Phenotypic Screening of Prospective Analgesics Among FDA-Approved Compounds using an iPSC-Based Model of Acute and Chronic Inflammatory Nociception.

Classical target-based drug screening is low-throughput, largely subjective, and costly. Phenotypic screening based on in vitro models is increasingly being used to identify candidate compounds that modulate complex cell/tissue functions. Chronic inflammatory nociception, and subsequent chronic pain conditions, affect peripheral sensory neuron activity (e.g., firing of action potentials) through myriad pathways, and remain unaddressed in regard to effective, non-addictive management/treatment options. Here, a chronic inflammatory nociception model is demonstrated based on induced pluripotent stem cell (iPSC) sensory neurons and glia, co-cultured on microelectrode arrays (MEAs). iPSC sensory co-cultures exhibit coordinated spontaneous extracellular action potential (EAP) firing, reaching a stable baseline after ≈27 days in vitro (DIV). Spontaneous and evoked EAP metrics are significantly modulated by 24-h incubation with tumor necrosis factor-alpha (TNF-α), representing an inflammatory phenotype. Compared with positive controls (lidocaine), this model is identified as an "excellent" stand-alone assay based on a modified Z' assay quality metric. This model is then used to screen 15 cherry-picked, off-label, Food and Drug Administration (FDA)-approved compounds; 10 of 15 are identified as "hits". Both hits and "misses" are discussed in turn. In total, this data suggests that iPSC sensory co-cultures on MEAs may represent a moderate-to-high-throughput assay for drug discovery targeting inflammatory nociception.

Biology and pathophysiology of symptomatic neuromas.

ABSTRACT: Neuromas are a substantial cause of morbidity and reduction in quality of life. This is not only caused by a disruption in motor and sensory function from the underlying nerve injury but also by the debilitating effects of neuropathic pain resulting from symptomatic neuromas. A wide range of surgical and therapeutic modalities have been introduced to mitigate this pain. Nevertheless, no single treatment option has been successful in completely resolving the associated constellation of symptoms. While certain novel surgical techniques have shown promising results in reducing neuroma-derived and phantom limb pain, their effectiveness and the exact mechanism behind their pain-relieving capacities have not yet been defined. Furthermore, surgery has inherent risks, may not be suitable for many patients, and may yet still fail to relieve pain. Therefore, there remains a great clinical need for additional therapeutic modalities to further improve treatment for patients with devastating injuries that lead to symptomatic neuromas. However, the molecular mechanisms and genetic contributions behind the regulatory programs that drive neuroma formation-as well as the resulting neuropathic pain-remain incompletely understood. Here, we review the histopathological features of symptomatic neuromas, our current understanding of the mechanisms that favor neuroma formation, and the putative contributory signals and regulatory programs that facilitate somatic pain, including neurotrophic factors, neuroinflammatory peptides, cytokines, along with transient receptor potential, and ionotropic channels that suggest possible approaches and innovations to identify novel clinical therapeutics.

Surgical resection criteria and neoadjuvant therapies for intrahepatic cholangiocarcinoma.

The staging of intrahepatic cholangiocarcinoma (ICC) is complex, and there is no consensus among international cancer groups on how to most appropriately select candidates with nonmetastatic disease for surgical resection. Factors contributing to a higher stage of disease include larger tumor size, multiple tumors, vascular invasion (either portal venous or arterial), biliary invasion, involvement of local hepatic structures, serosal invasion, and regional lymph node metastases. For patients selected to undergo surgery, it is well-documented that R0 resection translates to a survival benefit. Estimating the risk of post-hepatectomy liver failure and post-surgical residual liver function is vital and may preclude some patients with significant tumor burden from undergoing surgery. Numerous serum and biliary biomarkers of the disease can help detect recurrence in patients undergoing surgical resection. Systemic and locoregional neoadjuvant treatments to facilitate better surgical outcomes have yielded mixed results regarding improving resectability and overall survival. Additional research is needed to identify optimal neoadjuvant treatment approaches and to evaluate which patients will benefit most from these strategies. Therapies targeting genetic mutations and protein aberrations found by tumor molecular profiling may offer additional options for future neoadjuvant treatment.

Electrically-evoked oscillating calcium transients in mono- and co-cultures of iPSC glia and sensory neurons.

Activated glia are known to exhibit either neuroprotective or neurodegenerative effects, depending on their phenotype, while participating in chronic pain regulation. Until recently, it has been believed that satellite glial cells and astrocytes are electrically slight and process stimuli only through intracellular calcium flux that triggers downstream signaling mechanisms. Though glia do not exhibit action potentials, they do express both voltage- and ligand-gated ion channels that facilitate measurable calcium transients, a measure of their own phenotypic excitability, and support and modulate sensory neuron excitability through ion buffering and secretion of excitatory or inhibitory neuropeptides (i.e., paracrine signaling). We recently developed a model of acute and chronic nociception using co-cultures of iPSC sensory neurons (SN) and spinal astrocytes on microelectrode arrays (MEAs). Until recently, only neuronal extracellular activity has been recorded using MEAs with a high signal-to-noise ratio and in a non-invasive manner. Unfortunately, this method has limited compatibility with simultaneous calcium transient imaging techniques, which is the most common method for monitoring the phenotypic activity of astrocytes. Moreover, both dye-based and genetically encoded calcium indicator imaging rely on calcium chelation, affecting the culture's long-term physiology. Therefore, it would be ideal to allow continuous and simultaneous direct phenotypic monitoring of both SNs and astrocytes in a high-to-moderate throughput non-invasive manner and would significantly advance the field of electrophysiology. Here, we characterize astrocytic oscillating calcium transients (OCa2+Ts) in mono- and co-cultures of iPSC astrocytes as well as iPSC SN-astrocyte co-cultures on 48 well plate MEAs. We demonstrate that astrocytes exhibit OCa2+Ts in an electrical stimulus amplitude- and duration-dependent manner. We show that OCa2+Ts can be pharmacologically inhibited with the gap junction antagonist, carbenoxolone (100 µM). Most importantly, we demonstrate that both neurons and glia can be phenotypically characterized in real time, repeatedly, over the duration of the culture. In total, our findings suggest that calcium transients in glial populations may serve as a stand-alone or supplemental screening technique for identifying potential analgesics or compounds targeting other glia-mediated pathologies.

Evidence of widespread endemic populations of highly multidrug resistant Klebsiella pneumoniae in hospital settings in Hanoi, Vietnam: a prospective cohort study.

BACKGROUND: Patients with prolonged hospitalisation have a significant risk of carriage of and subsequent infection with extended spectrum ß-lactamase (ESBL)-producing and carbapenemase-producing Klebsiella pneumoniae. However, the distinctive roles of the community and hospital environments in the transmission of ESBL-producing or carbapenemase-producing K pneumoniae remain elusive. We aimed to investigate the prevalence and transmission of K pneumoniae within and between the two tertiary hospitals in Hanoi, Viet Nam, using whole-genome sequencing. METHODS: We did a prospective cohort study of 69 patients in intensive care units (ICUs) from two hospitals in Hanoi, Viet Nam. Patients were included if they were aged 18 years or older, admitted for longer than the mean length of stay in their ICU, and cultured K pneumoniae from their clinical samples. Longitudinally collected samples from patients (collected weekly) and the ICU environment (collected monthly) were cultured on selective media, and whole-genome sequences from K pneumoniae colonies analysed. We did phylogenetic analyses and correlated phenotypic antimicrobial susceptibility testing with genotypic features of K pneumoniae isolates. We constructed transmission networks of patient samples, relating ICU admission times and locations with genetic similarity of infecting K pneumoniae. FINDINGS: Between June 1, 2017, and Jan 31, 2018, 69 patients were in the ICUs and eligible for inclusion, and a total of 357 K pneumoniae isolates were cultured and successfully sequenced. 228 (64%) of K pneumoniae isolates carried between two and four different ESBL-encoding and carbapenemase-encoding genes, with 164 (46%) isolates carrying genes encoding both, with high minimum inhibitory concentrations. We found a novel co-occurrence of blaKPC-2 and blaNDM-1 in 46·6% of samples from the globally successful ST15 lineage. Despite being physically and clinically separated, the two hospitals shared closely related strains carrying the same array of antimicrobial resistance genes. INTERPRETATION: These results highlight the high prevalence of ESBL-positive carbapenem-resistant K pneumoniae in ICUs in Viet Nam. Through studying K pneumoniae ST15 in detail, we showed how important resistance genes are contained within these strains that are carried broadly by patients entering the two hospitals directly or through referral. FUNDING: Medical Research Council Newton Fund, Ministry of Science and Technology, Wellcome Trust, Academy of Medical Sciences, Health Foundation, and National Institute for Health and Care Research Cambridge Biomedical Research Centre.

Genomic characterisation of multidrug-resistant Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii in two intensive care units in Hanoi, Viet Nam: a prospective observational cohort study.

BACKGROUND: Viet Nam has high rates of antimicrobial resistance (AMR) but little capacity for genomic surveillance. This study used whole genome sequencing to examine the prevalence and transmission of three key AMR pathogens in two intensive care units (ICUs) in Hanoi, Viet Nam. METHODS: A prospective surveillance study of all adults admitted to ICUs at the National Hospital for Tropical Diseases and Bach Mai Hospital was done between June 19, 2017, and Jan 16, 2018. Clinical and environmental samples were cultured on selective media, characterised with MALDI TOF mass spectrometry, and sequenced with Illumina. Phylogenies based on the de-novo assemblies (SPAdes) were constructed with MAFFT (PARsnp), Gubbins, and RAxML. Resistance genes were detected with Abricate against the US National Center for Biotechnology Information database. FINDINGS: 3153 Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii isolates from 369 patients were analysed. Phylogenetic analysis revealed predominant lineages within A baumannii (global clone 2, sequence types ST2 and ST571) and K pneumoniae (ST15, ST16, ST656, ST11, and ST147) isolates. Isolation from stool was most common with E coli (87·0%) followed by K pneumoniae (62·5%). Of the E coli, 85·0% carried a blaCTX-M variant, while 81·8% of K pneumoniae isolates carried blaNDM (54·4%), or blaKPC (45·1%), or both. Transmission analysis with single nucleotide polymorphisms identified 167 clusters involving 251 (68%) of 369 patients, in some cases involving patients from both ICUs. There were no clear differences between the lineages or AMR genes recovered between the two ICUs. INTERPRETATION: This study represents the largest prospective surveillance study of key AMR pathogens in Vietnamese ICUs. Clusters of closely related isolates in patients across both ICUs suggests recent transmission before ICU admission in other health-care settings or in the community. FUNDING: UK Medical Research Council Newton Fund, Viet Nam Ministry of Science and Technology, Wellcome Trust, Academy of Medical Sciences, Health Foundation, and UK National Institute for Health and Care Research Cambridge Biomedical Research Centre.

A Novel 3D Helical Microelectrode Array for In Vitro Extracellular Action Potential Recording.

Recent advances in cell and tissue engineering have enabled long-term three-dimensional (3D) in vitro cultures of human-derived neuronal tissues. Analogous two-dimensional (2D) tissue cultures have been used for decades in combination with substrate integrated microelectrode arrays (MEA) for pharmacological and toxicological assessments. While the phenotypic and cytoarchitectural arguments for 3D culture are clear, 3D MEA technologies are presently inadequate. This is mostly due to the technical challenge of creating vertical electrical conduction paths (or 'traces') using standardized biocompatible materials and fabrication techniques. Here, we have circumvented that challenge by designing and fabricating a novel helical 3D MEA comprised of polyimide, amorphous silicon carbide (a-SiC), gold/titanium, and sputtered iridium oxide films (SIROF). Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) testing confirmed fully-fabricated MEAs should be capable of recording extracellular action potentials (EAPs) with high signal-to-noise ratios (SNR). We then seeded induced pluripotent stems cell (iPSC) sensory neurons (SNs) in a 3D collagen-based hydrogel integrated with the helical MEAs and recorded EAPs for up to 28 days in vitro from across the MEA volume. Importantly, this highly adaptable design does not intrinsically limit cell/tissue type, channel count, height, or total volume.

Two cases of catastrophic deterioration and multiple leaflet detachment in Trifecta valves.

Reports of early and catastrophic acute structural valve deterioration (SVD) in Trifecta valve (Abbott, St Paul, MN, USA) with multiple leaflet detachment are rare. We encountered two cases of early SVD in Trifecta valve with tears on two leaflets. Both cases presented with acute heart failure because of aortic insufficiency, and underwent redo aortic valve replacement; one patient died due to multiple organ failure caused by cardiogenic shock. Durability issues with the Trifecta valves; thus, necessitates long-term vigilance in aortic replacement patients.

Cochlear Implantation in Children with Autism Spectrum Disorder: A Systematic Review and Pooled Analysis.

OBJECTIVE: To determine outcomes following cochlear implantation (CI) in children with autism spectrum disorder (ASD). DATABASES REVIEWED: MEDLINE, Embase, Web of science, Cochrane Library, and Clinicaltrial.gov. METHODS: The review was performed according to the PRISMA statement. Primary outcomes measures were changes in speech perception and speech production scores. Secondary outcome measures included communication mode, device use, parental recommendation of implant, postoperative hyperacusis, and quality of life measures. Pooled analysis of outcomes was performed if possible. RESULTS: Twenty-four studies reported on 159 children with ASD. There were improvements in speech perception in 78% of cases and in speech expression in 63% of cases, though the extent of this improvement was variable. Seventy-four percent of children with ASD and CI are nonoral communicators. Intermittent/nonuse rate was 31%. Hearing outcomes are worse compared to children with other disabilities. The vast majority of parents would recommend CI based on their experiences. CONCLUSION: Outcome in children with ASD and CI are highly variable and significantly poorer compared to non-ASD children. Despite this, most parents report positive experiences and the evidence supports the use of CI in children with ASD.

Characteristics of patients presenting to emergency department for primary atrial fibrillation or flutter at an academic medical center.

OBJECTIVE: In the United States, atrial fibrillation (AF) accounts for over 400,000 hospitalizations annually. Emergency Department (ED) physicians have few resources available to guide AF/AFL (atrial flutter) patient triage, and the majority of these patients are subsequently admitted. Our aim is to describe the characteristics and disposition of AF/AFL patients presenting to the University of North Carolina (UNC) ED with the goal of developing a protocol to prevent unnecessary hospitalizations. METHODS: We performed a retrospective electronic medical chart review of AF/AFL patients presenting to the UNC ED over a 15-month period from January 2015 to March 2016. Demographic and ED visit variables were collected. Additionally, patients were designated as either having primary or secondary AF/AFL where primary AF/AFL patients were those in whom AF/AFL was the primary reason for ED presentation. These primary AF/AFL patients were categorized by AF symptom severity score according to the Canadian Cardiovascular Society Severity of Atrial Fibrillation (CCS-SAF) Scale. RESULTS: A total of 935 patients presented to the ED during the study period with 202 (21.5%) having primary AF/AFL. Of the primary AF/AFL patients, 189 (93.6%) had mild-moderate symptom severity (CCS-SAF ≤ 3). The majority of primary AF/AFL patients were hemodynamically stable, with a mean (SD) SBP of 123.8 (21.3), DBP of 76.6 (14.1), and ventricular rate of 93 (21.9). Patients with secondary AF/AFL were older 76 (13.1), p < 0.001 with a longer mean length of stay 6.1 (7.7), p = 0.31. Despite their mild-moderate symptom severity and hemodynamic stability, nearly 2/3 of primary AF/AFL patients were admitted. CONCLUSION: Developing a protocol to triage and discharge hemodynamically stable AF/AFL patients without severe AF/AFL symptoms to a dedicated AF/AFL clinic may help to conserve healthcare resources and potentially deliver more effective care.

Clinical Cancer Advances 2020: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.

A MESSAGE FROM ASCO'S PRESIDENT: Shortly before I was elected President of ASCO, I attended the 65th birthday party of a current patient. She had been diagnosed 10 years earlier with metastatic breast cancer and hadn't been sure she wanted to move forward with further treatment. With encouragement, she elected to participate in a clinical trial of an investigational drug that is now widely used to treat breast cancer. Happily, here we were, celebrating with her now-married daughters, their husbands, and three beautiful grandchildren, ages 2, 4, and 8. Such is the importance of clinical trials and promising new therapies.Clinical research is about saving and improving the lives of individuals with cancer. It's a continuing story that builds on the efforts of untold numbers of researchers, clinicians, caregivers, and patients. ASCO's Clinical Cancer Advances report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology.ASCO's 2020 Advance of the Year-Refinement of Surgical Treatment of Cancer-highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery.Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer.While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can't rest on our laurels. With ASCO's Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we've identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress.Of course, the effectiveness or number of new treatments is meaningless if patients don't have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge.Sincerely,Howard A. "Skip" Burris III, MD, FACP, FASCOASCO President, 2019-2020.

The management and referral of iliofemoral deep venous thrombosis in North West London.

BACKGROUND: Post-thrombotic syndrome is a common complication of iliofemoral deep venous thrombosis (IFDVT). Existing evidence and National Institute for Health and Care Excellence guidelines suggest that this can be reduced by prompt thrombolytic therapy or thrombectomy. We aimed to evaluate the characteristics of IFDVT patients and to identify whether patients are being offered the recommended treatment pathway. METHODS: A multicenter cross-sectional study was conducted across eight hospital sites in the North West London region, of which two were hub hospitals in their local vascular service networks. Patients with proximal DVT were identified using International Classification of Diseases, Tenth Revision coding during a 1-year period. Data on demographics, diagnostic methods used, interventions, and referrals were extracted from electronic and paper medical records. RESULTS: During the study period, 132 patients with IFDVT were identified (mean age, 59.4 years; 55% female); 75% of these patients had an IFDVT. In this cohort, the biggest predisposing factors were previous DVT (n = 35), malignant disease (n = 35), and immobility (n = 20). In total, 104 patients were administered anticoagulation, and 88 of these patients received anticoagulation within 24 hours. The cases of 45 patients were either discussed with or promptly referred to a vascular service, after which 20 patients were treated solely with anticoagulation, whereas 20 patients received thrombolysis of varying methods. CONCLUSIONS: A significant proportion (56%) of symptomatic IFDVT patients are not being appropriately referred to or discussed with vascular services. Of these, 43% would have been eligible for consideration of early thrombus removal. Adherence to the National Institute for Health and Care Excellence guidelines could be improved by increasing awareness among emergency department colleagues.

Effect of Adding Motolimod to Standard Combination Chemotherapy and Cetuximab Treatment of Patients With Squamous Cell Carcinoma of the Head and Neck: The Active8 Randomized Clinical Trial.

Importance: Immunotherapy for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8 (TLR8) agonist motolimod may stimulate innate and adaptive immunity. Objective: To determine whether motolimod improves outcomes for R/M SCCHN when combined with standard therapy. Design, Setting, and Participants: The Active8 study was a multicenter, randomized, double-blind, placebo-controlled clinical trial enrolling adult patients (age ≥18 years) with histologically confirmed R/M SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx between October 2013 and August 2015. Follow-up ended September 2016. Analysis for the present report was conducted between June 2016 and December 2017. Interventions: Combination treatment with platinum (carboplatin or cisplatin), fluorouracil, cetuximab (the EXTREME regimen), and either placebo or motolimod, each administered intravenously every 3 weeks. Patients received a maximum of 6 chemotherapy cycles, after which patients received weekly cetuximab with either placebo or motolimod every 4 weeks. Main Outcomes and Measures: Progression-free survival (PFS) as determined by independent central review using immune-related RECIST (Response Evaluation Criteria in Solid Tumors). Key secondary end points included overall survival (OS) and safety. Results: Of 195 patients enrolled, 85% were men (n = 166); 82% were white (n = 159); median age was 58 years (range 23-81 years). Median PFS was 6.1 vs 5.9 months (hazard ratio [HR], 0.99; 1-sided 90% CI, 0.00-1.22; P = .47), and median OS was 13.5 vs 11.3 months (HR, 0.95; 1-sided 90% CI, 0.00-1.22; P = .40) for motolimod vs placebo. Increased incidence of injection site reactions, pyrexia, chills, anemia, and acneiform rash were noted with motolimod. Of 83 cases oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV) positive. In a prespecified subgroup analysis of HPV-positive participants, motolimod vs placebo resulted in significantly longer PFS (7.8 vs 5.9 months; HR, 0.58; 1-sided 90% CI, 0.00-0.90; P = .046) and OS (15.2 vs 12.6 months; HR, 0.41; 1-sided 90% CI, 0.00-0.77; P = .03). In an exploratory analysis, patients with injection site reactions had longer PFS and OS (median PFS, 7.1 vs 5.9 months; HR, 0.69; 1-sided 90% CI, 0.00-0.93; P = .06; and median OS, 18.7 vs 12.6; HR, 0.56; 1-sided 90% CI, 0.00-0.81; P = .02). Conclusions and Relevance: Adding motolimod to the EXTREME regimen was well tolerated but did not improve PFS or OS in the intent-to-treat population. Significant benefit was observed in HPV-positive patients and those with injection site reactions, suggesting that TLR8 stimulation may benefit subset- and biomarker-selected patients. Trial Registration: ClinicalTrials.gov identifier: NCT01836029.

Predictors of Pericardial Effusion in Patients Undergoing Pulmonary Artery Banding.

BACKGROUND: Although pulmonary artery banding (PAB) is a common palliative procedure for pediatric heart malformation, there are concerns of pressure overload and concomitant immune reactions in the right ventricle causing postsurgical complications such as pericardial effusion. At this time, no clear guidelines as to potential risk factors or procedural contraindications have been widely disseminated. Therefore, a study was undertaken to examine wide-ranging factors to find potential biomarkers for postsurgical pericardial effusion formation risk. METHODS: A retrospective study was conducted on all cardiac surgeries performed over an eight-year period, and the main inclusion criterion was pericardial effusion development after PAB that required surgical drainage. Nine cases were then analyzed against a control group of 45 cases with respect to body measurements, concomitant surgeries, genetic screens, laboratory tests results, and cardiac function parameters. RESULTS: Trisomy 21 was strongly associated with the development of severe pericardial effusion after PAB, and postoperative serum albumin levels in patients with trisomy 21 were associated with pericardial effusion development. Other parameters showed no significant correlation with pericardial effusion development. CONCLUSIONS: Our data indicate a strong association between trisomy 21 and pericardial effusion requiring drainage after PAB, which is in line with translational research findings. Pressure overload from PAB may play a role in the formation of severe pericardial effusion that is exacerbated by cardiac structural defects commonly associated with trisomy 21. Surgical teams should therefore use caution and plan to implement drainage in PAB cases, and postoperative serum albumin may serve as a useful biomarker for pericardial effusion formation.

Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 Stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals.

Purpose: The response rate of patients with head and neck squamous cell carcinoma (HNSCC) to cetuximab therapy is only 15% to 20%, despite frequent EGFR overexpression. Because immunosuppression is common in HNSCC, we hypothesized that adding a proinflammatory TLR8 agonist to cetuximab therapy might result in enhanced T-lymphocyte stimulation and anti-EGFR-specific priming.Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3 to 4 weekly doses of motolimod (2.5 mg/m2) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells.Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed myeloid-derived suppressor cell (MDSC) suppression of T-cell proliferation in vitro These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in tumor-infiltrating lymphocytes. Motolimod plus cetuximab also decreased induction of Treg and reduced markers of suppression, including CTLA-4, CD73, and membrane-bound TGFß. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8+ T-cell infiltration into tumors. These T cells manifested increased T-cell receptor (TCR) clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT.Conclusions: Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC. Clin Cancer Res; 24(1); 62-72. ©2017 AACR.

Cardiopulmonary resuscitation on television: are we miseducating the public?

BACKGROUND: Out-of-hospital cardiac arrest survival rates in the UK are poor, and non-medically trained individuals have been identified to perform substandard cardiopulmonary resuscitation (CPR). Millions watch televised medical dramas and, for many, these comprise their only education on CPR. This study aims to investigate the quality of CPR portrayed on these programmes and whether this has an effect on public knowledge. METHODS: Prospective observational study of 30 consecutive episodes of three popular medical dramas. Public knowledge of CPR and viewing habits were assessed with a survey of non-medically trained personnel. RESULTS: 90 episodes were reviewed with 39 resuscitation attempts shown. Chest compression rates varied from 60 to 204 compressions per minute with a median of 122 (95% CI 113 to 132). Depth varied from 1.5 to 7.5 cm with a median of 3 (3.15-4.31). Rate and depth were significantly different from the UK Resuscitation Council Guidelines (2010) (p<0.05, t-test). Survey participants (n=160, 80% response rate) documented what they thought was the correct rate and depth of chest compressions and were scored accordingly. Those who documented watching medical dramas regularly scored significantly worse than those who watched occasionally (p<0.05, Mann-Whitney test). CONCLUSION: Televised medical dramas depict CPR inaccurately and laypersons may be less well informed about the correct technique the more they tune into these programmes. While there may be other confounding variables, given the popularity of television medical dramas, the poor depiction may be significantly contributing to poor public CPR knowledge and represent a potential new avenue of public education.

Phase Ib Trial of the Toll-like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN.

Purpose: As Toll-like receptors (TLR) are key mediators of immune responses, TLR agonists may be important for augmenting the efficacy of therapies for squamous cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective small-molecule agonist of TLR8, stimulates natural killer (NK) cells, dendritic cells, and monocytes. A phase Ib clinical trial assessed the safety and antitumor activity of motolimod in combination with cetuximab in patients with SCCHN. Correlative biomarkers of immune activity were explored.Experimental Design: Thirteen patients with recurrent or metastatic SCCHN were enrolled in this open-label, dose-escalation study using a standard 3 + 3 design. Doses of motolimod (2.5, 3.0, or 3.5 mg/m2) were given on days 1, 8, and 15, in combination with fixed weekly doses of cetuximab in 28-day cycles.Results: There were no protocol-defined dose-limiting toxicities, drug-related deaths, or evidence of synergistic toxicities between motolimod and cetuximab. Clinical tolerability at the 3.5 mg/m2 dose level was not optimal for repeated dosing and 3.0 mg/m2 was identified as the MTD. Two patients achieved partial responses for an overall response rate of 15%. Five patients had disease stabilization equating to a disease control rate of 54%. Statistically significant increases in plasma cytokines and in the frequency and activation of circulating NK cells were observed.Conclusions: Motolimod can be safely administered in combination with cetuximab with an acceptable toxicity profile. Encouraging antitumor activity and robust pharmacodynamic responses were observed. Motolimod is being further investigated in a phase II trial in patients with SCCHN (ClinicalTrials.gov ID: NCT01836029). Clin Cancer Res; 23(10); 2442-50. ©2016 AACR.

Assessment of Emergency Department Eye Examinations in Patients Presenting with Mid-Face Injury.

BACKGROUND: One-fifth of patients with severe facial trauma suffer ophthalmic injury. Currently, patients presenting with mid-face injury to the emergency department (ED) undergo visual examination and then further assessment by ophthalmologists and with computed tomography (CT) scanning. The utility of the initial visual examination in the ED, performed by nonophthalmologists, remains unclear. OBJECTIVE: We aimed to objectively identify whether a more thorough initial visual assessment, performed by nonophthalmologists in the ED, was associated with improved ophthalmic outcomes. METHODS: Patients (n = 100) were retrospectively recruited from a tertiary craniomaxillofacial center. Visual examinations performed in the ED were scored objectively and measured against defined management and prognostic outcomes. RESULTS: There was no significant difference between more thorough initial visual examination and reduced time to ophthalmology assessment or reduced visual complications. There was no correlation between more comprehensive examination and incidence of CT scanning. CONCLUSIONS: We identified no significant difference between a comprehensive visual examination performed by nonophthalmologists in the ED, and improved ophthalmic outcomes. Physicians assessing patients with mid-face trauma in the ED should rule out eye emergencies, including retrobulbar hemorrhage and penetrating globe injury, and initiate expeditious CT scan and assessment by specialist ophthalmologists.