A three-arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel in metastatic uveal melanoma.

AIMS: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel. PATIENTS AND METHODS: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level. RESULTS: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved. CONCLUSIONS: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing.

Editor's Choice - Comparison of Open Surgery and Endovascular Techniques for Juxtarenal and Complex Neck Aortic Aneurysms: The UK COMPlex AneurySm Study (UK-COMPASS) - Peri-operative and Midterm Outcomes.

OBJECTIVE: Treatment of juxtarenal and complex neck abdominal aortic aneurysms (AAAs) is now commonly by endovascular rather than open surgical repair (OSR). Published comparisons show poor validity and scientific precision. UK-COMPASS is a comparative cohort study of endovascular treatments vs. OSR for patients with an AAA unsuitable for standard on label endovascular aneurysm repair (EVAR). METHODS: All procedures for AAA in England (November 2017 to October 2019) were identified, AAA anatomy assessed in a Corelab, peri-operative risk scores determined, and propensity scoring used to identify patients suitable for either endovascular treatment or OSR. Patients were stratified by aneurysm neck length (0 - 4 mm, 5 - 9 mm, or ≥ 10 mm) and operative risk; the highest quartile was considered high risk and the remainder standard risk. Death was the primary outcome measure. Endovascular treatments included fenestrated EVAR (FEVAR) and off label standard EVAR (± adjuncts). RESULTS: Among 8 994 patients, 2 757 had AAAs that were juxtarenal, short neck, or complex neck in morphology. Propensity score stratification and adjustment method comparisons included 1 916 patients. Widespread off label use of standard EVAR devices was noted (35.6% of patients). The adjusted peri-operative mortality rate was 2.9%, lower for EVAR (1.2%; p = .001) and FEVAR (2.2%; p = .001) than OSR (4.5%). In standard risk patients with a 0 - 4 mm neck, the mortality rate was 7.4% following OSR and 2.3% following FEVAR. Differences were smaller for patients with a neck length ≥ 5 mm: 2.1% OSR vs. 1.0% FEVAR. At 3.5 years of follow up, the overall mortality rate was 20.7% in the whole study population, higher following FEVAR (27.6%) and EVAR (25.2%) than after OSR (14.2%). However, in the 0 - 4 mm neck subgroup, overall survival remained equivalent. The aneurysm related mortality rate was equivalent between treatments, but re-intervention was more common after EVAR and FEVAR than OSR. CONCLUSION: FEVAR proves notably safer than OSR in the peri-operative period for juxtarenal aneurysms (0 - 4 mm neck length), with comparable midterm survival. For patients with short neck (5 - 9 mm) and complex neck (≥ 10 mm) AAAs, overall survival was worse in endovascularly treated patients compared with OSR despite relative peri-operative safety. This warrants further research and a re-appraisal of the current clinical application of endovascular strategies, particularly in patients with poor general survival outlook owing to comorbidity and age.

Tumor-Infiltrating CD103+ Tissue-Resident Memory T Cells and CD103-CD8+ T Cells in HNSCC Are Linked to Outcome in Primary but not Metastatic Disease.

PURPOSE: High numbers of tumor-infiltrating lymphocytes (TIL) are linked to better survival in patients with cancer. Tissue-resident memory T cells (TRM; CD8+CD103+) are recognized as a key player of anticancer immune response. To assess TRM cells in primary, metastatic, and recurrent head and neck squamous cell carcinoma (HNSCC), we developed a tissue microarray (TMA) and used multiplex IHC (MxIHC). EXPERIMENTAL DESIGN: Samples from primary tumors of 379 HNSCC cases treated at Southampton Hospitals between 2000 and 2016 were collected and analyzed. Of these, 105 cases had lymph node metastases and 82 recurrences. A TMA was generated with triplicate cores for each sample. MxIHC with a stain-and-strip approach was performed using CD8, CD103, and TIM3. Scanned slides were analyzed (digital image analysis) and quality checked (QC). RESULTS: After QC, 194 primary tumors, 76 lymph node metastases, and 65 recurrences were evaluable. Alcohol consumption was statistically significantly correlated with a reduction of TRM cells in primary tumors (nondrinker vs. heavy drinker: P = 0.0036). The known survival benefit of TRM cell infiltration in primary tumors was not found for lymph node metastasis. In recurrences, a high TRM cell number led to a favorable outcome after 12 months. The checkpoint molecule TIM3, was expressed significantly higher on TRM and non-TRM cells in the lymph node compared with primary tumors (P < 0.0001), which was also seen in recurrences (P = 0.0134 and P = 0.0007, respectively). CONCLUSIONS: We confirm the prognostic impact of TIL in primary tumors and in recurrences. TRM cell density in lymph node metastases was not linked to outcome. The role of TIM3, as a therapeutic target remains to be defined.

Determining the Effectiveness of Fibrin Sealants in Reducing Complications in Patients Undergoing Lateral Neck Dissection (DEFeND): A Randomised External Pilot Trial.

OBJECTIVES: High-quality randomised controlled trials (RCT) to support the use of Fibrin Sealants (FS) in neck dissection (ND) are lacking. The DEFeND trial assessed critical pilot/feasibility questions and signals from clinical outcomes to inform a future definitive trial. PATIENTS AND METHODS: The study design piloted was a blinded surgical RCT. All participants underwent unilateral ND for head and neck cancer. Interventional arm: ND with application of FS. CONTROL ARM: ND alone. Feasibility outcomes included recruitment, effectiveness of blinding, protocol adherence and evaluating administrative processes. Clinical outcomes included surgical complications (primary outcome), drainage volume, time to drain removal, length of hospital stay, pain and the Neck Dissection Impairment Index. RESULTS: Recruitment completed ahead of time. Fifty-three patients were recruited, and 48 were randomised at a rate of 5.3 patients/month. Blinding of patients, research nurses and outcome assessors was effective. Two protocol deviations occurred. Two patients were lost to follow-up. The mean (SD) Comprehensive Complication Index in the interventional arm was 6.5 (12.8), and it was 9.9 (14.2) in the control arm. The median (IQR) time to drain removal (days) was shorter in the interventional arm (2.67 (2.42, 3.58) vs. 3.40 (2.50, 4.27)). However, this did not translate to a clinically significant reduction in median (IQR) length of hospital stay in days (intervention: 3.48 (2.64, 4.54), control: 3.74 (3.11, 4.62)). CONCLUSION: The proposed trial design was effective, and a definitive surgical trial is feasible. Whilst there was a tendency for FS to improve clinical outcomes, the effect size did not reach clinical or statistical significance. (ISRCTN99181100).

Study protocol: PreOperative Brain Irradiation in Glioblastoma (POBIG) - A phase I trial.

Background: Glioblastoma is a high-grade aggressive neoplasm whose outcomes have not changed in decades. In the current treatment pathway, tumour growth continues and remains untreated for several weeks post-diagnosis. Intensified upfront therapy could target otherwise untreated tumour cells and improve the treatment outcome. POBIG will evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma, assessed by the maximum tolerated dose (MTD) and maximum tolerated irradiation volume (MTIV). Methods: POBIG is an open-label, dual-centre phase I dose and volume escalation trial that has received ethical approval. Patients with a new radiological diagnosis of glioblastoma will be screened for eligibility. This is deemed sufficient due to the high accuracy of imaging and to avoid treatment delay. Eligible patients will receive a single fraction of preoperative radiotherapy ranging from 6 to 14 Gy followed by their standard of care treatment comprising maximal safe resection and postoperative chemoradiotherapy (60 Gy/30 fr) with concurrent and adjuvant temozolomide). Preoperative radiotherapy will be directed to the part of the tumour that is highest risk for remaining as postoperative residual disease (hot spot). Part of the tumour will remain unirradiated (cold spot) and sampled separately for diagnostic purposes. Dose/volume escalation will be guided by a Continual Reassessment Method (CRM) model. Translational opportunities will be afforded through comparison of irradiated and unirradiated primary glioblastoma tissue. Discussion: POBIG will help establish the role of radiotherapy in preoperative modalities for glioblastoma. Trial registration: NCT03582514 (clinicaltrials.gov).

BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification.

The nuclear deubiquitylase BRCA1-associated protein 1 (BAP1) is frequently inactivated in malignant pleural mesothelioma (MPM) and germline BAP1 mutation predisposes to cancers including MPM. To explore the influence on cell physiology and drug sensitivity, we sequentially edited a predisposition mutation (w-) and a promoter trap (KO) into human mesothelial cells. BAP1w-/KO MeT5A cells express less BAP1 protein and phenocopy key aspects of BAP1 loss in MPM. Stable isotope labeling with amino acids in cell culture-mass spectrometry revealed evidence of metabolic adaptation, with concomitant alteration of cellular metabolites. In MeT5A, BAP1 deficiency reduces glycolytic enzyme levels but increases enzymes involved in the tricarboxylic acid cycle and anaplerotic pathways. Notably both argininosuccinate synthase 1 (ASS1), essential for cellular synthesis of arginine, and its substrate aspartate, are elevated in BAP1w-/KO MeT5A cells. Likewise, ASS1 expression is higher in BAP1-altered MPM cell lines, and inversely correlates with BAP1 in The Cancer Genome Atlas MESO dataset. Elevated ASS1 is also evident by IHC staining in epithelioid MPM lacking nuclear BAP1 expression, with improved survival among patients with BAP1-negative/ASS1-expressing tumors. Alterations in arginine metabolism may sensitize cells to metabolic drugs and we find that BAP1-negative/ASS1-expressing MPM cell lines are more sensitive to ASS1 inhibition, although not to inhibition of purine synthesis by mizoribine. Importantly, BAP1w-/KO MeT5A become desensitized to arginine deprivation by pegylated arginine deiminase (ADI-PEG20), phenocopying BAP1-negative/ASS1-expressing MPM cell lines. IMPLICATIONS: Our data reveal an interrelationship between BAP1 and arginine metabolism, providing a potential means of identifying patients with epithelioid MPM likely to benefit from ADI-PEG20.

Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma.

OBJECTIVE: GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy. DESIGN: We analysed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4 knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models. RESULTS: GATA4 messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 had a minor transcriptional impact but low expression of GATA4 enhanced the effects of GATA6 low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. CONCLUSIONS: GATA4 and GATA6 cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.

Effects of Nitisinone on Oxidative and Inflammatory Markers in Alkaptonuria: Results from SONIA1 and SONIA2 Studies.

Nitisinone (NTBC) was recently approved to treat alkaptonuria (AKU), but there is no information on its impact on oxidative stress and inflammation, which are observed in AKU. Therefore, serum samples collected during the clinical studies SONIA1 (40 AKU patients) and SONIA2 (138 AKU patients) were tested for Serum Amyloid A (SAA), CRP and IL-8 by ELISA; Advanced Oxidation Protein Products (AOPP) by spectrophotometry; and protein carbonyls by Western blot. Our results show that NTBC had no significant effects on the tested markers except for a slight but statistically significant effect for NTBC, but not for the combination of time and NTBC, on SAA levels in SONIA2 patients. Notably, the majority of SONIA2 patients presented with SAA > 10 mg/L, and 30 patients in the control group (43.5%) and 40 patients (58.0%) in the NTBC-treated group showed persistently elevated SAA > 10 mg/L at each visit during SONIA2. Higher serum SAA correlated with lower quality of life and higher morbidity. Despite no quantitative differences in AOPP, the preliminary analysis of protein carbonyls highlighted patterns that deserve further investigation. Overall, our results suggest that NTBC cannot control the sub-clinical inflammation due to increased SAA observed in AKU, which is also a risk factor for developing secondary amyloidosis.

A Multicenter, Randomized, Double-Blinded, Clinical Trial Comparing Cattell-Warren and Blumgart Anastomoses Following Partial Pancreatoduodenectomy: PANasta Trial.

Whether a Blumgart anastomosis (BA) is superior to Cattell-Warren anastomosis (CWA) in terms of postoperative pancreatic fistula (POPF) following pancreatoduodenectomy. Importance: Complications driven by POPF following pancreatic cancer resection may hinder adjuvant therapy, shortening survival. BA may reduce complications compared to CWA, improving the use of adjuvant therapy and prolonging survival. Methods: A multicenter double-blind, controlled trial of patients undergoing resection for suspected pancreatic head cancer, randomized during surgery to a BA or CWA, stratified by pancreatic consistency and duct diameter. The primary end point was POPF, and secondary outcome measures were adjuvant therapy use, specified surgical complications, quality of life, and survival from the date of randomization. For a 10% POPF reduction, 416 patients were required, 208 per arm (two-sided α = 0·05; power = 80%). Results: Z-score at planned interim analysis was 0.474 so recruitment was held to 238 patients; 236 patients were analyzed (112 BA and 124 CWA). No significant differences in POPF were observed between BA and CWA, odds ratio (95% confidence interval [CI]) 1·04 (0.58-1.88), P = 0.887, nor in serious adverse events. Adjuvant therapy was delivered to 98 (62%) of 159 eligible patients with any malignancy; statistically unrelated to arm or postoperative complications. Twelve-month overall survival, hazard ratio (95% CI), did not differ between anastomoses; BA 0.787 (0.713-0.868) and CWA 0.854 (0.792-0.921), P = 0.266, nor for the 58 patients with complications, median (IQR), 0.83 (0.74-0.91) compared to 101 patients without complications 0.82 (0.76-0.89) (P = 0.977). Conclusions: PANasta represents the most robust analysis of BA versus CWA to date.

United Kingdom Early Detection Initiative (UK-EDI): protocol for establishing a national multicentre cohort of individuals with new-onset diabetes for early detection of pancreatic cancer.

INTRODUCTION: Pancreatic cancer is a leading cause of cancer deaths worldwide. Screening for this disease has potential to improve survival. It is not feasible, with current screening modalities, to screen the asymptomatic adult population. However, screening of individuals in high-risk groups is recommended. Our study aims to provide resources and data that will inform strategies to screen individuals with new-onset diabetes (NOD) for pancreatic cancer. METHODS AND ANALYSIS: The United Kingdom Early Detection Initiative (UK-EDI) for pancreatic cancer is a national, prospective, observational cohort study that aims to recruit 2500 individuals with NOD (<6 months postdiagnosis) aged 50 years and over, with follow-up every 6 months, over a 3-year period. For study eligibility, diagnosis of diabetes is considered to be clinical measurement of haemoglobin A1c ≥48 mmol/mol. Detailed clinical information and biospecimens will be collected at baseline and follow-up to support the development of molecular, epidemiological and demographic biomarkers for earlier detection of pancreatic cancer in the high-risk NOD group. Socioeconomic impacts and cost-effectiveness of earlier detection of pancreatic cancer in individuals with NOD will be evaluated. The UK-EDI NOD cohort will provide a bioresource for future early detection research to be conducted. ETHICS AND DISSEMINATION: The UK-EDI study has been reviewed and approved by the London-West London and GTAC Research Ethics Committee (Ref 20/LO/0058). Study results will be disseminated through presentations at national and international symposia and publication in peer-reviewed, Open Access journals.

Quantitation of phosphohistidine in proteins in a mammalian cell line by 31P NMR.

There is growing evidence to suggest that phosphohistidines are present at significant levels in mammalian cells and play a part in regulating cellular activity, in particular signaling pathways related to cancer. Because of the chemical instability of phosphohistidine at neutral or acid pH, it remains unclear how much phosphohistidine is present in cells. Here we describe a protocol for extracting proteins from mammalian cells in a way that avoids loss of covalent phosphates from proteins, and use it to measure phosphohistidine concentrations in human bronchial epithelial cell (16HBE14o-) lysate using 31P NMR spectroscopic analysis. Phosphohistidine is determined on average to be approximately one third as abundant as phosphoserine and phosphothreonine combined (and thus roughly 15 times more abundant than phosphotyrosine). The amount of phosphohistidine, and phosphoserine/phosphothreonine per gram of protein from a cell lysate was determined to be 23 µmol/g and 68 µmol/g respectively. The amount of phosphohistidine, and phosphoserine/phosphothreonine per cell was determined to be 1.8 fmol/cell, and 5.8 fmol/cell respectively. Phosphorylation is largely at the N3 (tele) position. Typical tryptic digest conditions result in loss of most of the phosphohistidine present, which may explain why the amounts reported here are greater than is generally seen using mass spectroscopy assays. The results further strengthen the case for a functional role of phosphohistidine in eukaryotic cells.

Postoperative Packing of Perianal Abscess Cavities (PPAC2): randomized clinical trial.

BACKGROUND: Perianal abscess is common. Traditionally, postoperative perianal abscess cavities are managed with internal wound packing, a practice not supported by evidence. The aim of this randomized clinical trial (RCT) was to assess if non-packing is less painful and if it is associated with adverse outcomes. METHODS: The Postoperative Packing of Perianal Abscess Cavities (PPAC2) trial was a multicentre, RCT (two-group parallel design) of adult participants admitted to an NHS hospital for incision and drainage of a primary perianal abscess. Participants were randomized 1:1 (via an online system) to receive continued postoperative wound packing or non-packing. Blinded data were collected via symptom diaries, telephone, and clinics over 6 months. The objective was to determine whether non-packing of perianal abscess cavities is less painful than packing, without an increase in perianal fistula or abscess recurrence. The primary outcome was pain (mean maximum pain score on a 100-point visual analogue scale). RESULTS: Between February 2018 and March 2020, 433 participants (mean age 42 years) were randomized across 50 sites. Two hundred and thirteen participants allocated to packing reported higher pain scores than 220 allocated to non-packing (38.2 versus 28.2, mean difference 9.9; P < 0.0001). The occurrence of fistula-in-ano was low in both groups: 32/213 (15 per cent) in the packing group and 24/220 (11 per cent) in the non-packing group (OR 0.69, 95 per cent c.i. 0.39 to 1.22; P = 0.20). The proportion of patients with abscess recurrence was also low: 13/223 (6 per cent) in the non-packing group and 7/213 (3 per cent) in the packing group (OR 1.85, 95 per cent c.i. 0.72 to 4.73; P = 0.20). CONCLUSION: Avoiding abscess cavity packing is less painful without a negative morbidity risk. REGISTRATION NUMBER: ISRCTN93273484 (https://www.isrctn.com/ISRCTN93273484). REGISTRATION NUMBER: NCT03315169 (http://clinicaltrials.gov).

Perianal abscess is a common, painful condition due to infection and swelling around the anus caused by blockage of the anal glands. The treatment of perianal abscess has stayed the same for over 50 years. An operation is performed under general anaesthetic to cut the skin and drain the infection. This is followed by continued internal dressing (packing) of the remaining cavity (hole) until the skin has healed over. Packing changes are needed multiple times a week for several weeks. Packing is the accepted treatment as it is believed to reduce the chance of the abscess coming back, and also reduces the chance of perianal fistula forming. There are no medical studies to support this idea. Perianal fistula (an abnormal passage between the skin around the anus, and the inside of the anal canal or rectum) is a long-term condition, which causes pain, and pus (and sometimes faeces) discharge, and often needs another operation (or multiple operations) to fix it. This trial was performed to demonstrate if no packing of a perianal abscess would result in a reduction of pain, with no increase in unwanted abscess recurrences and fistulas, in comparison to the standard treatment of packing. The trial recruited 433 people, who were randomly chosen to enter one of two groups; one to have their wound packed and the other to have no packing of the wound. After being discharged from hospital following surgery, the patients attended or were visited by a community nurse for the dressing to be changed or wound packed. Each patient provided information on pain from their wound, including worst pain each day and pain before, during, and after the changing of their dressing or packing. This and other information was gathered for the first 10 days after surgery and periodically until 6 months after surgery. The no-packing group experienced much less pain than the packing group. There was no difference in abscess recurrence and fistula formation between the non-packing and packing groups. The findings demonstrate that no packing of perianal abscess wounds after drainage operation is the best treatment.

Neoadjuvant Trastuzumab and Pertuzumab for Early HER2-Positive Breast Cancer: A Real World Experience.

Background: Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods: HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results: 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3-57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3-4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8-46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75-99%). Conclusion: This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate.

Paratracheal lymph node dissection during total (pharyngo-)laryngectomy: A systematic review and meta-analysis.

OBJECTIVES: The objective of this review was to determine the rate and risk factors of paratracheal lymph node (PTLN) involvement during total laryngectomy (TL) or total pharyngolaryngectomy (TPL). In addition, we aimed to assess its prognostic significance in terms of survival and peristomal recurrence. METHODS: A comprehensive electronic search was performed on PubMed, EMBASE, and CENTRAL databases. We searched for studies reporting outcomes of PTLN dissection during radical laryngeal surgery for squamous cell carcinoma of the larynx, hypopharynx or cervical oesophagus. RESULTS: We included a total of ten studies (838 patients). The overall rate of PTLN dissection positivity was 18.6% (20.7% for primary TL, 8.7% for salvage TL). Random-effects meta-analysis identified T4 stage, N+ stage of the lateral neck, subglottis involvement and primary tumour arising from the hypopharynx or cervical oesophagus as significant risk factors for PTLN involvement. CONCLUSIONS: This meta-analysis allowed to better define the risk of PTLN involvement during TL or TPL, in a bid to guide indication for PTLN dissection. There is a need for further large studies reporting rigorously the outcomes of PTLN dissection in order to establish stronger evidence-based recommendations.

Web-Based Psychological Interventions for People Living With and Beyond Cancer: Meta-Review of What Works and What Does Not for Maximizing Recruitment, Engagement, and Efficacy.

BACKGROUND: Despite high levels of psychological distress experienced by many patients with cancer, previous research has identified several barriers to accessing traditional face-to-face psychological support. Web-based psychosocial interventions have emerged as a promising alternative. OBJECTIVE: This meta-review aimed to synthesize evidence on recruitment challenges and enablers, factors that promote engagement and adherence to web-based intervention content, and factors that promote the efficacy of web-based psychosocial interventions for patients with cancer and cancer survivors. METHODS: We conducted a systematic search of previous reviews that investigated the recruitment, engagement, and efficacy of web-based and app-based psychosocial interventions in adult patients with cancer and cancer survivors. We searched PubMed, CINAHL, PsycINFO, and the Cochrane Library database for relevant literature. The search terms focused on a combination of topics pertaining to neoplasms and telemedicine. Two independent authors conducted abstract screening, full text screening, and data extraction for each identified article. RESULTS: A total of 20 articles met eligibility criteria. There was inconsistency in the reporting of uptake and engagement data; however, anxiety about technology and perceived time burden were identified as 2 key barriers. Web-based psychosocial oncology interventions demonstrated efficacy in reducing depression and stress but reported weak to mixed findings for distress, anxiety, quality of life, and well-being. Although no factors consistently moderated intervention efficacy, preliminary evidence indicated that multicomponent interventions and greater communication with a health care professional were preferred by participants and were associated with superior effects. CONCLUSIONS: Several consistently cited barriers to intervention uptake and recruitment have emerged, which we recommend future intervention studies address. Preliminary evidence also supports the superior efficacy of multicomponent interventions and interventions that facilitate communication with a health care professional. However, a greater number of appropriately powered clinical trials, including randomized trials with head-to-head comparisons, are needed to enable more confident conclusions regarding which web-based psychosocial oncology interventions work best and for whom. TRIAL REGISTRATION: PROSPERO CRD42020202633; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=202633.

Magnetic cryogels as a shape-selective and customizable platform for hyperthermia-mediated drug delivery.

Cryogels consisting of polyvinyl alcohol and iron (II, III) oxide magnetic nanoparticles coated with a model drug-acetaminophen, were developed as a tunable platform for thermally triggered drug release, based on shape-selective heat transfer. Two different shapes of cryogels; discs and spherical caps, were formed via adding polymer-nanoparticle-drug mixtures into 3D printed molds, followed by freeze-thawing five times. No additional chemical crosslinking agents were used for gel formation and the iron oxide nanoparticles were coated with acetaminophen using only citric acid as a hydrogen-bonding linker. The two gel shapes displayed varying levels of acetaminophen release within 42-50 °C, which are ideal temperatures for hyperthermia induced drug delivery. The amount and time of drug-release were shown to be tunable by changing the temperature of the medium and the shape of the gels, while keeping all other factors (ex. gel volume, surface area, polymer/nanoparticle concentrations and drug-loading) constant. The discs displayed higher drug release at all temperatures while being particularly effective at lower temperatures (42-46 °C), in contrast to the spherical caps, which were more effective at higher temperatures (48-50 °C). Magnetic hyperthermia-mediated thermal imaging and temperature profiling studies revealed starkly different heat transfer behavior from the two shapes of gels. The disc gels retained their structural integrity up to 51 °C, while the spherical caps were stable up to 59 °C, demonstrating shape-dependent robustness. The highly customizable physicochemical features, facile synthesis, biocompatibility and tunable drug release ability of these cryogels offer potential for their application as a low cost, safe and effective platform for hyperthermia-mediated drug delivery, for external applications such as wound care/muscle repair or internal applications such as melanoma treatment.

Addition of nintedanib or placebo to neoadjuvant gemcitabine and cisplatin in locally advanced muscle-invasive bladder cancer (NEOBLADE): a double-blind, randomised, phase 2 trial.

BACKGROUND: Recurrence is common after neoadjuvant chemotherapy and radical treatment for muscle-invasive bladder cancer. We investigated the effect of adding nintedanib to neoadjuvant chemotherapy on response and survival in muscle-invasive bladder cancer. METHODS: NEOBLADE was a parallel-arm, double-blind, randomised, placebo-controlled, phase 2 trial of neoadjuvant gemcitabine and cisplatin chemotherapy with nintedanib or placebo in locally advanced muscle-invasive bladder cancer. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 15 hospitals in the UK. Patients were randomly assigned (1:1) to nintedanib or placebo using permuted blocks with random block sizes of two or four, stratified by centre and glomerular filtration rate. Treatments were allocated using an interactive web-based system, and patients and investigators were masked to treatment allocation throughout the study. Patients received oral nintedanib (150 mg or 200 mg twice daily for 12 weeks) or placebo, in addition to usual neoadjuvant chemotherapy with intravenous gemcitabine 1000 mg/m2 on days 1 and 8 and intravenous cisplatin 70 mg/m2 on day 1 of a 3-weekly cycle. The primary endpoint was pathological complete response rate, assessed at cystectomy or at day 8 of cyclde 3 (plus or minus 7 days) if cystectomy did not occur. Primary analyses were done in the intention-to-treat population. The trial is registered with EudraCT, 2012-004895-01, and ISRCTN, 56349930, and has completed planned recruitment. FINDINGS: Between Dec 4, 2014, and Sept 3, 2018, 120 patients were recruited and were randomly allocated to receive nintedanib (n=57) or placebo (n=63). The median follow-up for the study was 33·5 months (IQR 14·0-44·0). Pathological complete response in the intention-to-treat population was reached in 21 (37%) of 57 patients in the nintedanib group and 20 (32%) of 63 in the placebo group (odds ratio [OR] 1·25, 70% CI 0·84-1·87; p=0·28). Grade 3 or worse toxicities were observed in 53 (93%) of 57 participants who received nintedanib and 50 (79%) of 63 patients in the placebo group (OR 1·65, 95% CI 0·74-3·65; p=0·24). The most common grade 3 or worse adverse events were thromboembolic events (17 [30%] of 57 patients in the nintedanib group vs 13 [21%] of 63 patients in the placebo group [OR 1·63, 95% CI 0·71-3·76; p=0·29]) and decreased neutrophil count (22 [39%] in the nintedanib group vs seven [11%] in the placebo group [5·03, 1·95-13·00; p=0·0006]). 45 treatment-related serious adverse events occurred in the nintedanib group and 43 occurred in the placebo group. One treatment-related death occurred in the placebo group, which was due to myocardial infarction. INTERPRETATION: The addition of nintedanib to chemotherapy was safe but did not improve the rate of pathological complete response in muscle-invasive bladder cancer. FUNDING: Boehringer Ingelheim.

Editor's Choice - Comparison of Open, Standard, and Complex Endovascular Aortic Repair Treatments for Juxtarenal/Short Neck Aneurysms: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Abdominal aortic aneurysms (AAAs) with adverse morphology of the aneurysm neck are "complex". Techniques employed to repair complex aneurysms include open surgical repair (OSR) and a number of on label endovascular techniques such as fenestrated endovascular aneurysm repair (FEVAR) and endovascular aneurysm repair (EVAR) with adjuncts (including chimneys and endo-anchors), as well as off label use of standard EVAR. The aim was to conduct a network meta-analysis (NMA) of published comparative outcomes. DATA SOURCES: An electronic search was performed in Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL). These databases were interrogated using the PubMed interface and the Healthcare Databases Advanced Search (HDAS) interface developed by the National Institute of Health and Care Excellence. REVIEW METHODS: Online databases were interrogated up to April 2020. Studies were included if they compared outcomes between at least two methods of repair for complex aneurysms (those with at least one adverse neck feature: absent/short neck, conicality, angulation, calcification, large diameter, and thrombus). The primary outcome measure was peri-operative death. Pre-registration was done in PROSPERO (CRD42020177482). RESULTS: The search identified 24 observational studies and 7854 patients who underwent OSR, FEVAR, off label EVAR, or chimney EVAR. No comparative studies included EVAR with endo-anchors. NMA was performed on 23 studies that reported outcomes of aneurysms with short/absent infrarenal neck. Compared with OSR, off label EVAR (relative risk [RR] 0.10, 95% confidence interval [CI] 0.01 - 0.41) and FEVAR (RR 0.62, 95% CI 0.32-0.94) were associated with lower peri-operative mortality. This difference was not seen at the midterm follow up (30 months). Compared with OSR, FEVAR was associated with a lower peri-operative myocardial infarction (MI) rate (RR 0.37, 95% CI 0.16 - 0.62) but a higher midterm re-intervention rate (hazard ratio 1.65, 95% CI 1.04 - 2.66). All studies had a "moderate" or "high" risk of bias. Confidence in the network findings (GRADE) was generally "low". CONCLUSION: This NMA demonstrated a peri-operative survival benefit for off label EVAR and FEVAR compared with OSR, potentially due to reduced risk of MI. FEVAR carries a greater midterm re-intervention risk than OSR, with potential implications for cost effectiveness. There is paucity of comparative data for cases with adverse neck features other than short length.

Rigid versus flexible endoscopy for managing ingested foreign bodies-can we improve pathways?

PURPOSE: This study aims to evaluate management pathways, outcomes and safety of rigid endoscopy (RE) and flexible endoscopy (FE) for the treatment of impacted foreign bodies of the upper gastrointestinal tract (UGIT) in adults. METHODS: Retrospective study, included all patients undergoing RE or FE for impacted UGIT foreign body over an 11-year-period. RESULTS: A total of 144 patients were included (95 FE and 49 RE). FE were performed under local anaesthetic or sedation, and RE under GA. Success rate of FE and RE were 95.8% and 95.9% respectively. During FE an intra-procedural biopsy was performed in 45/95 (47.3%); with 26/95(27.4%) identifying mucosal pathology. Complications was significantly higher in patients having RE (40.8% versus 6.3%, p = .001). CONCLUSION: FE and RE are effective for the therapeutic management of impacted UGIT foreign bodies. However, FE can be performed under LA and was associated with fewer complications, favouring FE where possible as a first line option.