressure (BP) should be < 185/110 to be eligible for intravenous tissue plasminogen activator (tPA). It is shown that door to needle (DTN) time is prolonged in patients who require anti-hypertensive medications prior to thrombolysis in the emergency department (ED). To our knowledge, no studies have focused on pre-hospital BP and its impact on DTN times. We hypothesize that DTN times are longer for patients with higher pre-hospital BP. Methods: We conducted a retrospective review of acute ischemic stroke patients who presented between 1/2010 and 12/2010 to our ED through Emergency Medical Services (EMS) within 3-hrs of symptom onset. Patients were identified from our registry and categorized into two groups: Pre-hospital BP ≥ 185/110 (Pre-hsp HBP) and < 185/110 (Pre-hsp LBP). BP records were abstracted from EMS sheets. Two groups were compared using two-sample t-test or Wilcoxon rank sum test for continuous variables and Chi-square test or Fisher’s exact test for categorical variables. Results: A total of 107 consecutive patients were identified. Out of these, 75 patients (70%) were treated with tPA. Among the patients who received thrombolysis, 35% had pre-hospital BP ≥ 185/110 (n= 26/75). Greater number of patients required anti-hypertensive medications in ED in high BP group compared to low BP group (Pre-hsp HBP n= 14/26, 54%; Pre-hsp LBP n= 13/49, 27%, p < 0.02). Mean door to needle times were significantly higher in Pre-hsp HBP group. (mean ± SD 87.5± 34.2 Vs. 59.7±18.3, p Conclusion: Higher pre-hospital BP is associated with prolonged DTN times and it stays prolonged if pre-hospital high BP remains untreated. Although the later finding was not statistical significant due to small sample size, pre-hospital blood pressure control could be a potential area for improvement to reduce door to needle times in acute ischemic stroke.

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.

Subcortical strokes (SCS) are associated with stroke progression. The primary objective was to assess the incidences of neurological deterioration and its spontaneous reversal in SCS patients. We also estimated the risk of poor outcome associated with deterioration. Methodology: A prospective cohort of SCS patients was enrolled based on clinical exam and imaging studies, and was followed through the course of hospitalization. NIH stroke scale (NIHSS) assessments were performed daily and whenever symptoms worsened (increase of ≥ 1 in motor scale). Modified Rankin Scale (mRS) score at discharge was used to assess outcomes. Patients received standard of care stroke therapy including IV t-PA as per AHA guidelines, and episodes of deterioration were managed conservatively. The Anderson Gill Cox proportional hazard model was used to analyze factors associated with time to deterioration and spontaneous reversal. Log binomial regression was performed for estimation of risk of poor outcome. Results: The cumulative incidence of deterioration was 43.3% and of those who deteriorated, spontaneous reversal occurred in 37.8%. The median time to deterioration was 21 hours from stroke onset. Use of IV t-PA was significantly associated with both deterioration (HR: 2.25, 95% CI: 1.13 - 4.49) (Figure 1a) and spontaneous reversal (HR: 4.36, 95% CI: 1.36 - 14.01) (Figure 1b). Deteriorated patients had a higher risk of poor discharge outcome (mRS ≥ 3) (RR: 1.80, 95% CI: 1.71 - 1.93), after adjusting for age, initial stroke severity, and use of IV t-PA. Conclusion: The results from this study establish a natural history of neurofluctuation in patients with SCS. Our data suggests that deterioration occurs early in these patients, and only about a third of deteriorated patients reverse spontaneously. Furthermore, deterioration is associated with poor short term functional outcome. There is a need to develop and test novel therapies to treat neurological deterioration in 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.

Background and Objectives: There is a paucity of data from recent trials analyzing outcomes and hospital complications in octogenarians after acute ischemic stroke (AIS). Stroke trials often set an arbitrary upper age limit (usually age 80) as an inclusion criterion. We hypothesized that based on hospital complication rates and outcome, age ≥80 does not justify exclusion from clinical trials testing new AIS therapies. Methods: From our prospectively compiled stroke registry, we identified AIS patients older than 50 from January 1, 2007 to March 30, 2012. Patients were excluded if they 1) had a baseline mRS >2, 2) received intra-arterial therapy, or 3) were enrolled in a trial. Demographic and clinical data were analyzed in patients ≥80 and 50-79 to determine if age ≥80 raises the odds for hospital complications and worse outcomes. Results: We identified 526 patients ≥80 and 1572 aged 50-79. Compared with their younger counterparts, patients ≥80 had a higher incidence of vascular risk factors, higher NIHSS scores, higher IV tPA rates, and a 1.3 times higher odds (95% confidence interval 1.01 - 1.7) of developing in-hospital complications, after controlling for all co-variates (including NIHSS, t-PA, vascular risk factors). However, higher complication rates appeared to be driven by UTIs. A stratified analysis of age cutoffs at 5 year intervals for all complications other than UTI did not show that ages 85 and above have significantly higher odds of complications as compared to those aged 50-74. Older patients had higher odds (OR 2.11 95% CI 1.34 - 3.31) of a poor outcome at 90 days (mRS >2) compared with younger patients, after adjusting for co-variates. Conclusion: Age ≥80 is a predictor of in-hospital complications but only the rates of UTI were significantly higher. These findings support re-considering age >80 as an exclusion from participating in clinical trials testing new AIS therapies. The higher odds for poor outcome also raise the need to design therapies for patients ≥80.

Background: Limited information has been published regarding standard procedures to ensure data quality in stroke registries. We share our experience regarding the establishment of enhanced quality assurance (QA) procedures for the University of Texas Houston Stroke Registry (UTHSR) and test whether these QA procedures have improved data quality in UTHSR. Methods: All 5092 patients’ records that were abstracted and entered in UTHSR, between January 1, 2008 and December 31, 2011, were considered in this study. A random subset of 30 records was used for re-abstraction of 24 key variables by two abstractors. From these 30 records, a subset of 13 was re-abstracted by a team of experts as the “gold standard”. We assessed inter-rater reliability (IRR) between the two abstractors as well as each abstractor with the gold standard. Depending on the scale of variables, IRR was assessed with Kappa or by intra-class correlations (ICC) using a 2-way, random effects ANOVA. For assessment of data quality we re-abstracted another set of 41 patients’ records and all discrepant entries were adjudicated by a team of experts. We used Chi-square test for trend to assess whether a significant improvement in data quality has been achieved during 2008-2011. Results: The error rate dropped from 3.8 in 2008 to 1.6% in 2011, with a significant (P < 0.001) downward trend in the error rate over the 4 years. The two abstractors had an excellent IRR (Kappa or ICC > 0.75) on almost all 24 variables checked. The only variable that had moderate reliability (0.40 ≤ Kappa ≤ 0.75) was mode of arrival to hospital. Agreement between each abstractor and the gold standard for both categorical and continues variables were also excellent, except for mode of arrival to hospital. Conclusions: Establishment of a rigorous data quality assurance for our UTHSR has helped to improve the quality of data. We have observed an excellent IRR for almost all key variables in UTHSR. We recommend training of chart abstractors and systematic assessment of IRR between the abstracted data with that of the gold standard for data quality assurance processes.

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.

Background Limited information has been published regarding standard quality assurance (QA) procedures for stroke registries. We share our experience regarding the establishment of enhanced QA procedures for the University of Texas Houston Stroke Registry (UTHSR) and evaluate whether these QA procedures have improved data quality in UTHSR. Methods All 5093 patient records that were abstracted and entered in UTHSR, between January 1, 2008 and December 31, 2011, were considered in this study. We conducted reliability and validity studies. For reliability and validity of data captured by abstractors, a random subset of 30 records was used for re-abstraction of select key variables by two abstractors. These 30 records were re-abstracted by a team of experts that included a vascular neurologist clinician as the “gold standard”. We assessed inter-rater reliability (IRR) between the two abstractors as well as validity of each abstractor with the “gold standard”. Depending on the scale of variables, IRR was assessed with Kappa or intra-class correlations (ICC) using a 2-way, random effects ANOVA. For assessment of validity of data in UTHSR we re-abstracted another set of 85 patient records for which all discrepant entries were adjudicated by a vascular neurology fellow clinician and added to the set of our “gold standard”. We assessed level of agreement between the registry data and the “gold standard” as well as sensitivity and specificity. We used logistic regression to compare error rates for different years to assess whether a significant improvement in data quality has been achieved during 2008–2011. Results The error rate dropped significantly, from 4.8% in 2008 to 2.2% in 2011 (P < 0.001). The two abstractors had an excellent IRR (Kappa or ICC ≥ 0.75) on almost all key variables checked. Agreement between data in UTHSR and the “gold standard” was excellent for almost all categorical and continuous variables. Conclusions Establishment of a rigorous data quality assurance for our UTHSR has helped to improve the validity of data. We observed an excellent IRR between the two abstractors. We recommend training of chart abstractors and systematic assessment of IRR between abstractors and validity of the abstracted data in stroke registries.