Hydrochlorothiazide and increased risk of atypical fibroxanthoma and pleomorphic dermal sarcoma.

BACKGROUND AND OBJECTIVES: Previous work has demonstrated that hydrochlorothiazide (HCTZ) is a risk factor for squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) due to pro-photocarcinogenic effects. Atypical fibroxanthoma (AFX) and pleomorphic sarcoma (PDS), both ultraviolet-induced cancers, display a rare but rising cutaneous tumor entity. This study aimed to evaluate if the use of HCTZ is higher in patients with AFX/PDS than in patients with SCC/BCC and subsequently may be a risk factor for AFX/PDS-development. PATIENTS AND METHODS: In a retrospective study of four German skin cancer centers, AFX/PDS cases and SCC/BCC controls were sex and age matched (1:3) over a time-period of 7 years (2013-2019) to evaluate the use of HCTZ, immunosuppressive medication, second malignancies, and presence of diabetes mellitus. RESULTS: Overall, 146 AFX/PDS and 438 controls (SCC/BCC) were included in the study. The use of HCTZ was significantly higher in patients with AFX/PDS (44.5%) compared to patients with SCC/BCC (25.3%). Additionally, the presence of diabetes mellitus was significantly higher in AFX/PDS patients. CONCLUSIONS: This study demonstrates a significantly higher use of HCTZ in patients with AFX/PDS compared to SCC/BCC. This result suggests that HCTZ may be a risk factor for AFX/PDS. Additionally, diabetes mellitus or its comorbidities may be associated with an increased risk for AFX/PDS.

A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma.

Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Patients were enrolled onto 2 of 3 planned cohorts (cohort 1 - rituximab/utomilumab/avelumab; cohort 2 - rituximab/ivuxolimab/utomilumab). 3+3 dose escalation was followed by dose expansion at the recommended phase 2 dose (RP2D). Twenty-four patients were enrolled (16 in cohort 1 and 9 in cohort 2, with one treated in both cohorts). No patients discontinued treatment due to adverse events and the RP2D was the highest dose level tested in both cohorts. In cohort 1, the objective and complete response rates were 44% and 19%, respectively (50% and 30%, respectively, at RP2D). In cohort 2, no responses were observed. The median progression-free survivals in cohorts 1 and 2 were 6.9 and 3.2 months, respectively. In cohort 1, higher density of PD-1+ tumor-infiltrating T-cells on baseline biopsies and lower density of 4-1BB+ and TIGIT+ T-cells in on-treatment biopsies were associated with response. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503).

A two-cohort study on the association between the gut microbiota and bone density, microarchitecture, and strength.

The gut microbiome affects the inflammatory environment through effects on T-cells, which influence the production of immune mediators and inflammatory cytokines that stimulate osteoclastogenesis and bone loss in mice. However, there are few large human studies of the gut microbiome and skeletal health. We investigated the association between the human gut microbiome and high resolution peripheral quantitative computed tomography (HR-pQCT) scans of the radius and tibia in two large cohorts; Framingham Heart Study (FHS [n=1227, age range: 32 - 89]), and the Osteoporosis in Men Study (MrOS [n=836, age range: 78 - 98]). Stool samples from study participants underwent amplification and sequencing of the V4 hypervariable region of the 16S rRNA gene. The resulting 16S rRNA sequencing data were processed separately for each cohort, with the DADA2 pipeline incorporated in the16S bioBakery workflow. Resulting amplicon sequence variants were assigned taxonomies using the SILVA reference database. Controlling for multiple covariates, we tested for associations between microbial taxa abundances and HR-pQCT measures using general linear models as implemented in microbiome multivariable association with linear model (MaAslin2). Abundance of 37 microbial genera in FHS, and 4 genera in MrOS, were associated with various skeletal measures (false discovery rate [FDR] ≤ 0.1) including the association of DTU089 with bone measures, which was independently replicated in the two cohorts. A meta-analysis of the taxa-bone associations further revealed (FDR ≤ 0.25) that greater abundances of the genera; Akkermansia and DTU089, were associated with lower radius total vBMD, and tibia cortical vBMD respectively. Conversely, higher abundances of the genera; Lachnospiraceae NK4A136 group, and Faecalibacterium were associated with greater tibia cortical vBMD. We also investigated functional capabilities of microbial taxa by testing for associations between predicted (based on 16S rRNA amplicon sequence data) metabolic pathways abundance and bone phenotypes in each cohort. While there were no concordant functional associations observed in both cohorts, a meta-analysis revealed 8 pathways including the super-pathway of histidine, purine, and pyrimidine biosynthesis, associated with bone measures of the tibia cortical compartment. In conclusion, our findings suggest that there is a link between the gut microbiome and skeletal metabolism.

Use of the Wearable Cardioverter-Defibrillator Among Patients With Myocarditis and Reduced Ejection Fraction or Ventricular Tachyarrhythmia: Data From a Multicenter Registry.

Background Data on the use of the wearable cardioverter-defibrillator (WCD) among patients with myocarditis remain sparse. Consequently, evidence for guideline recommendations in this patient population is lacking. Methods and Results In total, 1596 consecutive patients were included in a multicenter registry from 8 European centers, with 124 patients (8%) having received the WCD due to myocarditis and reduced left ventricular ejection fraction or prior ventricular tachyarrhythmia. The mean age was 51.6±16.3 years, with 74% being male. Patients were discharged after index hospitalization on heart failure medication: Angiotensin-converting enzyme inhibitors (62.5%), angiotensin-receptor-neprilysin inhibitor (22.9%), aldosterone-antagonists (51%), or beta blockers (91.4%). The initial median left ventricular ejection fraction was 30% (22%-45%) and increased to 48% (39%-55%) over long-term follow-up (P<0.001). The median BNP (brain natriuretic peptide) level at baseline was 1702 pg/mL (565-3748) and decreased to 188 pg/mL (26-348) over long-term follow-up (P=0.022). The mean wear time was 79.7±52.1 days and 21.0±4.9 hours per day. Arrhythmic event rates documented by the WCD were 9.7% for nonsustained ventricular tachycardia, 6.5% for sustained ventricular tachycardia, and 0% for ventricular fibrillation. Subsequently, 2.4% of patients experienced an appropriate WCD shock. The rate of inappropriate WCD shocks was 0.8%. All 3 patients with appropriate WCD shock had experienced ventricular tachycardia/ventricular fibrillation before WCD prescription, with only 1 patient showing a left ventricular ejection fraction <35%. Conclusions Patients with myocarditis and risk for occurrence of ventricular tachyarrhythmia may benefit from WCD use. Prior ventricular arrhythmia might appear as a better risk predictor than a reduced left ventricular ejection fraction <35% in this population.

Metagenomic assessment of gut microbial communities and risk of severe COVID-19.

BACKGROUND: The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional alterations in severe COVID-19, defined as acute respiratory or other organ failure. METHODS: We profiled 127 hospitalized patients with COVID-19 (n = 79 with severe COVID-19 and 48 with moderate) who collectively provided 241 stool samples from April 2020 to May 2021 to identify links between COVID-19 severity and gut microbial taxa, their biochemical pathways, and stool metabolites. RESULTS: Forty-eight species were associated with severe disease after accounting for antibiotic use, age, sex, and various comorbidities. These included significant in-hospital depletions of Fusicatenibacter saccharivorans and Roseburia hominis, each previously linked to post-acute COVID syndrome or "long COVID," suggesting these microbes may serve as early biomarkers for the eventual development of long COVID. A random forest classifier achieved excellent performance when tasked with classifying whether stool was obtained from patients with severe vs. moderate COVID-19, a finding that was externally validated in an independent cohort. Dedicated network analyses demonstrated fragile microbial ecology in severe disease, characterized by fracturing of clusters and reduced negative selection. We also observed shifts in predicted stool metabolite pools, implicating perturbed bile acid metabolism in severe disease. CONCLUSIONS: Here, we show that the gut microbiome differentiates individuals with a more severe disease course after infection with COVID-19 and offer several tractable and biologically plausible mechanisms through which gut microbial communities may influence COVID-19 disease course. Further studies are needed to expand upon these observations to better leverage the gut microbiome as a potential biomarker for disease severity and as a target for therapeutic intervention.

Zunahme des atypischen Fibroxanthoms und pleomorphen dermalen Sarkoms: eine retrospektive Analyse vier deutscher Hauttumorzentren.

HINTERGRUND UND ZIELE: In den letzten Jahren konnten umfassende Erkenntnisse über die Pathogenese, Diagnostik und Behandlung von kutanen Sarkomen, insbesondere des atypischen Fibroxanthoms (AFX) und pleomorphen dermalen Sarkoms (PDS) gesammelt werden. Beide Entitäten zeigten innerhalb der letzten Dekade steigende Inzidenzraten. Die vorliegende Studie diente der Untersuchung, welchen Einfluss die neuen Erkenntnisse auf die Fallzahlen von AFX/PDS im Vergleich zu anderen Sarkom-Entitäten haben. PATIENTEN UND METHODIK: Diese retrospektive Studie wurde an vier deutschen Hauttumorzentren durchgeführt und alle von zertifizierten Dermatopathologen bestätigten histopathologischen Befunde von kutanen Sarkomen (AFX, PDS, Dermatofibrosarcoma protuberans, kutanes Leiomyosarkom, Angiosarkom und Kaposi-Sarkom) in einem Zeitraum von sieben Jahren (2013-2019) evaluiert. Zusätzlich wurde der Einsatz von immunhistochemischen Markern als diagnostische Hilfe (Panzytokeratin, S100, Desmin, CD34, CD10, Prokollagen-1, CD99, CD14 und CD68) erfasst. ERGEBNISSE: Insgesamt konnten 255 kutane Sarkome in die vorliegende Studie eingeschlossen werden. Die Zahl der kutanen Sarkome nahm kontinuierlich von 2013 bis 2019 zu (von 16 auf 52 Fälle im Jahr). Die Diagnose eines AFX/PDS konnte in 2019 4,6-mal häufiger als in 2013 gestellt werden. Das AFX stellte mit 49,3 % aller kutanen Sarkome den häufigsten Sarkom-Subtypen dar. Zusätzlich war der Anstieg von AFX/PDS mit dem Einsatz von Immunhistochemie assoziiert. Der Einsatz von spezifischen Immunhistochemischen Markern stieg von 57,1 % im Jahr 2013 auf 100 % in 2019. SCHLUSSFOLGERUNGEN: Diese retrospektive Studie von vier deutschen Hauttumorzentren demonstriert eine substanzielle Zunahme von AFX/PDS, wahrscheinlich infolge kürzlich etablierter beziehungsweise verbesserter diagnostischer und terminologischer Standards. Dieser Anstieg ist vermutlich mit dem vermehrten Einsatz von bestimmten immunhistochemischen Markern assoziiert. AFX/PDS treten wahrscheinlich häufiger auf als bisher vermutet und repräsentieren möglicherweise den häufigsten kutanen Sarkom-Subtyp.

Increase of atypical fibroxanthoma and pleomorphic dermal sarcoma: a retrospective analysis of four German skin cancer centers.

BACKGROUND AND OBJECTIVES: In recent years, considerable insight has been gained into the pathogenesis, diagnosis and treatment of cutaneous sarcomas, including atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). Both entities have shown increasing incidence rates in the last decade. This study was initiated to evaluate how these new insights impact the number of diagnoses of AFX/PDS compared to other cutaneous sarcoma entities. PATIENTS AND METHODS: In a retrospective study of four German skin cancer centers, all histopathological reports of cutaneous sarcomas (AFX, PDS, dermatofibrosarcoma protuberans, cutaneous leiomyosarcoma, angiosarcoma, and Kaposi sarcoma) confirmed by board-certified dermatopathologists were analyzed during a time-period of seven years (2013-2019). Additionally, utilization of immunohistochemical markers (including pan-cytokeratin, S100, desmin, CD34, CD10, procollagen-1, CD99, CD14, and CD68) as an adjunct to diagnose AFX/PDS was recorded. RESULTS: Overall, 255 cutaneous sarcomas were included in the present study. The diagnosis of a cutaneous sarcoma has consequently risen from 2013 to 2019 (from 16 to 52 annual cases). The results of AFX/PDS revealed 4.6 times more diagnoses in 2019 than in 2013. Atypical fibroxanthoma represented the most common subtype, displaying 49.3 % of all diagnosed cutaneous sarcomas. Additionally, the increase of AFX/PDS was linked to the use of immunohistochemistry, with specific immunohistochemical markers used in 57.1 % of cases in 2013 compared to 100 % in 2019. CONCLUSIONS: This retrospective study of four German skin cancer centers demonstrates a substantial rise of AFX/PDS, possibly due to recently established diagnostic and terminology standards. This rise is probably linked to increased utilization of specific immunohistochemical markers. Atypical fibroxanthoma/PDS may be more common than previously thought and seems to represent the most frequent cutaneous sarcoma subtype.

Metagenomic assessment of gut microbial communities and risk of severe COVID-19.

The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional alterations in severe COVID-19, defined as acute respiratory or other organ failure. We profiled 127 hospitalized patients with COVID-19 (n=79 with severe COVID-19 and 48 with moderate) who collectively provided 241 stool samples from April 2020 to May 2021 to identify links between COVID-19 severity and gut microbial taxa, their biochemical pathways, and stool metabolites. 48 species were associated with severe disease after accounting for antibiotic use, age, sex, and various comorbidities. These included significant in-hospital depletions of Fusicatenibacter saccharivorans and Roseburia hominis, each previously linked to post-acute COVID syndrome or "long COVID", suggesting these microbes may serve as early biomarkers for the eventual development of long COVID. A random forest classifier achieved excellent performance when tasked with predicting whether stool was obtained from patients with severe vs. moderate COVID-19. Dedicated network analyses demonstrated fragile microbial ecology in severe disease, characterized by fracturing of clusters and reduced negative selection. We also observed shifts in predicted stool metabolite pools, implicating perturbed bile acid metabolism in severe disease. Here, we show that the gut microbiome differentiates individuals with a more severe disease course after infection with COVID-19 and offer several tractable and biologically plausible mechanisms through which gut microbial communities may influence COVID-19 disease course. Further studies are needed to validate these observations to better leverage the gut microbiome as a potential biomarker for disease severity and as a target for therapeutic intervention.

Differences of the Nasal Microbiome and Mycobiome by Clinical Characteristics of COPD Patients.

Rationale: While studies suggest that the lung microbiome may influence risk of chronic obstructive pulmonary disease (COPD) exacerbations, little is known about the relationship between the nasal biome and clinical characteristics of COPD patients. Methods: We sampled the nasal lining fluid by nasosorption of both nares of 20 people with moderate-to-severe COPD. All 40 samples, plus 4 negative controls, underwent DNA extraction, and 16SV4 ribosomal RNA (rRNA) (bacterial) and ribosomal internal transcribed spacer 2 (ITS2) (fungal) sequencing. We measured the proportion of variance (R2) in beta diversity explained by clinical factors, including age, sex, body mass index (BMI), COPD treatment, disease severity (forced expiratory volume in 1 second [FEV1], symptom/exacerbation frequency), peripheral eosinophil level (≥150 versus <150 cells/µL) and season of sampling, with the PERMANOVA test on the Bray-Curtis dissimilarities, accounting for within-person correlation of samples. We assessed the relative abundance of microbial features in the nasal community and their associations with clinical characteristics using the Microbiome Multivariable Association with Linear Models (MaAsLin2) package. Results: The most abundant nasal fluid bacterial taxa were Corynebacterium, Staphylococcus, Streptococcus, Moraxella, and Dolosigranulum, and fungal taxa were Malassezia, Candida, Malasseziales, Cladosporium and Aspergillus. Bacterial microbiome composition was associated with short-acting muscarinic antagonist use (R2 11.8%, p=0.002), sex (R2 8.3%, p=0.044), nasal steroid use (R2 7.7%, p=0.064), and higher eosinophil level (R2 7.6%, p=0.084). Mycobiome composition was associated with higher eosinophil level (R2 14.4%, p=0.004) and low FEV1 (R2 7.5%, p=0.071). No specific bacterium or fungus differed significantly in relative abundance by clinical characteristics in the multivariate per-feature analysis. Conclusion: The taxonomical composition of the nasal biome is heterogeneous in COPD patients and may be explained in part by clinical characteristics.

Human threat learning is associated with gut microbiota composition.

The ability to learn about threat and safety is critical for survival. Studies in rodent models have shown that the gut microbiota can modulate such behaviors. In humans, evidence showing an association with threat or extinction learning is lacking. Here, we tested whether individual variability in threat and extinction learning was related to gut microbiota composition in healthy adults. We found that threat, but not extinction learning, varies with individuals' microbiome composition. Our results provide evidence that the gut microbiota is associated with excitatory threat learning across species.

Avoiding implantation of a cardioverter-defibrillator by bridging with wearable defibrillator vest.

BACKGROUND: Patients with a left ventricular ejection fraction (LVEF) ≤35% should be protected from sudden cardiac death with an implantable cardioverter-defibrillator (ICD). The onset of the effect of optimal medical therapy (OMT) is unclear, and a wearable cardioverter-defibrillator (WCD) can bridge this period. PATIENTS AND METHODS: Our study analyzed 104 patients (age, 68.9 ± 11.7 years; 81% [84/104] male) whose first diagnosis included an LVEF <35%. After exclusion of reversible causes for LVEF reduction and initiation/adjustment of the OMT, the WCD was employed. The LVEF and indication for ICD were re-evaluated after 62 ± 36 days. The LVEF development and implantation rate were correlated with underlying disease (ischemic [ICM] or nonischemic cardiomyopathy [NICM]), comorbidities, and age/gender. RESULTS: The wearing time of the WCD was 22.8 ± 1.9 h/day. An LVEF improvement from 28.5 ± 6.4% to 40 ± 11.7% was achieved through OMT (p < 0.0001). An improvement in LVEF of up to more than 35% was achieved in 66 of 104 patients (63%), and only 37% of patients were subsequently given an ICD. This affected 41% of patients with ICM and 30% of patients with NICM (p = 0.205). Notably, no ICD interventions were observed over 362 ± 89.5 days after implantation in the ICD-receiver group. CONCLUSION: The indication for ICD can be re-evaluated after 2 months. Patients with NICM respond better to OMT compared with ICM patients. The LVEF recovered to >35% in >60% of cases.

Acquired lymphangioma circumscriptum in high-grade penile intraepithelial neoplasia.

Lymphangioma circumscriptum (LC) is a rare, benign vascular malformation induced by abnormal lymphatic vessels of the skin. LC might be either congenital or acquired, and is predominantly located on the trunk, buttock, axillary region, or thighs. Penile LC is rare. This case report describes a patient with acquired LC associated with high-grade penile intraepithelial neoplasia induced by human papillomavirus type 66. As the patient had multifocal lesions on the glans penis and prepuce we decided to perform circumcision, followed by electrocoagulation of the lesions on the glans. Electrocautery should be considered as a first choice for treatment of LC located at surgically challenging regions such as the glans penis.

[Squamous cell carcinoma arising in oral lichen planus : Report of two cases]. / Plattenepithelkarzinom auf dem Boden eines oralen Lichen planus : Bericht zweier Fälle.

Lichen planus is a chronic inflammatory, immunologically mediated mucocutaneous dermatosis. Lichen planus mucosae predominantly affects the oral cavity. Various trigger factors such as bacterial or viral infections, drugs or physical stimuli are discussed in the development of the disease. An association with human papillomavirus infections has also been described, but is not sufficiently proven. Lichen planus mucosae is considered as a premalignant condition, but the malignant transformation rate is low. The risk of malignant transformation is significantly increased in patients with oral lichen planus who smoke, drink alcohol or have hepatitis C. We describe two patients with locally advanced squamous cell carcinoma that developed on a longstanding oral lichen planus. Both cases were successfully treated with radical tumor resection, subsequent tissue reconstruction, and adjuvant radiation/radiochemotherapy.