CCC publication: CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer

Citation: Cancers. 2020, 12(10), E2963

Author: Fleming JC(1)(2)(3), Woo J(4), Moutasim K(1), Hanley CJ(1), Frampton SJ(1), Wood O(1), Ward M(1), Woelk CH(4)(5), Ottensmeier CH(1)(2)(3)(6), Hafizi S(7), Kim D(8), Thomas GJ(1)

Abstract: Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic targets and aid treatment selection. C-terminal tensin-like (CTEN) is a member of the tensin family, upregulated in several cancers, although its expression and function in HNSCC are unknown. We found that CTEN is commonly upregulated in HNSCC, particularly HPV-ve tumours. In vitro CTEN was upregulated in HPV-ve (n = 5) and HPV+ve (n = 2) HNSCC cell lines. Stable shRNA knockdown of CTEN in vivo significantly reduced tumour growth (SCC-25), and functional analyses in vitro showed that CTEN promoted tumour cell invasion, colony formation and growth in 3D-culture (SCC-25, Detroit 562). RNA sequencing of SCC-25 cells following CTEN siRNA knockdown identified 349 differentially expressed genes (logFC > 1, p < 0.05). Gene ontology analysis highlighted terms relating to cell locomotion and apoptosis, consistent with in vitro findings. A membrane-based antibody array confirmed that CTEN regulated multiple apoptosis-associated proteins, including HSP60 and cleaved caspase-3. Notably, in a mixed cohort of HPV+ve and HPV-ve HNSCC patients (n = 259), we found a significant, independent negative association of CTEN with prognosis, limited to those patients treated with (chemo)radiotherapy, not surgery, irrespective of human papillomavirus (HPV) status. These data show that CTEN is commonly upregulated in HNSCC and exerts several functional effects. Its potential role in modulating apoptotic response to therapy suggests utility as a predictive biomarker or radio-sensitising target.

Keywords: CTEN; apoptosis; biomarker; head and neck cancer; human papillomavirus; invasion; radiotherapy; tensin.

Link to PubMed record

CCC publication: A phase II randomised, placebo-controlled trial of low dose (metronomic) cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or primary peritoneal cancer

Citation: Gynecologic Oncology. 2020, 159(3), 692-698. 2020, S0090-8258(20), 33958-5. Online ahead of print

Author: Hall MR(1), Dehbi HM(2), Banerjee S(3), Lord R(4), Clamp A(5), Ledermann JA(6), Nicum S(7), Lilleywhite R(8), Bowen R(9), Michael A(10), Feeney A(11), Glasspool R(12), Hackshaw A(13), Rustin G(14).

Abstract: Background: We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer.

Patients and methods: Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life.

Results: 117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P < 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms.

Conclusions: This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used.

Clinical trial registration: Clinicaltrials.govNCT01610869.

Keywords: Late stage relapsed ovarian cancer; Nintedanib; Oral cyclophosphamide; Prior bevacizumab.

Link to PubMed record

CCC publication: Genomic profiles of de novo high and low-volume metastatic prostate cancer: Results from a 2-stage feasibility and prevalence study in the STAMPEDE trial

Citation: JCO Precision Oncology. 2020, 4, 882-897 

Author: Gilson C.; Ingleby F.; Gilbert D.C.; Atako N.B.; Gannon M.; Wanstall C.; Brawley C.; Amos C.; Parmar M.K.B.; Langley R.E.; Sydes M.R.; Parry M.A.; Attard G. (g.attard@ucl.ac.uk); Ali A.; Hoyle A.; Clarke N.W.; Mason M.D.; Parry-Jones A.; Malik Z.; Simmons A.; Loehr A.; Eeles R.; Kote-Jarai Z.; James N.D.; Chowdhury S.

WUTH publication: Prevalence and risk factors of depressive symptoms among dialysis patients with end-stage renal disease (ESRD) in Khartoum, Sudan: A cross-sectional study

Citation: Journal of Family Medicine and Primary Care. 2020, 9(7), 3639-3643
Author: Elkheir HK, Wagaella AS, Badi S, Khalil A, Elzubair TH, Khalil A, Ahmed MH

Abstract: Background: Depression is the most common prevalent psychiatric condition among patients with chronic kidney disease (CKD), and especially during dialysis. This study aimed to evaluate depression symptoms in Sudanese patients with end-stage renal diseases (ESRD) who undergo hemodialysis.

Methods: This is a case finding, hospital-based study recruited 75 patients on dialysis in Khartoum, Sudan. Data were analyzed by statistical package for social science (SPSS, version 23).

Results: The percentage of depression symptoms that satisfies the criteria for the diagnosis of major depression disorders in patients with ESRD undergoes dialysis was 68%. The new patients who undergo dialysis for less than 1 year had more depression symptoms (66.7%) than those on dialysis for 2-3 years (21.6%) or more than 3 years with a percentage of11.8%. Chi-square test showed significant associations between depression and age, the duration of dialysis, signs of significant weight loss when no dieting, and when the clinical symptoms related to distress or social or functional impairment (P = 0.016, 0.000, 0.004, and 0.000, respectively). Logistic regression test showed that age and duration of dialysis were significantly associated with depression with (odds ratios [OR]: 0.724, 0.211).

Conclusion: More than two-thirds of patients on dialysis have depressive symptoms. Risk factors associated with depression in Sudanese patients on dialysis were age, duration of dialysis, weight loss, and social and functional impairment. Future research is needed in order to assess the benefit of antidepressants in patients on dialysis. Family physicians should be aware of the association between depression and dialysis, in order to provide early treatment and prevent suicide.

Keywords: Depressive symptoms; Khartoum; Sudan; dialysis patients; end-stage renal disease (ESRD).

Link to PubMed record

WUTH publication: The Role of the Computed Tomography (CT) Thorax in the Diagnosis of COVID-19 for Patients Presenting with Acute Surgical Emergencies. A Single Institute Experience

Citation: The Indian Journal of Surgery. 2020 Oct 20, 1-6. Online ahead of print
Author: Majeed T, Ali RS, Solomon J, Mesri M, Sharma S, Shamim S, Aiynattu S, Ishak R, Wilson J, Magee C
Abstract: The current Coronavirus disease 2019 (COVID-19) pandemic has had a huge impact on emergency surgical services in the UK. The Royal College of Surgeons (RCS) published guidelines about COVID-19 pandemic in March, 2020 to aid decision making for the surgeons. These guidelines recommended that all patients requiring urgent surgery should have reverse transcriptase polymerase chain reaction (RT-PCR) and/or computed tomography (CT) thorax pre-operatively. However, it is currently unclear whether the use of CT thorax is a sensitive and specific diagnostic test. The objective of this study was to find out whether CT thorax is a reliable and accurate test in the diagnosis of COVID-19 compared to RT-PCR. This is particularly important in surgical patients where there is no time to wait for RT-PCR results. A prospective cohort study of patients presented with acute surgical emergencies at a University Teaching Hospital was conducted. Data was collected from March 23, to May 15, 2020, during the peak of the crisis in the UK. All adult patients presented with operable general surgical emergencies were considered eligible. Another group of patients, admitted with acute medical emergencies but with suspected COVID-19 infection, was used for comparison. Data was manually collected, and sensitivity, specificity and predictive value were calculated using the MedCalc statistical software version 19.2.6. Standard reporting for COVID-19 infection for CT chest based on guidelines from British Society of Thoracic Imaging (BSTI) and Radiological Society of North America (RSNA) was used. Patients who had their CT thorax reported as typical or classic of COVID 19 (high probability) were treated as infected cases with extra precautions in the wards and surgical theatres as suggested by health and safety executive (HSE). These patients had serial RT-PCR during their admissions or in the post-operative phase, if the first swab was negative. For the study, 259 patients were considered eligible for inclusion from both groups. Patients admitted for acute surgical emergencies were treated according to RCS guidelines and subjected to RT-PCR test and/or CT scan of the thorax. There were 207 patients with high clinical suspicion of COVID-19. Of those 207 patients, 77 patients had CT thorax with radiographic features consistent with COVID-19 pneumonia. However, only 40 patients had a positive RT-PCR result. CT thorax was normal in 130 patients, out of which 29 patients were found to have COVID-19 diagnosis after swab test. Sensitivity of CT scan to diagnose COVID-19 infection was found to be 58% (95% CI; 45.48% to 69.76%) whilst specificity was 73% (95% CI; 64.99% to 80.37%) with a negative predictive value of 77.69% (95% CI; 72.17% to 82.39%). CT scan was found to be a reliable tool in the diagnosis of COVID-19. With a negative predictive value of up to 82.4%, CT thorax can play an important role to help surgeons in their decision making for asymptomatic suspected cases of COVID-19. However, over-reliance on CT scan which also has a high false positive rate for diagnosis of COVID-19 infections can lead to overtreatment, overuse of resources and delays in decision-making process. Hence, results should be interpreted with caution and correlated with clinical presentation and swab test results.

Keywords: COVID-19; CT chest; Pandemic; RT-PCR; SARS-CoV-2; Surgery; Viral pneumonia.

Link to PubMed record

WUTH publication: Digital healthcare and shifting equipoise in radiation oncology: The butterfly effect of the COVID-19 pandemic

Citation: Journal of Medical Imaging and Radiation Sciences. 2021, 52(1), 11-13

Author: Boon IS, Lim JS, Au Yong TPT, Boon CS

Link to PubMed record

COVID-19 Information

The World Health Organization have written a very useful post on navigating the continuous stream of information regarding COVID-19.

https://www.who.int/news-room/spotlight/let-s-flatten-the-infodemic-curve

 

We are receive this information through multiple channels every day, and not all of it is reliable.

 

Includes info on the following:

 

·       Assessing the source

·       Going beyond the headlines

·       Identifying the author

·       Checking the date

·       Examining supporting evidence

·       Checking your biases

·       Consult a fact-checker

 

Our training sessions on ‘Finding the Evidence’ and ‘Critical Appraisal’ also give you the skills to quickly find and assess the evidence that you are reading.

 

If you are interested in booking a virtual training session, either 1:1 or for your team, please email us at wuth.lks@nhs.net

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: Gray N, Calleja D, Wimbush A, Miralles-Dolz E, Gray A, De Angelis M, Derrer-Merk E, Oparaji BU, Stepanov V, Clearkin L, Ferson S

Abstract: Testing is viewed as a critical aspect of any strategy to tackle epidemics. Much of the dialogue around testing has concentrated on how countries can scale up capacity, but the uncertainty in testing has not received nearly as much attention beyond asking if a test is accurate enough to be used. Even for highly accurate tests, false positives and false negatives will accumulate as mass testing strategies are employed under pressure, and these misdiagnoses could have major implications on the ability of governments to suppress the virus. The present analysis uses a modified SIR model to understand the implication and magnitude of misdiagnosis in the context of ending lockdown measures. The results indicate that increased testing capacity alone will not provide a solution to lockdown measures. The progression of the epidemic and peak infections is shown to depend heavily on test characteristics, test targeting, and prevalence of the infection. Antibody based immunity passports are rejected as a solution to ending lockdown, as they can put the population at risk if poorly targeted. Similarly, mass screening for active viral infection may only be beneficial if it can be sufficiently well targeted, otherwise reliance on this approach for protection of the population can again put them at risk. A well targeted active viral test combined with a slow release rate is a viable strategy for continuous suppression of the virus.

Link to PubMed record

WUTH publication: Acute ischaemic stroke management: Concepts and Controversies. A narrative review

Citation: Expert review of neurotherapeutics. 2020 Oct 13. Online ahead of print

Author: Li KHC, Jesuthasan A, Kui C, Davies R, Tse G, Lip GYH

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, it is important for future studies 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 towards 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.

Link to PubMed record

Visit the library

Please do come along and visit the McArdle Library.

We have a number of measures in place to limit COVID. Please:

·         wear a face mask

·         sign the visitor's book

·         sanitise hands frequently & use wipes provided to clean PCs/desk

·         observe social distancing

Let's work together & keep everyone safe

WUTH publication: Guidance for the assessment and management of prostate cancer treatment-induced bone loss. A consensus position statement from an expert group

Citation: Journal of Bone Oncology. 2020, 25, 100311

Author: Brown JE, Handforth C, Compston JE, Cross W, Parr N, Selby P, Wood S, Drudge-Coates L, Walsh JS, Mitchell C, Collinson FJ, Coleman RE, James N, Francis R, Reid DM, McCloskey E

Abstract: Context and objective: Incidence of prostate cancer (PC) is increasing, but androgen deprivation therapy (ADT) and other therapies are substantially improving survival. In this context, careful consideration of skeletal health is required to reduce the risk of treatment-related fragility fractures and their associated morbidity and mortality. This risk is currently not well-managed. ADT causes significant loss of bone mineral density (BMD). In the metastatic setting, systemic treatments (e.g. chemotherapy, abiraterone, enzalutamide) are used alongside ADT and may require concomitant glucocorticoids. Both ADT and glucocorticoids pose significant challenges to skeletal health in a population of patients already likely to have ongoing age-related bone loss and/or comorbid conditions. Current PC guidelines lack specific recommendations for optimising bone health. This guidance presents evidence for assessment and management of bone health in this population, with specific recommendations for clinical practitioners in day-to-day PC management.

Methods: Structured meetings of key opinion leaders were integrated with a systematic literature review. Input and endorsement was sought from patients, nursing representatives and specialist societies.

Summary of guidance: All men starting or continuing long-term ADT should receive lifestyle advice regarding bone health. Calcium/vitamin D supplementation should be offered if required. Fracture risk should be calculated (using the FRAX® tool), with BMD assessment included where feasible. BMD should always be assessed where fracture risk calculated using FRAX® alone is close to the intervention threshold. Intervention should be provided if indicated by local or national guidelines e.g. UK National Osteoporosis Guideline Group (NOGG) thresholds. Men requiring bone protection therapy should be further assessed (e.g. renal function), with referral to specialist centres if available and offered appropriate treatment to reduce fracture risk. Those near to, but below an intervention threshold, and patients going on to additional systemic therapies (particularly those requiring glucocorticoids), should have FRAX® (including BMD) repeated after 12-18 months.

Patient summary: Modern treatments for prostate cancer have led to significant improvements in survival and quality of life. However, some of these treatments may lead to weakening of patient's bones with risk of fracture and it is therefore important to monitor patients' bone health and provide bone protection where needed. This paper provides specific guidance to clinical teams, based on the most recent research evidence, to ensure optimal bone health in their patients.

Keywords: Fracture risk; Guidelines; Osteoporosis; Prostate cancer; Skeletal health.

Link to PubMed record

WUTH publication: A prospective, multi-centre external validation study of the Liverpool Peritonsillar abscess Score (LPS) with a no-examination Covid-19 modification

Citation: Clinical Otolaryngology. 2020 Sep 30. Online ahead of print.

Author: Selwyn D, Yang D, Heward E, Kerai A, Thompson E, Shommakhi A, Faulkner S, Siau R, Walijee H, Hampton T, Chudek D, Singhera S, Din W, Lau AS

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) was0.888 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: Peri-tonsillar abscess; diagnosis; dysphagia; swallowing.

Link to PubMed record