Eradication of skin microbiota restores cytokine production and release in polymorphic light eruption.

Polymorphic light eruption (PLE) has been mechanistically linked to cytokine abnormalities. Emerging preclinical evidence posits the skin microbiome as a critical modulator of ultraviolet (UV)-induced cytokine expression, thereby influencing subsequent immune responses. This intricate relationship remains underexplored in the context of PLE. Hence, we investigated the differential responses between disinfected and non-disinfected skin following both single and repetitive exposures to solar-simulated UV radiation in patients with PLE. An experimental, half-body pilot study was conducted involving six PLE patients and 15 healthy controls. Participants' skin was exposed to single and multiple doses of solar-simulated UV radiation, both in disinfected and in non-disinfected skin areas. The co-primary outcomes were PLE score and cytokine expression in blister fluid analysed through OLINK proteomic profiling. Secondary outcomes were erythema, pigmentation, induction of apoptotic cells in vacuum-generated suction blisters, and density of infiltrate in skin biopsies of PLE patients. Among the 71 cytokines analysed, baseline expression levels of 20 specific cytokines-integral to processes such as apoptosis, inflammation, immune cell recruitment, cellular growth, and differentiation-were significantly impaired in PLE patients compared with healthy controls. Notably, skin disinfection reversed the observed cytokine imbalances following a single UV exposure at the minimal erythema dose (MED) level and exhibited even more pronounced effects after multiple UV exposures. However, no significant differences were evident in PLE score, erythema, pigmentation, or rates of apoptotic cell induction upon UV radiation. These findings provide evidence for UV-driven cytokine regulation by the skin microbiota and imply microbiome involvement in the PLE immune response.

Evolution of characteristics and biologic treatment effectiveness in patients of the Austrian psoriasis registry from 2004-2022.

BACKGROUND AND OBJECTIVES: This study analyzed the extent to which the recent introduction of more effective treatments has led to an improvement in real-world psoriasis patients. PATIENTS AND METHODS: Patient characteristics and the first-year treatment effectiveness in biologic-naive patients have been analyzed since 2004 until now, irrespective of treatment switches. RESULTS: Data from 2,729 patients were eligible for this analysis. The proportion of female patients increased significantly over the years from 29.9% to 36.2% (p < 0.028), while the number of patients with psoriatic arthritis declined from 36.6% to 30.0% (p < 0.001). Moreover, the duration of psoriatic disease and PASI at the start of the treatment significantly decreased. Last observation carrief forward (LOCF) analysis indicated that PASI 90 response increased from 18.9 to 44.6% at 3 months and from 32.9 to 66.8% at 12 months after treatment started. Similary, the PASI ≤ 3 rates increased from 33.2% to 66.0% at 3 months and from 41.9% to 78.9% at 12 months after the treatment started. CONCLUSIONS: The continuous introduction of more efficient biologics has led to significant improvements in patient care and clinical outcomes. Though one out of three to five patients, depending on the endpoint selected, nowadays still does not achieve an entirely satisfactory treatment response (i.e., PASI 90 or PASI ≤ 3).

Rhabdoid tumors in patients conceived following ART: is there an association?

STUDY QUESTION: In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART? SUMMARY ANSWER: We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT. WHAT IS KNOWN ALREADY: Anecdotal evidence suggests an association of ART with RT. STUDY DESIGN, SIZE, DURATION: This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0-120 months) for children with RT_ART and 18.5 months (range 0-153 months) for the EU-RHAB control cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age). MAIN RESULTS AND THE ROLE OF CHANCE: The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0-66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0-253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205). LIMITATIONS, REASONS FOR CAUTION: RTs are very rare malignancies and our results are based on a small number of children with RT_ART. WIDER IMPLICATIONS OF THE FINDINGS: This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series. STUDY FUNDING/COMPETING INTEREST(S): M.C.F. is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.10, by the 'Deutsche Forschungsgemeinschaft' DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.05. We declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Narrowband-ultraviolet B vs Broadband-ultraviolet B in Treatment of Chronic Pruritus: A Randomized, Single-blinded, Non-inferiority Study.

Narrowband-ultraviolet B has shown increased efficacy over broadband-ultraviolet B in pruritic skin diseases, such as psoriasis and atopic dermatitis. In patients with chronic pruritus, e.g. in end-stage renal disease, broadband-ultraviolet B is recommended, but narrowband-ultraviolet B has also shown efficacy in reducing pruritus. This randomized, single blinded, non-inferiority study investigated the effects of narrowband-ultraviolet B compared with broadband-ultraviolet B. Patients with chronic pruritus were treated with either broadband- or narrowband-UVB 3 times a week for 6 weeks and clinical response was monitored. Pruritus, sleep disturbance, and the patients' subjective overall response to treatment were evaluated by the patients on a visual analogue scale (0-10). Skin excoriations were evaluated by investigators on a 4-point scale (0-3). Both phototherapeutic modalities showed significant antipruritic activity (itch reduction 48% and 66.4%, respectively) by broadband-ultraviolet B and narrowband-ultraviolet B. Narrowband-ultraviolet B proved to be not inferior to broadband-ultraviolet B in treating pruritus in patients with chronic pruritus, assuming a 20% non-inferiority margin.

Indications for surgical resection of complicated infantile hemangiomas in the ß-blocker's era: a single-institution experience from a retrospective cohort study.

BACKGROUND AND OBJECTIVES: This study aims to review how the introduction of propranolol as the primary treatment option for children with infantile hemangiomas (IHs) has affected the use of other treatment options at our institution and to determine the indications for surgical treatment of children with IHs in the propranolol era. PATIENTS AND METHODS: The authors conducted a single-center, noncompeting, historical/retrospective cohort study to review all cases referred to the institution for IH evaluation from 2005 to 2020. The authors analyzed the complete charts of patients who received surgery from 2011 to 2020 and evaluated the reasons for each surgical intervention. Detailed descriptive statistics are provided. Logistic regression analysis and Pearson's χ2 -test were applied. RESULTS: During the study period, 592 children received treatment. From 2011, oral propranolol ( n =268; 74%) and surgery ( n =95; 26%) were the only treatments of choice for complicated IH cases. A significant decrease in the frequency of surgical treatment was observed ( P =0.01). The authors identified four main indications for surgical treatment: (1) patients with ulceration and IH size appropriate for surgical resection (15%); (2) patients whose parents preferred surgical treatment (19%); (3) patients who presented late and underwent surgery before the age of three (29%); and (4) patients with sequelae after IH involution and excision after the third year of life (37%). CONCLUSIONS: Despite the significant decrease in the need for surgical treatment of children with IHs since the introduction of propranolol, there are still several clear indications for treating IH cases where surgery plays a crucial role.

Splint Duration and Not the Mode of Anesthesia Is the Main Factor Influencing Avascular Necrosis After Closed Reduction for Developmental Dysplasia of the Hip in Kosovo.

The aim of this study was to determine whether the use of analgesia and sedation (AS) as opposed to general anesthesia (GA) for closed reduction and spica casting of children with severe developmental dysplasia of the hip (DDH) influenced the long-term incidence of avascular necrosis (AVN). In a prospective, randomized, single-blinded clinical trial we investigated 100 pediatric patients with DDH type IIIa, IIIb, and IV (according to Graf classification), who were randomly assigned into the group receiving AS, and the group receiving GA. Baseline demographics, splint duration, and type of DDH were carefully assessed. The presence of AVN was assessed at the follow-up visits at 1 and 7 years after the end of treatment. The AS-group consisted of 50 patients (46 girls) with 76 hips affected (n = 11/Type-IIIa, n = 32/Type-IIIb, and n = 33/Type-IV). The GA-group consisted also of 50 patients (44 girls) with 78 hips involved (n = 15/Type-IIIa, n = 34/Type-IIIb, and n = 29/Type-IV). At 7-years follow-up, AVN was diagnosed in 9 of 154 hips (5.8%), 5 hips in the AS-group and 4 hips in the GA group. The logistic regression model showed no significant difference in AVN incidence between the AS and GA groups at 7-years follow-up (p = 0.27). The multivariate regression analysis showed that neither the type of DDH nor the age at diagnosis influenced the incidence of AVN (p = 0.48 and p = 0.28, respectively). Splint duration was identified as the only significant factor for the long-term incidence of AVN in the treatment of severe DDH. For every month of longer splint duration, the odds of AVN at 7-years follow-up increased by a factor of 3.81 (95%CI: 1.35-13.73, p = 0.02). Closed reduction and spica casting of children with severe DDH under AS can be considered a feasible alternative to management under GA. All efforts must be made to diagnose patients with DDH as early as possible and shorten the duration of splint treatment to prevent the development of AVN. Level of Evidence. Level II-1.

The Immune Deficiency and Dysregulation Activity (IDDA2.1 'Kaleidoscope') Score and Other Clinical Measures in Inborn Errors of Immunity.

Quantifying the phenotypic features of rare diseases such as inborn errors of immunity (IEI) helps clinicians make diagnoses, classify disorders, and objectify the disease severity at its first presentation as well as during therapy and follow-up. Furthermore, it may allow cross-sectional and cohort comparisons and support treatment decisions such as an evaluation for transplantation. On the basis of a literature review, we provide a descriptive comparison of ten selected scores and measures frequently used in IEI and divide these into three categories: (1) diagnostic tools (for Hyper-IgE syndrome, hemophagocytic lymphohistiocytosis, and Wiskott-Aldrich syndrome), (2) morbidity and disease activity measures (for common variable immune deficiency [CVID], profound combined immune deficiency, CTLA-4 haploinsufficiency, immune deficiency and dysregulation activity [IDDA], IPEX organ impairment, and the autoinflammatory disease activity index), and (3) treatment stratification scores (shown for hypogammaglobulinemia). The depth of preclinical and statistical validations varies among the presented tools, and disease-inherent and user-dependent factors complicate their broader application. To support a comparable, standardized evaluation for prospective monitoring of diseases with immune dysregulation, we propose the IDDA2.1 score (comprising 22 parameters on a 2-5-step scale) as a simple yet comprehensive and powerful tool. Originally developed for use in a retrospective study in LRBA deficiency, this new version may be applied to all IEI with immune dysregulation. Reviewing published aggregate cohort data from hundreds of patients, the IDDA kaleidoscope function is presented for 18 exemplary IEI as an instructive phenotype-pattern visualization tool, and an unsupervised, hierarchically clustered heatmap mathematically confirms similarities and differences in their phenotype expression profiles.

The value of MRI compared to conventional radiography in analysing morphologic changes in the spine in axial spondyloarthritis.

BACKGROUND: Imaging of morphologic changes in the vertebral spine in axial spondyloarthritis (SpA) is routinely performed with conventional radiography limited by superposition in the thoracic segments and radiation exposure. The objective was to assess the reliability of MRI compared to conventional radiography in depicting morphologic vertebral lesions in patients with axial SpA. Forty patients diagnosed with axial SpA were included in this cross-sectional study. Patients underwent MRI of the whole spine with T1-weighted and TIRM sequences in the sagittal plane and conventional radiography of the cervical and lumbar spine in lateral projections. Morphologic changes (syndesmophytes and erosions) in the anterior vertebral endplates on MRI and conventional radiography were independently evaluated by two radiologists. Inter-modality and interobserver agreement were calculated using Cohen's Kappa. RESULTS: Inter-modality agreement was low for cervical and lumbar syndesmophytes and erosions (κ ≤ 0.2 ± 0.07-0.1). Interobserver agreement on conventional radiography was highest for cervical and lumbar anterior syndesmophytes/bridging (κ = 0.92 ± 0.02-0.03). Syndesmophytes in thoracic anterior vertebral units were the most frequent MRI finding with a high interobserver agreement (κ = 0.83 ± 0.05). CONCLUSIONS: In imaging morphologic changes in the spine in patients with axial SpA, MRI was shown to be not an equivalent substitute but a complementary imaging modality to conventional radiography. Conventional radiography seems superior to depict morphologic cervical and lumbar vertebral changes compared to MRI, whereas MRI may visualise morphologic lesions in the thoracic spine.

Long-Term Course of Polymorphic Light Eruption: A Registry Analysis.

Background: Little is known about the long-term course of polymorphic light eruption (PLE). Objective: To predict disease course, a questionnaire was sent to patients whose PLE had been diagnosed between March 1990 and December 2018 and documented in the Austrian Cooperative Registry for Photodermatoses. Methods: In January 2019, 205 PLE patients were contacted by mail and asked to complete a questionnaire on their disease course, including whether the skin's sun sensitivity had normalized (i.e., PLE symptoms had disappeared), improved, stayed the same, or worsened over time. Patients who reported normalization of sun sensitivity were asked to report when it had occurred. Results: Ninety-seven patients (79 females, 18 males) returned a completed questionnaire. The mean (range) duration of follow-up from PLE onset was 29.6 (17-54) years for females and 29.4 (16-47) years for males. The disease disappeared in 32 (41%) females after 17.4 (2-41) years and in 4 (24%) males after 11.8 (5-26) years. Twenty-nine (37%) females and 6 (35%) males reported improvement of symptoms over time; 15 females (19%) and 7 males (41%) reported no change; and 3 females (4%) and no males reported worsening of symptoms. Kaplan-Meier analysis revealed that after 20 years 74% (95%CI, 64-82%) of patients still suffered from PLE. PLE lesion persistence (>1 week) tended to predict a prolonged course of PLE. Conclusions: PLE usually takes a long-term course over many years though in most patients its symptoms improve or disappear over time. How improvement relates to the pathophysiology of the disease remains to be determined.

Effectiveness and clinical predictors of drug survival in psoriasis patients receiving apremilast: A registry analysis.

BACKGROUND: Little is known about the effectiveness and drug survival associated with apremilast under real-world conditions. OBJECTIVE: To investigate the influence of patient and disease characteristics on drug survival associated with apremilast and to elucidate clinical effectiveness with regard to the psoriasis area and severity index (PASI) reduction. METHODS: This was an observational, retrospective, multicenter analysis from the Austrian Psoriasis Registry. RESULTS: Data from 367 patients were eligible for analysis. The 12-month drug survival rate associated with apremilast (ie, the proportion of patients on the drug) was 57.3% and decreased significantly in patients younger than 40 years (relative hazard ratio = 1.49, P = .007918). Sex; concomitant arthritis; previous biologic therapy; obesity; and palmoplantar, scalp, nail, and intertriginous involvement did not significantly affect drug survival. At 12 months, the response rates in patients receiving apremilast per protocol with a PASI of 50, 75, 90, and 100 were 80.0%, 56.4%, 38.2%, and 22.7%, respectively. LIMITATIONS: Inclusion of a substantial number of patients with no record of absolute PASI at study entry and lack of PASI reduction follow-up data of 103 patients (28.1%) after starting apremilast treatment. CONCLUSION: Apremilast is a robust antipsoriatic drug for which the drug survival is not strongly influenced by most patient- or disease-related factors except age. Drug survival is significantly shorter in patients younger than 40 years.

Higher cMET dependence of sacral compared to clival chordoma cells: contributing to a better understanding of cMET in chordoma.

Chordomas are rare slow growing, malignant bone tumors of the axial skeleton with no approved medical treatment. As the majority of chordomas express cMET and its ligand, HGF, and crosstalks between EGFR and MET-signaling exist, we aimed to explore cMET activity in chordoma cell lines and clinical samples. We investigated nine chordoma patients and four chordoma cell lines for cMET expression. Two clival and two sacral chordoma cell lines were tested for chromosomal abnormalities of the MET gene locus; we studied the influence of HGF on the autocrine secretion and migration behavior, as well as protein expression and phosphorylation. Two MET/ALK inhibitors were investigated for their effects on cell viability, cell cycle, cyclin alterations, apoptosis, and downstream signaling pathways. Moderate and strong expression of membrane and cytoplasmic cMET in chordoma patients and cell lines used, as well as concentration-dependent increase in phospho cMET expression after HGF stimulation in all four chordoma cell lines was shown. U-CH2, MUG-Chor1, and UM-Chor1 are polysomic for MET. Chordoma cell lines secreted EGF, VEGF, IL-6, and MMP9 upon HGF-stimulation. Sacral cell lines showed a distinct HGF-induced migration. Both inhibitors dose-dependently inhibited cell growth, induce apoptosis and cell-cycle arrest, and suppress downstream pathways. Heterogeneous responses obtained in our in vitro setting indicate that cMET inhibitors alone or in combination with other drugs might particularly benefit patients with sacral chordomas.

Contrast media dose adjustment to allometric parameters of body mass in multiphasic CT of the liver: A comparison of different metrics.

PURPOSE: To assess correlations of lean body weight (LBW) calculated with various formulas, total body weight (TBW), body height (BH), body mass index (BMI), body surface area (BSA) and fat-free mass (FFM) with vascular and parenchymal enhancement in multiphasic CT of the liver. METHOD: Thirty consecutive patients underwent multiphasic CT of the liver using constant iodine dose and flow rate. Contrast enhancement of aorta, portal vein and liver was calculated by measuring mean vascular and parenchymal attenuation in pre-contrast and post-contrast phases. Correlations of TBW, BH, BMI, BSA, FFM, and LBW (calculated with formulas of Boer, Hume, James and Green&Duffull) with enhancement were tested using Spearman's correlation coefficient. The method of Fieller et al. was used to calculate 95 % confidence intervals. A p-value ≤ 0.05 was considered statistically significant. RESULTS: Aortal enhancement correlated strongly with TBW, BSA, LBWBoer and LBWHume and moderately with BH, BMI, FFM, LBWJames and LBWGreen&Duffull. Liver enhancement in the late arterial phase correlated moderately with TBW, FFM, LBWBoer, LBWHume and LBWGreen&Duffull and weakly with BSA. Liver enhancement in the portal venous phase correlated strongly with TBW, BSA, FFM, LBWBoer, LBWHume and LBWGreen&Duffull, whereby overlap of the 95 % CI graphs demonstrated that the differences in the correlation coefficients were not statistically significant. Liver enhancement in the delayed phase correlated moderately with BH but did not correlate significantly with any other parameter. CONCLUSION: Regardless of the form used for calculation, LBW did not correlate statistically significantly stronger than TBW with vascular or parenchymal enhancement of the liver.

The clinical relevance of anti-dsDNA antibodies determined by the Elia™ dsDNA assay in patients with negative indirect immunofluorescence on the HEp-2 cell.

OBJECTIVES: Data on the clinical importance of the detection of anti-dsDNA antibodies in patients with negative indirect immunofluorescence on the HEp-2 cell (IIF) are sparse and are especially not available for all common commercially available assays. This study aimed to assess the clinical significance of anti-dsDNA antibodies determined by the Elia™ dsDNA assay in patients with negative IIF. METHODS: We retrospectively examined the medical records of 234 consecutive subjects with detectable anti-dsDNA antibodies determined by the Elia™ dsDNA assay. RESULTS: A total of 124 subjects with detectable anti-dsDNA autoantibodies were IIF-negative, but yielded positive or borderline results in the Elia™ CTD screen assay for antinuclear antibodies (ANA). Within this group, 6/49 IIF-negative patients (12%) with ANA-associated systemic autoimmune rheumatic disorders (AASARD) and 118/185 subjects (64%) with various other diseases (Non-AASARD) were identified. There was no statistically significant difference with regard to the concentrations of anti-dsDNA antibodies (p=0.53) between the AASARD and the Non-AASARD group. Within the AASARD group, four patients diagnosed with systemic lupus erythematosus (SLE, treated), discoid lupus erythematosus (untreated), indetermined connective tissue disease (untreated) and polymyositis (treated) had positive anti-dsDNA autoantibodies, whereas two patients with treated SLE, thereby one in remission, had borderline concentrations of anti-dsDNA antibodies. CONCLUSIONS: Our findings suggest that the detection of anti-dsDNA antibodies in IIF-negative patients can be of clinical relevance in some cases. Our results further support the combined use of IIF and solid-phase assays in screening algorithms for ANA, in order to avoid overlooking potentially important autoantibody entities.

High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group.

BACKGROUND: Knowledge on management of pediatric spinal cord low-grade glioma (LGG) is scarce. METHODS: We analyzed clinical datasets of 128 pediatric patients with spinal LGG followed within the prospective multicenter trials HIT-LGG 1996 (n = 36), SIOP-LGG 2004 (n = 56), and the subsequent LGG-Interim registry (n = 36). RESULTS: Spinal LGG, predominantly pilocytic astrocytomas (76%), harbored KIAA1549-BRAF fusion in 14/35 patients (40%) and FGFR1-TACC1 fusion in 3/26 patients (12%), as well as BRAFV600E mutation in 2/66 patients (3%). 10-year overall survival (OS) and event-free survival (EFS) was 93% ± 2% and 38% ± 5%, respectively. Disseminated disease (n = 16) was associated with inferior OS and EFS, while age ≥11 years and total resection were favorable factors for EFS. We observed 117 patients following total (n = 24) or subtotal/partial resection (n = 74), biopsy (n = 16), or radiologic diagnosis only (n = 3). Eleven patients were treated first with chemotherapy (n = 9) or irradiation (n = 2). Up to 20.8 years after diagnosis/initial intervention, 73/128 patients experienced one (n = 43) or up to six (n = 30) radiological/clinical disease progressions. Tumor resections were repeated in 36 patients (range, 2-6) and 47 patients required nonsurgical treatment (chemotherapy, n = 20; radiotherapy, n = 10; multiple treatment lines, n = 17). Long-term disease control for a median of 6.5 (range, 0.02-20) years was achieved in 73/77 patients following one (n = 57) or repeated (n = 16) resections, and in 35/47 patients after nonsurgical treatment. CONCLUSIONS: The majority of patients experienced disease progression, even after years. Multiple interventions were required for more than a third, yet multimodal treatment enabled long-term disease control. Molecular testing may reveal therapeutic targets.

Periodontal treatment and vascular inflammation in patients with advanced peripheral arterial disease: A randomized controlled trial.

BACKGROUND AND AIMS: Observational studies support an association between periodontitis and cardiovascular diseases. The study objective was to assess vascular inflammation after periodontal treatment in patients with peripheral arterial disease. METHODS: Ninety patients with peripheral arterial disease (PAD) and severe periodontitis were enrolled in a randomized, controlled trial. Thirty patients underwent non-surgical periodontal therapy and received additional systemic antibiotics (PT1 group), while 30 patients received the same therapy without antibiotics (PT2 group). The remaining thirty patients did not receive periodontal therapy (CG, control group). The primary outcome of this treatment was a reduction in vascular inflammation three months after periodontal treatment as determined by 18F-FDG PET/CT values. Secondary outcomes were changes in the inflamed periodontal surface area (PISA) and other periodontal parameters, changes in vascular biomarkers, and adverse cardiovascular events. RESULTS: After three months of treatment, a significant improvement in periodontal health was observed in the treatment groups. However, no difference in the primary outcome in the aorta was observed in the three study groups (median target to background ratio follow-up/baseline, PT1 1.00; 95% CI 0.97-1.10, PT2 1.00; 95% CI 0.98-1.1, CG 1.1; 95% CI 0.99-1.1, p = 0.75). No significant differences were detected in most diseased segments and active segments. In addition, no differences were observed in 18F-FDG uptake in the carotid, iliac, femoral, and popliteal arteries. No differences with regard to relative changes in vascular biomarkers were noted, and no serious cardiovascular adverse events occurred. CONCLUSIONS: Periodontal treatment was effective and safe but did not reduce vascular inflammation in patients with PAD.

Quality of Life, Anxiety, and Depression in Patients With Early-Stage Mycosis Fungoides and the Effect of Oral Psoralen Plus UV-A (PUVA) Photochemotherapy on it.

Background: Little is known about psychological discomfort and quality of life (QoL) in early stage mycosis fungoides (MF) and the effect of psoralen plus UV-A (PUVA) on it. Objective: To evaluate QoL, anxiety, and depression with validated instruments in early stage MF patients and whether PUVA treatment improves it. Methods: Patients with stage IA to IIA MF were treated with PUVA twice weekly for 12-24 weeks, followed by maintenance treatment or not, in a prospective randomized clinical trial. Patients completed a questionnaire on DLQI as well as the Hospital Anxiety and Depression Scale (HADS) prior to therapy, after their last PUVA exposure, and after the PUVA maintenance or observance phase. Results: For 24 patients with early stage MF, completed questionnaires were available and analyzed. Prior to treatment, 17% reported strong (DLQI > 10) and 29% moderate impairment (DLQI 6-10) in QoL; 33% of patients reported HADS scores indicating anxiety, and 21% reported scores indicating depression. PUVA significantly improved overall QoL by reducing mean DLQI scores by 58.6% (p = 0.003), HADS-A by 30% (p = 0.045), and HADS-D by 44% (p = 0.002). Improvements in QoL and psychological well-being seemed to be sustained, irrespective of maintenance treatment or not. Limitations: Small sample size. Conclusions: PUVA sustainably improves QoL and psychological well-being in patients with early stage MF. Clinical trial registration: ClinicalTrials.gov identifier: NCT01686594.

Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer.

Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. Abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood. Here, we analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non-small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was inferred from The Cancer Genome Atlas (TCGA) datasets. We found that PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. However, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3-dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin and hypoxia regulated both, glycolysis and gluconeogenesis, in NSCLC cells in vitro, albeit in opposite directions. PCK1/2 expression was enhanced in metastases compared to primary tumors, possibly related to the different environment. The results of this study show that glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co-activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.

Sensitive and broadly applicable residual disease detection in acute myeloid leukemia using flow cytometry-based leukemic cell enrichment followed by mutational profiling.

Persistent measurable residual disease (MRD) is an increasingly important prognostic marker in acute myeloid leukemia (AML). Currently, MRD is determined by multi-parameter flow cytometry (MFC) or PCR-based methods detecting leukemia-specific fusion transcripts and mutations. However, while MFC is highly operator-dependent and difficult to standardize, PCR-based methods are only available for a minority of AML patients. Here we describe a novel, highly sensitive and broadly applicable method for MRD detection by combining MFC-based leukemic cell enrichment using an optimized combinatorial antibody panel targeting CLL-1, TIM-3, CD123 and CD117, followed by mutational analysis of recurrently mutated genes in AML. In dilution experiments this method showed a sensitivity of 10-4 to 10-5 for residual disease detection. In prospectively collected remission samples this marker combination allowed for a median 67-fold cell enrichment with sufficient DNA quality for mutational analysis using next generation sequencing (NGS) or digital PCR in 39 out of 41 patients. Twenty-one samples (53.8%) tested MRD positive, whereas 18 (46.2%) were negative. With a median follow-up of 559 days, 71.4% of MRD positive (15/21) and 27.8% (5/18) of MRD negative patients relapsed (P = .007). The cumulative incidence of relapse (CIR) was higher for MRD positive patients (5-year CIR: 90.5% vs 28%, P < .001). In multivariate analysis, MRD positivity was a prominent factor for CIR. Thus, MFC-based leukemic cell enrichment using antibodies against CLL-1, TIM-3, CD123 and CD117 followed by mutational analysis allows high sensitive MRD detection and is informative on relapse risk in the majority of AML patients.