Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization - systematic review and recommendations from the HS ALLIANCE working group.

Hidradenitis suppurativa (HS)/acne inversa is a debilitating chronic disease that remains poorly understood and difficult to manage. Clinical practice is variable, and there is a need for international, evidence-based and easily applicable consensus on HS management. We report here the findings of a systematic literature review, which were subsequently used as a basis for the development of international consensus recommendations for the management of patients with HS. A systematic literature review was performed for each of nine clinical questions in HS (defined by an expert steering committee), covering comorbidity assessment, therapy (medical, surgical and combinations) and response to treatment. Included articles underwent data extraction and were graded according to the Oxford Centre for Evidence-based Medicine criteria. Evidence-based recommendations were then drafted, refined and voted upon, using a modified Delphi process. Overall, 5310 articles were screened, 171 articles were analysed, and 65 were used to derive recommendations. These articles included six randomized controlled trials plus cohort studies and case series. The highest level of evidence concerned dosing recommendations for topical clindamycin in mild disease (with systemic tetracyclines for more frequent/widespread lesions) and biologic therapy (especially adalimumab) as second-line agents (following conventional therapy failure). Good-quality evidence was available for the hidradenitis suppurativa clinical response (HiSCR) as a dichotomous outcome measure in inflammatory areas under treatment. Lower-level evidence supported recommendations for topical triclosan and oral zinc in mild-to-moderate HS, systemic clindamycin and rifampicin in moderate HS and intravenous ertapenem in selected patients with more severe disease. Intralesional or systemic steroids may also be considered. Local surgical excision is suggested for mild-to-moderate HS, with wide excision for more extensive disease. Despite a paucity of good-quality data on management decisions in HS, this systematic review has enabled the development of robust and easily applicable clinical recommendations for international physicians based on graded evidence.

Personality and behavioural changes do not precede memory problems as possible signs of dementia in ageing people with Down syndrome.

OBJECTIVE: The objective was to find out whether changes in personality and adaptive functioning or memory processes decline first in ageing people with Down syndrome. METHODS: We measured these variables cross-sectionally in a Dutch sample (22 to 62 years of age) of 68 institutionalised people with Down syndrome. RESULTS: The scores on all the variables except one of the temperament scales were found to decline gradually with increasing age, but deterioration of episodic memory started earlier. CONCLUSIONS: We argued that a subset of our sample suffered from dementia. Furthermore, the data suggested that immediate memory impairment is one of the earliest signs of the disease in people with Down syndrome, just as it is in the general population. Copyright © 2016 John Wiley & Sons, Ltd.

Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum.

BACKGROUND: Treatment of hidradenitis suppurativa (HS) is difficult and the search for effective therapies continues. OBJECTIVES: To evaluate the efficacy of ustekinumab and to discover a potential biomarker for HS. METHODS: Seventeen patients were included in this open-label study and treated with 45 or 90 mg ustekinumab at weeks 0, 4, 16 and 28. Proteomic technology and enzyme-linked assay analysis was applied to sera. RESULTS: Twelve patients completed the protocol. Moderate-to-marked improvement of the modified Sartorius score was achieved in 82% of patients at week 40 and the Hidradenitis Suppurativa Clinical Response 50 in 47%. With regard to the expression of 54 serum proteins, at baseline, a significant difference was observed between patients and healthy controls. Involved pathways were related to inflammation, immune cell signalling and tissue morphology/development. Good responders had milder disease and lower expression of leukotriene A4-hydrolase (LTA4H). Interleukin (IL)-2R, tumour necrosis factor-α, IL-17A and IL-17F were not elevated and did not change during treatment. CONCLUSIONS: The majority of patients improved with ustekinumab. Although no biomarker was discovered, low LTA4H concentrations with mild disease severity may be predictive of the effectiveness of ustekinumab.

Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP): a surgical treatment option for severe hidradenitis suppurativa Hurley stage II/III.

BACKGROUND: Surgery is the only curative treatment for removal of the persistent sinus tracts in the skin that are characteristic of severe hidradenitis suppurativa (HS). Complete resection of the affected tissue by wide excision is currently regarded as the preferred surgical technique in these cases. However, relatively large amounts of healthy tissue are removed with this method and suitable skin-tissue-saving techniques aiming at creating less-extensive surgical defects are therefore needed in severe HS. METHOD: We describe a skin-tissue-saving surgical technique for HS Hurley stage II-III disease: the Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP) procedure. DISCUSSION: In contrast to wide excisions that generally reach into the deep subcutaneous fat, the fat is maximally spared with the STEEP procedure by performing successive tangential excisions of lesional tissue until the epithelialized bottom of the sinus tracts has been reached. From here, secondary intention healing can occur. In addition, fibrotic tissue is completely removed in the same manner as this also serves as a source of recurrence. This tissue-sparing technique results in low recurrence rates, high patient satisfaction with relatively short healing times and favourable cosmetic outcomes without contractures.

Surgery under general anaesthesia in severe hidradenitis suppurativa: a study of 363 primary operations in 113 patients.

BACKGROUND: Treatment of hidradenitis suppurativa (HS) is a difficult undertaking, especially as there is no consensus on what surgical technique is preferred. At our centre severe HS (Hurley II/III) is operated under general anaesthesia, mostly with the STEEP procedure. OBJECTIVES: To investigate characteristics, surgical outcomes and patient satisfaction of HS patients who underwent deroofing or STEEP under general anaesthesia. METHODS: A clinical records-based retrospective analysis was conducted of all patients who had surgery under general anaesthesia between 1999 and 2013. Patient satisfaction was retrospectively investigated with questionnaires. RESULTS: A total of 482 operations (363 primary operations and 119 re-operations) were performed during the study period. The proportion of women in the included population was 68%. The median diagnostic delay (patient's and doctor's delay) was 6.5 years. Relapses occurred after 29.2% of primary operations. Women had higher relapse rates than men [odds ratio 2.85 (1.07;7.61)]. Hypergranulation of the wound was the most common complication and occurred in 7% of all operations. The median score patients attributed to the medical effect of surgery was eight of 10 (zero corresponding to very dissatisfied and 10 to very satisfied). CONCLUSION: The diagnostic delay in HS is long due to a lack of knowledge in both patients and health care professionals, indicating that there is a need for education. Deroofing and the STEEP are effective surgical procedures in severe cases of HS and lead to a relatively high patient satisfaction. The postoperative relapse risk is higher in women. Prospective studies are required for the development of clear guidelines on the appropriate choice of surgery.

Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review.

Hidradenitis suppurativa (HS) is a difficult disease to treat. Although the pathogenesis of this inflammatory skin disease is largely unknown, the important role of the immune system has been demonstrated in both experimental and clinical studies. Clinicians are therefore increasingly prescribing systemic treatments with immunosuppressive agents, but the more traditionally used systemic retinoids, especially isotretinoin, also remain relatively common therapies. In order to provide an overview of all currently available systemic immunosuppressive agents and retinoids for the treatment of HS, a systematic search was performed using the Medline and Embase databases. All published papers concerning systemic retinoids or immunosuppressive treatments for HS in adults were included. The primary endpoints were the percentages of significant responders, moderate responders and nonresponders. Other endpoints were the relapse rate and adverse events. In total 87 papers were included, comprising 518 patients with HS who were treated with systemic retinoids, biological agents or another immunosuppressive agents, including colchicine, ciclosporin, dapsone or methotrexate. The highest response rates were observed with infliximab, adalimumab and acitretin. Overall, the quality of evidence was low and differed between the agents, making direct comparisons difficult. However, based on the amount of evidence, infliximab and adalimumab were the most effective agents. Acitretin was also effective in HS, although the quality of the evidence was low. The therapeutic effect of isotretinoin is questionable. Randomized controlled trials are needed to confirm the effectiveness of acitretin, and to identify the most effective immunosuppressive agents in HS.

Decreased excitability of the distal motor nerve of young patients with type 1 diabetes mellitus.

OBJECTIVE: The compound muscle action potential (CMAP) scan is a novel neurophysiological technique that appears more sensitive in detecting peripheral motor neuropathy than conventional methods. This study explores the value of the CMAP scan for the detection of subclinical diabetic peripheral motor neuropathy. METHODS: In this cross-sectional pilot study, CMAP scanning of the peroneal nerve was performed in (i) 13 well-controlled patients (8-25 yr old) with type 1 diabetes mellitus (T1DM) duration between 2.5 and 5 yr; (ii) 17 patients (10-25 yr old) with a duration of T1DM of at least 10 yr, poorly controlled and/or with microvascular complications and (iii) 13 adults with T1DM and established clinical diabetic peripheral neuropathy (DPN). Various CMAP scan variables, including measures of axonal excitability and axonal loss and reinnervation, were compared between patients and healthy controls. RESULTS: Axonal excitability was significantly decreased in the young patient groups as compared to their controls. The CMAP scan measures of axonal loss and reinnervation differed only between patients with clinical DPN and their controls. CONCLUSIONS: Motor nerve axonal excitability seems to be reduced early in T1DM, even in well-controlled young patients, and probably before (irreversible) axonal damage occurs. These changes can be measured by the CMAP scan, which makes this a promising tool for detecting nerve dysfunction in T1DM.

The Eurotransplant donor risk index in liver transplantation: ET-DRI.

Recently we validated the donor risk index (DRI) as conducted by Feng et al. for the Eurotransplant region. Although this scoring system is a valid tool for scoring donor liver quality, for allocation purposes a scoring system tailored for the Eurotransplant region may be more appropriate. Objective of our study was to investigate various donor and transplant risk factors and design a risk model for the Eurotransplant region. This study is a database analysis of all 5939 liver transplantations from deceased donors into adult recipients from the 1st of January 2003 until the 31st of December 2007 in Eurotransplant. Data were analyzed with Kaplan-Meier and Cox regression models. From 5723 patients follow-up data were available with a mean of 2.5 years. After multivariate analysis the DRI (p < 0.0001), latest lab GGT (p = 0.005) and rescue allocation (p = 0.007) remained significant. These factors were used to create the Eurotransplant Donor Risk Index (ET-DRI). Concordance-index calculation shows this ET-DRI to have high predictive value for outcome after liver transplantation. Therefore, we advise the use of this ET-DRI for risk indication and possibly for allocation purposes within the Eurotrans-plant region.

Insulin-induced translocation of glucose transporters from post-Golgi compartments to the plasma membrane of 3T3-L1 adipocytes.

A semiquantitative method using immunocytochemistry on ultrathin cryosections and the protein A-gold technique was performed to study the effect of insulin on the cellular distribution of the glucose transporters in cultured 3T3-L1 adipocytes. In basal cells a substantial portion of the label was present in a tubulovesicular structure at the trans side of the Golgi apparatus, likely to represent the trans-Golgi reticulum, and in small vesicles present in the cytoplasm. Treatment with insulin induced a rapid translocation of transporters from the tubulovesicular structure to the plasma membrane. The transporter labeling of the plasma membrane increased three-fold and that of the tubulovesicular structure decreased by half. There was no effect of insulin on the degree of label in the small cytoplasmic vesicles. Removal of insulin from stimulated cells rapidly reversed the distribution of transporters to that seen in basal cells. This study thus provides the first morphological evidence for the occurrence of transporter translocation in insulin action and identifies for the first time the intracellular location of the responsive transporters.

Automated neonatal seizure detection mimicking a human observer reading EEG.

OBJECTIVE: The description and evaluation of a novel patient-independent seizure detection for the EEG of the newborn term infant. METHODS: We identified characteristics of neonatal seizures by which a human observer is able to detect them. Neonatal seizures were divided into two types. For each type, a fully automated detection algorithm was developed based on the identified human observer characteristics. The first algorithm analyzes the correlation between high-energetic segments of the EEG. The second detects increases in low-frequency activity (<8 Hz) with high autocorrelation. RESULTS: The complete algorithm was tested on multi-channel EEG recordings of 21 patients with and 5 patients without electrographic seizures, totaling 217 h of EEG. Sensitivity of the combined algorithms was found to be 88%, Positive Predictive Value (PPV) 75% and the false positive rate 0.66 per hour. CONCLUSIONS: Our approach to separate neonatal seizures into two types yields a high sensitivity combined with a good PPV and much lower false positive rate than previously published algorithms. SIGNIFICANCE: The proposed algorithm significantly improves neonatal seizure detection and monitoring.

S1-phase cells of the leukemic cell cycle sensitive to 1-beta-D-arabinofuranosylcytosine at a high-dose level.

To investigate the effects of 1-beta-D-arabinofuranosylcytosine (ara-C) at high doses as applied in human acute leukemia, the cytotoxic effect of high-dose ara-C was studied in L1210 leukemia cells grown in tissue culture or as tumors in syngeneic mice. Exponentially growing cells displayed the expected S-phase specificity and dose saturation properties of drug action. In contrast, in stationary cultures, progressively more cells were killed by increasing the concentration of the drug. Moreover, the fraction of cells killed at high doses exceeded by 2- to 3-fold the number of cells in drug-sensitive S phase detectable by flow cytometry or [3H]thymidine radioautography. To identify these apparent non-S targets of ara-C at high doses, L1210 cells were separated according to cell cycle position by velocity sedimentation at unit gravity. Large fractions of cells, accumulating at the G1-S boundary by nutrient starvation, were detected in stationary tissue culture cells as well as in ascites or solid tumor cells. The cells located in this cell cycle compartment (termed S1 cells) were sensitive to the cytotoxic effect of high-dose ara-C. The putative presence of similar S1 fractions in advanced human acute nonlymphocytic leukemia may explain in part the clinical efficacy of a high-dose application of the drug.

Promoter hypermethylation: a common cause of reduced p16(INK4a) expression in uveal melanoma.

Tumors often display unrestricted cell cycling attributable to a dysfunctional G(1)-S checkpoint. One of the mechanisms leading to such a defect is the inactivation of the cyclin-dependent kinase inhibitor p16(INK4a). Although inactivation of p16(INK4a) is observed in a wide range of tumors, including cutaneous melanoma, genetic alteration of p16(INK4a) is reportedly uncommon in uveal melanoma. Here we show that the p16(INK4a) promoter is hypermethylated in 6 of 12 uveal melanoma cell lines and in 7 of 22 primary uveal melanomas analyzed. Five of seven patients with a methylated primary tumor died of metastatic disease compared with 2 of 15 patients with a nonmethylated primary tumor. We also show that all uveal melanoma cell lines with a hypermethylated p16(INK4a) promoter have lost p16(INK4a) expression but have maintained the expression of p14(ARF). Treatment of uveal melanoma cell lines with 5-aza-2'-deoxycytidine results in demethylation of p16(INK4a) and in reexpression of p16(INK4a) mRNA, which is maintained upon withdrawal of the 5-aza-2'-deoxycytidine. In conclusion, p16(INK4a) promoter methylation appears to be a common event in uveal melanoma and is accompanied by the loss of p16(INK4a) expression.

Normal HLA class I, II, and MICA gene distribution in uveal melanoma.

PURPOSE: The molecules of the HLA class I and II molecules as well as the MHC class I chain-related gene A (MICA), a polymorphic and stress-induced cell surface molecule, are involved in T-cell and natural killer-cell (NK-cell) mediated immune responses. In this study we looked for any genetic susceptibility contributed by HLA class I, class II, or MICA genes with regard to the development of uveal melanoma. METHODS: Between 1998 and 2001, 159 uveal melanoma patients were typed for HLA class I and II, and 168 uveal melanoma patients were evaluated for MICA by microsatellite typing. The HLA antigen and MICA allele frequencies were compared with control groups of, respectively, 2,440 and 247 healthy Dutch individuals. RESULTS: HLA class I, HLA class II, and MICA gene frequencies in uveal melanoma patients and healthy Dutch controls showed no significant deviations after correction for the number of comparisons. CONCLUSIONS: We conclude that there is no genetic susceptibility or increased risk attributed to any HLA class I, class II, and MICA polymorphism with regard to the development of uveal melanoma.

Prognostic implication of hyperdiploidy as based on DNA flow cytometric measurement in childhood acute lymphocytic leukemia--a multicenter study.

The pretreatment distribution of DNA content was determined in the leukemic blasts of 114 children with standard risk acute lymphocytic leukemia. The patients were admitted to four different centers for pediatric oncology, participating in a national study ALL-V. In 39 of 107 evaluable patients (36.4%), a single aneuploid leukemic line was detected with a median DNA Index of 1.22 (range 1.10-1.40). These hyperdiploid patients did not differ from those with diploid disease for the presenting features of age, sex, FAB classification, immunophenotype, or white blood cell count. However, patients with hyperdiploid acute lymphocytic leukemia had a significantly longer (p = 0.021) disease-free survival after a median observation period of 52 months. These observations indicate that routinely applied flow cytometry of DNA content can identify a fairly large subgroup of children with standard risk acute lymphocytic leukemia who have a low probability of relapse. It may be considered to exempt these patients from more intensive treatment regimens.