Stress signalling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa.

BACKGROUND: The pathogenetic factors generating the innate immune signal necessary for T-cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that a defective keratinocyte function critically contributes to HS disease development and progression. OBJECTIVES: To elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of lesional and perilesional epidermis isolated from HS patients by RNA sequencing (RNA Seq). METHODS: Pairwise-matched lesional and perilesional HS skin samples of five different donors were obtained and epidermal keratinocytes freshly isolated and processed for RNA extraction and RNA seq. Lesionally regulated genes were analysed by large-scale promoter analysis and functional annotation clustering to identify epidermally overrepresented transcription factor binding sites and functionally related gene groups. Results were experimentally validated with independent epidermal isolates of patient-matched lesional and perilesional HS skin employing qRT-PCR, cell culture, immunoblot and immunostaining. RESULTS: We show that HS is characterized by a strong epidermal stress state evident by a significant overrepresentation of an AP-1-driven gene signature and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFNγ production and triggered expression of key inflammatory genes coordinating innate immune activation and the adaptive T-cell response in HS. CONCLUSIONS: Our data implicate a key role of stress signalling and JAK/STAT1 activation in disease progression of HS and suggest interference with JAK/STAT1 signalling as a potentially promising therapeutic approach for HS.

[Epidemiology, patient quality of life, and treatment costs of hidradenitis suppurativa/acne inversa]. / Epidemiologie, Patientenlebensqualität und Behandlungskosten der Hidradenitis suppurativa/Acne inversa.

Hidradenitis suppurativa/acne inversa (HS) is associated with numerous and relevant restrictions on the quality of life for those affected and their relatives. The exact prevalence of HS varies significantly across studies, but it is likely to be higher than suggested in previous publications. HS care is associated with high costs for the healthcare system and for those affected. The introduction of biologic therapy has led to additional costs, but also to considerable additional benefits in terms of care. In view of the complexity of diagnostics and therapy, there is a particular need for optimized care concepts in order to reduce the burden on those affected, their relatives and the healthcare system.

Partial-volume correction in dynamic PET-CT: effect on tumor kinetic parameter estimation and validation of simplified metrics.

BACKGROUND: Partial-volume effects generally result in an underestimation of tumor tracer uptake on PET-CT for small lesions, necessitating partial-volume correction (PVC) for accurate quantification. However, investigation of PVC in dynamic oncological PET studies to date is scarce. The aim of this study was to investigate PVC's impact on tumor kinetic parameter estimation from dynamic PET-CT acquisitions and subsequent validation of simplified semi-quantitative metrics. Ten patients with EGFR-mutated non-small cell lung cancer underwent dynamic 18F-fluorothymidine PET-CT before, 7 days after, and 28 days after commencing treatment with a tyrosine kinase inhibitor. Parametric PVC was applied using iterative deconvolution without and with highly constrained backprojection (HYPR) denoising, respectively. Using an image-derived input function with venous parent plasma calibration, we estimated full kinetic parameters VT, K1, and k3/k4 (BPND) using a reversible two-tissue compartment model, and simplified metrics (SUV and tumor-to-blood ratio) at 50-60 min post-injection. RESULTS: PVC had a non-linear effect on measured activity concentrations per timeframe. PVC significantly changed each kinetic parameter, with a median increase in VT of 11.8% (up to 25.1%) and 10.8% (up to 21.7%) without and with HYPR, respectively. Relative changes in kinetic parameter estimates vs. simplified metrics after applying PVC were poorly correlated (correlations 0.36-0.62; p < 0.01). PVC increased correlations between simplified metrics and VT from 0.82 and 0.81 (p < 0.01) to 0.90 and 0.88 (p < 0.01) for SUV and TBR, respectively, albeit non-significantly. PVC also increased correlations between treatment-induced changes in simplified metrics vs. VT at 7 (SUV) and 28 (SUV and TBR) days after treatment start non-significantly. Delineation on partial-volume corrected PET images resulted in a median decrease in metabolic tumor volume of 14.3% (IQR - 22.1 to - 7.5%), and increased the effect of PVC on kinetic parameter estimates. CONCLUSION: PVC has a significant impact on tumor kinetic parameter estimation from dynamic PET-CT data, which differs from its effect on simplified metrics. However, it affected validation of these simplified metrics both as single measurements and as biomarkers of treatment response only to a small extent. Future dynamic PET studies should preferably incorporate PVC. TRIAL REGISTRATION: Dutch Trial Register, NTR3557 .

Validation of [18F]FLT as a perfusion-independent imaging biomarker of tumour response in EGFR-mutated NSCLC patients undergoing treatment with an EGFR tyrosine kinase inhibitor.

BACKGROUND: 3'-Deoxy-3'-[18F]fluorothymidine ([18F]FLT) was proposed as an imaging biomarker for the assessment of in vivo cellular proliferation with positron emission tomography (PET). The current study aimed to validate [18F]FLT as a perfusion-independent PET tracer, by gaining insight in the intra-tumoural relationship between [18F]FLT uptake and perfusion in non-small cell lung cancer (NSCLC) patients undergoing treatment with a tyrosine kinase inhibitor (TKI). Six patients with metastatic NSCLC, having an activating epidermal growth factor receptor (EGFR) mutation, were included in this study. Patients underwent [15O]H2O and [18F]FLT PET/CT scans at three time points: before treatment and 7 and 28 days after treatment with a TKI (erlotinib or gefitinib). Parametric analyses were performed to generate quantitative 3D images of both perfusion measured with [15O]H2O and proliferation measured with [18F]FLT volume of distribution (V T ). A multiparametric classification was performed by classifying voxels as low and high perfusion and/or low and high [18F]FLT V T using a single global threshold for all scans and subjects. By combining these initial classifications, voxels were allocated to four categories (low perfusion-low V T , low perfusion-high V T , high perfusion-low V T and high perfusion-high V T ). RESULTS: A total of 17 perfusion and 18 [18F]FLT PET/CT scans were evaluated. The average tumour values across all lesions were 0.53 ± 0.26 mL cm- 3 min- 1 and 4.25 ± 1.71 mL cm- 3 for perfusion and [18F]FLT V T , respectively. Multiparametric analysis suggested a shift in voxel distribution, particularly regarding the V T : from an average of ≥ 77% voxels classified in the "high V T category" to ≥ 85% voxels classified in the "low V T category". The shift was most prominent 7 days after treatment and remained relatively similar afterwards. Changes in perfusion and its spatial distribution were minimal. CONCLUSION: The present study suggests that [18F]FLT might be a perfusion-independent PET tracer for measuring tumour response as parametric changes in [18F]FLT uptake occurred independent from changes in perfusion. TRIAL REGISTRATION: Nederlands Trial Register (NTR), NTR3557 . Registered 2 August 2012.

Outcomes of concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer and significant comorbidity.

BACKGROUND: published trials of concurrent chemoradiotherapy (CCRT) in stage III non-small-cell lung cancer (NSCLC) generally excluded patients with significant comorbidity. We evaluated outcomes in patients who were selected by using radiation planning parameters and were considered, despite comorbidity, fit enough to receive cisplatin-based chemotherapy. PATIENTS AND METHODS: from 2003 to 2008, 89 patients with stage III NSCLC fit to receive cisplatin-based chemotherapy and a V(20) <42% underwent CCRT at one center outside clinical trials. Most received one cycle of cisplatin-gemcitabine, followed by two to three cycles of cisplatin-etoposide concurrent with involved-field thoracic radiotherapy between 46 and 66 Gy. RESULTS: median age was 64 years; performance status (PS) of zero, one or two in 20/64/5 patients; one or more comorbidities in 41.6%; 14% were treated previously for NSCLC. Median V(20) was 26.6% (range 4%-39.4%). Grade III esophagitis and pneumonitis occurred in 28.1% and 7.9% of patients, respectively, while 4.5% died during treatment. Median overall survival was 18.2 months [95% confidence interval (CI) 13.1-23.3 months]. Independent prognostic factors for overall survival were PS (0 versus ≥ 1, P = 0.041) and planning target volume (P = 0.022). CONCLUSIONS: patients with significant comorbidity who are fit to undergo cisplatin-based CCRT achieve median survivals similar to that reported in phase III trials and with relatively few late toxic effects.