Pilot Study of Intensive Trismus Intervention Using Restorabite™ During Unilateral Adjuvant Radiation for Head and Neck Cancer.

Trismus commonly arises after surgery for head and neck cancer (HNC) and its severity is potentiated by postoperative radiotherapy. While the benefit of trismus rehabilitation after surgery and radiotherapy is well established, the evidence during radiotherapy is less clear. This may be due to poor adherence to trismus exercises secondary to acute mucositis. This study assessed the feasibility of using a novel trismus device during adjuvant radiotherapy for HNC in patients with acute postoperative trismus. Prospective single-arm cohort feasibility study. Eligible patients had undergone surgery with curative intent for HNC, planned for adjuvant radiotherapy, and were suitable for trismus rehabilitation. Participants completed a 10-week exercise program using a novel jaw stretching device. Study outcomes were adherence, maximal incisal opening (MIO), and trismus-related function and quality of life scores, assessed at baseline, 10 weeks, and 6 months after commencing exercises. Nine patients diagnosed with trismus after primary surgery were recruited. The mean increase in MIO at 10 weeks was 7.8 mm (range -4 to 15 mm, p = 0.03), and at 6 months was 10.6 mm (range 1-26 mm, p = 0.03). Significant improvements were observed in trismus-related quality of life (Gothenburg Trismus Questionnaire; p = 0.04). Adherence to the exercises was 100% in week 1-2, 67% in weeks 3-6, and 100% at 10 weeks (1 month post radiation). This study demonstrates the feasibility of using a novel jaw stretching device during adjuvant radiotherapy. Further evaluation is warranted to assess the effectiveness of early intervention and prevention of trismus during HNC radiotherapy.Level of Evidence: IV.

The impact of jejunostomy feeding on nutritional outcomes after oesophagectomy.

BACKGROUND: Nutritional status is compromised long-term following oesophagectomy. Controversy surrounds the optimal route for nutrition support postoperatively and there is wide variation in the use of feeding jejunostomy tubes. METHODS: A retrospective service evaluation was conducted for all consecutive adults who underwent oesophagectomy for a cancer diagnosis within a specialist centre between April 2016 and July 2019 (n = 165). Nutritional and clinical outcomes were compared for patients who received jejunostomy feeding (n = 24), versus those who did not (n = 141). RESULTS: Patients with feeding jejunostomy lost significantly less weight at both 6 and 12 months postoperatively compared to those without jejunostomy (p ≤ 0.001 and p = 0.001, respectively). This remained statistically significant in multiple regression, controlling for age, gender, preoperative tumour staging and adjuvant treatment (p ≤ 0.001 and p = 0.03, respectively). Median length of home enteral feeding was 10 weeks after discharge in the jejunostomy group. We observed minor jejunostomy tube-related complications in four patients (16.7%). Of those readmitted within 90 days of surgery in the non-jejunostomy group, nutritional failure was a factor in 43.2% of these readmissions. "Rescue tube feeding" was required by 8.5% of the non-jejunostomy group within the first postoperative year, including 6.4% within 90 days of surgery. CONCLUSIONS: Use of short-term supplementary jejunal feeding in addition to oral intake after hospital discharge is beneficial for maintaining weight after oesophagectomy. We suggest a future randomised-controlled trial to confirm these findings.

Co-crystallisation and humanisation of an anti-HER2 single-domain antibody as a theranostic tool.

Human epidermal growth factor receptor-2 (HER2) is a well-recognised biomarker associated with 25% of breast cancers. In most cases, early detection and/or treatment correlates with an increased chance of survival. This study, has identified and characterised a highly specific anti-HER2 single-domain antibody (sdAb), NM-02, as a potential theranostic tool. Complete structural description by X-ray crystallography has revealed a non-overlapping epitope with current anti-HER2 antibodies. To reduce the immunogenicity risk, NM-02 underwent a humanisation process and retained wild type-like binding properties. To further de-risk the progression towards chemistry, manufacturing and control (CMC) we performed full developability profiling revealing favourable thermal and physical biochemical 'drug-like' properties. Finally, the application of the lead humanised NM-02 candidate (variant K) for HER2-specific imaging purposes was demonstrated using breast cancer HER2+/BT474 xenograft mice.

Emergency paediatric medicine consultation-a practical guide to a consultation with refugee and asylum-seeking children within the paediatric emergency department.

There are increasing numbers of refugee and asylum-seeking children entering the UK annually who face significant barriers to accessing healthcare services. Clinicians working in the emergency department should have an awareness of the journeys children may have taken and the barriers they face in accessing care and have a holistic approach to care provision. We conducted a narrative literature review and used experiential knowledge of paediatricians working in the Paediatric Emergency Department to formulate a step-by-step screening tool. We have formulated a step-by-step screening tool, CCHILDS (Communication, Communicable diseases, Health-physical and mental, Immunisation, Look after (safeguarding), Deficiencies, Sexual health) which can be used by healthcare professionals in the emergency department. CONCLUSION: Due to increasing numbers of refugee and asylum-seeking children, it is important that every point of contact with healthcare professionals is an impactful one on their health, well-being and development. Future work would include validation of our tool. WHAT IS KNOWN: •The number of refugees globally are rapidly increasing, leading to an increase in the number of presentations to the PED. These patients are often medically complex and may have unique and sometimes unexpected presentations that could be attributed to by their past. There are a multitude of resources available outlining guidance on the assessment and management of refugee children. WHAT IS NEW: •This review aims to succinctly summarise the guidance surrounding the assessment of refugee children presenting to the PED and ensure that healthcare professionals are aware of the pertinent information regarding this cohort. It introduces the CCHILDS assessment tool which has been formulated through a narrative review of the literature and acts as a mnemonic to aid professionals in their assessment of refugee children in the PED.

Manufacturing a chimpanzee adenovirus-vectored SARS-CoV-2 vaccine to meet global needs.

Manufacturing has been the key factor limiting rollout of vaccination during the COVID-19 pandemic, requiring rapid development and large-scale implementation of novel manufacturing technologies. ChAdOx1 nCoV-19 (AZD1222, Vaxzevria) is an efficacious vaccine against SARS-CoV-2, based upon an adenovirus vector. We describe the development of a process for the production of this vaccine and others based upon the same platform, including novel features to facilitate very large-scale production. We discuss the process economics and the "distributed manufacturing" approach we have taken to provide the vaccine at globally-relevant scale and with international security of supply. Together, these approaches have enabled the largest viral vector manufacturing campaign to date, providing a substantial proportion of global COVID-19 vaccine supply at low cost.

Swallowing and communication outcomes following primary transoral robotic surgery for advanced or recurrent oropharyngeal cancer: Case series.

Purpose: Transoral robotic surgery (TORS) is most commonly undertaken as a minimally invasive approach for early staged oropharyngeal cancers (OPC), with good expectations for a functional recovery. A small number of patients, however, require TORS for recurrent or advanced OPC tumours. Their prospects for longer term recovery of communication and swallowing are both unreported and hypothesised to be poorer than the majority of TORS cases. This case-series describes the recovery of swallowing and communication function post-TORS for this unique group of patients.Method: Consecutive recruitment was carried out prospectively at a quaternity oncology referral centre. Participants were aged 18 years and older, with reconstruction involving a free-flap and tracheostomy. Patients were assessed using Fibreoptic Endoscopic Evaluation of Swallowing, and clinician and patient-reported outcomes 12-months post-TORS. Their pre-operative baseline and three-month post-TORS FOIS scores were collated retrospectively.Result: Six participants were recruited over an 18-month period of which three patients underwent TORS for recurrent, and three for advanced OPC. Those with recurrent-OPC did not return to their baseline diet and demonstrated post-swallow silent aspiration of pharyngeal residue. Three of the six were rehabilitated back to their baseline intelligibility (100%).Conclusion: TORS in the recurrent OPC setting appears congruent with high rates of silent aspiration and prolonged reliance on a feeding tube due to oropharyngeal dysphagia, as well as compromised intelligibility. This is the first study that evaluates this instrumentally and provides clinically relevant evidence to inform practice.

Characterizing environmental stress responses of aposymbiotic Astrangia poculata to divergent thermal challenges.

Anthropogenic climate change threatens corals globally and both high and low temperatures are known to induce coral bleaching. However, coral stress responses across wide thermal breadths remain understudied. Disentangling the role of symbiosis on the stress response in obligately symbiotic corals is challenging because this response is inherently coupled with nutritional stress. Here, we leverage aposymbiotic colonies of the facultatively symbiotic coral, Astrangia poculata, which lives naturally with and without its algal symbionts, to examine how broad thermal challenges influence coral hosts in the absence of symbiosis. A. poculata were collected from their northern range limit and thermally challenged in two independent 16-day common garden experiments (heat and cold challenge) and behavioural responses to food stimuli and genome-wide gene expression profiling (TagSeq) were performed. Both thermal challenges elicited significant reductions in polyp extension. However, there were five times as many differentially expressed genes (DEGs) under cold challenge compared to heat challenge. Despite an overall stronger response to cold challenge, there was significant overlap in DEGs between thermal challenges. We contrasted these responses to a previously identified module of genes associated with the environmental stress response (ESR) in tropical reef-building corals. Cold challenged corals exhibited a pattern consistent with more severe stressors while the heat challenge response was consistent with lower intensity stressors. Given that these responses were observed in aposymbiotic colonies, many genes previously implicated in ESRs in tropical symbiotic species may represent the coral host's stress response in or out of symbiosis.

Nutrition Care Process Model Approach to Surgical Prehabilitation in Oncology.

The nutrition care process is a standardized and systematic method used by nutrition professionals to assess, diagnose, treat, and monitor patients. Using the nutrition care process model, we demonstrate how nutrition prehabilitation can be applied to the pre-surgical oncology patient.

Current Landscape of Nutrition Within Prehabilitation Oncology Research: A Scoping Review.

Background: Prehabilitation aims to improve functional capacity prior to cancer treatment to achieve better psychosocial and clinical outcomes. Prehabilitation interventions vary considerably in design and delivery. In order to identify gaps in knowledge and facilitate the design of future studies, we undertook a scoping review of prehabilitation studies to map the range of work on prehabilitation being carried out in any cancer type and with a particular focus on diet or nutrition interventions. Objectives: Firstly, to describe the type of prehabilitation programs currently being conducted. Secondly, to describe the extent to which prehabilitation studies involved aspects of nutrition, including assessment, interventions, implementation, and outcomes. Eligibility Criteria: Any study of quantitative or qualitative design that employed a formal prehabilitation program before cancer treatment ("prehabilitation" listed in keywords, title, or abstract). Sources of Evidence: Search was conducted in July 2020 using MEDLINE, PubMed, EMBASE, EMCARE, CINAHL, and AMED. Charting Methods: Quantitative data were reported as frequencies. Qualitative nutrition data were charted using a framework analysis that reflects the Nutrition Care Process Model: assessment, intervention, and monitoring/evaluation of the nutrition intervention. Results: Five hundred fifty unique articles were identified: 110 studies met inclusion criteria of a formal prehabilitation study in oncology. prehabilitation studies were mostly cohort studies (41%) or randomized-controlled trials (38%) of multimodal (49%), or exercise-only (44%) interventions that were applied before surgery (94%). Nutrition assessment was inconsistently applied across these studies, and often conducted without validated tools (46%). Of the 110 studies, 37 (34%) included a nutrition treatment component. Half of these studies provided the goal for the nutrition component of their prehabilitation program; of these goals, less than half referenced accepted nutrition guidelines in surgery or oncology. Nutrition interventions largely consisted of counseling with dietary supplementation. The nutrition intervention was indiscernible in 24% of studies. Two-thirds of studies did not monitor the nutrition intervention nor evaluate nutrition outcomes. Conclusion: Prehabilitation literature lacks standardized and validated nutritional assessment, is frequently conducted without evidence-based nutrition interventions, and is typically implemented without monitoring the nutrition intervention or evaluating the intervention's contribution to outcomes. We suggest that the development of a core outcome set could improve the quality of the studies, enable pooling of evidence, and address some of the research gaps identified.

Swallowing and communication outcomes following primary transoral robotic surgery.

BACKGROUND: Heterogeneity within studies examining transoral robotic surgery (TORS) for oropharyngeal cancer (OPC) has made it challenging to make clear conclusions on functional outcomes. Infrequent use of instrumental swallow examinations compounds uncertainty surrounding the proposed functional advantage to TORS. METHODS: A prospective cohort of 49 patients underwent speech and swallowing assessment 12 months following treatment for OPC. Patients were assessed using fibreoptic endoscopic evaluation of swallowing (FEES), clinician- and patient-reported outcomes. Participants were matched according to tumor site, T category, and age. Speech and swallowing outcomes were compared for those receiving TORS versus chemoradiation. RESULTS: When adjuvant radiotherapy to the primary site could be avoided, TORS demonstrated an advantage for feeding tube duration, secretion severity, penetration/aspiration, M. D. Anderson Dysphagia Inventory (MDADI), and airway protection. CONCLUSION: This explorative study suggests that a treatment philosophy of selecting patients for TORS where adjuvant therapy can be omitted or confined to the neck warrants further evaluation.

Diagnostic performance of a faecal immunochemical test for patients with low-risk symptoms of colorectal cancer in primary care: an evaluation in the South West of England.

BACKGROUND: The faecal immunochemical test (FIT) was introduced to triage patients with low-risk symptoms of possible colorectal cancer in English primary care in 2017, underpinned by little primary care evidence. METHODS: All healthcare providers in the South West of England (population 4 million) participated in this evaluation. 3890 patients aged ≥50 years presenting in primary care with low-risk symptoms of colorectal cancer had a FIT from 01/06/2018 to 31/12/2018. A threshold of 10 µg Hb/g faeces defined a positive test. RESULTS: Six hundred and eighteen (15.9%) patients tested positive; 458 (74.1%) had an urgent referral to specialist lower gastrointestinal (GI) services within three months. Forty-three were diagnosed with colorectal cancer within 12 months. 3272 tested negative; 324 (9.9%) had an urgent referral within three months. Eight were diagnosed with colorectal cancer within 12 months. Positive predictive value was 7.0% (95% CI 5.1-9.3%). Negative predictive value was 99.8% (CI 99.5-99.9%). Sensitivity was 84.3% (CI 71.4-93.0%), specificity 85.0% (CI 83.8-86.1%). The area under the ROC curve was 0.92 (CI 0.86-0.96). A threshold of 37 µg Hb/g faeces would identify patients with an individual 3% risk of cancer. CONCLUSIONS: FIT performs exceptionally well to triage patients with low-risk symptoms of colorectal cancer in primary care; a higher threshold may be appropriate in the wake of the COVID-19 crisis.

Gross, microscopic, radiologic, echocardiographic and haematological findings in rats experimentally infected with Angiostrongylus cantonensis.

Although the gross and microscopic pathology in rats infected with Angiostrongylus cantonensis has been well described, corresponding changes detected using diagnostic imaging modalities have not been reported. This work describes the cardiopulmonary changes in mature Wistar rats chronically infected with moderate burdens of A. cantonensis using radiology, computed tomography (CT), CT angiography, echocardiography, necropsy and histological examinations. Haematology and coagulation studies were also performed. Thoracic radiography, CT and CT angiography showed moderately severe alveolar pulmonary patterns mainly affecting caudal portions of the caudal lung lobes and associated dilatation of the caudal lobar pulmonary arteries. Presumptive worm profiles could be detected using echocardiography, with worms seen in the right ventricular outflow tract or straddling either the pulmonary and/or the tricuspid valves. Extensive, multifocal, coalescing dark areas and multiple pale foci affecting the caudal lung lobes were observed at necropsy. Histologically, these were composed of numerous large, confluent granulomas and fibrotic nodules. Adult worms were found predominantly in the mid- to distal pulmonary arteries. An inflammatory leukogram, hyperproteinaemia and hyperfibrinogenaemia were found in most rats. These findings provide a comparative model for A. cantonensis in its accidental hosts, such as humans and dogs. In addition, the pathological and imaging changes are comparable to those seen in dogs infected with Angiostrongylus vasorum, suggesting rats infected with A. cantonensis could be a model for dogs with A. vasorum infection.

Robust Production of Merkel Cell Polyomavirus Oncogene Specific T Cells From Healthy Donors for Adoptive Transfer.

Virus positive Merkel cell carcinoma (VP-MCC) is an aggressive but immunogenic skin malignancy driven by Merkel cell polyomavirus (MCPyV) T antigen (TAg). Since adoptive T cell transfer (ACT) can be effective against virus-driven malignancies, we set out to develop a methodology for generating MCPyV TAg specific T cells. MCPyV is a common, asymptomatic infection and virus-exposed healthy donors represent a potential source of MCPyV TAg specific T cells for ACT. Virus specific T cells were generated using monocyte-derived dendritic cells (moDCs) pulsed with MCPyV TAg peptide libraries and co-cultured with autologous T cells in supplemented with pro-inflammatory and homeostatic cytokines for 14 days. Specific reactivity was observed predominantly within the CD4+ T cell compartment in the cultures generated from 21/46 random healthy donors. Notably, responses were more often seen in donors aged 50 years and older. TAg specific CD4+ T cells specifically secreted Th1 cytokines and upregulated CD137 upon challenge with MCPyV TAg peptide libraries and autologous transduced antigen presenting cells. Expanded T cells from healthy donors recognized epitopes of both TAg splice variants found in VP-MCC tumors, and minimally expressed exhaustion markers. Our data show that MCPyV specific T cells can be expanded from healthy donors using methods appropriate for the manufacture of clinical grade ACT products.

Early fiberoptic endoscopic evaluation of swallow in transoral robotic surgery: Description of swallow function and recovery in the acute postoperative period for oropharyngeal squamous cell carcinoma.

BACKGROUND: Transoral robotic surgery (TORS) is a minimally invasive approach for the treatment of oropharyngeal cancer. The effects on swallowing and speech need to be comprehensively evaluated to understand the associated morbidity. METHODS: A prospective cohort of 21 patients was recruited to undergo pre-TORS and post-TORS swallowing and communication assessment. Fiberoptic endoscopic evaluation of swallowing (FEES) was used in the first postoperative week. RESULTS: Sixteen participants (76.2%) had penetration-aspiration scores ≥3 or higher, seven (33.3%) aspirated on thin liquids, three (14.3%) did so silently. Prolonged recovery trajectory occurred for the majority of the cohort, particularly if TORS was followed by adjuvant radiotherapy. Swallowing and communication scores were significantly worse in base of tongue primary tumors and with advanced age. CONCLUSION: Early FEES demonstrates a significant decline in swallowing function, including increased secretion load, pharyngeal residue, laryngeal penetration, and aspiration. Silent aspiration occurred in 14% and thus highlights the necessity for instrumental assessment to ascertain aspiration risk.

A Microfluidic Co-Flow Route for Human Serum Albumin-Drug-Nanoparticle Assembly.

Nanoparticles are widely studied as carrier vehicles in biological systems because their size readily allows access through cellular membranes. Moreover, they have the potential to carry cargo molecules and as such, these factors make them especially attractive for intravenous drug delivery purposes. Interest in protein-based nanoparticles has recently gained attraction due to particle biocompatibility and lack of toxicity. However, the production of homogeneous protein nanoparticles with high encapsulation efficiencies, without the need for additional cross-linking or further engineering of the molecule, remains challenging. Herein, we present a microfluidic 3D co-flow device to generate human serum albumin/celastrol nanoparticles by co-flowing an aqueous protein solution with celastrol in ethanol. This microscale co-flow method resulted in the formation of nanoparticles with a homogeneous size distribution and an average size, which could be tuned from ≈100 nm to 1 µm by modulating the flow rates used. We show that the high stability of the particles stems from the covalent cross-linking of the naturally present cysteine residues within the particles formed during the assembly step. By choosing optimal flow rates during synthesis an encapsulation efficiency of 75±24 % was achieved. Finally, we show that this approach achieves significantly enhanced solubility of celastrol in the aqueous phase and, crucially, reduced cellular toxicity.

Expression of the muscle-associated gene MYF6 in hairy cell leukemia.

Hairy cell leukemia (HCL) is a purine analog-responsive B-cell malignancy containing the BRAF V600E mutation, expressing CD22, CD11c, CD103, tartrate resistant acid phosphatase (TRAP) CD25, CD123, and annexin 1A. BRAF V600E and the latter 4 markers are usually absent in the more aggressive and chemoresistant variant HCLv. To evaluate differences between HCL and HCLv, expression microarrays comparing HCL with HCLv were performed for 24694 genes using 47323 probes. Microarray data from 35 HCL and 27 HCLv purified samples showed the greatest HCL-HCLv difference in the muscle-associated gene MYF6, expressed by its 2 probes 18.5- and 10.8-fold higher in HCL than HCLv (p<0.0001). By real-time quantitative PCR (RQ-PCR), 100% of 152 classic HCL samples were MYF6-positive, vs 5 (6%) of 90 blood donors. MYF6-expression was also detected in 18 (35%) of 51 with HCLv, 11 (92%) of 12 with HCL expressing unmutated IGHV4-34, 35 (73%) of 48 with chronic lymphocytic leukemia (CLL), and 1 (8%) of 12 with mantle cell lymphoma. Hypomethylation status of MYF6 supported expression in HCL more than HCLv. Posttreatment blood samples becoming negative by flow cytometry remained MYF6+ by RQ-PCR in 42 (48%) of 87 HCL patients, and MYF6 RQ-PCR could detect 1 HCL in 105 normal cells. MYF6, universally expressed in HCL and in most CLL samples, may be a useful biomarker for these leukemias. Further studies are underway to determine the role of MYF6 in HCL.

Oral Janus kinase inhibitors for maintenance of remission in ulcerative colitis.

BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis (UC). The etiology of UC is poorly understood, however research suggests the development and progression of the disease is due to a dysregulated immune response leading to inflammation of the colonic mucosa in genetically predisposed individuals. Additional medications are currently required since some patients do not respond to the available medications and some medications are associated with serious adverse events (SAEs). JAK inhibitors have been widely studied in diseases including rheumatoid arthritis and Crohn's disease and may represent a promising and novel therapeutic option for the treatment of UC. OBJECTIVES: The primary objective was to assess the efficacy and safety of oral JAK inhibitors for the maintenance of remission in participants with quiescent UC. SEARCH METHODS: We searched the following databases from inception to 20 September 2019: MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register, WHO trials registry and clinicaltrials.gov. References and conference abstracts were searched to identify additional studies. SELECTION CRITERIA: Randomized control trial (RCTs) in which an oral JAK inhibitor was compared with placebo or active comparator in the treatment of quiescent UC were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion and extraction. Bias was assessed using the Cochrane 'Risk of bias' tool. The primary outcome was the proportion of participants who failed to maintain remission as defined by any included studies. Secondary outcomes included failure to maintain clinical response, failure to maintain endoscopic remission, failure to maintain endoscopic response, disease-specific quality of life, adverse events (AEs), withdrawal due to AEs and SAEs. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each dichotomous outcome. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: One RCT (593 participants) including patients with moderately to severely active UC met the inclusion criteria. Patients were randomly assigned in a 1:1:1 ratio to receive maintenance therapy with tofacitinib at 5 mg twice daily, 10 mg twice daily or placebo for 52 weeks. The primary endpoint was remission at 52 weeks and the secondary endpoints included mucosal healing at 52 weeks, sustained remission at 24 and 52 weeks and glucocorticosteroid-free remission. This study was rated as low risk of bias. The study reported on most of the pre-specified primary and secondary outcomes for this review including clinical remission, clinical response, endoscopic remission, AEs, SAEs and withdrawal due to AEs. However, the included study did not report on endoscopic response or disease-specific quality of life. Sixty-three per cent (247/395) of tofacitinib participants failed to maintain clinical remission at 52 weeks compared to 89% (176/198) of placebo participants (RR 0.70, 95% CI 0.64 to 0.77; high-certainty evidence). Forty-three per cent (171/395) of tofacitinib participants failed to maintain clinical response at 52 weeks compared to 80% (158/198) of placebo participants (RR 0.54, 95% CI 0.48 to 0.62; high-certainty evidence). Eighty-four per cent (333/395) of tofacitinib participants failed to maintain endoscopic remission at 52 weeks compared to 96% (190/198) of placebo participants (RR 0.88, 95% CI 0.83 to 0.92; high-certainty evidence). AEs were reported in 76% (299/394) of tofacitinib participants compared with 75% (149/198) of placebo participants (RR 1.01, 95% CI 0.92 to 1.11; high-certainty evidence). Commonly reported AEs included worsening UC, nasopharyngitis, arthralgia (joint pain)and headache. SAEs were reported in 5% (21/394) of tofacitinib participants compared with 7% (13/198) of placebo participants (RR 0.81, 95% CI 0.42 to 1.59; low-certainty evidence). SAEs included non-melanoma skin cancers, cardiovascular events, cancer other than non-melanoma skin cancer, Bowen's disease, skin papilloma and uterine leiomyoma (a tumour in the uterus). There was a higher proportion of participants who withdrew due to an AE in the placebo group compared to the tofacitinib group. Nine per cent (37/394) of participants taking tofacitinib withdrew due to an AE compared to 19% (37/198) of participants taking placebo (RR 0.50, 95% CI 0.33 to 0.77; moderate-certainty evidence). The most common reason for withdrawal due to an AE was worsening UC. The included study did not report on endoscopic response or on mean disease-specific quality of life scores. AUTHORS' CONCLUSIONS: High-certainty evidence suggests that tofacitinib is superior to placebo for maintenance of clinical and endoscopic remission at 52 weeks in participants with moderate-to-severe UC in remission. The optimal dose of tofacitinib for maintenance therapy is unknown. High-certainty evidence suggests that there is no increased risk of AEs with tofacitinib compared to placebo. However, we are uncertain about the effect of tofacitinib on SAEs due to the low number of events. Further studies are required to look at the long-term effectiveness and safety of using tofacitinib and other oral JAK inhibitors as maintenance therapy in participants with moderate-to-severe UC in remission.

Anti-IL-12/23p40 antibodies for maintenance of remission in Crohn's disease.

BACKGROUND: Ustekinumab and briakinumab are monoclonal antibodies that target the standard p40 subunit of cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of Crohn's disease (CD). A significant proportion of people with Crohn's disease fail conventional therapy or therapy with biologics (e.g. infliximab) or develop significant adverse events. Anti-IL-12/23p40 antibodies such as ustekinumab may be an effective alternative for these individuals. OBJECTIVES: The objectives of this review were to assess the efficacy and safety of anti-IL-12/23p40 antibodies for maintenance of remission in CD. SEARCH METHODS: We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, and trials registers from inception to 17 September 2019. We searched references and conference abstracts for additional studies. SELECTION CRITERIA: We considered for inclusion randomized controlled trials in which monoclonal antibodies against IL-12/23p40 were compared to placebo or another active comparator in participants with quiescent CD. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion, extracted data, and assessed bias using the Cochrane 'Risk of bias' tool. The primary outcome measure was failure to maintain clinical remission, defined as a Crohn's disease activity index (CDAI) of < 150 points. Secondary outcomes included failure to maintain clinical response, adverse events (AE), serious adverse events (SAE), and withdrawals due to AEs. Clinical response was defined as a decrease in CDAI score of ≥ 100 points from baseline score. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. We analyzed all data on an intention-to-treat basis. We used GRADE to evaluate the overall certainty of the evidence supporting the outcomes. MAIN RESULTS: Three randomized controlled trials (646 participants) met the inclusion criteria. Two trials assessed the efficacy of ustekinumab (542 participants), and one study assessed the efficacy of briakinumab (104 participants). We assessed all of the included studies as at low risk of bias. One study (N = 145) compared subcutaneous ustekinumab (90 mg) administered at 8 and 16 weeks compared to placebo. Fifty-eight per cent (42/72) of ustekinumab participants failed to maintain clinical remission at 22 weeks compared to 73% (53/73) of placebo participants (RR 0.80, 95% CI 0.63 to 1.02; moderate-certainty evidence). Failure to maintain clinical response at 22 weeks was seen in 31% (22/72) of ustekinumab participants compared to 58% (42/73) of placebo participants (RR 0.53, 95% CI 0.36 to 0.79; moderate-certainty evidence). One study (N = 388) compared subcutaneous ustekinumab (90 mg) administered every 8 weeks or every 12 weeks to placebo for 44 weeks. Forty-nine per cent (126/257) of ustekinumab participants failed to maintain clinical remission at 44 weeks compared to 64% (84/131) of placebo participants (RR 0.76, 95% CI 0.64 to 0.91; moderate-certainty evidence). Forty-one per cent (106/257) of ustekinumab participants failed to maintain clinical response at 44 weeks compared to 56% (73/131) of placebo participants (RR 0.74, 95% CI 0.60 to 0.91; moderate-certainty evidence). Eighty per cent (267/335) of ustekinumab participants had an AE compared to 84% (173/206) of placebo participants (RR 0.94, 95% CI 0.87 to 1.03; high-certainty evidence). Commonly reported adverse events included infections, injection site reactions, CD event, abdominal pain, nausea, arthralgia, and headache. Eleven per cent of ustekinumab participants had an SAE compared to 16% (32/206) of placebo participants (RR 0.74, 95% CI 0.48 to 1.15; moderate-certainty evidence). SAEs included serious infections, malignant neoplasm, and basal cell carcinoma. Seven per cent (5/73) of ustekinumab participants withdrew from the study due to an AE compared to 1% (1/72) of placebo participants (RR 4.93, 95% CI 0.59 to 41.18; low-certainty evidence). Worsening CD was the most common reason for withdrawal due to an AE. One study compared intravenous briakinumab (200 mg, 400 mg, or 700 mg) administered at weeks 12, 16, and 20 with placebo. Failure to maintain clinical remission at 24 weeks was seen in 51% (32/63) of briakinumab participants compared to 61% (22/36) of placebo participants (RR 0.84, 95% CI 0.58 to 1.20; low-certainty evidence). Failure to maintain clinical response at 24 weeks was seen in 33% (21/63) of briakinumab participants compared to 53% (19/36) of placebo participants (RR 0.64, 95% CI 0.40 to 1.02; low-certainty evidence). Sixty-six per cent (59/90) of briakinumab participants had an AE compared to 64% (9/14) of placebo participants (RR 1.02, 95% CI 0.67 to 1.55; low-certainty evidence). Common AEs included upper respiratory tract infection, nausea, abdominal pain, headache, and injection site reaction. Two per cent (2/90) of briakinumab participants had an SAE compared to 7% (1/14) of placebo participants (RR 0.31, 95% CI 0.03 to 3.21; low-certainty evidence). SAEs included small bowel obstruction, deep vein thrombosis, and respiratory distress. Withdrawal due to an AE was noted in 2% of briakinumab participants compared to 0% (0/14) of placebo participants (RR 0.82, 95% CI 0.04 to 16.34; low-certainty evidence). The AEs leading to study withdrawal were not described. AUTHORS' CONCLUSIONS: Moderate-certainty evidence suggests that ustekinumab is probably effective for the maintenance of clinical remission and response in people with moderate to severe CD in remission without an increased risk of adverse events (high-certainty evidence) or serious adverse events (moderate-certainty evidence) relative to placebo. The effect of briakinumab on maintenance of clinical remission and response in people with moderate to severe Crohn's disease in remission was uncertain as the certainty of the evidence was low. The effect of briakinumab on adverse events and serious adverse events was also uncertain due to low-certainty evidence. Further studies are required to determine the long-term efficacy and safety of subcutaneous ustekinumab maintenance therapy in Crohn's disease and whether it should be used by itself or in combination with other agents. Future research comparing ustekinumab with other biologic medications will help to determine when treatment with ustekinumab in CD is most appropriate. Currently, there is an ongoing study that compares ustekinumab with adalimumab. This review will be updated when the results of this study become available. The manufacturers of briakinumab have stopped production of this medication, thus further studies of briakinumab are unlikely.