The effect of delay of excisional biopsy on upstage rate for atypical ductal hyperplasia, flat epithelial atypia, intraductal papilloma, and radial scar.

PURPOSE: When Core Needle Biopsy (CNB) demonstrates Atypical Ductal Hyperplasia (ADH), Flat Epithelial Atypia (FEA), Intraductal Papilloma (IDP), or Radial Scar/Complex Sclerosing Lesion (RS), excisional biopsy (EB) is often performed to rule out underlying malignancy with upstage rates (UR) ranging between 1 and 20%. The COVID-19 pandemic led to delayed EB for many patients. We sought to evaluate whether this delay was associated with higher UR. METHODS: We performed a retrospective analysis of women who underwent CNB and then EB for ADH, FEA, IDP, or RS between 2017 and 2021 using an IRB-approved repository. UR was evaluated by days between CNB and EB. RESULTS: 473 patients met inclusion. 55 were upstaged to cancer (11.6%). 178 patients had pure ADH on CNB and 37 were upstaged (20.8%). 50 patients had pure FEA and 3 were upstaged (6%). 132 had pure IDP and 7 were upstaged (5.3%). 98 had pure RS and 1 was upstaged (1%). 7/15 (46.7%) had a combination of diagnoses or diagnosis with palpable mass and were upstaged. Days between CNB and EB were < 60 for 275 patients (58.1%), 60-90 for 108 (22.8%), 91-120 for 43 (9.1%), and > 120 for 47 (9.9%). There was no significant difference in UR (10.9% for < 60, 14.8% for 60-90, 7% for 90-120, and 12.8% for > 120, p = 0.54). UR for ADH was clinically increased after 60 days (27.8 vs. 17.5%), but this did not reach statistical significance (p = 0.1). CONCLUSION: Surgical delay was not associated with an increased UR.

A Scoping Review of Treatment Outcome Measures for Vulvar Intraepithelial Neoplasia.

OBJECTIVE: The goal of this study is to identify a list of clinician-reported outcome measures (CROMs) and patient-reported outcome measures (PROMs) through a review of published studies reporting on any therapeutic interventions for vulvar intraepithelial neoplasia (VIN). MATERIALS AND METHODS: A systematic search of published studies reporting on any therapeutic interventions for VIN was performed on MEDLINE, Embase, Cochrane Database, PsychInfo, and CINAHL from inception to September 20, 2021, based on predetermined study selection criteria. Data were extracted and analyzed by 2 authors independently using Covidence software. RESULTS: Thirty two of 2386 studies identified met study selection criteria. None of the 32 studies provided an explicit definition of VIN treatment "success." The most common CROM was "clinical response to treatment." The most common scale used to measure this outcome was "complete response/partial response/no response"; however, 17 of 23 studies (73.9%) did not define these values. Laboratory CROMs were reported in 12/32 (37.5%) studies. Patient-reported outcome measures were reported in only 10 of 32 studies(31.3%) -the most common PROM was "symptoms." Only 2 of 32 studies measured PROMs related to "quality of life" domains. Adverse events/treatment-related adverse effects were reported in 24 of 32 studies (75%), although 71% of studies provided no details on how these data were collected. CONCLUSIONS: There is a large variation in outcome measures, instruments, and scales used for any clinician-reported treatment outcome such as "clinical response." Most studies do not include patient-reported outcome measures assessing quality of life domains. A Core Outcome Set for the treatment of VIN is needed to improve the quality of VIN research.

Dual spatially resolved transcriptomics for SARS-CoV-2 host-pathogen colocalization studies in humans (preprint)

To advance our understanding of cellular host-pathogen interactions, technologies that facilitate the co-capture of both host and pathogen spatial transcriptome information are needed. Here, we present an approach to simultaneously capture host and pathogen spatial gene expression information from the same formalin-fixed paraffin embedded (FFPE) tissue section using the spatial transcriptomics technology. We applied the method to COVID-19 patient lung samples and enabled the dual detection of human and SARS-CoV-2 transcriptomes at 55 m resolution. We validated our spatial detection of SARS-CoV-2 and identified an average specificity of 94.92% in comparison to RNAScope and 82.20% in comparison to in situ sequencing (ISS). COVID-19 tissues showed an upregulation of host immune response, such as increased expression of inflammatory cytokines, lymphocyte and fibroblast markers. Our colocalization analysis revealed that SARS-CoV-2 + spots presented shifts in host RNA metabolism, autophagy, NF{kappa}B, and interferon response pathways. Future applications of our approach will enable new insights into host response to pathogen infection through the simultaneous, unbiased detection of two transcriptomes.

Acantholytic Dyskeratosis Post-COVID Vaccination.

ABSTRACT: Acantholytic dyskeratosis mimicking Grover disease as a cutaneous manifestation of a side effect to the Moderna (mRNA-1273) COVID vaccine is rare with only one documented case in the literature to date. Herein, we present a case of an eruptive, erythematous, vesiculopapular rash developing in a patient after the Moderna vaccine. Histopathology of a representative biopsy [x2, done 8 weeks apart] of the rash revealed similar histopathologic findings of patchy suprabasal acantholysis with dyskeratotic keratinocytes and an underlying inflammatory infiltrate of lymphocytes and neutrophils. Direct immunofluorescence was negative. In contrast to the only case previously reported in the literature, a confounding feature in our case, was that patient had a medical history significant for Grover disease, which had been successfully treated with complete resolution and seemed to be in remission. Given the temporal relationship of the onset of the rash to vaccine administration, the changes were likely vaccine-related with the caveat that, in light of the medical history, the differential diagnosis includes reactivation of Grover disease by the vaccine as a trigger factor.

Patients with benign breast disease and breast cancer need more COVID-19 vaccines (preprint)

Albeit the efficacy of COVID-19 vaccines in immunocompromised patients is undermined, it is still found beneficial. Patients with cancer have a much lower COVID-19 vaccination rate globally, and the vaccination coverage in breast cancer patients in China remains elusive. A total of 23029 patients with benign breast diseases and breast cancers were included in the study, and the vaccination rates of patients with benign breast tumors and other benign breast diseases, nonmetastatic and metastatic breast cancer were 44.0%, 54.7%, 19.2% and 9.6%, respectively. Breast cancer in situ patients had a similar vaccination rate with patients with benign breast tumors (45.9% vs 44.0%) while those with invasive breast cancer had much lower vaccination rates. The overall vaccination rate remains meager in breast cancer patients, and gap was found in patients with lower clinical stage. Hence vaccination should be further promoted among patients with benign breast diseases and breast cancer.

Human Taste Cells Express ACE2: A Portal for SARS-CoV-2 Infection (preprint)

Loss and changes in taste and smell are well-reported symptoms of SARS-CoV-2 infection. The virus targets cells for entry by high affinity binding of its spike protein to cell-surface angiotensin-converting enzyme- 2 (ACE2). It was not known whether ACE2 is expressed on taste receptor cells (TRCs) nor if TRCs are infected directly. Using an in-situ hybridization (ISH) probe and an antibody specific to ACE2, it seems evident that ACE2 is present on a subpopulation of specialized TRCs, namely, PLC{beta}2 positive, Type II cells in taste buds in taste papillae. Fungiform papillae (FP) of a SARS-CoV-2+ patient exhibiting symptoms of COVID-19, including taste changes, were biopsied. Based on ISH, replicating SARS-CoV-2 was present in Type II cells of this patient. Therefore, taste Type II cells provide a portal for viral entry that predicts vulnerabilities to SARS-CoV-2 in the oral cavity. The continuity and cell turnover of the FP taste stem cell layer of the patient were disrupted during infection and had not fully recovered 6 weeks post symptom onset. Another patient suffering post-COVID-19 taste disturbances also had disrupted stem cells. These results indicate that a COVID-19 patient who experienced taste changes had replicating virus in their taste buds and that SARS-CoV-2 infection results in deficient stem cell turnover needed for differentiation into TRCs.

Fully digital pathology laboratory routine and remote reporting of oral and maxillofacial diagnosis during the COVID-19 pandemic: a validation study.

The role of digital pathology in remote reporting has seen an increase during the COVID-19 pandemic. Recently, recommendations had been made regarding the urgent need of reorganizing head and neck cancer diagnostic services to provide a safe work environment for the staff. A total of 162 glass slides from 109 patients over a period of 5 weeks were included in this validation and were assessed by all pathologists in both analyses (digital and conventional) to allow intraobserver comparison. The intraobserver agreement between the digital method (DM) and conventional method (CM) was considered almost perfect (κ ranged from 0.85 to 0.98, with 95% CI, ranging from 0.81 to 1). The most significant and frequent disagreements within trainees encompassed epithelial dysplasia grading and differentiation among severe dysplasia (carcinoma in situ) and oral squamous cell carcinoma. The most frequent pitfall from DM was lag in screen mirroring. The lack of details of inflammatory cells and the need for a higher magnification to assess dysplasia were pointed in one case each. The COVID-19 crisis has accelerated and consolidated the use of online meeting tools, which would be a valuable resource even in the post-pandemic scenario. Adaptation in laboratory workflow, the advent of digital pathology and remote reporting can mitigate the impact of similar future disruptions to the oral and maxillofacial pathology laboratory workflow avoiding delays in diagnosis and report, to facilitate timely management of head and neck cancer patients. Graphical abstract.

Hospitalizations, resource use and outcomes of acute pulmonary embolism in Germany during the Covid-19 pandemic - Emergence of different phenotypes of thrombotic disease? (preprint)

Background: There is discussion evolving around the emergence of different phenotypes of Covid-19-associated thromboembolic disease, i.e. acute pulmonary embolism vs pulmonary thrombosis and different phenotypes of in situ thrombosis. With this study, we wish to provide hospitalization, treatment and in-hospital outcome data for pulmonary embolism during the 2020 Covid-19 pandemic and a corresponding 2016-2019 control period. Methods: We performed a retrospective analysis of claims data of Helios hospitals in Germany. Consecutive cases with a hospital admission between January 1 and December 15, 2020 and pulmonary embolism as primary discharge diagnosis were analyzed and compared to a corresponding period covering the same weeks in 2016-2019. Results: As previously reported for other emergent medical conditions, there was a hospitalization deficit coinciding with the 1st pandemic wave. Beginning with the 12-week interval May 6 - July 28, there was a stable surplus of hospital admissions in 2020. During this surplus period (May 6 - December 15, 2020), there were 2,449 hospitalizations including 45 PCR-confirmed Covid-19 cases (1.8%) as opposed to 8,717 in 2016-2019 (IRR 1.12, 95% CI 1.07-1.18, P<0.01). When excluding Covid-19 cases IRR was 1.10 (95% CI 1.05-1.15, P<0.01). While overall comorbidities expressed as weighted AHRQ Elixhauser Comorbidity Index (14.1+/-10.1 vs. 13.9+/-10.3, P=0.28), the presence of thrombosis (46.1 vs 45.4%, P=0.55) and surgery (3.8 vs. 4.3%, P=0.33) were comparable, coagulopathy (3.3 vs 4.5%, P=0.01) and metastatic cancer (3.0 vs 4.0%, P=0.03) as contributing factors were less frequently observed during the 2020 surplus. Interventional treatments (thrombolytic therapy, thrombectomy or inferior vena cava filter placement) were less frequently used (4.7 vs 6.6%, OR 0.72, 95% CI 0.58-0.89, P< 0.01). Similarly, intensive care (35.1 vs 38.8%, OR 0.83, 95% CI 0.75-0.92, P< 0.01) and mechanical ventilation utilization (7.2 vs 8.1%, OR 0.88, 95% CI 0.74-1.04, P=0.14) as well as in-hospital-mortality rates (7.8 vs 9.8%, OR 0.76, 95% CI 0.64-0.90, P< 0.01) were lower in 2020 compared with 2016-2019. This was associated with a shorter length of hospital stay (6.4+/-5.4 vs. 7.2+/-5.7 days, P< 0.01) during the 2020 surplus period. Conclusions: Only a minority of cases were associated with PCR-confirmed Covid-19 but this does not rule out preceding or undetected SARS-CoV-2 infection. Although there is a shift towards milder disease course, the increased incidence of hospitalizations for pulmonary embolism requires immediate attention, close surveillance and further studies.

Molecular Detection of SARS-CoV-2 in Formalin Fixed Paraffin Embedded Specimens (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of human coronavirus disease 2019 (COVID-19), emerged in Wuhan, China in December 2019. The virus rapidly spread globally, resulting in a public-health crisis including more than one million cases and tens of thousands of deaths. Here, we describe the identification and evaluation of commercially available reagents and assays for the molecular detection of SARS-CoV-2 in infected formalin fixed paraffin embedded (FFPE) cell pellets. We identified a suitable rabbit polyclonal anti-SARS-CoV spike protein antibody and a mouse monoclonal anti-SARS-CoV nucleocapsid protein (NP) antibody for cross detection of the respective SARS-CoV-2 proteins by immunohistochemistry (IHC) and immunofluorescence assay (IFA). Next, we established RNAscope in situ hybridization (ISH) to detect SARS-CoV-2 RNA. Furthermore, we established a multiplex fluorescence ISH (mFISH) to detect positive-sense SARS-CoV-2 RNA and negative-sense SARS-CoV-2 RNA (a replicative intermediate indicating viral replication). Finally, we developed a dual staining assay using IHC and ISH to detect SARS-CoV-2 antigen and RNA in the same FFPE section. These reagents and assays will accelerate COVID-19 pathogenesis studies in humans and in COVID-19 animal models.