The association of the lipid profile with knee and hand osteoarthritis severity: the IMI-APPROACH cohort.

OBJECTIVE: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. DESIGN: We used baseline data from the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort, comprising persons with knee OA fulfilling the clinical American College of Rheumatology classification criteria. Radiographic knee and hand OA severity was quantified with Kellgren-Lawrence sum scores. Knee and hand pain and function were assessed with validated questionnaires. We quantified fasted plasma higher order lipids and oxylipins with liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based platforms. Using penalised linear regression, we assessed the variance in OA severity explained by lipidomics, with adjustment for clinical covariates (age, sex, body mass index (BMI) and lipid lowering medication), measurement batch and clinical centre. RESULTS: In 216 participants (mean age 66 years, mean BMI 27.3 kg/m2, 75% women) we quantified 603 higher order lipids (triacylglycerols, diacylglycerols, cholesteryl esters, ceramides, free fatty acids, sphingomyelins, phospholipids) and 28 oxylipins. Lipidomics explained 3% and 2% of the variance in radiographic knee and hand OA severity, respectively. Lipids were not associated with knee pain or function. Lipidomics accounted for 12% and 6% of variance in hand pain and function, respectively. The investigated OA severity outcomes were associated with the lipidomic fraction of bound and free arachidonic acid, bound palmitoleic acid, oleic acid, linoleic acid and docosapentaenoic acid. CONCLUSIONS: Within the APPROACH cohort lipidomics explained a minor portion of the variation in OA severity, which was most evident for the outcome hand pain. Our results suggest that eicosanoids may be involved in OA severity.

Early vs. standard reversal ileostomy: a systematic review and meta-analysis.

BACKGROUND: Formation of a defunctioning loop ileostomy is common after mid and low rectal resection. Historically, they were reversed between 3 and 6 months after initial resection. Recently, earlier closure (< 14 days) has been suggested by some current randomised controlled trials. The aim of this study was to investigate the effect of early stoma closure on surgical and patient outcomes. METHODS: A systematic review of the current randomised controlled trial literature comparing early and standard ileostomy closure after rectal surgery was performed. Specifically, we examined surgical outcomes including; morbidity, mortality and quality of life. RESULTS: Six studies met the predefined criteria and were included in our analysis. 275 patients underwent early stoma closure compared with 259 patients having standard closure. Overall morbidity was similar between both groups (25.5% vs. 21.6%) (OR, 1.47; 95% CI 0.75-2.87). However, there tended to be more reoperations (8.4 vs. 4.2%) (OR, 2.02, 95% CI 0.99-4.14) and small bowel obstructions/postoperative ileus (9.3% vs. 4.4%) (OR 0.44, 95% CI 0.22-0.90) in the early closure group, but no difference across the other domains. CONCLUSIONS: Early closure appears to be a feasible in highly selective cases after good perioperative counselling and shared decision-making. Further research on quality of life outcomes and long term benefits is necessary to help define which patients are suitable candidates for early closure.

Immunotherapy use outside clinical trial populations: never say never?

BACKGROUND: Based on favourable outcomes in clinical trials, immune checkpoint inhibitors (ICIs), most notably programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, are now widely used across multiple cancer types. However, due to their strict inclusion and exclusion criteria, clinical studies often do not address challenges presented by non-trial populations. DESIGN: This review summarises available data on the efficacy and safety of ICIs in trial-ineligible patients, including those with autoimmune disease, chronic viral infections, organ transplants, organ dysfunction, poor performance status, and brain metastases, as well as the elderly, children, and those who are pregnant. In addition, we review data concerning other real-world challenges with ICIs, including timing of therapy switch, relationships to radiotherapy or surgery, re-treatment after an immune-related toxicity, vaccinations in patients on ICIs, and current experience around ICI and coronavirus disease-19. Where possible, we provide recommendations to aid the often-difficult decision-making process in those settings. CONCLUSIONS: Data suggest that ICIs are often active and have an acceptable safety profile in the populations described above, with the exception of PD-1 inhibitors in solid organ transplant recipients. Decisions about whether to treat with ICIs should be personalised and require multidisciplinary input and careful counselling of patients with respect to potential risks and benefits. Clinical judgements need to be carefully weighed, considering factors such as underlying cancer type, feasibility of alternative treatment options, or activity in trial-eligible patients.

Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study.

BACKGROUND: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. PATIENTS AND METHODS: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. RESULTS: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. CONCLUSION: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.

The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers.

BACKGROUND: KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12CKRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective. DESIGN: The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers. RESULTS: We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options. CONCLUSIONS: New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.

Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH.

PURPOSE: Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis. METHODS: A retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis. RESULTS AND CONCLUSIONS: Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P < 0.001), TSH index (P < 0.001) and standardised TSH index (P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis.

Cutaneous toxicities in patients with melanoma receiving checkpoint inhibitor therapy: a retrospective review. The experience of a single large specialist institution.

Checkpoint inhibitor (CPI) therapy has significantly improved overall survival for metastatic melanoma, and is now approved for use in the adjuvant setting. Modulating the immune system is recognized to cause cutaneous immune-related adverse events (irAEs). We conducted a retrospective observational cohort study of adult patients with melanoma at our tertiary referral centre, who received CPI therapy from 2006 to March 2018. This is the single largest study of cutaneous irAEs occurring on CPI therapy in patients with melanoma to date and encompasses 12 years. The results showed that cutaneous toxicity occurs in 24% of patients but is generally manageable, with < 5% patients discontinuing treatment.

Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy.

Patients with cancer and with preexisting active autoimmune diseases (ADs) have been excluded from immunotherapy clinical trials because of concerns for high susceptibility to the development of severe adverse events resulting from exacerbation of their preexisting ADs. However, a growing body of evidence indicates that immune-checkpoint inhibitors (ICIs) may be safe and effective in this patient population. However, baseline corticosteroids and other nonselective immunosuppressants appear to negatively impact drug efficacy, whereas retrospective and case report data suggest that use of specific immunosuppressants may not have the same consequences. Therefore, we propose here a two-step strategy. First, to lower the risk of compromising ICI efficacy before their initiation, nonselective immunosuppressants could be replaced by specific selective immunosuppressant drugs following a short rotation phase. Subsequently, combining ICI with the selective immunosuppressant could prevent exacerbation of the AD. For the most common active ADs encountered in the context of cancer, we propose specific algorithms to optimize ICI therapy. These preventive strategies go beyond current practices and recommendations, and should be practiced in ICI-specialized clinics, as these require multidisciplinary teams with extensive knowledge in the field of clinical immunology and oncology. In addition, we challenge the exclusion from ICI therapy for patients with cancer and active ADs and propose the implementation of an international registry to study such novel strategies in a prospective fashion.

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.

Collateral damage: the impact on outcomes from cancer surgery of the COVID-19 pandemic.

BACKGROUND: Cancer diagnostics and surgery have been disrupted by the response of health care services to the coronavirus disease 2019 (COVID-19) pandemic. Progression of cancers during delay will impact on patients' long-term survival. PATIENTS AND METHODS: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of 3 and 6 months and periods of disruption of 1 and 2 years. Using health care resource costing, we contextualise attributable lives saved and life-years gained (LYGs) from cancer surgery to equivalent volumes of COVID-19 hospitalisations. RESULTS: Per year, 94 912 resections for major cancers result in 80 406 long-term survivors and 1 717 051 LYGs. Per-patient delay of 3/6 months would cause attributable death of 4755/10 760 of these individuals with loss of 92 214/208 275 life-years, respectively. For cancer surgery, average LYGs per patient are 18.1 under standard conditions and 17.1/15.9 with a delay of 3/6 months (an average loss of 0.97/2.19 LYGs per patient), respectively. Taking into account health care resource units (HCRUs), surgery results on average per patient in 2.25 resource-adjusted life-years gained (RALYGs) under standard conditions and 2.12/1.97 RALYGs following delay of 3/6 months. For 94 912 hospital COVID-19 admissions, there are 482 022 LYGs requiring 1 052 949 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.08 LYG and 0.46 RALYGs. CONCLUSIONS: Modest delays in surgery for cancer incur significant impact on survival. Delay of 3/6 months in surgery for incident cancers would mitigate 19%/43% of LYGs, respectively, by hospitalisation of an equivalent volume of admissions for community-acquired COVID-19. This rises to 26%/59%, respectively, when considering RALYGs. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued.

Robust estimation of quantitative perfusion from multi-phase pseudo-continuous arterial spin labeling.

PURPOSE: Multi-phase PCASL has been proposed as a means to achieve accurate perfusion quantification that is robust to imperfect shim in the labeling plane. However, there exists a bias in the estimation process that is a function of noise in the data. In this work, this bias is characterized and then addressed in animal and human data. METHODS: The proposed algorithm to overcome bias uses the initial biased voxel-wise estimate of phase tracking error to cluster regions with different off-resonance phase shifts, from which a high-SNR estimate of regional phase offset is derived. Simulations were used to predict the bias expected at typical SNR. Multi-phase PCASL in 3 rat strains (n = 21) at 9.4 T was considered, along with 20 human subjects previously imaged using ASL at 3 T. The algorithm was extended to include estimation of arterial blood flow velocity. RESULTS: Based on simulations, a perfusion estimation bias of 6-8% was expected using 8-phase data at typical SNR. This bias was eliminated when a high-precision estimate of phase error was available. In the preclinical data, the bias-corrected measure of perfusion (107 ± 14 mL/100g/min) was lower than the standard analysis (116 ± 14 mL/100g/min), corresponding to a mean observed bias across strains of 8.0%. In the human data, bias correction resulted in a 15% decrease in the estimate of perfusion. CONCLUSIONS: Using a retrospective algorithmic approach, it was possible to exploit common information found in multiple voxels within a whole region of the brain, offering superior SNR and thus overcoming the bias in perfusion quantification from multi-phase PCASL.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Management options for chronic anal fissure: a systematic review of randomised controlled trials.

INTRODUCTION: Anal fissure is the most common cause of severe anorectal pain in adults, contributing significantly to coloproctology workloads. There are a wide variety of management options available, including topical nitrites, calcium channel blockers, botulinum toxin injection and sphincterotomy. The aim of this study was to review current options for the treatment of chronic anal fissure. METHODS: A comprehensive search identifying randomized controlled trials comparing treatment options for anal fissure published between January 2000 and February 2020 was performed. The primary outcome assessed was healing at 8 weeks post commencing treatment. Secondary outcomes included recurrence, intolerance of treatment and complications. RESULTS: A total of 2822 studies were identified. After removal of duplicates and non-relevant studies, we identified nine randomized controlled trials which met pre-defined criteria. There was a total of 775 patients. At 8 weeks, healing rates were 95.13% in those treated with sphincterotomy, 66.7% in the botulinum toxin group, 63.8% in the nitrate group, 52.3% for topical diltiazem and 50% for topical minoxidil. Recurrence was highest amongst those treated with botulinum toxin injection (41.7%) and lowest for sphincterotomy (6.9%). Although the absolute number is low, there was a risk of permanent incontinence with sphincterotomy. CONCLUSION: This review of the randomized control data demonstrates that healing was significantly higher amongst those treated with sphincterotomy versus more conservative modalities. Topical nitrites had similar outcomes to botulinum toxin injection but were poorly tolerated in comparison to other treatments. The benefit of sphincterotomy was at a cost of increased complications, notably permanent incontinence.

Management of anal intraepithelial neoplasia and anal squamous cell carcinoma at a tertiary referral centre with a dedicated infectious diseases unit: an 18-year review.

INTRODUCTION: Anal squamous cell carcinoma (ASCC) is a rare malignancy with rising incidence rates. Risk factors include human immunodeficiency virus (HIV) infection, high-risk sexual activity and HPV-related genitourinary dysplasia/neoplasia. There is an overlap between high-risk patients and those attending HIV Medicine/Sexual Health (HMSH) services. We hypothesised that HMSH involvement may facilitate earlier referral to colorectal surgeons, with better outcomes. METHODS: Retrospective review of all ASCC and anal intraepithelial neoplasia (AIN) treated at a tertiary-referral hospital with a dedicated HMSH clinic between 2000 and 2018. Comparative analysis was performed of demographics, management and outcomes between HMSH and non-HMSH patients. RESULTS: One hundred and nine patients had anal pathology, eighty-five with ASCC (78%) and twenty-four with AIN (22%). Seventy (64%) were male. Median (range) age at ASCC diagnosis was 51 years (26-88). Thirty-six percent of all patients attended HMSH services, 28% were HIV positive, and 41% of males were men-who-have-sex-with-men (MSM). Eighty-one ASCC patients (97.5%) were treated with curative intent. Sixty-seven (80%) had primary chemoradiation therapy. Fifteen (17.5%) had primary surgical excision. Twelve (14%) developed recurrent disease. Ultimately, seven required salvage APR. Overall 3-year survival (3YS) was 76%. HMSH patients were significantly younger at ASCC diagnosis (p < 0.001), with a higher prevalence of HIV, HPV and MSM. HMSH attenders also tended to be diagnosed at earlier stages, were less likely to develop recurrence and achieved better overall outcomes, with a superior overall 3YS than non-HMSH patients (92% vs 72%, p = 0.037). CONCLUSION: ASCC incidence is increasing worldwide. The HMSH cohort has emerged as a distinct subpopulation of younger, high-risk, male patients. Collaboration between HMSH and colorectal surgeons offers an opportunity for risk reduction strategies and earlier intervention.

Prospective cohort study of ultrasound surveillance of regional lymph nodes in patients with intermediate-risk cutaneous melanoma.

BACKGROUND: For patients with intermediate-thickness melanoma, surveillance of regional lymph node basins by clinical examination alone has been reported to result in a larger number of lymph nodes involved by melanoma than if patients had initial sentinel node biopsy and completion dissection. This may result in worse regional control. A prospective study of both regular clinical examination and ultrasound surveillance was conducted to assess the effectiveness of these modalities. METHODS: Between 2010 and 2014, patients with melanoma of thickness 1·2-3·5 mm who had under-gone wide local excision but not sentinel node biopsy were recruited to a prospective observational study of regular clinical and ultrasound nodal surveillance. The primary endpoint was nodal burden within a dissected regional lymph node basin. Secondary endpoints included locoregional or distant relapse, progression-free and overall survival. RESULTS: Ninety patients were included in the study. After a median follow-up of 52 months, ten patients had developed nodal relapse as first recurrence, four had locoregional disease outside of an anatomical nodal basin as the first site of relapse and six had relapse with distant disease. None of the patients who developed relapse within a nodal basin presented with unresectable nodal disease. The median number of involved lymph nodes in patients undergoing lymphadenectomy for nodal relapse was 1 (range 1-2; mean 1·2). CONCLUSION: This study suggests that ultrasound surveillance of regional lymph node basins is safe for patients with melanoma who undergo a policy of nodal surveillance.

Colonic stenting as a bridge to surgery in malignant large bowel obstruction: oncological outcomes.

INTRODUCTION: Stenting of obstructing colorectal cancers obviates the need for emergency surgery, reducing initial morbidity and mortality rate associated with emergency surgery and facilitates full staging of the neoplastic process with an opportunity to optimize the patient for surgery. Some recent publications have suggested however that this approach may be associated with higher local recurrence rates. We examined our outcomes following colonic stenting as a bridge to resection. METHODS: A database was reviewed (2006-2018) of patients presenting with acute colorectal obstruction that proceeded to endoscopic stenting. We assessed the bridge to surgery strategy, its success, complication rate, and impact on recurrence and survival. RESULTS: Of a total of 103 patients who presented with acute malignant large bowel obstruction over this time period, 26 patients had potentially curable disease at presentation and underwent stenting as a bridge to surgery. The technical success rate for stenting in those managed as a bridge to surgery was 92% (n = 24/26) with 7.69% (n = 2/26) having a complication. There was one stent-related perforation. Median follow-up of this cohort was 31 months, with a 5-year overall survival of 53.5%. CONCLUSION: Colorectal stenting as a bridge to resection is a successful management strategy for those presenting with obstructing colorectal obstruction. Selective use is associated with lower rates of stoma formation, greater rates of laparoscopic resections with low complication rates, and acceptable oncological outcomes.

Outcomes following colonic stenting for malignant left-sided bowel obstruction: a systematic review of randomised controlled trials.

PURPOSE: Malignant bowel obstruction is a common presentation and is associated with high morbidity and mortality. Emergency resection is the traditional treatment modality. In recent years, colonic stenting as a bridge to surgery has become more prevalent. However, there is considerable debate surrounding its use. The aim of this review was to examine the technical and clinical success of self-expanding metal stent (SEMS) as a bridge to surgery for obstructing colorectal tumours. METHODS: We systematically reviewed randomised controlled trials using PubMed, Cochrane and SCOPUS databases. Included studies must have compared outcomes in SEMS as a bridge to surgery with those proceeding straight to emergency resection. RESULTS: A total of 1245 studies were identified. After removal of duplicates and non-relevant studies, we identified seven articles which met the predefined criteria. This review observed that 81% of SEMS were technically successful, with 76% of patients having restoration of gastrointestinal function. Iatrogenic perforation rate was 5%. One-fifth of patients required emergency surgery following stent placement, and permanent stoma rate was 8.7%. CONCLUSION: This study observed that SEMS as a bridge to surgery is associated with good technical and clinical success, with low rates of perforation and permanent stoma. SEMS should be part of the treatment armamentarium for obstructing colorectal neoplasms, but careful patient selection and institutional expertise are important factors for success.

Should MRI Be the Imaging Modality of Choice in Suspected Appendicitis During Pregnancy?

Aim The aim of this review was to evaluate the efficacy of magnetic resonance imaging (MRI) in determining appendicitis during pregnancy. Methods We retrospectively reviewed the clinical course for all pregnant patients with suspected appendicitis from 2013-2018. We evaluated the efficacy of MRI and Alvarado scoring and its impact on management. Results Twenty-nine pregnant patients with suspected appendicitis had an MRI. The majority (90%, n=26/29) had normal diagnostics with two patients (10.3%) having findings consistent with acute appendicitis. Two other patients proceeded to laparoscopy, one with an inconclusive MRI, and one patient with clinical appendicitis. We found no accurate correlation between pregnancy and Alvarado scoring. Conclusion MRI is a safe adjunct in accurately diagnosing appendicitis in pregnancy. Its routine use could help reduce rates of negative appendectomies and the potential risk to maternal and fetal health.

Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature.

Background: Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following large Phase III trials. Immune-related neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as <1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab. We also review the existing literature and propose an investigation and management algorithm. Methods: All patients with advanced melanoma treated with ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab (ipi + nivo), managed at the Royal Marsden Hospital between September 2010 and December 2015, including patients on (published) clinical trials were included. Medical records for each patient were reviewed and information on neurotoxicity recorded. A systematic search strategy was performed to collate existing reports of neurological toxicity. Results: In total, 413 immunotherapy treatment episodes in 352 patients were included, with median follow-up of 26.7 months. Ten cases of neurotoxicity were recorded, affecting 2.8% of patients overall, ranging from grade 1 to 4, affecting both central and peripheral nervous systems. A rate of 14% was noted with ipi + nivo. Three of five patients commenced on corticosteroids responded to these. Six patients had made a full recovery at the time of reporting. A favorable radiological response was found in 7 of the 10 cases. Unusual presentations are described in detail. Conclusions: Neurological toxicity is not uncommon, and may be more frequent in patients treated with combination ipi + nivo. Patterns of presentation and response to treatment are varied. A prompt and considered approach is required to optimize outcomes in this group of patients.