Citations

ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell‐released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV‐associated functional activities. Finally, a checklist is provided with summaries of key points.

Abstract Background: The GALAD score is a serum biomarker–based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison with liver ultrasound for detection of HCC. Methods: A single-center cohort of 111 HCC patients and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) phase II HCC Study were analyzed. Results: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI), 0.93–97], which was higher than the AUC of ultrasound (0.82, P <0.01). At a cutoff of −0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early-stage HCC detection remained high at 0.92 (95% CI, 0.88–0.96; cutoff −1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85–0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single-center cohort, achieving an AUC of 0.98 (95% CI, 0.96–0.99; cutoff −0.18, sensitivity 95%, specificity 91%). Conclusions: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score. Impact: The GALAD score was validated in the United States.

Purpose: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. Methods: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. Results: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. Conclusion: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

Abstract Background Early phase clinical trials evaluate the safety and efficacy of new treatments. The exclusion/inclusion criteria in these trials are usually rigorous and may exclude many patients seen in clinical practice. Our objective was to study the comorbidities limiting the participation of patients with breast, colorectal, or lung cancer in clinical trials. Materials and Methods We queried ClinicalTrials.gov on December 31, 2016. We reviewed the eligibility criteria of 1,103 trials. Logistic regression analyses were completed, and exclusion was studied as a binary variable. Results Out of 1,103 trials, 70 trials (6%) excluded patients >75 years of age, and 45% made no reference to age. Eighty-six percent of trials placed restrictions on patients with history of prior malignancies. Regarding central nervous system (CNS) metastasis, 416 trials (38%) excluded all patients with CNS metastasis, and 373 (34%) only allowed asymptomatic CNS metastasis. Regarding chronic viral infections, 347 trials (31%) excluded all patients with human immunodeficiency virus, and 228 trials (21%) excluded all patients with hepatitis B or C infection. On univariate analysis, chemotherapy trials were more likely to exclude patients with CNS metastasis and history of other malignancies than targeted therapy trials. Multivariate analysis demonstrated that industry-sponsored trials had higher odds of excluding patients with compromised liver function. Conclusion Many clinical trials excluded large segments of the population of patients with cancer. Frequent exclusion criteria included patients with CNS metastasis, history of prior malignancies, and chronic viral infections. The criteria for participation in some clinical trials may be overly restrictive and limit enrollment. Implications for Practice The results of this study revealed that most early phase clinic trials contain strict exclusion criteria, potentially excluding the patients who may be more likely to represent the population treated in clinical settings, leaving patients susceptible to unintended harm from inappropriate generalization of trial results. Careful liberalization of the inclusion/exclusion criteria in clinical trials will allow investigators to understand the benefits and drawbacks of the experimental drug for a broader population, and possibly improve recruitment of patients with cancer into clinical trials.

Objectives: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. Materials and Methods: Patients received gemcitabine 1000 mg/m² intravenously on days 1 and 8, capecitabine 1300 mg/m² oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle. The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. Results: A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. Conclusions: Dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.

SummaryBackgroundWell informed patients who are in cohesive partnership with physicians and who have realistic expectations towards therapy are more likely to be adherent, which results in better disease control.AimTo assess which therapy goals adults with eosinophilic oesophagitis consider relevant.MethodsFollowing refinement during three focus groups, a study brochure and questionnaire were sent to 148 patients. Patients ranked the importance (five levels) of short‐term (in the next 3 months) and long‐term (≥1 year) treatment effect on symptoms, quality of life (QoL), histologically‐detected inflammation and fibrosis, endoscopically‐detected inflammation, and stricture formation as well as achieving histological remission while asymptomatic. Patients’ characteristics associated with treatment goals were identified using logistic regression.ResultsOf 109 respondents (mean age 43 years), 85 were men. Over 90% chose symptoms and QoL improvement as important short‐ and long‐term therapy goals. A greater proportion attributed more importance to long‐term reduction in endoscopic (90% vs 73%, P < 0.001) and histological (81% vs 62%, P = 0.002) inflammation, and histologically‐detected fibrosis (79% vs 64%, P = 0.018) when compared to short‐term reduction in these features. Patients (88%) ranked achieving histological remission while being asymptomatic as important. Gender, therapy use, education level, QoL, symptom severity, and history of dilation were associated with patients’ choice of treatment goals.ConclusionsPatients attributed most importance to improvement in symptoms and QoL. Reduction in biological activity was judged less important, but more relevant in the long‐ compared to the short‐term.

Abstract. Acute limb ischemia (ALI), a subclass of critical limb ischemia, is a medical emergency. The cause of ALI is usually thrombotic or embolic in nature, and the specific etiology often dictates the appropriate therapy. While the diagnosis is a clinical with common presenting symptoms, advances in ultrasound, computed tomography, and magnetic resonance technology have impacted the diagnosis and subsequent therapy. In ALI, the time to revascularization is critical and computed tomography angiography (CTA) provides a highly sensitive and specific technique for rapidly identifying occlusions and precisely defining vascular anatomy prior to interventions. In patients with significant renal disease, magnetic resonance angiography with or without contrast provides effective alternatives at the expense of imaging time. Treatment can include a variety of endovascular or surgical interventions, including thromboembolectomy, angioplasty, or bypass. Proper evaluation of the etiology of the ischemia, affected vasculature, and medical history is critical to select appropriate treatment and improve patient outcomes. Here, we examine the presentation, evaluation, and treatment of ALI and the role of CTA in diagnosis and therapy.