The use of artificial intelligence will transform clinical practice over the next decade and the early impact of this will likely be the integration of image analysis and machine learning into routine histopathology. In the UK and around the world, a digital revolution is transforming the reporting practice of diagnostic histopathology and this has sparked a proliferation of image analysis software tools. While this is an exciting development that could discover novel predictive clinical information and potentially address international pathology workforce shortages, there is a clear need for a robust and evidence‐based framework in which to develop these new tools in a collaborative manner that meets regulatory approval. With these issues in mind, the NCRI Cellular Molecular Pathology (CM‐Path) initiative and the British In Vitro Diagnostics Association (BIVDA) have set out a roadmap to help academia, industry, and clinicians develop new software tools to the point of approved clinical use. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

In this review we note that the placenta and cancer both develop in microenvironments in which there are gradients of oxygen availability. Whilst fundamentally different in that placental development is organised and physiological whilst cancer is chaotic and pathological, there are similarities in their respective capacities to proliferate, invade adjacent tissues, generate a blood supply and avoid rejection by the immune system. We provide a brief description of the hypoxia-inducible factor (HIF) pathway and indicate the ways by which HIF activity can be regulated to achieve oxygen homeostasis. We then exemplify the potential role of the HIF pathway in contributing to those functions shared between the placenta and cancer through effects on cellular proliferation, cell death, angiogenesis, blood vessel co-option, vascular mimicry, cell adhesion molecules, secretion of matrix metalloproteinases, antigen presentation mechanisms and immunosuppressive factors. We advocate future studies to explore these similarities and differences in the hope of improving our understanding of both systems and hence treatments of placental disorders and cancer.

The role of percutaneous renal tumour biopsy (RTB) in the management of radiological indeterminate renal masses is long established. Patients with small renal masses who have biopsy-proven renal cell carcinoma (RCC) may be offered surgery, ablative therapy, or active surveillance, and RTB can provide diagnostic tissue from patients with metastatic disease who might benefit from systemic therapy. Current guidelines suggest that tumour seeding along the needle tract is anecdotal, but several cases have been reported recently, although some have been associated with lack of a coaxial sheath. We report on seven patients who underwent surgical resection of RCC in our tertiary referral institution following diagnostic RTB between 2014 and 2017 for whom RTB tract seeding by tumour was identified on histological examination of the resection specimen. One of these patients subsequently developed local tumour recurrence at the site of the previous biopsy.

Highly resolved spatial data of complex systems encode rich and nonlinear information. Quantification of heterogeneous and noisy data—often with outliers, artifacts, and mislabeled points—such as those from tissues, remains a challenge. The mathematical field that extracts information from the shape of data, topological data analysis (TDA), has expanded its capability for analyzing real-world datasets in recent years by extending theory, statistics, and computation. An extension to the standard theory to handle heterogeneous data is multiparameter persistent homology (MPH). Here we provide an application of MPH landscapes, a statistical tool with theoretical underpinnings. MPH landscapes, computed for (noisy) data from agent-based model simulations of immune cells infiltrating into a spheroid, are shown to surpass existing spatial statistics and one-parameter persistent homology. We then apply MPH landscapes to study immune cell location in digital histology images from head and neck cancer. We quantify intratumoral immune cells and find that infiltrating regulatory T cells have more prominent voids in their spatial patterns than macrophages. Finally, we consider how TDA can integrate and interrogate data of different types and scales, e.g., immune cell locations and regions with differing levels of oxygenation. This work highlights the power of MPH landscapes for quantifying, characterizing, and comparing features within the tumor microenvironment in synthetic and real datasets.

Purpose-Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC).Patients and methods-Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: Cohort 1 received oral atovaquone at the standard clinical dose 750 mg twice-daily, whilst Cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Inter-cohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed.Results-Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction with median change −28.0% [95% confidence interval (CI), −58.2 to −4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, −6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24% to 74%) lower in Cohort 1 compared to Cohort 2 (p=0.004), adjusting for cohort, tumor volume and baseline HV. A key pharmacodynamic endpoint was reduction in hypoxia regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported.Conclusions-This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant anti-tumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.

Rituximab is a B-lymphocyte depleting agent that is used to treat hematological malignancies and autoimmune diseases. Recently, it has gained interest as an immunomodulatory agent in renal transplantation. This systematic review evaluates the evidence for its use in the treatment of acute and chronic antibody-mediated renal transplant rejection (AAMR; CAMR). A systematic search of four databases and three trial registries was conducted. The small number and heterogeneous nature of included studies precluded meta-analysis and thus a narrative review was conducted. A total of 28 records met the inclusion criteria (AAMR, 18 records relating to 9 studies; CAMR, 10 records relating to 7 studies). Two systematic reviews were identified that had differing inclusion criteria to this current review. Of seven primary studies in the setting of AAMR, four reported increased graft survival and one reported improved graft function with rituximab. This contrasts with CAMR in which only one of seven studies reported improved graft outcomes with a rituximab-based regimen; three studies reported inferior outcomes and three reported no difference. Only one study reported that rituximab was associated with an increase in adverse effects. The included studies suggest that rituximab may be of some benefit in the setting of AAMR but a lack of high quality evidence precludes firm conclusions from being drawn. Rituximab does not appear to reliably improve outcomes in CAMR. Further well-conducted studies are required to better define the effects and long-term safety profile of rituximab in the treatment of antibody-mediated renal transplant rejection.

Evidence of limited quality was identified to support the use of rituximab desensitization in highly sensitized recipients. Among ABO-incompatible recipients, rituximab was found to be equivalent to splenectomy, indicating that this invasive surgical procedure is not necessary. Further randomized controlled trials are required to better define the efficacy, long-term safety, and optimal dosing regimen of rituximab in this setting.

Physiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes, which regulate HIFs. Genetic interventions on HIF/PHD pathways have revealed multiple phenotypes that extend the known biology of hypoxia. Recent studies have unexpectedly implicated HIF in aspects of multiple immune and inflammatory pathways. However, such studies are often limited by systemic lethal effects and/or use tissue-specific recombination systems, which are inherently irreversible, unphysiologically restricted, and difficult to time. To study these processes better, we developed recombinant mice that expressed tetracycline-regulated shRNAs broadly targeting the main components of the HIF/PHD pathway, permitting timed bidirectional intervention. We show that stabilization of HIF levels in adult mice through PHD2 enzyme silencing by RNA interference or inducible recombination of floxed alleles results in multilineage leukocytosis and features of autoimmunity. This phenotype was rapidly normalized on reestablishment of the hypoxia-sensing machinery when shRNA expression was discontinued. In both situations, these effects were mediated principally through the Hif2a isoform. Assessment of cells bearing Treg markers from these mice revealed defective function and proinflammatory effects in vivo. We believe our findings reveal a new role for the PHD2/HIF2α pathway in the reversible regulation of T cell and immune activity.