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Adalimumab, a tumor necrosis factor-α inhibitor, is a biologic used for the treatment of moderate-to-severe hidradenitis suppurativa (HS). It is well known that patients may experience loss of efficacy from its use in other conditions, and it is suggested that developing a strategy for therapeutic drug monitoring (TDM) may help secure optimal clinical outcomes. We sought to determine serum adalimumab concentrations and anti-adalimumab antibody (AAA) status in patients with moderate-to-severe HS. A retrospective case series of 38 patients with suboptimal response to adalimumab 40 mg weekly was conducted at a community dermatology clinic. Adalimumab serum trough levels, AAA status, and inflammatory biomarkers were collected. Blood was drawn on identification of suboptimal response (after a minimum of 12 weeks) and was collected once prior to receiving the next scheduled dose. Kruskal–Wallis and Chi-squared tests were used for data analysis. A total of 38 patients had a median adalimumab trough concentration of 8.76 (interquartile range [IQR] 1.3–12.5) µg/mL. The median duration of adalimumab therapy of all patients was 21 (IQR 12–24) months. AAAs were detected in nine patients (24%), and all had subtherapeutic serum concentrations (

Background Esophageal strictures are the common gastrointestinal complications in patients with epidermolysis bullosa (EB) requiring dilation. There is limited information on the best type of intervention, outcomes, and predictors for re-stenosis. Objectives We aimed to investigate the frequency, clinical presentation of esophageal strictures in EB patients, and to ascertain the predictors of re-stenosis. Methods We conducted a retrospective, multicenter cohort study involving 7 specialized, international EB centers on patients who were 0 to 50 years of age. Descriptive statistics and hazard risks for re-stenosis were calculated. Results We identified 125 patients with 497 esophageal stricture episodes over a mean period of observation of 17 (standard deviation [SD] = 11.91) years. Dilations were attempted in 90.74% of episodes, using guided fluoroscopy 45.23%, retrograde endoscopy 33.04%, and antegrade endoscopy 19.07%. Successful dilation was accomplished in 99.33% of attempts. Patients experienced a median of 2 (interquartile range [IQR]: 1-7) stricture episodes with a median interval between dilations of 7 (IQR: 4-12) months. Predictors for re-stenosis included: number of strictures (2 vs 1 stricture: χ = 4.293, P = 0.038, hazard ratio [HR] = 1.294 (95% confidence interval [CI]: 1.014--1.652 and 3 vs 1 stricture:χ = 7.986, P = 0.005, HR = 1.785 [95% CI: 1.194, 2.667]) and a long (≥1 cm) segment stricture (χ = 4.599, P = 0.032, HR = 1.347 (95% CI: 1.026--1.769). Complications were more common with the endoscopic approach (8/86, antegrade endoscopy; 2 /149, retrograde endoscopy vs 2/204, fluoroscopy; χ = 17.39, P-value Conclusions We found excellent dilation outcomes irrespective of the dilation procedure; however, with higher complications in the endoscopic approach. Long (>1 cm) segment involvement and multiple locations were predictive of stricture reoccurrence.

Objective: The aim of this systematic review was to identify patient-reported outcome (PRO) instruments used in research with children/youth with conditions associated with facial differences to identify the health concepts measured. Design: MEDLINE, EMBASE, CINAHL, and PsycINFO were searched from 2004 to 2016 to identify PRO instruments used in acne vulgaris, birthmarks, burns, ear anomalies, facial asymmetries, and facial paralysis patients. We performed a content analysis whereby the items were coded to identify concepts and categorized as positive or negative content or phrasing. Results: A total of 7,835 articles were screened; 6 generic and 11 condition-specific PRO instruments were used in 96 publications. Condition-specific instruments were for acne (four), oral health (two), dermatology (one), facial asymmetries (two), microtia (one), and burns (one). The PRO instruments provided 554 items (295 generic; 259 condition specific) that were sorted into 4 domains, 11 subdomains, and 91 health concepts. The most common domain was psychological (n = 224 items). Of the identified items, 76% had negative content or phrasing (e.g., “Because of the way my face looks I wish I had never been born”). Given the small number of items measuring facial appearance (n = 19) and function (n = 22), the PRO instruments reviewed lacked content validity for patients whose condition impacted facial function and/or appearance. Conclusions: Treatments can change facial appearance and function. This review draws attention to a problem with content validity in existing PRO instruments. Our team is now developing a new PRO instrument called FACE-Q Kids to address this problem.

The requirement for bone-marrow aspirates for genomic profiling of multiple myeloma poses an obstacle to enrolment and retention of patients in clinical trials. We evaluated whether circulating cell-free DNA (cfDNA) analysis is comparable to molecular profiling of myeloma using bone-marrow tumour cells. We report here a hybrid-capture-based Liquid Biopsy Sequencing (LB-Seq) method used to sequence all protein-coding exons of KRAS, NRAS, BRAF, EGFR and PIK3CA in 64 cfDNA specimens from 53 myeloma patients to >20,000 × median coverage. This method includes a variant filtering algorithm that enables detection of tumour-derived fragments present in cfDNA at allele frequencies as low as 0.25% (median 3.2%, range 0.25–46%). Using LB-Seq analysis of 48 cfDNA specimens with matched bone-marrow data, we detect 49/51 likely somatic mutations, with subclonal hierarchies reflecting tumour profiling (96% concordance), and four additional mutations likely missed by bone-marrow testing (>98% specificity). Overall, LB-Seq is a high fidelity adjunct to genetic profiling of bone-marrow in multiple myeloma., Genetic profiling of multiple myeloma requires painful bone marrow biopsies. Here, the authors develop an alternative non-invasive method for sequencing of five oncogenes in circulating cell-free DNA from myeloma patients, demonstrating 96% concordance with bone marrow tumour profiling results.

The use of liquid biopsies for cancer detection and management is rapidly gaining prominence1. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations2–5. By contrast, large-scale epigenetic alterations—which are tissue- and cancer-type specific—are not similarly constrained6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns. An immunoprecipitation-based protocol is developed to analyse DNA methylation in small quantities of circulating cell-free DNA, and can detect and classify cancers in plasma samples from several tumour types.

Background Congenital morphea is a form of localized scleroderma that presents at birth. There is limited information on its presentation and progression. Methods Patients with congenital morphea were identified from five pediatric dermatology and rheumatology tertiary care centers in Canada, the United States, and Italy from 2001 to 2016. Cases from the literature were identified by searching Ovid (EMBASE and MEDLINE) from inception to June 30, 2017. Disease characteristics and prevalence of extracutaneous involvement were analyzed. Results Thirteen patients were identified from the five centers, and 13 cases were described in the literature, representing 25 patients, with one duplication. Fourteen patients (56%) were female. Median age at diagnosis was 2.9 years (interquartile range 1.2-5.1 years). Linear morphea, including en coup de sabre and Parry-Romberg syndrome, was the most common subtype observed (n = 19, 76%), followed by circumscribed (n = 5, 20%), generalized (n = 2, 8%), and mixed (n = 2, 8%). The face (n = 14, 56%), scalp (n = 8, 32%), and trunk (n = 6, 24%) were the most common locations affected. Most lesions were active at diagnosis (n = 19, 76%), but all patients with follow-up later became inactive. Extracutaneous involvement was seen in 12 (48%) patients, all of whom had linear morphea. Musculoskeletal sequelae were seen in those with linear morphea of the extremities (4/5, 80%), and neurologic involvement was seen in those with linear morphea of the head (8/13, 62%). Conclusion Congenital morphea is associated with extracutaneous manifestations and delayed diagnosis. More research is needed to determine whether early recognition, monitoring, and treatment can alter the disease course.

Objectives In recent years, great progress has been made in the development of diagnostic tools, therapeutic approaches, and validated outcome measures in the understanding of the pathogenesis of ankylosing spondylitis (AS). The purpose of this review was to summarize these developments. Methods We performed a PubMed search for the period 1978 to 2005, using the keyword, "ankylosing spondylitis," resulting in a total of 4878 publications, including 778 reviews. Articles were then selected based on their discussion of recent diagnostic tools and new treatment approaches in the pathogenesis of AS, leading to a final total of 104 articles. Results In recent years, there have been 2 major developments in the management of AS that make earlier diagnosis possible and offer the hope of alleviating pain and preventing structural changes that result in loss of function. These developments include the use of magnetic resonance imaging to visualize the inflammatory changes in the sacroiliac joint and the axial spine, and the demonstration that tumor necrosis factor blocking agents are highly efficacious in reducing spinal inflammation and possibly in slowing radiographic progression. Conclusions There have been major advances in both the diagnostic tools and the therapeutic regimens available for patients with AS.

Although the Codex Allmentarius Commission has functioned as part of the United Nations Food and Agriculture Organization since 1962, its activities have been of little more than occasional interest until recent years. However, with the advent of the World Trade Organization (WTO) and the establishment of the North American Free Trade Agreement (NAFTA) and other trading blocs, the dellberations of Codex have become significantly more important to the international trade interests of government and industry groups alike. Increased interest in the elaboration of Codex standards, guidelines, and recommendations may be attributed to increased International awareness of 2 very practical functions of the Commission and its numerorts committees. First, some countries have become aware that the guldance and information needed to fill in their own regulatory gaps are often made available in the Codex. Second, multinational corporations and trade association have become aware of the role that Codex has been given in the WTO agreements as the means by which dispates over trade in food products may be resolved. Increased awareness of the practical function of Codex activites in shaping national legislation and establishing loternational trade standards appears to have strengthened Codex's role as the focal point of efforts to achieve internationaly harmonized food standards. However, many international regulatory gaps show signs of being filled by legislation that imposes burdens on industry without demonstrable benefits to public welfare. In their most troublesome manifestations, some of these measures, especially recent regulations concerning biotech food labelding, could be viewed as technical barriers to trade.

Background: Genome sequencing of multiple myeloma (MM) tumors has revealed recurrent mutations that serve as a fertile ground for targeted therapies. Indeed, activating mutations of KRAS, NRAS and BRAF have been reported in approximately 27%, 24% and 4% of MM cases. Based on this observation, we initiated a Phase II NCI-CTEP sponsored clinical trial of trametinib in patients with MM (PHL-9460). Detection of mutations currently require bone marrow aspirates that are invasive and can yield suboptimal samples. Targeted, ultra-deep sequencing of circulating tumor DNA (ctDNA) is a promising tool for accessing the tumor genome that has not been well studied in MM. We set out to determine the feasibility of detecting ctDNA in MM and of identifying actionable mutations and mutational load using liquid biopsy through ctDNA analysis. Methods: MM patients enrolled onto PHL-9460 or those with heavy tumor burden were identified and consented to have their peripheral blood drawn for analysis. Where possible, matched tumor DNA was also obtained. Cell-free DNA was extracted from 7-15 mL of plasma isolated within ¬1 hour of blood draw using the QIAamp Circulating Nucleic Acid Kit and tagged with barcoded sequencing adapters for subsequent pooling. All exons of KRAS, NRAS, BRAF, PIK3CA and EGFR genes were isolated using a custom hybrid capture panel (IDT xGen Lockdown) and sequenced on an Illumina HiSeq 2000. Reads were aligned to the human genome reference (hg19) using bwa and somatic mutations were detected using muTect. Results: We have collected 25 samples from 23 patients, 7 from patients on PHL-9460, 5 newly diagnosed, and 13 from relapsed patients having received 3.3 median prior lines of therapy (range 1-7). To date, 11 samples from 10 patients have been sequenced. The sample with the lowest DNA yield failed due to low library complexity (range 16.6-3872 ng, median yield: 197 ng). From the remaining 10 samples, the mean target coverage ranged from 31,500 to 32,500. Somatic mutations in KRAS, NRAS, or PIK3CA genes were present in 5 of 9 patients with mutant allele frequencies ranging from 1.1% to 32% (3 KRAS and 2 NRAS of which 2 cases also had a low frequency PIK3CA mutation). We did not uncover mutations in BRAF or EGFR. For patients with matched tumor DNA, mutations in ctDNA concurred with those found in tumor DNA sequencing (4 of 4 tumors with known genotypes). Two patients with NRAS mutations enrolled onto PHL-9460 have responded to trametinib (1 partial and 1 minor response) and remain on therapy. Conclusion: ctDNA analysis in this cohort has identified key mutations in MM. The rate of RAS or RAF mutations in ctDNA compared to matched tumors and correlation to response to trametinib is ongoing and will be presented. Preliminary data suggest that ctDNA may be a reliable method of detecting mutations in MM and an alternative to bone marrow biopsy. Citation Format: Rayan Kaedbey, Olena Kis, Arnavaz Danesh, Mark Dowar, Tiantian Li, Zhihua Li, Jessica Liu, Mark Mansour, Mahadeo Sukhai, Tong Zhang, Suzanne Kamel-Reid, Trevor J. Pugh, Suzanne Trudel. Noninvasive diagnosis of actionable mutations by deep sequencing of circulating tumor DNA in multiple myeloma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 615. doi:10.1158/1538-7445.AM2015-615

Biotechnology has the potential to meet the ever-increasing demand for enhanced food production. However, several factors besides scientific and agricultural advances can disrupt the progress of this field. This article reviews the interactions between political, regulatory, international, activist, consumer, and scientific entities. A discussion of the precautionary principle is included.