CCC publication: Dyspnea in Patients Receiving Radical Radiotherapy for Non-Small Cell Lung Cancer: A Prospective Study

Citation: Frontiers in oncology. 2020 Dec 23. eCollection 2020

Author: Angela Sardaro, Fiona McDonald, Lilia Bardoscia, Konstantin Lavrenkov, Shalini Singh, Sue Ashley, Daphne Traish, Cristina Ferrari, Icro Meattini, Artor Niccoli Asabella, Michael Brada

Abstract: Background and purpose: Dyspnea is an important symptomatic endpoint for assessment of radiation-induced lung injury (RILI) following radical radiotherapy in locally advanced disease, which remains the mainstay of treatment at the time of significant advances in therapy including combination treatments with immunotherapy and chemotherapy and the use of local ablative radiotherapy techniques. We investigated the relationship between dose-volume parameters and subjective changes in dyspnea as a measure of RILI and the relationship to spirometry.

Material and methods: Eighty patients receiving radical radiotherapy for non-small cell lung cancer were prospectively assessed for dyspnea using two patient-completed tools: EORTC QLQ-LC13 dyspnea quality of life assessment and dyspnea visual analogue scale (VAS). Global quality of life, spirometry and radiation pneumonitis grade were also assessed. Comparisons were made with lung dose-volume parameters.

Results: The median survival of the cohort was 26 months. In the evaluable group of 59 patients there were positive correlations between lung dose-volume parameters and a change in dyspnea quality of life scale at 3 months (V30 p=0.017; V40 p=0.026; V50 p=0.049; mean lung dose p=0.05), and a change in dyspnea VAS at 6 months (V30 p=0.05; V40 p=0.026; V50 p=0.028) after radiotherapy. Lung dose-volume parameters predicted a 10% increase in dyspnea quality of life score at 3 months (V40; p=0.041, V50; p=0.037) and dyspnea VAS score at 6 months (V40; p=0.027) post-treatment.

Conclusions: Worsening of dyspnea is an important symptom of RILI. We demonstrate a relationship between lung dose-volume parameters and a 10% worsening of subjective dyspnea scores. Our findings support the use of subjective dyspnea tools in future studies on radiation-induced lung toxicity, particularly at doses below conventional lung radiation tolerance limits.

Keywords: dose-volume parameters; dyspnea; non-small cell lung cancer; radiation-induced lung injury; radiotherapy.

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CCC publication: Role of MYC and BCL2 expression in a cohort of 43 patients with DLBCL: a retrospective study

Citation: Journal of Clinical Pathology. 2020. Online ahead of print

Author: Umair Tahir Khan, Michael Kelly, James Dodd, Sammy Fergiani, Barbara Hammer, Jeffrey Smith, Arvind Arumainathan, Mark Atherton, Anthony Carter, Igor Racu-Amoasii, Nagesh Kalakonda, Andrew Pettitt, Geetha Menon

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CCC publication: The genomic landscape of breast cancer brain metastases: a systematic review

Citation: The Lancet. Oncology. 2021, 22(1), e7-e17. 

Author: Alexander J Morgan, Athina Giannoudis, Carlo Palmieri 

Abstract: Breast cancer brain metastases are an increasing clinical problem. Studies have shown that brain metastases from breast cancer have a distinct genomic landscape to that of the primary tumour, including the presence of mutations that are absent in the primary breast tumour. In this Review, we aim to review and evaluate genomic sequencing data for breast cancer brain metastases by searching PubMed, Embase, and Scopus for relevant articles published in English between database inception and May 30, 2020. Extracted information includes data for mutations, receptor status (eg, immunohistochemistry and Prediction Analysis of Microarray 50 [PAM50]), and copy number alterations from published manuscripts and supplementary materials. Of the 431 articles returned by the database search, 13 (3%) breast cancer brain metastases sequencing studies, comprising 164 patients with sequenced brain metastases, met all our inclusion criteria. We identified 268 mutated genes that were present in two or more breast cancer brain metastases samples. Of these 268 genes, 22 (8%) were mutated in five or more patients and pathway enrichment analysis showed their involvement in breast cancer-related signalling pathways, regulation of gene transcription, cell cycle, and DNA repair. Actionability analysis using the Drug Gene Interaction Database revealed that 15 (68%) of these 22 genes are actionable drug targets. In addition, immunohistochemistry and PAM50 data showed receptor discordancy between primary breast cancers and their paired brain metastases. This systematic review provides a detailed overview of the most commonly mutated genes identified in samples of breast cancer brain metastases and their clinical relevance. These data highlight the differences between primary breast cancers and brain metastases and the importance of acquiring and analysing brain metastasis samples for further study.

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CCC publication: 1'-Acetoxychavicol Acetate from Alpinia galanga Represses Proliferation and Invasion, and Induces Apoptosis via HER2-signaling in Endocrine-Resistant Breast Cancer Cells

Citation: Planta Medica. 2021 Online ahead of print

Author: Nalinee Pradubyat, Athina Giannoudis, Taha Elmetwali, Panupong Mahalapbutr, Carlo Palmieri, Chalermchai Mitrpant, Wannarasmi Ketchart

Abstract: Estrogen receptor-positive breast cancer patients have a good prognosis, but 30% of these patients will experience recurrence due to the development of resistance through various signaling pathways. This study aimed to evaluate the mode of anticancer effects of 1'-acetoxychavicol acetate, which is isolated from the rhizomes of Alpinia galanga in estrogen receptor positive (MCF7) human epidermal growth factor receptor 2-overexpressed (MCF7/HER2), and endocrine-resistant breast cancer cells (MCF7/LCC2 and MCF7/LCC9). 1'-Acetoxychavicol acetate showed antiproliferation in a concentration- and time-dependent fashion and had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines. This was associated with down-regulation of human epidermal growth factor receptor 2, pERK1/2, pAKT, estrogen receptor coactivator, cyclin D1, and MYC proto-oncogene while in vivo and significant reduction in the tumor mass of 1'-acetoxychavicol acetate-treated zebrafish-engrafted breast cancer groups. The anti-invasive effects of 1'-acetoxychavicol acetate were confirmed in vitro by the matrigel invasion assay and with down-regulation of C - X-C chemokine receptor type 4, urokinase plasminogen activator, vascular endothelial growth factor, and basic fibroblast growth factor 2 genes. The down-regulation of urokinase plasminogen activator and fibroblast growth factor 2 proteins was also validated by molecular docking analysis. Moreover, 1'-acetoxychavicol acetate-treated cells exhibited lower expression levels of the anti-apoptotic Bcl-2 and Mcl-1 proteins in addition to enhanced stress-activated kinases/c-Jun N-terminal kinase 1/2 and poly-ADP ribose polymerase cleavage, indicating apoptotic cell induction by 1'-acetoxychavicol acetate. Moreover, 1'-acetoxychavicol acetate had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines regarding its inhibition on human epidermal growth factor receptor 2, pAKT, pERK1/2, PSer118, and PSer167-ERα proteins. Our findings suggest 1'-acetoxychavicol acetate mediates its anti-cancer effects via human epidermal growth factor receptor 2 signaling pathway.

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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: Miller AS, Boyce K, Box B, Clarke MD, Duff SE, Foley NM, Guy RJ, Massey LH, Ramsay G, Slade DAJ, Stephenson JA, Tozer PJ, Wright D

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.

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Cervical Cancer Prevention Week 2021

Today marks the start of #CervicalCancerPreventionWeek

We are highlighting some key sources on this topic through the week on social media and in this blog post.

UpToDate (WUTH/CCC)

Society guideline links: Cervical cancer screening and prevention

BMJ Best Practice (WUTH/CCC/WCHC)

Cervical cancer: prevention

NICE Guidelines

Cervical Cancer

Including one recently updated guideline (NG12) and three new guidelines that are in progress:

Suspected cancer: recognition and referral (NG12)

Product type: Guidance

Programme: NICE guideline

Last updated: 11 September 2020 Published date: 23 June 2015

Minimally invasive radical hysterectomy for early stage cervical cancer

Status: In development

Programme: Interventional procedures guidance

Expected publication date: 27 January 2021

Pembrolizumab with chemotherapy for treating recurrent, persistent or metastatic cervical cancer [ID3798]

Status: In development

Programme: Technology appraisal guidance

Expected publication date: TBC

LN-145 for treating recurrent, persistent or metastatic cervical cancer [ID3844]

Status: Proposed

Programme: Technology appraisal guidance

Expected publication date: TBC

NICE Clinical Knowledge Summary (CKS)

Cervical Cancer and HPV: Scenario: Prevention

Cancer Research UK

Cervical Cancer

Jo's Trust

Cervical Cancer Prevention Week

If you would like more information on this topic, please get in touch with us at wuth.lks@nhs.net

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: 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), 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.

Link to PubMed record

WUTH publication: Cerebral blood flow predicts recovery in children with persistent post-concussion symptoms following mild traumatic brain injury

Citation: Journal of Neurotrauma. 2021 Jan 11. Online ahead of print

Author: Barlow KM, Iyer K, Yan T, Scurfield A, Carlson HL, Wang Y

Abstract: Persistent post-concussion symptoms (PPCS) following pediatric mild traumatic brain injury (mTBI) are associated with differential changes in cerebral blood flow (CBF). Given its potential as a therapeutic target, we examined CBF changes during recovery in children with PPCS. We hypothesized that CBF would decrease and that such decreases would mirror clinical recovery. In a prospective cohort study, 61 children (mean age 14 (SD=2.6) years; 41% male) with PPCS were imaged with 3D pseudo-continuous arterial spin-labelled (pCASL) MRI at 4-6 and 8-10 weeks post-injury. Exclusion criteria included any significant past medical history and/or previous concussion within three months. 23 participants had clinically recovered at the time of the second scan. We found that relative and mean absolute CBF were higher in participants with poor recovery, 44.0 (95%CI: 43.32, 44.67) compared to those with good recovery, 42.19 (95%CI: 41.77, 42.60) ml/min/100g grey tissue and decreased over time (Beta=-1.75; p<.001). The decrease was greater in those with good recovery (Beta=2.29; p<.001) and predicted outcome in 77% of children with PPCS (OR .54, 95%CI: .36, .80; p=.002). Future studies are warranted to validate the utility of CBF as a useful predictive biomarker of outcome in PPCS.

Keywords: BLOOD FLOW; CBF autoregulation; OUTCOME MEASURES; PEDIATRIC BRAIN INJURY; TRAUMATIC BRAIN INJURY.

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WUTH publication: Pre-clinical atherosclerosis is found at post-mortem, in the brains of men with HIV

Citation: Journal of Neurovirology. 2021 Jan 6. Online ahead of print

Author: Daramola O, Ali H, Mckenzie CA, Smith C, Benjamin LA, Solomon T

Abstract: The aim of this study is to ascertain the burden of pre-clinical atherosclerotic changes in the brains of young adult males with HIV and explore the impact of anti-retroviral therapy (ART). The study design is case-control, cross-sectional. Histological sections from HIV-positive post-mortem brain samples, with no associated opportunistic infection, from the MRC Edinburgh brain bank were evaluated. These were age and sex matched with HIV-negative controls. Immunohistochemical stains were performed to evaluate characteristics of atherosclerosis. The pathological changes were graded blinded to the HIV status and a second histopathologist reassessed 15%. Univariable models were used for statistical analyses; p≤0.05 was considered significant. Nineteen HIV-positive post-mortem cases fulfilled our inclusion criteria. Nineteen HIV-negative controls were selected. We assessed mostly small- to medium-sized vessels. For inflammation (CD45), 7 (36%) of the HIV+ had moderate/severe changes compared with none for the HIV- group (p<0.001). Moderate/severe increase in smooth muscle remodeling (SMA) was found in 8 (42%) HIV+ and 0 HIV- brains (p<0.001). Moderate/severe lipoprotein deposition (LOX-1) was found in 3 (15%) and 0 HIV- brains (p<0.001). ART was associated with less inflammation [5 (63%) no ART versus 2 (18%) on ART (p=0.028)] but was not associated with reduced lipid deposition or smooth muscle damage. In HIV infection, there are pre-clinical small- to medium-sized vessel atherosclerotic changes and ART may have limited impact on these changes. This could have implications on the increasing burden of cerebrovascular disease in HIV populations and warrants further investigation.

Keywords: Art; Atherosclerosis; Cerebrovascular disease; HIV; Post-mortem.

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WUTH publication: Role of MYC and BCL2 expression in a cohort of 43 patients with DLBCL: a retrospective study

Citation: Journal of Clinical Pathology. 2020 Dec 30. Online ahead of print.

Author: Khan UT, Kelly M, Dodd J, Fergiani S, Hammer B, Smith J, Arumainathan A, Atherton M, Carter A, Racu-Amoasii I, Kalakonda N, Pettitt A, Menon G

Link to PubMed record