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Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

Lymph node ratio (LNR) and margin status have prognostic significance in pancreatic cancer. Herein we examined the pathologic and clinical outcomes in patients with borderline resectable pancreatic cancer (BRPC) following neoadjuvant therapy (NAT) and pancreaticoduodenectomy.

Modern neural language models can be used by malicious actors to automatically produce textual content looking as it has been written by genuine human users. Due to progress in the controllability of computer-generated text, there is a risk that state-sponsored actors may start using such methods for conducting large-scale information operations. Various detection algorithms have been suggested in the research literature to identify texts produced by language model-based generators, but these are often mainly evaluated on test data from the same distribution as they have been trained on. We evaluate promising Transformer-based detection algorithms in a large variety of experiments involving both in-distribution and out-of-distribution test data, as well as evaluation on more realistic in-the-wild data. It is shown that the generalizability of the detectors can be questioned, especially when applied to short social media posts. Moreover, the best performing (RoBERTa-based) detector is shown to be non-robust also to basic adversarial attacks, illustrating how easy it is for malicious actors to avoid detection by the current state-of-the-art detection algorithms.

Two methods of hematopoietic stem cell (HSC) cryopreservation exist: 10% DMSO alone using rate-controlled freezing with storage in liquid nitrogen (LN2) and 5% DMSO/6%HES with ‘dump’ into and storage in mechanical freezers at -80C. Long-term storage at LN2 is clinically efficacious, but clinical data for long-term storage in DMSO/HES is lacking. To assess clinical benefit of HSC stored long term in DMSO+HES at -80C, we report on first and second autologous stem cell transplants (ASCT1 and 2) in patients undergoing sequential transplants for multiple myeloma (MM) using HSC stored >2 years.

Supplemental Digital Content is available in the text.Neuroblastoma RAS viral oncogene homolog is a commonly mutated oncogene in melanoma, and therapeutic targeting of neuroblastoma RAS viral oncogene homolog has proven difficult. We characterized the expression and phenotypic functions of five recently discovered splice isoforms of neuroblastoma RAS viral oncogene homolog in melanoma. Canonical neuroblastoma RAS viral oncogene homolog (isoform-1) was expressed to the highest degree and its expression was significantly increased in melanoma metastases compared to primary lesions. Isoform-5 expression in metastases showed a significant, positive correlation with survival and tumours over-expressing isoform-5 had significantly decreased growth in a xenograft model. In contrast, over-expression of any isoform resulted in enhanced proliferation, and invasiveness was increased with over-expression of isoform-1 or isoform-2. Downstream signalling analysis indicated that the isoforms signalled differentially through the mitogen-activated protein kinase and PI3K pathways and A375 cells over-expressing isoform-2 or isoform-5 showed resistance to vemurafenib treatment in vitro. The neuroblastoma RAS viral oncogene homolog isoforms appear to play varying roles in melanoma phenotype and could potentially serve as biomarkers for therapeutic response and disease prognosis.

AbstractThis paper investigates a gap in the relationship between the physical city and current “smart city” solutions in the context of rapidly developing urban regions. In particular it reconsiders these two “realities”: the material, spatial and social qualities of cities, and the immersive qualities of hybrid digital interfaces such as augmented and virtual reality. With regard to both analog and digital realms, our research proposes an inclusive and participatory approach to the design and implementation of smart city technologies. Using Ho Chi Minh City (or HCMC) as a case study, it explores how a city’s tacit feedback, combined with mixed reality tools, can expand public accessibility of cities, and in particular of high-density districts. Activating the city through its citizens rather than relying on top-down political policies, this form of “augmented urbanism” advocates a community-based approach to transcending the smartness divide. Ho Chi Minh City offers many examples of shared, multifunctional spaces with localized forms of use and administration. However, these are under threat from intense urban development and subsequent environmental impact. This paper will suggest ways in which mixed reality tools could strengthen community engagement in neighborhoods that are marginalized or threatened by ongoing development, and how this process might also inform and bolster governmental support for locally-based initiatives. The research argues for the city itself (material and empirical) to identify, harness and leverage its own inherent forms of “smartness”. Integrating the city’s tacit knowledge with open-source platforms can ensure that the ongoing transformation of the city is a collective and intelligent one. This is also a way to provide persistent experiences within a radically and rapidly shifting urban environment.

Previous studies have demonstrated the prognostic significance of pathologic tumor response in pancreatic adenocarcinoma following neoadjuvant therapy (NAT). The aim of this study was to determine the incidence of significant pathologic response to NAT in borderline resectable pancreatic cancer (BRPC), and association of NAT regimen and other clinico-pathologic characteristics with pathologic response.

IMPORTANCE: Research demonstrates adenoma detection rate (ADR) and proximal sessile serrated polyp detection rate (pSSPDR) are associated with endoscopist characteristics including sex, specialty, and years in practice. However, many studies have not adjusted for other risk factors associated with colonic neoplasia. OBJECTIVE: To assess the association between endoscopist characteristics and polyp detection after adjusting the factors included in previous studies as well as other factors. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted in the Cleveland Clinic health system with data from individuals undergoing screening colonoscopies between January 2015 and June 2017. The study analyzed data using methods from previous studies that have demonstrated significant associations between endoscopist characteristics and ADR or pSSPDR. Multilevel mixed-effects logistic regression was performed to examine 7 endoscopist characteristics associated with ADRs and pSSPDRs after controlling for patient demographic, clinical, and colonoscopy-associated factors. EXPOSURES: Seven characteristics of endoscopists performing colonoscopy. MAIN OUTCOMES AND MEASURES: The ADR and pSSPDR, with a hypothesis created after data collection began. RESULTS: A total of 16 089 colonoscopies were performed in 16 089 patients by 56 clinicians. Of these, 8339 patients were male (51.8%), and the median (range) age of the cohort was 59 (52-66) years. Analyzing the data by the methods used in 4 previous studies yielded an association between endoscopist and polyp detection; surgeons (OR, 0.49 [95% CI, 0.28-0.83]) and nongastroenterologists (OR, 0.50 [95% CI 0.29-0.85]) had reduced odds of pSSPDR, which was similar to results in previous studies. In a multilevel mixed-effects logistic regression analysis, ADR was not significantly associated with any endoscopist characteristic, and pSSPDR was only associated with years in practice (odds ratio, 0.86 [95% CI, 0.83-0.89] per increment of 10 years; P &lt; .001) and number of annual colonoscopies performed (odds ratio, 1.05 [95% CI, 1.01-1.09] per 50 colonoscopies/year; P = .02). CONCLUSIONS AND RELEVANCE: The differences in ADRs that were associated with 7 of 7 endoscopist characteristics and differences in pSSPDRs that were associated with 5 of 7 endoscopist characteristics in previous studies may have been associated with residual confounding, because they were not replicated in this analysis. Therefore, these characteristics should not influence the choice of endoscopist for colorectal cancer screening. However, clinicians further from their training and those with lower colonoscopy volumes have lower adjusted pSSPDRs and may need additional training to help increase pSSPDRs.

Pancreatic ductal adenocarcinoma (PDAC) is lethal, and the majority of patients present with locally advanced or metastatic disease that is not amenable to cure. Thus, with surgical resection being the only curative modality, it is critical that disease is identified at an earlier stage to allow the appropriate therapy to be applied. Unfortunately, a specific biomarker for early diagnosis has not yet been identified; hence, no screening process exists. Recently, high-throughput screening and next-generation sequencing (NGS) have led to the identification of novel biomarkers for many disease processes, and work has commenced in PDAC. Genomic data generated by NGS not only have the potential to assist clinicians in early diagnosis and screening, especially in high-risk populations, but also may eventually allow the development of personalized treatment programs with targeted therapies, given the large number of gene mutations seen in PDAC. This review introduces the basic concepts of NGS and provides a comprehensive review of the current understanding of genetics in PDAC as related to discoveries made using NGS.

ABSTRACTIntroduction: Atopic dermatitis (AD) is one of the most common childhood skin disorders. Multiple mechanisms contribute to the pathology of AD and treatment approaches are directed at these processes.Areas covered: The purpose of this review is to discuss the chemical treatment options for pediatric atopic dermatitis, including immunomodulators and small molecule inhibitors. A systematic literature search was conducted, and publications were reviewed for applicable treatment guidelines.Expert opinion: Topical therapy is first-line for pediatric atopic dermatitis. Providers should work closely with patients and caregivers to promote the success of topical treatments. In disease refractory to topical treatments, systemic agents may be considered. Clinical trials are ongoing for the use of biologics in the treatment of pediatric AD. When choosing the most appropriate treatment, physicians should consider the drug efficacy, potential adverse effects, patient adherence, and quality of life for both patients and caregivers. Additional studies are required to determine the safest and most effective doses for systemic therapy in childhood AD.

Hybrid perovskites incorporating conjugated organic cations enable unusual charge carrier interactions among organic and inorganic structural components, but are difficult to prepare as films due to disparate component chemical/physical characteristics (e.g., solubility, thermal stability). Here we demonstrate that resonant infrared matrix-assisted pulsed laser evaporation (RIR-MAPLE) mitigates these challenges, enabling facile deposition of lead-halide-based perovskite films incorporating variable-length oligothiophene cations. Density functional theory (DFT) predicts suitable organic and inorganic moieties that form quantum-well-like structures with targeted luminescence or exciton separation/quenching. RIR-MAPLE-deposited films enable confirmation of these predictions by optical measurements, which further display excited state behavior transcending traditional quantum-well models—i.e., with appropriate selection of specially synthesized organic/inorganic moieties, intercomponent carrier transfer efficiently converts excitons from singlet to triplet states in organics for which intersystem crossing cannot ordinarily compete with recombination. These observations demonstrate the uniquely versatile excited-state behavior in hybrid perovskite quantum wells, and the value of integrating DFT, organic synthesis, RIR-MAPLE and spectroscopy for screening/preparing rationally devised complex structures.

The phase 3 AETHERA trial established brentuximab vedotin (BV) as a consolidative treatment option for adult patients with classical Hodgkin lymphoma (cHL) at high risk of relapse or progression after autologous hematopoietic stem-cell transplantation (auto-HSCT). Results showed that BV significantly improved progression-free survival (PFS) vs placebo plus best supportive care alone. At 5-year follow-up, BV continued to provide patients with sustained PFS benefit; 5-year PFS was 59% (95% confidence interval [CI], 51-66) with BV vs 41% (95% CI, 33-49) with placebo (hazard ratio [HR], 0.521; 95% CI, 0.379-0.717). Similarly, patients with ≥2 risk factors in the BV arm experienced significantly higher PFS at 5 years than patients in the placebo arm (HR, 0.424; 95% CI, 0.302-0.596). Upfront consolidation with BV significantly delayed time to second subsequent therapy, an indicator of ongoing disease control, vs placebo. Peripheral neuropathy, the most common adverse event in patients receiving BV, continued to improve and/or resolve in 90% of patients. In summary, consolidation with BV in adult patients with cHL at high risk of relapse or progression after auto-HSCT confers a sustained PFS benefit and is safe and well tolerated. Physicians should consider each patient’s HL risk factor profile when making treatment decisions. This trial was registered at www.clinicaltrials.gov as #NCT01100502.