Head and neck cancer in the UK: what is expected of cytopathology?

Objective:  This review highlights the role of cytopathology in cancer management within UK Head and Neck Cancer Networks and informs on the issues raised by recent UK Department of Health documents and other UK professional guidance. UK guidance requires the formal involvement of cytopathologists within multidisciplinary cancer teams, with medical and non-medical cytopathology staff setting up and running rapid access lump clinics, and support for image-guided fine needle aspiration cytology (FNAC) services. UK guidance also makes recommendations for training, resources and quality control. This review also highlights the resource gap between best practice evidence-based guidance for head and neck (HN) cancer services and existing UK provision for cytopathology, as evidenced by lack of availability of experienced staff and adequacy of training and quality control (QC). Finally, it stresses the importance in the UK of the Royal College of Pathologists' guidance, which defines the need for training, the experience needed for new consultants, the requirements for audit and QC. The implications for the additional resources required for HN cancer cytopathology services are discussed. Recent professional guidance specifying the provision of HN cancer services in the UK includes a cytopathology service for cancer networks, such as rapid access FNAC clinics. Although these clinics already operate in some institutions, there are many institutions where they do not and where the provision of cytopathology services would have to be restructured. This would need the support of local cancer networks and their acceptance of the detailed requirements for cytopathology, including resources, training and QC. The standards are not defined locally, as Strategic Health Authorities and Primary Care Trusts have been instructed by the Department of Health to support, invest and implement them.     

Ethical problems in cytology

Great advances in medical science have raised a number of ethical issues, many of which affect cytopathology. Some of the main issues addressed in this paper relate to the organization of a cytology laboratory: internal and external quality control, adequate staffing levels and staff education, cytopathology reporting format and contents, confidentiality issues, relationship with the clinicians and involvement of cytopathologists in clinical management teams. Quality control has to be provided within cytology departments but external quality assurance is also essential, with national monitoring. New technologies should be used according to the best scientific methods, following cytological analysis. Scientific work in cytology has to respect the general principles of scientific ethics. The patient's interest has to be the main reason for such work.     

The EU medical device regulation: Implications for artificial intelligence-based medical device software in medical physics

Medical device manufacturers are increasingly applying artificial intelligence (AI) to innovate their products and to improve patient outcomes. Health institutions are also developing their own algorithms, to address specific needs for which no commercial product exists.Although AI-based algorithms offer good prospects for improving patient outcomes, their wide adoption in clinical practice is still limited. The most significant barriers to the trust required for wider implementation are safety and clinical performance assurance .Qualified medical physicist experts (MPEs) play a key role in safety and performance assessment of such tools, before and during integration in clinical practice. As AI methods drive clinical decision-making, their quality should be assured and tested. Occasionally, an MPE may be also involved in the in-house development of such an AI algorithm. It is therefore important for MPEs to be well informed about the current regulatory framework for Medical Devices.The new European Medical Device Regulation (EU MDR), with date of application set for 26 of May 2021, imposes stringent requirements that need to be met before such tools can be applied in clinical practice.The objective of this paper is to give MPEs perspective on how the EU MDR affects the development of AI-based medical device software. We present our perspective regarding how to implement a regulatory roadmap, from early-stage consideration through design and development, regulatory submission, and post-market surveillance. We have further included an explanation of how to set up a compliant quality management system to ensure reliable and consistent product quality, safety, and performance .     

Fine needle aspiration cytology: a survey of current European practice

Fine needle aspiration cytology (FNAC) is practised widely throughout Europe. The majority of countries have dedicated cytopathologists as well as histopathologists practicing cytology. Despite this, FNAC is performed mostly by clinicians and radiologists except in the larger centres with dedicated staff with a special interest in cytopathology. The advent of One-Stop diagnostic services and image-guided procedures are prompting further development of FNAC clinics where cytopathologists take their own samples, issue reports in the same clinical session and take extra material for ancillary tests to complete the diagnosis. The volume of FNAC work varies accordingly; in dedicated centres FNAC represents up to 80% of the workload whilst, in the majority of countries, it represents one quarter or less. Hence, the rate of inadequate FNAC varies widely, depending on the local sampling policies and the organ, but does not exceed 25% in any of the countries. The most sampled organs are breast and thyroid, followed by lymph nodes. Most countries have dedicated training in cytopathology for pathology trainees, the duration varying between 6 months and 2 years of the total training time. This discussion, focusing on European practices, highlights the heterogeneity of FNAC activity but also its success in many centres where it is practiced to a high standard, particularly in breast, thyroid and lymph node pathology. The relatively high rate of inadequate material in some centres reflects local policies and calls for greater uniformity of FNAC practice, particularly specimen sampling. To achieve this, the future direction should concentrate on specialist training, to include performing as well as interpreting FNAC, as part of the curriculum. Current emphasis on web-based training may not provide first hand experience of the FNAC procedure and should be supplemented by attending FNAC clinics and developing the technique to its full potential.     

Molecular diagnosis on tissues and cells: how it affects training and will affect practice in the future

C. Boyd and D. P. Boyle Molecular diagnosis on tissues and cells: how it affects training and will affect practice in the future On 25th November 2011, a symposium organized by the Royal College of Pathologists, entitled 'Molecular diagnosis on tissues and cells', took place in London. As trainees in histopathology and cytopathology, we were stimulated to consider the role that molecular biology is likely to play in future practice and how this is addressed by our own training. The symposium provided a basis for this article. Routine samples requiring molecular analysis are equally relevant to histopathologists and cytopathologists, and molecular biology laboratories are now using cytological as well as histological material for diagnostic testing, allowing different specimen types to be used as and when they are most appropriate. The most widely used types of molecular analysis in routine cellular pathology are EGFR testing in lung cancer, molecular testing of thyroid nodules, fluorescence in?situ hybridization testing of urine samples, clonality analysis in lymphoma testing, HER2 testing in breast and gastric cancer, KRAS testing in colorectal cancer, intraoperative assessment of breast cancer sentinel nodes, molecular testing of gastrointestinal stromal tumours and mismatch repair protein analysis. Of these, the majority in the UK are carried out on histopathology samples, although many are applicable to cytological samples if adequate material is obtained. We are particularly encouraged by the potential of molecular diagnostic cytology in traditionally difficult areas, such as intraoperative assessment. We believe that increasing reliance on molecular diagnostic techniques will also herald changes in training.     

Artificial intelligence and machine learning for medical imaging: A technology review

Artificial intelligence (AI) has recently become a very popular buzzword, as a consequence of disruptive technical advances and impressive experimental results, notably in the field of image analysis and processing. In medicine, specialties where images are central, like radiology, pathology or oncology, have seized the opportunity and considerable efforts in research and development have been deployed to transfer the potential of AI to clinical applications. With AI becoming a more mainstream tool for typical medical imaging analysis tasks, such as diagnosis, segmentation, or classification, the key for a safe and efficient use of clinical AI applications relies, in part, on informed practitioners. The aim of this review is to present the basic technological pillars of AI, together with the state-of-the-art machine learning methods and their application to medical imaging. In addition, we discuss the new trends and future research directions. This will help the reader to understand how AI methods are now becoming an ubiquitous tool in any medical image analysis workflow and pave the way for the clinical implementation of AI-based solutions.     

Impact of aromatase inhibitors on bone health in breast cancer patients

Following the implementation of the third generation aromatase inhibitors in the treatment algorithms for early breast cancer, special attention has been given to the influence of these drugs on bone health. Due to their potent estrogen suppression, the aromatase inhibitors anastrozole and letrozole, as well as the aromatase inactivator exemestane, enhance bone loss in postmenopausal women reflected in decreasing levels of bone mineral density. Moreover, all major phase III trials involving aromatase inhibitors in the adjuvant setting have reported increased fracture rates. All in all, there is no hard evidence to suggest major differences between the individual compounds concerning their side-effects on bone. The consequences of AI therapy on bone are in addition modified by a variety of factors like the BMD level prior to therapy, time since menopause, and vitamin D status. Strategies to avoid bone loss during AI therapy have shown promising results. Thus, bisphosphonates have been shown to prohibit bone loss during AI therapy if used upfront. Novel treatment strategies, like antibodies against RANKL have been developed and promising preliminary results have been published from early trials. Standardized guidelines to avoid or minimize bone loss during AI therapy have been developed, in most countries involving calcium and vitamin D supplementation, as well as BMD measurements to identify patient subgroups demanding bisphosphonate therapy.     

Artificial intelligence in radiotherapy

Artificial intelligence (AI) has already been implemented widely in the medical field in the recent years. This paper first reviews the background of AI and radiotherapy. Then it explores the basic concepts of different AI algorithms and machine learning methods, such as neural networks, that are available to us today and how they are being implemented in radiotherapy and diagnostic processes, such as medical imaging, treatment planning, patient simulation, quality assurance and radiation dose delivery. It also explores the ongoing research on AI methods that are to be implemented in radiotherapy in the future. The review shows very promising progress and future for AI to be widely used in various areas of radiotherapy. However, basing on various concerns such as availability and security of using big data, and further work on polishing and testing AI algorithms, it is found that we may not ready to use AI primarily in radiotherapy at the moment.     

Cytopathology in Slovenia

Cytopathology started in Slovenia in the early 50s with exfoliative cytology, while fine needle aspiration biopsy (FNAB) was introduced some 10 years later. Today cytopathology is a well accepted diagnostic method in Slovenia and there are currently 20 cytopathological laboratories and 17 cytopathologists. The number of specimens examined in 2001 was 26 230 FNABs, 13 355 exfoliative non cervical and 323 888 cervical smears. FNABs are performed by cytopathologists, by clinical doctors and by radiologists. So far only the cytopathologists have a supervised training period in performing biopsies. In future the same requirement will be obligatory for non pathologists. In four laboratories immunocytochemistry is used as an ancillary technique to morphology and one laboratory is using also flow cytometry for immunophenotyping of lymphomas. The classification system used in Slovenia for reporting the findings in cervical cytology is a combination of Papanicolaou's classification and assessment of dyskariosis. In spite of a long tradition in opportunistic screening for cervical cancer (Cca) an organised screening programme was started late. A four year pilot study, which included one third of the women population of Slovenia, was concluded in 2002 and an organised screening programme was introduced to the whole country in 2003. The incidence rate of Cca in Slovenia has been rising slowly since 1994 and it reached 19.6/100 000 in the year 2000. The mortality rate has remained roughly constant at 5-7/100 000 for the last 20 years. During the last few years quality assurance measures have been taken for improving the performance in cervical cytology.     

A review of thermochemical upgrading of pyrolysis bio‐oil: Techno‐economic analysis,life cycle assessment,and technology readiness

Technologies for upgrading fast pyrolysis bio‐oil to drop‐in fuels and coproducts are under development and show promise for decarbonizing energy supply for transportation and chemicals markets. The successful commercialization of these fuels and the technologies deployed to produce them depend on production costs, scalability, and yield. To meet environmental regulations, pyrolysis‐based biofuels need to adhere to life cycle greenhouse gas intensity standards relative to their petroleum‐based counterparts. We review literature on fast pyrolysis bio‐oil upgrading and explore key metrics that influence their commercial viability through life cycle assessment (LCA) and techno‐economic analysis (TEA) methods together with technology readiness level (TRL) evaluation. We investigate the trade‐offs among economic, environmental, and technological metrics derived from these methods for individual technologies as a means of understanding their nearness to commercialization. Although the technologies reviewed have not attained commercial investment, some have been pilot tested. Predicting the projected performance at scale‐up through models can, with industrial experience, guide decision‐making to competitively meet energy policy goals. LCA and TEA methods that ensure consistent and reproducible models at a given TRL are needed to compare alternative technologies. This study highlights the importance of integrated analysis of multiple economic, environmental, and technological metrics for understanding performance prospects and barriers among early stage technologies.     

Closing the translation gap: AI applications in digital pathology

Recent advances in artificial intelligence show tremendous promise to improve the accuracy, reproducibility, and availability of medical diagnostics across a number of medical subspecialities. This is especially true in the field of digital pathology, which has recently witnessed a surge in publications describing state-of-the-art performance for machine learning models across a wide range of diagnostic applications. Nonetheless, despite this promise, there remain significant gaps in translating applications for any of these technologies into actual clinical practice. In this review, we will first give a brief overview of the recent progress in applying AI to digitized pathology images, focusing on how these tools might be applied in clinical workflows in the near term to improve the accuracy and efficiency of pathologists. Then we define and describe in detail the various factors that need to be addressed in order to successfully close the “translation gap” for AI applications in digital pathology.     

Expert systems in histopathology. I. Introduction and overview

An introduction to, and overview of, expert systems is presented, along with some preliminary comments on their application in diagnostic and analytical histopathology and cytopathology. The terminology common to expert systems is defined, and the nature of expert systems is discussed. In particular, the differences between expert systems and other types of computer programs (e.g., algorithms) or means of solving problems are explored. The rationale for their use and the types of tasks for which they are appropriate are also discussed.     

The frequency of 'atypia of undetermined significance' interpretations for thyroid fine-needle aspirations is negatively correlated with histologically proven malignant outcomes

Objective: Cytopathologists' usage patterns for 'atypia of undetermined significance' (AUS) in thyroid fine-needle aspiration (FNA) are not well understood. AUS rates over a 5-year period were analyzed to quantify variability and identify correlations with experience and histologic outcomes. Study Design: A retrospective review of thyroid FNAs from a tertiary-care hospital from 2005 to 2009 was performed. Results were compiled for individual cytopathologists, stratified by year, and correlated with histologic outcomes. Results: Thyroid FNAs (5,327) were evaluated by 7 cytopathologists, with an overall AUS rate of 11.2%. The annual AUS rate remained relatively constant over this time period, though notable inter- and intrapathologist variability was seen. The AUS rate was significantly lower for those with cytopathology boards (10.3%) compared to those without (14.0%). There was no correlation between the AUS rate and cytopathologist experience or thyroid FNA volume. The AUS rate and malignant outcome were inversely related: the higher an individual's AUS rate was, the lower the rate of malignancy for that AUS cohort was. Conclusions: Individual cytopathologist AUS rates were variable and often exceeded the recommended target of 7%. The application of recently published defined diagnostic criteria, along with directed cytopathologist feedback, may reduce observer variability and appropriately lower AUS utilization.     

Education and training for cytopathologists. Its role in quality assurance

The role of education and training for cytopathologists in assuring quality in cytology laboratories is discussed, with particular attention given to (1) the problems in the diagnosis of Papanicolaou smears and (2) the contributions of the American Society of Cytology to cytology education. While many people contribute to the success or failure of gynecologic screening programs, poorly trained pathologists can be an especially weak link in the chain given their position in the diagnostic process. Well-formulated residency programs and the use of other educational resources can produce higher-caliber cytopathologists. The problems in Papanicolaou smear screening need to be defined, discussed and resolved by well-trained cytopathologists in conjunction with the clinicians and cytotechnologists involved.     

Getting a Grip on Complexes

We are witnessing tremendous advances in our understanding of the organization of life. Complete genomes are being deciphered with ever increasing speed and accuracy, thereby setting the stage for addressing the entire gene product repertoire of cells, towards understanding whole biological systems. Advances in bioinformatics and mass spectrometric techniques have revealed the multitude of interactions present in the proteome. Multiprotein complexes are emerging as a paramount cornerstone of biological activity, as many proteins appear to participate, stably or transiently, in large multisubunit assemblies. Analysis of the architecture of these assemblies and their manifold interactions is imperative for understanding their function at the molecular level. Structural genomics efforts have fostered the development of many technologies towards achieving the throughput required for studying system-wide single proteins and small interaction motifs at high resolution. The present shift in focus towards large multiprotein complexes, in particular in eukaryotes, now calls for a likewise concerted effort to develop and provide new technologies that are urgently required to produce in quality and quantity the plethora of multiprotein assemblies that form the complexome, and to routinely study their structure and function at the molecular level. Current efforts towards this objective are summarized and reviewed in this contribution.Key Words: Proteome, interactome, multiprotein assemblies, structural genomics, robotics, multigene expression, multiBac, BEVS, ACEMBL, complexomics.     

VPM tokens: virtual machine-aware power budgeting in datacenters

Power consumption and cooling overheads are becoming increasingly significant for enterprise datacenters, affecting overall costs and the ability to extend resource capacities. To help mitigate these issues, active power management technologies are being deployed aggressively, including power budgeting, which enables improved power provisioning and can address critical periods when power delivery or cooling capabilities are temporarily reduced. Given the use of virtualization to encapsulate application components into virtual machines (VMs), however, such power management capabilities must address the interplay between budgeting physical resources and the performance of the virtual machines used to run these applications. This paper proposes a set of management components and abstractions for use by software power budgeting policies. The key idea is to manage power from a VM-centric point of view, where the goal is to be aware of global utility tradeoffs between different virtual machines (and their applications) when maintaining power constraints for the physical hardware on which they run. Our approach to VM-aware power budgeting uses multiple distributed managers integrated into the VirtualPower Management (VPM) framework whose actions are coordinated via a new abstraction, termed VPM tokens. An implementation with the Xen hypervisor illustrates technical benefits of VPM tokens that include up to 43% improvements in global utility, highlighting the ability to dynamically improve cluster performance while still meeting power budgets. We also demonstrate how VirtualPower based budgeting technologies can be leveraged to improve datacenter efficiency in the context of cooling infrastructure management.

Impact factor in cytopathology journals: what does it reflect and how much does it matter?

B. AbdullGaffar
Impact factor in cytopathology journals: what does it reflect and how much does it matter? Objective: To study the trends of impact factor (IF) in four cytopathology journals. To investigate the factors that might influence IF in cytopathology literature and whether IF has any impact on cytopathology practice. Methods: The IFs of four cytopathology journals were searched from 2005 to 2009. The IFs and their relationships with the types and number of publications, publishers, the official societies, readership, the quality of their contents, the topics covered and the levels of evidence were compared. Results: Cancer Cytopathology (CC) had the highest IF. Acta Cytologica (AC) had the lowest IF, which appeared to be in decline. Cytopathology (C) and Diagnostic Cytopathology (DC) had a slow but steady increase in their IF. Components that might influence these differences could include the category and the society of the journal, targeted readers and certain types of publications. Publishers, the number of publications, the types of topics covered and the levels of evidence probably have no major effect on IF. Conclusions: IF has its own benefits and original applications. IF is a quantitative measure that does not reflect the levels of evidence in cytopathology journals. IF should not be abandoned because it might encourage competition between cytopathology journals, but it should not dictate their contents.     

BSCC Code of Practice – fine needle aspiration cytology

The British Society for Clinical Cytology Code of Practice on fine needle aspiration cytology complements that on exfoliative cytopathology, which was published in the last issue ( Cytopathology 2009; 20 :211–23). Both have been prepared with wide consultation within and outside the BSCC and have been endorsed by the Royal College of Pathologists. A separate code of practice for gynaecological cytopathology is in preparation. Fine needle aspiration (FNA) cytology is an accepted first line investigation for mass lesions, which may be targeted by palpation or a variety of imaging methods. Although FNA cytology has been shown to be a cost-effective, reliable technique its accurate interpretation depends on obtaining adequately cellular samples prepared to a high standard. Its accuracy and cost-effectiveness can be seriously compromised by inadequate samples. Although cytopathologists, radiologists, nurses or clinicians may take FNAs, they must be adequately trained, experienced and subject to regular audit. The best results are obtained when a pathologist or an experienced and trained biomedical scientist (cytotechnologist) provides immediate on-site assessment of sample adequacy whether or not the FNA requires image-guidance. This COP provides evidence-based recommendations for setting up FNA services, managing the patients, taking the samples, preparing the slides, collecting material for ancillary tests, providing rapid on-site assessment, classifying the diagnosis and providing a final report. Costs, cost-effectiveness and rare complications are taken into account as well as the time and resources required for quality control, audit and correlation of cytology with histology and outcome. Laboratories are expected to have an effective quality management system conforming to the requirements of a recognised accreditation scheme such as Clinical Pathology Accreditation (UK) Ltd.     

Quantitation of viral load using real-time amplification techniques

Real-time PCR amplification techniques are currently used to determine the viral load in clinical samples for an increasing number of targets. Real-time PCR reduces the time necessary to generate results after amplification. In-house developed PCR and nucleic acid sequence-based amplification (NASBA)-based systems combined with several detection strategies are being employed in a clinical diagnostic setting. The importance of these assays in disease management is still in an exploration phase. Although these technologies have the implicit capability of accurately measuring DNA and RNA in clinical samples, issues related to standardization and quality control must be resolved to enable routine implementation of these technologies in molecular diagnostics.     

Apoptotic index from fine needle aspiration cytology as a criterion to predict histologic grade of non-Hodgkin's lymphoma

OBJECTIVE: To investigate whether the assessment of apoptotic index (AI) from fine needle aspiration (FNA) smears of non-Hodgkin's lymphomas (NHL) is reliable and has potential utility as a criterion to predict histologic grade. STUDY DESIGN: AI was independently determined by four cytopathologists as a percentage from routine FNA smears in 96 NHLs and 15 lymphoid hyperplasias. Working formulation (WF) grades from corresponding surgical biopsies were modified to include mantle zone-derived NHLs as intermediate grade and to make diffuse large cell NHL a separate category called "high" grade, whereas WF high grade NHLs were called "very high" grade. Histologic grades were also derived from the Revised European American Lymphoma (REAL) classification. AI was compared with histologic grade using the unpaired, two-tailed Student t test. These data were used to determine potential thresholds for AI that separate lower from higher grade NHLs. RESULTS: Measurements of AI strongly correlated between cytopathologists (median r = .93). Low and intermediate grade NHLs had indistinguishable AIs, whereas higher grade NHLs had significantly higher AIs. Appropriate potential AI thresholds between low or intermediate grade and higher grade NHLs were in the range of 1.5-2.5% (modified WF) and 1-2% (REAL). CONCLUSION: There is excellent interobserver reliability in the measurement of AI from FNAs of NHLs. Higher AIs distinguish higher from lower grade NHLs. Diffuse large cell NHLs had AIs that were similar to WF high grade NHLs.