Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC.

Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be immune cold and hence immunotherapy resistant tumors, and EA TNBC as inflamed tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes.

Spatial mapping of the DNA adducts in cancer.

DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including cancer, aging, and neurodegeneration. The continuous acquisition of DNA damage from exogenous and endogenous stressors coupled with defects in DNA repair pathways contribute to the accumulation of DNA damage within the genome and genomic instability. While mutational burden offers some insight into the level of DNA damage a cell may have experienced and subsequently repaired, it does not quantify DNA adducts and strand breaks. Mutational burden also infers the identity of the DNA damage. With advances in DNA adduct detection and quantification methods, there is an opportunity to identify DNA adducts driving mutagenesis and correlate with a known exposome. However, most DNA adduct detection methods require isolation or separation of the DNA and its adducts from the context of the nuclei. Mass spectrometry, comet assays, and other techniques precisely quantify lesion types but lose the nuclear context and even tissue context of the DNA damage. The growth in spatial analysis technologies offers a novel opportunity to leverage DNA damage detection with nuclear and tissue context. However, we lack a wealth of techniques capable of detecting DNA damage in situ. Here, we review the limited existing in situ DNA damage detection methods and examine their potential to offer spatial analysis of DNA adducts in tumors or other tissues. We also offer a perspective on the need for spatial analysis of DNA damage in situ and highlight Repair Assisted Damage Detection (RADD) as an in situ DNA adduct technique with the potential to integrate with spatial analysis and the challenges to be addressed.

Thrombotic microangiopathy with multiorgan involvement following COVID-19.

Acute kidney injury is common among hospitalized COVID-19 patients, with the incidence ranging from 0.5% to 80%, due to diverse pathologies including acute tubular injury, collapsing glomerulopathy, and thrombotic microangiopathy (TMA). While macrovascular thrombosis is common in these individuals, the frequent finding of extensive microvascular thromboses in several series and case reports raises the possibility of thrombotic microangiopathy (TMA) being a contributing factor in the thrombotic and multiorgan complications of the disease. TMA has been described as either the primary finding or in concert with other pathologic findings in COVID-19 patients and carries a poor prognosis, with all patients requiring dialysis. We present a case of TMA with retinal injury and bowel perforation in addition to pulmonary and renal manifestations.

Endocervicosis in an Intramammary Lymph Node.

Benign müllerian inclusions are frequently encountered within infra-diaphragmatic locations such as pelvic lymph nodes, bladder, cervix and vagina. Supra-diaphragmatic müllerian inclusions, especially endocervicosis, are exceedingly rare. We report a case of endocervicosis within an intramammary lymph node in a 49-year-old woman. To the best of our knowledge, this is the second reported case.

Educational Case: Antiglomerular Basement Membrane Disease as an Example of Antibody-Mediated Glomerulonephritis.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Mercury in natural health products as a cause of membranous nephropathy.

Membranous nephropathy is a glomerular disease characterized by diffuse subepithelial immune complex deposition along the glomerular basement membrane. It can be both primary and secondary to malignancy and various drugs. An emerging area of concern is heavy metal exposure from use of largely unregulated natural health products. Here we present a case of biopsy-proven membranous nephropathy due to natural health products contaminated with mercury.

Educational Case: Lupus Nephritis as an Example of Immune Complex-Mediated Glomerulonephritis.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Educational Case: Dysproteinemic Nephropathies: Renal Amyloidosis as an Example.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms.

Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.

Acute fibrinous organising pneumonia presenting as a cavitary lung lesion and treatment response to azithromycin.

Acute fibrinous organising pneumonia is distinct from the classic diffuse alveolar damage, organising pneumonia and eosinophilic pneumonia. A 52-year-old woman presented with fever, productive cough, night sweats and left-sided pleuritic chest pain for a week. Physical examination was significant only for decreased breath sounds in the left infraclavicular area laterally. Imaging studies revealed a peripheral thick-walled left upper lobe cavitary lesion, left lower lobe consolidation and an enlarged subcarinal lymph node. She was treated with doxycycline for 10 days without improvement. Pertinent laboratory tests, microbiologic workup and fibre-optic bronchoscopy were non-diagnostic and a CT-guided left upper lobe lung biopsy revealed acute fibrinous organising pneumonia. She was treated with azithromycin with complete resolution of symptoms. To our knowledge, this is the first reported case of acute fibrinous organising pneumonia presenting as a cavitary lung lesion and the first with treatment response to azithromycin.

Risk of cytomegalovirus transmission by blood products after solid organ transplantation.

Cytomegalovirus (CMV) infection and CMV disease are significant contributors to increased morbidity, mortality, and cost for immunocompromised solid organ transplant recipients. Although the most significant risk for CMV transmission is the CMV serological status of the transplant donor and recipient, exposure to blood products is another potential risk factor. Before the era of leukocyte reduction, CMV seronegative products were issued to reduce the risk of CMV transmission, thus rendering the products CMV safe. This approach requires maintenance of two inventories of blood products and continuous donor testing. Leukocyte-reduced cellular transfusion products are also considered CMV safe and are essentially universally available. To minimize the risk of CMV infection in transplant recipients, strategies include use of seronegative blood products or prestorage leukocyte reduction. However, no recent randomized prospective controlled trial directly compares the two CMV safety approaches for transplant recipients. Hence, current policy relies on historic trials and more recent observational studies. As a consequence, though generally considered equivalent approaches, preferred practice varies between centers. This review provides guidance to inform an acceptable practice approach.

Acute kidney injury and undiagnosed immunoglobulin A nephropathy after dabigatran therapy.

Dabigatran, a new oral anticoagulant, is a direct thrombin inhibitor used as an alternative to warfarin to reduce the risk of stroke and systemic embolism with nonvalvular atrial fibrillation. We report a case of a man who resumed dabigatran after 6 weeks of prior therapy and began experiencing hematuria with worsening kidney function. Renal biopsy with immunofluorescence and electron microscopy showed mesangial deposits consistent with immunoglobulin A nephropathy. With discontinuation of dabigatran and addition of methylprednisolone, the gross hematuria cleared and urine output improved.