Melanoma - investigation and primary treatment. / Melanom ­ utredning og primærbehandling.

Melanoma is a relatively common diagnosis, both in the primary and specialist health service. Ongoing research and new evidence base means that the recommendations for investigation and treatment are continually changing. This can lead to uncertainty among doctors who do not treat this patient group regularly. In this clinical review we give a summary of the latest recommendations, primarily aimed at general practitioners, dermatologists and doctors in local hospitals.

Merkel cell carcinoma. / Merkelcellekarsinom.

Merkel cell carcinoma is an uncommon but aggressive tumour with a high metastatic potential. A rapidly growing, non-tender cutaneous tumour on sun-exposed areas of the body in older patients should raise suspicion of the condition. It may be necessary to combine the patient history with clinical, radiological and pathological findings in order to make the correct diagnosis. Excision with a 1-2 cm margin, direct closure and simultaneous sentinel-node biopsy should be performed without delay. Adjuvant radiation therapy of the tumour site may be relevant. After the diagnosis is made, assessment and treatment should take place in hospitals with special experience of the condition.

Reduction of immunosuppression combined with whole-brain radiotherapy and concurrent systemic rituximab is an effective yet toxic treatment of primary central nervous system post-transplant lymphoproliferative disorder (pCNS-PTLD): 14 cases from the prospective German PTLD registry.

Post-transplant lymphoproliferative disorders (PTLD) exclusively affecting the central nervous system-primary CNS-PTLD (pCNS-PTLD)-are rare. There is no standard therapy, and previous case series have included heterogeneous treatment approaches. We performed a retrospective, multi-centre analysis of 14 patients with pCNS-PTLD after solid organ transplantation (SOT) treated in the prospective German PTLD registry with reduction of immunosuppression (RI), whole-brain radiotherapy (WBRT), and concurrent systemic rituximab between 2001 and 2018. Twelve of fourteen patients were kidney transplant recipients and median age at diagnosis was 65 years. Thirteen of fourteen cases (93%) were monomorphic PTLD of the diffuse large B-cell lymphoma type, and 12/13 were EBV-associated. The median dose of WBRT administered was 40 Gy with a median fraction of 2 Gy. The median number of administered doses of rituximab (375 mg/m2) IV was four. All ten patients evaluated responded to treatment (100%). Median OS was 2.5 years with a 2-year Kaplan-Meier estimate of 63% (95% confidence interval 30-83%) without any recorded relapses after a median follow-up of 2.6 years. Seven of fourteen patients (50%) suffered grade III/IV infections under therapy (fatal in two cases, 14%). During follow-up, imaging demonstrated grey matter changes interpreted as radiation toxicity in 7/10 evaluated patients (70%). The combination of RI, WBRT, and rituximab was an effective yet toxic treatment of pCNS-PTLD in this series of 14 patients. Future treatment approaches in pCNS-PTLD should take into account the significant risk of infections as well as radiation-induced neurotoxicity.

Randomized Study of Wound Drainage on Early Complications After Lymph Node Dissection for Melanoma.

INTRODUCTION: The complication rate after axillary lymph node dissection (ALND) and inguinal lymph node dissection (ILND) in melanoma patients is high. The aim of this randomized non-inferiority study was to evaluate the effect of postoperative wound drainage on early complications after ALND and ILND. MATERIALS AND METHODS: Between 2018 and 2020, 104 stage III melanoma patients operated on with ALND or ILND were randomized to a study group with complete wound drain removal 3 wk after surgery or a control group with progressive drain removal. The primary end point was overall early complications graded according to the modified Clavien-Dindo classification. Secondary endpoints were length of hospital stay and prognostic factors for early complications. RESULTS: Of the 99 patients analyzed, ALND was performed in 58 patients and ILND in 41 patients. Overall, 62 patients (62.6%) developed early complications: 30 in the study group and 32 in the control group (P = 0.53). The confidence interval for the difference in proportions of patients without early complications in the two groups was -0.27 to 0.11 (P = 0.42), hence non-inferiority could be claimed. Length of hospital stay was 5 d in the study group compared to 6 in the control group (P < 0.01). ILND was associated with increased risk of early complications compared to ALND (75.6% versus 53.4%, P = 0.04). CONCLUSIONS: Complete drain removal 3 wk after ALN and ILND in stage III melanoma patients did not increase the risk of early complications compared to progressive drain removal.

[Stereotactic body radiation therapy: radiobiological characteristics, physical-technical prerequisites, clinical applications]. / Extrakranielle Stereotaxie: strahlenbiologische Besonderheiten, physikalisch-technische Voraussetzungen, klinische Einsatzmöglichkeiten.

Radiotherapy of small targets with very high single doses administered in 1 to approximately 12 fractions-carried out under image guidance and with the intention of "tumour ablation"-is called stereotactic body radiation therapy (SBRT) for extracranial tumours or metastases. Radiobiologically, besides damaging the DNA of the tumour cells, the tumour vessels are also occluded and immunological effects are triggered. The safe performance of SBRT requires a very high physical-technical effort in order to ensure sufficient protection of healthy organs. Clinically, SBRT offers a wide range of applications in curative therapy (e.g. non-small-cell lung cancer stage I). Furthermore, it is a conservative, effective and well-tolerated option for the treatment of individual metastases and an optimal combination partner in the therapy of oligometastatic tumours.

Effects of cladribine tablets on heart rate, atrio-ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis.

AIMS: Cladribine tablets have shown significant efficacy for the treatment of relapsing multiple sclerosis, a chronic and debilitating immune-mediated disorder. This study was conducted to examine acute and/or cumulative effects of cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dose over 2 years) on heart rate, AV conduction and cardiac repolarization in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: CLARITY was a 96-week, double-blind, placebo-controlled, multicentre trial which evaluated the safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg body weight in patients with RRMS. A total of 135 patients were included in the ECG substudy, providing a total of 1534 post-dose ECGs. ECG data were collected 15 minutes pre-dose and between 0.5 and 3 hours post-dose at pre-study evaluation, study Day 1 and Weeks 5, 9, 13, 48 and 52. RESULTS: For cladribine tablets 3.5 mg/kg, the maximum change in placebo-adjusted post-dose QTcF vs. visit-baseline (BL) was -0.42 ms (90% CI: -3.61-4.44) at Week 1 (acute effects), and 3.20 ms (90% CI: -0.08-6.33) for cladribine tablets 5.25 mg/kg. The greatest observed differences in post-dose QTcF vs. study BL occurred at Week 48 for both the 3.5 and 5.25 mg/kg doses of cladribine tablets with 5.99 ms (90% CI: 0.53-11.44) and 8.74 ms (90% CI: 3.18-14.31), respectively. No significant changes were observed in T-wave morphology in either treatment group. CONCLUSIONS: Cladribine tablets 3.5 mg/kg (approved dose in Europe/other regions) did not confer clinically meaningful effects on heart rate, AV conduction and ventricular repolarization.

Nuclear factor-kappaB regulates multiple steps of gliogenesis in the developing murine cerebral cortex.

Nuclear factor-kappaB (NF-κB) is activated in neural progenitor cells in the developing murine cerebral cortex during the neurogenic phase, when it acts to prevent premature neuronal differentiation. Here we show that NF-κB activation continues in mouse neocortical neural progenitor cells during the neurogenic-to-gliogenic switch. Blockade of endogenous NF-κB activity during neocortical gliogenesis leads to the formation of supernumerary committed gliogenic progenitors and premature glial cell differentiation. Conversely, forced NF-κB activation during the neocortical neurogenic-to-gliogenic transition causes delayed gliogenic commitment and decreased astroglial gene expression. NF-κB activation continues in neocortical gliogenic progenitors following commitment and is important to inhibit the differentiation of oligodendrocyte precursor cells and to maintain persistent expression of glial fibrillary acidic protein in maturing astrocytes. These results reveal a number of previously uncharacterized roles for NF-κB during different phases of neocortical gliogenesis and identify NF-κB as an inhibitor of early oligodendrocyte development in the cerebral cortex.

Association between interferon-induced helicase (IFIH1) rs1990760 polymorphism and seasonal variation in the onset of type 1 diabetes mellitus.

BACKGROUND: Infections, mostly of viral origin, may contribute to the seasonal variation in the onset of type 1 diabetes mellitus (T1DM). The rs1990760 (A>G, Ala946Thr) polymorphism (GG genotype) of the interferon induced helicase (IFIH1), a virus recognition receptor, confers a modest protection for T1DM. The aim of our study was to evaluate a possible association between this IFIH1 polymorphism and the seasonal variation in the onset of T1DM. MATERIALS AND METHODS: The IFIH1 rs1990760 polymorphism was genotyped in 1055 patients of Central-Eastern European ancestry with T1DM (median age at diagnosis: 8.2 [interquartile range, IQR 4.8-11.8] years). T1DM onset was recorded in monthly intervals. RESULTS: The IFIH1 genotype distribution was the following: 436 patients (41.3%) had AA genotype, 483 patients (45.8%) had AG genotype, and 136 patients (12.9%) had GG genotype. Significant seasonal variation in manifestation of T1DM (highest rate in winter and lowest rate in summer period) was observed in the total cohort (n = 1055), irrespective of gender. The disease predisposing AA genotype was more frequently found among new cases with onset in summer vs in those with onset in winter (44.3% vs 37.9%); conversely, the protective GG genotype was less frequent (9.3% vs 12.9%, respectively; P = .0268 for trend). Significant effect of genotype (P = .0418) was found on the seasonal variability of T1DM onset in the total cohort. CONCLUSIONS: The IFIH1 rs1990760 polymorphism seems to be associated with the seasonal manifestation of T1DM. Our findings suggest that this virus receptor gene may contribute to T1DM manifestation primarily in the summer period.

Low-dose external beam radiotherapy for greater trochanteric pain syndrome : Target volume definition and treatment outcome.

PURPOSE: Low-dose external beam radiotherapy (ED-EBRT) is frequently used in the therapy of refractory greater trochanteric pain syndrome (GTPS). As studies reporting treatment results are scarce, we retrospectively analyzed our own patient collectives. PATIENTS AND METHODS: In all, 60 patients (74 hips) received LD-EBRT (6 × 0.5 Gy in 29 hips, 6 × 1 Gy in 45). The endpoint was the patient's reported subjective response to treatment. The influence of different patient and treatment characteristics on treatment outcome was investigated. RESULTS: At the end of LD-EBRT, 69% reported partial remission, 4% complete remission, no change 28%. A total of 3 months later (n = 52 hips), the results were 37, 33, and 30% and 18 months after LD-EBRT (n = 47) 21, 51, and 28%. In univariate analysis "inclusion of the total femoral head into the PTV" and "night pain before LD-EBRT" were correlated with symptom remission at the end of LD-EBRT, while "initial increase in pain during LD-EBRT" was significantly associated with treatment failure. In multivariable modeling "initial increase in pain" was identified as a risk factor for treatment failure (p = 0.007; odds ratio [OR] 0.209; 95% confidence interval [CI] 0.048-0.957), while "night pain" was an independent factor for remission (p = 0.038; OR 3.484; 95% CI 1.004-12.6). Three months after LD-EBRT "night pain" and "inclusion of the complete femoral neck circumference into the PTV" were predictive for remission. CONCLUSION: LD-EBRT represents a useful treatment option for patients suffering from GTPS. Three months after therapy two-thirds of the patients reported a partial or complete symptom remission. Especially patients who suffered from nocturnal pain seemed to benefit. Treatment appeared to be more effective when the entire circumference of the femoral neck was encompassed.

Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial.

BACKGROUND: High-permeability pulmonary edema is a hallmark of acute respiratory distress syndrome (ARDS) and is frequently accompanied by impaired alveolar fluid clearance (AFC). AP301 enhances AFC by activating epithelial sodium channels (ENaCs) on alveolar epithelial cells, and we investigated its effect on extravascular lung water index (EVLWI) in mechanically ventilated patients with ARDS. METHODS: Forty adult mechanically ventilated patients with ARDS were included in a randomized, double-blind, placebo-controlled trial for proof of concept. Patients were treated with inhaled AP301 (n = 20) or placebo (0.9% NaCl; n = 20) twice daily for 7 days. EVLWI was measured by thermodilution (PiCCO®), and treatment groups were compared using the nonparametric Mann-Whitney U test. RESULTS: AP301 inhalation was well tolerated. No differences in mean baseline-adjusted change in EVLWI from screening to day 7 were found between the AP301 and placebo group (p = 0.196). There was no difference in the PaO2/FiO2 ratio, ventilation pressures, Murray lung injury score, or 28-day mortality between the treatment groups. An exploratory subgroup analysis according to severity of illness showed reductions in EVLWI (p = 0.04) and ventilation pressures (p < 0.05) over 7 days in patients with initial sequential organ failure assessment (SOFA) scores ≥11 inhaling AP301 versus placebo, but not in patients with SOFA scores ≤10. CONCLUSIONS: There was no difference in mean baseline-adjusted EVLWI between the AP301 and placebo group. An exploratory post-hoc subgroup analysis indicated reduced EVLWI in patients with SOFA scores ≥11 receiving AP301. These results suggest further confirmation in future clinical trials of inhaled AP301 for treatment of pulmonary edema in patients with ARDS. TRIAL REGISTRATION: The study was prospectively registered at clinicaltrials.gov, NCT01627613 . Registered 20 June 2012.

The field size matters: low dose external beam radiotherapy for thumb carpometacarpal osteoarthritis : Importance of field size.

The purpose of this work was to evaluate the efficacy of low-dose radiotherapy (RT) for thumb carpometacarpal osteoarthritis (rhizarthrosis). The responses of 84 patients (n = 101 joints) were analyzed 3 months after therapy (n = 65) and at 12 months (n = 27). Patients were treated with 6 fractions of 1 Gy, two times a week, with a linear accelerator. At the end of therapy, about 70 % of patients reported a response (partial remission or complete remission), 3 months later about 60 %, and 1 year after treatment 70 %. In univariate regression analysis, higher patient age and field size greater than 6 × 4 cm were associated with response to treatment, while initial increase of pain under treatment was predictive for treatment failure. Duration of RT series (more than 18 days), gender, time of symptoms before RT, stress pain or rest pain, or prior ortheses use, injections, or surgery of the joint were not associated with treatment efficacy. In multivariate regression analysis, only field size and initial pain increase were highly correlated with treatment outcome. In conclusion, RT represents a useful treatment option for patients suffering from carpometacarpal osteoarthritis. In contrast to other benign indications, a larger field size (>6 × 4 cm) seems to be more effective than smaller fields and should be evaluated in further prospective studies.

Botulinum Toxin: Pharmacology and Therapeutic Roles in Pain States.

Botulinum toxin, also known as Botox, is produced by Clostridium botulinum, a gram-positive anaerobic bacterium, and botulinum toxin injections are among the most commonly practiced cosmetic procedures in the USA. Although botulinum toxin is typically associated with cosmetic procedures, it can be used to treat a variety of other conditions, including pain. Botulinum toxin blocks the release of acetylcholine from nerve endings to paralyze muscles and to decrease the pain response. Botulinum toxin has a long duration of action, lasting up to 5 months after initial treatment which makes it an excellent treatment for chronic pain patients. This manuscript will outline in detail why botulinum toxin is used as a successful treatment for pain in multiple conditions as well as outline the risks associated with using botulinum toxin in certain individuals. As of today, the only FDA-approved chronic condition that botulinum toxin can be used to treat is migraines and this is related to its ability to decrease muscle tension and increase muscle relaxation. Contraindications to botulinum toxin treatments are limited to a hypersensitivity to the toxin or an infection at the site of injection, and there are no known drug interactions with botulinum toxin. Botulinum toxin is an advantageous and effective alternative pain treatment and a therapy to consider for those that do not respond to opioid treatment. In summary, botulinum toxin is a relatively safe and effective treatment for individuals with certain pain conditions, including migraines. More research is warranted to elucidate chronic and long-term implications of botulinum toxin treatment as well as effects in pregnant, elderly, and adolescent patients.

Landfill mining: Developing a comprehensive assessment method.

In Austria, the first basic technological and economic examinations of mass-waste landfills with the purpose to recover secondary raw materials have been carried out by the 'LAMIS - Landfill Mining Österreich' pilot project. A main focus of its research, and the subject of this article, is the first conceptual design of a comprehensive assessment method for landfill mining plans, including not only monetary factors (like costs and proceeds) but also non-monetary ones, such as the concerns of adjoining owners or the environmental impact. Detailed reviews of references, the identification of influences and system boundaries to be included in planning landfill mining, several expert workshops and talks with landfill operators have been performed followed by a division of the whole assessment method into preliminary and main assessment. Preliminary assessment is carried out with a questionnaire to rate juridical feasibility, the risk and the expenditure of a landfill mining project. The results of this questionnaire are compiled in a portfolio chart that is used to recommend, or not, further assessment. If a detailed main assessment is recommended, defined economic criteria are rated by net present value calculations, while ecological and socio-economic criteria are examined in a utility analysis and then transferred into a utility-net present value chart. If this chart does not support making a definite statement on the feasibility of the project, the results must be further examined in a cost-effectiveness analysis. Here, the benefit of the particular landfill mining project per capital unit (utility-net present value ratio) is determined to make a final distinct statement on the general benefit of a landfill mining project.

Landfill mining: Development of a cost simulation model.

Landfill mining permits recovering secondary raw materials from landfills. Whether this purpose is economically feasible, however, is a matter of various aspects. One is the amount of recoverable secondary raw material (like metals) that can be exploited with a profit. Other influences are the costs for excavation, for processing the waste at the landfill site and for paying charges on the secondary disposal of waste. Depending on the objectives of a landfill mining project (like the recovery of a ferrous and/or a calorific fraction) these expenses and revenues are difficult to assess in advance. This situation complicates any previous assessment of the economic feasibility and is the reason why many landfills that might be suitable for landfill mining are continuingly operated as active landfills, generating aftercare costs and leaving potential hazards to later generations. This article presents a newly developed simulation model for landfill mining projects. It permits identifying the quantities and qualities of output flows that can be recovered by mining and by mobile on-site processing of the waste based on treatment equipment selected by the landfill operator. Thus, charges for disposal and expected revenues from secondary raw materials can be assessed. Furthermore, investment, personnel, operation, servicing and insurance costs are assessed and displayed, based on the selected mobile processing procedure and its throughput, among other things. For clarity, the simulation model is described in this article using the example of a real Austrian sanitary landfill.