•A detailed analysis of fouling mechanisms in MBR systems was carried out;•The RIS model was applied to a protocol encompassing manual physical washing;•We re-evaluated the fouling mechanisms using a ...standard computational approach;•Very high reproducibility of the method across eight different MBR installations;•Delineation of different contributions from cake layer, reversible or irreversible;
Cake layer deposition on a membrane surface can determine both external and internal membrane fouling through negatively affecting the total filtration resistance while exerting a positive effect as a pre-filter. Membranes are usually subjected to a periodic cake layer removal through routine physical cleaning, specifically permeate backwashing of hollow fiber membranes, or enhanced cleaning through, for example, chemically-enhanced backwashing. Physical cake layer removal is crucial for sustaining permeability, yet the effect of different physical cleaning modes remains poorly evaluated. The present work attempts to analyze physical cake layer removal through the application of specific cleaning methods and the impact of these on the subsequent resistance. The constituent contributions to the overall resistance are appraised by means of the Resistances In-Series model, with the aim of producing a robust protocol for quantifying these discrete contributors. The results, based in part on published data, show the proposed approach to reliably determine the relative contribution of the different resistance components to within 0.1 · 1012 m−1 across a range of different bench and pilot-scale plants, confirming the resilience of the method.
We established an international consortium to review and discuss relevant clinical evidence in order to develop expert consensus statements related to cancer management during the severe acute ...respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic. The steering committee prepared 10 working packages addressing significant clinical questions from diagnosis to surgery. During a virtual consensus meeting of 62 global experts and one patient advocate, led by the European Society for Medical Oncology, statements were discussed, amended and voted upon. When consensus could not be reached, the panel revised statements until a consensus was reached. Overall, the expert panel agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty ranging from diagnosis to therapeutic planning and treatment during the COVID-19 pandemic.
Aged or mature leachate, produced by old landfills, can be very refractory; for this reason mature leachate is difficult to treat alone, but it can be co-treated with sewage or domestic wastewater. ...The aim of the study was to investigate the feasibility of leachate co-treatment with synthetic wastewater, in terms of process performance and biomass activity, by means of respirometric techniques. Two sequencing batch reactors (SBRs), named SBR1 and SBR2, were fed with synthetic wastewater and two different percentages of landfill leachate (respectively 10% and 50% v v(-1) in SBR1 and SBR2). The results showed good chemical oxygen demand (COD) removal efficiency for both reactors, with average COD removals equal to 91.64 and 89.04% respectively for SBR1 and SBR2. Furthermore, both SBRs showed good ammonia-nitrogen (AN) removal efficiencies, higher than 60%, thus confirming the feasibility of leachate co-treatment with a readily biodegradable wastewater. Significant respiration rates were obtained for the heterotrophic population (average values of maximum oxygen uptake rate equal to 37.30 and 56.68 mg O2 L(-1) h(-1) respectively for SBR1 and SBR2), thus suggesting the feasibility of leachate co-treatment with synthetic wastewater.
Human epidermal growth factor receptor 2 (HER2)-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 ...antibody–drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from nine different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer; and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This article presents the developed statements, including findings from the expert panel discussions, expert opinion, and a summary of evidence supporting each statement.
•Targeting HER2-low expression with novel antibody-drug conjugates has reshaped the treatment of metastatic breast cancer.•This advancement raised relevant questions pertaining to the definition, diagnosis and management of HER2-low breast cancer.•We gathered 32 international experts to build consensus regarding key controversial topics pertaining HER2-low breast cancer.•A modified Delphi voting methodology was deployed, leading to 20 consensus statements, each with at least 90% consensus among experts.•Ongoing studies may lead to further refinement in our understanding of HER2-low breast cancer.
•The study provides information about MBR operated in alternated aeration condition.•The influence of anoxic phase duration in denitrification efficiency is discussed.•The duration of anoxic phase ...strongly influences soluble EPS production.
The effect of intermittent aeration (IA) on a MBR system was investigated. The study was aimed at analyzing different working conditions and the influence of different IA cycles on the biological performance of the MBR pilot plant, in terms of organic carbon and ammonium removal as well as extracellular polymeric substances (EPSs) production. The membrane modules were placed in a separate compartment, continuously aerated. This configuration allowed to disconnect from the filtration stage the biological phenomena occurring into the IA bioreactor. The observed results highlighted good efficiencies, in terms of organic carbon and ammonium removal. It was noticed a significant soluble microbial products (SMPs) release, likely related to the higher metabolic stress that anoxic conditions exerted on the biomass. However, the proposed configuration, with the membranes in a separate compartment, allowed to reduce the EPSs in the membrane tank even during the non-aerated phase, thus lowering fouling development.
•We explored the role of adjuvant chemotherapy in the treatment of patients with localized lobular breast cancer (ILC)?•In this systematic review of the literature and metanalysis, a role of the ...adjuvant chemotherapy in the setting of ILC was not confirmed. The analysis on 38,387 patients across 8 studies did not show an additional benefit of chemotherapy (Hazard Ratio for Overall Survival: 0.99; 95%CI 0.86–1.14). However, all the investigations were retrospective, and subgroup analyses in high-risk patients showed some signals of possible adjunctive benefits.•Prospective investigations of adjuvant therapies in high-risk patients with ILC are highly warranted. The current decision- making is largely based on evidence from non-randomized clinical investigations, prompting controlled clinical studies.
The role of adjuvant chemotherapy (aCT) for patients with localized lobular breast cancer (ILC) is still controversial. It is unclear what is the magnitude of benefit of the CT in this setting. In this systematic review of the literature and metanalysis, we aimed to estimate the benefit of aCT in addition to the standard treatments in the early ILC setting. We identified the records by searching Medline, CENTRAL, Web of Science, SCOPUS, and Google Scholar, and the meeting proceeding of the principal oncology meetings of the last 10 years, with no language or time restriction. A research strategy was developed with mapped and MeSH terms. Studies on the clinical use of aCT reporting survival outcomes in the ILC setting were double-screened and tabulated. PRISMA methodology was used for data extraction and synthesis. We extracted information on the study design and setting, eligible population and population size, histology variants, menopausal status, treatment regimens, follow-up duration. Hazard ratios (HR) and 95% confidence interval (CI) were extracted and transformed into logHR and corresponding standard error to obtain the Summary HR (SHR). Heterogeneity (I2 statistics) and publication bias (Macaskill test) were tested; a random effect models provided by SAS Proc Mixed was used for data analysis. Sensitivity analysis was conducted to examine the impact of inclusion criteria on the summary results.
Disease-free (DFS), overall (OS) and cancer-specific survival (BCSS) were the primary endpoints of the investigation. The systematic review and metanalysis included 38,387 patients across 8 clinical studies. aCT was not associated with an improvement of OS (SHR 0.99; 95%CI 0.86–1.14), with low heterogeneity (I2 = 28%) and no publication bias (p = 0.43). Sensitivity analysis resulted in unchanged conclusions. We did not perform a metanalysis of the DFS estimates, as only reported in 3 studies. The value of aCT in improving DFS was unconfirmed, consistently with the OS results. Our research did not confirm a certain role of aCT for patients with ILC. Research gaps were identified, warranting the development of prospective, controlled ad hoc investigations.
•Drug development for the treatment of patients with kidney cancer (RCC) is mainly concentrated in high- income countries.•The Regional distribution of clinical trials for RCC is not aligned with the ...burden of RCC.•The polarization of drug development in few countries can widen the ample gaps in the knowledge of benefit of pharmacological agents in different populations.•Generalizability of clinical findings from trials may not be generalizable to non-Caucasian populations, when inclusiveness of diverse ethnic groups is poor.•The implementation of clinical trials can be instrumental to improve the knowledge in poorly- included populations, thus being strategic to benefit patients broadly.
Renal cell cancer (RCC) is the third most diagnosed genitourinary malignancy in the world. Nearly a half of the diagnoses and 60% of related deaths occur in low-middle income countries (LMs), where prognosis is generally poor. We conducted a systematic research of ClinicalTrials.gov, searching RCC ongoing studies for adult patients. We included 205 trials in the final analysis. The enrolling centers were mainly distributed in high-income settings (88.9%). We estimated 94.6% of the trial population was enrolled in only five countries and none in LMs. Clinical drug development for RCC is driven by early phase studies, mainly assessing small molecule tyrosine kinase inhibitors and immunotherapy or the combination. Sixty percent of the trials were industry sponsored. Only a minority of the trials were in the early setting of care, adjuvant or neoadjuvant therapy. Disparities in drug development in LMs mirror a common underestimation of the value of research among the national priorities in cancer health planning, resulting in poor ethnic diversity and inclusiveness. This commonly results in incomplete knowledge of activity and safety of medicines across different ethnic groups, with consequences on priorities for cancer interventions and estimates of benefit in LMs patients. The use of RCC as a case study for inclusiveness suggests poor inclusion of non– Caucasian populations in the trials, especially trials testing new immunotherapy and targeted agents where RCC drug development is more pronounced, resulting in issues of generalizability in other ethnic groups when these compounds are approved with no ethnic restrictions or specifications.
In this study, real marine sediments polluted by petroleum compounds were treated by means of a bioslurry pilot scale reactor. The treatment performance was evaluated by measuring the removal of ...total petroleum hydrocarbon (TPH), coupled to further analyses required to understand the mechanisms involved in the biodegradation process. The maximum TPH-removal efficiency reached 86 % at the end of experiments. Moreover, high throughput 16S RNA gene sequencing was used to describe the microbiome composition in sediment prior to, and after, bioslurry treatment, in order to identify the taxa mostly entailed in the TPH removal process. The raw sediment was mostly colonized by members of Sulfurimonas genus; after bioslurry treatment, it was noticed a shift in the microbial community composition, with Proteobacteria phylum dominating the remediation environment (high increase in terms of growth for Hydrogenophaga and Sphingorhabdus genera) along with the Phaeodactylibacter genus (Bacteroidetes). Furthermore, the assessment of gaseous emissions from the system allowed to quantify the volatile hydrocarbon component and, consequently, to obtain a more accurate evaluation of TPH-removal pathway by the bioslurry system. Finally, phytotoxicity tests on sediment samples highlighted an increase of the treated sample quality status compared to the untreated one.
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•High removal efficiency of total petroleum hydrocarbons (TPH) with bioslurry reactor•Volatilization contributed only marginally to contaminant removal.•Taxonomic groups originally present with low abundance developed predominantly.•Phytotoxicity tests showed higher quality characteristics after bioslurry treatment.
•Current anticancer drug trial designs are often not suitable to determine an optimal efficacy threshold.•This implies potential overtreatment with unnecessary toxicities and undermines the success ...rates of trials.•De-escalation non-inferiority trials require considerable resources and time.•We propose a new Framework for Cautious Escalation for clinical trials in oncology.•The FCE may prevent overtreatment, optimize use of resources and obviate the need for de-escalation trials.
The developmental workflow of the currently performed phase 1, 2 and 3 cancer trial stages lacks essential information required for the determination of the optimal efficacy threshold of new anticancer regimens. Due to this there is a serious risk of overdosing and/or treating for an unnecessary long time, leading to excess toxicity and a higher financial burden for society. But often post-approval de-escalation trials for dose-optimization and treatment de-intensification are not performed due to failing resources and time. Therefore, the developmental workflow needs to be restructured toward cautious systemic cancer treatment escalation, in order to guarantee optimal efficacy and sustainability.
In this manuscript we discuss opportunities to produce the information needed for cautious escalation, based on models of cancer growth and cancer kill kinetics as well as exploratory biomarkers, for the purpose of designing the optimal phase 3 superiority trial. Subsequently, we compare the sample size needed for a phase 3 superiority trial, followed by a necessary de-escalation trial with the sample size needed for a multi-arm phase 3 trial with intervention arms of differing intensity. All essential items are structured within a Framework for Cautious Escalation (FCE). The discussion uses illustrations from the breast cancer setting, but aims to be applicable for all cancers.
The FCE is a promising model of clinical development in oncology to prevent overtreatment and associated issues, especially with regard to the number of repetitive treatment cycles. It will hopefully increase the relevance and success rate of clinical trials, to deliver improved patient-centric outcomes.
The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex. Multiple trial designs, endpoints, and thresholds for non-inferiority have been used; however, no ...consensus or convention has ever been agreed to categorise biomarkers useful to inform the treatment intensity modulation of cancer treatments.
An expert subgroup under the European Society for Medical Oncology (ESMO) Precision Medicine Working Group shaped an international collaborative project to develop a classification system for biomarkers used in the cancer treatment de-intensification, based on a tiered approach. A group of disease-oriented clinical, translational, methodology and public health experts, and patients’ representatives provided an analysis of the status quo, and scanned the horizon of ongoing clinical trials. The classification was developed through multiple rounds of expert revisions and inputs.
The working group agreed on a univocal definition of treatment de-intensification. Evidence of reduction in the dose-density, intensity, or cumulative dose, including intermittent schedules or shorter treatment duration or deletion of segment(s) of the standard regimens, compound(s), or treatment modality must be demonstrated, to define a treatment de-intensification. De-intensified regimens must also portend a positive impact on toxicity, quality of life, health system burden, or financial toxicity. ESMO classification categorises the biomarkers for treatment modulation in three tiers, based on the level of evidence. Tier A includes biomarkers validated in prospective, randomised, non-inferiority clinical trials. The working group agreed that in non-inferiority clinical trials, boundaries are highly dependent upon the disease scenario and endpoint being studied and that the absolute differences in the outcomes are the most relevant measures, rather than relative differences. Biomarkers tested in single-arm studies with a threshold of non-inferiority are classified as Tier B. Tier C is when the validation occurs in prospective-retrospective quality cohort investigations.
ESMO classification for the risk-guided intensity modulation of cancer treatments provides a set of evidence-based criteria to categorise biomarkers deemed to inform de-intensification of cancer treatments, in risk-defined patients. The classification aims at harmonising definitions on this matter, therefore offering a common language for all the relevant stakeholders, including clinicians, patients, decision-makers, and for clinical trials.
•The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex.•Several trial designs and endpoints are used to evaluate de-intensified cancer therapies.•ESMO has developed a classification to categorise biomarkers to inform risk-guided intensity modulation of cancer treatments.•The classification includes three tiers, based on the clinical trial methodology and results.•The ESMO classification will help harmonise definitions, thereby facilitating communication with all relevant stakeholders.
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