Biologic drug survival rates in the era of anti-interleukin-17 antibodies: a time-period-adjusted registry analysis.

BACKGROUND: Drug survival rates reflect efficacy and safety and may be influenced by the availability of alternative treatment options. Little is known about time-dependent drug survival in psoriasis and the effect of increasing numbers of biologic treatment options. OBJECTIVES: To determine whether drug survival is influenced by the availability of treatment options and by factors such as gender, psoriatic arthritis or previous biologic treatment. METHODS: This observational, retrospective, multicentre cohort study analysed data from patients registered in the Austrian Psoriasis Registry (PsoRA) who were treated with biologics between 1 January 2015 and 30 November 2019. RESULTS: A total of 1572 patients who received 1848 treatment cycles were included in this analysis. The highest long-term Psoriasis Area and Severity Index improvement was observed after treatment with ixekizumab, followed by ustekinumab and secukinumab, adalimumab and etanercept. Overall, ustekinumab surpassed all other biologics in drug survival up to 48 months. However, when adjusted for biologic naïvety, its superiority vanished and drug survival rates were similar for ixekizumab (91·6%), secukinumab (90·2%) and ustekinumab (92·8%), all of them superior to adalimumab (76·5%) and etanercept (71·9%) at 12 months and beyond. Besides biologic non-naïvety (2·10, P < 0·001), the introduction of a new drug such as secukinumab or ixekizumab (relative hazard ratio 1·6, P = 0·001) and female gender (1·50, P = 0·019) increased the risk of treatment discontinuation overall, whereas psoriatic arthritis did not (1·12, P = 0·21). CONCLUSIONS: The time-dependent availability of drugs should be considered when analysing and comparing drug survival. Previous biologic exposure significantly influences drug survival. Women are more likely to stop treatment.

Biologics combined with conventional systemic agents or phototherapy for the treatment of psoriasis: real-life data from PSONET registries.

BACKGROUND: Biologics have greatly improved psoriasis management. However, primary and secondary non-response to treatment requires innovative strategies to optimize outcomes. OBJECTIVE: To describe the use of combined treatment of biologics with conventional systemic agents or phototherapy in daily clinical practice. METHODS: We collected data on frequency of use, demographics, treatment characteristics and drug survival of biologics combined with conventional systemic agents or phototherapy in five PSONET registries. RESULTS: Of 9922 biologic treatment cycles, 982 (9.9%) were identified as combination treatment. 72.9% of treatment cycles concerned concomitant use of methotrexate, 25.3% concerned concomitant UVB therapy, acitretin or cyclosporin and 1.8% concerned combined treatment with PUVA, fumaric acids or a second biologic. Substantial variation was detected in type and frequency of combination treatments prescribed across registries. Patients initiated on combined treatment had generally severe disease and were affected with psoriasis for many years. The extent to which patients had been priory treated with biologic monotherapy and the proportion of patients affected with psoriatic arthritis differed between registries. Survival rates for etanercept, adalimumab, infliximab and ustekinumab with methotrexate ranged between 43 and 92%, 28 and 83%, 65 and 87% and 53 and 77%, respectively, across registries after one year with no consistent superior survival for a particular biologic. Longest survival on a biologic combined with methotrexate, acitretin or cyclosporin was 103, 78 and 34 months, respectively. CONCLUSION: Methotrexate was the most commonly used concomitant treatment for patients on a biologic. Wide geographical variations in treatment selection and persistence of combination treatment exist. Data derived from ongoing studies may help to determine whether combined treatment is superior to biologic monotherapy.

Influence of the season on vitamin D levels and regulatory T cells in patients with polymorphic light eruption.

The exact mechanisms of photohardening in polymorphic light eruption (PLE) are still unknown, but medical photohardening was shown to increase regulatory T cell (Treg) numbers in the blood of PLE patients, similar to natural hardening. Furthermore, oral vitamin D supplementation increased peripheral Tregs in healthy individuals. We herein report on a post hoc analysis of 26 screened PLE patients of a clinical trial (ClinicalTrials.gov No. NCT01595893), in which the influence of the progressing season was investigated on baseline CD4+CD25+FoxP3+CD127- Treg numbers by flow cytometry and Treg suppressive function by co-culture assays with T effector cells as a secondary endpoint, together with 25-hydroxy vitamin D (25(OH)D) serum levels at the study's screening visit, taking place in the period from January to June. The mean 25(OH)D serum level of all patients was 33.2 ng ml(-1). Ten of those patients (38.5%) were identified with low 25(OH)D levels (<30 ng ml(-1)). Significantly higher baseline 25(OH)D serum levels (plus 34.4%; P = 0.0182) as well as higher relative Treg percentages in CD4+ population (plus 62.8%; P = 0.0157) and in total lymphocyte population (plus 59.6%; P = 0.0372) and higher absolute Treg numbers (plus 100.2%; P = 0.0042) were observed in the late spring/early summer period (April to June) compared to the winter period (January to February). No significant relationship was observed when Treg numbers and function were correlated with 25(OH)D levels. These data indicate that in PLE patients Treg numbers and their suppressive function are independent of vitamin D serum levels and suggest that UV light and/or other seasonal factors may affect these cells via the non-vitamin D related pathway(s).

Diabetic neuropathy increases stimulation threshold during popliteal sciatic nerve block.

BACKGROUND: Peripheral nerve stimulation is commonly used for nerve localization in regional anaesthesia, but recommended stimulation currents of 0.3-0.5 mA do not reliably produce motor activity in the absence of intraneural needle placement. As this may be particularly true in patients with diabetic neuropathy, we examined the stimulation threshold in patients with and without diabetes. METHODS: Preoperative evaluation included a neurological exam and electroneurography. During ultrasound-guided popliteal sciatic nerve block, we measured the current required to produce motor activity for the tibial and common peroneal nerve in diabetic and non-diabetic patients. Proximity to the nerve was evaluated post-hoc using ultrasound imaging. RESULTS: Average stimulation currents did not differ between diabetic (n=55) and non-diabetic patients (n=52). Although the planned number of patients was not reached, the power goal for the mean stimulation current was met. Subjects with diminished pressure perception showed increased thresholds for the common peroneal nerve (median 1.30 vs. 0.57 mA in subjects with normal perception, P=0.042), as did subjects with decreased pain sensation (1.60 vs. 0.50 mA in subjects with normal sensation, P=0.038). Slowed ulnar nerve conduction velocity predicted elevated mean stimulation current (r=-0.35, P=0.002). Finally, 15 diabetic patients required more than 0.5 mA to evoke a motor response, despite intraneural needle placement (n=4), or required currents ≥2 mA despite needle-nerve contact, vs three such patients (1 intraneural, 2 with ≥2 mA) among non-diabetic patients (P=0.003). CONCLUSIONS: These findings suggest that stimulation thresholds of 0.3-0.5 mA may not reliably determine close needle-nerve contact during popliteal sciatic nerve block, particularly in patients with diabetic neuropathy. CLINICAL TRIAL REGISTRATION: NCT01488474.

Levels and function of regulatory T cells in patients with polymorphic light eruption: relation to photohardening.

BACKGROUND: We hypothesized that regulatory T cells (Tregs) are involved in the immunological abnormalities seen in patients with polymorphic light eruption (PLE). OBJECTIVES: To investigate the number and suppressive function of peripheral Tregs in patients with PLE compared with healthy controls. METHODS: Blood sampling was done in 30 patients with PLE [seeking or not seeking 311-nm ultraviolet (UV)B photohardening] as well as 19 healthy controls at two time points: TP1, March to June (before phototherapy); and TP2, May to August (after phototherapy). We compared the number of CD4(+) CD25(high) CD127(-) FoxP3(+) Tregs by flow cytometry and their function by assessing FoxP3 mRNA levels and effector T cell/Treg suppression assays. RESULTS: Tregs isolated from healthy controls significantly suppressed the proliferation of effector T cells at TP1 by 68% (P = 0·0156). In contrast, Tregs from patients with PLE entirely lacked the capacity to suppress effector T-cell proliferation at that time point. The medical photohardening seen in 23 patients with PLE resulted in a significant increase in the median percentage of circulating Tregs [both as a proportion of all lymphocytes; 65 6% increase (P = 0·0049), and as a proportion of CD4(+) T cells; 32.5% increase (P = 0·0049)]. This was accompanied by an increase in the expression of FoxP3 mRNA (P = 0·0083) and relative immunosuppressive function of Tregs (P = 0·083) comparing the two time points in representative subsets of patients with healthy controls tested. Seven patients with PLE not receiving 311-nm UVB also exhibited an increase in the number of Tregs but this was not statistically significant. No significant differences in Treg numbers were observed in healthy subjects between the two time points. CONCLUSIONS: An impaired Treg function is likely to play a role in PLE pathogenesis. A UV-induced increase in the number of Tregs (either naturally or therapeutically) may be a compensatory mechanism by which the immune system counteracts the susceptibility to PLE.

Mobile teledermatology helping patients control high-need acne: a randomized controlled trial.

BACKGROUND: Acne is an important health issue with a major psychological impact in addition to the physical problems it causes. OBJECTIVES: To investigate the superiority of mobile teledermatology in the care of patients with high-need facial acne in comparison to outpatient services with particular attention to treatment efficacy, safety, and patient compliance. Further, patient satisfaction with remote care was evaluated. METHODS: Sixty-nine consecutive patients (f: 25, m: 44, median age: 19 years, range: 13-37 years) were randomly allocated to either the teleconsultation (TCA) or the outpatient consultation (OCA) arm of the trial to receive isotretinoin treatment in weight and severity-dependent dosages over 24 weeks. Acne grading was performed by one examiner using the Global Acne Severity Scale (GEA) and the total lesion counting (TLC). RESULTS: Due to noncompliance issues, 17 of 69 (24.6%) patients were excluded from the study, of who 10 had been assigned to the TCA (10/34; 29.4%) and 7 to the OCA (7/35; 20%). Both, in the TCA (GEA-score: ∆ = 2.25; TLC: ∆ = 89.08) and in the OCA (GEA-score: ∆ = 2.0; TLC: ∆ = 91.21) excellent and almost equivalent therapeutic outcomes were achieved. In the TCA, however, less patients experienced adverse reactions (P = 0.55). Even though additional live supervision would have been appreciated in some teledermatology cases, patients were satisfied with the mobile service and no consultation request was created. CONCLUSION: Mobile teledermatology is an efficient, safe and well-accepted tool among patients with high-need acne constituting at least a valuable adjunct to outpatient care services. Further larger studies would be useful to confirm our findings.

The burden of pneumococcal meningitis in Austrian children between 2001 and 2008.

UNLABELLED: The present study was conducted to evaluate the burden of pneumococcal meningitis in Austrian children between 2001 and 2008. Clinical outcome was retrospectively analyzed both on discharge and on follow-up investigations. This study was based on a prospective multicentre surveillance study on hospitalized invasive pneumococcal infections in Austrian children with a total annual "study population" of about 399,000 children aged below 5 years per year. Between 2001 and 2008, 74 cases of pneumococcal meningitis were identified in children aged below 5 years. The mean annual incidence rate for pneumococcal meningitis was 2.3 per 100,000 children in this age group. In 57/74 children (mean age on admission 14.5 ± 13.3 months), outcome data on hospital discharge were available: 5 deaths (8.8%), 20 children (35.1%) with sequelae and 32 children (56.1%) without sequelae were observed. Sequelae on discharge included motor impairment in 8 children (14.0%), hearing impairment in 9 children (15.8%) and/or other complications in 14 children (24.6%). In 7/8 children with motor deficits, matching cerebral lesions were identified by neuroimaging: cerebral infarction in five children, cerebral vasculitis and cerebral abscess in one child each. In 40/57 children, long-term outcome (18.9 ± 20.2 months after discharge) could be assessed: 1 child (2.5%) died 9 months after hospital discharge, 11 children (27.5%) had one or two long-term sequelae and 28 children (70.0%) had no sequelae. Long-term sequelae included motor impairment in three children (7.5%), hearing impairment in nine children (22.5%) and other deficits in two children (5.0%). CONCLUSION: Our study confirms that pneumococcal meningitis causes high mortality and severe long-term sequelae. On long-term follow-up, we observed improvements of motor impairment, but not of hearing impairment.

Methotrexate vs. fumaric acid esters in moderate-to-severe chronic plaque psoriasis: data registry report on the efficacy under daily life conditions.

OBJECTIVE: To compare the clinical efficacy of methotrexate (MTX) vs. fumaric acid esters (FAE) in psoriasis treated under daily life conditions. METHODS: Data were extracted from a registry (http://www.psoriasisregistry.at) of 272 adult patients with moderate-to-severe chronic plaque psoriasis treated primarily with MTX (n = 72) or FAE (n = 200) between 2004 and 2011. Data from all patients, including those who did not complete at least 3 months of monotherapy, were included in an intention-to-treat (ITT) worst-case analysis. RESULTS: Thirty of 72 (41.7%) patients treated with MTX and 85 of 200 (42.5%) patients treated with FAE discontinued early, mainly due to side-effects or lack of response. Among patients who completed at least 3 months of treatment, the response to primary treatment with MTX vs. FAE did not differ significantly at any time point. In the ITT worst-case analysis at month 3, complete remission rate, PASI90, PASI75 and PASI50 rates were 6%, 7%, 24% and 39% in MTX-treated patients vs. 1%, 5%, 27% and 44% in FAE-treated patients. Overall mean PASI reduction score improved significantly in response to primary MTX and FAE treatment (by 10.6% and 12.6%, respectively) between 3 and 6 months (P = 0.0005; exact Wilcoxon test), but not between 6 and 12 months (P = 0.16). A subset of 32 patients who did not respond satisfactorily to primary treatment with FAE responded better to subsequent MTX therapy (P < 0.0001; paired Wilcoxon test). CONCLUSIONS: As shown by retrospective analysis, the primary efficacy of FAE was similar to that of MTX under daily life conditions.

Interdisciplinary treatment of glioblastoma: analysis of prognostic factors and treatment results in unselected patients.

Aim of the present study was to investigate survival rates of unselected patients with glioblastoma after multimodal treatment and estimation of prognostic factors. Data of 189 patients (118 men; 71 women; median age: 59 years) with histologically confirmed glioblastoma treated from 1999 to 2009 were analyzed retrospectively. Complete tumor resection was performed in 99 patients (52%), subtotal excision in 65 patients (34%), and stereotactic biopsy in 25 patients (13%). In 135 patients (71%), residual tumors were detectable in post-surgical imaging. All patients underwent three-dimensional conformal radiotherapy of the tumor region in shrinking-field technique to a total dose of 60 Gy. Beginning in 2002, 124 patients (66%) received concomitant temozolomide (TMZ) treatment, 76 patients among them were additionally treated with adjuvant TMZ. After disease progression, 74 patients underwent salvage therapy (salvage chemotherapy, n=61; local therapy, n=30). Actuarial 1- and 2- year progression-free survival (PFS) rates were 32% and 7%, overall survival (OS) rates were 54% and 22%, respectively. Without TMZ, 1- and 2- year OS rates were 47% and 11%, with concomitant TMZ 57% and 28%, and with concomitant and adjuvant TMZ 72% and 44%. In multivariate Cox proportional hazards regression models, age (p<0.001), extent of resection (p = 0.001), and TMZ (p < 0.001) were significantly associated with OS. Furthermore, a significant association between salvage therapy and improved survival was observed (p=0.020). RT with concomitant TMZ was well tolerated in the majority of patients and completed as scheduled in 78% of patients. Multimodal treatment including extensive surgical resection, radiotherapy and chemotherapy significantly improves prognosis of patients with glioblastoma and is feasible with acceptable toxicity in routine practice. To achieve optimal results, close coordination among all disciplines is required.

Patient acceptance and diagnostic utility of automated digital image analysis of pigmented skin lesions.

BACKGROUND: Computerized analysis of pigmented skin lesions may help to increase diagnostic accuracy for melanoma, help to avoid unnecessary procedures and reduce health care costs. OBJECTIVES: We evaluated both the patient acceptance and diagnostic utility of such an analysis tool in a real clinical setting. METHODS: Two hundred nine consecutive patients (median age: 34 years, range: 2-73 years), who were concerned about a pigmented skin lesion, answered a questionnaire about their attitude towards computerized analysis and their confidence in the resulting findings. Using a dermoscopy analyser, their skin lesions (n = 219) were then grouped into the categories, benign, suspicious and malignant, and results were compared with those obtained by in-person examination of dermato-oncologic experts. RESULTS: More than half of the patients (n = 114) would accept the use of computer analysis for melanoma screening; although 16 (14.0%) patients would accept this method solely, 98 (86.0%) patients would prefer an additional in-person examination by a dermatologist. Of the 219 pigmented skin lesions, the dermoscopic experts rated 171 (78.1%) as benign, 36 (16.4%) as suspicious and 12 (5.5%) as malignant, whereas computer analysis revealed 102 (46.6%) benign, 78 (35.6%) suspicious and 39 (17.8%) malignant lesions. At the expense of specificity (48.8%), the sensitivity of computerized analysis was excellent (100%) and equal to that of in-person examination. CONCLUSIONS: Most patients would accept computer analysis for melanoma screening, some of them even without reservations. However, due to a high rate of false positive computer assessments, it cannot be recommended as a screening tool at this time.

Real-world effectiveness of anti-interleukin-23 antibodies in chronic plaque-type psoriasis of patients from the Austrian Psoriasis Registry (PsoRA).

With the introduction of the latest class of biologic drugs targeting interleukin (IL)-23p19, three new, highly effective drugs can be used for the treatment of chronic plaque psoriasis. However, poorer skin improvement as well as higher rates of serious adverse events have been reported for patients under real-world conditions (outside clinical trials). This accounts especially for patients who have already been treated with biologic drugs. We therefore aimed to determine effectiveness and safety of IL-23p19 inhibitors in real-world patients by analysing data from the Psoriasis Registry Austria (PsoRA) in this observational, retrospective, multicentre cohort study. Data for 197 patients (52.3% biologic-non-naïve), who were treated with anti-IL-23p19 antibodies (127 guselkumab, 55 risankizumab and 15 tildrakizumab) for at least 3 months, were eligible for analysis. In general, biologic-non-naïve patients displayed a less favourable response to anti-IL-23 treatment as compared to biologic-naïve patients. However, after correction for previous biologic exposure, few differences in PASI improvement were detected among biologic-naïve and -non-naïve patients treated with different IL-23p19 inhibitors. This indicates that treatment effectiveness is not related to the class of the previously administered therapy in biologic-non-naïve patients. Therefore, IL-23p19 inhibitors represent a promising treatment alternative for patients who have not responded to previous biologics. However, as with other biologic agents (including IL-17 inhibitors), we did not observe an entirely satisfactory treatment response (i.e. PASI < 3 and/or PASI 75) to anti-IL-23 treatment in one out of four to five patients. Adverse events (mainly non-severe infections) were observed in 23 (11.7%) patients with no major differences regarding the administered IL-23 inhibitor or previous biologic exposure.

Efficacy of psoralen plus ultraviolet A therapy vs. biologics in moderate to severe chronic plaque psoriasis: retrospective data analysis of a patient registry.

BACKGROUND: Few studies have directly compared the clinical efficacy of psoralen plus ultraviolet A (PUVA) vs. biologics in the treatment of psoriasis. OBJECTIVES: To compare the clinical efficacy of PUVA and biologic therapies for psoriasis under daily life conditions. METHODS: Data from a psoriasis registry (http://www.psoriasis-therapieregister.at) of 172 adult patients with moderate to severe chronic plaque psoriasis treated between 2003 and 2010 were analysed retrospectively. These patients had received oral PUVA [118 treatment courses including 5-methoxypsoralen (5-MOP; n = 32) and 8-methoxypsoralen (8-MOP; n = 86)] and/or biologic agents [130 treatment courses including adalimumab (n = 18), alefacept (n = 32), efalizumab (n = 17), etanercept (n = 38), infliximab (n = 7) and ustekinumab (n = 18)]. Treatment responses were analysed in terms of Psoriasis Area and Severity Index (PASI) improvement, including complete remission (CR) and reduction of PASI by at least 90% (PASI 90) or 75% (PASI 75), at treatment completion for PUVA (median time 10·3 and 9·2 weeks, for 8-MOP and 5-MOP, respectively) and at week 12 for biologics. RESULTS: Intention-to-treat-as observed CR, PASI 90 and PASI 75 rate was 22%, 69% and 86% for PUVA compared with 6%, 22% and 56% for adalimumab (P = 0·0034 by adapted Wilcoxon test), 3%, 3% and 25% for alefacept (P = 0·000000002), 6%, 6% and 59% for efalizumab (P = 0·000053), 6%, 29% and 39% for etanercept (P = 0·0000086), 29%, 71% and 100% for infliximab (P = 0·36) and 6%, 39% and 67% for ustekinumab (P = 0·028). When applying a more conservative post-hoc modified worst-case scenario analysis, with CR of 15%, PASI 90 of 58% and PASI 75 of 69%, PUVA was superior only to alefacept (P = 0·000013), efalizumab (P = 0·015) and etanercept (P = 0·0037). There were no statistically significant differences in PASI reduction rates between PUVA and infliximab. CONCLUSIONS: Retrospective analysis of registry data revealed that the primary efficacy of PUVA was superior to that of certain biologics. Prospective head-to-head studies of PUVA and biologics are warranted to confirm these observations.

Randomized double-blinded placebo-controlled intra-individual trial on topical treatment with a 1,25-dihydroxyvitamin D3 analogue in polymorphic light eruption.

BACKGROUND: Polymorphic light eruption (PLE) is a very frequent photodermatosis whose pathogenesis may involve resistance to ultraviolet (UV)-induced immune suppression. Similar to UV radiation, calcitriol (1,25-dihydroxyvitamin D3) and its analogues such as calcipotriol have been shown to exhibit immunosuppressive properties. OBJECTIVES: We performed a randomized double-blinded placebo-controlled intraindividual half-body trial (NCT00871052) to investigate the preventive effect of a calcipotriol-containing cream in PLE. METHODS: Thirteen patients with PLE (10 women, three men; mean age 37 years) pretreated their skin on two symmetrically located test fields with calcipotriol or placebo cream twice daily for 7 days before the start of photoprovocation testing with solar-simulated UV radiation. We established a specific PLE test score [AA + SI + 0·4 P (range 0-12), where AA is affected area score (range 0-4), SI is skin infiltration score (range 0-4) and P is pruritus score on a visual analogue scale (range 0-10)] to quantify PLE severity. RESULTS: Photoprovocation led to PLE lesions in 12/13 (92%) patients. As shown by the PLE test score, compared with placebo calcipotrial pretreatment significantly reduced PLE symptoms in average by 32% (95% confidence interval 21-44%; P = 0·0022, exact Wilcoxon signed-rank test) throughout the observation period starting at 48 h until 144 h after the first photoprovocation exposure. At 48, 72 and 144 h calcipotriol pretreatment resulted in a lower PLE test score in 7 (58%), 9 (75%) and 10 (83%) of the 12 cases, respectively. Considering all time points together, calcipotriol diminished the PLE test score in all 12 photoprovocable patients (P = 0·0005; Wilcoxon signed-rank test). CONCLUSIONS: These results suggest a potential therapeutic benefit of topical 1,25-dihydroxyvitamin D3 analogues as prophylactic treatment in patients with PLE.

Evaluating bleeding severity in children with newly diagnosed immune thrombocytopenia: a pilot study.

BACKGROUND: Childhood immune thrombocytopenia (ITP) is a bleeding disorder characterized by decreased platelet counts. Assessment of the individual bleeding risk during the course of the disease would allow more accurately guiding treatment-related decisions in these patients. PATIENTS AND METHODS: We conducted a pilot study and prospectively evaluated platelet counts and bleeding signs using an established bleeding (Buchanan) score in 30 patients with newly diagnosed ITP at 3 different time points (at diagnosis [TP1], on day 2-3 [TP2], and on day 5-8 [TP3]) during the first week after diagnosis. 15 patients received immune modulatory therapy. RESULTS: Median platelet counts at the 3 different time points were 13, 19, 32×10 (9)/L (untreated patients) and 2, 7, 37×10 (9)/L (treated patients). Corresponding median cumulative bleeding scores were 5, 2, 0 (untreated patients) and 7, 6, 2 (treated patients). Cumulative median bleeding scores and platelet counts were inversely correlated in treated and untreated patients at all 3 time points. Cumulative median bleeding scores significantly decreased in both groups. CONCLUSIONS: Bleeding signs in children with newly diagnosed ITP rapidly improve within one week after diagnosis. Serial grading of bleeding severity seems to be useful to comprehensively assess and monitor the individual bleeding risk in these patients, but has to be evaluated and validated in a larger cohort.

Does the time interval between sentinel lymph node biopsy and completion lymph node dissection affect outcome in malignant melanoma? A retrospective cohort study.

Nodal clearance was recommended after positive sentinel lymph node biopsy (SLNB) despite further metastases to the regional lymph node basin being found in only 6-21% in the literature. This retrospective study was conducted to determine the role of the time interval between excision of primary melanoma and confirmed metastasis in the sentinel lymph node biopsy as well as the one between positive sentinel lymph node biopsy (SLNB-positive patients) and subsequent completion lymph node dissection (CLND) on the presence of metastases. The monocentric analysis included 121 patients with a history of completion lymph node dissection after positive SLNB from January 2005 to October 2013. Additional metastases in the regional lymph node basin (non-sentinels) were found in 14.05% (n = 17). Significant risk factors for the presence of metastases in CLND were the time between confirmed primary tumour to metastasis in sentinel lymph nodes (SLN) (p = 0.0034), N-category of TNM-classification (p = 0.0066) and independent of thickness of primary tumour (p = 0.11). If SLNB was performed up to forty-three days after confirmed primary melanoma, subsequent lymph node dissection was positive in less than 9.1%. When SLNB was performed with a delay of more than 80 days, all patients had metastases in the CLND specimens. Our data analysis suggests that delays in subsequent procedures of SLNB after diagnosis of primary melanoma may have a greater impact on positivity of non-sentinel lymph nodes than previously assumed. Our retrospective analysis may indicate the reconsideration of time schedule in the management of primary melanoma to potentially avoid local relapse in the draining lymph node region after positive SLNB.

EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an asbestos related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of our study was to assess possible differences within signalling pathways between short term survivors (survival <3 years; STS) and long term survivors (survival >3 years; LTS) of MPM. METHODS: 37 antibodies detecting proteins engaged in cell signalling pathways, enforcing proliferation, antiapoptosis, angiogenesis and other cellular activities were investigated by tissue microarray (TMA) technology. RESULTS: Epidermal growth factor receptor (EGFR) was expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling was more abundant in STS. Expression of TIE2/Tek, a receptor for tyrosine kinases involved in angiogenesis, was differentially regulated via PDGFR and thus is more important in STS. Antiapoptosis was upregulated in STS by signal transducer and activator of transcription 1 (STAT1)-survivin and related molecules, but not in LTS. Our study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS. CONCLUSION: We have demonstrated that small scale proteomics can be carried out by powerful linkage of TMA, immunohistochemistry and statistical methods to identify proteins which might be relevant targets for therapeutic intervention.

The frequency of occurrence of atypical lymphocytes in peripheral blood smears of natalizumab-treated patients with multiple sclerosis.

INTRODUCTION: Aside from the extensive published data on immunophenotypic lymphocyte subsets in natalizumab-treated patients with multiple sclerosis (MS), an impact of natalizumab on lymphocyte morphology has rarely been studied. As patients treated with immunomodulating or immunosuppressive drugs are at risk for infectious disorders such as viral infections, knowledge of drug-derived changes in lymphocyte morphology may be beneficial in the diagnostic work-up in such clinical situations. This study aimed to determine the frequency of occurrence of atypical lymphocytes and defined subtypes of variant lymphocytes in natalizumab-treated patients with MS. METHODS: We compared eight defined morphological lymphocyte subtypes in peripheral blood smears between 14 natalizumab-treated, 13 interferon-treated and 10 untreated subjects with relapse-remitting MS. RESULTS: Atypical lymphocytes were significantly enhanced in natalizumab-treated patients compared to the interferon and control group (P<.0001). Binucleated lymphocytes were restricted to the natalizumab group (P=.0058, P=.018), and plasmacytoid lymphocytes were more frequently found in the natalizumab group (P<.0001). CONCLUSION: Our data indicate that natalizumab enhances the fraction of atypical lymphocytes, and thereby especially the binucleated and plasmacytoid lymphocytes. Knowledge of these natalizumab-associated changes in lymphocyte morphology may be relevant in clinical routine, to avoid unnecessary diagnostic procedures or even a discontinuation of natalizumab treatment.