Variability in biopsy quality informs translational research applications in hepatocellular carcinoma.

In the era of precision medicine, biopsies are playing an increasingly central role in cancer research and treatment paradigms; however, patient outcomes and analyses of biopsy quality, as well as impact on downstream clinical and research applications, remain underreported. Herein, we report biopsy safety and quality outcomes for percutaneous core biopsies of hepatocellular carcinoma (HCC) performed as part of a prospective clinical trial. Patients with a clinical diagnosis of HCC were enrolled in a prospective cohort study for the genetic, proteomic, and metabolomic profiling of HCC at two academic medical centers from April 2016 to July 2020. Under image guidance, 18G core biopsies were obtained using coaxial technique at the time of locoregional therapy. The primary outcome was biopsy quality, defined as tumor fraction in the core biopsy. 56 HCC lesions from 50 patients underwent 60 biopsy events with a median of 8 core biopsies per procedure (interquartile range, IQR, 7-10). Malignancy was identified in 45/56 (80.4%, 4 without pathology) biopsy events, including HCC (40/56, 71.4%) and cholangiocarcinoma (CCA) or combined HCC-CCA (5/56, 8.9%). Biopsy quality was highly variable with a median of 40% tumor in each biopsy core (IQR 10-75). Only 43/56 (76.8%) and 23/56 (41.1%) samples met quality thresholds for genomic or metabolomic/proteomic profiling, respectively, requiring expansion of the clinical trial. Overall and major complication rates were 5/60 (8.3%) and 3/60 (5.0%), respectively. Despite uniform biopsy protocol, biopsy quality varied widely with up to 59% of samples to be inadequate for intended purpose. This finding has important consequences for clinical trial design and highlights the need for quality control prior to applications in which the presence of benign cell types may substantially alter findings.

Single-cell sequencing in translational cancer research and challenges to meet clinical diagnostic needs.

The ability to capture alterations in the genome or transcriptome by next-generation sequencing has provided critical insight into molecular changes and programs underlying cancer biology. With the rapid technological development in single-cell sequencing, it has become possible to study individual cells at the transcriptional, genetic, epigenetic, and protein level. Using single-cell analysis, an increased resolution of fundamental processes underlying cancer development is obtained, providing comprehensive insights otherwise lost by sequencing of entire (bulk) samples, in which molecular signatures of individual cells are averaged across the entire cell population. Here, we provide a concise overview on the application of single-cell analysis of different modalities within cancer research by highlighting key articles of their respective fields. We furthermore examine the potential of existing technologies to meet clinical diagnostic needs and discuss current challenges associated with this translation.

Keeping It Clean: The Cell Culture Quality Control Experience at the National Center for Advancing Translational Sciences.

Quality control monitoring of cell lines utilized in biomedical research is of utmost importance and is critical for the reproducibility of data. Two key pitfalls in tissue culture are 1) cell line authenticity and 2) Mycoplasma contamination. As a collaborative research institute, the National Center for Advancing Translational Sciences (NCATS) receives cell lines from a range of commercial and academic sources, which are adapted for high-throughput screening. Here, we describe the implementation of routine NCATS-wide Mycoplasma testing and short tandem repeat (STR) testing for cell lines. Initial testing identified a >10% Mycoplasma contamination rate. While the implementation of systematic testing has not fully suppressed Mycoplasma contamination rates, clearly defined protocols that include the immediate destruction of contaminated cell lines wherever possible has enabled rapid intervention and removal of compromised cell lines. Data for >2000 cell line samples tested over 3 years, and case studies are provided. STR testing of 186 cell lines with established STR profiles revealed only five misidentified cell lines, all of which were received from external labs. The data collected over the 3 years since implementation of this systematic testing demonstrate the importance of continual vigilance for rapid identification of "problem" cell lines, for ensuring reproducible data in translational science research.

Summary of a workshop on preclinical and translational safety assessment of CD3 bispecifics.

Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized.

Translating Science into Survival: Report on the Fifth International Cancer Immunotherapy Conference.

From September 25 to 28, 2019, in Paris, France, the Fifth International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research. This year, roughly 1,300 people attended the 4-day event, which covered the latest advances in cancer immunology and immunotherapy.

Palliative Care Evidence Review Service (PaCERS): a knowledge transfer partnership.

The importance of linking evidence into practice and policy is recognised as a key pillar of a prudent approach to healthcare; it is of importance to healthcare professionals and decision-makers across the world in every speciality. However, rapid access to evidence to support service redesign, or to change practice at pace, is challenging. This is particularly so in smaller specialties such as Palliative Care, where pressured multidisciplinary clinicians lack time and skill sets to locate and appraise the literature relevant to a particular area. Therefore, we have initiated the Palliative Care Evidence Review Service (PaCERS), a knowledge transfer partnership through which we have developed a clear methodology to conduct evidence reviews to support professionals and other decision-makers working in palliative care.PaCERS methodology utilises modified systematic review methods as there is no agreed definition or an accepted methodology for conducting rapid reviews. This paper describes the stages involved based on our iterative recent experiences and engagement with stakeholders, who are the potential beneficiaries of the research. Uniquely, we emphasise the process and opportunities of engagement with the clinical workforce and policy-makers throughout the review, from developing and refining the review question at the start through to the importance of demonstrating impact. We are faced with the challenge of the trade-off between the timely transfer of evidence against the risk of impacting on rigour. To address this issue, we try to ensure transparency throughout the review process. Our methodology aligns with key principles of knowledge synthesis in defining a process that is transparent, robust and improving the efficiency and timeliness of the review.Our reviews are clinically or policy driven and, although we use modified systematic review methods, one of the key differences between published review processes and our review process is in our relationship with the requester. This streamlining approach to synthesising evidence in a timely manner helps to inform decisions faced by clinicians and decision-makers in healthcare settings, supporting, at pace, knowledge transfer and mobilisation.

High-Quality Biobanks: Pivotal Assets for Reproducibility of OMICS-Data in Biomedical Translational Research.

Human biospecimen samples (HBS) and associated data stored in biobanks (also called "biotrusts," "biorepositories," or "biodistributors") are very critical resources for translational research. As HBS quality is decisive to the reproducibility of research results, biobanks are also key assets for new developments in precision medicine. Biobanks are more than infrastructures providing HBS and associated data. Biobanks have pioneered in identifying and standardizing sources of preanalytical variations in HBS, thus paving the way for the current biospecimen science. To achieve this milestone, biobankers have successively assumed the role of "detective," and then "architect," to identify new detrimental impact of preanalytical variables on the tissue integrity. While standardized methods in omics are required to be practiced throughout research communities, the accepted best practices and standards on biospecimen handling are generally not known nor applied by researchers. Therefore, it is mandatory to raise the awareness within omics communities regarding not only the basic concepts of collecting, storing, and utilizing HBS today, but also to suggest insights on biobanking in the cancer omics context.

ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research.

BACKGROUND: NTRK1, NTRK2 and NTRK3 fusions are present in a plethora of malignancies across different histologies. These fusions represent the most frequent mechanism of oncogenic activation of these receptor tyrosine kinases, and biomarkers for the use of TRK small molecule inhibitors. Given the varying frequency of NTRK1/2/3 fusions, crucial to the administration of NTRK inhibitors is the development of optimal approaches for the detection of human cancers harbouring activating NTRK1/2/3 fusion genes. MATERIALS AND METHODS: Experts from several Institutions were recruited by the European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) to review the available methods for the detection of NTRK gene fusions, their potential applications, and strategies for the implementation of a rational approach for the detection of NTRK1/2/3 fusion genes in human malignancies. A consensus on the most reasonable strategy to adopt when screening for NTRK fusions in oncologic patients was sought, and further reviewed and approved by the ESMO TR and PM WG and the ESMO leadership. RESULTS: The main techniques employed for NTRK fusion gene detection include immunohistochemistry, fluorescence in situ hybridization (FISH), RT-PCR, and both RNA-based and DNA-based next generation sequencing (NGS). Each technique has advantages and limitations, and the choice of assays for screening and final diagnosis should also take into account the resources and clinical context. CONCLUSION: In tumours where NTRK fusions are highly recurrent, FISH, RT-PCR or RNA-based sequencing panels can be used as confirmatory techniques, whereas in the scenario of testing an unselected population where NTRK1/2/3 fusions are uncommon, either front-line sequencing (preferentially RNA-sequencing) or screening by immunohistochemistry followed by sequencing of positive cases should be pursued.

Evaluating the impact of image guidance in the surgical setting: a systematic review.

BACKGROUND: Image guidance has been clinically available for over a period of 20 years. Although research increasingly has a translational emphasis, overall the clinical uptake of image guidance systems in surgery remains low. The objective of this review was to establish the metrics used to report on the impact of surgical image guidance systems used in a clinical setting. METHODS: A systematic review of the literature was carried out on all relevant publications between January 2000 and April 2016. Ovid MEDLINE and Embase databases were searched using a title strategy. Reported outcome metrics were grouped into clinically relevant domains and subsequent sub-categories for analysis. RESULTS: In total, 232 publications were eligible for inclusion. Analysis showed that clinical outcomes and system interaction were consistently reported. However, metrics focusing on surgeon, patient and economic impact were reported less often. No increase in the quality of reporting was observed during the study time period, associated with study design, or when the clinical setting involved a surgical specialty that had been using image guidance for longer. CONCLUSIONS: Publications reporting on the clinical use of image guidance systems are evaluating traditional surgical outcomes and neglecting important human and economic factors, which are pertinent to the uptake, diffusion and sustainability of image-guided surgery. A framework is proposed to assist researchers in providing comprehensive evaluation metrics, which should also be considered in the design phase. Use of these would help demonstrate the impact in the clinical setting leading to increased clinical integration of image guidance systems.

Antibody-Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index.

Since the first approval of gemtuzumab ozogamicin (Mylotarg; Pfizer; CD33 targeted), two additional antibody-drug conjugates (ADC), brentuximab vedotin (Adcetris; Seattle Genetics, Inc.; CD30 targeted) and inotuzumab ozogamicin (Besponsa; Pfizer; CD22 targeted), have been approved for hematologic cancers and 1 ADC, trastuzumab emtansine (Kadcyla; Genentech; HER2 targeted), has been approved to treat breast cancer. Despite a clear clinical benefit being demonstrated for all 4 approved ADCs, the toxicity profiles are comparable with those of standard-of-care chemotherapeutics, with dose-limiting toxicities associated with the mechanism of activity of the cytotoxic warhead. However, the enthusiasm to develop ADCs has not been dampened; approximately 80 ADCs are in clinical development in nearly 600 clinical trials, and 2 to 3 novel ADCs are likely to be approved within the next few years. While the promise of a more targeted chemotherapy with less toxicity has not yet been realized with ADCs, improvements in technology combined with a wealth of clinical data are helping to shape the future development of ADCs. In this review, we discuss the clinical and translational strategies associated with improving the therapeutic index for ADCs.

QIN Benchmarks for Clinical Translation of Quantitative Imaging Tools.

The Quantitative Imaging Network of the National Cancer Institute is in its 10th year of operation, and research teams within the network are developing and validating clinical decision support software tools to measure or predict the response of cancers to various therapies. As projects progress from development activities to validation of quantitative imaging tools and methods, it is important to evaluate the performance and clinical readiness of the tools before committing them to prospective clinical trials. A variety of tests, including special challenges and tool benchmarking, have been instituted within the network to prepare the quantitative imaging tools for service in clinical trials. This article highlights the benchmarking process and provides a current evaluation of several tools in their transition from development to validation.

Quality-assured research environments for translational cancer research.

In order to secure high-quality cancer care for increasing numbers of cancer patients in the upcoming decades, the complete continuum of cancer research and cancer care needs a thorough overhaul, with more emphasis on prevention and early detection, and a greater focus on the development of innovative treatments that are also scrutinised for effectiveness and quality-of-life aspects. Therefore, under-resourced research areas, such as primary prevention, early diagnosis/secondary prevention (Song et al., ; Wild et al., ) and outcomes research (Cavers et al., ), should be given more emphasis, whereas basic, preclinical and clinical cancer research requires more innovation and effective collaboration to develop more effective treatments at an affordable cost. Innovative collaborative research in this translational trajectory requires the participation of well-resourced and well-organised institutions that are committed to high scientific and ethical standards. Offering focused funding to distinct segments of this research continuum concomitant with incentives to aspire to high-quality standards is the most effective route to achieve these goals. Therefore, a rigorous quality assessment system for institutions operating in this research continuum is a high priority.

Animal models of NAFLD from the pathologist's point of view.

Fatty liver disease is a multifactorial world-wide health problem resulting from a complex interplay between liver, adipose tissue and intestine and initiated by alcohol abuse, overeating, various types of intoxication, adverse drug reactions and genetic or acquired metabolic defects. Depending on etiology fatty liver disease is commonly categorized as alcoholic or non-alcoholic. Both types may progress from simple steatosis to the necro-inflammatory lesion of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH), respectively, and finally to cirrhosis and hepatocellular carcinoma. Animal models are helpful to clarify aspects of pathogenesis and progression. Generally, they are classified as nutritional (dietary), toxin-induced and genetic, respectively, or represent a combination of these factors. Numerous reviews are dealing with NASH animal models designed to imitate as closely as possible the metabolic situation associated with human disease. This review focuses on currently used mouse models of NASH with particular emphasis on liver morphology. Despite metabolic similarities most models (except those with chemically or genetically induced porphyria or keratin 18-deficiency) fail to develop the morphologic key features of NASH, namely hepatocyte ballooning and formation of histologically and immunohistochemically well-defined Mallory-Denk-Bodies (MDBs). Although MDBs are not universally detectable in ballooned hepatocytes in NASH their experimental reproduction and analysis may, however, significantly contribute to our understanding of important pathogenic aspects of NASH despite the obvious differences in etiology.

Training the Twenty-First Century Cancer Epidemiologist.

To assess and advance training of twenty-first century cancer epidemiologists, the National Cancer Institute (NCI) sought to obtain a snapshot of the cancer epidemiology training landscape by conducting a survey across academic institutions and cancer centers, focusing on four key training areas driving current cancer epidemiology research ("drivers"): (1) collaboration, (2) novel methods/technologies, (3) multilevel analysis, and (4) knowledge integration. Complementary to the survey, we conducted a portfolio analysis of active NCI-funded training grants. In the present report, we provide our findings from this effort and contribute to the on-going conversation regarding the training of next-generation cancer epidemiologists. Analyses and insights gained from conversations with leaders/educators across 24 academic institutions/cancer centers and the portfolio analysis of training grants echoed contemporaneous conversation that cancer epidemiology training must adapt to meet the needs of the changing research environment. Currently, with the exception of novel methods/technologies, cancer epidemiology trainees receive the majority of their training in collaboration, multilevel approaches, and knowledge integration/translation either informally, ad hoc, or not at all; exposure to these identified drivers varied considerably by institution, mentor, and other external as well as internal factors.

On the architecture of translational research designed to control chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) has been 1 of the most dynamic fields of clinical research over the last 2 decades. Important advances in understanding the biology of CLL have led to the development of new prognostic and diagnostic tools. Concurrently, several recently approved new agents hold the potential to fundamentally change the management of this leukemia and have started to improve clinical outcomes for patients. This conceptual review summarizes the major recent insights regarding the biology of CLL, the technological advances that have allowed refinement of the prognostication of the clinical course, and the new therapeutic strategies that are currently under investigation to further ameliorate the outcome for patients with CLL.

Enhancing anticancer effects, decreasing risks and solving practical problems facing 3-bromopyruvate in clinical oncology: 10 years of research experience.

3-Bromopyruvate (3BP) is a promising powerful general anticancer agent. Unfortunately, 3BP release faces many practical and biochemical problems in clinical human oncology, for example, 3BP induces burning venous sensation (during intravenous infusion) and rapid inactivation by thiol groups of glutathione and proteins. 3BP exhibits resistance in glutathione-rich tumors without being able to exert selective targeting. 3BP does not cross the blood-brain barrier and cannot treat nervous system tumors. Importantly, 3BP cannot persist in tumor tissues due to the phenomenon of enhanced permeability and retention effect. Here, the author presents the practical solutions for clinical problems facing 3BP use in clinical oncology, based on over 10 years of experience in 3BP research. Crude (unformulated 3BP that is purchased from chemical companies without being formulated in liposomes or other nanocarriers) should not be administered in clinical oncology. Instead, 3BP is better formulated with liposomes, polyethylene glycol (PEG), PEGylated liposomes (stealth liposomes) or perillyl alcohol that are used currently with many chemotherapeutics for treating clinical tumors in cancer patients. Formulating 3BP with targeted liposomes, for example, with folate, transferrin or other ligands, improves tumor targeting. Formulating 3BP with liposomes, PEG, stealth liposomes or perillyl alcohol may improve its pharmacokinetics, hide it from thiols in the circulation, protect it from serum proteins and enzymes, prevent burning sensation, prolong 3BP's longevity and facilitate crossing the BBB. Formulating 3BP with stealth liposomes protects 3BP from the reticuloendothelial cells. Liposomal 3BP formulations may retain 3BP better inside the relatively large tumor capillary pores (abolish enhanced permeability and retention effect) sparing normal tissues, facilitate new delivery routes for 3BP (eg, topical and intranasal 3BP administration using perillyl alcohol) and improve cancer cytotoxicity. Formulating 3BP may be promising in overcoming many obstacles in clinical oncology.

Biological material collection to advance translational research and treatment of children with CNS tumours: position paper from the SIOPE Brain Tumour Group.

Paediatric CNS tumours are the most common cause of childhood cancer-related morbidity and mortality, and improvements in their diagnosis and treatment are needed. New genetic and epigenetic information about paediatric CNS tumours is transforming the field dramatically. For most paediatric CNS tumour entities, subgroups with distinct biological characteristics have been identified, and these characteristics are increasingly used to facilitate accurate diagnoses and therapeutic recommendations. Future treatments will be further tailored to specific molecular subtypes of disease, specific tumour predisposition syndromes, and other biological criteria. Successful biomaterial collection is a key requirement for the application of contemporary methodologies for the validation of candidate prognostic factors, the discovery of new biomarkers, the establishment of appropriate preclinical research models for targeted agents, a quicker clinical implementation of precision medicine, and for other therapeutic uses (eg, for immunotherapies). However, deficits in organisational structures and interdisciplinary cooperation are impeding the collection of high-quality biomaterial from CNS tumours in most centres. Practical, legal, and ethical guidelines for consent, storage, material transfer, biobanking, data sharing, and funding should be established by research consortia and local institutions to allow optimal collection of primary and subsequent tumour tissue, body fluids, and normal tissue. Procedures for the collection and storage of biomaterials and related data should be implemented according to the individual and organisational structures of the local institutions.