Citation: Wounds. 2021, 33(1), E1-E5
Author: Caroline Lyons
Abstract: Introduction: Delayed healing and recurrence of diabetic foot ulcerations (DFUs) is often related to excessive pressure. Offloading, a mainstay of treatment, can be achieved through a variety of methods. Although pressure mitigation should be continued after wound resolution to prevent recurrence, many offloading modalities are discontinued at that point, with providers instead relying on patient self-directed use of appropriate inserts and shoe gear. Use of a novel offloading modality continued upon wound healing may help break the cycle of recurrent DFUs.
Case report: A patient presented with a 2-year history of recurrent DFU to the right fourth metatarsal head following amputation of the fourth digit. Recurrence continued despite self-reported compliance with therapeutic footwear use. Use of a novel offloading modality that incorporates intermittent pneumatic compression, smart technology for monitoring of patient compliance with use, and the ability to continue therapeutic shoe gear use upon wound resolution was initiated. Wound resolution was achieved, allowing for reconstructive surgery to further mitigate the potential for recurrence. The patient remains free of DFU recurrence for 3 years with continued use of the device's shoe gear.
Conclusions: Implementation of a novel offloading device, which facilitates enhanced perfusion, monitors patient compliance with use, and can be continued upon wound resolution, was able to break the cycle of a recurrent DFU.
Friday 30 April 2021
WUTH publication: Breaking the Cycle of Recurrent Diabetic Foot Ulceration: A Novel and Sustainable Offloading Modality to Treat Diabetic Foot Ulceration and Prevent Recurrence
WUTH publication: Do we achieve the Montgomery standard for consent in orthopaedic surgery?
Citation: British journal of hospital medicine. 2021, 82(4), 1-7
Author: Xenia N Tonge, Henry Crouch-Smith, Vijay Bhalaik, William D Harrison
Abstract: Aims/background: The Montgomery v Lanarkshire Health Board (2015) case set a precedent that has driven the modernisation of consenting practice. Failure to demonstrate informed consent is a common source of litigation. This quality improvement project aimed to provide pragmatic guidance for surgeons on consent and to improve the patient experience during decision making.
Methods: Elective orthopaedic patients were assessed and the quality of documented consent was recorded. Data were collected over two discrete cycles, with cycle 1 used as a baseline in practice. The following criteria were reviewed: grade of consenting clinician, alternative treatment options, description of specific risks, place and timing of consent and whether the patient received written information or a copied clinic letter. Cycle 1 results were presented to clinicians; a teaching session was provided for clinicians on the standard of consent expected and implementation of a change in practice was established with a re-audit in cycle 2.
Results: There were 111 patients included in cycle 1, and 96 patients in cycle 2. Consent was undertaken mostly by consultants (54%). Specific patient risks were documented in 50% of patients in cycle 1 and 60% in cycle 2. Risks associated with a specific procedure were documented in 42% in cycle 1 and 76% in cycle 2, alternative options in 48% (cycle 1) and 66% (cycle 2). A total of 14% of patients in cycle 1 and 8% in cycle 2 had documented written information provision. Copied letters to patients was only seen in 12% of all cycles. Documentation from dedicated consenting clinics outperformed standard clinics.
Conclusions: Highlighting poor documentation habits and refining departmental education can lead to improvements in practice. The use of consenting clinics should be considered and clinicians should individually reflect on how to address their own shortcomings. Other units should strongly consider a similar audit. This article provides stepwise advice to improve consent and specifics from which to audit.
Keywords: Consent; Elective surgery; Medicolegal; Montgomery; Orthopaedic surgery; Quality improvement; Surgery; Trauma and orthopaedics.
Thursday 29 April 2021
WUTH publication: Safety and Cost-Effectiveness of Interscalene Brachial Plexus Block With Sedation in Reverse Total Shoulder Replacement
Citation: Cureus. 2021, 13(3), e14106
Author: Kiran Ramesh, Muhammad Yusuf, Navnit Makaram, Ross Milton, Aji Mathew, Makaram Srinivasan
Abstract: Aims To investigate the safety and cost-effectiveness of interscalene brachial plexus block/regional anaesthesia (ISB-RA) in patients undergoing reverse total shoulder replacement. Patients and methods This retrospective study included 15 patients with symptomatic rotator cuff arthropathy who underwent reverse total shoulder arthroplasty (rTSA) under ISB-RA without general anaesthesia in the beach chair position from 2010 to 2018. The mean patient age was 77 years (range 59-82 years). Patients had associated medical comorbidities: American Society of Anesthesiologists (ASA) grade 2-4. Assessed parameters were: duration of anaesthesia, intra-operative systolic blood pressure variation, sedation and vasopressor use, duration of post-operative recovery, recovery scores, length of stay, and complications. A robust cost analysis was also performed. Results The mean (range) duration of anaesthesia was 38.66 (20-60) min. Maximum and minimum intra-operative systolic blood pressure ranges were 130-210 and 75-145 mmHg, respectively (mean [range] drop, 74.13 [33-125] mmHg). Mean (range) propofol dose was 1.74 (1-3.0) mg/kg/h. The Median (interquartile range) post-operative recovery time was 30 (20-50) min. The mean (range) postoperative recovery score (local scale, range 5-28 where lower values are superior) was 5.2 (5-8). The mean (range) length of stay was 8 (1-20 days); the two included patients with ASA grade 2 were both discharged within 24 hours. One patient with predisposing history developed pneumonia; however, there were no complications related to ISB-RA. The mean (range) cost per patient was £101.36 (£59.80-£132.20). Conclusions Our data demonstrate that rTSA under ISB-RA is safe, comfortable, and cost-effective. Notably, patients with ASA grade 2 who underwent rTSA under ISB-RA had a reduced length of stay and were discharged within 24 hours. Clinical relevance rTSA under ISB-RA is potentially a safe, cost-effective, and viable alternative for patients with multiple comorbidities.
Keywords: cost effectiveness; inter-scalene brachial plexus block; regional anaesthesia; reverse total shoulder replacement.
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Wednesday 28 April 2021
CCC publication: A phase III, double-blind, randomized study of nivolumab (NIVO) and ipilimumab (IPI), nivo monotherapy or placebo plus transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC)
Citation: Journal of Vascular and Interventional Radiology. 2021, 32(5 Sup), S52-3
Author: B. Sangro, J. Harding, M. Johnson, D. Palmer, J. Edeline, G. Abou-Alfa, A. Cheng, T. Decaens, A. El-Khoueiry, R. Finn, P. Galle, J. Park, T. Yau, D. Begic, Y. Shen, J. Neely, A. Sama, M. Kudo,
Abstract: Background: TACE is the most widely used locoregional therapy recommended for patients with intermediate-stage HCC (Barcelona Clinic Liver Cancer stage B). Despite the significant tumor responses that can be achieved with TACE, tumors commonly recur, progress, or are refractory. Clinical trials have explored the combination of TACE with tyrosine kinase inhibitors; however, these have not reported improved outcomes. HCC possesses a unique immunosuppressive microenvironment, which makes it an attractive target for immunotherapies, particularly immune checkpoint inhibitors. Furthermore, there is evidence that locoregional interventions induce changes in the immune environment that could promote synergy with checkpoint inhibitors. Preliminary data for the combination of TACE with nivolumab indicate an acceptable safety profile and promising efficacy (Harding et al. ASCO-GI 2020). NIVO monotherapy and NIVO+IPI combination therapy are both approved in the United States for patients with HCC previously treated with sorafenib. Together, these findings support investigation of TACE plus NIVO, IPI, or NIVO+IPI to address the therapeutic needs of patients with intermediate HCC. Methods: CheckMate 74W is a global, double-blind, placebo-controlled, 3-arm, randomized phase III trial. Patients with tumors that exceed the Beyond Milan and Up-to-7 criteria (7 being the sum of size [in centimeters] and number of tumors), eligible for TACE, with Eastern Cooperative Oncology Group performance status of 0 to 1 are eligible for enrollment. Patients must not have received prior locoregional therapies. Approximately 765 patients will be randomized in a 1:1:1 ratio to NIVO+IPI+TACE (arm A), NIVO+IPI placebo+TACE (arm B), or NIVO placebo+IPI placebo+TACE (arm C). Primary endpoints are the time to TACE progression (TTTP), assessed by blinded independent central review, and overall survival in arm A versus arm C. Secondary endpoints are TTTP and overall survival in arm B versus arm C, event-free survival, and progression-free survival. Clinical trial registry: NCT04340193
CCC publication: ESMO pays tribute to Professor José Baselga
Citation: Immuno-Oncology Technology. 2021, 6(3), 100130
Author: S. Peters, J. Tabernero, A. Cervantes, S. Banerjee, R. Giuliani, F. Lordick,
CCC publication: Human Mass Balance and Metabolite Profiling of [ 14 C]-Pamiparib, a Poly (ADP-Ribose) Polymerase Inhibitor, in Patients With Advanced Cancer
Citation: Clinical Pharmacology in Drug Development. 2021 Apr 19. Online ahead of print
Author: Song Mu, Daniel Palmer, Richard Fitzgerald, Claudia Andreu-Vieyra, Heather Zhang, Zhiyu Tang, Dan Su, Srikumar Sahasranaman
Abstract: Pamiparib, a selective poly (ADP-ribose) polymerase 1/2 inhibitor, demonstrated tolerability and antitumor activity in patients with solid tumors at 60 mg orally twice daily. This phase 1 open-label study (NCT03991494; BGB-290-106) investigated the absorption, metabolism, and excretion (AME) of 60 mg [14 C]-pamiparib in 4 patients with solid tumors. The mass balance in excreta, blood, and plasma radioactivity and plasma pamiparib concentration were determined along with metabolite profiles in plasma, urine, and feces. Unchanged pamiparib accounted for the most plasma radioactivity (67.2% ± 10.2%). Pamiparib was rapidly absorbed with a median time to maximum plasma concentration (Cmax ) of 2.00 hours (range, 1.00-3.05 hours). After reaching Cmax , pamiparib declined in a biphasic manner, with a geometric mean terminal half-life (t1/2 ) of 28.7 hours. Mean cumulative [14 C]-pamiparib excretion was 84.7% ± 3.5%. Pamiparib was mainly cleared through metabolism, primarily via N-oxidation and oxidation of the pyrrolidine ring. A dehydrogenated oxidative product (M3) was the most abundant metabolite in biosamples. A mean of 2.11% and 1.11% of [14 C]-pamiparib was excreted as unchanged pamiparib in feces and urine, respectively, indicating near-complete absorption and low renal clearance of parent drug. Cytochrome P450 (CYP) phenotyping demonstrated CYP2C8 and CYP3A involvement in pamiparib metabolism. These findings provide an understanding of pamiparib AME mechanisms and potential drug-drug interaction liability.
Keywords: DNA repair; absorption/metabolism/excretion; metabolite identification; pamiparib; pharmacokinetics.
CCC publication: Evaluation of failure modes and effect analysis for routine risk assessment of lung radiotherapy at a UK center
Citation: Journal of applied clinical medical physics. 2021, 22(5), 36-47. Epub 2021 Apr 9.
Author: Martyn D F Gilmore, Carl G Rowbottom
Abstract: Purpose: Explore the feasibility of adopting failure modes and effects analysis (FMEA) for risk assessment of a high volume clinical service at a UK radiotherapy center. Compare hypothetical failure modes to locally reported incidents.
Method: An FMEA for a lung radiotherapy service was conducted at a hospital that treats ~ 350 lung cancer patients annually with radical radiotherapy. A multidisciplinary team of seven people was identified including a nominated facilitator. A process map was agreed and failure modes identified and scored independently, final failure modes and scores were then agreed at a face-to-face meeting. Risk stratification methods were explored and staff effort recorded. Radiation incidents related to lung radiotherapy reported locally in a 2-year period were analyzed to determine their relation to the identified failure modes. The final FMEA was therefore a combination of prospective evaluation and retrospective analysis from an incident learning system.
Results: Thirty-six failure modes were identified for the pre-existing clinical service. The top failure modes varied according to the ranking method chosen. The process required 30 h of combined staff time. Over the 2-year period chosen, 38 voluntarily reported incidents were identified as relating to lung radiotherapy. Of these, 13 were not predicted by the identified failure modes, with six relating to delays in the process, three issues with appointment times, one communication error, two instances of a failure to image, and one technical fault deemed unpredictable by the manufacturer. Four additional failure modes were added to the FMEA following the incident analysis.
Conclusion: FMEA can be effectively applied to an established high volume service as a risk assessment method. Facilitation by an individual familiar with the FMEA process can reduce resource requirement. Prospective evaluation of risks should be combined with an incident reporting and learning system to produce a more comprehensive analysis of risk.
Keywords: FMEA; incident reporting; radiotherapy; risk analysis; risk assessment.
CCC publication: Estimates of Alpha/Beta (α/β) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP Trial
Citation: International journal of radiation oncology, biology, physics. 2021, 110(2), 596-608. 2021, S0360-3016(20), 34737-4. Online ahead of print.
Author: Douglas H Brand, Sarah C Brüningk, Anna Wilkins, Katie Fernandez, Olivia Naismith, Annie Gao, Isabel Syndikus, David P Dearnaley, Alison C Tree, Nicholas van As, Emma Hall, Sarah Gulliford, CHHiP Trial Management Group
Abstract: Purpose: Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy.
Methods and materials: The CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/β ratios. The α/β ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the models.
Results: Late rectal α/β ratio estimates (without DMF) ranged from bleeding (G1 + α/β = 1.6 Gy; 95% CI, 0.9-2.5 Gy) to sphincter control (G1 + α/β = 3.1 Gy; 95% CI, 1.4-9.1 Gy). Bowel pain modelled poorly (α/β, 3.6 Gy; 95% CI, 0.0-840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (P = .00041) and proctitis G1+ (P = .00046). However, the α/β ratios were similar in these no-DMF versus DMF models for both stool frequency G2+ (α/β 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/β 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/β ratios produced: G1 + α/β ratio = 2.4 Gy; G2 + α/β ratio = 2.3 Gy.
Conclusions: We estimated α/β ratios for several common late adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/β ratio ≤ 3 Gy.
WUTH publication: Defining a Safe Corridor of Cervical Branch Preservation in Lateral Platysmaplasty Surgery During Facial Rejuvenation Surgery
Citation: Aesthetic Surgery Journal. 2021 Apr 27. Online ahead of print
Author: William L E Malins, Hamish Walker, John Guirguis, Muhammad Riaz, Daniel B Saleh
Abstract: Background: During rhytidectomies, the cervical branch of the facial nerve (CBFN) can easily be encountered, and potentially injured, when releasing the cervical retaining ligaments in the lateral neck. This nerve has been shown to occasionally co-innervate the depressor anguli oris muscle, and damage to it can thus potentially compromise outcomes with a post-operative palsy.
Objectives: To examine the lateral cervical anatomy specific to the CBFN, to ascertain if the position of the nerve can be predicted, enhancing safety of the platysmal flap separation and dissection from this lateral zone of adhesion.
Methods: Eleven cadaveric hemifaces were dissected and the distance between the medial border of sternocleidomastoid (SCM), and the CBFN was measured at three key points: (1) 'Superior': the distance between SCM and the nerve at the level of the angle of the mandible in neutral. (2) 'Narrowest': the narrowest distance measurable between the 'superior' and 'inferior' points as the CBFN descends into the neck medial to the SCM. (3) 'Inferior': the distance at the most distal part of the cervical nerve identified before its final intramuscular course.
Results: The average distances (in mms) were: Superior = 12.1 (range: 10.1-15.4), Narrowest = 8.8 (range: 5.6-12.2) and Inferior = 10.9 (range: 7.9-16.7).
Conclusions: There is a narrow range between the nerve and the anterior border of SCM. We thus propose a safe corridor where lateral deep plane dissection can be performed to offer cervical retaining ligament release, with reduced risk of endangering the CBFN.
WUTH publication: Arteriovenous Fistula Surveillance Using Tomographic 3D Ultrasound
Citation: European Journal of Vascular and Endovascular Surgery. 2021, S1078-5884(21), 00239-2. Online ahead of print.
Author: Steven Rogers, Katie Simm, Charles McCollum, Sharifah Kiyegga, Adam Haque, Simon Lea, Ramasubramanyan Chandrasekar
Abstract: Objective: A well functioning arteriovenous fistula (AVF) is essential for haemodialysis. Despite regular duplex ultrasound (DUS) a significant number of AVFs fail. Tomographic 3D ultrasound (tUS) creates a 3D image of the AVF that can be interpreted by the clinician. DUS, tUS, and fistulograms were compared for the identification and measurement of flow limiting stenosis.
Methods: Patients with AVF dysfunction on routine Transonic surveillance, defined as (1) > 15% reduction in flow on two consecutive occasions, (2) > 30% reduction in flow on one occasion, (3) flow of < 600 mL/sec, (4) presence of recirculation, underwent DUS. AVF tUS imaging was performed prior to fistulography. All fistulograms were reported by the same consultant radiologist and tUS images by the same vascular scientist blinded to the fistulogram results. Maximum diameter reduction in all stenoses were measured using all three imaging techniques.
Results: In 97 patients with 101 stenoses, the mean (± standard deviation [SD]) severity of stenosis was 63.0 ± 13.9%, 65.0 ± 11.6%, and 64.8 ± 11.7% for the fistulograms, DUS, and tUS respectively. The mean (± SD) time between ultrasound and fistulography imaging was 15.0 ± 14.5 days. Assuming the fistulogram as the "gold standard", Bland-Altman agreement for DUS was -1.9 ± 15.5% (limit of agreement [LOA] -32.2 - 28.4) compared with -1.7 ± 15.4% (LOA -31.9 - 28.4) for tUS. Median (± interquartile range) time to complete the investigation was 09:00 ± 03:19 minutes for DUS and 03:13 ± 01:56 minutes for tUS (p < .001).
Conclusion: DUS and tUS were equally accurate at detecting AVF complications but tUS investigation requires less skill and was significantly quicker than DUS.
Keywords: Arteriovenous fistula surveillance; Duplex imaging; Fistulography; Tomographic 3D ultrasound (tUS).
Friday 23 April 2021
WUTH publication: Sarcopenia estimation using psoas major enhances P-POSSUM mortality prediction in older patients undergoing emergency laparotomy: cross-sectional study
Citation: European Journal of Trauma and Emergency Surgery. 2021 Apr 21. Online ahead of print
Author: Gregory Simpson, Jeremy Wilson, Dale Vimalachandran, Frances McNicol, Conor Magee
Abstract: Introduction: Emergency laparotomy is a considerable component of a colorectal surgeon's workload and conveys substantial morbidity and mortality, particularly in older patients. Frailty is associated with poorer surgical outcomes. Frailty and sarcopenia assessment using Computed Tomography (CT) calculation of psoas major area predicts outcomes in elective and emergency surgery. Current risk predictors do not incorporate frailty metrics. We investigated whether sarcopenia measurement enhanced mortality prediction in over-65 s who underwent emergency laparotomy and emergency colorectal resection.
Methods: An analysis of data collected prospectively during the National Emergency Laparotomy Audit (NELA) was conducted. Psoas major (PM) cross-sectional area was measured at the L3 level and a ratio of PM to L3 vertebral body area (PML3) was calculated. Outcome measures included inpatient, 30-day and 90-day mortality. Statistical analysis was conducted using Mann-Whitney, Chi-squared and receiver operating characteristics (ROC). Logistic regression was conducted using P-POSSUM variables with and without the addition of PML3.
Results: Nine-hundred and forty-four over-65 s underwent emergency laparotomy from three United Kingdom hospitals were included. Median age was 76 years (IQR 70-82 years). Inpatient mortality was 21.9%, 30-day mortality was 16.3% and 90-day mortality was 20.7%. PML3 less than 0.39 for males and 0.31 for females indicated significantly worse outcomes (inpatient mortality 68% vs 5.6%, 30-day mortality 50.6% vs 4.0%,90-day mortality 64% vs 5.2%, p < 0.0001). PML3 was independently associated with mortality in multivariate analysis (p < 0.0001). Addition of PML3 to P-POSSUM variables improved area under the curve (AUC) on ROC analysis for inpatient mortality (P-POSSUM:0.78 vs P-POSSUM + PML3:0.917), 30-day mortality(P-POSSUM:0.802 vs P-POSSUM + PML3: 0.91) and 90-day mortality (P-POSSUM:0.79 vs P-POSSUM + PML3: 0.91).
Conclusion: PML3 is an accurate predictor of mortality in over-65 s undergoing emergency laparotomy. Addition of PML3 to POSSUM appears to improve mortality risk prediction.
Keywords: Emergency laparotomy; Risk prediction; Sarcopenia.
Thursday 22 April 2021
WUTH publication: 2. Labour and birth
Citation: Best practice & research. Clinical obstetrics and gynaecology. 2021, S1521-6934(21), 00052-3. Online ahead of print
Author: Mary Ross-Davie, Alison Brodrick, Wendy Randall, Angela Kerrigan, Maureen McSherry
Abstract: This chapter describes the national guidance for care during labour and childbirth in the United Kingdom during the COVID-19 pandemic. The content largely draws attention on the guidance developed by the Royal College of Obstetricians (RCOG) and the Royal College of Midwives (RCM), and specific guidance on infection prevention and control measures from Public Health England. The key areas addressed are as follows: The chapter refers to some of the ways in which the guidance was translated in practice. The guidance was developed using a rapid analysis approach to emerging research and evidence, along with evidence from previous experiences of coronavirus combined with consensus expert opinion from all key professionals providing maternity care in the UK. WHAT IS KNOWN: The UK RCOG/RCM COVID-19 guidance was widely accepted across the UK maternity services and also worldwide as a reliable and credible source of information to shape care during the pandemic. WHAT IS NOT KNOWN: The full impact of the pandemic on the experiences and outcomes for babies and women of pregnancy, childbirth, and early parenting in the UK. The impact of the new approaches to intrapartum care on experiences and outcomes for women, babies, and families. The impact of the changes required to intrapartum care as a result of the pandemic on the professional care provided; in terms of pressure created by rapidly changing approaches to care and restrictions on the ability to provide normal levels of care.
Keywords: COVID-19; Foetal monitoring; Intrapartum care; Pandemic; Skin to skin; Waterbirth.
Monday 12 April 2021
WUTH publication: Risk of Major Bleeding With Potent Antiplatelet Agents After an Acute Coronary Event: A Comparison of Ticagrelor and Clopidogrel in 5116 Consecutive Patients in Clinical Practice
Citation: Journal of the American Heart Association. 2021 Apr 9, e019467. Online ahead of print
Author: Liam Mullen, Mohammed N Meah, Ahmed Elamin, Suneil Aggarwal, Adeel Shahzad, Matthew Shaw, Jaroslav Hasara, Muhammad Rashid, Michael Fisher, Turab Ali, Billal Patel, Wern Y Ding, Ruth Grainger, Thomas Heseltine, Bilal H Kirmani, Mohammed Obeidat, Yande Kasolo, Jecko Thatchil, Aleem Khand
Abstract: Background Major bleeding after acute coronary syndrome predicts a poor outcome but is challenging to define. The choice of antiplatelet influences bleeding risk. Methods and Results Major bleeding, subsequent myocardial infarction (MI), and all-cause mortality to 1 year were compared in consecutive patients with acute coronary syndrome treated with clopidogrel (n=2491 between 2011 and 2013) and ticagrelor (n=2625 between 2012 and 2015) in 5 English hospitals. Clinical outcomes were identified from national hospital episode statistics. Bleeding and MI events were independently adjudicated by 2 experienced clinicians, blinded to drug, sequence, and year. Bleeding events were categorized using Bleeding Academic Research Consortium 3 to 5 and PLATO (Platelet Inhibition and Patient Outcomes) criteria and MI by the Third Universal Definition. Multivariable regression analysis was used to adjust outcomes for case mix. The median age was 68 years and 34% were women. 39% underwent percutaneous coronary intervention and 13% coronary artery bypass graft surgery. Clinical outcome data were 100% complete for bleeding and 99.7% for MI. No statistically significant difference was seen in crude or adjusted major bleeding for ticagrelor compared with clopidogrel (Bleeding Academic Research Consortium 3-5, hazard ratio [HR], 1.23; 95% CI, 0.90-1.68; P=0.2, PLATO major adjusted HR, 1.30; 95% CI, 0.98-1.74; P=0.07) except in the non-coronary artery bypass graft cohort (n=4464), where bleeding was more frequent with ticagrelor (Bleeding Academic Research Consortium 3-5, adjusted HR, 1.58; 95% CI, 1.09-2.31; P=0.017; and PLATO major HR, 1.67; 95% CI, 1.18-2.37; P=0.004). There was no difference in crude or adjusted subsequent MI (adjusted HR, 1.20; 95% CI, 0.87-1.64; P=0.27). Crude mortality was higher in the clopidogrel group but not after adjustment, using either Cox proportional hazards or propensity matched population (HR, 0.90; 95% CI, 0.76-1.10; P=0.21) as was the case for stroke (HR, 0.82; 95% CI, 0.52-1.32; P=0.42). Conclusions This observational study indicates that the apparent benefit of ticagrelor demonstrated in a clinical trial population may not be observed in the broader population encountered in clinical practice. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02484924.
Keywords: acute coronary syndrome; antiplatelet; bleeding.
Friday 9 April 2021
WUTH publication: X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis
Citation: Gastroenterology. 2021, S0016-5085(21), 00466-2. Online ahead of print
Author: Rosanna Asselta, Elvezia Maria Paraboschi, Alessio Gerussi, Heather J Cordell, George F Mells, Richard N Sandford, David E Jones, Minoru Nakamura, Kazuko Ueno, Yuki Hitomi, Minae Kawashima, Nao Nishida, Katsushi Tokunaga, Masao Nagasaki, Atsushi Tanaka, Ruqi Tang, Zhiqiang Li, Yongyong Shi, Xiangdong Liu, Ma Xiong, Gideon Hirschfield, Katherine A Siminovitch, Canadian-US PBC Consortium; Italian PBC Genetics Study Group; UK-PBC Consortium; Japan PBC-GWAS Consortium; Marco Carbone, Giulia Cardamone, Stefano Duga, M Eric Gershwin, Michael F Seldin, Pietro Invernizzi
Abstract: Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease.
Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals).
Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively).
Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
Keywords: Meta-analysis; Superenhancer; X-Wide Association Study.
Thursday 8 April 2021
CCC publication: Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles
Citation: British Journal of Cancer. 2021, 124(10), 1661-69. 2021 Mar 15. Online ahead of print.
Author: Ye W.; Olsson-Brown A.; Akbani U.; Sacco J.J.; Watson R.A.; Nassiri I.; Cooper R.; Taylor C.A.; Matin R.N.; Coupe N.; Middleton M.R.; Payne M.J.; Fairfax B.P.; Cheung V.T.F.; Brain O.; Morgan R.D.; Coles M.
Abstract: Background: Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.
Methods: Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed.
Results: 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10-6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.
Conclusions: Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.
CCC publication: What is the recovery rate and risk of long-term consequences following a diagnosis of COVID-19? A harmonised, global longitudinal observational study protocol
Citation: BMJ Open. 2021, 11(3), e043887
Author: Sigfrid L.; Carson G.; Cevik M.; Jesudason E.; Lim W.S.; Rello J.; Amuasi J.; Bozza F.; Palmieri C.; Munblit D.; Holter J.C.; Kildal A.B.; Reyes L.F.; Russell C.D.; Ho A.; Turtle L.; Drake T.M.; Beltrame A.; Hann K.; Lakoh S.; Bangura I.R.; Fowler R.; Berry C.; Lowe D.J.; Mcpeake J.; Hashmi M.; Dyrhol-Riise A.M.; Donohue C.; Hardwick H.; Plotkin D.; Elkheir N.; Lone N.I.; Docherty A.; Harrison E.; Baille J.K.; Semple M.G.; Scott J.T
Abstract: Introduction: Very little is known about possible clinical sequelae that may persist after resolution of acute COVID-19. A recent longitudinal cohort from Italy including 143 patients followed up after hospitalisation with COVID-19 reported that 87% had at least one ongoing symptom at 60-day follow-up. Early indications suggest that patients with COVID-19 may need even more psychological support than typical intensive care unit patients. The assessment of risk factors for longer term consequences requires a longitudinal study linked to data on pre-existing conditions and care received during the acute phase of illness. The primary aim of this study is to characterise physical and psychosocial sequelae in patients post-COVID-19 hospital discharge.
Methods and analysis: This is an international open-access prospective, observational multisite study. This protocol is linked with the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) and the WHO's Clinical Characterisation Protocol, which includes patients with suspected or confirmed COVID-19 during hospitalisation. This protocol will follow-up a subset of patients with confirmed COVID-19 using standardised surveys to measure longer term physical and psychosocial sequelae. The data will be linked with the acute phase data. Statistical analyses will be undertaken to characterise groups most likely to be affected by sequelae of COVID-19. The open-access follow-up survey can be used as a data collection tool by other follow-up studies, to facilitate data harmonisation and to identify subsets of patients for further in-depth follow-up. The outcomes of this study will inform strategies to prevent long-term consequences; inform clinical management, interventional studies, rehabilitation and public health management to reduce overall morbidity; and improve long-term outcomes of COVID-19.
Ethics and dissemination: The protocol and survey are open access to enable low-resourced sites to join the study to facilitate global standardised, longitudinal data collection. Ethical approval has been given by sites in Colombia, Ghana, Italy, Norway, Russia, the UK and South Africa. New sites are welcome to join this collaborative study at any time. Sites interested in adopting the protocol as it is or in an adapted version are responsible for ensuring that local sponsorship and ethical approvals in place as appropriate. The tools are available on the ISARIC website (www.isaric.org). PROTOCOL REGISTRATION NUMBER: osf.io/c5rw3/ PROTOCOL VERSION: 3 August 2020 EUROQOL ID: 37035.
Keywords: COVID-19; infectious diseases; public health.
CCC publication: Immunophenotypical characterization of paraneoplastic neurological syndrome patients: a multicentric study
Citation: Journal of Biosciences. 2021, 46, 13
Author: Lorenzo Lorusso, Vincenza Precone, Ian K Hart, Bruno Giometto, Raffaele Pezzani, Gaelle K Ngonga, Gaelle K Ngonga K Ngonga, Stefano Paolacci, Daniela Ferrari, Giovanni Ricevuti, Ernie Marshall, Matteo Bertelli
Abstract: Paraneoplastic neurological syndromes (PNS) are a group of rare and severe immune-mediated disorders that affect the nervous system in patients with cancer. The best way to diagnose a paraneoplastic neurological disorder is to identify anti-onconeural protein antibodies that are specifically associated with various cancers. The aim of this multicentric study was to clinically and immunologically characterize patients with PNS and study their association with cancer. Patients suspected to have PNS were enrolled from various clinical centres and were characterized immunologically. This study population consisted of 112 patients. Onset of PNS was mainly subacute (76 %). PNS patients had various neurological disorders and symptoms. PNS developed before the diagnosis of cancer in 28 definite PNS patients and in six suspected PNS patients. The most frequent autoantibodies detected in PNS patients were anti-Hu and anti-Yo. One definite PNS patient with cerebellar syndrome had anti-Tr antibody and seven patients had atypical antibodies. The literature associates these antibodies with various neurological disorders and cancers. Our observations confirm the important role of autoantibodies in PNS and their importance for the early diagnosis of cancer in PNS patients.
CCC publication: Classification of tolerable/intolerable mucosal toxicity of head-and-neck radiotherapy schedules with a biomathematical model of cell dynamics
Citation: Medical Physics. 2021 Mar 11. Online ahead of print
Author: Juan Pardo-Montero, Martín Parga-Pazos, John D Fenwick
Abstract: Purpose: To present a biomathematical model based on the dynamics of cell populations to predict the tolerability/intolerability of mucosal toxicity in head-and-neck radiotherapy.
Methods and materials: Our model is based on the dynamics of proliferative and functional cells populations in irradiated mucosa, and incorporates the three A's: Accelerated proliferation, loss of Asymmetric proliferation, Abortive divisions. The model consist of a set of delay differential equations, and tolerability is based on the depletion of functional cells during treatment. We calculate the sensitivity (sen) and specificity (spe) of the model in a dataset of 108 radiotherapy schedules, and compare the results with those obtained with three phenomenological classification models, two based on a Biologically Effective Dose (BED) function describing the tolerability boundary (Fowler and Fenwick), and one based on an Equivalent Dose in 2 Gy-fractions (EQD2 ) boundary (Strigari). We also perform a machine-learning-like cross-validation of all the models, splitting the database in two, one for training and one for validation.
Results: When fitting our model to the whole dataset we obtain predictive values (sen+spe) up to 1.824. The predictive value of our model is very similar to that of the phenomenological models of Fowler (1.785), Fenwick (1.806) and Strigari (1.774). When performing a k=2 cross-validation, the specificity and sensitivity in the validation dataset decrease for all models, from ~1.82 to ~1.55-1.63. For Fowler the worsening is higher, down to 1.49.
Conclusions: Our model has proved useful to predict the tolerability/intolerability of a dataset of 108 schedules. As the model is more mechanistic that other available models, it could prove helpful when designing unconventional dose fractionations, schedules not covered by datasets to which phenomenological models of toxicity have been fitted.
Keywords: classification; head-and-neck; linear-quadratic model; mucositis; radiotherapy.
CCC publication: DNA methyltransferase inhibitor guadecitabine combined with cisplatin and gemcitabine chemotherapy (SPIRE): Randomized expansion phase as neoadjuvant therapy for bladder urothelial carcinoma
Citation: Journal of Clinical Oncology. 2021, 39(6)
Author: Crabb S.J.; Danson S.; Catto J.W.F.; Hussain S.A.; Dunkley D.; Downs N.; Saunders G.; Light M.; Sarwar N.; Enting D.; Jane Birtle A.; El Ghzal A.; Johnson B.; Huddart R.A.; Griffiths G.O.
Abstract: Purpose: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers.
CCC publication: Ipilimumab and nivolumab (I+N) as first-line treatment of metastatic renal cell carcinoma (mRCC): A real-world review in North West of England, United Kingdom
Citation: Journal of Clinical Oncology. 2021, 39(6)
Author: Allison J.; Griffiths R.; Waddell T.; Pillai M.R.
Wednesday 7 April 2021
CCC publication: A phase III, double-blind,randomized study of nivolumab(NIVO) and ipilimumab (IPI), nivomonotherapy or placebo plustransarterial chemoembolization(TACE) in patients withintermediate-stage hepatocellularcarcinoma (HCC)
Citation: Journal of Clinical Oncology. 2021, 39(3)
Author: Sangro B.; Harding J.J.; Johnson M.; Palmer D.H.; Edeline J.; Abou-Alfa G.K.; Cheng A.-L.; Decaens T.; El Khoueiry A.B.; Finn R.S.; Galle P.R.; Park J.-W.; Yau T.; Begic D.; Shen Y.; Neely J.; Sama A.R.; Kudo
CCC publication: Does non-TME surgery of rectalcancer compromise the chance of cure? Preliminary surgical salvagedata from OPERA phase III randomized trial
Citation: Journal of Clinical Oncology. 2021, 39(3)
Author: Myint A.S.; Thamphya B.; Gerard J.-P
CCC publication: The EMA review of trastuzumab emtansine (T-DM1) for the adjuvant treatment of adult patients with HER2-positive early breast cancer
Citation: ESMO Open. 2021, 6(2), 100074. Online ahead of print.
Author: J Delgado, C Vleminckx, S Sarac, A Sosa, J Bergh, R Giuliani, H Enzmann, F Pignatti
Abstract: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate of trastuzumab [a monoclonal antibody against human epidermal growth factor receptor 2 (HER2)] and DM1 (an inhibitor of tubulin polymerisation). It was initially approved in the European Union for the treatment of adult patients with HER2-positive unresectable locally advanced or metastatic breast cancer (BC) who had previously received trastuzumab and taxanes. On 18 December 2019, a variation of the marketing authorisation was approved extending this use to the adjuvant therapy of adult patients with HER2-positive early BC who have residual invasive disease in the breast and/or lymph nodes after neoadjuvant taxane-based and HER2-targeted therapy. A phase III randomised, multicentre, open-label trial compared T-DM1 with trastuzumab as adjuvant therapy in patients with HER2-positive early BC who had received preoperative chemotherapy and HER2-targeted therapy followed by surgery, with a finding of invasive residual disease in the breast and/or axillary lymph nodes. The study met its primary endpoint by showing an increased 3-year invasive disease-free survival rate in the T-DM1 arm (88.3%) compared with the trastuzumab arm (77.0%), with an unstratified hazard ratio of 0.50 (95% confidence interval: 0.39-0.64). There was a higher incidence of hepatotoxicity (37.3% versus 10.6%), thrombocytopenia (28.5% versus 2.4%), peripheral neuropathy (32.3% versus 16.9%), haemorrhage (29.2% versus 9.6%) and pulmonary toxicity (2.8% versus 0.8%) in the T-DM1 arm compared with the control arm. The aim of this manuscript was to summarise the scientific review of the application leading to regulatory approval of this additional indication in the European Union.
Keywords: HER2; T-DM1; adjuvant; breast cancer; trastuzumab emtansine.
CCC publication: A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma
Citation: British Journal of Cancer. 2021, 124(8), 1379-87
Author: Chris Twelves, Michael Sabel, Daniel Checketts, Sharon Miller, Bola Tayo, Maria Jove, Lucy Brazil, Susan C Short, GWCA1208 study group
Abstract: Background: Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM.
Methods: Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored.
Results: The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK.
Conclusions: With personalised dosing, nabiximols had acceptable safety and tolerability with no drug-drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial.
Clinical trial registration: ClinicalTrials.gov: Part 1- NCT01812603; Part 2- NCT01812616.
CCC publication: Answer to photo quiz: Disseminated varicella-zoster virus
Citation: Journal of Clinical Microbiology. 2021, 59(3)
Author: Adler H.; Cruise J.; Beadsworth M.B.J.; Beeching N.J.; Yong J.; Patel A.; Mikhail M.
CCC publication: Photo quiz: Disseminated violaceous skin lesions following allogeneic stem cell transplant
Citation: Journal of Clinical Microbiology. 2021, 59(3)
Author: Adler H.; Cruise J.; Beadsworth M.B.J.; Beeching N.J.; Yong J.; Patel A.; Mikhail M
CCC publication: Erratum to 'Longitudinal characterisation of haematological and biochemical parameters in cancer patients prior to and during COVID-19 reveals features associated with outcome': [ESMO Open Volume 6, Issue 1, February 2021, 100005]
Citation: ESMO Open. 2021, 6(2), 100056
Author: R J Lee, O Wysocki, T Bhogal, R Shotton, A Tivey, A Angelakas, T Aung, K Banfill, M Baxter, H Boyce, G Brearton, E Copson, E Dickens, L Eastlake, F Gomes, C Hague, M Harrison, L Horsley, P Huddar, Z Hudson, S Khan, U T Khan, A Maynard, H McKenzie, D Palmer, T Robinson, M Rowe, A Thomas, J Tweedy, R Sheehan, A Stockdale, J Weaver, S Williams, C Wilson, C Zhou, C Dive, T Cooksley, C Palmieri, A Freitas, A C Armstrong
CCC publication: Management of newly diagnosed metastatic hormone-sensitive prostate cancer: A survey of UK Uro-oncologists
Citation: International Journal of Clinical Practice. 2021, 75(4) e13874
Author: Amit Bahl, Simon Crabb, Dan Ford, Rob Jones, Zaf Malik, Danish Mazhar, Joe O'Sullivan, Heather Payne
Abstract: Aim: To explore the practice and views of uro-oncologists in the United Kingdom regarding their use of chemotherapy and androgen receptor-targeted agents (ARTAs) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC).
Methods: An expert-devised paper or online questionnaire was completed by members of the British Uro-oncology Group.
Results: All respondents stated that they would offer patients with newly diagnosed mHSPC docetaxel and androgen deprivation therapy (ADT) if they were sufficiently fit to receive chemotherapy (this was the only option available at the time of the survey); 64% would strongly recommend docetaxel for those with high-volume metastatic disease and 31% for those with low-volume disease. Hypothetically, if both docetaxel and ARTAs were available in the United Kingdom for mHSPC, almost 65% of respondents would recommend an ARTA with ADT to these patients in at least one-half of all cases, with the strongest recommendations to patients with high-risk disease. Imaging for the response was conducted according to suspicion of disease progression, regardless of treatment, with the minority of clinicians recommending routine imaging. If a choice of therapy was available, docetaxel would be more likely to be offered to patients with liver or lung metastases, and ARTAs to patients with bone or lymph node only metastases. Almost all respondents would offer local radiotherapy to the primary tumour in patients with low-volume disease.
Conclusion: All the UK uro-oncologists surveyed stated that they would offer docetaxel in combination with ADT to all newly diagnosed patients with mHSPC if fit enough for chemotherapy. ARTAs would be offered to many patients if available, especially those with high-risk disease or those unfit to receive chemotherapy. Scanning was typically conducted following treatment only at the suspicion of disease progression.
CCC publication: Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study
Citation: BMC Cancer. 2021, 21(1), 1-8
Author: Mahmood ; Shaw, Danielle; Descamps, Tine; Zhou, Cong; Morgan, Robert D.; Mullamitha, Saifee; Saunders, Mark; Mescallado, Nerissa; Backen, Alison; Morris, Karen; Little, Ross A.; Cheung, Susan; Watson, Yvonne; O'Connor, James P. B.; Jackson, Alan; Parker, Geoff J. M.; Dive, Caroline; Jayson, Gordon C.
Abstract: Background: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. Method(s): A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). Result(s): Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025). Conclusion(s): In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.
CCC publication: Eribulin, Child-Pugh score, and liver-function tests: lessons from pivotal breast cancer studies 301 and 305
Citation: Breast Cancer Research. 2021, 23(1), 33
Author: Iain R Macpherson, Yaohua He, Carlo Palmieri
Abstract: Background: The recommended starting dose of eribulin in patients with hepatic impairment is based on the Child-Pugh score, largely informed by a pharmacokinetic study of 18 patients. In the pivotal studies of eribulin in metastatic breast cancer (Study 301 and Study 305 [EMBRACE]), entry criteria and dose modifications were based on liver-function test (LFT) results rather than Child-Pugh score. In populations such as patients with metastatic breast cancer, in which metastatic infiltration is the predominant cause of hepatic impairment, using Child-Pugh score may be problematic; in clinical practice, it has been more common for oncologists to make dosing decisions based on LFTs. To address this, the effects of abnormal baseline LFT results on eribulin efficacy and safety were investigated.
Methods: In this pooled post hoc analysis, 1062 patients who were randomized to receive eribulin in Studies 301 and 305 were divided into 4 groups: (A) no elevated LFT results (no liver impairment); (B) increased levels of aspartate aminotransferase and/or alanine aminotransferase; (C) decreased albumin and/or increased levels of aspartate aminotransferase and/or alanine aminotransferase but not increased bilirubin; and (D) increased bilirubin. Patients were subcategorized by presence of liver metastasis. Drug exposure, dose intensity, and treatment-emergent adverse events (TEAEs) were analyzed.
Results: Eribulin mesylate mean dosage was 0.82 (group A)-0.65 mg/m2/week (group D). Group D had shorter treatment, more dose reductions/delays, more TEAEs leading to dose modifications, and numerically lower objective response rates and clinical benefit rates versus groups A-C. TEAE rates leading to dose modification were similar between group D (45.5%) and groups A-C (range, 43.5-54.9%) in the absence of liver metastases, but higher in group D (91.3%) compared with groups A-C (range, 41.7-54.3%) if liver metastases were present.
Conclusions: Mild elevations in bilirubin levels were associated with increased toxicity and a greater requirement for dose modifications. Based both on these study data and existing recommendations, we propose a novel scheme to guide initial dose selection in patients with metastatic breast cancer and hepatic impairment that is based on LFTs rather than Child-Pugh score.
Keywords: Bilirubin; Breast cancer; Child-Pugh score; Eribulin; Liver-function tests.
CCC publication: Treatment-at-work service puts cancer patients at the centre of care
Citation: British Journal of Nursing. 2021, 30(4), S44
Author: Luxton
Abstract: Clatterbridge in the Community nurses are the runners-up in the BJN Awards 2020 Oncology Nurse of the Year.
CCC publication: Reduction in the resident intestinal myelomonocytic cell population occurs during Apc Min/+ mouse intestinal tumorigenesis
Citation: Oncology letters. 2021, 21(4), 263
Author: Olusola O Faluyi, Mark A Hull, Alexander F Markham, Constanze Bonifer, P Louise Coletta
Abstract: With its significant contribution to cancer mortality globally, advanced colorectal cancer (CRC) requires new treatment strategies. However, despite recent good results for mismatch repair (MMR)-deficient CRC and other malignancies, such as melanoma, the vast majority of MMR-proficient CRCs are resistant to checkpoint inhibitor (CKI) therapy. MMR-proficient CRCs commonly develop from precursor adenomas with enhanced Wnt-signalling due to adenomatous polyposis coli (APC) mutations. In melanomas with enhanced Wnt signalling due to stabilized β-catenin, immune anergy and resistance to CKI therapy has been observed, which is dependent on micro-environmental myelomonocytic (MM) cell depletion in melanoma models. However, MM populations of colorectal adenomas or CRC have not been studied. To characterize resident intestinal MM cell populations during the early stages of tumorigenesis, the present study utilized the ApcMin/+ mouse as a model of MMR-proficient CRC, using enhanced green fluorescent protein (EGFP) expression in the mouse lysozyme (M-lys) lys-EGFP/+ mouse as a pan-myelomonocytic cell marker and a panel of murine macrophage surface markers. Total intestinal lamina propria mononuclear cell (LPMNC) numbers significantly decreased with age (2.32±1.39×107 [n=4] at 33 days of age vs. 1.06±0.24×107 [n=8] at 109 days of age) during intestinal adenoma development in ApcMin/+ mice (P=0.05; unpaired Student's t-test), but not in wild-type littermates (P=0.35). Decreased total LPMNC numbers were associated with atrophy of intestinal lymphoid follicles and the absence of MM/lymphoid cell aggregates in ApcMin/+ mouse intestine, but not spleen, compared with wild-type mice. Furthermore, during the early stage of intestinal adenoma development, there was a two-fold reduction of M-lys expressing cells (P=0.05) and four-fold reduction of ER-HR3 (macrophage sub-set) expressing cells (P=0.05; two tailed Mann-Whitney U test) in mice with reduced total intestinal LPMNCs (n=3). Further studies are necessary to determine the relevance of these findings to immune-surveillance of colorectal adenomas or MMR-proficient CRC CKI therapy resistance.
Keywords: Apc; ApcMin/+ mouse; intestine; mouse lysozyme; myelomonocytic; tumorigenesis.
CCC publication: The Enzyme-Modified Neutral Comet (EMNC) Assay for Complex DNA Damage Detection
Citation: Methods and protocols. 2021, 4(1), 14
Author: Maria Rita Fabbrizi, Jonathan R Hughes, Jason L Parsons
Abstract: The comet assay is a versatile, simple, and sensitive gel electrophoresis-based method that can be used to measure and accurately quantify DNA damage, particularly single and double DNA strand breaks, in single cells. While generally this is used to measure variation in DNA strand break levels and repair capacity within a population of cells, the technique has more recently been adapted and evolved into more complex analysis and detection of specific DNA lesions, such as oxidized purines and pyrimidines, achieved through the utilization of damage-specific DNA repair enzymes following cell lysis. Here, we detail a version of the enzyme-modified neutral comet (EMNC) assay for the specific detection of complex DNA damage (CDD), defined as two or more DNA damage lesions within 1-2 helical turns of the DNA. CDD induction is specifically relevant to ionizing radiation (IR), particularly of increasing linear energy transfer (LET), and is known to contribute to the cell-killing effects of IR due to the difficult nature of its repair. Consequently, the EMNC assay reveals important details regarding the extent and complexity of DNA damage induced by IR, but also has potential for the study of other genotoxic agents that may induce CDD.
Keywords: DNA damage; DNA repair; comet assay; complex DNA damage; ionising radiation; protons.
CCC publication: FP04.02 Feasibility of Radiotherapy Planning in the First 50 Patients Recruited to the ADSCaN Clinical Trial,
Citation: Journal of Thoracic Oncology. 2021, 16(3 Sup), S197. Conference Abstract
Author: R. Mir, C. Faivre-Finn, C. Lawless, E. Mccartney, C. Peedell, T. Pope, A. Shaw, R. Simoes, M. Hatton,
CCC publication: P03.02 Neoadjuvant Osimertinib with/without Chemotherapy vs Chemotherapy for EGFR Mutated Resectable NSCLC: NeoADAURA
Citation: Journal of Thoracic Oncology. 2021, 16(3), S258. Conference Abstract
Author: M. Tsuboi, W. Weder, C. Escriu, C. Blakely, J. He, S. Dacic, Y. Yatabe, L. Zeng, A. Walding, J. Chaft,
CCC publication: 203MO Changes in management for patients with lung cancer treated with radical radiotherapy during the first wave of the COVID-19 pandemic in the UK (COVID-RT Lung),
Citation: Journal of Thoracic Oncology. 2021, 16(4 Sup), S808
Author: K. Banfill, G. Price, K. Wicks, A. Britten, C. Carson, M. Hatton, K. Thippu Jayaprakash, A. Jegannathen, C.L. Lee, N. Panakis, C. Peedell, C. Stilwell, T. Pope, C. Powell, V. Wood, S. Zhou, C. Faivre-Finn,
CCC publication: Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial
Citation: The Lancet. Oncology. 2021, 22(5), 690-701. 2021, S1470-2045(21), 00027-9. Online ahead of print.
Author: Angela Lamarca, Daniel H Palmer, Harpreet Singh Wasan, Paul J Ross, Yuk Ting Ma, Arvind Arora, Stephen Falk, Roopinder Gillmore, Jonathan Wadsley, Kinnari Patel, Alan Anthoney, Anthony Maraveyas, Tim Iveson, Justin S Waters, Claire Hobbs, Safia Barber, W David Ryder, John Ramage, Linda M Davies, John A Bridgewater, Juan W Valle,
Abstract: Background: Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer.
Methods: The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30.
Findings: Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients).
Interpretation: The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials.
Funding: Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.