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Background: Daratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3 CASTOR study. We report the results of a prespecified interim analysis of the phase 3 LEPUS study of D-Vd versus Vd in Chinese patients with RRMM., Patients and Methods: Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to receive 8 cycles (21 days/cycle) of bortezomib (1.3 mg/m 2 subcutaneously) and dexamethasone (20 mg orally/intravenously) ± daratumumab (16 mg/kg intravenously). The primary endpoint was progression-free survival (PFS)., Results: A total of 211 patients were randomized (D-Vd, 141; Vd, 70). After an 8.2-month median follow-up, D-Vd significantly prolonged PFS versus Vd (median, not reached vs. 6.3 months; hazard ratio, 0.28; 95% confidence interval, 0.17-0.47; P < .00001) and significantly improved the rates of overall response (83% vs. 65%; P = .00527), ≥ very good partial response (65% vs. 33%; P = .00002), ≥ complete response (33% vs. 11%; P = .00079), and minimal residual disease negativity (10 -5 sensitivity; 22% vs. 3%; P = .0002). The PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib treatment and with high-risk cytogenetics. Thrombocytopenia (D-Vd, 51%; Vd, 37%), lymphopenia (44%; 29%), and lung infection (30%; 22%) were the 3 most common grade 3/4 treatment-emergent adverse events. Although patients in both treatment groups experienced higher rates of grade 3/4 lymphopenia and infections versus patients in CASTOR, the safety profile was generally consistent with that of CASTOR., Conclusion: These data support the use of D-Vd in Chinese patients with RRMM., Competing Interests: Disclosure MQ, SS, XG, and XY are employees of Janssen and own Johnson & Johnson stock. WeipingLiu and WenyuLiu are employees of Janssen. JL, WF, WLi, JH, GA, YW, CF, LC, JJ, XC, ZG, ZC, TN, and XH have no conflicts of interest to disclose. This study (ClinicalTrials.gov Identifier: NCT03234972) was sponsored by Janssen Research & Development, LLC, which provided support for collection, analysis, and interpretation of data; Janssen employee-authors were involved in the decision to submit the article for publication. Medical writing and editorial support were provided by Grace Wang, PharmD, of Cello Health Communications/MedErgy, and were funded by Janssen Global Services, LLC., (Copyright © 2021 Janssen Research & Development, LLC. Published by Elsevier Inc. All rights reserved.)

The estimand framework included in the addendum to the ICH E9 guideline facilitates discussions to ensure alignment between the key question of interest, the analysis, and interpretation. Therapeutic knowledge and drug mechanism play a crucial role in determining the strategy and defining the estimand for clinical trial designs. Clinical trials in patients with hematological malignancies often present unique challenges for trial design due to complexity of treatment options and existence of potential curative but highly risky procedures, for example, stem cell transplant or treatment sequence across different phases (induction, consolidation, maintenance). Here, we illustrate how to apply the estimand framework in hematological clinical trials and how the estimand framework can address potential difficulties in trial result interpretation. This paper is a result of a cross-industry collaboration to connect the International Conference on Harmonisation (ICH) E9 addendum concepts to applications. Three randomized phase 3 trials will be used to consider common challenges including intercurrent events in hematologic oncology trials to illustrate different scientific questions and the consequences of the estimand choice for trial design, data collection, analysis, and interpretation. Template language for describing estimand in both study protocols and statistical analysis plans is suggested for statisticians' reference., (© 2021 John Wiley & Sons Ltd.)

Purpose: In relapsed and/or refractory multiple myeloma, daratumumab reduced the risk of progression or death by > 60% in POLLUX (daratumumab/lenalidomide/dexamethasone [D-Rd]) and CASTOR (daratumumab/bortezomib/dexamethasone [D-Vd]). Minimal residual disease (MRD) is a sensitive measure of disease control. Sustained MRD negativity and outcomes were evaluated in these studies., Methods: MRD was assessed via next-generation sequencing (10 -5 ) at suspected complete response (CR), 3 and 6 months following confirmed CR (POLLUX), 6 and 12 months following the first dose (CASTOR), and every 12 months post-CR in both studies. Sustained MRD negativity (≥ 6 or ≥ 12 months) was evaluated in the intention-to-treat (ITT) and ≥ CR populations., Results: The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD-negativity rates were 32.5% versus 6.7% for D-Rd versus lenalidomide and dexamethasone (Rd) and 15.1% versus 1.6% for D-Vd versus bortezomib and dexamethasone (Vd; both P < .0001). Higher MRD negativity rates were achieved in ≥ CR patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%; P = .0001) and CASTOR (D-Vd, 52.8%; Vd, 17.4%; P = .0035). More patients in the ITT population achieved sustained MRD negativity ≥ 6 months with D-Rd versus Rd (20.3% v 2.1%; P < .0001) and D-Vd versus Vd (10.4% v 1.2%; P < .0001), and ≥ 12 months with D-Rd versus Rd (16.1% v 1.4%; P < .0001) and D-Vd versus Vd (6.8% v 0%). Similar results for sustained MRD negativity were observed among ≥ CR patients. More patients in the daratumumab-containing arms achieved MRD negativity and sustained MRD negativity, which were associated with prolonged progression-free survival., Conclusion: Daratumumab-based combinations induce higher rates of sustained MRD negativity versus standard of care, which are associated with durable remissions and prolonged clinical outcomes.

Background: fluorescent nanodiamonds (FND) are nontoxic, infinitely photostable nanoparticles that emit near-infrared fluorescence and have a modifiable surface allowing for the generation of protein-FND conjugates. FND-mediated immune cell targeting may serve as a strategy to visualize immune cells and promote immune cell activation., Methods: uncoated-FND (uFND) were fabricated, coated with glycidol (gFND), and conjugated with immunoglobulin G (IgG-gFND). In vitro studies were performed using a breast cancer/natural killer/monocyte co-culture system, and in vivo studies were performed using a breast cancer mouse model., Results: in vitro studies demonstrated the targeted immune cell uptake of IgG-gFND, resulting in significant immune cell activation and no compromise in immune cell viability. IgG-gFND remained at the tumor site following intratumoral injection compared to uFND which migrated to the liver and kidneys., Conclusion: antibody-conjugated FND may serve as immune drug delivery vehicles with "track and trace capabilities" to promote directed antitumor activity and minimize systemic toxicities., Competing Interests: The authors declare the following competing financial interest(s): The authors from Columbus NanoWorks commercially develop nanodiamond imaging technologies. All other authors declare no competing interests.

A number of important drugs used to treat cancer-many of which serve as the backbone of modern chemotherapy regimens-have outdated prescribing information in their drug labeling. The Food and Drug Administration is undertaking a pilot project to develop a process and criteria for updating prescribing information for longstanding oncology drugs, based on the breadth of knowledge the cancer community has accumulated with the use of these drugs over time. This article highlights a number of considerations for labeling updates, including selecting priorities for updating; data sources and evidentiary criteria; as well as the risks, challenges, and opportunities for iterative review to ensure prescribing information for oncology drugs remains relevant to current clinical practice., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Purpose: Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL., Patients and Methods: Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety., Results: A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%)., Conclusion: The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.

Background: The number of patients in the United States (US) who speak a language other than English is increasing. We evaluated the impact of English proficiency on self-reported patient-provider communication and shared decision-making., Methods: The 2013-2014 Medical Expenditure Panel Survey database was utilized to identify respondents who spoke a language other than English. Patient-provider communication (PPC) and shared decision-making (SDM) scores from 4-12 were categorized as "poor" (4-7), "average" (8-11), and "optimal." The relationship between PPC, SDM, and English proficiency was analyzed., Results: Among 13,880 respondents, most were white (n = 10,281, 75%), age 18-39 (n = 6,677, 48%), male (n = 7,275, 52%), middle income (n = 4,125, 30%), and born outside of the US (n = 9,125, 65%). English proficiency was rated as "very well" (n = 7,221, 52%), "well" (n = 2,378, 17%), "not well" (n = 2,820, 20%), or "not at all" (n = 1,463, 10%). On multivariable analysis, patients who rated their English as "well" (OR 1.73, 95% CI 1.37-2.18) or "not well" (OR 1.53, 95% CI 1.10-2.14) were more likely to report "poor" PPC (both P < .01). Similarly, SDM was more commonly self-reported as "poor" among patients who reported English proficiency as "not well" (OR 1.31, 95% CI 1.04-1.65, P = .02)., Conclusion: Decreased English proficiency was associated with worse self-reported patient-provider communication and shared decision-making. Attention to patients' language needs is critical to patient satisfaction and improved perception of care., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Ruptured hepatocellular (rHCC) is a rare but life-threatening presentation that often requires acute intervention. In this systematic review we identified 67 eligible studies reporting on 4941 patients with rHCC. Here we present the treatment approaches for the management of rHCC both in the acute setting with regards to management of hemorrhage, as well long-term with regards to oncological treatment., (© 2017 Wiley Periodicals, Inc.)

Background: Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma., Methods: The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m(2) intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m(2) on day 1 of cycle 1, and 500 mg/m(2) on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090., Findings: Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted., Interpretation: In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile., Funding: Janssen Research & Development., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

There is a well-recognized need for low cost biodetection technologies for resource-poor settings with minimal medical infrastructure. Lab-on-a-chip (LOC) technology has the ability to perform biological assays in such settings. The aim of this work is to develop a low cost, high-throughput detection system for the analysis of 96 samples simultaneously outside the laboratory setting. To achieve this aim, several biosensing elements were combined: a syringe operated ELISA lab-on-a-chip (ELISA-LOC) which integrates fluid delivery system into a miniature 96-well plate; a simplified non-enzymatic reporter and detection approach using a gold nanoparticle-antibody conjugate as a secondary antibody and silver enhancement of the visual signal; and Carbon nanotubes (CNT) to increase primary antibody immobilization and improve assay sensitivity. Combined, these elements obviate the need for an ELISA washer, electrical power for operation and a sophisticated detector. We demonstrate the use of the device for detection of Staphylococcal enterotoxin B, a major foodborne toxin using three modes of detection, visual detection, CCD camera and document scanner. With visual detection or using a document scanner to measure the signal, the limit of detection (LOD) was 0.5ng/ml. In addition to visual detection, for precise quantitation of signal using densitometry and a CCD camera, the LOD was 0.1ng/ml for the CCD analysis and 0.5 ng/ml for the document scanner. The observed sensitivity is in the same range as laboratory-based ELISA testing. The point of care device can analyze 96 samples simultaneously, permitting high throughput diagnostics in the field and in resource poor areas without ready access to laboratory facilities or electricity.

Electrical percolation-based biosensing is a new technology. This is the first report of an electrical percolation-based biosensor for real-time detection. The label-free biosensor is based on electrical percolation through a single-walled carbon nanotubes (SWNTs)-antibody complex that forms a network functioning as a "Biological Semiconductor" (BSC). The conductivity of a BSC is directly related to the number of contacts facilitated by the antibody-antigen "connectors" within the SWNT network. BSCs are fabricated by immobilizing a pre-functionalized SWNTs-antibody complex directly on a poly(methyl methacrylate) (PMMA) and polycarbonate (PC) surface. Each BSC is connected via silver electrodes to a computerized ohmmeter, thereby enabling a continuous electronic measurement of molecular interactions (e.g. antibody-antigen binding) via the change in resistance. Using anti-staphylococcal enterotoxin B (SEB) IgG to functionalize the BSC, we demonstrate that the biosensor was able to detect SEB at concentrations as low as 5 ng/mL at a signal to baseline (S/B) ratio of 2. Such measurements were performed on the chip in wet conditions. The actuation of the chip by SEB is immediate, permitting real-time signal measurements. In addition to this "direct" label-free detection mode, a secondary antibody can be used to "label" the target molecule bound to the BSC in a manner analogous to an immunological sandwich "indirect" detection-type assay. Although a secondary antibody is not needed for direct detection, the indirect mode of detection may be useful as an additional measurement to verify or amplify signals from direct detection in clinical, food safety and other critical assays. The BSC was used to measure SEB both in buffer and in milk, a complex matrix, demonstrating the potential of electrical percolation-based biosensors for real-time label-free multi-analyte detection in clinical and complex samples. Assembly of BSCs is simple enough that multiple sensors can be fabricated on the same chip, thereby creating "Biological Central Processing Units (BCPUs)" capable of parallel processing and sorting out information on multiple analytes simultaneously which may be used for complex analysis and for point of care diagnostics., (Published by Elsevier B.V.)

A portable and rapid detection system for the activity analysis of Botulinum Neurotoxins (BoNT) is needed for food safety and bio-security applications. To improve BoNT activity detection, a previously designed portable charge-coupled device (CCD) based detector was modified and equipped with a higher intensity more versatile multi-wavelength spatial light-emitting diode (LED) illumination, a faster CCD detector and the capability to simultaneously detect 30 samples. A FITC/DABCYL Förster Resonance Energy Transfer (FRET)-labeled peptide substrate (SNAP-25), with BoNT-A target cleavage site sequence was used to measure BoNT-A light chain (LcA) activity through the FITC fluorescence increase that occurs upon peptide substrate cleavage. For fluorescence excitation, a multi-wavelength spatial LED illuminator was used and compared to our previous electroluminescent (EL) strips. The LED illuminator was equipped with blue, green, red and white LEDs, covering a spectrum of 450-680 nm (red 610-650 nm, green 492-550 nm, blue 450-495 nm, and white LED 440-680 nm). In terms of light intensity, the blue LED was found to be ~80 fold higher than the previously used blue EL strips. When measuring the activity of LcA the CCD detector limit of detection (LOD) was found to be 0.08 nM LcA for both the blue LED (2 s exposure) and the blue EL (which require ≥60 s exposure) while the limits of quantitation (LOQ) is about 1 nM. The LOD for white LED was higher at 1.4 nM while the white EL was not used for the assay due to a high variable background. Unlike the weaker intensity EL illumination the high intensity LED illumination enabled shorter exposure times and allowed multi-wavelength illumination without the need to physically change the excitation strip, thus making spectrum excitation of multiple fluorophores possible increasing the versatility of the detector platform for a variety of optical detection assays.

A previously developed fluorescence sensing platform, combining spatial illumination using electroluminescence (EL) semiconductor strips with charge coupled device (CCD)-based detection (EL-CCD), was adapted to a new 96-well chip for colorimetric immunological assays, enhancing the capabilities of the EL-CCD platform. The modified system was demonstrated using a colorimetric-based enzyme linked immunosorbent assay (ELISA) for detection of staphylococcal enterotoxin B (SEB). Limits of detection (LODs) of 3.9 ng/mL (+/-2.4 ng/mL) SEB were determined with the ELISA chip measured using the EL-CCD platform, following a standard 4-h ELISA protocol. The LODs were comparable to those obtained using standard 96-well ELISA plates measured using a standard laboratory 96-well plate reader. The miniature 96-well ELISA chip however required as little as 5-microL samples, representing a tenfold reduction in sample volume compared to a standard 96-well ELISA plates. The ELISA chip also demonstrated detection of SEB spiked into various food matrices (milk, mushrooms, and mayonnaise) using limited-to-no sample preparation, with LODs ranging from 3.9 to 18.5 ng/mL depending on the matrix. The EL-CCD platform is versatile, capable of multi-mode detection (e.g., fluorescent and colorimetric along with solution and solid phase assays), and could readily be applied to other field portable or point-of-care applications.

Current biodetection illumination technologies (laser, LED, tungsten lamp, etc.) are based on spot illumination with additional optics required when spatial excitation is required. Herein we describe a new approach of spatial illumination based on electroluminescence (EL) semiconductor strips available in several wavelengths, greatly simplifying the biosensor design by eliminating the need for additional optics. This work combines EL excitation with charge-coupled device (CCD) based detection (EL-CCD detector) of fluorescence for developing a simple portable detector for botulinum neurotoxin A (BoTN-A) activity analysis. A Förster Resonance Energy Transfer (FRET) activity assay for BoTN-A was used to both characterize and optimize the EL-CCD detector. The system consists of two modules: (1) the detection module which houses the CCD camera and emission filters, and (2) the excitation and sample module, containing the EL strip, the excitation filter and the 9-well sample chip. The FRET activity assay used in this study utilized a FITC/DABCYL-SNAP-25 peptide substrate in which cleavage of the substrate by BoTN-A, or its light chain derivative (LcA), produced an increase in fluorescence emission. EL-CCD detector measured limits of detection (LODs) were similar to those measured using a standard fluorescent plate reader with valves between 0.625 and 1.25 nM (31-62 ng/ml) for LcA and 0.313 nM (45 ng/ml) for the full toxin, BoTN-A. As far as the authors are aware this is the first demonstration of phosphor-based EL strips being used for the spatial illumination/excitation of a surface, coupled with CCD for point of care detection.

Purpose: We report the results of a retrospective study of the use of tricorticocancellous iliac crest bone graft in 12 patients with acute AO type C3.2 or type C3.3 fractures of the distal radius who were followed up for at least 1 year., Methods: Twelve of 17 patients treated with the protocol were available for follow-up evaluation. All fractures were treated with open reduction and combined internal and external fixation. Five fractures were plated dorsally, 1 volarly, and 5 volarly and dorsally., Results: Five patients had AO type C3.2 fractures and 7 had AO type C3.3 fractures. Nine of 10 radiographic parameters that were restored to near-normal values during the surgery were maintained at near-normal levels at the final follow-up evaluation at a mean of 28 months after surgery. Nine fractures had less than 2 mm of articular step-off of the distal radius and 8 had less than 3 mm of total articular incongruity (gap plus step-off). In 10 patients the radial length was restored to at least 10 mm. The mean arc of flexion-extension was 67% and the mean grip strength was 57% of that of the uninjured side. According to the Gartland and Werley demerit-point system 5 of the patients had good or excellent results. According to the modified Green and O'Brien clinical rating system 2 patients had good or excellent results. Poor results for 2 patients according to the demerit-point system and for 6 patients according to the Green and O'Brien clinical rating system were associated with severe ipsilateral soft-tissue and osseous injuries of the wrist, forearm, and arm. The total articular incongruity had a moderately strong correlation with the outcome as assessed by the demerit-point system., Conclusions: Tricorticocancellous bone grafting in conjunction with combined internal and external fixation is a satisfactory treatment that can lead to a high rate of return to work and sports, a high level of patient satisfaction, and a low rate of complications., Type of Study/level of Evidence: Therapeutic, Level IV.