Immune phenotype-genotype associations in primary clear cell renal cell carcinoma and matched metastatic tissue.

Adjuvant immunotherapy has been recently recommended for patients with metastatic ccRCC, but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched metastases, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant metastases (METs) by comprehensive targeted parallel sequencing, whole-genome copy number variation (CNV) analysis, determination of microsatellite instability (MSI) and tumor mutational burden (TMB). We quantified the spatial distribution of tumor-infiltrating CD8+ T cells, and co-expression of the T-cell-exhaustion marker TOX by digital immunoprofiling and quantified tertiary lymphoid structures (TLS). Most METs were pathologically "cold". Inflamed, pathologically "hot" PTs were associated with a decreased disease-free survival (DFS), worst for patients with high levels of CD8+TOX+ T cells. Interestingly, inflamed METs showed a relative increase of exhausted CD8+TOX+ T cells and increased accumulative size of TLS compared to PTs. Integrative analysis of molecular and immune phenotypes revealed BAP1 and CDKN2A/B deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations.

High throughput spatial immune mapping reveals an innate immune scar in post-COVID-19 brains.

The underlying pathogenesis of neurological sequelae in post-COVID-19 patients remains unclear. Here, we used multidimensional spatial immune phenotyping and machine learning methods on brains from initial COVID-19 survivors to identify the biological correlate associated with previous SARS-CoV-2 challenge. Compared to healthy controls, individuals with post-COVID-19 revealed a high percentage of TMEM119+P2RY12+CD68+Iba1+HLA-DR+CD11c+SCAMP2+ microglia assembled in prototypical cellular nodules. In contrast to acute SARS-CoV-2 cases, the frequency of CD8+ parenchymal T cells was reduced, suggesting an immune shift toward innate immune activation that may contribute to neurological alterations in post-COVID-19 patients.

The Grafting of Hydroxyaromatic Organics within Layered Perovskites via a Microwave-Assisted Method.

A new series of inorganic-organic hybrid perovskite materials were prepared by microwave-assisted grafting reactions. Simple carboxylic acids, acetic acid, and propionic acid, as well as hydroxyaromatic carboxylic acids, 3,5-dihydroxy benzoic acid (DBA), 5-hydroxyisophthalic acid (HPA), 4-hydroxybenzoic acid (HBA), and 4-hydroxy-4-biphenyl carboxylic acid (HBCA), were reacted with the Dion-Jacobson double-layered perovskite, HLaNb2O7, and its alcoxy derivatives. Grafting was found to not occur with simple carboxylic acids, while those molecules with hydroxyls were all attached to the perovskite interlayers. Reactivity of the hydroxyaromatic carboxylic acids varied with the different layered perovskite hosts where reactions with HLaNb2O7 did not occur, and those with n-propoxy-LaNb2O7 were limited; the greatest extent of reactivity was seen with n-decoxy-LaNb2O7. This is attributed to the larger interlayer spacing available for the insertion of the various hydroxyaromatic carboxylic acid compounds. The loading exhibited by the grafting species was less than that seen with well-known long-chain alkoxy grafting groups. It is expected that the width of the molecules contributes to this where, due to the benzyl groups, the interlayer volume of the grafted moieties occupies a larger horizontal fraction, therefore minimizing the loading to the below half. X-ray powder diffraction and transmission electron microscopy studies found that grafting of the n-decoxy-LaNb2O7 intermediates with the series of hydroxyaromatics resulted in a reduction in crystallinity along with a disruption of the layer structure. Raman data on the series show little variation in local structure except for HBCA, where there appears to be a lengthening of the Nb-O apical linkage and a possible reduction in the distortion of inner-layer NbO6 octahedra. The optical properties of the hydroxyaromatic carboxylic acid grafted perovskites were also investigated using diffuse-reflectance UV-Vis spectroscopy. The band gaps of DBA, HPA, and HBA were found to be similar to the parent (Eg ≈ 3.4 eV), while the HBCA was significantly less by ca. 0.6 eV. This difference is attributed to electron withdrawal from the perovskite block to the HBCA ligand, leading to a lower band gap for the HBCA compound. The methods described herein allow for the formation of a new series of inorganic-organic hybrid materials where the products are of interest as precursors to more complex architectures as well as models for band gap modification of metal oxide photocatalysts.

The Genetic Landscape of Primary Breast Marginal Zone Lymphoma Identifies a Mutational-driven Disease With Similarities to Ocular Adnexal Lymphoma.

Extranodal marginal zone lymphomas (eMZL) can occur in any organ and site of the body. Recent research has shown that they differ from organ to organ in terms of their mutational profile. In this study, we investigated a cohort of primary breast marginal zone lymphomas (PBMZL) to get a better insight into their morphologic and molecular profile. A cohort of 15 cases (14 female and 1 male) was characterized by immunohistochemistry (IHC) for 19 markers, fluorescence in situ hybridization (FISH), and high throughput sequencing (HTS) using a lymphoma panel comprising 172 genes. In addition, PCR for the specific detection of Borrelia spp. and metagenomics whole genome sequencing were performed for infectious agent profiling. Follicular colonization was observed in most cases, while lymphoepithelial lesions, though seen in many cases, were not striking. All 15 cases were negative for CD5, CD11c, and CD21 and positive for BCL2 and pan B-cell markers. There were no cases with BCL2, BCL10, IRF4, MALT1, or MYC translocation; only 1 had a BCL6 rearrangement. HTS highlighted TNFAIP3 (n=4), KMT2D (n=2), and SPEN (n=2) as the most frequently mutated genes. There were no Borrelia spp., and no other pathogens detected in our cohort. One patient had a clinical history of erythema chronicum migrans affecting the same breast. PBMZL is a mutation-driven disease rather than fusion-driven. It exhibits mutations in genes encoding components affecting the NF-κB pathway, chromatin modifier-encoding genes, and NOTCH pathway-related genes. Its mutational profile shares similarities with ocular adnexal and nodal MZL.

Tracing Tumor Heterogeneity of Pleomorphic Carcinoma of the Lung.

INTRODUCTION: Pulmonary pleomorphic carcinoma (PPC) is an aggressive and highly heterogeneous NSCLC whose underlying biology is still poorly understood. METHODS: A total of 42 tumor areas from 20 patients with PPC were microdissected, including 39 primary tumors and three metastases, and the histologically distinct components were subjected to whole exome sequencing separately. We further performed in silico analysis of microdissected bulk RNA sequencing and methylation data of 28 samples from 14 patients with PPC. We validated our findings using immunohistochemistry. RESULTS: The epithelial and the sarcomatoid components of PPCs shared a large number of genomic alterations. Most mutations in cancer driver genes were clonal and truncal between the two components of PPCs suggesting a common ancestor. The high number of alterations in the RTK-RAS pathway suggests that it plays an important role in the evolution of PPC. The metastases morphologically and genetically resembled the epithelial or the sarcomatoid components of the tumor. The transcriptomic and epigenetic profiles of the sarcomatoid components of PPCs with matched squamous-like or adenocarcinoma-like components differed from each other, and they shared more similarities to their matched epithelial components. NCAM1/CD56 was preferentially expressed in the sarcomatoid component of squamous-like PPCs, whereas CDH1/E-Cadherin expression was down-regulated in the sarcomatoid component of most PPCs. CONCLUSION: Lung adenocarcinoma-like PPCs are mainly driven by RTK-RAS signaling, whereas epithelial-mesenchymal transition programs as highlighted by increased NCAM1 and decreased CDH1 expression govern the epithelial-sarcomatoid transition between the clonally related tumor components. Several alterations in PPCs pinpoint therapeutic opportunities.

Supporting re-engagement with HIV services after treatment interruption in South Africa: a mixed method program evaluation of MSF's Welcome Service.

Psychosocial challenges impact patients' ability to remain on antiretroviral therapy lifelong, magnified by disorganized health-systems and healthcare worker (HCW) attitudes. To address this, Médecins Sans Frontières and the Department of Health developed the Welcome Service intervention, to provide person-centered care at re-engagement after HIV treatment interruption. Implemented in Khayelitsha, South Africa, between August 2020 and February 2021, the intervention aimed to reorganize triage, optimize clinical and counselling services and address HCW attitudes. The study used a mixed-methods design, incorporating in-depth interviews, and analyses of programmatic and routine health data. Interviews demonstrated positive patient care experiences. HCWs understood the potential impact of attitudes on patient engagement, however, some continued to demonstrate judgmental attitude. Clinical objectives were variably met at re-engagement: 98% were re-initiated the same day, 50% had a CD4 done, and 45% received tuberculosis prevention. Nevertheless, 4-month retention was 66%, and 88% had a VL < 1000 c/mL. Despite HCWs' understanding of person-centered care not translating into supportive behaviors, patients had positive care experiences and the intervention ended with a high rate of VL suppression. More efforts are needed to design interventions building on Welcome Service principles to provide person-centered care and sustain retention after re-engagement.

Early outcomes of endovascular repairs of the aortic arch using thoracic branch endoprosthesis.

OBJECTIVE: The only commercially available thoracic branched endoprosthesis (TBE) for treatment of the aortic arch was released in 2022. Limited data outside of clinical trial results have been reported. This study describes the demographics, anatomic details, and outcomes for patients treated for zone 0 to 2 using TBEs outside of a clinical trial. METHODS: All patients treated using TBEs for zone 0 to 2 were included. Patients treated as part of the clinical trial for zone 0 to 1 (n = 6) were excluded. Patient demographics, comorbidities, anatomic and operative details, and outcomes were reported. Outcomes and survival were then compared between groups. RESULTS: Of 40 patients, six patients underwent repair of zone 0, three of zone 1, and 31 of zone 2. There were no differences in demographics, comorbidities, or operative details by zone of treatment; however, the frequency of genetic aortopathy differed (zone 0: 0%; zone 1: 67%; and zone 2: 6.4%; P < .01). Seventy-three percent of patients were treated for dissection vs 27% with isolated aneurysms. Of the patients, 2.5% were treated for rupture, 22% were treated for symptomatic aneurysms, and 75% were treated electively. Forty-eight percent of repairs included a proximal cuff, and 83% received distal extension. Technical success was achieved in 100% of patients. Mean fluoroscopy time was 18 minutes, and median fluoroscopy dose was 416 mGy. Sixty percent of patients had prior aortic ascending/arch repair. TBE was planned as part of a complete thoracoabdominal repair in 45% of patients. Thirty-day mortality was 2.5% overall, with a single death in a zone 0 patient that occurred at day 1 due to a myocardial infarction. There were no reinterventions within 30 days. All other outcomes were similar. The 30-day stroke rate was 5.0%. The strokes occurred at day 6 (zone 1) and day 15 (zone 2); however, both were due to occlusion of a prior proximal surgical bypass and unrelated to the TBE side branch or embolization. Specifically, both patients had occlusion of a branch of their prior zone 1 or zone 2 arch replacement. An endoleak occurred in 7.5% of patients at 30-day follow-up (type II: 5.0%; unknown: 2.5%). At a mean follow-up of 6.6 months, 100% of side branches were patent. CONCLUSIONS: Repair of the aortic arch including TBE can be performed electively and urgently with acceptable stroke and death rates. TBE provides a valuable tool for patients requiring complete repair of a thoracoabdominal aneurysm. Continued investigation is underway to assess long-term safety and efficacy outside of the clinical trial.

National trends in utilization of surgeon-modified grafts for complex and thoracoabdominal aortic aneurysms.

INTRODUCTION: Custom-branched/fenestrated grafts are widely available in other countries, but in the United States, they are limited to a handful of centers, with the exception of a 3-vessel juxtarenal device (ZFEN). Consequently, many surgeons have turned to alternative strategies such as physician-modified endografts (PMEGs). We therefore sought to determine how widespread the use of these grafts is. METHODS: We studied all complex endovascular repairs of complex and thoracoabdominal aortic aneurysms in the Vascular Quality Initiative from 2014 to 2022 to examine temporal trends. RESULTS: A total of 5826 repairs were performed during the study period: 1895 ZFEN, 3241 PMEG, 595 parallel grafting, and 95 where parallel grafting was used in addition to ZFEN, with a mean of 2.7 ± 0.98 vessels incorporated. Over time, the number of PMEGs steadily increased, both overall and for juxtarenal aneurysms, whereas the number of ZFENs essentially leveled off by 2017 and has remained steady ever since. In the most recent complete year (2021), PMEGs outnumbered ZFENs by over 2:1 overall (567 to 256) and nearly twofold for juxtarenal repairs. In three-vessel cases involving juxtarenal aneurysms, PMEGs were used as frequently as ZFENs (43% vs 43%), whereas the proportion of juxtarenal aneurysms repaired using a four-vessel graft configuration increased from 20% in 2014 to 29% in 2021 (P < .001). The differences in PMEG use were more pronounced as surgeon volume increased. Surgeons in the lowest quartile of volume performed <2 complex repairs annually, evenly split between PMEGs and ZFENs. However, surgeons in the highest quartile of volume performed a median of 18 (interquartile range: 10-21) PMEGs/y, but only 1.6 (interquartile range: 0.8-3.4) ZFENs/y. The number of physician-sponsored investigational device exemption trials of PMEGs has expanded from 1 in 2012 to 8 currently enrolling. As those data are not included in the Vascular Quality Initiative, the true number of PMEGs is likely substantially higher. CONCLUSIONS: PMEGs have become the dominant endovascular repair modality of complex abdominal and thoracoabdominal aortic aneurysms outside of investigational device exemptions. The field of endovascular aortic surgery and patients with complex aneurysms would benefit from broader publication of PMEG techniques, outcomes, and comparisons to custom-manufactured grafts.

Editor's Choice - An Endovascular Approach to Abdominal Aortic Aneurysm Rupture is Associated With Improved Outcomes for Patients With Prior Aortic Repair.

OBJECTIVE: To assess whether outcomes of rupture repair differ by aortic repair history and determine the ideal approach for rupture repair in patients with previous aortic repair. METHODS: This retrospective review included all patients who underwent repair of a ruptured infrarenal abdominal aortic aneurysm from 2003 - 2021 recorded in the Vascular Quality Initiative (VQI) registry. Pre-operative characteristics and post-operative outcomes and long term survival were compared between patients with and without prior aortic repair. To assess the impact of open and endovascular approaches to rupture, a subgroup analysis was then performed among patients who ruptured after a prior infrarenal aortic repair. Univariable and adjusted analyses were performed to account for differences in patient characteristics and operative details. RESULTS: A total of 6 197 patients underwent rupture repair during the study period, including 337 (5.4%) with prior aortic repairs. Univariable analysis demonstrated an increased 30 day mortality rate in patients with prior repairs vs. without (42 vs. 36%; p = .034), and prior repair was associated with increased post-operative renal failure (35 vs. 21%; p < .001), respiratory complications (32 vs. 24%; p < .001), and wound complications (9 vs. 4%; p < .001). Following adjustment, all outcomes were similar with the exception of bowel ischaemia, which was decreased among patients with prior repair (OR 0.7, 95% CI 0.6 - 0.9). Subgroup analysis demonstrated that patients with a prior aortic repair history who underwent open rupture repair had increased odds for 30 day death (OR 1.3, 95% CI 1.2 - 1.7) and adverse secondary outcomes compared with those managed endovascularly. CONCLUSION: Prior infrarenal aortic repair was not independently associated with increased morbidity or mortality following rupture repair. Patients with a prior aortic repair history demonstrated statistically significantly higher mortality and morbidity when treated with an open repair compared with an endovascular approach. An endovascular first approach to rupture should be strongly encouraged whenever feasible in patients with prior aortic repair.

Dancing in the purple rain: color affinity and oviposition choices in Aedes sierrensis (Diptera: Culicidae).

The western tree hole mosquito, Aedes sierrensis (Ludlow) (Diptera: Clucidae), is a pestiferous mosquito with a range extending over the entire pacific seaboard and into portions of the intermountain west. As a peridomestic heartworm vector, it demands at least some level of surveillance to understand its abundance. However, the species is refractory to a majority of conventional vector surveillance approaches for tracking mosquitoes. To find more options for Aedes sierrensis surveillance, a variety of oviposition attractants were evaluated in arena-style choice assays using colony reared adults. A range of infusion treatments (e.g., alfalfa, oak, and beetroot) were examined and then combined with investigations of liquid color as well as ovicup color and entryway position. These studies revealed that Ae. sierrensis have an affinity for purple coloration, plain water, and larger entryway sizes for oviposition cups. A prototype ovicup was 3D-printed using purple filament and multiple types of entryways, and used to re-test infusion waters. No particular attraction differences were detected after normalizing for purple color. Comparisons to black 3D-printed cups yielded surprising observations that male mosquitoes also aggregated on purple cups while females sheltered, but not necessarily oviposited, in black cups. Although this was only a laboratory-based assessment, these studies provide useful information for future field trials of potential oviposition traps for surveillance of Ae. sierrensis.

Swiss digital pathology recommendations: results from a Delphi process conducted by the Swiss Digital Pathology Consortium of the Swiss Society of Pathology.

Integration of digital pathology (DP) into clinical diagnostic workflows is increasingly receiving attention as new hardware and software become available. To facilitate the adoption of DP, the Swiss Digital Pathology Consortium (SDiPath) organized a Delphi process to produce a series of recommendations for DP integration within Swiss clinical environments. This process saw the creation of 4 working groups, focusing on the various components of a DP system (1) scanners, quality assurance and validation of scans, (2) integration of Whole Slide Image (WSI)-scanners and DP systems into the Pathology Laboratory Information System, (3) digital workflow-compliance with general quality guidelines, and (4) image analysis (IA)/artificial intelligence (AI), with topic experts for each recruited for discussion and statement generation. The work product of the Delphi process is 83 consensus statements presented here, forming the basis for "SDiPath Recommendations for Digital Pathology". They represent an up-to-date resource for national and international hospitals, researchers, device manufacturers, algorithm developers, and all supporting fields, with the intent of providing expectations and best practices to help ensure safe and efficient DP usage.

Inescapable foot shock induces a PTSD-like phenotype and negatively impacts adult murine bone.

Post-traumatic stress disorder (PTSD) is associated with osteopenia, osteoporosis and increased fracture risk in the clinical population. Yet, the development of preclinical models to study PTSD-induced bone loss remains limited. In this study, we present a previously unreported model of PTSD in adult female C57BL/6 mice, by employing inescapable foot shock and social isolation, that demonstrates high face and construct validity. A subset of mice exposed to this paradigm (i.e. PTSD mice) display long-term alterations in behavioral and inflammatory indices. Using three-dimensional morphometric calculations, cyclic reference point indentation (cRPI) testing and histological analyses, we find that PTSD mice exhibit loss of trabecular bone, altered bone material quality, and aberrant changes in bone tissue architecture and cellular activity. This adult murine model of PTSD exhibits clinically relevant changes in bone physiology and provides a valuable tool for investigating the cellular and molecular mechanisms underlying PTSD-induced bone loss.

Outcomes of Staged Repairs of Complex Endovascular Repairs of Thoracoabdominal Aortic Aneurysms.

BACKGROUND: Endovascular treatment allows for the staging of thoracoabdominal aortic aneurysm repairs (eTAAAs) in an effort to decrease the risk of spinal cord ischemia (SCI), but data are limited. METHODS: We studied all eTAAAs in the Vascular Quality Initiative from 2014 to 2021. Inverse probability weighting was used to compare perioperative and long-term outcomes of staged and single-stage repairs. Thoracoabdominal life-altering events (TALEs) are the composite endpoint consisting of death/stroke/permanent SCI/permanent dialysis. RESULTS: There were 3,258 total operations during the study period. In total, 841 cases (26%) were staged repairs, and 2,417 (74%) were completed in a single stage, but in the cohort of patients with extensive aneurysms, 44% were staged. Staging methods included thoracic endograft (78%), branch (23%), and iliac (5%). Staged repairs were more often employed by high-volume surgeons at high-volume centers; for larger, more extensive aneurysms, with higher rates of prior aortic surgery. After adjustment, staged repair and single-stage treatment were associated with similar odds of all perioperative outcomes and including mortality, TALE, acute kidney injury, stroke, dialysis, and SCI, as well as long-term survival. This was consistent in the subgroups of patients with extensive aneurysms undergoing elective procedures. Of note, first-stage thoracic endografts were associated with 2.6% mortality, 7.3% TALE, 1.5% dialysis, and 4.1% SCI, and 25% of patients did not undergo a second stage. First-stage procedures accounted for one-third of perioperative complications including half of the deaths in the staged cohort. CONCLUSIONS: Staged eTAAA repairs were associated with similar perioperative and long-term complications to single-stage treatments. However, first stage procedures are associated with significant morbidity and mortality, and one-quarter of patients never complete their repairs. These data demonstrate the necessity of evaluating the outcomes of all patients planned for staged procedures, not only those who make it to the final stage. More data are needed as to the optimal method of spinal cord protection for these challenging aneurysms.

Digital image analysis and artificial intelligence in pathology diagnostics-the Swiss view.

Digital pathology (DP) is increasingly entering routine clinical pathology diagnostics. As digitization of the routine caseload advances, implementation of digital image analysis algorithms and artificial intelligence tools becomes not only attainable, but also desirable in daily sign out. The Swiss Digital Pathology Consortium (SDiPath) has initiated a Delphi process to generate best-practice recommendations for various phases of the process of digitization in pathology for the local Swiss environment, encompassing the following four topics: i) scanners, quality assurance, and validation of scans; ii) integration of scanners and systems into the pathology laboratory information system; iii) the digital workflow; and iv) digital image analysis (DIA)/artificial intelligence (AI). The current article focuses on the DIA-/AI-related recommendations generated and agreed upon by the working group and further verified by the Delphi process among the members of SDiPath. Importantly, they include the view and the currently perceived needs of practicing pathologists from multiple academic and cantonal hospitals as well as private practices.

Using autopsies to dissect COVID-19 pathogenesis.

The emergence of SARS-CoV-2 has resulted in millions of deaths as a result of COVID-19. Suitable models were missing at the beginning of the pandemic, and studies investigating disease pathogenesis relied on patients who had succumbed to COVID-19. Since then, autopsies of patients have substantially contributed to our understanding of the pathogenesis of COVID-19 and associated major organ complications. Here we summarize how autopsies have complemented experimental studies, mainly in animal models, and how they have facilitated critical knowledge of COVID-19 to improve daily clinical practice and develop therapeutic interventions. Employing advanced histopathologic and molecular genetic methods in post-mortem tissues, the COVID-19 pandemic has highlighted the importance of autopsies for virology research and clinical practice in current and emerging infectious diseases.

Von Willebrand factor and the thrombophilia of severe COVID-19: in situ evidence from autopsies.

Background: COVID-19 is accompanied by a hypercoagulable state and characterized by microvascular and macrovascular thrombotic complications. In plasma samples from patients with COVID-19, von Willebrand factor (VWF) levels are highly elevated and predictive of adverse outcomes, especially mortality. Yet, VWF is usually not included in routine coagulation analyses, and histologic evidence of its involvement in thrombus formation is lacking. Objectives: To determine whether VWF, an acute-phase protein, is a bystander, ie, a biomarker of endothelial dysfunction, or a causal factor in the pathogenesis of COVID-19. Methods: We compared autopsy samples from 28 patients with lethal COVID-19 to those from matched controls and systematically assessed for VWF and platelets by immunohistochemistry. The control group comprised 24 lungs, 23 lymph nodes, and 9 hearts and did not differ significantly from the COVID-19 group in age, sex, body mass index (BMI), blood group, or anticoagulant use. Results: In lungs, assessed for platelets by immunohistochemistry for CD42b, microthrombi were more frequent in patients with COVID-19 (10/28 [36%] vs 2/24 [8%]; P = .02). A completely normal pattern of VWF was rare in both groups. Accentuated endothelial staining was found in controls, while VWF-rich thrombi were only found in patients with COVID-19 (11/28 [39%] vs 0/24 [0%], respectively; P < .01), as were NETosis thrombi enriched with VWF (7/28 [25%] vs 0/24 [0%], respectively; P < .01). Forty-six percent of the patients with COVID-19 had VWF-rich thrombi, NETosis thrombi, or both. Trends were also seen in pulmonary draining lymph nodes (7/20 [35%] vs 4/24 [17%]; P = .147), where the overall presence of VWF was very high. Conclusion: We provide in situ evidence of VWF-rich thrombi, likely attributable to COVID-19, and suggest that VWF may be a therapeutic target in severe COVID-19.

Bone marrow haematopoiesis in patients with COVID-19.

AIMS: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection broadly affects organ homeostasis, including the haematopoietic system. Autopsy studies are a crucial tool for investigation of organ-specific pathologies. Here we perform an in-depth analysis of the impact of severe coronavirus disease 2019 (COVID-19) on bone marrow haematopoiesis in correlation with clinical and laboratory parameters. METHODS AND RESULTS: Twenty-eight autopsy cases and five controls from two academic centres were included in the study. We performed a comprehensive analysis of bone marrow pathology and microenvironment features with clinical and laboratory parameters and assessed SARS-CoV-2 infection of the bone marrow by quantitative polymerase chain reaction (qPCR) analysis. In COVID-19 patients, bone marrow specimens showed a left-shifted myelopoiesis (19 of 28, 64%), increased myeloid-erythroid ratio (eight of 28, 28%), increased megakaryopoiesis (six of 28, 21%) and lymphocytosis (four of 28, 14%). Strikingly, a high proportion of COVID-19 specimens showed erythrophagocytosis (15 of 28, 54%) and the presence of siderophages (11 of 15, 73%) compared to control cases (none of five, 0%). Clinically, erythrophagocytosis correlated with lower haemoglobin levels and was more frequently observed in patients from the second wave. Analysis of the immune environment showed a strong increase in CD68+ macrophages (16 of 28, 57%) and a borderline lymphocytosis (five of 28, 18%). The stromal microenvironment showed oedema (two of 28, 7%) and severe capillary congestion (one of 28, 4%) in isolated cases. No stromal fibrosis or microvascular thrombosis was found. While all cases had confirmed positive testing of SARS-CoV-2 in the respiratory system, SARS-CoV-2 was not detected in the bone marrow by high-sensitivity PCR, suggesting that SARS-CoV-2 does not commonly replicate in the haematopoietic microenvironment. CONCLUSIONS: SARS-CoV-2 infection indirectly impacts the haematological compartment and the bone marrow immune environment. Erythrophagocytosis is frequent and associated with lower haemoglobin levels in patients with severe COVID-19.

Nicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer.

Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal-like subtype of breast cancer that is driven by the NAD+ metabolic enzyme nicotinamide N-methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre-clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methylation at the promoters of PR/SET Domain-5 (PRDM5) and extracellular matrix-related genes. PRDM5 emerged in this study as a pro-metastatic gene acting via induction of cancer-cell intrinsic transcription of collagens. Depletion of PRDM5 in tumor cells decreases COL1A1 deposition and impairs metastatic colonization of the lungs. These findings reveal a critical activity of the NNMT-PRDM5-COL1A1 axis for cancer cell plasticity and metastasis in basal-like breast cancer.

Preferred and actual involvement of caregivers in oncologic treatment decision-making: A systematic review.

INTRODUCTION: Treatment decision-making in cancer is complex and many patients bring their caregiver to appointments to help them make those decisions. Multiple studies show the importance of involving caregivers in the treatment decision-making process. We aimed to explore the preferred and actual involvement of caregivers in the decision-making process of patients with cancer and to see if there are age or cultural background related differences in caregiver involvement. MATERIALS AND METHODS: A systematic review of Pubmed and Embase was performed on January 2, 2022. Studies containing numerical data regarding caregiver involvement were included, as were studies describing the agreement between patients and caregivers regarding treatment decisions. Studies assessing solely patients aged younger than 18 years old or terminally ill patients, and studies without extractable data were excluded. Risk of bias was assessed by two independent reviewers using an adapted version of the Newcastle-Ottawa scale. Results were analysed in two separate age groups, one <62 years and one ≥62 years. RESULTS: Twenty-two studies with a total of 11,986 patients and 6,260 caregivers were included in this review. A median of 75% of patients preferred caregivers to be involved in decision-making and a median of 85% of caregivers preferred to be involved. With regards to age groups, the preferred involvement of caregivers was more frequent in the younger study populations. With regards to geographical differences, studies performed in Western countries showed a lower preference for caregiver's involvement compared to studies from Asian countries. A median of 72% of the patients reported the caregiver was actually involved in the treatment decision-making and a median of 78% of the caregivers reported they were actually involved. The most important role of caregivers was to listen and provide emotional support. DISCUSSION: Patients and caregivers both want caregivers to be involved in the treatment decision-making process and most caregivers are actually involved. An ongoing dialogue between clinicians, patients and caregivers about decision-making is important to meet the individual patient's and caregiver's needs when involved in the decision-making process. Important limitations were a lack of studies in older patients and significant differences in outcome measures among studies.

Outcomes of Complex Endovascular Treatment of Post-Dissection Aneurysms.

OBJECTIVE: Reports of endovascular treatment of chronic post-dissection aneurysms are limited to high volumes centres, posing questions about generalisability. METHODS: All endovascular repairs of intact pararenal and thoraco-abdominal aneurysms in the Vascular Quality Initiative from 2014 to 2021 were studied, and peri-operative and long term outcomes were compared between repairs of degenerative and post-dissection aneurysms. Peri-operative outcomes were compared using mixed effects logistic regression, and long term outcomes using Medicare linkage. RESULTS: There were 123 patients who completed treatment for post-dissection aneurysms and 3 635 for degenerative aneurysms, with 36% of post-dissection repairs and 6.7% of degenerative repairs performed in a staged fashion (p < .001). The majority (84%) of post-dissection aneurysms were extensive thoraco-abdominal aneurysms (TAAAs: Crawford Type 1, 2, 3, 5), compared with 22% of degenerative aneurysms (p < .001). Physician modified endografts were the primary repair type for post-dissection (73%), while commercially available fenestrated grafts were the dominant repair for degenerative (48%). The first stage of staged procedures was associated with a 2.8% peri-operative mortality rate, 5.1% spinal cord ischaemia, and 8.9% thoraco-abdominal life altering events (the composite of peri-operative death, stroke, permanent spinal cord ischaemia, and dialysis). Th final stage procedure and fluoroscopy times were similar, but technical success was lower in post-dissection repairs (75% vs. 83%, p = .018), both due to issues with the main endograft or bridging vessels (11% vs. 6.6%, p = .055), and types 1and 3 endoleak at completion (17% vs. 10%, p = .035). In addition, high volume surgeons had two fold higher odds of technical success than their low volume counterparts. Adjusted peri-operative outcomes were similar between pathology types, including when comparisons were restricted to extensive TAAAs. Crude and adjusted three year survival were similar, but three year re-interventions were significantly higher following post-dissection repairs (p < .001). CONCLUSION: Complex endovascular repair of chronic post-dissection aneurysms is feasible but is associated with high rates of re-interventions and non-trivial rates of lack of technical success. More data are needed to evaluate the long term durability of these procedures, and the utility of centralising these complex procedures.