PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available

Using Rich Pictures to Verify, Contradict, or Enhance Verbal Data

The problem addressed in this case study stemmed from recognition of qualitative researchers’ desire to triangulate findings with two or more data sources. In this study, I describe the process of using visual data to verify, contradict, or enhance verbal data using a soft systems methodology tool called rich pictures. To date, the process of comparing verbal data and visual data has not been well explored. I use secondary data from a Ph.D. study about faculty members’ perceptions of academic quality to compare two data sources: participants’ verbal definitions of academic quality and participants’ verbal descriptions of rich pictures representing their visual conceptions of academic quality. Three rich picture examples illustrate the varying degrees to which rich picture descriptions may align with verbal definitions. Some participants’ rich picture descriptions were partially or completely consistent with their initial definitions of the phenomenon under study. However, in most cases, participants’ descriptions of their rich pictures added new data to their initial definitions of academic quality, thus generating new insights. I recommend asking participants to describe their rich pictures in their own words, thereby facilitating a direct comparison of participants’ verbal and visual data

Post-mortem culture of Balamuthia mandrillaris from the brain and cerebrospinal fluid of a case of granulomatous amoebic meningoencephalitis, using human brain microvascular endothelial cells

The first isolation in the UK of Balamuthia mandrillaris amoebae from a fatal case of granulomatous amoebic meningoencephalitis is reported. Using primary cultures of human brain microvascular endothelial cells (HBMECs), amoebae were isolated from the brain and cerebrospinal fluid (CSF). The cultures showed a cytopathic effect at 20–28 days, but morphologically identifiable B. mandrillaris amoebae were seen in cleared plaques in subcultures at 45 days. The identification of the organism was later confirmed using PCR on Chelex-treated extracts. Serum taken while the patient was still alive reacted strongly with slide antigen prepared from cultures of the post-mortem isolate, and also with those from a baboon B. mandrillaris strain at 1 : 10 000 in indirect immunofluorescence, but with Acanthamoeba castellanii (Neff) at 1 : 160, supporting B. mandrillaris to be the causative agent. If the presence of amoebae in the post-mortem CSF reflects the condition in life, PCR studies on CSF and on biopsies of cutaneous lesions may also be a valuable tool. The role of HBMECs in understanding the interactions of B. mandrillaris with the blood–brain barrier is discussed

Communications Biophysics

Contains reports on three research projects

Modeling of single mode optical fiber having a complicated refractive index profile by using modified scalar finite element method

A numerical method based on modified scalar finite element method (SC-FEM) is presented and programmed on MATLAB platform for optical fiber modeling purpose. We have estimated the dispersion graph, mode cut off condition, and group delay and waveguide dispersion for highly complicated chirped type refractive index profile fiber. The convergence study of our FEM formulation is carried out with respect to the number of division in core. It has been found that the numerical error becomes less than 2 % when the number of divisions in the core is more then 30. To predict the accurate waveguide dispersion characteristics, we need to compute expression (d^2 (Vb))/(dV^2 ) numerically by the FEM method. For that the normalized propagation constant b (in terms of β) should be an accurate enough up to around 6 decimal points. To achieve this target, we have used 1 million sampling points in our FEM simulations. Further to validate our results we have derived the higher order polynomial expression for each case. Comparison with other methods in calculation of normalized propagation constant is found to be satisfactory. In traditional FEM analysis a spurious solution is generated because the functional does not satisfy the boundary conditions in the original waveguide problem, However in our analysis a new term that compensate the missing boundary condition has been added in the functional to eliminate the spurious solutions. Our study will be useful for the analysis of optical fiber having varying refractive index profile

Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability

Aurora kinases are key regulators of chromosome segregation during mitosis. We have previously shown by microarray analysis of primary lung carcinomas and matched normal tissue that AURKB (22 out of 37) and AURKA (15 out of 37) transcripts are frequently over-represented in these tumours. We now confirm these observations in a second series of 44 carcinomas and also show that aurora B kinase protein levels are raised in the tumours compared to normal tissue. Elevated levels of expression in tumours are not a consequence of high-level amplification of the AURKB gene. Using a coding sequence polymorphism we show that in most cases (seven out of nine) tumour expression is predominantly driven from one AURKB allele. Given the function of aurora B kinase, we examined whether there was an association between expression levels and genetic instability. We defined two groups of high and low AURKB expression. Using a panel of 10 microsatellite markers, we found that the group showing the higher level of expression had a higher frequency of allelic imbalance (P=0.0012). Analysis of a number of other genes that are strongly and specifically expressed in tumour over normal lung, including SERPINB5, TERT and PRAME, showed marked allelic expression imbalances in the tumour tissue in the context of balanced or only marginally imbalanced relative allelic copy numbers. Our data support a model of early carcinogenesis wherein defects in the process of inactivation of lung stem-cell associated genes during differentiation, contributes to the development of carcinogenesis

The impact of disruptions due to COVID‐19 on HIV transmission and control among men who have sex with men in China

INTRODUCTION: The COVID-19 pandemic is impacting HIV care globally, with gaps in HIV treatment expected to increase HIV transmission and HIV-related mortality. We estimated how COVID-19-related disruptions could impact HIV transmission and mortality among men who have sex with men (MSM) in four cities in China, over a one- and five-year time horizon. METHODS: Regional data from China indicated that the number of MSM undergoing facility-based HIV testing reduced by 59% during the COVID-19 pandemic, alongside reductions in ART initiation (34%), numbers of all sexual partners (62%) and consistency of condom use (25%), but initial data indicated no change in viral suppression. A mathematical model of HIV transmission/treatment among MSM was used to estimate the impact of disruptions on HIV infections/HIV-related deaths. Disruption scenarios were assessed for their individual and combined impact over one and five years for 3/4/6-month disruption periods, starting from 1 January 2020. RESULTS: Our model predicted new HIV infections and HIV-related deaths would be increased most by disruptions to viral suppression, with 25% reductions (25% virally suppressed MSM stop taking ART) for a three-month period increasing HIV infections by 5% to 14% over one year and deaths by 7% to 12%. Observed reductions in condom use increased HIV infections by 5% to 14% but had minimal impact (<1%) on deaths. Smaller impacts on infections and deaths (<3%) were seen for disruptions to facility HIV testing and ART initiation, but reduced partner numbers resulted in 11% to 23% fewer infections and 0.4% to 1.0% fewer deaths. Longer disruption periods (4/6 months) amplified the impact of disruption scenarios. When realistic disruptions were modelled simultaneously, an overall decrease in new HIV infections occurred over one year (3% to 17%), but not for five years (1% increase to 4% decrease), whereas deaths mostly increased over one year (1% to 2%) and five years (1.2 increase to 0.3 decrease). CONCLUSIONS: The overall impact of COVID-19 on new HIV infections and HIV-related deaths is dependent on the nature, scale and length of the various disruptions. Resources should be directed to ensuring levels of viral suppression and condom use are maintained to mitigate any adverse effects of COVID-19-related disruption on HIV transmission and control among MSM in China

Modelling the impact of an HIV testing intervention on HIV transmission among men who have sex with men in China

OBJECTIVES: An intervention developed through participatory crowdsourcing methods increased HIV self-testing among men who have sex with men [MSM; relative risk (RR) = 1.89]. We estimated the long-term impact of this intervention on HIV transmission among MSM in four cities (Guangzhou, Shenzhen, Jinan and Qingdao). METHODS: A mathematical model of HIV transmission, testing and treatment among MSM in China was parameterized using city-level demographic and sexual behaviour data and calibrated to HIV prevalence, diagnosis and antiretroviral therapy (ART) coverage data. The model was used to project the HIV infections averted over 20 years (2016-2036) from the intervention to increase self-testing, compared with current testing rates. RESULTS: Running the intervention once would avert < 2.2% infections over 20 years. Repeating the intervention (RR = 1.89) annually would avert 6.4-10.7% of new infections, while further increases in the self-testing rate (hypothetical RR = 3) would avert 11.7-20.7% of new infections. CONCLUSIONS: Repeated annual interventions would give a three- to seven-fold increase in long-term impact compared with a one-off intervention. Other interventions will be needed to more effectively reduce the HIV burden in this population

Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention.

INTRODUCTION: Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure--a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development. METHODS AND ANALYSIS: In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians' discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year. ETHICS AND DISSEMINATION: PIT was approved by NRES Committee North West-Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018. TRIAL REGISTRATION NUMBER: ISRCTN04240319; NCT01604005; Pre-results

Clinical expert guidelines for the management of cough in lung cancer: report of a UK task group on cough

Background Cough is a common and distressing symptom in lung cancer patients. The clinical management of cough in lung cancer patients is suboptimal with limited high quality research evidence available. The aim of the present paper is to present a clinical guideline developed in the UK through scrutiny of the literature and expert opinion, in order to aid decision making in clinicians and highlight good practice. Methods Two systematic reviews, one focusing on the management of cough in respiratory illness and one Cochrane review specifically on cancer, were conducted. Also, data from reviews, phase II trials and case studies were synthesized. A panel of experts in the field was also convened in an expert consensus meeting to make sense of the data and make clinical propositions. Results A pyramid of cough management was developed, starting with the treatment of reversible causes of cough/specific pathology. Initial cough management should focus on peripherally acting and intermittent treatment; more resistant symptoms require the addition of (or replacement by) centrally acting and continuous treatment. The pyramid for the symptomatic management starts from the simpler and most practical regimens (demulcents, simple linctus) to weak opioids to morphine and methadone before considering less well-researched and experimental approaches. Conclusion The clinical guidelines presented aim to provide a sensible clinical approach to the management of cough in lung cancer. High quality research in this field is urgently required to provide more evidence-based recommendations