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).

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.

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.

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.

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.

Microbiota composition modulates inflammation and neointimal hyperplasia after arterial angioplasty.

BACKGROUND: Neointimal hyperplasia is a major contributor to restenosis after arterial interventions, but the genetic and environmental mechanisms underlying the variable propensity for neointimal hyperplasia between individuals, including the role of commensal microbiota, are not well understood. We sought to characterize how shifting the microbiome using cage sharing and bedding mixing between rats with differing restenosis phenotypes after carotid artery balloon angioplasty could alter arterial remodeling. METHODS: We co-housed and mixed bedding between genetically distinct rats (Lewis [LE] and Sprague-Dawley [SD]) that harbor different commensal microbes and that are known to have different neointimal hyperplasia responses to carotid artery balloon angioplasty. Sequencing of the 16S ribosomal RNA gene was used to monitor changes in the gut microbiome. RESULTS: There were significant differences in neointimal hyperplasia between non-co-housed LE and SD rats 14 days after carotid artery angioplasty (mean intima + media [I + M] area, 0.117 ± 0.014 mm2 LE vs 0.275 ± 0.021 mm2 SD; P < .001) that were diminished by co-housing. Co-housing also altered local adventitial Ki67 immunoreactivity, local accumulation of leukocytes and macrophages (total and M2), and interleukin 17A concentration 3 days after surgery in each strain. Non-co-housed SD and LE rats had microbiomes distinguished by both weighted (P = .012) and unweighted (P < .001) UniFrac beta diversity distances, although without significant differences in alpha diversity. The difference in unweighted beta diversity between the fecal microbiota of SD and LE rats was significantly reduced by co-housing. Operational taxonomic units that significantly correlated with average I + M area include Parabacteroides distasonis, Desulfovibrio, Methanosphaera, Peptococcus, and Prevotella. Finally, serum concentrations of microbe-derived metabolites hydroxyanthranilic acid and kynurenine/tryptophan ratio were significantly associated with I + M area in both rat strains independent of co-housing. CONCLUSIONS: We describe a novel mechanism for how microbiome manipulations affect arterial remodeling and the inflammatory response after arterial injury. A greater understanding of the host inflammatory-microbe axis could uncover novel therapeutic targets for the prevention and treatment of restenosis.

[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.

Human Papillomavirus Type 16 Induced Squamous Cell Carcinoma (In situ) of the Toes.

is missing (Short communication).

[Atypical variant of hand-foot-mouth disease]. / Atypische Hand-Fuß-Mund-Krankheit.

An atypical variant of hand-foot-mouth disease (HFMD) has sporadically been reported in recent years, with outbreaks in Europe, Asia, the USA and South America. A new lineage of Coxsackie virus A6 has been identified as the causative agent, a virus-type belonging to the group of enteroviruses. HFMD is transmitted through droplet infection or through faecal-oral transmission. The disease may begin with a prodromal stage and is often accompanied by fever and malaise. Typical skin findings include a papular and vesiculobullous exanthema that might be accompanied by confluent blisters (bullae), crusting, and ulceration. In contrast to "classic" HFMD, predilection sites include the dorsal aspects of the hands and feet, forearms, lower legs, neck and trunk. Oral lesions may be present, but are less often seen compared to "classic" HFMD. The course of the disease is self-limiting, with complete resolution usually within 7-14 days after disease onset. The treatment of atypical HFMD is usually symptomatic. A diagnosis of atypical HFMD might be challenging due to the polymorphous presentation of the disease. This review describes a rarely reported but more frequently diagnosed viral condition.

Testosterone treatment impacts the intestinal microbiome of transgender individuals.

Medical modulation of sex hormone levels is a cornerstone of treatment for many conditions that impact well-being, including cancer, fertility/infertility, gender dysphoria, and chronic metabolic diseases such as diabetes and obesity. The microbial residents of the intestine, known as the microbiota, interact with sex hormones in the intestine, and there is correlative evidence that this interaction is bidirectional. Based on these published findings, we hypothesized that transgender individuals receiving exogenous testosterone as part of their gender-affirming medical treatment might undergo changes in their intestinal microbiome. To test this, we collected 26 stool samples from nine individuals before and up to 8 months after initiation of treatment with exogenous testosterone and subjected these samples to metagenomic analysis. While no species were significantly associated with the duration of testosterone therapy, pathways that generate glutamate increased in abundance, while those that consume glutamate decreased. Glutamate is a precursor of arginine, and testosterone is known to increase levels of arginine and its metabolites in the plasma. We hypothesize that testosterone increases the uptake of glutamate by enterocytes, thus decreasing access of the microbiota to this amino acid. While this pilot study establishes the impact of testosterone therapy on the intestinal microbiome, a more comprehensive study is necessary to establish the impact of testosterone-driven metagenomic shifts on the stool metatranscriptome, the stool metabolome, and the plasma metabolome.IMPORTANCEThe human intestine is inhabited by a large community of microbes known as the microbiome. Members of the microbiome consume the diet along with their human host. Thus, the metabolomes of the host and microbe are intricately linked. Testosterone alters the plasma metabolome. In particular, plasma levels of arginine and its metabolites and testosterone are positively correlated. To investigate the impact of exogenous testosterone on the microbiome, we analyzed the stool metagenomes of transgender individuals before and after the initiation of testosterone treatment. In this pilot project, we found a modest impact on the microbiome community structure but an increase in the abundance of metabolic pathways that generate glutamate and spare glutamate consumption. We propose that the host uses glutamate to generate arginine, decreasing the amount available for the microbiome.

No beneficial use of the wearable cardioverter defibrillator among patients suffering from inherited and congenital heart disease: data from a European multicenter registry.

Background: Data on the use of the wearable cardioverter defibrillator in patients suffering from inherited and congenital heart disease are limited. Consequently, evidence for guideline recommendations in this patient population is lacking. Methods: In total 1,675 patients were included in a multicenter registry of eight European centers. In the present cohort, we included 18 patients suffering from congenital and inherited heart disease. Results: Nine patients (50%) were male with a mean age of 41.3 ± 16.4 years. Four patients suffered from hypertrophic cardiomyopathy (HCM), four patients suffered from non-compaction cardiomyopathy (NCCM), two patients were diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one patient suffered from muscular dystrophy of the limb-girdle type with cardiac involvement, secondary cardiomyopathy. Three patients presented with Brugada syndrome (BrS). One patient suffered from long-QT syndrome type 1 (LQTS1). Furthermore, two patients had congenital heart defects and one patient suffered from cardiac sarcoidosis (CS). There were no appropriate/inappropriate shocks with the WCD in this cohort. One patient had recurrent self-limiting sustained ventricular tachycardia during the wear time, but actively inhibited a shock and was hospitalized. The compliance rate in this cohort was 77.8% with a mean wear time of 45.3 ± 26.9 days with a mean follow-up time of 570 ± 734 days. 55.6% (10/18) of the patients received an ICD after WCD wear time. Conclusions: This retrospective study of patients with inherited and congenital heart disease shows that WCD use is not beneficial in the majority of patients with inherited and congenital heart disease.

Predictors of ventricular tachyarrhythmia in patients with a wearable cardioverter defibrillator: an international multicenter registry.

BACKGROUND AND AIMS: Wearable cardioverter defibrillator (WCD) can protect patients from sudden cardiac death due to ventricular tachyarrhythmias and serve as a bridge to decision of definite defibrillator implantation. The aim of this analysis from an international, multicenter WCD registry was to identify predictors of sustained ventricular tachycardia (VT) and/or ventricular fibrillation (VF) in this population. METHODS: One thousand six hundred seventy-five patients with WCD were included in a multicenter registry from 9 European centers, with a median follow-up of 440 days (IQR 120-893). The primary study end point was the occurrence of sustained VT/VF. RESULTS: Sustained VT was detected by WCD in 5.4% and VF in 0.9% of all patients. Of the 30.3% of patients receiving ICD implantation during follow-up, sustained VT was recorded in 9.3% and VF in 2.6%. Non-ischemic cardiomyopathy (HR 0.5, p < 0.001), and medication with angiotensin-converting enzyme inhibitors (HR 0.7, p = 0.027) and aldosterone antagonists (HR 0.7, p = 0.005) were associated with a significantly lower risk of VT/VF. CONCLUSIONS: Patients who received WCD due to a transient increased risk of sudden cardiac death have a comparatively lower risk of VT/VF in the presence of non-ischemic cardiomyopathy. Of note, optimal medical treatment for heart failure not only results in an improvement in left ventricular ejection fraction but also in a reduction in the risk for VT/VF.

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.