Breaking the Boilerplate Habit in Civil Discovery

No more boilerplate in discovery requests or responses. That is the clear message of the 2015 amendments to the Federal Rules of Civil Procedure. Inspired by that message, some judges have taken a firm stand, warning lawyers to change their ways or face serious sanctions. Will it be enough to root out practices deeply engrained in discovery culture? This Article examines the “anti boilerplate” rule changes and the cases applying them. We endorse the rule changes and applaud the judges who have spoken out. But if real change is to occur, more judges—many more judges—must join them. As judges consider how they might contribute to the cause, we offer three points of guidance. First, while boilerplate objections get the most attention, boilerplate requests are an equal part of the problem. The 2015 amendments target both. Second, we must be careful not to equate “pattern” with boilerplate. As several recent projects have shown, the use of topic-specific discovery protocols—which use carefully-crafted standard requests—can start the parties on the path to tailored, targeted, efficient, and fair discovery. Third, judges should resist using waiver as a standard sanction for boilerplate objections. When the responding party has no viable objections to make, waiver provides no deterrence against boilerplate objections. And when the discovery requests exceed the boundaries of permissible discovery, waiver can lead to the parties getting bogged down in the discovery of irrelevant matters. While judges are often reluctant to go down the path of imposing cost sanctions, in many cases that approach will supply both a more effective deterrent and a more calibrated response. The goal is worth it; reducing boilerplate in discovery is an important step toward achieving proportional discovery

The Reappearing Judge

This is the published version

Efficacy and safety of ixekizumab through 52 weeks in two phase 3, randomised, controlled clinical trials in patients with active radiographic axial spondyloarthritis (COAST-V and COAST-W).

OBJECTIVES: To investigate the efficacy and safety of ixekizumab for up to 52 weeks in two phase 3 studies of patients with active radiographic axial spondyloarthritis (r-axSpA) who were biological disease-modifying antirheumatic drug (bDMARD)-naive (COAST-V) or tumour necrosis factor inhibitor (TNFi)-experienced (COAST-W). METHODS: Adults with active r-axSpA were randomised 1:1:1:1 (n=341) to 80 mg ixekizumab every 2 (IXE Q2W) or 4 weeks (IXE Q4W), placebo (PBO) or 40 mg adalimumab Q2W (ADA) in COAST-V and 1:1:1 (n=316) to IXE Q2W, IXE Q4W or PBO in COAST-W. At week 16, patients receiving ixekizumab continued their assigned treatment; patients receiving PBO or ADA were rerandomised 1:1 to IXE Q2W or IXE Q4W (PBO/IXE, ADA/IXE) through week 52. RESULTS: In COAST-V, Assessment of SpondyloArthritis international Society 40 (ASAS40) responses rates (intent-to-treat population, non-responder imputation) at weeks 16 and 52 were 48% and 53% (IXE Q4W); 52% and 51% (IXE Q2W); 36% and 51% (ADA/IXE); 19% and 47% (PBO/IXE). Corresponding ASAS40 response rates in COAST-W were 25% and 34% (IXE Q4W); 31% and 31% (IXE Q2W); 14% and 39% (PBO/IXE). Both ixekizumab regimens sustained improvements in disease activity, physical function, objective markers of inflammation, QoL, health status and overall function up to 52 weeks. Safety through 52 weeks of ixekizumab was consistent with safety through 16 weeks. CONCLUSION: The significant efficacy demonstrated with ixekizumab at week 16 was sustained for up to 52 weeks in bDMARD-naive and TNFi-experienced patients. bDMARD-naive patients initially treated with ADA demonstrated further numerical improvements after switching to ixekizumab. Safety findings were consistent with the known safety profile of ixekizumab. TRIAL REGISTRATION NUMBER: NCT02696785/NCT02696798

Achievement of Remission Endpoints with Secukinumab Over 3 Years in Active Ankylosing Spondylitis: Pooled Analysis of Two Phase 3 Studies

INTRODUCTION: Clinical remission in patients with ankylosing spondylitis (AS) has been determined using composite indices such as the AS Disease Activity Score inactive disease (ASDAS-ID), Assessment of SpondyloArthritis international Society criteria partial remission (ASAS-PR), and low Bath AS Disease Activity Index (BASDAI) scores. The objective of this exploratory analysis was to evaluate the proportion of secukinumab-treated patients with AS achieving remission defined based on the ASDAS-ID (score < 1.3), ASAS-PR or BASDAI score ≤  2. METHODS: The analysis pooled data from the MEASURE 1 and 2 studies over 3 years. The proportion of patients who achieved ASDAS-ID, ASAS-PR, or BASDAI ≤ 2 with secukinumab was compared with placebo at week 16; results for secukinumab-treated patients were summarized through week 156. Sustainability of each criterion was assessed from week 16 to 156 using shift analysis. The association between each of these criteria and specific patient-reported outcomes (PROs), such as health-related quality of life, function, fatigue, and work impairment, was also explored. RESULTS: At week 16, a higher proportion of secukinumab-treated patients versus placebo achieved ASDAS-ID (17.6 vs. 3.5%), ASAS-PR (15.4 vs. 4.1%), or BASDAI ≤ 2 (22.3 vs. 6.4%) criteria (all P < 0.0001), which were sustained through 156 weeks. Shift analysis showed that the majority of secukinumab-treated patients achieving remission at week 16 maintained their status at week 156 (ASDAS-ID, 57.1%; ASAS-PR, 68.0% and BASDAI ≤ 2, 74.3%). Remission was also associated with improved PROs over 156 weeks. CONCLUSIONS: Secukinumab-treated patients maintained ASDAS-ID, ASAS-PR, or BASDAI ≤ 2 from week 16 up to 3 years. Patients who achieved at least one of the three responses/states, reported improvement in PROs, which suggests an association of clinical remission/ID with PROs in patients with active AS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01358175, NCT01863732, and NCT01649375

Molecular restoration of archived transcriptional profiles by complementary-template reverse-transcription (CT-RT)

Gene expression profiling of formalin-fixed and paraffin-embedded (FFPE) specimens, banked from completed clinical trials and routine clinical care, has the potential to yield valuable information implicating and linking genes with clinical parameters. In order to prepare high-quality cDNA from highly fragmented FFPE-RNA, previously precluded from high-throughput analyses, we have designed a novel strategy based on the nucleic acid restoration of incomplete cDNA sequences prior to T7 in vitro transcription (IVT) amplification. We describe this strategy as complementary-template reverse-transcription (CT-RT) because short single-stranded T7-oligo-dT24-VN-DNA sequences, obtained from FFPE-RNA, are used as primers for the RT of complementary RNA templates contained in a sense-RNA library. We validated our assay by determining the correlation between expression profiles of a matched 10-year-old frozen and FFPE breast cancer sample. We show that T7 IVT-amplification of cDNA transcripts restored by CT-RT is a specific and reliable process that allows recovery of transcriptional features undetectable by direct T7 IVT-amplification of FFPE-RNA. Furthermore, CT-RT restored 35–41% of the transcripts from archived breast and cervical specimens when compared to matched frozen tissue; and profiles included tissue-specific transcripts. Our results indicate that CT-RT allows microarray profiling of severely degraded RNA that could not be analyzed by previous methods

Examining Treatment Decision-Making Among Patients With Axial Spondyloarthritis: Insights From a Conjoint Analysis Survey

OBJECTIVE: The number of therapies for axial spondyloarthritis (axSpA) is increasing. Thus, it has become more challenging for patients and physicians to navigate the risk-benefit profiles of the various treatment options. In this study, we used conjoint analysis-a form of trade-off analysis that elucidates how people make complex decisions by balancing competing factors-to examine patient decision-making surrounding medication options for axSpA. METHODS: We conducted an adaptive choice-based conjoint analysis survey for patients with axSpA to assess the relative importance of medication attributes (eg, chance of symptom improvement, risk of side effects, route of administration, etc) in their decision-making. We also performed logistic regression to explore whether patient demographics and disease characteristics predicted decision-making. RESULTS: Overall, 397 patients with axSpA completed the conjoint analysis survey. Patients prioritized medication efficacy (importance score 26.8%), cost (26.3%), and route of administration (13.9%) as most important in their decision-making. These were followed by risk of lymphoma (9.5%), dosing frequency (7.2%), risk of serious infection (6.0%), tolerability of side effects (5.3%), and clinic visit and laboratory test frequency (4.8%). In regression analyses, there were few significant associations between patients\u27 treatment preferences and sociodemographic and axSpA characteristics. CONCLUSIONS: Treatment decision-making in axSpA is highly individualized, and demographics and baseline disease characteristics are poor predictors of individual preferences. This calls for the development of online shared decision-making tools for patients and providers, with the goal of selecting a treatment that is consistent with patients\u27 preferences

Direct cooling of the catheter tip increases safety for CMR-guided electrophysiological procedures

<p>Abstract</p> <p>Background</p> <p>One of the safety concerns when performing electrophysiological (EP) procedures under magnetic resonance (MR) guidance is the risk of passive tissue heating due to the EP catheter being exposed to the radiofrequency (RF) field of the RF transmitting body coil. Ablation procedures that use catheters with irrigated tips are well established therapeutic options for the treatment of cardiac arrhythmias and when used in a modified mode might offer an additional system for suppressing passive catheter heating.</p> <p>Methods</p> <p>A two-step approach was chosen. Firstly, tests on passive catheter heating were performed in a 1.5 T Avanto system (Siemens Healthcare Sector, Erlangen, Germany) using a ASTM Phantom in order to determine a possible maximum temperature rise. Secondly, a phantom was designed for simulation of the interface between blood and the vascular wall. The MR-RF induced temperature rise was simulated by catheter tip heating via a standard ablation generator. Power levels from 1 to 6 W were selected. Ablation duration was 120 s with no tip irrigation during the first 60 s and irrigation at rates from 2 ml/min to 35 ml/min for the remaining 60 s (Biotronik Qiona Pump, Berlin, Germany). The temperature was measured with fluoroscopic sensors (Luxtron, Santa Barbara, CA, USA) at a distance of 0 mm, 2 mm, 4 mm, and 6 mm from the catheter tip.</p> <p>Results</p> <p>A maximum temperature rise of 22.4°C at the catheter tip was documented in the MR scanner. This temperature rise is equivalent to the heating effect of an ablator's power output of 6 W at a contact force of the weight of 90 g (0.883 N). The catheter tip irrigation was able to limit the temperature rise to less than 2°C for the majority of examined power levels, and for all examined power levels the residual temperature rise was less than 8°C.</p> <p>Conclusion</p> <p>Up to a maximum of 22.4°C, the temperature rise at the tissue surface can be entirely suppressed by using the catheter's own irrigation system. The irrigated tip system can be used to increase MR safety of EP catheters by suppressing the effects of unwanted passive catheter heating due to RF exposure from the MR scanner.</p

Biopolymers for Antitumor Implantable Drug Delivery Systems: Recent Advances and Future Outlook

In spite of remarkable improvements in cancer treatments and survivorship, cancer still remains as one of the major causes of death worldwide. Although current standards of care provide encouraging results, they still cause severe systemic toxicity and also fail in preventing recurrence of the disease. In order to address these issues, biomaterial-based implantable drug delivery systems (DDSs) have emerged as promising therapeutic platforms, which allow local administration of drugs directly to the tumor site. Owing to the unique properties of biopolymers, they have been used in a variety of ways to institute biodegradable implantable DDSs that exert precise spatiotemporal control over the release of therapeutic drug. Here, the most recent advances in biopolymer-based DDSs for suppressing tumor growth and preventing tumor recurrence are reviewed. Novel emerging biopolymers as well as cutting-edge polymeric microdevices deployed as implantable antitumor DDSs are discussed. Finally, a review of a new therapeutic modality within the field, which is based on implantable biopolymeric DDSs, is given

Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+ B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma

<p>Abstract</p> <p>Background</p> <p>Tumour infiltrating lymphocytes (TIL) are generally considered to represent a host immune response directed against tumour antigens. TIL are also increasingly recognised as possible prognostic parameters. However, the effects observed are variable indicating that results cannot be extrapolated from type of tumour to another. Moreover, it has been suggested that primary solid tumours may be ignored by the immune system and that a meaningful immune response is only mounted in regional lymph nodes.</p> <p>Methods</p> <p>We have examined the local distribution of immune cells in tumour-related compartments in head and neck squamous cell carcinomas (HNSCC). In a second step, the prognostic impact of these cells on disease-free survival (DFS) was analysed. A total of 198 tissue cores from 33 patients were evaluated using tissue mircroarray technique and immunohistochemistry. Tumour-infiltrating immune cells were identified using antibodies specific for CD3, CD8, GranzymeB, FoxP3, CD20 and CD68 and quantified using an image analysis system.</p> <p>Results</p> <p>We demonstrate a relative expansion of FoxP3⁺regulatory T-cells (Treg) and of cytotoxic T-cells among tumour infitrating T-cells. We also show that intratumoural CD20⁺B-cells are significantly more frequent in metastatic deposits than in primary tumours. Furthermore, we observed a reduced number of peritumoural CD8⁺T-cells in metastatic lymph nodes as compared to univolved regional nodes suggesting a local down-modulation of cellular immunity. All other immune cells did not show significant alterations in distribution. We did not observe an association of tumour infiltrating immune cells at the primary site with outcome. However, increased numbers of intraepithelial CD8⁺TIL in metastatic tumours as well as large numbers of peritumoural B-cells in lymph node metastases were associated with favourable outcome. Unexpectedly, no effect on patient outcome was observed for Treg in any compartment.</p> <p>Conclusion</p> <p>Our results suggest that alterations in lymphocyte distribution in regional lymph nodes rather than at the primary tumour site may be relevant for patient prognosis. Moreover, we demonstrate that in addition to cellular immunity humoral immune responses may be clinically relevant in anti-tumour immunity.</p

Two-year imaging outcomes from a phase 3 randomized trial of secukinumab in patients with non-radiographic axial spondyloarthritis

Background: Radiographic progression and course of inflammation over 2 years in patients with non-radiographic axial spondyloarthritis (nr-axSpA) from the phase 3, randomized, PREVENT study are reported here. Methods: In the PREVENT study, adult patients fulfilling the Assessment of SpondyloArthritis International Society classification criteria for nr-axSpA with elevated CRP and/or MRI inflammation received secukinumab 150 mg or placebo. All patients received open-label secukinumab from week 52 onward. Sacroiliac (SI) joint and spinal radiographs were scored using the modified New York (mNY) grading (total sacroiliitis score; range, 0-8) and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS; range, 0-72), respectively. SI joint bone marrow edema (BME) was assessed using the Berlin Active Inflammatory Lesions Scoring (0-24) and spinal MRI using the Berlin modification of the AS spine MRI (ASspiMRI) scoring (0-69). Results: Overall, 78.9% (438/555) of patients completed week 104 of the study. Over 2 years, minimal changes were observed in total radiographic SI joint scores (mean [SD] change, - 0.04 [0.49] and 0.04 [0.36]) and mSASSS scores (0.04 [0.47] and 0.07 [0.36]) in the secukinumab and placebo-secukinumab groups. Most of the patients showed no structural progression (increase = 1 new syndesmophyte over 2 years. Reduction in SI joint BME observed at week 16 with secukinumab (mean [SD], - 1.23 [2.81] vs - 0.37 [1.90] with placebo) was sustained through week 104 (- 1.73 [3.49]). Spinal inflammation on MRI was low at baseline (mean score, 0.82 and 1.07 in the secukinumab and placebo groups, respectively) and remained low (mean score, 0.56 at week 104). Conclusion: Structural damage was low at baseline and most patients showed no radiographic progression in SI joints and spine over 2 years in the secukinumab and placebo-secukinumab groups. Secukinumab reduced SI joint inflammation, which was sustained over 2 years.Pathophysiology and treatment of rheumatic disease