Twenty-first Century Trends in the Global Epidemiology of Pediatric-Onset Inflammatory Bowel Disease: Systematic Review.

BACKGROUND & AIMS: The incidence of inflammatory bowel disease (IBD) is increasing internationally, particularly in nations with historically low rates. Previous reports of the epidemiology of pediatric-onset IBD identified a paucity of data. We systematically reviewed the global trends in incidence and prevalence of IBD diagnosed in individuals <21 years old over the first 2 decades of the 21st century. METHODS: We systematically reviewed studies indexed in MEDLINE, EMBASE, Airiti Library, and SciELO from January 2010 to February 2020 to identify population-based studies reporting the incidence and/or prevalence of IBD, Crohn's disease, ulcerative colitis, and/or IBD-unclassified. Data from studies published before 2000 were derived from a previously published systematic review. We described the geographic distribution and trends in children of all ages and limiting to very early onset (VEO) IBD. RESULTS: A total of 131 studies from 48 countries were included. The incidence and prevalence of pediatric-onset IBD is highest in Northern Europe and North America and lowest in Southern Europe, Asia, and the Middle East. Among studies evaluating trends over time, most (31 of 37, 84%) studies reported significant increases in incidence and all (7 of 7) reported significant increases in prevalence. Data on the incidence and prevalence of VEO-IBD are limited to countries with historically high rates of IBD. Time trends in the incidence of VEO-IBD were visually heterogeneous. CONCLUSIONS: Rates of pediatric-onset IBD continue to rise around the world and data are emerging from regions where it was not previously reported; however, there remains a paucity of data on VEO-IBD and on pediatric IBD from developing and recently developed countries.

Understanding and Responding to the Impact of COVID-19 on Paediatric Gastroenterology Training & Practice of Young ESPGHAN Members.

OBJECTIVES: Limited data exist about the impact of the coronavirus disease 2019 (COVID-19) pandemic on the training and clinical practice of young doctors. The aim of this study was to evaluate the impact on paediatric gastroenterologists in training posts during the first wave of the European COVID pandemic. METHODS: All Young members of European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) (YE) members received a multiple-choice questionnaire concerning the impact (if any) on their clinical practice, mental health, quality of care provided and fellowship/training experience. The survey was conducted between May 22, 2020 and June 10, 2020. RESULTS: Of the 144 responders (40% of YE members), 85% (n = 123) reported an impact of COVID-19. Ninety-six percent reported an impact on their clinical practice, including more virtual patient consultation (n = 91), underutilization of ambulatory care (n = 113) and reduced or lack of planned admissions (n = 75). Endoscopy restrictions to semi-urgent or emergency cases were reported in 82 and lack of medical equipment/drugs (n = 47) were also reported.Reported adverse mental health issues included poor concentration, increased stress levels, an impact on family life in 62% and a reduced quality of care in 45%; this was more often reported in doctors from Southern Europe (54%) than in those from other geographical areas.Seventy-seven percent reported an impact on the content of their fellowship, including lack of participation in national/international meetings, withdrawn research time and limited mentoring. CONCLUSIONS: The impact of the COVID-19 pandemic has been shown to affect the clinical practice, training and mental health of YE members. Adaptations of training programmes and targeted strategies to improve the clinical practice of young practitioners are needed and proposed in this manuscript.

Transition Services for Paediatric Inflammatory Bowel Disease: A Multicentre Study of Practice in the United Kingdom.

OBJECTIVES: Patients with paediatric inflammatory bowel disease (IBD) constitute one of the largest cohorts requiring transition from paediatric to adult services. Standardised transition care improves short and long-term patient outcomes. This study aimed to detail the current state of transition services for IBD in the United Kingdom (UK). METHODS: We performed a nationwide study to ascertain current practice, facilities and resources for children and young people with IBD. Specialist paediatric IBD centres were invited to contribute data on: timing of transition/transfer of care; transition resources available including clinics, staff and patient information; planning for future improvement. RESULTS: Twenty of 21 (95%) of invited centres responded. Over 90% of centres began the transition process below 16 years of age and all had completed transfer to adult care at 18 years of age. The proportion of patients in the transition process at individual centres varied from 10% to 50%.Joint clinics were held in every centre, with a mean of 12.9 clinics per year. Adult and paediatric gastroenterologists attended at all sites. Availability of additional team members was patchy across the UK, with dietetic, psychological and surgical attendance available in <50% centres. A structured transition tool was used in 75% of centres. Sexual health, contraception and pregnancy were discussed by <60% of teams. CONCLUSIONS: This study provides real-world clinical data on UK-wide transition services. These data can be used to develop a national strategy to complement current transition guidelines, focused on standardising services whilst allowing for local implementation.

From Paris to Montreal: disease regression is common during long term follow-up of paediatric Crohn's disease.

Introduction: Paediatric Crohn's disease (PCD) often presents with extensive and a frequent pan-enteric phenotype at onset. However, its long term evolution into adulthood, especially since the widespread use of biological agents, is not well characterised. We conducted a single centre cohort study of all PCD patients transitioned to adult care to assess the long term disease evolution in the era of biologic therapy.Methods: We conducted a retrospective observational, study of all PCD patients who were subsequently transferred to the care of an adult gastroenterology unit and had a minimum follow up of 2 years. We examined the case notes for evolution of disease location and behaviour. Disease location and behaviour was characterised using Paris classification at diagnosis and Montreal classification at last follow-up. In addition, we examined variables associated with complicated disease behaviour and the need for CD related intestinal resection.Results: In total, 132 patients were included with a median age at diagnosis of 13 (IQR 11-14) and a median follow up of 11 years (range 4-14). At diagnosis, 23 (17.4%), 39 (29.6%) and 70 (53%) patients had ileal, colonic and ileocolonic disease respectively. In addition, 31 (23.5%) patients had L4a or L4b disease at diagnosis (proximal or distal to the ligament of treitz respectively) and 13 patients (9.8%) had both whilst 27 (20.4%) patients had perianal disease. At diagnosis, 27 (20.4%) patients had complicated disease behaviour but 83 (62.9)% of patients had an extensive 'pan-enteric' phenotype. Of these patients only 55 (66.3%) retained the pan-enteric phenotype at last follow-up (p = .0002). Disease extension was noted in 25 (18.9%) of patients and regression was noted in 47 (35.6%) of patients, whereas upper GI disease was noted in significantly fewer patients at last follow-up (21, 15.9%) (p = .0001). More patients had complicated disease behaviour (46 patients, 34.9%, p = .0018) at last follow-up. There was a high exposure to both thiopurines 121 (91.7%) and biologics 84 (63.6%). The cumulative probability (95% CI) of surgery was 0.05 (0.02, 0.11) at 1 year, 0.17 (0.11, 0.24) at 3 years and 0.22 (0.15, 0.30) at 5 years. Neither disease location nor behaviour were associated with the need for intestinal resectional surgery.Conclusions: Over the course of an extended follow-up period, there appeared to be changes in both disease location and behaviour in PCD. Interestingly, a significant proportion of patients had disease involution which may be related to a high rate of exposure to thiopurines and biologics. We were unable to identify any variables associated with complicated disease course or the need for intestinal surgery.

Disease Status and Pubertal Stage Predict Improved Growth in Antitumor Necrosis Factor Therapy for Pediatric Inflammatory Bowel Disease.

BACKGROUND: Growth failure is well-recognized in pediatric inflammatory bowel disease (PIBD; <18 years). We aimed to examine whether antitumor necrosis factor (TNF) therapy improves growth in a PIBD population-based cohort. METHODS: A retrospective review of all Scottish children receiving anti-TNF (infliximab [IFX] and adalimumab [ADA]) from 2000 to 2012 was performed; height was collected at 12 months before anti-TNF (T-12), start (T0), and 12 (T+12) months after anti-TNF. RESULTS: Ninety-three of 201 treated with IFX and 28 of 49 with ADA had satisfactory growth data; 66 had full pubertal data. Univariate analysis demonstrated early pubertal stages (Tanner 1-3 n = 44 vs T4-5 n = 22), disease remission, disease duration ≥2 years, and duration of IFX ≥12 months were associated with improved linear growth for IFX; for ADA only improvement was seen in Tanner 1-3. For IFX, Tanner 1-3 median Δ standard deviation scores for height (Ht SDS) -0.3 (-0.7, 0.2) at T0 changed to 0.04 (-0.5, 0.7) at T+12 (P < 0.001) versus -0.01 (-0.5, 0.9) at T0 in T4-5 changed to -0.01 (-0.4, 0.2) at T+12 (P > 0.05). For IFX disease duration ≥2 year, median Δ Ht SDS was -0.13 (-0.6, 0.3) at T0 then 0.07 (-0.3, 0.6) at T+12 (P < 0.001). Remission improved Δ Ht SDS (median Δ Ht SDS -0.14 [-0.6, 0.3] at T0 to 0.17 [-0.2, 0.7] at T+12 [P < 0.001]). Multiple regression analysis demonstrated corticosteroid usage at T0 predicted improved Δ Ht SDS at T+12 for IFX and ADA. CONCLUSIONS: Anti-TNF therapy is more likely to be associated with growth improvement when used at earlier stages of puberty with remission a key growth-promoting strategy in pediatric Crohn disease.

A structural investigation of ionic liquid mixtures.

The structures of mixtures of ionic liquids (ILs) featuring a common 1-butyl-3-methylimidazolium ([C4C1im](+)) cation but different anions have been investigated both experimentally and computationally. (1)H and (13)C NMR of the ILs and their mixtures has been performed both on the undiluted liquids and those diluted by CD2Cl2. These experiments have been complemented by quantum chemical density functional theory calculations and molecular dynamics simulations. These techniques have identified the formation of preferential interactions between H(2) of the imidazolium cation and the most strongly hydrogen bond (H-bond) accepting anion. In addition, a preference for the more weakly H-bond accepting anion to interact above the imidazolium ring through anion-π(+) interactions has been identified. The modelling of these data has identified that the magnitude of these preferences are small, of the order of only a few kJ mol(-1), for all IL mixtures. No clustering of the anions around a specific cation could be observed, indicating that these interactions arise from the reorientation of the cation within a randomly assigned network of anions. π(+)-π(+) stacking of the imidazolium cations was also studied and found to be promoted by ILs with a strong H-bond accepting anion. Stacking interactions are easily disrupted by the introduction of small proportions (<50 mol%) of a weakly coordinating anion due to their propensity to form anion-π(+) interactions. These results suggest that the formation of IL mixtures with different anions leads to subtle structural changes of much lower energy than the Coulombic ordering of ions, accounting for why most IL mixtures exhibit ideal, or nearly ideal, behaviour.

Pediatric Inflammatory Bowel Disease Type Unclassified: A Nationwide Cohort Study in Scotland With up to 20 Years Follow-up Shows Reclassification in the Majority and Mild Course in Those Whose Diagnosis Is Unchanged.

BACKGROUND: Given the paucity of long-term longitudinal data for inflammatory bowel disease type unclassified (IBDU), we aimed to clarify IBDU disease course and reclassification rate by presenting nationwide data with up to 20 years of follow-up. METHODS: We analyzed a prospectively identified 11-year cohort of pediatric patients diagnosed with IBDU between January 1, 2003 and December 31, 2013 at all Scottish pediatric IBD centers and followed up into adult services until December 31, 2022. Data were obtained from electronic medical records at fixed timepoints (5 and 10 years post-diagnosis) and at the final follow-up. RESULTS: Overall, 102 patients were included in the analysis (57/102 [56%] male, median [interquartile range {IQR}] age at diagnosis: 11.5 [9.1-13.2] years) with a median (IQR) follow-up length of 10.5 (8.6-14.0) years. A change of diagnosis was made in 61 of 102 patients (60%); of these, 30 patients (29%) were reclassified to Crohn's disease (CD) and 31 patients (30%) to ulcerative colitis (UC). Patients who remained with IBDU had higher 1- to 5-year remission rates (IBDU 30/39 [77%] vs reclassified 16/57 [28%], P < .05), with lower rates of moderate-to-severe disease (IBDU 3/39 [8%] vs reclassified 31/57 [54%], P < .05) and less need for biologics across all timepoints (IBDU vs reclassified: first timepoint 1/39 [3%] vs 17/57 [30%], second timepoint 1/33 [3%] vs 26/56 [46%], third timepoint 0/18 [0%] vs 16/33 [49%]; all P < .05). Higher rates of surgical resections were observed in reclassified patients (reclassified 11/61 [18%] vs IBDU 1/41 [2%], P = .02). CONCLUSIONS: In our nationwide pediatric IBDU cohort, 60% of patients were reclassified to either UC or CD over 10.5 years of median follow-up; those who remained with IBDU had a milder disease course.

We present a nationwide cohort of pediatric patients with inflammatory bowel disease unclassified with up to 20 years of follow-up, showing that 60% of patients were reclassified to either Crohn's disease or ulcerative colitis. Those whose diagnosis remained unchanged had a milder disease course.

Improved clinical outcomes with early anti-tumour necrosis factor alpha therapy in children with newly diagnosed Crohn's disease: real world data from the international prospective PIBD-SETQuality inception cohort study.

BACKGROUND & AIMS: Treatment guidelines for paediatric Crohn's disease (CD) suggest early use of anti-tumour necrosis factor alpha (anti-TNF) in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. METHODS: Children with newly-diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF (<90 days after diagnosis) and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission (SSFR) without treatment intensification (specified as SSFR*) and sustained steroid-free mild/inactive disease without treatment intensification (specified as SSFMI*). Penalised logistic regression model-based standardisation was applied to estimate the relative risks (RR) of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients based on presence of predictors of poor outcome (POPOs) and disease activity at diagnosis. RESULTS: In total, 331 children (median age 13.9 years [IQR 12.2 - 15.3]) were enrolled, with 135 (41%) receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* (30% vs. 14%, p<0.001) and SSFMI* (69% vs. 33%, p<0.001), with RRs of 2.95 (95%CI 1.63-5.36) and 4.67 (95%CI 2.46-8.87) respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared to mild/inactive disease at diagnosis (5.50 [95%CI 2.51-12.05]) vs. 2.91 [95%CI 0.92-9.11]), and those with any POPO compared to no POPO (5.05 [95%CI 2.45-10.43] vs. 3.41 [95%CI 0.54-21.7]). CONCLUSION: In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.

Homecoming-Dignity Through Movement at the End of Life: A Qualitative Interview Study With Healthcare Professionals.

AIM: To describe healthcare professionals' and volunteers' experiences of a pathway for movement on a hospice ward. METHOD: This was a qualitative study with an inductive approach. Data were collected in a hospice setting through 4 focus group interviews with healthcare professionals and volunteers (n = 12). The focus group participants varied in age, profession, and length of experience in palliative care. The interviews were audio recorded, transcribed and analyzed with qualitative content analysis. RESULTS: Dignity through movement at the end of life was the main theme, complemented by 4 sub-themes. Two descriptive sub-themes: "A practical tool to facilitate physical activity" and "Companionship and goals give meaning to the day," and 2 interpretative sub-themes: "Regaining control and having a choice" and "Feeling normal and alive" based on participants' views of patient experiences. SIGNIFICANCE OF RESULTS: Indications are that the pathway for movement addresses a wide range of experiences related to different aspects of being human in a difficult situation. Experiences of movement and physical activity can promote wellbeing, dignity, and a sense of feeling "at home" for patients within hospice care. The pathway for movement is simple to set up, offers access to appropriate physical activity and seems to benefit patients both in the early and later phases of palliative care.

A national survey of pain clinics within the United Kingdom and Ireland focusing on the multidisciplinary team and the incorporation of the extended nursing role.

Inconsistencies in the availability and quality of pain service provision have been noted nationally, as have lengthy waiting times for appointments and lack of awareness of the Pain Clinic role. The 2013 NHS England report stated that specialist pain services must offer multispecialty and multidisciplinary pain clinics. This national survey of multidisciplinary pain service provision in the United Kingdom and Ireland provides a snapshot of pain service provision in order to review and highlight what variations exist in multidisciplinary team (MDT) provision and working patterns. A common perception among clinicians is that financial pressures have led to alternate ways of staff utilisation with variable degrees of success. The survey included 143 pain clinics, focusing principally on MDT working patterns, MDT composition and adoption of the extended role. The results identified that the majority of Pain Clinics utilise the MDT approach. However, provision of critical components such as regular MDT meetings is highly variable as is the composition of the MDT itself and also working patterns of the individual clinicians. The survey reports the successful use of the extended roles for specialist nurses in follow up clinics. In contrast, the survey highlights that a large proportion of clinicians surveyed have reservations about both the effectiveness and the safety of utilising specialist nurses in the extended role to see new referrals of complex pain patients to pain clinics. This survey underlines the essential requirement for incorporation of greater MDT working locally and nationally and allocation of appropriate resources to facilitate this.

Production and release testing of ovine atadenovirus vectors.

Gene-directed enzyme prodrug therapy (GDEPT) is an emerging approach for the treatment of cancers. A variety of viral vectors have been used to deliver genes that encode the relevant enzymes, and some have been tested in clinical trials. To ensure the potency and efficacy of such vectors and to obtain regulatory approval to administer them to humans, it is necessary to develop a suite of assays that provide quality assurance. New GDEPT vectors based on ovine atadenovirus and Escherichia coli purine nucleoside phosphorylase (PNP) have been developed for first time use in humans in a phase I trial for the treatment of prostate cancer. Here we describe methods for their production together with several quality-control assays. In particular, a functional cell killing assay was devised to measure the potency of PNP-GDEPT vectors, the principles of which could easily be adapted to other systems.

Development and Validation of Diagnostic Criteria for IBD Subtypes Including IBD-unclassified in Children: a Multicentre Study From the Pediatric IBD Porto Group of ESPGHAN.

BACKGROUND: The revised Porto criteria identify subtypes of paediatric inflammatory bowel diseases: ulcerative colitis [UC], atypical UC, inflammatory bowel disease unclassified [IBDU], and Crohn's disease [CD]. Others have proposed another subclassifiction of Crohn's colitis. In continuation of the Porto criteria, we aimed to derive and validate criteria, termed "PIBD-classes," for standardising the classification of the different IBD subtypes. METHODS: This was a multicentre retrospective longitudinal study from 23 centres affiliated with the Port -group of ESPGHAN. Both a hypothesis-driven judgmental approach and mathematical classification and regression tree [CART] modelling were used for creating a diagnostic algorithm. Since small bowel inflammation is easily recognised as CD, we focused here primarily on the phenotype of colitis. RESULTS: In all, 749 IBD children were enrolled: 236 [32%] Crohn's colitis, 272 [36%] UC and 241 [32%] IBDU [age 10.9 ± 3.6 years] with a median follow-up of 2.8 years (interquartile range [IQR] 1.7-4.3). A total of 23 features were clustered in three classes according to their prevalence in UC: six class-1 features [0% prevalence in UC], 12 class-2 features [< 5% prevalence], and five class-3 features [5-10% prevalence]. According to the algorithm, the disease should be classified as UC if no features exist in any of the classes. When at least one feature exists, different combinations classify the disease into atypical UC, IBDU or CD. The algorithm differentiated UC from CD and IBDU with 80% sensitivity (95% confidence interval [CI] 71-88%) and 84% specificity [77-89%], and CD from IBDU and UC with 78% sensitivity [67-87%] and 94% specificity [89-97%]. CONCLUSIONS: The validated PIBD-classes algorithm can adequately classify children with IBD into small bowel CD, colonic CD, IBDU, atypical UC, and UC.

The Impact of Structured Incentives on the Adoption of a Serious Game for Hand Hygiene Training in a Hospital Setting.

Hand hygiene is recognized by the CDC as the most effective method of preventing Hospital Acquired Infections (HAIs) which cost the US healthcare system $14 Billion. However, training and promotion of hand hygiene in healthcare settings is an on-going challenge. This paper describes a hand hygiene improvement campaign in Edinburgh Royal Infirmary (Scotland, UK) using the SureWash gesture recognition system (SureWash, IRL). The campaign consisted of two phases of three-months each; the first phase involved technology evaluation and familiarization in a variety of settings within the hospital. The second phase involved rotation between two units with specific changes to the incentives for completing the training. There were 2,010 individual training sessions with over 30% outside of office hours. Individuals completed an average of 2.72 training sessions each and 90% of staff passed the assessment. Senior staff noted a change in hand hygiene culture following the campaign and the good-natured competition between staff to demonstrate hand hygiene competence using the SureWash serious game. While the new technology did facilitate the culture change its successful implementation was dependent on a set of incentives for staff and a structured implementation plan.

Serum C-reactive protein and CRP genotype in pediatric inflammatory bowel disease: influence on phenotype, natural history, and response to therapy.

BACKGROUND: C-reactive protein (CRP) is an acute phase reactant. Patients with pediatric inflammatory bowel disease (PIBD) differ from adult patients with inflammatory bowel disease with regard to phenotype, inflammatory profile, and treatment response. We hypothesized that variations in CRP and CRP genotype influence PIBD phenotype, natural history, and remission after anti-tumor necrosis factor alpha therapy. METHODS: Six single nucleotide polymorphisms tagging CRP (rs1935193, rs1130864, rs1205, rs1417938, rs11265263, and rs1800947) were genotyped in 465 patients with PIBD (diagnosed <17 yr). Phenotyping was serially performed until last follow-up and serum CRP levels recorded at diagnosis and before biological therapy in a subgroup. RESULTS: CRP haplotype (ATGCTC) differed in those diagnosed <10 years, with rs1205T more frequent in Crohn's disease (CD) than ulcerative colitis (UC) (P = 0.009); the haplotype ATGCTC was less frequent in UC (P = 0.002). Three single nucleotide polymorphisms (rs1205, rs1130864, and rs1417938) showed association with elevated CRP levels at diagnosis. CRP genotype had no association with CD phenotype or natural history. CRP was more frequently raised at diagnosis in CD than UC (63% versus 22%, P < 0.0001). Elevated CRP at diagnosis was associated with a higher risk of progression to surgery in patients with CD (P < 0.0001) and the need for azathioprine in the overall PIBD cohort (P = 0.002). There was no effect of CRP genotype or serum CRP on the achievement of remission using anti-tumor necrosis factor alpha therapy. CONCLUSIONS: CRP and CRP genotype differ between pediatric patients with CD and UC with a high inflammatory burden at diagnosis suggesting a worse prognosis. Additional evaluation of CRP in inflammatory bowel disease pathogenesis and natural history is now warranted.

The relationship between factors that impair wound healing and the severity of acute radiation skin and mucosal toxicities in head and neck cancer.

PURPOSE: To determine which wound-healing factors impact on the severity of radiation skin and oral mucosal reactions in head and neck cancer and to test modifications to the Radiation Therapy Oncology Group (RTOG) acute toxicity scoring system. METHODS: A consecutive sample of 53 head and neck cancer patients who were scheduled for curative or palliative radiation therapy. Therapy was planned using traditional computerized techniques. A new RTOG subscale for tongue reactions was developed. Information on potential predictors was collected during the first week of treatment. Reactions were observed and documented each week throughout treatment using the RTOG Acute Reaction Scoring System scores of acute oropharyngeal reactions and various personal factors. RESULTS: Significant relationships were found between severe skin and oral reactions and age, commencing radiation within 2 months of surgery and smoking. Significant relationships for severe oral mucosal reactions were found with weight at the commencement of treatment, inadequate or poor diet, having had mucositis with previous chemotherapy, and the use of a custom-made Perspex tongue immobilizer. CONCLUSIONS: Three conclusions can be derived from this study: (1) structures within the oral cavity should be considered separately for toxicity scoring, (2) the newly developed tongue RTOG subscale adds accuracy and specificity to the RTOG acute toxicity scoring system, and (3) wound healing factors are an important component of understanding risk for side effects in head and neck cancer treatment.

Ibrutinib: first global approval.

Ibrutinib (Imbruvica™) is a small molecule, first-in-class, once-daily, orally available, Bruton's tyrosine kinase inhibitor that is under development for the treatment of B cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL), as well as multiple myeloma (MM), follicular lymphoma (FL) and Waldenstrom's macroglobulinemia (WM). It has been developed by Pharmacyclics, Inc. and Janssen Biotech, Inc. Ibrutinib acts by blocking B-cell antigen receptor signalling, thereby reducing malignant proliferation of B cells and inducing cell death. Based chiefly on findings from a phase Ib/II study, ibrutinib has been approved in the USA for the treatment of MCL in previously treated patients and is one of the first approvals through the US FDA's Breakthrough Therapy Designation Pathway. An application has been filed in the EU seeking regulatory approval in this indication. In both the USA and EU, further applications have been filed with regulatory bodies seeking approval for the use of ibrutinib in patients with previously treated CLL/small lymphocytic lymphoma (SLL). Phase III trials are underway worldwide to evaluate ibrutinib in the treatment of patients with CLL/SLL, DLBCL and MCL, and the agent is in phase II development for use in WM, FL and MM. This article summarizes the milestones in the development of ibrutinib leading to its first approval in MCL.

Obinutuzumab: first global approval.

Obinutuzumab (Gazyva™) is an intravenously administered, humanized and glycoengineered, type II anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. It is approved in the US for use in combination with chlorambucil for the first-line treatment of chronic lymphocytic leukaemia (CLL), and has been filed for approval in the EU in this indication. The antibody is based on GlycArt Biotechnology's (later Roche Glycart AG) proprietary GlycoMAb® technology, which uses glycoengineered antibodies that specifically increase antibody-dependent cellular cytotoxicity and thereby increase immune-mediated target cell death. Obinutuzumab is a type II anti-CD20 antibody that induces enhanced direct cell death. The monoclonal antibody is in worldwide phase III development with Roche and its subsidiaries, Genentech and Chugai Pharmaceutical, as well as Biogen Idec, for diffuse large B-cell lymphoma and non-Hodgkin's lymphoma generally, and is also in phase III development in countries outside of the US and EU for CLL.

Mipomersen sodium: first global approval.

Mipomersen sodium (Kynamro™) (henceforth mipomersen) is a second-generation antisense oligonucleotide inhibitor of apolipoprotein B-100, which is the main structural component of atherogenic lipid particles. Mipomersen is administered via subcutaneous injection and is indicated as adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH). The drug was developed by Isis Pharmaceuticals, which now collaborates with Genzyme Corporation for on-going development and product marketing. Multinational phase III trials of mipomersen as adjunctive therapy were completed in patients with HoFH, severe FH, heterozygous FH (HeFH) with coronary artery disease (CAD), and in those with hypercholesterolaemia at high risk of CAD. Mipomersen 200 mg once weekly has been approved in the USA as an adjunct to lipid-lowering medications and diet in HoFH patients and is undergoing regulatory review in the EU for the same indication. Genzyme is also conducting a multinational phase III, open-label extension study to evaluate long-term treatment in HoFH and HeFH patients, as well as a multinational trial to evaluate a three-times-per-week mipomersen regimen in patients with severe FH. This article summarises the milestones in the development of once-weekly, subcutaneous mipomersen leading to this first approval.

Levomilnacipran extended release: first global approval.

Pierre Fabre and Forest Laboratories are developing levomilnacipran extended release (ER) [FETZIMA™], an enantiomer of milnacipran, for the treatment of major depressive disorder (MDD). In addition, Pierre Fabre (the originator of the compound) is developing the drug to improve recovery in patients with ischaemic stroke. Levomilnacipran ER exerts its effects by selectively inhibiting the reuptake of norepinephrine and serotonin (two neurotransmitters known to play an essential role in regulating mood) without directly affecting the uptake of dopamine or other neurotransmitters. The agent is being developed as an extended-release capsule formulation for once-daily dosing. Levomilnacipran ER is approved and launched in the US for the treatment of MDD; phase III development in this indication was completed in the US and Canada. In Europe, a phase II trial for MDD was completed, and development is in progress for improving functional recovery of patients with ischaemic stroke. A completed phase II trial in the US investigated levomilnacipran ER for the treatment of fatigue associated with MDD. This article summarizes the milestones in the development of levomilnacipran ER leading to the first approval for major depressive disorder.

Phentermine and topiramate extended release (Qsymia™): first global approval.

Vivus' proprietary oral capsule containing phentermine and extended-release (ER) topiramate has been approved in the US for the treatment of obesity. Phentermine is an appetite suppressant, while topiramate is an anti-epileptic medication. The once-daily formulation, known as Qsymia™, is designed to produce weight loss by decreasing appetite and increasing satiety. The product is also in clinical development for sleep apnoea syndrome and type 2 diabetes mellitus. This article summarizes the milestones in the development of phentermine/topiramate ER leading to this first approval for obesity.