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).

No evidence of compensatory changes in energy balance, despite reductions in body weight and liver fat, during dapagliflozin treatment in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled, cross-over trial (ENERGIZE).

AIM: This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by 1 H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI). RESULTS: In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m2 , glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (-2.84 vs. -0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI -127.9 to 139.3, p = .933); 15.8 g (95% CI -147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction -4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin. CONCLUSIONS: The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.

Biomedical relation extraction with knowledge base-refined weak supervision.

Biomedical relation extraction (BioRE) is the task of automatically extracting and classifying relations between two biomedical entities in biomedical literature. Recent advances in BioRE research have largely been powered by supervised learning and large language models (LLMs). However, training of LLMs for BioRE with supervised learning requires human-annotated data, and the annotation process often accompanies challenging and expensive work. As a result, the quantity and coverage of annotated data are limiting factors for BioRE systems. In this paper, we present our system for the BioCreative VII challenge-DrugProt track, a BioRE system that leverages a language model structure and weak supervision. Our system is trained on weakly labelled data and then fine-tuned using human-labelled data. To create the weakly labelled dataset, we combined two approaches. First, we trained a model on the original dataset to predict labels on external literature, which will become a model-labelled dataset. Then, we refined the model-labelled dataset using an external knowledge base. Based on our experiment, our approach using refined weak supervision showed significant performance gain over the model trained using standard human-labelled datasets. Our final model showed outstanding performance at the BioCreative VII challenge, achieving 3rd place (this paper focuses on our participating system in the BioCreative VII challenge). Database URL: http://wonjin.info/biore-yoon-et-al-2022.

Preliminary Data on Free Use of Fruits and Vegetables Containing Phenylalanine 76-100 mg/100 g of Food in 16 Children with Phenylketonuria: 6 Months Follow-Up.

In phenylketonuria (PKU), a previous intervention study assessing the patients ability to tolerate fruits and vegetables containing phenylalanine 76-100 mg/100 g without limit or measurement, found that an extra 50 mg/day phenylalanine, but not 100 mg/day, was tolerated from these fruits and vegetables. In a further 6-month extension study, we examined the effect of the 'free' use of this group of fruits and vegetables on blood phenylalanine control. For 6 months, the patients ate fruits and vegetables containing phenylalanine 76-100 mg/100 g without limit or measurement. Three-day diet diaries and the patients' weights were collected monthly. Blood phenylalanine spots were collected weekly aiming for blood phenylalanine levels <360 µmol/L. Retrospective blood phenylalanine was collected 6 months pre-trial. All 16 patients (69% females) from the intervention study took part in the extension study. Most of the patients (n = 14/16) had classical PKU with a median age of 10.5 years (range: 6-13). There was no statistically significant difference in the median blood phenylalanine pre-study (270, range: 50-760 µmol/L) compared to the 6-month extension study (250, range: 20-750 µmol/L) (p= 0.4867). The patients had a median of 21 and 22 bloodspots, pre- and post-trial, respectively. In the extension study, the patients had an actual mean intake of 11 g/day (4-37) natural protein and 65 g/day (60-80) protein equivalent from a protein substitute. The mean phenylalanine intake was 563 mg/day (200-1850) with only 19 mg/day (0-146) phenylalanine from fruits and vegetables containing phenylalanine 76-100 mg/100 g. The weight z-scores remained unchanged (1.52 vs. 1.60, p = 0.4715). There was no adverse impact on blood phenylalanine control when fruits and vegetables containing phenylalanine 76-100 mg/100 g were eaten without limit or measurement. However, the fruits and vegetable portion sizes eaten were small (60 g/week). Further longitudinal work is necessary to examine the 'free' use of fruits and vegetables containing phenylalanine 76-100 mg/100 g on metabolic control in patients with PKU.

Chemical Tools for Studying Phosphohistidine: Generation of Selective τ-Phosphohistidine and π-Phosphohistidine Antibodies.

Nonhydrolysable stable analogues of τ-phosphohistidine (τ-pHis) and π-pHis have been designed, aided by electrostatic surface potential calculations, and subsequently synthesized. The τ-pHis and π-pHis analogues (phosphopyrazole 8 and pyridyl amino amide 13, respectively) were used as haptens to generate pHis polyclonal antibodies. Both τ-pHis and π-pHis conjugates in the form of BSA-glutaraldehyde-τ-pHis and BSA-glutaraldehyde-π-pHis were synthesized and characterized by 31 P NMR spectroscopy. Commercially available τ-pHis (SC56-2) and π-pHis (SC1-1; SC50-3) monoclonal antibodies were used to show that the BSA-G-τ-pHis and BSA-G-π-pHis conjugates could be used to assess the selectivity of pHis antibodies in a competitive ELISA. Subsequently, the selectivity of the pHis antibodies generated by using phosphopyrazole 8 and pyridyl amino amide 13 as haptens was assessed by competitive ELISA against His, pSer, pThr, pTyr, τ-pHis and π-pHis. Antibodies generated by using phosphopyrazole 8 as a hapten were found to be selective for τ-pHis, and antibodies generated by using pyridyl amino amide 13 were found to be selective for π-pHis. Both τ- and π-pHis antibodies were shown to be effective in immunological experiments, including ELISA, western blot, and immunofluorescence. The τ-pHis antibody was also shown to be useful in the immunoprecipitation of proteins containing pHis.

Pyrroloiminoquinone Alkaloids: Total Synthesis of Makaluvamines A and K.

Herein, an efficient, scalable, and concise approach to an advanced pyrroloiminoquinone synthetic intermediate (6b) by way of a Larock indole synthesis is reported. The synthetic utility of this intermediate is demonstrated by its ready conversion to makaluvamines A (1) and K (4).

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.

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.

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.

Impact-Tardive Dyskinesia (Impact-TD) Scale: A Clinical Tool to Assess the Impact of Tardive Dyskinesia.

Objective: Tardive dyskinesia (TD) is a movement disorder that can negatively affect health-related quality of life. However, the impact of TD is not necessarily dependent solely on the objective severity of TD movements. There is currently no easy-to-use, standardized, clinician-rated assessment of the impact of TD on functioning. The aim of this consensus panel was to develop a scale (Impact-TD scale) to assess the impact of TD on patients' daily functioning in practice settings.Participants: Nine health care professionals with expertise in TD and clinical scale development met to discuss how TD negatively impacts the functional activities of patients.Evidence: This panel comprised 7 individuals from a previous panel that developed recommendations on the importance of optimally assessing the functional impact of TD. The previous panel published a narrative literature review that summarized the existing approaches to assess the impact of TD in clinical research and practice.Consensus Process: A modified Delphi process was used to assess agreement on the format and content of the Impact-TD scale. The panel discussed key features of the Impact-TD scale (ie, simplicity, usability, assessment of frequency of impact versus interference/distress). The scale aimed to describe specific consequences of TD symptoms with which patients may have difficulty.Conclusions: Consensus was reached on a list of consequences of TD symptoms that have a functional impact and were categorized in 4 functional domains: social, psychological/psychiatric, physical, and vocational/educational/recreational. The Impact-TD scale offers an easy-to-use clinical scale to measure the functional impact of TD in practice settings.

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.

Impact of Fruit and Vegetable Protein vs. Milk Protein on Metabolic Control of Children with Phenylketonuria: A Randomized Crossover Controlled Trial.

Fruits and vegetables containing phenylalanine ≤ 75 mg/100 g (except potatoes) have little impact on blood phenylalanine in phenylketonuria (PKU). In a randomized, controlled, crossover intervention trial, we examined the effect of increasing phenylalanine intake from fruits and vegetables, containing phenylalanine 76−100 mg /100 g, compared with milk protein sources on blood phenylalanine control. This was a five-phase study (4 weeks each phase). In Phase A, patients remained on their usual diet and then were randomly allocated to start Phase B and C (an additional phenylalanine intake of 50 mg/day, then 100 mg from fruits and vegetables containing phenylalanine 76−100 mg/100 g) or Phase D and E (an additional phenylalanine intake of 50 mg/day then 100 mg/day from milk sources). There was a 7-day washout with the usual phenylalanine-restricted diet between Phase B/C and D/E. Blood phenylalanine was measured on the last 3 days of each week. If four out of six consecutive blood phenylalanine levels were >360 µmol/L in one arm, this intervention was stopped. Sixteen patients (median age 10.5 y; range 6−12 y) were recruited. At baseline, a median of 6 g/day (range: 3−25) natural protein and 60 g/day (range: 60−80) protein equivalent from protein substitute were prescribed. Median phenylalanine levels were: Phase A­240 µmol/L; Phase B­260 µmol/L; Phase C­280 µmol/L; Phase D­270 µmol/L and Phase E­280 µmol/L. All patients tolerated an extra 50 mg/day of phenylalanine from fruit and vegetables, containing phenylalanine 76−100 mg/100 g, but only 11/16 (69%) tolerated an additional 100 mg /day. With milk protein, only 8/16 (50%) tolerated an extra 50 mg/day and only 5/16 (31%) tolerated an additional 100 mg/day of phenylalanine. Tolerance was defined as maintaining consistent blood phenylalanine levels < 360 µmol/L throughout each study arm. There was a trend that vegetable protein had less impact on blood phenylalanine control than milk protein, but overall, the differences were not statistically significant (p = 0.152). This evidence supports the PKU European Guidelines cutoff that fruit and vegetables containing 76−100 mg phenylalanine/100 g should be calculated as part of the phenylalanine exchange system. Tolerance of the 'free use' of these fruits and vegetables depends on inter-patient variability but cannot be recommended for all patients with PKU.

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.