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IntroductionMulti-professional interdisciplinary tumor boards (ITB) are essential institutions to discuss all newly diagnosed, relapsed or complex cancer patients in a team of specialists to find an optimal cancer care plan for each individual patient with regard to national and international clinical practice guidelines, patient´s preference and comorbidities. In a high-volume cancer center, entity-specific ITBs take place at least once a week discussing a large number of patients. To a high level of expertise and dedication, this also requires an enormous amount of time for physicians, cancer specialists and administrative support colleagues, especially for radiologists, pathologists, medical oncologists and radiation oncologists, who must attend all cancer-specific boards according to certification requirements.MethodsIn this 15-month prospective German single-center analysis, we examined the established structures of 12 different cancer-specific ITBs at the certified Oncology Center and demonstrate tools helping to optimize processes before, during and after the boards for optimal, time-saving procedures.ResultsBy changing pathways, introducing revised registration protocols and new digital supports we could show that the workload of preparation by radiologists and pathologists could be reduced significantly by 22.9% (p=DiscussionThere are several ways to reduce the workload of all ITB team members while maintaining high quality recommendations and adherence to national and international guidelines.

BackgroundThe advent of immune checkpoint inhibitors (ICIs) has powerfully broadened the scope of treatment options for malignancies with an ongoing increase of indications, but immune-related adverse events (irAEs) represent a serious threat to treatment success. Agents directed against programmed cell death protein 1 (PD-1) or its ligand 1 (PD-L1) are known to cause renal complications with an incidence of 3%. In contrast, subclinical renal involvement is estimated to be much higher, up to 29%. We recently reported about urinary flow cytometry-based detection of urinary PD-L1-positive (PD-L1+) kidney cells correlating with tubular PD-L1-positivity that reflected susceptibility to develop ICI-related nephrotoxicity as an irAE attending ICI treatment. Therefore, we designed a study protocol to evaluate urinary detection of PD-L1+ kidney cells as a tool for non-invasive biomonitoring of renal complications in cancer patients treated with ICIs.MethodsA prospective, controlled, non-interventional, longitudinal, single-center observational study will be conducted at the Department of Nephrology and Rheumatology of the University Medical Center Göttingen, Germany. We intend to enroll approximately 200 patients treated with immunotherapy from the Departments of Urology, Dermatology, and Hematology and Medical Oncology of the University Medical Center Göttingen, Germany. First, we will assess clinical, laboratory, histopathological, and urinary parameters in addition to urinary cell collection. Then, we will perform a correlative analysis between urinary flow cytometry of different PD-L1+ cell of renal origin with the onset of ICI-related nephrotoxicity.DiscussionBecause of growing ICI-treatment applicability with an expectable incidence of renal complications, providing cost-efficient and easily performable diagnostic tools for treatment-attendant and non-invasive biomonitoring becomes vital to improve both renal and overall survival rates in cancer patients receiving immunotherapy.Trial registrationhttps://www.drks.de, DRKS-ID DRKS00030999.

The Clarence River (New South Wales, Australia) was the main transport corridor for the sugar cane industry operating in the area from the 1860s to the 1970s. Using archaeological, documentary and oral historical resources we explore some of the anthropogenic impacts of this industry upon river channels and hydrology, in particular through the deliberate abandonment of obsolete vessels. These deliberately discarded former cane barges have been used as erosion control devices in several areas around the Harwood Island sugar mill, resulting in the accumulation of sediments and the establishment of mangrove environments in what were degraded areas.

Aim Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear. Patients and methods Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres. Results We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1–181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels. Conclusion Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency.

Zusammenfassung Hintergrund Aktinische Keratosen (AK) zeichnen sich durch einen chronischen Verlauf aus, und häufig ist ein ganzes Hautareal betroffen (Feldkanzerisierung). Die patientenindividuelle Abwägung therapiespezifischer Vor- und Nachteile einer feldgerichteten Therapie ist herausfordernd. Fragestellung Ziel der vorliegenden Arbeit war die Entwicklung und Evaluierung patientenorientierter Entscheidungskriterien, die sich für die pragmatische Einordnung einer AK-Feldtherapie im Behandlungsalltag bei Patienten mit besonderer Prädisposition zur Feldkanzerisierung eignen (Patiententyp 1 bis 3). Material und Methoden Die Entwicklung der Entscheidungskriterien und der Patiententypologie erfolgte im Rahmen eines nominalen bzw. strukturierten Multi-level-Gruppenprozesses. Anhand der patientenrelevanten Entscheidungskriterien, der verfügbaren Evidenz aus klinischen Studien und entlang der Patiententypologie wurde ein Bewertungsalgorithmus etabliert, und feldgerichtete AK-Therapieoptionen wurden systematisch evaluiert. Ergebnisse Als patientenrelevante Kriterien für die Therapieentscheidung wurden u. a. Effektivität, Sicherheit, Praktikabilität der Therapie, Adhärenz, Kosmetik, Patientenpräferenz und Komorbiditäten identifiziert und näher spezifiziert. In Bezug auf diese Entscheidungskriterien und Patiententypen, bei denen eine Feldtherapie vorrangig indiziert ist, erfüllte die photodynamische Therapie mit Tageslicht das therapiebezogene Anforderungsprofil in besonderem Maße. Schlussfolgerung Die Definition von patientenrelevanten und therapiebezogenen Entscheidungskriterien in der AK-Feldtherapie erlaubt eine strukturierte und gleichzeitig praxisorientierte Herangehensweise, um spezifische Therapieoptionen einzuordnen und individuelle Therapieentscheidungen herzuleiten.

Background Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies of the skin. Even though most patients are sufficiently treated by surgical resection, some will eventually metastasize and need systemic therapy. Phase I and II studies have shown efficacy for programmed cell death protein 1 (PD-1) inhibitors, but cohort sizes are low and real-world data especially on long-term outcome are pending. Methods Patients from six German skin cancer centers treated with PD-1 inhibitors (pembrolizumab, nivolumab or cemiplimab) for advanced cSCC were retrospectively studied. Internal patient records were analyzed for clinical outcome including response, progression-free survival (PFS), overall survival (OS) and toxicity. Results Of 46 evaluable patients (median age: 76 years), the overall response rate (RR) was 58.7%, including 15.2% with complete response. The disease control rate was 80.4%. Both median PFS and OS were not reached, Kaplan–Meier estimated 1-year PFS was 58.8%. Patients responding to therapy showed durable remission. Response was independent of the PD-1 inhibitor used and also independent of the presence of distant metastases vs. locally advanced disease. Two predictive factors were found: Patients with primaries located on the leg had a poorer therapy outcome and patients with high lactate dehydrogenase serum levels at baseline. Treatment was overall tolerated well, with less than 10% of patients discontinuing therapy due to toxicity. Conclusions PD-1 inhibitors fulfill the need for an efficient systemic therapy for advanced cSCC and should be the new standard of care. With high RRs and durable disease control, neoadjuvant and adjuvant regimens should be evaluated.

Floodplains are complex adaptive ecosystems that provide an array of ecosystem services. Despite the growing focus on resilience as a fundamental feature of floodplain ecosystems, and as an aim in floodplain management, few studies have quantified the resilience of floodplain landscapes over meaningful timescales. This study examines the resilience of floodplain vegetation communities over medium (decadal) and long term (multi-decadal) times scales through an analysis of the spatial organisation of different vegetation communities. The floodplain vegetation landscape is conceived as having two basins of attraction represented by; (1). Natural vegetation, which incorporates two domains of flood dependent (FD) and non-flood dependent (NFD) vegetation communities; and, (2). Cleared vegetation (CL). We examine change in the spatial organisation of vegetation communities on the Yanga floodplain, located on the Murrumbidgee River, Australia, over a forty-year period (1965–2005). Detailed vegetation community maps, constructed from orthorectified aerial photographs for the years 1965, 1973, 1997 and 2005, were used. Substantial changes in the extent and spatial configuration of vegetation communities occurred over the 40-year period. Many changes were bidirectional transitions between FD and NFD vegetation communities, representing transitions in response to variations in flood frequency. However, the predominant unidirectional transition of the FD and NFD vegetation communities were to CL. The dynamic character of the Yanga Floodplain vegetation landscape is shown by 91 detectable transitions among vegetation community types. Despite large areas of the floodplain vegetation landscape having undergone persistent community change, some areas of the floodplain display resilience over the 40-year period. This suggests floodplain vegetation communities are well adapted to substantial changes in environmental conditions as a result of episodic flooding and drying. However, large net changes and an increase in CL, which did not revert back to previous vegetation community types, suggest a transition to a different basin of attraction, and a loss of system resilience.

Unter chronischen Wunden der Beine leiden etwa 1–2 % der westlichen Bevolkerung. Sie schranken die Lebensqualitat der Betroffenen erheblich ein. Neben der Identifizierung und Behandlung der Ursachen ist die Kompressionstherapie ein entscheidendes und etabliertes Therapieverfahren. Eine zielgerichtete Kompression wirkt einerseits durch eine Reduktion von Odemen als auch durch eine Verbesserung der Hamodynamik. Nach dem Ausschluss von Kontraindikationen werden klinisch verschiedene Systeme sowohl zur Entstauung als auch zur Prophylaxe eingesetzt. Dabei sollten die Optionen gemeinsam mit dem Patienten und dessen Angehorigen erortert und geubt werden, damit die Wirkung optimiert und die Therapieadharenz gesteigert wird.

Background and aims Infantile hemangiomas can be successfully treated by both systemic propranolol and neodymium:YAG (Nd:YAG)-dye laser combination therapy. In this retrospective study, the efficacy and safety of sequential and parallel therapy of complicated hemangiomas treated with both methods were evaluated. Patients and methods 30 children with 48 complicated hemangiomas were treated with propranolol and Nd:YAG-dye laser combination therapy. Using photo comparison, the percentage remission rate was evaluated by three investigators on a four-step scale (I: 0-25 %, II: 26-50 %, III: 51-75 % and IV: 76-100 %). Results Eleven children received propranolol and laser therapy in parallel (A), twelve children received laser therapy after propranolol (B) and seven children received propranolol after laser therapy (C). Due to emigration abroad, one child was lost to follow-up. A strong improvement (IV) was observed in 23/29 (79.3 %) of all treated children (A: 90.9 %, B 75 %, C 66.7 %). The mean duration of propranolol therapy in all children was 8.6 months (A: 8.9 months, B: 8.2 months, C: 8.9 months). On average, 2.33 laser treatments were performed per hemangioma (A: 1.95, B: 3.2, C: 1.91). Serious side effects caused by propranolol and laser therapy were not observed. Conclusions Propranolol and Nd:YAG-dye laser combination therapy can be used sequentially or in parallel safely and effectively. They complement each other in a meaningful manner.

Zusammenfassung CTLA-4 und PD-1 sind mogliche Angriffspunkte fur eine Tumor-bedingte Herunterregulation lymphozytarer Immunantworten. Immuncheckpoint-modulierende monoklonale Antikorper wirken gegenteilig und induzieren eine Immunantwort gegen diverse Tumoren. CTLA-4- und PD1-Antikorper modulieren die Interaktion von Tumor, Antigen-prasentierenden Zellen und T-Lymphozyten. Die Therapie mit dem CTLA-4-Antikorper Ipilimumab und den PD1-Antikorpern Nivolumab und Pembrolizumab konnte in klinischen Studien einen Vorteil fur das Gesamtuberleben der Patienten zeigen, so dass nach einer Zulassung fur Ipilimumab im Jahr 2011 dann im Sommer 2015 die Zulassung der beiden PD1-Antikorper erfolgte. Eine derartig induzierte und verstarkte Immunantwort bringt unweigerlich in analoger Wirkung Autoimmunphanomene mit sich. Die Kenntnis dieses Nebenwirkungsspektrums ist fur Prophylaxe und Management durch den behandelnden Arzt unerlasslich. Als schwere Nebenwirkung ist mit einer Kolitis zu rechnen, welche sich schon fruh in ausgepragten und anhaltenden Diarrhoen bemerkbar macht. Daneben sind auch andere immunvermittelte Erkrankungen wie die Dermatitis, die Hypophysitis, die Thyreoiditis, die Hepatitis, Iridozyklitis und weitere, eher seltenere Autoimmunphanomene beschrieben worden. Durch eine fruhzeitige Diagnosestellung und Therapieeinleitung konnen Risiken und Folgeschaden fur Patienten reduziert werden. Diese Ubersichtsarbeit beschreibt die Wirkung einer Immun-Checkpoint-Blockade beim metastasierten Melanom und stellt detailliert das Nebenwirkungsspektrum und -management dieser Therapeutika dar.

European settlement has led to increased loads of fine suspended sediment (SS) entering the River Murray, Australia's largest, and arguably, most important river. The River Murray's anthropogenic sediment history can be divided into four periods with varying source areas, sediment loads, and seasonal patterns. The Aboriginal period (before 1840) was characterized by clear water at summer low-flows in the River Murray and its southern tributaries, with more sediment coming from the northern catchment than the southern, and the Darling River being turbid at all flows. There is little evidence that Aboriginal burning resulted in any measurable increase in SS. SS loads peaked in the 1870s and 1880s (the gold and gully period, 1850–1930) as valley floors were incised by gullies (mostly in northern tributaries), and gold sluicing flushed huge amounts of sludge into southern tributaries. Sedimentation in wetlands and on floodplains increased by 2–10 times in this period, and the biota in wetlands switched from clear water to turbid water communities. In the hiatus period (1930–1960) sediment supply from gullies and gold mining waned and low flow SS concentrations returned to low levels. Dam construction through the 1960s and 1970s (the regulation period, 1960 on) disconnected the River Murray from catchment derived sediment. Despite this, SS levels increased again: now largely derived from instream sources including bank erosion from long duration summer irrigation flows, the spread of bottom-feeding carp (Cyprinus carpio), and wave erosion from boats. Erosion switched from winter to summer dominated. Significant investment in securing water for the environment in the Murray-Darling Basin could be complemented by addressing in-channel sediment sources in the River Murray itself to reduce turbidity. Overall, European era SS concentrations remain relatively low with small sediment delivery to the ocean (0.1 Mt per annum), despite high catchment erosion rates. This is due to poor sediment delivery efficiency through the low-gradient landscape.

Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60–70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency.

International audience; Actinic keratosis (AK) is a chronic skin condition that can be a precursor to cutaneous squamous cell carcinoma. AK can recur and patients are likely to undergo multiple treatments. It is important that AK lesions are managed appropriately, and that patients are involved in treatment decisions. Materials and methods The Supporting Professional Expertise in AK (SPEAK) program aims to facilitate this patient-centered care by identifying patient needs and aiding healthcare practitioners (HCPs) in selecting optimal treatment and communication strategies for different types of patients. Twenty-two dermato-oncologists with established expertise in the treatment of AK collaborated to describe commonly encountered psychosocial patient profiles, and to develop respective communication and treatment strategies. Results and conclusion Six patient profiles were defined based on different psychosocial characteristics and were used to develop appropriate management approaches. We provide a systematic way of identifying these patient profiles in clinical practice and we outline communication strategies tailored to the primary needs of each type of patient. In addition, we provide recommendations for potential field-treatments that may be best suited for each profile. The recommendations provided here may help improve the communication and relationship between patients and HCPs, resulting in higher treatment adherence and improved patient outcomes.

As water crises become severe, the desire to explore alternative strategies that focus on the demand-side of water-conservation increase. Changing behaviour through persuasion (message framing) can be an integral part of providing water demand solutions. In this study, we examined the effectiveness of messages related to household water use on water scarcity and intentions to act. We tested whether relationships between communication and water conservation were mediated via increasing capability, opportunity, and motivation behaviour (COM-B dimensions). We applied two message types related to concern about severe water scarcity and conservation strategies to the behaviour change conditions in two combinations: (1) severe water scarcity and water-saving tips/strategies, and (2) severe water scarcity and no water-saving tips/strategies. There was broad support for the hypothesis that COM-B dimensions would mediate the effect of message type on water scarcity concern and intentions to act in conservation activities. Households that received the message framed in terms of water-saving tips/strategies expressed greater water scarcity concern and higher intention to act than those that received the no water-saving tips/strategies message. Mediation analyses showed that the message framed in terms of specific water-saving tips/strategies was mediated by increasing households’ capacity (self-efficacy), opportunity and/or motivation in water-conservation actions. Thus, specific water-conservation strategies made available to households have a stronger impact on water-conservation behaviour because these messages appeal to behavioural change conditions.

Aim: Riparian ecosystems are regarded as vulnerable to the effects of climate change. Because of their reliance on passive dispersal to migrate from areas where conditions have become unfavourable, plants are particularly susceptible. On dryland river floodplains, the species diversity of herbaceous annuals is often high while that of structurally dominant woody perennials is low. We examined gene flow genetic structure and dispersal in Acacia stenophylla, a small perennial tree widely distributed throughout river systems of inland Australia. The role of the river corridor in shaping patterns of gene flow and genetic structure is also investigated. Location: Murray-Darling Basin, south eastern Australia. Methods: A total of 127 individuals, from 12 subpopulations located on seven rivers were genotyped at 13 microsatellite loci. Several population and landscape genetic tools were applied to the microsatellite data to evaluate spatial patterns of gene flow and genetic structure and make inferences regarding possible modes of dispersal. Results: High gene flow and weak genetic structure was identified for the 12 subpopulations of A. stenophylla sampled, a surprising result given large distances between subpopulations. Pairwise genetic distance between subpopulations was low to moderate and could largely be explained (R2 = 0.68) by two variables: distance along the river and the proportion of no flow days. structure analysis revealed two genetic clusters. Subpopulations located on the Darling and Lower Balonne rivers were dominated by cluster one while subpopulations from the Warrego and Paroo rivers showed largely mixed ancestry with individuals descending from both clusters one and two. Main Conclusions: These results indicate that the river corridor facilitates extensive gene flow between subpopulations of A. stenophylla in this system. Hydrochory appears to be the dominant process; however, upstream movements of propagules most probably via animal movement are sufficient to negate effects expected under unidirectional dispersal.

River networks have the potential to permanently remove nitrogen through denitrification. Few studies have measured denitrification rates within an entire river network or assessed how land use affect rates at larger spatial scales. We sampled 108 sites throughout the network of the Fox River watershed, Wisconsin, to determine if land use influence sediment denitrification rates, and to identify zones of elevated sediment denitrification rates (hot spots) within the river network. Partial least squares regression models identified variables from four levels of organization (river bed sediment, water column, riparian zone, and watershed) that best predicted denitrification rates throughout the river network. Nitrate availability was the most important predictor of denitrification rates, while land cover was not always a good predictor of local-scale nitrate concentrations. Thus, land cover and denitrification rate were not strongly related across the Fox River watershed. A direct relationship between denitrification rate and watershed land cover occurred only in the Wolf River sub-watershed, the least anthropogenically disturbed of the sub-watersheds. Denitrification hot spots were located throughout the river network, regardless of watershed land use, with hot spot location being determined primarily by nitrate availability. In the Fox River watershed, when nitrate was abundant, river bed sediment character influenced denitrification rate, with higher denitrification rates at sites with fine, organic sediments. These findings suggest that denitrification occurring throughout an entire river network, from headwater streams to larger rivers, can help reduce nitrogen loads to downstream water bodies.

Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months, p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%, p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.

In the face of mounting environmental problems, it is essential that accurate and timely scientific information is available to inform policy development and guide management. Scientists have specialised knowledge necessary for evidenced-based decision making, but despite extensive literature on the interface between science and policy, there is little guidance on achieving policy relevance while maintaining high standards of scientific integrity. Here, we provide a set of principles for environmental scientists to engage with policy makers and environmental water managers. We propose the adoption of a contemporary pluralistic approach using a diversity of modes of engagement between scientists, policy makers, and managers. We define a set of ‘roles’ for environmental scientists to engage effectively with policy and management, and discuss the advantages and pitfalls of each. We illustrate the breadth of modes of engagement at the science-policy-management interface using an example from Australia’s largest river system, the Murray-Darling Basin. We challenge the anachronistic, yet persistent concept that engaging with industry or government compromises the objectivity of involved scientists. We argue that there are multiple assurance processes in place to protect scientific integrity. Society needs scientists to be actively involved in finding solutions to the many urgent environmental issues we are facing, and if our principles are followed there are opportunities for healthy interaction between science, policy, and management.

Author contributions: MWS and MCT contributed equally to all aspects of this research and manuscript preparation. Key Points 1. The physical character of different functional process zones (FPZs)-r...

BackgroundThe combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome.MethodsThis multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS).ResultsA total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema.ConclusionsThe development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment.

Introduction Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients. Methods In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast ( Results Median follow-up time was 30.5 (range 0.8–154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40–0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45–1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%. Conclusion Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.

Background Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. Methods This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. Results Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4–1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2–2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3–1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8–2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6–1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5–1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. Conclusions Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

Hydropeaking leads to major anthropogenic disturbance of river networks worldwide. Flow variations imposed by hydropeaking may significantly affect macroinvertebrate assemblages within the river network. As such, the responses of macroinvertebrate assemblages to hydropeaking are expected to be complex and vary across spatial and temporal scales as well as ecological organization levels. To unpack this complexity, we assessed the interplay of geomorphic and hydrological variables as drivers of the responses of macroinvertebrate assemblages to hydropeaking. Specifically, we studied different levels of ecological organization of macroinvertebrate assemblages in two functional process zones (FPZs; Sub-Andean and Central Valley Gravel Dominated) subjected to different flow management in two Chilean Andean river networks. Hydropeaking caused significant reduction of macroinvertebrate abundances in both FPZs and at all ecological organization levels with the exception of one feeding guild (scrapers). Furthermore, the response of macroinvertebrate assemblage variance was stronger in the Central Valley Gravel Dominated FPZ. Both geomorphic and hydrological variables influenced macroinvertebrate assemblage responses. However, the effects of the principal geomorphic variables operated at valley (meso) spatial scale and the main hydrological variables operated at the sub-daily (micro) temporal scale. Therefore, to minimise the effects of hydropeaking on macroinvertebrate assemblages, flow management should consider reduction of sub-daily variability. Furthermore, placement of new barriers should take into account not only their position within the river network but also their effects downstream that strongly depend on characteristics of river valley.

Chronic wounds of the lower extremities affect 1-2% of the western population and represent a significant impairment of the quality of life of the patients. In addition to the identification and treatment of the underlying causes, compression therapy represents a decisive and established therapeutic method. A targeted compression works by reducing edema and also by improving the hemodynamics. After the exclusion of contraindications, clinically different systems are used in the decongestion phase as well as for prophylaxis. Therapeutic options should be discussed together with the patient and family members in order to optimize the effect and increase the adherence to the chosen therapy.

The approval of BRAF and MEK inhibitors has signifi-cantly improved treatment outcomes for patients with BRAF-mutated metastatic melanoma. The 3 first-line targeted therapy trials have provided similar results, and thus the identification of predictive biomarkers may generate a more precise basis for clinical deci-sion-making. Elevated baseline lactate dehydrogenase (LDH) has already been determined as a strong prog-nostic factor. Therefore, this indirect analysis compa-red subgroups with elevated baseline LDH across the pivotal targeted therapy trials co-BRIM, COMBI-v and COLUMBUS part 1. The Bucher method was used to compare progression-free survival, objective response rate and overall survival indirectly. The results show a non-significant risk reduction for progression in the subgroup with elevated baseline LDH receiving vemu-rafenib plus cobimetinib compared with dabrafenib plus trametinib and encorafenib plus binimetinib. Al-though an indirect comparison, these data might pro-vide some guidance for treatment recommendations in melanoma patients with elevated LDH.

Resilience is a well‐used term in many disciplines, but inconsistently or little applied in river geomorphology and river science. Recent developments in ecosystem ecology conceptualize resilience as comprising system resistance to, and recovery from disturbance. The objectives of this paper are to consider how the concept of resilience in this bivariate form applies to river geomorphology and provide a framework for bridging the disciplines of ecology and geomorphology within the setting of river management, using principles of resilience. River geomorphology sets the physical template upon which lotic processes act, thus, understanding the resilience of this template is critical. The importance of consistency in defining the principles of resilience thinking within the context of river science and management is important especially when promoting ecosystem resilience as a river management goal. The application of resilience thinking with respect to river habitat is provided through a series of examples from Australian and New Zealand river systems. AIM: How is the concept of resilience applied to river geomorphology, and what does a geomorphologically resilient river look like?

PURPOSE BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K–mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively ( P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.