Unraveling spatial heterogeneity of soil legacy phosphorus in subtropical grasslands.

Humans have profoundly altered phosphorus (P) cycling across scales. Agriculturally driven changes (e.g., excessive P-fertilization and manure addition), in particular, have resulted in pronounced P accumulations in soils, often known as "soil legacy P." These legacy P reserves serve as persistent and long-term nonpoint sources, inducing downstream eutrophication and ecosystem services degradation. While there is considerable scientific and policy interest in legacy P, its fine-scale spatial heterogeneity, underlying drivers, and scales of variance remain unclear. Here we present an extensive field sampling (150-m interval grid) and analysis of 1438 surface soils (0-15 cm) in 2020 for two typical subtropical grassland types managed for livestock production: Intensively managed (IM) and Semi-natural (SN) pastures. We ask the following questions: (1) What is the spatial variability, and are there hotspots of soil legacy P? (2) Does soil legacy P vary primarily within pastures, among pastures, or between pasture types? (3) How does soil legacy P relate to pasture management intensity, soil and geographic characteristics? and (4) What is the relationship between soil legacy P and aboveground plant tissue P concentration? Our results showed that three measurements of soil legacy P (total P, Mehlich-1, and Mehlich-3 extractable P representing labile P pools) varied substantially across the landscape. Spatial autoregressive models revealed that soil organic matter, pH, available Fe and Al, elevation, and pasture management intensity were crucial predictors for spatial patterns of soil P, although models were more reliable for predicting total P (68.9%) than labile P. Our analysis further demonstrated that total variance in soil legacy P was greater in IM than SN pastures, and intensified pasture management rescaled spatial patterns of soil legacy P. In particular, after controlling for sample size, soil P was extremely variable at small scales, with variance diminished as spatial scale increased. Our results suggest that broad pasture- or farm-level best management practices may be limited and less efficient, especially for more IM pastures. Rather, management to curtail soil legacy P and mitigate P loading and losses should be implemented at fine scales designed to target spatially distinct P hotspots across the landscape.

Enhanced immune reconstitution with albuvirtide in HIV-infected immunological non-responders.

Background: Incomplete immune recovery in people living with HIV/AIDS (PLWHA) remains an important clinical challenge with the lack of an effective strategy currently available to restore their T-cell immune response. This study aimed to evaluate the effect of Albuvirtide (ABT) on immune recovery in immunological non-responders (INRs) and attempted to explore potential mechanisms of ABT on the functionality of immune cells. Methods: In this prospective, open-label, controlled clinical study, participants with incomplete immune reconstitution (continuous ART over 5 years and CD4+T lymphocyte absolute count of <500 cells/µl or ART for 2-5 years and CD4+T cell count of <200 cells/µl with undetectable viral load) were received intensive treatment with ABT or maintained on the original ART regimen at a ratio of 1:1. Immune response and safety were examined within 24 weeks. In the cytological study, T subsets, cell apoptosis and cell autophagy were analyzed using immunofluorescence staining and flow cytometry from 25 blood specimens. Results: Both groups (n=25 each) were comparable in age, gender, and ART duration. At week 12, CD4+T cell count increased significantly in the intensive ABT group compared with control group (the change from baseline in CD4+T cell count: 45 vs. -5 cells/µL, p<0.001). After ABT discontinuation, CD4+T cell counts remained significantly higher in the intensive ABT group at week 24 (55 vs. -5 cells/µL, p=0.012). In laboratory analysis, naïve CD4+ T cell amounts were lowest among participants with unsatisfactory immune response (uIR) to ABT (p=0.001). The proportion of caspase 3+CD45RA+CD31+CD4+ T cells was significantly lower in participants with satisfactory immune response (sIR) to ABT (p<0.05). Conclusion: Significant CD4+T cell count increase suggests ABT enhances immune function in INRs which may be attributed to its antiviral properties as well as its ability to increase thymic cell output and decrease cell apoptosis.

Digital design of an integrated purification system for continuous pharmaceutical manufacturing.

In this work dynamic models of the continuous crystallization, filtration, deliquoring, washing, and drying steps are introduced, which are developed in the open-source pharmaceutical modeling tool PharmaPy. These models enable the simulation and digital design of an integrated continuous two-stage crystallization and filtration-drying carousel system. The carousel offers an intensified process that can manufacture products with tailored properties through optimal design and control. Results show that improved crystallization design enhances overall process efficiency by improving critical material attributes of the crystal slurry for downstream filtration and drying operations. The digital design of the integrated process achieves enhanced productivity while satisfying multiple design and product quality constraints. Additionally, the impact of model uncertainty on the optimal operating conditions is investigated. The findings demonstrate the systematic process development potential of PharmaPy, providing improved process understanding, design space identification, and optimized robust operation.

Is There an Opportunity to De-Escalate Treatments in Selected Patients with Metastatic Hormone-Sensitive Prostate Cancer?

The treatment landscape for metastatic hormone-sensitive prostate cancer continues to evolve, with systemic treatment being the mainstay of current treatment. Prognostic and predictive factors such as tumour volume and disease presentation have been studied to assess responses to different treatments. Intensification and de-escalation strategies arouse great interest, so several trials are being developed to further personalize the therapy in these populations. Is there an optimal sequence and a possible option to de-intensify treatment in selected patients with a favourable profile? This and other goals will be the subject of this review.

Treatment intensification in Kawasaki disease - current perspectives.

INTRODUCTION: Intravenous immunoglobulin is the standard of care in Kawasaki disease. However, a subset of patients exhibits resistance to intravenous immunoglobulin treatment, even when Kawasaki disease is promptly diagnosed and managed. While intravenous immunoglobulin reduces the occurrence of coronary artery abnormalities from 15-25% to 3-5%, it does not entirely eliminate the risk. Besides, management guidelines for non-coronary complications of Kawasaki disease, for instance, myocarditis, remain speculative. AREAS COVERED: Recent literature suggests that a subset of patients with Kawasaki disease may benefit from treatment intensification with drugs, such as corticosteroids, infliximab, anakinra, and/or ciclosporin. In this manuscript, we have reviewed recent advances in the management of Kawasaki disease, especially with regard to preemptive intensification of therapy in children at high risk of cardiac complications. A comprehensive search was made using Web of Science, Scopus, and PubMed databases to gather English articles published from 1967 to 2023 on the treatment of Kawasaki disease. We incorporated the following words in the search strategy: 'Kawasaki disease,' 'intravenous immunoglobulin/IVIg,' 'intravenous immunoglobulin/IVIg-resistant Kawasaki disease,' 'treatment intensification,' or 'primary intensification of treatment/therapy.' EXPERT OPINION: The 'high-risk' group in Kawasaki disease needs to be identified with early intensification of primary therapy for better coronary and myocardial outcomes.

Process intensification of pharmaceutical powder blending at commercial throughputs by utilizing semi-continuous mini-blending.

Process intensification involves the miniaturization of equipment while retaining process throughput and performance. The pharmaceutical industry can benefit from this approach especially during drug product development, where the availability of active pharmaceutical ingredients (API) is often limited. It reduces the need for process scale up, as equipment used during product development and commercial production is identical. However, applications of process intensification for processing pharmaceutical powders are limited so far. Here we show that semi-continuous mini-blending can be utilized for process intensification of blending of API and excipients. Uniform blending at commercially relevant throughputs was achieved through mini-blends with a volume of less than ten liters. Our results demonstrate that blending speed, cycle time and blender fill level can be optimized without compromising blending performance. Acceptable blend uniformity is obtained over a broad range of operating parameters, by choosing the right excipients. The optimized throughput of the mini-blending process is in line with the desired throughput of a commercial Continuous Direct Compression (CDC) process.

One-pot, microwave (MW)-assisted production of furfural from almond-, oil-, and wine-derived co-products through biorefinery-based approaches.

This work outlines the first microwave (MW)-assisted protocol for the production of biofuel precursor furfural (FF) from the raw agricultural waste almond hull (AH), olive stone (OS), and the winemaking-derived grape stalk (GS), grape marc (GM) and exhausted grape marc (EGM) through a one-pot synthesis process. To enhance the overall yield, a catalytic process was firstly developed from xylose, major constituent of hemicellulose present in lignocellulosic biomass. This method afforded FF with 100 % selectivity, yielding over 85 % in isolated product when using H2SO4, as opposed to a 37 % yield with AlCl3·6H2O, at 150 °C in only 10 min. For both catalysts, the developed methodology was further validated, proving adaptable and efficient in producing the targeted FF from the aforementioned lignocellulosic raw materials. More specifically, the employment of AlCl3·6H2O resulted in the highest selectivity (up to 89 % from GM) and FF yield (42 % and 39 % molar from OS and AH, respectively), maintaining notable selectivity for the latter (61 and 48 % from AH and OS). At this regard, and considering the environmental factor of sustainability, it is important to point out the role of AlCl3·6H2O in contrast to H2SO4, thus mitigating detrimental substances. This study provides an important management of agricultural waste through sustainable practises for the development of potential bio-based chemicals, aligning with Green Chemistry and process intensification principles.

Innovations in cell culture-based influenza vaccine manufacturing - from static cultures to high cell density cultivations.

Influenza remains a serious global health concern, causing significant morbidity and mortality each year. Vaccination is crucial to mitigate its impact, but requires rapid and efficient manufacturing strategies to handle timing and supply. Traditionally relying on egg-based production, the field has witnessed a paradigm shift toward cell culture-based methods offering enhanced flexibility, scalability, and process safety. This review provides a concise overview of available cell substrates and technological advancements. We summarize crucial steps toward process intensification - from roller bottle production to dynamic cultures on carriers and from suspension cultures in batch mode to high cell density perfusion using various cell retention devices. Moreover, we compare single-use and conventional systems and address challenges including defective interfering particles. Taken together, we describe the current state-of-the-art in cell culture-based influenza virus production to sustainably meet vaccine demands, guarantee a timely supply, and keep up with the challenges of seasonal epidemics and global pandemics.

Intensification of Cr(VI) adsorption using activated carbon adsorbent modified with ammonium persulfate.

Granular activated carbon has been modified by ammonium persulfate as a new adsorbent for Cr(VI) adsorption from aqueous solutions. The adsorbent was characterized by nitrogen adsorption-desorption isotherm data and infrared spectroscopy. The impact of different factors, such as the initial pH level of the solution, time, temperature, ionic strength, and initial concentration of the Cr(VI) ion, on the adsorption efficiencies of the adsorbent has been studied by batch experiments. Kinetic studies and the adsorption thermodynamics of Cr(VI) with ammonium persulfate-modified activated carbon adsorbent were carefully studied. The results showed that the Cr(VI) adsorption follows a pseudo-second-order kinetic model and the adsorption reaction is endothermic and spontaneous. The adsorption isotherm was scrutinized, and the fitting results showed that the Langmuir model could well represent the adsorption process. The maximum adsorption capacity of Cr(VI) onto persulfate-modified activated carbon was 108.69 mg g-1. The research results showed that using persulfate-modified activated carbon adsorbent can greatly remove Cr(VI) from aqueous solutions.

A Real World Observational Study Characterizing Patients With Advanced Prostate Cancer Treated With or Without Androgen Receptor-Pathway-Inhibitor Therapies in Alberta, Canada.

BACKGROUND: Data are needed to improve the current understanding of clinical management and characteristics of patients with advanced prostate cancer (PC) treated with androgen receptor pathway inhibition (ARPI) therapy. METHODS: This retrospective cohort study using real-world, population-level data from Alberta, Canada included all individuals diagnosed in 2017-2020 with de novo metastatic castration-sensitive PC (mCSPC) or nonmetastatic castration-resistant PC (nmCRPC) who initiated androgen deprivation therapy (ADT). For mCSPC, patients were classified as ARPI-exposed if they received an ARPI within 180 days of initiating ADT, while patients with nmCRPC were classified as ARPI-exposed if they received an ARPI within 2 years of diagnosis. RESULTS: This study included 976 patients with mCSPC and 233 with nmCRPC of which 33.5% and 25.3% received an ARPI, respectively. The proportion of patients with mCSPC treated with an ARPI increased considerably for patients diagnosed in 2020 compared to 2017 (56.2% vs. 6.0%). In contrast, the use of ARPI to treat nmCRPC only increased marginally from 2017 to 2019/2020 (19.7% vs. 28.9%). Patients with mHSPC who were ARPI-exposed had longer median survival than patients who were ARPI-naive (38.47 (95% CI = 32.84-NA) vs. 34.19 (95% CI = 33.33-38.83; P = .03)), with a higher proportion of patients surviving to 2-years. For nmCRPC, survival was similar between ARPI-exposed and ARPI-naive. In multivariable analyses, receiving ARPI for mCSPC was associated with younger patient age, more recent diagnoses, fewer comorbidities, a higher number of metastatic sites, referral to a medical oncologist as well as receiving surgery and radiation before ADT. Receiving ARPI for nmCRPC was associated with referral to a medical oncologist, younger age, and more recent diagnoses. CONCLUSIONS: Outcome analyses in this population suggest a continued unmet clinical need and complex clinical management pathways. Given that treatment pathways have evolved considerably, continued follow-up to understand the impact of these advancements on patient outcomes are warranted.

Intensively Reared Nelore Steers with Levels of Concentrate and Protein Sources during the Dry Season.

The objective of this study was to evaluate the effect of different nutritional strategies on the intensification of beef cattle farming on pastures during the dry period of the year. Eighty male cattle (testers) were randomly allocated to 16 paddocks formed with Mombaça grass (Megathyrsus maximus), totaling five animals (testers) per paddock. The strategies consisted of two LCs [10 and 16.7 g·kg-1 body weight (BW)] and two PSs with DDGS and SBM in a completely randomized design with a 2 × 2 factorial arrangement. The chemical, structural, and productive characteristics of the forage were evaluated, as well as the performance, productivity, and serum parameters of the supplemented animals. The forage presented a greater L:C (p = 0.033) and CP content (p = 0.007) when the lowest LC was used. Animals that received the highest LC had the highest supplement intake (p < 0.001) and the lowest pasture intake (p < 0.001). The nutritional strategy with an LC of 16.7 g·kg-1 of body weight (BW) resulted in a greater increase in total BW, i.e., 200 kg·BW ha-1 more. Therefore, higher levels of concentrate ensure greater productivity for beef cattle grazing, and DDGS can replace SBM in supplements used in the intensive raising of beef cattle on pasture without compromising the performance and productivity of the animals.

Subsurface wastewater infiltration systems for nitrogen pollution control.

Subsurface wastewater infiltration systems (SWISs) are suggested to be a cost-effective and environmentally friendly method for sewage treatment. However, a comprehensive summary of the relevant mechanisms and optimization methods for nitrogen (N) removal in SWIS is currently lacking. In this review, we first summarize the N transformation mechanisms in SWIS. The impact of operational parameters on the N removal efficiency is then delineated. To enhance pollutant removal and minimize resource wastage, it is advisable to maintain a wet-dry ratio of 1:1 and a hydraulic loading rate of 8-10 cm/day. The organic load should be determined based on influent characteristics to optimize the balance between sewage treatment and nitrous oxide (N2O) emission. Finally, various strategies and modifications have been suggested to enhance pollutant removal efficiency and reduce N2O emissions in SWIS, such as artificial aeration, supply electron donors, and well-designed structures. Overall, greater emphasis should be placed on the design and management of SWIS to optimize their co-benefits while effectively controlling N pollution. PRACTITIONER POINTS: SWISs are often considered black boxes with their efficiency depending on hydraulic characteristics, biological characteristics, and substrate properties. Biological nitrification coupled with denitrification is considered to be the major N removal process. Increasing the reduction of N2O to the inert N2 form is a potential mechanism to mitigate global warming. Strategies such as artificial aeration, supply electron donors, and well-designed structures are suggested to improve N removal performance.

Land-use intensification exerts a greater influence on soil microbial communities than seasonal variations in the Taihu Lake region, China.

The Taihu Lake region has undergone intensive land-use conversions from natural wetlands (NW) to conventional rice-wheat rotation fields (RW) and further to greenhouse vegetable fields (GH). Nevertheless, the effects of these conversions on soil microbes, particularly in wetland ecosystem, are not well explicit. To explore the impact of land-use intensification on soil microbial communities, monthly soil samples were obtained from replicate plots representing three land-use types (NW, RW, and GH) in subtropical wetlands and then subjected to amplicon sequencing. Land-use intensification had direct effects on bacterial and fungal community composition, with a more pronounced impact on bacteria than on fungi. These changes in bacterial communities were closely correlated with variations in soil environmental variables, such as NO3--N, pH, and electrical conductivity. Land-use intensification led to a decrease in bacterial deterministic processes, with an opposing trend observed in the fungal community. In addition, arable lands (RW and GH), which are affected by anthropogenic activities, exhibited more complex networks. Potential metabolic functional groups in GH had higher absolute abundance. Seasonal variations significantly influenced microbial diversity, composition, and potential metabolic functional groups within each land-use type, particularly in summer, although the magnitude of this impact was much smaller than the impact of land-use intensification. Our findings emphasize the importance of comprehending the ecological consequences of land-use intensification in wetlands for sustainable resource management and biodiversity conservation.

Multidisciplinary real-world management of metastatic castration-sensitive prostate cancer: A French national study (PROFILE study).

While androgen deprivation therapy (ADT) has been the standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC), recent strategies like intensification of systemic treatment (Rozet et al., 2020) (i.e. adding another treatment to ADT) and radiotherapy have improved overall survival. PROFILE, a national retrospective multicentric real-world study, involved patients with mCSPC recruited by medical oncologists, urologists, and radiation oncologists, and who started treatment between November 2020 and May 2021. Patients by sites were included consecutively. Data were collected from medical records. Primary objectives were to: (1) describe retrospectively the characteristics of whole population of patients with mCSPC as well as subgroups defined by prognostic factors in France at diagnosis; (2) identify current practices for managing mCSPC in a real-life clinical setting. Among the 416 patients with mCSPC included in the PROFILE study, 315 (76%) were synchronous (metastasis at the initial diagnosis) and 101 (24%) were metachronous patients (metastasis diagnosed post-progression). A majority (83% of synchronous and 73% of metachronous patients) received an intensified systemic treatment (ADT plus ARSI [androgen-receptor signaling inhibitors]±chemotherapy±primary tumour radiotherapy±metastasis-directed therapy [MDT]), while only 40% of low-volume patients received prostate radiotherapy. This study depicts the standardization of new therapeutic strategies for patients with mCSPC in France with most of them receiving an intensified treatment, mainly with ADT+ARSI (64% of synchronous intensified patients and 76% of metachronous intensified patients). Most of patients were assessed using conventional imaging (CT scan and/or bone scan). Overall, PROFILE results are in line with French and European guidelines for diagnosis, management, and follow-up of such patients (Rozet et al., 2020; Cornford et al., 2021).

Expert Opinion on Optimising Type 2 Diabetes Treatment Using Fixed-Ratio Combination of Basal Insulin and GLP-1 RA for Treatment Intensification and Simplification.

The management of type 2 diabetes (T2D) often necessitates treatment intensification, and sometimes simplification to achieve glycaemic targets and mitigate complications. This expert opinion paper evaluates the use and positioning of the fixed-ratio combinations (FRCs) of basal insulin (BI) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in optimising T2D management. On the basis of the evidence presented and discussions, these FRCs offer a promising approach for both treatment intensification and simplification in people with suboptimal glucose control despite receiving various therapies. In treatment intensification, FRCs provide a synergistic effect by addressing multiple pathophysiological defects contributing to hyperglycaemia. These FRCs effectively control both fasting and postprandial glucose (PPG) excursions, offering significantly improved glycaemic control with a lower hypoglycaemia risk and weight neutrality compared to traditional or complex insulin regimens. Moreover, the reduced injection frequency (once daily) and flexibility in the dosing schedule (with any major meal of the day) help mitigate patient resistance to insulin initiation or titration. This further reduces treatment burden, facilitating treatment adherence and enhancing patient convenience. These key benefits of FRCs over complex insulin regimens play a crucial role in long-term glycaemic management and overall treatment outcomes. Hence, the timely use of FRCs in the treatment algorithm for people with T2D represents a valuable strategy for optimising glycaemic control, addressing treatment barriers and enhancing patient-reported outcomes.

Investigations on cavitation flow and vorticity transport in a jet pump cavitation reactor with variable area ratios.

Hydrodynamic cavitation (HC) has emerged as a promising technology for water disinfection. Interestingly, when subjected to specific cavitation pressures, jet pump cavitation reactors (JPCRs) exhibit effective water treatment capabilities. This study investigated the cavitation flow and vorticty transport in a JPCR with various area ratios by utilizing computational fluid dynamics. The results reveal that cavitation is more likely to occur within the JPCR as the area ratio becomes smaller. While as the area ratio decreases, the limit flow ratio also decreases, leading to a reduced operational range for the JPCR. During the cavitation inception stage, only a few bubbles with limited travel distances are generated at the throat inlet. A stable cavitation layer developed between the throat and downstream wall during the limited cavitation stage. In this phase, the primary flow carried the bubbles towards the outlet. In addition, it was found that the vortex stretching, compression expansion, and baroclinic torque terms primarily influence the vorticity transport equation in this context. This work may provide a reference value to the design of JPCRs for water treatment.

Quasi-perfusion studies for intensified lentiviral vector production using a continuous stable producer cell line.

Quasi-perfusion culture was employed to intensify lentiviral vector (LV) manufacturing using a continuous stable producer cell line in an 8-day process. Initial studies aimed to identify a scalable seeding density, with 3, 4, and 5 × 104 cells cm-2 providing similar specific productivities of infectious LV. Seeding at 3 × 104 cells cm-2 was selected, and the quasi-perfusion was modulated to minimize inhibitory metabolite accumulation and vector exposure at 37°C. Similar specific productivities of infectious LV and physical LV were achieved at 1, 2, and 3 vessel volumes per day (VVD), with 1 VVD selected to minimize downstream processing volumes. The optimized process was scaled 50-fold to 1,264 cm2 flasks, achieving similar LV titers. However, scaling up beyond this to a 6,320 cm2 multilayer flask reduced titers, possibly from suboptimal gas exchange. Across three independent processes in 25 cm2 to 6,320 cm2 flasks, reproducibility was high with a coefficient of variation of 7.7% ± 2.9% and 11.9% ± 3.0% for infectious and physical LV titers, respectively. The optimized flask process was successfully transferred to the iCELLis Nano (Cytiva) fixed-bed bioreactor, with quasi-perfusion at 1 VVD yielding 1.62 × 108 TU.

Effects of floral resources on honey bee populations in Mexico: Using dietary metabarcoding to examine landscape quality in agroecosystems.

The decline of honey bee populations significantly impacts the human food supply due to poor pollination and yield decreases of essential crop species. Given the reduction of pollinators, research into critical landscape components, such as floral resource availability and land use change, might provide valuable information about the nutritional status and health of honey bee colonies. To address this issue, we examine the effects of landscape factors like agricultural area, urban area, and climatic factors, including maximum temperature, minimum temperature, relative humidity, and precipitation, on honey bee hive populations and nutritional health of 326 honey bee colonies across varying landscapes in Mexico. DNA metabarcoding facilitated the precise identification of pollen from 267 plant species, encompassing 243 genera and 80 families, revealing a primary herb-based diet. Areas characterized by high landscape diversity exhibited greater pollen diversity within the colony. Conversely, colonies situated in regions with higher proportions of agricultural and urban landscapes demonstrated lower bee density. The maximum ambient temperature outside hives positively correlated with pollen diversity, aligning with a simultaneous decrease in bee density. Conversely, higher relative humidity positively influenced both the bee density of the colony and the diversity of foraged pollen. Our national-level study investigated pollen dietary availability and colony size in different habitat types, latitudes, climatic conditions, and varied levels and types of disturbances. This effort was taken to gain a better insight into the mechanisms driving declines in honey bee populations. This study illustrates the need for more biodiverse agricultural landscapes, the preservation of diverse habitats, and the conservation of natural and semi-natural spaces. These measures can help to improve the habitat quality of other bee species, as well as restore essential ecosystem processes, such as pollination and pest control.

Erectile function preservation after salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: Five-year results of the SAKK 09/10 randomized phase 3 trial.

Objectives: To evaluate effects of dose intensified salvage radiotherapy (sRT) on erectile function in biochemically recurrent prostate cancer (PC) after radical prostatectomy (RP). Materials and methods: Eligible patients had evidence of biochemical failure after RP and a PSA at randomization of ≤ 2 ng/ml. Erectile dysfunction (ED) was investigated as secondary endpoint within the multicentre randomized trial (February 2011 to April 2014) in patients receiving either 64 Gy or 70 Gy sRT. ED and quality of life (QoL) were assessed using CTCAE v4.0 and the EORTC QoL questionnaires C30 and PR25 at baseline and up to 5 years after sRT. Results: 344 patients were evaluable. After RP 197 (57.3 %) patients had G0-2 ED while G3 ED was recorded in 147 (42.7 %) patients. Subsequently, sexual activity and functioning was impaired. 5 years after sRT, 101 (29.4 %) patients noted G0-2 ED. During follow-up, 44.2 % of patients with baseline G3 ED showed any improvement and 61.4 % of patients with baseline G0-2 ED showed worsening. Shorter time interval between RP and start of sRT (p = 0.007) and older age at randomization (p = 0.005) were significant predictors to more baseline ED and low sexual activity in the long-term. Age (p = 0.010) and RT technique (p = 0.031) had a significant impact on occurrence of long-term ED grade 3 and worse sexual functioning. During follow-up, no differences were found in erectile function, sexual activity, and sexual functioning between the 64 Gy and 70 Gy arm. Conclusion: ED after RP is a known long-term side effect with significant impact on patients' QoL. ED was further affected by sRT, but dose intensification of sRT showed no significant impact on erectile function recovery or prevalence of de novo ED after sRT. Age, tumor stage, prostatectomy and RT-techniques, nerve-sparing and observation time were associated with long-term erectile function outcome.ClinicalTrials.gov. Identifier: NCT01272050.

Risk-stratification for treatment de-intensification in WNT-pathway medulloblastoma: finding the optimal balance between survival and quality of survivorship.

INTRODUCTION: Advances in molecular biology have led to consensus classification of medulloblastoma into four broad molecular subgroups - wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4, respectively. Traditionally, children >3 years of age, with no/minimal residual tumor (<1.5 cm2) and lack of metastasis were classified as average-risk disease with >80% long-term survival. Younger age (<3 years), large residual disease (≥1.5 cm2), and leptomeningeal metastases either alone or in combination were considered high-risk features yielding much worse 5-year survival (30-60%). This clinico-radiological risk-stratification has been refined by incorporating molecular/genetic information. Contemporary multi-modality management for non-infantile medulloblastoma entails maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. Aggressive multi-modality management achieves good survival but is associated with substantial dose-dependent treatment-related toxicity prompting conduct of subgroup-specific prospective clinical trials. AREAS COVERED: We conducted literature search on PubMed from 1969 till 2023 to identify putative prognostic factors and risk-stratification for medulloblastoma, including molecular subgrouping. Based on previously published data, including our own institutional experience, we discuss molecular risk-stratification focusing on WNT-pathway medulloblastoma to identify candidates suitable for treatment de-intensification to strike the optimal balance between survival and quality of survivorship. EXPERT OPINION: Prospective clinical trials and emerging biological information should further refine risk-stratification in WNT-pathway medulloblastoma.