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Breast ductal carcinoma in situ is a common non-invasive clinical finding that can progress to invasive breast cancer (IBC). Spatial proteomics can provide an additional dimension to our understanding of this disease and its capacity to progress. A subset ( n  = 103 patients) of a previously established cohort of primary DCIS specimens with known clinical outcomes was analyzed using a multiplexed proteomic platform (Nanostring GeoMx) for simultaneous quantitative measurement of 53 antigens. 1262 spatially distinct regions of interest (ROIs) (1226 ROIs after filtering) were collected, including inside DCIS epithelium, adjacent stroma, co-existing benign breast epithelium, and biopsy sites. We identified two predominant subgroups of DCIS, ER high/HER2 low and ER low/HER2 high. Levels of tumor associated proteins varied between benign and DCIS, between ER + and ER- patients, and between different regions within the DCIS epithelium. In addition, we identified several immune-related antigens (CD127, CD8, and PD-L2) within the DCIS epithelium that are associated with invasive progression. Comparison of antigen levels in matched ipsilateral breast events (both DCIS recurrences and IBC) demonstrates an effect of hormonal therapy on the phenotype of subsequent cancers. This study adds a spatially resolved proteomic dimension to our understanding of DCIS, its microenvironment, and its propensity to progress to IBC.

Children in sub-Saharan Africa continue to acquire and die from cerebral malaria, despite efforts to control or eliminate the causative agent, Plasmodium falciparum. We present a quantitative histopathological assessment of the sequestration of parasitized erythrocytes in multiple organs obtained during a prospective series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi, on pediatric patients who died from cerebral malaria and controls. After the brain, sequestration of parasites was most intense in the gastrointestinal tract, both in patients with cerebral malaria and those with parasitemia in other organs. Within cases of histologically defined cerebral malaria, which includes phenotypes termed \"sequestration only\" (CM1) and \"sequestration with extravascular pathology\" (CM2), CM1 was associated with large parasite numbers in the spleen and CM2 with intense parasite sequestration in the skin. A striking histological finding overall was the marked sequestration of parasitized erythrocytes across most organs in patients with fatal cerebral malaria, supporting the hypothesis that the disease is, in part, a result of a high level of totalbody parasite sequestration.

Background Several recent studies have investigated the utility of 19-, 22-, and 25-gauge needles in endoscopic ultrasound-guided fine needle aspiration (EUS–FNA) of pancreatic and peri-pancreatic tumors. Aim The objective of this study was to summarize data from these studies and estimate the effect of needle size on reported outcomes such as accuracy, adequacy, and complications. Methods Systematic review and meta-analysis comparing the effect of needle size (19, 22, and 25G) on diagnostic accuracy, adequacy, number of needle passes, and complications. Results 25G appear to confer an advantage in adequacy rates relative to 22G needles (risk difference = 0.12 %, 95 % CI 0.01, 0.25). There was no significant difference in accuracy with an overall sensitivity and specificity for 22G being 0.78 (95 % CI 0.74–0.81) and 1.00 (95 % CI 0.98–1.00) and an overall sensitivity and specificity for 25G being 0.91 (95 % CI 0.87–0.94) and 1.00 (95 % CI 0.97–1.00). There was no difference in number of passes or complications between 25 and 22G. The limited data available regarding 19G needles do not show evidence of improved outcomes with these devices. Conclusions In the evaluation of pancreatic and peri-pancreatic lesions by EUS–FNA, 25G needles may confer an advantage in adequacy relative to 22G needles but confer no advantages with respect to accuracy, number of passes, or complications.

Advances in imaging and early cancer detection have increased interest in magnetic resonance (MR) guided focused ultrasound (MRgFUS) technologies for cancer treatment. MRgFUS ablation treatments could reduce surgical risks, preserve organ tissue and function, and improve patient quality of life. However, surgical resection and histological analysis remain the gold standard to assess cancer treatment response. For non-invasive ablation therapies such as MRgFUS, the treatment response must be determined through MR imaging biomarkers. However, current MR biomarkers are inconclusive and have not been rigorously evaluated against histology via accurate registration. Existing registration methods rely on anatomical features to directly register in vivo MR and histology. For MRgFUS applications in anatomies such as liver, kidney, or breast, anatomical features that are not caused by the treatment are often insufficient to drive direct registration. We present a novel MR to histology registration workflow that utilizes intermediate imaging and does not rely on anatomical MR features being visible in histology. The presented workflow yields an overall registration accuracy of 1.00 ± 0.13 mm. The developed registration pipeline is used to evaluate a common MRgFUS treatment assessment biomarker against histology. Evaluating MR biomarkers against histology using this registration pipeline will facilitate validating novel MRgFUS biomarkers to improve treatment assessment without surgical intervention. While the presented registration technique has been evaluated in a MRgFUS ablation treatment model, this technique could be potentially applied in any tissue to evaluate a variety of therapeutic options.

Key Points Nuclear morphology is often altered in cancer. Irregularity in nuclear contours is a feature used by pathologists in diagnostic cytology. The nuclear envelope provides a specialized microenvironment within the nucleus. It is also the site where a series of protein–protein interactions take place to connect the cytoskeleton to the interior of the nucleus. Constituents of the nuclear envelope — lamins, nuclear pore complexes and lipid membranes — have key roles in several processes that affect tumour cell biology and response to therapy. Changes in the abundance or the function of components of the nuclear envelope in tumour cells can cause the occurrence of dysmorphic nuclei and can deregulate cell migration, intracellular signalling, DNA repair, cell division and gene expression. Tracking the abundance of molecular components of the nuclear envelope environment and enhanced methods to visualize changes at the nuclear envelope could potentially be used for the prognostic assessment of cancer patients. Aberrant nuclear morphology is already used as a diagnostic criterion for cancer, but why is the nucleus deformed in cancer cells? This Review discusses how components of the nuclear envelope and the adjoining lamina are deregulated in cancer cells and the consequences of this change in cell morphology. Because of the association between aberrant nuclear structure and tumour grade, nuclear morphology is an indispensible criterion in the current pathological assessment of cancer. Components of the nuclear envelope environment have central roles in many aspects of cell function that affect tumour development and progression. As the roles of the nuclear envelope components, including nuclear pore complexes and nuclear lamina, are being deciphered in molecular detail there are opportunities to harness this knowledge for cancer therapeutics and biomarker development. In this Review, we summarize the progress that has been made in our understanding of the nuclear envelope and the implications of changes in this environment for cancer biology.

Background Metastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult and thus poorly understood. Methods Via rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole-genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumor’s evolution at subclonal resolution. Results The most unique, previously unreported aspect of the tumor’s evolution that we observed in this patient was the presence of “subclone incubators,” defined as metastatic sites where substantial tumor evolution occurs before colonization of additional sites and organs by subclones that initially evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g., abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion, subclones at this site were likely the source of all four subsequent metastatic waves, and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known drivers or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patient’s metastases for effective clinical intervention. Conclusions Our analysis revealed the presence of substantial tumor evolution at metastatic incubator sites in a patient, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.

Telepathology is a digital, microscope-independent method of diagnosing pathology from scanned slides. Frozen sections (FS) can be performed and read by a pathologist at any site. At our institution, telepathology is used for diagnosis of frozen sections of sentinel lymph nodes (SLN) in patients who have undergone neoadjuvant chemotherapy and are enrolled in a clinical trial. We investigated the accuracy of diagnosing SLN frozen sections in the neoadjuvant setting using telepathology. SLN were entirely submitted for frozen section. A pathology assistant prepared the frozen and scanned the slides using VisionTek M6 digital microscope ecosystem (East Dundee, IL). Cases were interpreted by trained, board-certified pathologists. All frozen sections remnants were submitted for formalin-fixed paraffin-embedded permanent sections. Frozen section diagnoses using telepathology were compared to final pathology. Turn-around time from specimen collection to frozen section diagnosis was recorded. 54 SLN from 22 breast neoadjuvant cases were diagnosed via telepathology from March 2017 to July 2019. 95% of SLNs interpreted as negative on frozen section and on permanents. A definitive diagnosis could not be rendered on six SLNs; diagnosed “atypical” at frozen. Sensitivity and specificity were 80% and 100% respectively with accuracy of 95.8%. The false-negative rate was 5%. There were no false positives. The average turn-around time was over an hour. Telepathology is an accurate method of diagnosing SLN frozen sections in the neoadjuvant setting, but lobular carcinomas and treatment effect pose diagnostic challenges and the time to report results is increased compared to standard microscopy.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. Recent studies have shown that MHC class II (MHCII) expression and tumor infiltrating lymphocytes are important prognostic factors in patients with TNBC, although the relative importance of lymphocyte subsets and associated protein expression is incompletely understood. NanoString Digital Spatial Profiling (DSP) allows for spatially resolved, highly multiplexed quantification of proteins in clinical samples. In this study, we sought to determine if DSP could be used to characterize expression of MHCII and other immune related proteins in tumor epithelial versus stromal compartments of patient-derived TNBCs (N = 10) using a panel of 39 markers. We confirmed that a subset of TNBCs have elevated expression of HLA-DR in tumor epithelial cells; HLA-DR expression was also significantly higher in the tumors of patients with long-term disease-free survival when compared to patients that relapsed. HLA-DR expression in the epithelial compartment was correlated with high expression of CD4 and ICOS in the stromal compartment of the same tumors. We also identified candidate protein biomarkers with significant differential expression between patients that relapsed versus those that did not. In conclusion, DSP is a powerful method that allows for quantification of proteins in the immune microenvironment of TNBCs.

Context .—Accuracy is an important feature of any diagnostic test. There has been an increasing awareness of deficiencies in study design that can create bias in estimates of test accuracy. Many pathologists are unaware of these sources of bias. Objective .—To explain the causes and increase awareness of several common types of bias that result from deficiencies in the design of diagnostic accuracy studies. Data Sources .—We cite examples from the literature and provide calculations to illustrate the impact of study design features on estimates of diagnostic accuracy. In a companion article by Schmidt et al in this issue, we use these principles to evaluate diagnostic studies associated with a specific diagnostic test for risk of bias and reporting quality. Conclusions .—There are several sources of bias that are unique to diagnostic accuracy studies. Because pathologists are both consumers and producers of such studies, it is important that they be aware of the risk of bias.