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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.

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.

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.

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.

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.

CTLA-4 and PD-1 play a key role in tumor-induced downregulation of lymphocytic immune responses. Immune checkpoint inhibitors have been shown to alter the immune response to various cancer types. Anti-CTLA-4 and anti-PD-1 antibodies affect the interaction between tumor, antigen-presenting cells and T lymphocytes. Clinical studies of the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab have provided evidence of their positive effects on overall survival in melanoma patients. Combined treatment using ipilimumab and nivolumab has been shown to achieve five-year survival rates of 52 %. Such enhancement of the immune response is inevitably associated with adverse events. Knowledge of the spectrum of side effects is essential, both in terms of prevention and management. Adverse events include colitis, dermatitis, hypophysitis, thyroiditis, hepatitis and other, less common autoimmune phenomena. In recent years, considerable progress has been made in the detection and treatment of the aforementioned immune-related adverse events. However, early diagnosis of rare neurological or cardiac side effects, which may be associated with increased mortality, frequently pose a challenge. The present update highlights our current understanding as well as new insights into the spectrum of side effects associated with checkpoint inhibitors and their management.

BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear. METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression. RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007). CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials. peerReviewed

Biocomplexity is an emergent property of ecosystems that captures the interplay of structures and processes at multiple scales. These interactions can establish a dynamic habitat template that serves as a filter to define ecological organization across landscapes. Studies of biocomplexity in floodplain rivers typically focus on hydrological variability or geomorphic heterogeneity separately, with their interactions being an output rather than the direct focus of investigations. This study examines the interaction of hydrological variability and geomorphic heterogeneity across 25 off‐channel habitats (OCHs) of the Upper Mississippi River, USA. Questions posed were as follows: What are the interactive effects of hydrological variability and geomorphic heterogeneity shaping the physical habitat template of OCHs? and How does the organization of the physical habitat template influence fish community composition within OCHs? Three distinct OCH groups emerged from this study: where hydrological variability defined Group 1 (Lake group); Group 2 was organized via geomorphic heterogeneity (Backwater group); and a combination of hydrological and geomorphological variables defined Group 3 (Slackwater group). Thus, the differential interaction of hydrology and geomorphology defined the dynamic physical habitat template of OCHs in this riverine landscape. No significant difference between the association matrices of the hydrogeomorphic template and fish community composition for the 25 OCH sites was recorded. A priori grouping of fish into the three OCH groups revealed marked differences in fish community composition. A subset of hydrogeomorphic variables that defined the physical character of the OCHs acted as an environmental filter for the fish community composition of the three OCH groups. A conceptual model explaining hydrogeomorphic–ecological interactions across the OCHs of this floodplain river system is provided.

Aim To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy. Methods The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised. Results Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III–IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases. Conclusion Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti–programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.

Factors that influence behavioral response (barriers and drivers) are important for household water-conservation practices. These factors either support or inhibit sustainable behavior. In this research, a latent profile analysis (LPA) was used within the capability-, opportunity-, and motivation-behavior (COM-B) framework to identify key barriers and drivers of household water-conservation behaviors. Participants (N = 510, mean age = 56.08 years, SD = 14.71) completed measures of psycho-social constructs related to barriers and drivers of water-conservation behavior. An LPA yielded a 3-profile statistical solution: capability (35.8%), opportunity (23.2%), and motivation (41.0%) conceptualizing levels of barriers and drivers of water-conservation behavior. Major identified barriers and drivers associated with these profile groupings were time constraints, acuity of water-efficient devices, lack of skills to adopt conservation practices, and availability of incentives/disincentives for water-saving devices. Validation analyses showed that the three COM-B groups diverged considerably based on socio-demographic status and actual water-conservation behavior. Results are pertinent to water authorities in identifying interventions to reduce barriers and promote drivers of positive household water-conservation behaviors by altering and directing appropriate COM-B dimensions to individual water consumers.

Floodplain surface topography is an important component of floodplain ecosystems. It is the primary physical template upon which ecosystem processes are acted out, and complexity in this template can contribute to the high biodiversity and productivity of floodplain ecosystems. There has been a limited appreciation of floodplain surface complexity because of the traditional focus on temporal variability in floodplains as well as limitations to quantifying spatial complexity. An index of floodplain surface complexity (FSC) is developed in this paper and applied to eight floodplains from different geographic settings. The index is based on two key indicators of complexity, variability in surface geometry (VSG) and the spatial organisation of surface conditions (SPO), and was determined at three sampling scales. FSC, VSG, and SPO varied between the eight floodplains and these differences depended upon sampling scale. Relationships between these measures of spatial complexity and seven geomorphological and hydrological drivers were investigated. There was a significant decline in all complexity measures with increasing floodplain width, which was explained by either a power, logarithmic, or exponential function. There was an initial rapid decline in surface complexity as floodplain width increased from 1.5 to 5 km, followed by little change in floodplains wider than 10 km. VSG also increased significantly with increasing sediment yield. No significant relationships were determined between any of the four hydrological variables and floodplain surface complexity.

International audience; Resilience thinking has many parallels in the study of geomorphology. Similarities and intersections exist between the scientific discipline of geomorphology and the scientific concept of resilience. Many of the core themes fundamental to geomorphology are closely related to the key themes of resilience. Applications of resilience thinking in the study of natural and human systems have expanded, based on the fundamental premise that ecosystems, economies, and societies must be managed as linked social-ecological systems. Despite geomorphology and resilience sharing core themes, appreciation is limited of the history and development of geomorphology as a field of scientific endeavor by many in the field of resilience, as well as a limited awareness of the foundations of the former in the more recent emergence of resilience. This potentially limits applications of resilience concepts to the study of geomorphology. In this manuscript we provide a collective examination of geomorphology and resilience as a means to conceptually advance both areas of study, as well as to further cement the relevance and importance of not only understanding the complexities of geomorphic systems in an emerging world of interdisciplinary challenges but also the importance of viewing humans as an intrinsic component of geomorphic systems rather than just an external driver. The application of the concepts of hierarchy and scale, fundamental tenets of the study of geomorphic systems, provide a means to overcome contemporary scale-limited approaches within resilience studies. Resilience offers a framework for geomorphology to expand its application into the broader social-ecological domain.

Spatial variation in hydraulic conditions in streams often results in distinct water surface patterns, or surface flow types. Visual assessments of the distribution of surface flow types have been used to provide rapid assessment of habitat heterogeneity. The efficacy of this approach is predicated on the notion that surface flow types consistently represent a distinct suite of hydraulic conditions with biological relevance. This study tested this notion, asking three specific questions. First, do surface flow types provide a characterisation of physical habitat that is relevant to macroinvertebrates? Second, how well do near-bed hydraulic conditions explain macroinvertebrate distributions? Third, what components of near-bed hydraulic conditions exert the strongest influence on macroinvertebrate distributions? Results show that hydraulic conditions (incorporating direct measurements of near-bed velocity and turbulence in three dimensions) and substratum character (incorporating estimates of particle size distribution, and biofilm and macrophyte cover) within each surface flow type were largely distinct and that macroinvertebrate assemblages differed across flow types in taxon richness and assemblage composition, thus supporting the notion that rapid assessments of surface flow type distributions provide biologically relevant information. Macroinvertebrate assemblages were most strongly correlated with water depth, size of a flow type patch, near-bed velocity in the downstream direction, turbulence in the transverse direction, % pebble, % sand, % silt and clay and macrophyte cover. This study suggests that surface flow type mapping provides an assessment of physical habitat that is relevant to macroinvertebrates. The strong relationship detected between macroinvertebrate assemblages and transverse turbulence also highlights the value of directly measuring near-bed hydraulics. Further investigations are required to test the mechanisms underlying this relationship.

Background: Concepts of reconstruction of intraoral structures may often include the transfer of flaps composed of external skin with hairs. Given that intraoral hair growth following myocutaneous flaps can cause discomfort, there is a need for effective treatments to relieve cancer patients of these symptoms. Objective: To describe the successful epilation of hairy intraoral flaps using Nd:YAG laser emitting a wavelength of 1,064 nm. Methods: We performed an interdisciplinary prospective clinical study with 9 patients suffering from intraoral hair growth after plastic reconstruction of a hairy donor site due to cancer. Eight male and one female patients were treated with 1-4 sessions of Nd:YAG laser at 5-15-week intervals. Results: Laser treatment resulted in effective hair reduction in 8/9 patients regardless of flap type. In 5/9 patients a hair clearance of >90% could be achieved, whereas laser treatment was ineffective in one male with white hair. Patients were very satisfied with the outcome and no side effects could be observed. Conclusion: Nd:YAG laser therapy appears to be a successful therapeutic option for patients suffering from growth of dark hair in the oral cavity after plastic reconstruction using a hairy donor site.

Murray-Darling Freshwater Research CentreMDFRC item.Soil seed banks are an important component of plant community diversity in ephemeral wetlands, allowing many species to persist through unpredictable periods of flood and drought. Spatial variation of extant vegetation in such habitats commonly reflects patterns of flood history and often varies predictably between broadly differing hydro-geomorphic habitat types. Here we investigate whether spatial variation of soil seed banks is similarly controlled by fluvial processes at this scale. Results are presented from a seedling emergence trial using samples collected from a range of habitat types, and at different scales within these, in the ephemeral Narran Lakes system in semi-arid Australia. Composition and structure of soil seed banks varied significantly between habitat types reflecting broad differences in flood frequency. As predicted, germinable seed abundance was found to be highest in intermediately flooded habitats. Variability in soil seed bank composition at a local scale was also found to be influenced by hydrology with greater spatial heterogeneity evident in the river channel as well as amongst the least frequently inundated riparian and floodplain habitats.