Citation: BMJ Open. 2021, 11(2), e042953
Author: Martin John Connor, Taimur Tariq Shah, Katarzyna Smigielska, Emily Day, Johanna Sukumar, Francesca Fiorentino, Naveed Sarwar, Michael Gonzalez, Alison Falconer, Natalia Klimowska-Nassar, Martin Evans, Olivia Frances Naismith, Kamalram Thippu Jayaprakash, Derek Price, Shiva Gayadeen, Dolan Basak, Gail Horan, John McGrath, Denise Sheehan, Manal Kumar, Azman Ibrahim, Cathryn Brock, Rachel A Pearson, Nicola Anyamene, Catherine Heath, Iqbal Shergill, Bhavan Rai, Giles Hellawell, Stuart McCracken, Bijan Khoubehi, Stephen Mangar, Vincent Khoo, Tim Dudderidge, John Nicholas Staffurth, Mathias Winkler, Hashim Uddin Ahmed
Abstract: Introduction: Survival in men diagnosed with de novo synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone.
Methods: A phase II, prospective, multicentre, three-arm randomised controlled trial incorporating an embedded feasibility pilot. All men with new histologically diagnosed, hormone-sensitive, metastatic prostate cancer, within 4 months of commencing ADT and of performance status 0 to 2 are eligible. Patients will be randomised to Control (standard of care (SOC)) OR Intervention 1 (minimally invasive ablative therapy to prostate±pelvic lymph node dissection (PLND)) OR Intervention 2 (cytoreductive radical prostatectomy±PLND OR prostate radiotherapy±pelvic lymph node radiotherapy (PLNRT)). Metastatic burden will be prespecified using the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) definition. Men with low burden disease in intervention arms are eligible for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy (SABR) or surgery. Standard systemic therapy will be administered in all arms with ADT±upfront systemic chemotherapy or androgen receptor agents. Patients will be followed-up for a minimum of 2 years.
Primary outcome: PFS. Secondary outcomes include predictive factors for PFS and overall survival; urinary, sexual and rectal side effects. Embedded feasibility sample size is 80, with 918 patients required in the main phase II component. Study recruitment commenced in April 2019, with planned follow-up completed by April 2024.
Ethics and dissemination: Approved by the Health Research Authority (HRA) Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for publication in peer-reviewed journals.
Trial registration number: NCT03763253; ISCRTN58401737.
Keywords: genitourinary imaging; prostate disease; radiation oncology; radiotherapy; urological tumours; urology.
Friday 26 February 2021
WUTH publication: Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial
Wednesday 24 February 2021
WUTH publication: The Association of coloproctology of great Britain and Ireland consensus guidelines in emergency colorectal surgery
Citation: Colorectal Disease. 2021 Jan 20. Online ahead of print.
Author: A S Miller, K Boyce, B Box, M D Clarke, S E Duff, N M Foley, R J Guy, L H Massey, G Ramsay, D A J Slade, J A Stephenson, P J Tozer, D Wright
Abstract: Aim: There is a requirement for an expansive and up to date review of the management of emergency colorectal conditions seen in adults. The primary objective is to provide detailed evidence -based guidelines for the target audience of general and colorectal surgeons who are responsible for an adult population and who practice in Great Britain and Ireland.
Methods: Surgeons who are elected members of the ACPGBI Emergency Surgery Sub-Committee were invited to contribute various sections to the guidelines. They were directed to produce a pathology-based document using literature searches that were systematic, comprehensible, transparent and reproducible. Levels of evidence were graded. Each author was asked to provide a set of recommendations which were evidence-based and unambiguous. These recommendations were submitted to the whole guideline group and scored. They were then refined and submitted to a second vote. Only those that achieved >80% consensus at level 5 (strongly agree) or level 4 (agree) after 2 votes were included in the guidelines.
Results: All aspects of care (excluding abdominal trauma) for emergency colorectal conditions have been included along with 122 recommendations for management CONCLUSION: These guidelines provide an up to date and evidence-based summary of the current surgical knowledge in the management of emergency colorectal conditions and should serve as practical text for clinicians managing colorectal conditions in the emergency setting.
WUTH publication: Is "no test is better than a bad test"? Impact of diagnostic uncertainty in mass testing on the spread of COVID-19
Citation: PloS One. 2020, 15(10), e0240775
Author: Nicholas Gray, Dominic Calleja, Alexander Wimbush, Enrique Miralles-Dolz, Ander Gray, Marco De Angelis, Elfriede Derrer-Merk, Bright Uchenna Oparaji, Vladimir Stepanov, Louis Clearkin, Scott Ferson
WUTH publication: Acute ischemic stroke management: concepts and controversies.A narrative review
Citation: Expert review of neurotherapeutics. 2021, 21(1), 65-79
Author: Ka Hou Christien Li, Aaron Jesuthasan, Christopher Kui, Ruth Davies, Gary Tse, Gregory Y H Lip
Abstract: Introduction: Amongst the 25.7 million survivors and 6.5 million deaths from stroke between 1990 and 2013, ischemic strokes accounted for approximately 70% and 50% of the cases, respectively. With patients still suffering from complications and stroke recurrence, more questions have been raised as to how we can better improve patient management.
Areas covered: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Newcastle-Ottawa Scale (NOS) were adopted to ensure a comprehensive inclusion of quality literature from various sources. PubMed and Embase were searched for evidence on thrombolysis, mechanical thrombectomy, artificial intelligence (AI), antiplatelet therapy, anticoagulation and hypertension management.
Expert opinion: The directions of future research in these areas are dependent on the current level of validation. Endovascular therapy and applications of AI are relatively new compared to the other areas discussed in this review. As such, future studies need to focus on validating their efficacy. As for thrombolysis, antiplatelet and anticoagulation therapy, their efficacy has been well-established and future research efforts should be directed toward adjusting its use according to patient-specific factors, starting with factors with the most clinical relevance and prevalence.
Keywords: Stroke; anticoagulation; antiplatelet; artificial intelligence; thrombectomy; thrombolysis.
WUTH publication: A prospective multicentre external validation study of the Liverpool Peritonsillar abscess Score (LPS) with a no-examination COVID-19 modification
Citation: Clinical Otolaryngology. 2021, 46(1) 229-33
Author: David Selwyn, Ding Yang, Elliot Heward, Ashwin Kerai, Elinor Thompson, Abulgasem Shommakhi, Scott Faulkner, Richard Siau, Hussein Walijee, Tom Hampton, Dorota Chudek, Supriya Singhera, Waqas Din, Andrew S Lau
Abstract: Objectives: Our primary aim was to validate the Liverpool Peritonsillar abscess Score (LPS) externally in a new patient cohort. Our secondary aim was to modify the LPS in the light of the COVID-19 pandemic to produce a no-examination variant for use in this instance.
Design: Prospective multicentre external validation study.
Setting: Six different secondary care institutions across the United Kingdom.
Participants: Patients over 16 years old who were referred to ENT with any uncomplicated sore throat such a tonsillitis or peritonsillar abscess (PTA).
Main outcome measures: Sensitivity, specificity, positive predictive value and negative predictive value for both the original LPS model and the modified model for COVID-19.
Results: The LPS model had sensitivity and specificity calculated at 98% and 79%, respectively. The LPS has a high negative predictive value (NPV) of 99%. The positive predictive value (PPV) was slightly lower at 63%. Receiver operating characteristic (ROC) curve, including the area under the curve (AUROC), was 0.888 which indicates very good accuracy.
Conclusions: External validation of the LPS against an independent geographically diverse population yields high NPV. This may support non-specialist colleagues who may have concerns about mis-diagnosing a PTA. The COVID-19 modification of the LPS has a similar NPV, which may be of use where routine oral examination is to be avoided during the COVID-19 pandemic.
Keywords: Peritonsillar abscess; diagnosis; dysphagia; swallowing.
Tuesday 23 February 2021
WUTH publication: 'Ball valve' small bowel obstruction caused by a large caecal faecolith
Citation: Annals of the Royal College of Surgeons of England. 2021, 103(2), e69-e71. Epub 2020 Nov 13
Author: Sharma S, Majeed T, Solomon J, Guy R
Abstract: Small bowel obstruction is a common surgical presentation, but intestinal faecoliths are rarely reported as a cause. A 75-year-old woman presented with small bowel obstruction from a large faecolith lodged in the caecum. This required removal at laparoscopy-assisted surgery. This case highlights the need to deal promptly with symptomatic intestinal faecoliths as they are unlikely to pass spontaneously and are prone to cause acute obstruction.
Keywords: Faecolith; Intestinal obstruction.
Thursday 18 February 2021
CCC publication: The ESMO Call to Action on COVID-19 vaccinations and patients with cancer: Vaccinate. Monitor. Educate
Citation: Annals of Oncology. 2021, 32(5), 579-81
Author: Marina Chiara Garassino, Malvika Vyas, Elisabeth de Vries, Ravindran Kanesvaran, Rosa Giuliani, Solange Peters, European Society for Medical Oncology
CCC publication: Phase 2 study of anastrozole in patients with estrogen receptor/progesterone receptor positive recurrent low-grade endometrial stromal sarcomas: The PARAGON trial (ANZGOG 0903)
Citation: Gynecologic Oncology. 2021, 161(1), 160-65
Author: M. Friedlander, C. Benson, R.L. O'Connell, N. Reed, A. Clamp, R. Lord, D. Millan, S. Nottley, F. Amant, C. Steer, A. Anand, L. Mileshkin, P. Beale, S. Banerjee, N. Bradshaw, C. Kelly, K. Carty, L. Divers, L. Alexander, R. Edmondson
Abstract: Background. Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers. Method. An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. Results. 15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48–89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2–29.8%), partial response in three (20%, 95% CI 7.1–45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2–NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5–63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects. Conclusion. The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers. Keywords. Aromatase inhibitors; Anastrazole; Endometrial stromal; sarcomas; Uterine sarcoma
CCC publication: Phase I Trial of DNA Methyltransferase Inhibitor Guadecitabine Combined with Cisplatin and Gemcitabine for Solid Malignancies Including Urothelial Carcinoma (SPIRE)
Citation: Clinical Cancer Research. 2021. Online ahead of print
Author: Simon J Crabb, Sarah Danson, James W F Catto, Syed Hussain, Danna Chan, Denise Dunkley, Nichola Downs, Ellice Marwood, Laura Day, Geoff Saunders, Michelle Light, Amy Whitehead, Deborah Ellis, Naveed Sarwar, Deborah Enting, Alison Birtle, Bernadette Johnson, Robert Huddart, Gareth Griffiths
Abstract: Purpose: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers.
Patient and methods: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2-4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1-5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228.
Results: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1-5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred.
Conclusions: The guadecitabine RP2D was 20 mg/m2, days 1-5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.
CCC publication: 4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial
Citation: The Lancet. Oncology. 2021, 22(3), 332-40
Author: Peter Hoskin, Biliana Popova, Oliver Schofield, Caroline Brammer, Martin Robinson, A Murray Brunt, Krishnaswamy Madhavan, Tim Illidge, Eve Gallop-Evans, Isabel Syndikus, Laura Clifton-Hadley, Amy A Kirkwood
Abstract: Background: The optimal radiotherapy dose for indolent non-Hodgkin lymphoma is uncertain. We aimed to compare 24 Gy in 12 fractions (representing the standard of care) with 4 Gy in two fractions (low-dose radiation).
Methods: FoRT (Follicular Radiotherapy Trial) is a randomised, multicentre, phase 3, non-inferiority trial at 43 study centres in the UK. We enrolled patients (aged >18 years) with indolent non-Hodgkin lymphoma who had histological confirmation of follicular lymphoma or marginal zone lymphoma requiring radical or palliative radiotherapy. No limit on performance status was stipulated, and previous chemotherapy or radiotherapy to another site was permitted. Radiotherapy target sites were randomly allocated (1:1) either 24 Gy in 12 fractions or 4 Gy in two fractions using minimisation and stratified by histology, treatment intent, and study centre. Randomisation was centralised through the Cancer Research UK and University College London Cancer Trials Centre. Patients, treating clinicians, and investigators were not masked to random assignments. The primary endpoint was time to local progression in the irradiated volume based on clinical and radiological evaluation and analysed on an intention-to-treat basis. The non-inferiority threshold aimed to exclude the chance that 4 Gy was more than 10% inferior to 24 Gy in terms of local control at 2 years (HR 1·37). Safety (in terms of adverse events) was analysed in patients who received any radiotherapy and who returned an adverse event form. FoRT is registered with ClinicalTrials.gov, NCT00310167, and the ISRCTN Registry, ISRCTN65687530, and this report represents the long-term follow-up.
Findings: Between April 7, 2006, and June 8, 2011, 614 target sites in 548 patients were randomly assigned either 24 Gy in 12 fractions (n=299) or 4 Gy in two fractions (n=315). At a median follow-up of 73·8 months (IQR 61·9-88·0), 117 local progression events were recorded, 27 in the 24 Gy group and 90 in the 4 Gy group. The 2-year local progression-free rate was 94·1% (95% CI 90·6-96·4) after 24 Gy and 79·8% (74·8-83·9) after 4 Gy; corresponding rates at 5 years were 89·9% (85·5-93·1) after 24 Gy and 70·4% (64·7-75·4) after 4 Gy (hazard ratio 3·46, 95% CI 2·25-5·33; p<0·0001). The difference at 2 years remains outside the non-inferiority margin of 10% at -13·0% (95% CI -21·7 to -6·9). The most common events at week 12 were alopecia (19 [7%] of 287 sites with 24 Gy vs six [2%] of 301 sites with 4 Gy), dry mouth (11 [4%] vs five [2%]), fatigue (seven [2%] vs five [2%]), mucositis (seven [2%] vs three [1%]), and pain (seven [2%] vs two [1%]). No treatment-related deaths were reported.
Interpretation: Our findings at 5 years show that the optimal radiotherapy dose for indolent lymphoma is 24 Gy in 12 fractions when durable local control is the aim of treatment.
Funding: Cancer Research UK.
CCC publication: Assessing technical and biological variation in SWATH-MS-based proteomic analysis of chronic lymphocytic leukaemia cells
Citation: Scientific reports. 2021, 11(1), 2932
Author: Gina L Eagle1, John M J Herbert, Jianguo Zhuang, Melanie Oates, Umair T Khan, Neil R Kitteringham, Kim Clarke, B Kevin Park, Andrew R Pettitt, Rosalind E Jenkins, Francesco Falciani
Abstract: Chronic lymphocytic leukaemia (CLL) exhibits variable clinical course and response to therapy, but the molecular basis of this variability remains incompletely understood. Data independent acquisition (DIA)-MS technologies, such as SWATH (Sequential Windowed Acquisition of all THeoretical fragments), provide an opportunity to study the pathophysiology of CLL at the proteome level. Here, a CLL-specific spectral library (7736 proteins) is described alongside an analysis of sample replication and data handling requirements for quantitative SWATH-MS analysis of clinical samples. The analysis was performed on 6 CLL samples, incorporating biological (IGHV mutational status), sample preparation and MS technical replicates. Quantitative information was obtained for 5169 proteins across 54 SWATH-MS acquisitions: the sources of variation and different computational approaches for batch correction were assessed. Functional enrichment analysis of proteins associated with IGHV mutational status showed significant overlap with previous studies based on gene expression profiling. Finally, an approach to perform statistical power analysis in proteomics studies was implemented. This study provides a valuable resource for researchers working on the proteomics of CLL. It also establishes a sound framework for the design of sufficiently powered clinical proteomics studies. Indeed, this study shows that it is possible to derive biologically plausible hypotheses from a relatively small dataset.
CCC publication: Local tumour control and radiation side effects for fractionated stereotactic photon beam radiotherapy compared to proton beam therapy in uveal melanoma
Citation: Radiotherapy and Oncology. 2021, 157, 219-224
Author: Jackelien G M van Beek, Wishal D Ramdas, Martina Angi, Caroline M van Rij, Nicole C Naus, Andrzej Kacperek, Roger D Errington, Bertil Damato, Heinrich Heimann, Emine Kiliç
CCC publication: Treatment outcomes for small cell carcinoma of the bladder: results from a UK patient retrospective cohort study
Citation: International journal of radiation oncology, biology, physics. 2021, S0360-3016(21), 00170-X. Online ahead of print.
Author: C Chau, Y Rimmer, A Choudhury, D Leaning, A Law, D Enting, J H Lim, S Hafeez, V Khoo, R Huddart, D Mitchell, D R Henderson, J McGrane, M Beresford, N Vasudev, S Beesley, S Hilman, C Manetta, R Sriram, A Sharma, C Eswar, S Treece, M Vilarino-Varela, M Varughese, H Glen, E Pintus, S Crabb
Abstract: Background: Small cell carcinoma of the bladder (SCCB) is rare, accounting for under 1% of all bladder carcinomas. It is aggressive and outcomes are poor due to early metastatic spread. Owing to its rarity, there are limitations on data to propose standardised management pathways.
Patients and methods: We conducted a retrospective analysis of patients presenting with pure or predominant histology SCCB to 26 UK institutions between 2006 and 2016. Data cut-off date was 1/2/2018. We report on patient characteristics, treatment received and subsequent clinical outcomes.
Results: 409 eligible patients were included. 306 (74.8%) were male, median age was 71 years (range 35-96) and 189 (46.2%) had pure histology SCCB. At data cut-off, 301 patients (73.6%) have died. Median overall survival (OS) was 15.9 (95% confidence interval (CI) 13.2-18.7) months. 200 patients (48.9%), were confirmed to have bladder confined disease (N0 M0), with a median OS of 28.3 (95% CI 20.9-35.8) months, versus 12.7 (95% CI 10.9-14.6) months for 172 (42.1%) patients with confirmed N1-3 and/or M1 disease (hazard ratio 2.03, 95% CI 1.58-2.60, p=<0.001). 247 patients (61.5%) received primary chemotherapy, with a median OS of 21.6 (95% CI 15.5-27.6) months, versus 9.1 (95% CI 5.4-12.8) months in those who did not (HR 0.46, 95%CI 0.37-0.59, p=<0.001). Choice of chemotherapy agent did not alter outcomes. For those with bladder confined disease, 61 patients (30.5%) had cystectomy and 104/200 (52.0%) had radiotherapy. Survival outcomes were similar despite choice of cystectomy or radiotherapy. Only 6 patients (1.5%) were identified to have brain metastases at any time point.
Conclusions: This is the largest retrospective study of all stage SCCB to date. Patients have a poor prognosis overall but with improved survival in those able to receive chemotherapy and with organ confined disease. Brain metastases are rare.
CCC publication: Haematological malignancy and nosocomial transmission are associated with an increased risk of death from COVID-19: results of a multi-center UK cohort
Citation: Leukemia & Lymphoma. 2021, 1-16. Online ahead of print
Author: Talvinder Bhogal, Umair T Khan, Rebecca Lee, Alexander Stockdale, Christian Hesford, Vaishnav Potti-Dhananjaya, Avith Jathanna, Shaun Rahman, Ann Tivey, Rohan Shotton, Ram Sundar, Christopher Valerio, Amir Norouzi, Philip Walker, Ruth Suckling, Anne Armstrong, Gillian Brearton, Andrew Pettitt, Nagesh Kalakonda, Daniel H Palmer, Richard Jackson, Lance Turtle, Carlo Palmieri
Abstract: The COVID-19 pandemic has been a disruptive event for cancer patients, especially those with haematological malignancies (HM). They may experience a more severe clinical course due to impaired immune responses. This multi-center retrospective UK audit identified cancer patients who had SARS-CoV-2 infection between 1 March and 10 June 2020 and collected data pertaining to cancer history, COVID-19 presentation and outcomes. In total, 179 patients were identified with a median age of 72 (IQR 61, 81) and follow-up of 44 days (IQR 42, 45). Forty-one percent were female and the overall mortality was 37%. Twenty-nine percent had HM and of these, those treated with chemotherapy in the preceding 28 days to COVID-19 diagnosis had worse outcome compared with solid malignancy (SM): 62% versus 19% died [HR 8.33 (95% CI, 2.56-25), p < 0.001]. Definite or probable nosocomial SARS-CoV-2 transmission accounted for 16% of cases and was associated with increased risk of death (HR 2.47, 95% CI 1.43-4.29, p = 0.001). Patients with haematological malignancies and those who acquire nosocomial transmission are at increased risk of death. Therefore, there is an urgent need to reassess shielding advice, reinforce stringent infection control, and ensure regular patient and staff testing to prevent nosocomial transmission.
Keywords: COVID-19; SARS-CoV-2; cancer; haematological; solid.
CCC publication: The NeST (Neoadjuvant systemic therapy in breast cancer) study: National Practice Questionnaire of United Kingdom multi-disciplinary decision making
Citation: BMC Cancer. 2021, 21(1), 90
Author: Whitehead ; Irwin, G. W.; Bannon, F.; Coles, C. E.; Copson, E.; Cutress, R. I.; Dave, R. V.; Gardiner, M. D.; Grayson, M.; Holcombe, C.; Irshad, S.; O'Brien, C.; O'Connell, R. L.; Palmieri, C.; Shaaban, A. M.; Sharma, N.; Singh, J. K.; Potter, S.; McIntosh, S. A.
Abstract: Background: Neoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management.
Methods: Multidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item.
Results: Thirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5-60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0-25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT.
Discussion: There is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes.
Keywords: Breast cancer; Chemotherapy; Endocrine therapy; Neoadjuvant treatment; Surgery.
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.
CCC publication: Price is What You Pay, Value is What You Get
Citation: Clinical Oncology. 2021, 33(5) 341
Author: Boon I.S.
WUTH publication: Seizure First Aid Training For people with Epilepsy (SAFE) frequently attending emergency departments and their significant others: results of a UK multi-centre randomised controlled pilot trial
Citation: BMJ Open. 2020, 10(4), e035516
Author: Noble AJ, Snape D, Nevitt S, Holmes EA, Morgan M, Tudur-Smith C, Hughes DA, Buchanan M, McVicar J, MacCallum E, Goodacre S, Ridsdale L, Marson AG
Abstract: Objective: To determine the feasibility and optimal design of a randomised controlled trial (RCT) of Seizure First Aid Training For Epilepsy (SAFE).
Design: Pilot RCT with embedded microcosting.
Setting: Three English hospital emergency departments (EDs).
Participants: Patients aged ≥16 with established epilepsy reporting ≥2 ED visits in the prior 12 months and their significant others (SOs).
Interventions: Patients (and their SOs) were randomly allocated (1:1) to SAFE plus treatment-as-usual (TAU) or TAU alone. SAFE is a 4-hour group course.
Main outcome measures: Two criteria evaluated a definitive RCT's feasibility: (1) ≥20% of eligible patients needed to be consented into the pilot trial; (2) routine data on use of ED over the 12 months postrandomisation needed securing for ≥75%. Other measures included eligibility, ease of obtaining routine data, availability of self-report ED data and comparability, SAFE's effect and intervention cost.
Results: Of ED attendees with a suspected seizure, 424 (10.6%) patients were eligible; 53 (12.5%) patients and 38 SOs consented. Fifty-one patients (and 37 SOs) were randomised. Routine data on ED use at 12 months were secured for 94.1% patients. Self-report ED data were available for 66.7% patients. Patients reported more visits compared with routine data. Most (76.9%) patients randomised to SAFE received it and no related serious adverse events occurred. ED use at 12 months was lower in the SAFE+TAU arm compared with TAU alone, but not significantly (rate ratio=0.62, 95% CI 0.33 to 1.17). A definitive trial would need ~674 patient participants and ~39 recruitment sites. Obtaining routine data was challenging, taking ~8.5 months.
Conclusions: In satisfying only one predetermined 'stop/go' criterion, a definitive RCT is not feasible. The low consent rate in the pilot trial raises concerns about a definitive trial's finding's external validity and means it would be expensive to conduct. Research is required into how to optimise recruitment from the target population.
Trial registration number: ISRCTN13871327.
Keywords: accident & emergency medicine; clinical trials; epilepsy; health economics; organisation of health services.
Wednesday 17 February 2021
WUTH publication: Reducing the risks of endoscopic sino-nasal surgery in the Covid-19 era
Citation: Clinical Otolaryngology. 2021 Feb 16. Online ahead of print
Author: Leong SC, Mogre D, Andrews P, Davies E
Abstract: Objectives: Many powered instruments used in routine sinonasal surgery are regarded as an aerosol generating procedure (AGP). This study aimed to assess assess how different instrument settings may affect detectable droplet spread and the patterns of aerosolised droplet spread during simulated sinonasal surgery with powered instrumentation in order to identify mitigation strategies.
Design: Simulation series using three-dimensional (3D) printed sinonasal model. Fluorescein droplet spread was assessed following microdebriding and drilling of fluorescein-soaked grapes and bones respectively.
Setting: University dry lab.
Participants: 3-D printed sinonasal model.
Main outcome measures: Patterns of aerosolised droplet spread.
Results and conclusion: There were no observable fluorescein droplets or splatter in the measured surgical field after microdebridement of nasal polyps at a specific irrigation rate and suction pressure. Droplet splatter occurred when suction pressure was reduced; simulating a surgical condition where there was excessive fluid in the nasal cavity irrigation. Drilling with either coarse diamond or cutting burr resulted in detectable droplets. Greater droplet spread was observed when drilling within the anterior nasal cavity. The addition of a suction catheter reduces droplet spread when drilling. Activation of the microdebrider when there is fluid excess fluid (reduced or blocked suction pressure, excessive mucosal bleeding or irrigation fluid) accumulating in the nasal cavity resulted in detectable droplet spread. High-speed drilling is a high-risk AGP especially when drilling in the anterior nasal cavity, but the addition of suction reduces detectable droplet spread outside the nasal cavity.
Keywords: COVID-19; aerosol-generating Procedure; droplet; nasal endoscopy; sinus surgery; skull base surgery.
Thursday 11 February 2021
WUTH publication: The "discordant doppelganger dilemma": SGLT2i mimics therapeutic carbohydrate restriction - food choice first over pharma?
Citation: Journal of human hypertension. 2021 Feb 9. Online ahead of print.
Author: Murray SW, McKelvey S, Heseltine TD, Henderson G, Singh J, Unwin D, Brady AJB
WUTH publication: Do stress and anxiety in early pregnancy affect the progress of labor: Evidence from the Wirral Child Health and Development Study
Citation: Acta Obstetricia et Gynecologica Scandinavica . 2021 Feb 5. Online ahead of print
Author: Slade P, Sheen K, Weeks A, Wray S, De Pascalis L, Lunt K, Bedwell C, Thompson B, Hill J, Sharp H
Abstract: Introduction: Despite widespread belief that anxiety causes longer labor, evidence of association is inconsistent. Data gathered as part of a prospective epidemiological longitudinal study were used to investigate associations between antenatal anxiety and pregnancy-specific stress, and labor progression was assessed by duration and use of augmentation.
Material and methods: Pregnant primiparous women completed measures for anxiety and pregnancy-specific stress at 20 weeks' gestation (n = 1145). Birth outcome data were extracted from medical records. Regression analyses and a path analysis assessed associations between antenatal anxiety and pregnancy-specific stress, and indices of labor progression (labor duration and augmentation).
Results: Anxiety/pregnancy-specific stress were not directly associated with duration of stage 1 labor (HIGH/LOW anxiety: mean difference = 13.94 minutes, SD = 20.66, 95% CI -26.60 to 54.49, P < .50)/(HIGH/LOW pregnancy-specific stress: mean difference = 12.05 minutes, SD = 16.09, 95% CI -19.52 to 43.63, P < .45). However, anxiety/pregnancy-specific stress were associated with epidural use (HIGH/LOW anxiety: 39% vs 31%, P < .042; HIGH/LOW pregnancy-specific stress: 38% vs 29%, P < .001), which was itself associated with longer labor (mean difference: 158.79 minutes, SD = 16.76, 95% CI 125.89-191.68, P < .001). Anxiety and pregnancy-specific stress were associated with increased likelihood of augmentation but these associations were nonsignificant after accounting for epidural, which was itself highly associated with augmentation. However, path analysis indicated an indirect effect linking pregnancy-specific stress, but not general anxiety, to labor duration and augmentation: elevated pregnancy-specific stress led to greater use of epidural, which was linked to both increased rates of augmentation, and increased labor duration.
Conclusions: Contrary to general belief, general anxiety and specific pregnancy stress were not directly linked to longer duration of stage one labor. However specific pregnancy stress was associated with epidural use, which in turn was significantly associated with risk of augmentation, and longer stage one labor. Identification of pregnancy-specific stress could help to identify women for whom psychological interventions could improve birth experience.
Keywords: anxiety; augmentation; epidural; fear of childbirth; labor duration; pregnancy-specific stress.
WUTH publication: SARS-CoV-2 infection in acute pancreatitis increases disease severity and 30-day mortality: COVID PAN collaborative study
Citation: Gut. 2021 Feb 5. Online ahead of print
Author: Pandanaboyana S, Moir J, Leeds JS, Oppong K, Kanwar A, Marzouk A, Belgaumkar A, Gupta A, K Siriwardena A, Haque AR, Awan A, Balakrishnan A, Rawashdeh A, Ivanov B, Parmar C, M Halloran C, Caruana C, Borg CM, Gomez D, Damaskos D, Karavias D, Finch G, Ebied H, K Pine J, R A Skipworth J, Milburn J, Latif J, Ratnam Apollos J, El Kafsi J, Windsor JA, Roberts K, Wang K, Ravi K, V Coats M, Hollyman M, Phillips M, Okocha M, Sj Wilson M, A Ameer N, Kumar N, Shah N, Lapolla P, Magee C, Al-Sarireh B, Lunevicius R, Benhmida R, Singhal R, Balachandra S, Demirli Atıcı S, Jaunoo S, Dwerryhouse S, Boyce T, Charalampakis V, Kanakala V, Abbas Z, Nayar M
Abstract: Objective: There is emerging evidence that the pancreas may be a target organ of SARS-CoV-2 infection. This aim of this study was to investigate the outcome of patients with acute pancreatitis (AP) and coexistent SARS-CoV-2 infection.
Design: A prospective international multicentre cohort study including consecutive patients admitted with AP during the current pandemic was undertaken. Primary outcome measure was severity of AP. Secondary outcome measures were aetiology of AP, intensive care unit (ICU) admission, length of hospital stay, local complications, acute respiratory distress syndrome (ARDS), persistent organ failure and 30-day mortality. Multilevel logistic regression was used to compare the two groups.
Results: 1777 patients with AP were included during the study period from 1 March to 23 July 2020. 149 patients (8.3%) had concomitant SARS-CoV-2 infection. Overall, SARS-CoV-2-positive patients were older male patients and more likely to develop severe AP and ARDS (p<0.001). Unadjusted analysis showed that SARS-CoV-2-positive patients with AP were more likely to require ICU admission (OR 5.21, p<0.001), local complications (OR 2.91, p<0.001), persistent organ failure (OR 7.32, p<0.001), prolonged hospital stay (OR 1.89, p<0.001) and a higher 30-day mortality (OR 6.56, p<0.001). Adjusted analysis showed length of stay (OR 1.32, p<0.001), persistent organ failure (OR 2.77, p<0.003) and 30-day mortality (OR 2.41, p<0.04) were significantly higher in SARS-CoV-2 co-infection.
Conclusion: Patients with AP and coexistent SARS-CoV-2 infection are at increased risk of severe AP, worse clinical outcomes, prolonged length of hospital stay and high 30-day mortality.
Keywords: COVID-19; acute pancreatitis; pancreatitis.
Thursday 4 February 2021
WUTH publication: Haematological malignancy and nosocomial transmission are associated with an increased risk of death from COVID-19: results of a multi-center UK cohort