bluuebunny/crossref_metadata_2025_split huggingface dataset:
ELARA: A phase II, single-arm, multicenter, open-label trial investigating the efficacy and safety of tisagenlecleucel in adult patients with refractory/relapsed follicular lymphoma (r/r FL).
Authors: Dickinson Michael , Popplewell Leslie , Kolstad Arne , Ho Joy , Teshima Takanori , Dreyling Martin H. , Schuster Stephen J. , Thieblemont Catherine , Yateman Nigel , Lehnhoff Katja , Lawniczek Tomasz , Bubuteishvili-Pacaud Lida , Fowler Nathan Hale 
Published: March 2020

TPS7573 Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor-T cell (CAR-T) therapy that was approved for the treatment of pediatric and young adult patients up to 25 years of age with r/r B-cell acute lymphoblastic leukemia in 2017 (Maude et al. NEJM. 2018), as well as for the treatment of adult patients with r/r diffuse large B-cell lymphoma in 2018 (Schuster et al. NEJM. 2018). FL is the second most common non-Hodgkin lymphoma in the Western hemisphere, with limited treatment options in patients refractory to or relapsing after standard therapies. In a phase 2a study of patients with r/r CD19+ lymphomas, 10 of 14 (71%) patients with r/r FL treated with tisagenlecleucel achieved a durable complete remission at a median follow-up of 28.6 months (Schuster et al. NEJM. 2017). Here we introduce ELARA, a phase 2 study evaluating the efficacy and safety of tisagenlecleucel in patients with r/r FL. Methods: ELARA is a phase 2, single-arm, multicenter, open label trial. Eligible patients must be ≥18 years of age, have radiographically measurable grade 1, 2, or 3A r/r FL that is refractory to a second or later line of systemic therapy (including an anti-CD20 antibody and an alkylator), or relapsed within 6 months after completion of a second or later line of systemic therapy, or relapsed during anti-CD20 antibody maintenance (following ≥2 lines of therapy as above) or within 6 months after maintenance completion, or relapsed after autologous hematopoietic stem cell transplant (HSCT). Patients with central nervous system involvement, or those who received prior anti-CD19 therapy, gene therapy, adoptive T-cell therapy, or allogeneic HSCT are not eligible. The primary endpoint of this study is complete response rate based on Lugano classification response criteria. Secondary outcomes include overall response rate, duration of response, overall survival, cellular kinetics, immunogenicity, safety, and patient-reported outcomes. Estimated enrollment for this study is 113 patients. The study is currently open to patient enrollment. Clinical trial information: NCT03568461.
ECOG-ACRIN EAA172: Phase 1/2 study of daratumumab, bortezomib, dexamethasone (DVd) with or without venetoclax in relapsed/refractory multiple myeloma (RRMM) with assessment for t(11;14) status.
Authors: Thompson Michael A. , Jacobus Susanna J. , Kumar Shaji , Janakiram Murali , Lonial Sagar , Weiss Matthias , Callander Natalie Scott , Rajkumar S. Vincent 
Published: March 2020

TPS8052 Background: The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32), present in approximately 20% of cases. MM cells with t(11;14) usually have a favorable high BCL-2 level and inferior outcomes compared to standard risk MM. Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in MM cell lines and primary samples. VEN has single agent activity in relapsed/refractory MM (RRMM) with an acceptable safety profile, especially in t(11;14) MM; however, non- t(11;14) MM patients may benefit from single agent VEN and VEN incorporated in multi-agent RRMM regimens. Dexamethasone (d) promotes Bcl-2 dependence in MM resulting in sensitivity to VEN and this combination with bortezomib (Vd-VEN) has an acceptable safety profile with high response rates in heavily pre-treated MM. Combination therapy with daratumumab and bortezomib (DVd) has become a standard of care in RRMM. Our hypotheses are that the addition of VEN will improve upon this standard and be most effective in the t(11;14) positive subset. Methods: Eligibility criteria include RRMM with measurable disease, not bortezomib refractory, platelet count > 100K. t(11;14) is an integral biomarker with status (positive or negative) established at registration. After a Ph1 study to determine the recommended phase 2 VEN dose, patients are randomized to DVd +/- VEN [stratified by prior lines of therapy and R-ISS]. The primary Ph2 objectives are to compare 8-cycle minimal residual disease (MRD) negative rate and to inform the role of t(11;14) as a biomarker. The Ph2 design proposed by Freidlin et al. follows a decision algorithm as outlined in the table below. Simulations were run to establish an optimal sample size given various parameters including biomarker prevalence and power to make appropriate decisions for a Ph3 design. Target Ph2 accrual is 240 patients with a 1/3 positive:2/3 negative t(11;14) split. Clinical trial information: NCT03701321. [Table: see text]
SGNBCMA-001: A phase 1 study of SEA-BCMA, a non-fucosylated monoclonal antibody, in subjects with relapsed or refractory multiple myeloma.
Authors: Abdallah Al-Ola A. , Hoffman James Edward , Schroeder Mark A. , Jacquemont Celine , Li Hong , Wang Yinghui , Van Epps Heather , Campbell Mary S. 
Published: March 2020

TPS8054 Background: Despite recent advances in treatment, multiple myeloma (MM) remains incurable in most patients. The standard of care for MM includes combinations of agents with different mechansims of action, e.g. proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies, alkylating agents, and corticosteroids. Sequential lines of treatment typically yield shorter durations of disease control with each subsequent relapse. Frail patients face a particularly high unmet need, given the toxicity profiles of many agents. SEA-BCMA is a humanized non-fucosylated IgG1 monoclonal antibody targeting BCMA, a plasma cell-specific protein that is expressed on MM cells of most patients. Based on preclinical data, SEA-BCMA displays enhanced antibody dependent cellular cytotoxicity through increased FcγRIII binding, antibody dependent cellular phagocytosis, and blocking of BCMA-mediated pro-survival and proliferative signaling. SEA-BCMA is active at 0.03 mg/kg in xenograft models and does not cause adverse effects in preclinical models, supporting clinical investigation for MM. Methods: This is a phase 1, open-label, multicenter, dose-escalation study to evaluate the safety, tolerability, and antitumor activity of SEA-BCMA in adults with relapsed/refractory MM. Enrollment began in November 2018 for adults aged ≥18 years with histologically confirmed MM, Eastern Cooperative Oncology Group performance status of ≤1, and no other therapeutic options available. Prior therapies must include a PI, an IMiD, and an anti-CD38 antibody. Prior receipt of BCMA targeted agents is prohibited. BCMA expression is not required for study entry, but will be tested retrospectively. Dose-escalation is being conducted in ~25 subjects using the modified toxicity probability interval method. During dose-expansion, ~40 subjects will be treated at the maximum tolerated or optimal dose. Responses are assessed per the 2016 International Myeloma Working Group criteria. Biomarker and pharmacokinetic evaluations will be performed on peripheral blood and bone marrow. Clinical trial information: NCT03582033.
Gemstone-301: A phase III clinical trial of CS1001 as consolidation therapy in subjects with locally advanced/unresectable (stage III) non-small cell lung cancer (NSCLC) who have not progressed after prior concurrent/sequential chemoradiotherapy (CRT).
Authors: Wu Yi-Long , Chen Ming , Zhou Qing , Li Hao , Sun Wenyi , He Hongyan , Lu Dongmei 
Published: March 2020

TPS8572 Background: In China, the standard of care for patients with unresectable Stage III NSCLC is platinum-based doublet chemotherapy given concurrently or sequentially with radiotherapy. However, the median progression-free survival (PFS) of those patients is poor (approximately 8-10 months) and 5-year overall survival (OS) rate is only 15%. Recently, treatment with durvalumab resulted in significantly longer PFS and OS than placebo for patients with locally advanced/unresectable NSCLC whose disease did not progress after definitive concurrent chemoradiotherapy (cCRT) in PACIFC trial. CS1001 is the first full-length, fully human programmed death ligand-1 (PD-L1) targeted immunoglobin G4 (IgG4, s228p) monoclonal antibody (mAb) developed by the OMT transgenic rat platform. The Phase Ia/Ib study (GEMSTONE-101, NCT03312842) demonstrated that CS1001 was well tolerated and had promising anti-tumor activities across a range of tumors including NSCLC. GEMSTONE-301 is a randomized, double-blind, Phase III study to compare the efficacy and safety of CS1001 versus placebo as consolidation therapy in Stage III unresectable NSCLC patients. This is the first Phase III trial on an anti-PD-(L)1 mAb initiated in China for this indication. Methods: In this trial, eligible patients with locally advanced/unresectable (Stage III) NSCLC who have not progressed after prior concurrent/sequential CRT are 2:1 randomized to receive CS1001 1200 mg, every 3 weeks or placebo, every 3 weeks. Stratification factors for randomization include ECOG status (0 versus 1), chemoradiotherapy (concurrent versus sequential) and total radiotherapy dose ( < 60 Gy versus ≥ 60 Gy). Study treatment will be given for up to 24 months or until disease progression, intolerable toxicity, consent withdrawal, or discontinuation for other reason. Tumor assessments will be performed every 9 weeks in the first year and every 12 weeks thereafter by RECIST v1.1. AEs will be monitored throughout the study and graded according to NCI-CTCAE v4.03. Primary endpoint is PFS evaluated by investigators according to RECIST v1.1. Secondary endpoints are PFS evaluated by Blinded Independent Center Review (BICR), objective response rate, OS, time to death/distant metastasis (TTDM), safety and pharmacokinetics (PK) profile. Enrollment is ongoing across sites in China and will continue until 402 patients are randomized. Clinical trial information: NCT03728556.
PACIFIC-2: Phase 3 study of concurrent durvalumab and platinum-based chemoradiotherapy in patients with unresectable, stage III NSCLC.
Authors: Bradley Jeffrey D. , Nishio Makoto , Okamoto Isamu , Newton Michael David , Trani Leonardo , Shire Norah J , Gu Yu , Dennis Philip A. , Lee Ki Hyeong 
Published: March 2020

TPS8573 Background: Durvalumab, a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80, is approved in the US, Japan and several other countries, for the treatment of patients (pts) with unresectable, stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent chemoradiotherapy (cCRT). These approvals were based on results from the phase 3 PACIFIC study, in which durvalumab was given 1–42 days after completion of definitive cCRT and significantly improved progression-free survival (PFS) vs placebo (median 16.8 vs 5.6 months; HR 0.52, 95% CI 0.42– 0.65; p<0.001) and overall survival (OS) vs placebo (stratified HR 0.68; 99.73% CI 0.47–0.997; p=0.0025). Increasing evidence suggests additional benefit when anti-PD-1/PD-L1 therapies are administered alongside cCRT. The PACIFIC 2 study therefore aims to assess whether durvalumab plus cCRT provides additional benefit, in terms of PFS and objective response rate (ORR), compared with cCRT alone. Methods: PACIFIC 2 is a phase 3, randomized, double-blind, placebo-controlled, multicenter, international study. Approximately 300 pts with unresectable stage III NSCLC will be randomized (2:1) to receive either durvalumab (intravenous 1500 mg) every 4 weeks (q4w) + cCRT, or placebo q4w + cCRT. Eligible pts must have histologically or cytologically confirmed stage III disease; ECOG performance status 0 or 1; and life expectancy >12 weeks at randomization. Pts who discontinue treatment will be followed for safety and OS. Primary endpoints are PFS and ORR (RECIST v1.1) assessed via blinded independent central review. Secondary endpoints include OS; OS at month 24; complete response (CR) rate; duration of response; disease control rate; time to death/distant metastases; time from randomization to second progression; safety; and symptoms, functioning and global health status. Pts with a CR, partial response or stable disease will continue to receive durvalumab or placebo until clinical or RECIST v1.1-defined disease progression, or until another discontinuation criterion is met. Study enrollment began in March 2018 and recruitment is ongoing. Clinical trial information: NCT03519971.
Cranial nerves: part 2
Authors: Kirk Andrew 
Published: March 2020

The clinical examination is an important part of any patient consultation. After the primary survey and history-taking, a more in-depth examination of the patient is sometimes required to aid the working diagnosis and help negate other differential diagnoses. The extent of this depends on the stability of the patient and it may not be possible in time-critical circumstances. However, it is becoming an increasing part of paramedic practice owing to the continued expansion of the scope of the paramedic role in both urgent and emergency care. Educational delivery of clinical examinations of each of the main body systems is now an integral part of undergraduate paramedic curricula. This clinical examination series provides a step-by-step overview for each of the main body systems. Continuing professional development (CPD) is an essential requirement for all clinicians in order to maintain and demonstrate currency and advancement within their roles. This series therefore provides an overview of each examination to support students, newly qualified paramedics and paramedics wishing to use these as a CPD development activity and an aide-memoire for clinical practice. These articles provide overviews of initial examination considerations, including first impressions. In this month's edition, cranial nerves VII–XII will be explored.
Development of a position–velocity–time-modulated two-dimensional ion beam figuring system for synchrotron x-ray mirror fabrication
Authors: Wang Tianyi , Huang Lei , Zhu Yi , Vescovi Matthew , Khune Denis , Kang Hyukmo , Choi Heejoo , Kim Dae Wook , Tayabaly Kashmira , Bouet Nathalie , Idir Mourad 
Published: March 2020

With the rapid evolution of synchrotron x-ray sources, the demand for high-quality precision x-ray mirrors has greatly increased. Single nanometer shape accuracy is required to keep imaging capabilities at the diffraction limit. Ion beam figuring (IBF) has been used frequently for ultra-precision finishing of mirrors, but achieving the ultimate accuracy depends on three important points: careful alignment, accurate dwell time calculation and implementation, and accurate optical metrology. The Optical Metrology Group at National Synchrotron Light Source II has designed and built a position–velocity–time-modulated two-dimensional IBF system (PVT-IBF) with three novel characteristics: (1) a beam footprint on the mirror was used as a reference to align the coordinate systems between the metrology and the IBF hardware; (2) the robust iterative Fourier transform-based dwell time algorithm proposed by our group was applied to obtain an accurate dwell time map; and (3) the dwell time was then transformed to velocities and implemented with the PVT motion scheme. In this study, the technical aspects of the PVT-IBF systems are described in detail, followed by an experimental demonstration of the figuring results. In our first experiment, the 2D RMS in a

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clear aperture was reduced from 3.4 to 1.1 nm after one IBF run. In our second experiment, due to a 5 mm pinhole installed in front of the source, the 2D RMS in a

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clear aperture was reduced from 39.1 to 1.9 nm after three IBF runs, demonstrating that our PVT-IBF solution is an effective and deterministic figuring process.
Single-cycle, MHz repetition rate THz source with 66 mW of average power
Authors: Meyer F. , Vogel T. , Ahmed S. , Saraceno C. J. 
Published: March 2020

We demonstrate terahertz (THz) generation using the tilted pulse front method in lithium niobate, driven at an unprecedented high average power of more than 100 W and at a 13.3 MHz repetition rate, provided by a compact amplifier-free mode-locked thin-disk oscillator. The conversion efficiency was optimized with respect to the pump spot size and pump pulse duration, enabling us to generate a maximum THz average power of 66 mW, which is, to the best of our knowledge, the highest reported to date from a laser-driven, few-cycle THz source. Furthermore, we identify beam walk-off as the main obstacle that currently limits the conversion efficiency in this excitation regime (with moderate pulse energies and small spot sizes). Further upscaling to the watt level and beyond is within reach, paving the way for linear and nonlinear high average power THz spectroscopy experiments with an exceptional signal-to-noise ratio at megahertz repetition rates.
Conical versus Gaussian terahertz emission from two-color laser-induced air plasma filaments
Authors: Sørensen Christian Buhl , Guiramand Léo , Degert Jérôme , Tondusson Marc , Skovsen Esben , Freysz Eric , Abraham Emmanuel 
Published: March 2020

In this Letter, we demonstrate that the far-field terahertz (THz) beam generated from a Ti:Sapphire two-color laser-induced filament can exhibit a conical or Gaussian distribution, depending on the filtering experimental conditions. Using both an incoherent Golay cell detector and a two-dimensional coherent electro-optic detection covering the 0.2–2.6 THz spectral range, in our experimental conditions, we provide evidence that the conical emission is due to photo-induced carriers in the silicon filter, typically used to block the remaining pump laser light. Moreover, the low-frequency THz beam retrieves an almost

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Gaussian spatial distribution when the silicon filter is preceded by a large bandgap ceramic filter, which stops the pump beam, thus preventing the carrier generation in the silicon filter.
Transient grating in a thin gas target for characterization of extremely short optical pulses
Authors: Kida Yuichiro 
Published: March 2020

A transient-grating cross-correlation frequency-resolved optical gating (TG XFROG) with a thin gas target toward characterization of sub-femtosecond optical pulses is discussed. For evaluation of the reliability, sub-10 fs near-infrared pulses are characterized, the results of which are compared with those given by the sum-frequency-generation XFROG. The TG XFROG covers the nanojoule energy range or that for the advanced few-cycle UV pulses recently reported. It is also shown that the TG XFROG fails to characterize and heavily underestimates the durations of intense test pulses. The FROG technique sensitively detects the onset of this anomalous behavior, which represents a serious issue for pulse characterizations.
Esophageal Motility Disorders Associated With Death or Allograft Dysfunction After Lung Transplantation? Results of a Retrospective Monocentric Study
Authors: Gouynou Célia , Philit François , Mion François , Tronc François , Sénéchal Agathe , Giai Joris , Rabain Anne-Marie , Mornex Jean-François , Roman Sabine 
Published: March 2020

OBJECTIVES:
Pathological gastroesophageal reflux (GER) is a known risk factor for bronchiolitis obliterans syndrome (BOS) after lung transplantation. This study aimed at determining whether functional esophageal evaluation might predict BOS occurrence and survival in this setting.

METHODS:
Ninety-three patients who underwent esophageal high-resolution manometry and 24-hour pH-impedance monitoring within the first year after lung transplantation were retrospectively included. A univariable analysis was performed to evaluate the parameters associated with GER disease and BOS occurrence. The Cox regression model was used to identify the prognostic factors of death or retransplantation.

RESULTS:
Thirteen percent of patients exhibited major esophageal motility disorders and 20% pathological GER. GER occurrence was associated with younger age, cystic fibrosis, and hypotensive esophagogastric junction. Within a median follow-up of 62 months, 10 patients (11%) developed BOS, and no predictive factors were identified. At the end of the follow-up, 10 patients died and 1 underwent retransplantation. The 5-year cumulative survival rate without retransplantation was lower in patients with major esophageal motility disorders compared with that in those without (75% vs 90%, P = 0.01) and in patients who developed BOS compared with that in those without (66% vs 91%; P = 0.005). However, in multivariable analysis, major esophageal motility disorders and BOS were no longer significant predictors of survival without retransplantation.

DISCUSSION:
Major esophageal motility disorders and BOS were associated with allograft survival in lung transplantation in the univariable analysis. Although the causes of this association remain to be determined, this observation confirms that esophageal motor dysfunction should be evaluated in the context of lung transplantation.
Abdominal Pain Response to Rifaximin in Patients With Irritable Bowel Syndrome With Diarrhea
Authors: Lembo Anthony , Rao Satish S. C. , Heimanson Zeev , Pimentel Mark 
Published: March 2020

INTRODUCTION:
Abdominal pain is the principal symptom of irritable bowel syndrome (IBS). This analysis examined abdominal pain response in adults with IBS with diarrhea (IBS-D) receiving the nonsystemic antibiotic rifaximin.

METHODS:
In the Targeted Nonsystemic Antibiotic Rifaximin Gut-Selective Evaluation of Treatment for IBS-D 3 trial, adults with IBS-D received open-label rifaximin 550 mg 3 times daily for 2 weeks, followed by the 4-week post-treatment phase assessing abdominal pain and stool consistency response. Responders were followed for up to 18 additional weeks; patients with recurrence were randomly assigned to receive two 2-week courses of double-blind rifaximin 550 mg 3 times daily or placebo, separated by 10 weeks. Analyses evaluated mean weekly improvements from baseline (e.g., ≥30%, ≥40%, and ≥50%) in abdominal pain during the 4-week post–repeat-treatment phases.

RESULTS:
Of the 2,438 evaluable patients, 1,384 (56.8%) had abdominal pain response to open-label rifaximin (≥30% improvement from baseline in the mean weekly abdominal pain score during ≥2 of the first 4 weeks post-treatment). Weekly decrease (improvement) in responders' mean abdominal pain score (scale range, 0–10) from baseline ranged from −2.6 to −3.3 points during the 18-week follow-up. After the first double-blind repeat treatment, a significantly higher percentage of rifaximin-treated patients were abdominal pain responders (53.9% [172/319]) vs placebo (44.4% [134/302], P = 0.02), with similar results after the second repeat treatment (52.9% [155/293] vs 44.7% [123/275], respectively, P = 0.047). A significantly higher percentage of rifaximin-treated patients were weekly abdominal pain responders for ≥50% of the 18-week double-blind repeat treatment phase (47.9% [138/288] vs 35.9% [97/270], P = 0.004).

DISCUSSION:
Rifaximin is efficacious in improving abdominal pain in adults with IBS-D.