Prognostic Performance of Inflammatory Biomarkers Based on Complete Blood Counts in COVID-19 Patients.

With the end of the pandemic, COVID-19 has entered an endemic phase with expected seasonal spikes. Consequently, the implementation of easily accessible prognostic biomarkers for patients with COVID-19 remains an important area of research. In this monocentric study at a German tertiary care hospital, we determined the prognostic performance of different clinical and blood-based parameters in 412 COVID-19 patients. We evaluated the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), and absolute eosinopenia (AEP, 0/µL) of COVID-19 patients (n = 412). The Siddiqui and Mehra staging proposal, the WHO clinical progression scale, and COVID-19-associated death were used as COVID-19 outcome measures. With respect to Siddiqi and Mehra staging, patient age of older than 75 years, high C-reactive protein (CRP), absolute eosinopenia (AEP), cardiovascular comorbidities, and high ferritin were significant independent predictors for severe COVID-19. When outcome was determined according to the WHO clinical progression scale, patient age of older than 75 years, high CRP, high LDH, AEP, high neutrophil-to-lymphocyte ratio (NLR), and the presence of pulmonal comorbidities were significant independent predictors for severe COVID-19. Finally, COVID-19-associated death was predicted independently by patient age of older than 75 years, high LDH, high NLR, and AEP. Eosinopenia (< 40/µL) was observed in 74.5% of patients, and AEP in almost 45%. In conclusion, the present real-world data indicate that the NLR is superior to more complex systemic immune-inflammation biomarkers (e.g., SII and PIV) in COVID-19 prognostication. A decreased eosinophil count emerged as a potential hallmark of COVID-19 infection, whereas AEP turned out to be an accessible independent biomarker for COVID-19 severity and mortality.

Atypical pediatric presentation of alopecic and aseptic nodules of the scalp with features of dissecting cellulitis.

Alopecic and aseptic nodules of the scalp (AANS) and dissecting cellulitis of the scalp (DCS) are rare, closely related conditions of young men that exclusively affect the hair-bearing scalp. We describe a 9-year-old boy who presented with a 6-year history of chronically relapsing, sterile, partially scarring nodules of the scalp and facial skin. Histopathology revealed mixed inflammatory infiltrates consisting of neutrophils, macrophages, lymphocytes, and plasma cells in the deep dermis, consistent with the morphological pattern of suppurative, partly granulomatous dermatitis. The present atypical case is characterized by prepubertal onset and facial involvement which, to our knowledge, has not yet been described before, may be included in the spectrum of "typical" AANS and "typical" DCS.

Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer.

The acquisition of mesenchymal traits is considered a hallmark of breast cancer progression. However, the functional relevance of epithelial-to-mesenchymal transition (EMT) remains controversial and context dependent. Here, we isolate epithelial and mesenchymal populations from human breast cancer metastatic biopsies and assess their functional potential in vivo. Strikingly, progressively decreasing epithelial cell adhesion molecule (EPCAM) levels correlate with declining disease propagation. Mechanistically, we find that persistent EPCAM expression marks epithelial clones that resist EMT induction and propagate competitively. In contrast, loss of EPCAM defines clones arrested in a mesenchymal state, with concomitant suppression of tumorigenicity and metastatic potential. This dichotomy results from distinct clonal trajectories impacting global epigenetic programs that are determined by the interplay between human ZEB1 and its target GRHL2. Collectively, our results indicate that susceptibility to irreversible EMT restrains clonal propagation, whereas resistance to mesenchymal reprogramming sustains disease spread in multiple models of human metastatic breast cancer, including patient-derived cells in vivo.

The Antineoplastic Effect of Dimethyl Fumarate on Virus-Negative Merkel Cell Carcinoma Cell Lines: Preliminary Results.

Merkel cell carcinoma (MCC) is a rare, difficult-to-treat skin cancer once immunotherapy has failed. MCC is associated either with the clonal integration of the Merkel cell polyomavirus (MCPyV) or mutagenic UV-radiation. Fumaric acid esters, including dimethyl fumarate (DMF), have been shown to inhibit cell growth in cutaneous melanoma and lymphoma. We aimed to explore the effects of DMF on MCPyV-negative MCC cell lines. Three MCC cell lines (MCC13, MCC14.2, and MCC26) were treated with different doses of DMF. The cytotoxic effects and cell proliferation were assessed by the MTT cytotoxicity assay and BrdU proliferation assay at different time points. A significant reduction in cell viability and proliferation were demonstrated for all the cell lines used, with DMF proving to be effective.

Immune Checkpoint Inhibitors in Solid Organ Transplant Recipients With Advanced Skin Cancers-Emerging Strategies for Clinical Management.

Use of immune checkpoint inhibitors (ICIs) in solid organ transplant recipients (SOTRs) with advanced skin cancers presents a significant clinical management dilemma. SOTRs and other immunosuppressed patients have been routinely excluded from ICI clinical trials with good reason: immune checkpoints play an important role in self- and allograft-tolerance and risk of acute allograft rejection reported in retrospective studies affects 10% to 65% of cases. These reports also confirm that cutaneous squamous cell carcinoma and melanoma respond to ICI therapy, although response rates are generally lower than those observed in immunocompetent populations. Prospective trials are now of critical importance in further establishing ICI efficacy and safety. However, based on current knowledge, we recommend that ICIs should be offered to kidney transplant recipients with advanced cutaneous squamous cell carcinoma, melanoma, or Merkel cell carcinoma if surgery and/or radiotherapy have failed. For kidney transplant recipients, this should be first line ahead of chemotherapy and targeted therapies. In SOTRs, the use of ICIs should be carefully considered with the benefits of ICIs versus risks of allograft rejection weighed up on a case-by-case basis as part of shared decision-making with patients. In all cases, parallel management of immunosuppression may be key to ICI responsiveness. We recommend maintaining immunosuppression before ICI initiation with a dual immunosuppressive regimen combining mammalian target of rapamycin inhibitors and either corticosteroids or calcineurin inhibitors. Such modification of immunosuppression must be considered in the context of allograft risk (both rejection and also its subsequent treatment) and risk of tumor progression. Ultimately, a multidisciplinary approach should underpin all clinical decision-making in this challenging scenario.

Undifferentiated pleomorphic sarcoma of the breast with neoplastic fever: case report and genomic characterization.

PURPOSE: Primary breast sarcomas are extraordinary rare, in particular undifferentiated pleomorphic sarcoma (UPS). UPS with neoplastic fever (UPS-NF) of the breast has not been reported yet. Here, we present an extended UPS-NF of the breast including its comprehensive molecular workup. METHODS: A 58-year-old female presented with general malaise, fever spikes, weight loss, and a massively swollen left breast. C-reactive protein and blood leucocytes were significantly increased. However, repeated blood cultures and smears were all sterile. Histopathology of the abscess-forming tumor revealed an undifferentiated malignancy with numerous of tumor giant cells as well as spindle-shaped cells with nuclear pleomorphism and hyperchromasia. Immunohistochemistry demonstrated partial, patchy desmin staining and weak heterogonous neuron-specific enolase immunoreactivity of tumor cells, but a focal staining for Melan-A. RESULTS: Neither common melanoma driver mutations nor an ultraviolet mutational signature was detected by whole genome sequencing. Using FISH and RT-PCR we also excluded translocations characteristic for clear cell sarcoma. Thus, the diagnosis of inflammatory UPS-NF of the breast was considered highly probable. Despite a complete mastectomy, the tumor recurred after only three months. This recurrence was treated with a combination of ipilimumab and nivolumab based on the primary tumor's TPS score for PD-L1 of 30%. After an initial response, however, the tumor was progressive again. CONCLUSION: We describe here the first case of UPS-NF of the breast, which shows great clinical and histopathologic resemblances to previously reported UPS-NF of other anatomic localizations.

Prognostic Potential of the Baseline Pan-Immune-Inflammation Value and Neutrophil/Lymphocyte Ratio in Stage I to III Melanoma Patients.

Prognostic biomarkers derived from complete blood count (CBC) have received marked interest as an indirect measure of the inflammatory pressure in cancers such as metastatic melanoma. Here, we evaluated the novel pan-immune-inflammation value (PIV) and the frequently assessed neutrophil/lymphocyte ratio (NLR) in a large cohort of patients with cutaneous melanoma (CM) without distant metastases (stages I to III). PIV and NLR were calculated at CM diagnosis. Healthy controls were also included. We used the Kaplan-Meier method to estimate crude survival probabilities and used Cox proportional hazards regression for multiple adjustment of hazard ratios. We observed that higher PIV (HR: 1.72, 95% CI 1.14 to 2.58 and HR: 1.696, 95% CI 1.029 to 2.795, respectively) and NLR (HR: 1.70, 95% CI 1.10 to 2.62) values were associated with CM relapse and CM-specific death in the crude analysis. However, when adjusting for potential confounders, in particular age and tumor thickness, the total effect of PIV and NLR on CM-relapse-free (HR: 1.28, 95% CI 0.83 to 1.98 and HR: 1.26, 95% CI 0.80 to 1.98, respectively) and CM-specific survival (HR: 1.36, 95% CI 0.80 to 2.30 and HR: 1.37, 95% CI 0.80 to 2.33, respectively) was substantially reduced. However, both PIV and NLR were positively correlated with age and tumor thickness, which are important independent predictors for CM relapse and CM-specific death. In conclusion, in stage I to III CM patients PIV as well as NLR appear to be confounded by age and tumor thickness and probably have no potential to further improve the prediction of survival of stage I to III CM patients beyond standard prognostic factors.

Antibody-Negative Paraneoplastic Autoimmune Multiorgan Syndrome (PAMS) in a Patient with Follicular Lymphoma Accompanied by an Excess of Peripheral Blood CD8+ Lymphocytes.

Paraneoplastic autoimmune multiorgan syndrome (PAMS) is a life-threatening autoimmune disease associated with malignancies. Here, we present a patient initially misdiagnosed with "chronic" Stevens-Johnson syndrome. Over a year later, the patient was diagnosed with stage IV follicular lymphoma and treated with an anti-CD20 antibody. At this time, his skin condition had significantly worsened, with erythroderma and massive mucosal involvement, including in the mouth, nose, eyes, and genital region. Histopathology revealed lichenoid infiltrates with interface dermatitis, dyskeratoses, necrotic keratinocytes, and a dense CD8+ infiltrate with strong epidermotropism. Direct and indirect immunofluorescence tests for autoantibodies were negative. Remarkably, we retrospectively discovered a chronic increase in peripheral CD8+ lymphocytes, persisting for over a year. Consequently, the patient was diagnosed with antibody-negative PAMS. Three weeks later, he succumbed to respiratory failure. This dramatic case highlights the challenges in diagnosing PAMS, particularly in cases where immunofluorescence assays are negative. Importantly, we observed, for the first time, a chronic excess of CD8+ peripheral blood lymphocytes, associated with PAMS, consistent with the systemic, autoreactive T-cell-driven processes that characterize this condition.

Outcome of extracorporeal photopheresis in mycosis fungoides patients is not predicted by quotients of systemic immune-inflammatory biomarkers.

BACKGROUND: Systemic immune-inflammatory biomarkers (SIIBs) have not been studied in mycosis fungoides (MF) patients undergoing extracorporeal photopheresis (ECP). OBJECTIVE: The objective was to determine whether recently proposed SIIBs are suitable to predict ECP treatment outcome and overall prognosis of patients with MF. METHODS: Twenty-nine MF patients were retrospectively evaluated who had undergone ECP. SIIBs included neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and pan-immune-inflammation value. RESULTS: Lymphocyte count (P = .021), CD4+/CD8+ cells (P = .00006), CD4+/CD56+ NK cells (P = .00008), and LDH levels (P = .0041) significantly declined after 6-month ECP. We could not detect significant cutoff values for baseline SIIBs capable of predicting advanced disease, overall response to 6-month ECP, or 5-year lymphoma-specific (LS) survival (P > .05). Circulating baseline counts of CD4+/CD7- cells (cutoff: ≤ 12.2; P = .010) and CD4+/CD26- cells (cutoff: ≤ 19.5; P < .0001) significantly predicted ECP treatment response after 6 months. Moreover, CD4+/CD8+ ratio (cutoff: > 1.34; P = .045) and increased thrombocyte counts (cutoff: >259 000; P = .010) were baseline predictors for 5-year LS death. CONCLUSION: ECP appears to be beneficial in early-stage CTCL as well. Lower percentages of circulating CD4+/CD7- and CD4+/CD26- lymphocytes at baseline correlate with response to ECP. In this study, however, baseline SIIBs did not appear to serve as suitable biomarkers for the prediction of treatment outcome and LS survival.

Transcriptional changes in the mammary gland during lactation revealed by single cell sequencing of cells from human milk.

Under normal conditions, the most significant expansion and differentiation of the adult mammary gland occurs in response to systemic reproductive hormones during pregnancy and lactation to enable milk synthesis and secretion to sustain the offspring. However, human mammary tissue remodelling that takes place during pregnancy and lactation remains poorly understood due to the challenge of acquiring samples. We report here single-cell transcriptomic analysis of 110,744 viable breast cells isolated from human milk or non-lactating breast tissue, isolated from nine and seven donors, respectively. We found that human milk largely contains epithelial cells belonging to the luminal lineage and a repertoire of immune cells. Further transcriptomic analysis of the milk cells identified two distinct secretory cell types that shared similarities with luminal progenitors, but no populations comparable to hormone-responsive cells. Taken together, our data offers a reference map and a window into the cellular dynamics that occur during human lactation and may provide further insights on the interplay between pregnancy, lactation and breast cancer.

Impact of Extracorporeal Photopheresis on Blood Parameters of Atopic Dermatitis Patients.

BACKGROUND: Extracorporeal photopheresis (ECP) is a safe treatment modality with immunomodulatory effects. The latter may also explain efficacy of ECP in patients with atopic dermatitis (AD). OBJECTIVE: We aimed to assess various blood parameters of AD patients who underwent ECP over a maximum 1-year treatment period. METHODS: We performed a retrospective single-center chart review (clinical data, laboratory data) of adult patients with AD who had received for at least 3 ECP cycles, in part combined with other treatment modalities. RESULTS: We studied 60 patients with AD (85% extrinsic type, 15% intrinsic type) who had median number of 14 (4-23) ECP cycles within a maximum 1-year treatment. When compared with baseline, leukocytes and lymphocytes remained significantly decreased after 3-, 6-, 9-, and 12-month ECP ( P = 0.014 and P = 0.0012, respectively). A significant decline of eosinophils, as well as eosinophilic cationic protein levels, was observed after 3-, 6-, 9-, and 12-month ECPs ( P = 0.011 and P = 0.0017, respectively). Total serum immunoglobulin E (IgE), as well as lactate dehydrogenase, were significantly decreased at 3-, 6-, 9-, and 12-month evaluation compared with baseline ( P < 0.00001 and P = 0.00007, respectively). Patients with slight or marked improvement of AD after their ECP treatment period had significantly higher median baseline serum IgE levels than patients who did not respond to ECP ( P = 0.0023). CONCLUSIONS: Several laboratory parameters, including eosinophils, eosinophilic cationic protein, total serum IgE, and lactate dehydrogenase, which declined under ECP, are well-known disease biomarkers for AD patients. With normalization of the abovementioned laboratory parameters, a clinical response to ECP treatment was observed in almost two thirds of patients, confirming that ECP may be an effective combination treatment modality for AD.

Generation of ductal organoids from normal mammary luminal cells reveals invasive potential.

Here we present an experimental model for human luminal progenitor cells that enables single, primary cells isolated from normal tissue to generate complex branched structures resembling the ductal morphology of low-grade carcinoma of no special type. Thereby, we find that ductal structures are generated through invasive branching morphogenesis via matrix remodeling and identify reduced actomyosin contractility as a prerequisite for invasion. In addition, we show that knockout of E-cadherin causes a dissolution of duct formation as observed in invasive lobular carcinoma, a subtype of invasive carcinomas where E-cadherin function is frequently lost. Thus, our model shows that invasive capacity can be elicited from normal luminal cells in specific environments, which results in low-grade no special type morphology. This assay offers a platform to investigate the dynamics of luminal cell invasion and unravel the impact of genetic and non-genetic aberrations on invasive morphology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.