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A group of experts from the Peritoneal Surface Oncology Group International (PSOGI) and the BIG-RENAPE group carried out a consensus among surgeons experienced in treating peritoneal malignancies from around the world to derive recommendations on indications of hyperthermic intraperitoneal chemotherapy (HIPEC), choice and details of HIPEC regimens, and areas for future research. This manuscript describes the methodology of achieving this consensus and the degree of participation of experts. The Delphi technique was used and the questionnaire comprised three categories: evidence-based recommendations using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system with the PICO (patient, intervention, comparison, and outcome) method, an opinion survey, and research recommendations. A consensus was achieved if any one option had >50% of votes, or positive or negative recommendations combined had > 70% of votes. Of the 145 experts solicited, 71.1% in round I and 72.2% in round II took the survey. Participation was highest among surgeons treating both gastrointestinal and gynecological malignancies. Of 113 questions, after round I, a consensus was achieved for 72 (63.7%) questions, and after the second round, consensus was achieved for another 22 (19.4%) questions, making a total of 94 (83.1%) questions for which a consensus was achieved. This consensus was carried out using a thorough review of literature and robust rating of evidence, and included key experts and opinion leaders from across the world. The results could guide clinicians on the use of HIPEC, both in their day-to-day clinical practice and in designing clinical trials.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is performed with a wide variation in methodology, drugs, and other elements vital to the procedure. Adoption of a limited number of regimens could increase the collective experience of peritoneal oncologists, make comparison between studies more meaningful, and lead to a greater acceptance of results from randomized trials. This study aimed to determine the possibility of standardizing HIPEC methodology and regimens and to identify the best method of performing such a standardization. A critical review of preclinical and clinical studies evaluating the pharmacokinetic aspects of different HIPEC drugs and drug regimens, the impact of hyperthermia, and the efficacy of various HIPEC regimens as well as studies comparing different regimens was performed. The preclinical and clinical data were limited, and studies comparing different regimens were scarce. Many of the regimens were neither supported by preclinical rationale or data nor validated by a dose-escalating formal phase 1 trial. All the regimens were based on pharmacokinetic data and did not take chemosensitivity of peritoneal metastases into account. Personalized medicine approaches such as patient-derived tumor organoids could offer a solution to this problem, although clinical validation is likely to be challenging. Apart from randomized trials, more translational research and phases 1 and 2 studies are needed. While waiting for better preclinical and clinical evidence, the best way to minimize heterogeneity is by an expert consensus that aims to identify and define a limited number of regimens for each indication and primary site. The choice of regimen then can be tailored to the patient profile and its expected toxicity and the methodology according regional factors.

Enhanced recovery after surgery (ERAS) pathways have been shown to considerably reduce complications, length of stay and costs after most of surgical procedures by standardised application of best evidence-based perioperative care. The aim was to elaborate dedicated recommendations for cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC) in a two-part series of guidelines based on expert consensus. The present part I of the guidelines highlights preoperative and intraoperative management. The core group assembled a multidisciplinary panel of 24 experts involved in peritoneal surface malignancy surgery representing the fields of general surgery (n = 12), gynaecological surgery (n = 6), and anaesthesia (n = 6). Experts systematically reviewed and summarized the available evidence on 72 identified perioperative care items, following the GRADE (grading of recommendations, assessment, development, evaluation) system. Final consensus (defined as ≥50%, or ≥70% of weak/strong recommendations combined) was reached by a standardised 2-round Delphi process, regarding the strength of recommendations. Response rates were 100% for both Delphi rounds. Quality of evidence was evaluated high, moderate low and very low, for 15 (21%), 26 (36%), 29 (40%) and 2 items, respectively. Consensus was reached for 71/72(98.6%) items. Strong recommendations were defined for 37 items, No consensus could be reached regarding the preemptive use of fresh frozen plasma. The present ERAS recommendations for CRS±HIPEC are based on a standardised expert consensus process providing clinicians with valuable guidance. There is an urgent need to produce high quality studies for CRS±HIPEC and to prospectively evaluate recommendations in clinical practice.

Enhanced recovery after surgery (ERAS) pathways have been shown to considerably reduce complications, length of stay and costs after most of surgical procedures by standardised application of best evidence-based perioperative care. The aim was to elaborate dedicated recommendations for cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC) in a two-part series of guidelines based on expert consensus. The present part II of the guidelines highlights postoperative management and special considerations. The core group assembled a multidisciplinary panel of 24 experts involved in peritoneal surface malignancy surgery representing the fields of general surgery (n = 12), gynaecological surgery (n = 6), and anaesthesia (n = 6). Experts systematically reviewed and summarized the available evidence on 72 identified perioperative care items, following the GRADE (grading of recommendations, assessment, development, evaluation) system. Final consensus (defined as ≥50%, or ≥70% of weak/strong recommendations combined) was reached by a standardised 2-round Delphi process, regarding the strength of recommendations. Response rates were 100% for both Delphi rounds. Quality of evidence was evaluated high, moderate low and very low, for 15 (21%), 26 (36%), 29 (40%) and 2 items, respectively. Consensus was reached for 71/72(98.6%) items. Strong recommendations were defined for 37 items. No consensus could be reached regarding the preemptive use of fresh frozen plasma. The present ERAS recommendations for CRS ± HIPEC are based on a standardised expert consensus process providing clinicians with valuable guidance. There is an urgent need to produce high quality studies for CRS ± HIPEC and to prospectively evaluate recommendations in clinical practice.

People across cultures differ in behaviours, thoughts and preferences. Cultural sensitivity – i.e., acknowledgment of these cultural differences – in development science is a postulate known since at least the 1960s, but has remained understudied. The goal of the current paper is to address this gap and to investigate folk theories of societal development, and in particular to identify both universal and culturally specific lay beliefs on what constitutes good societal development. In this study we collected data on preferences in social developmental from 2,684 participants across nine countries from five continents. We measured preferences towards twenty-eight different development aims, and separately for preferences towards three aims constituting Human Development Index. We used a comprehensive analysis approach, consisting of multidimensional scaling, analysis of variance, and pairwise comparisons to characterize universal and country specific preference patterns. Our results demonstrate that what people understand as modernization remains substantially universal across countries, but specific pathways of development and preferences towards these pathways tend to be different between countries. We also distinguished three facets of modernization: basics for modernization (e.g., trust, safety, economic development), welfare aims (e.g., poverty eradication, education), and inclusive aims (e.g., openness, gender equality, human rights). Importantly, in all studied countries, we found that each of the three types of modernization is much more preferred than conventional aims (e.g., military, demographic, religion). Cultural sensitivity may be reflected in how development is conceptualised and measured, and in this paper we propose a method of implementing our findings into development indexes

Pressurised intraperitoneal aerosol chemotherapy (PIPAC) was introduced as a new treatment for patients with peritoneal metastases in November, 2011. Reports of its feasibility, tolerance, and efficacy have encouraged centres worldwide to adopt PIPAC as a novel drug delivery technique. In this Review, we detail the technique and rationale of PIPAC and critically assess its evidence and potential indications. A systematic search was done to identify all relevant literature on PIPAC published between Jan 1, 2011, and Jan 31, 2019. A total of 106 articles or reports on PIPAC were identified, and 45 clinical studies on 1810 PIPAC procedures in 838 patients were included for analysis. Repeated PIPAC delivery was feasible in 64% of patients with few intraoperative and postoperative surgical complications (3% for each in prospective studies). Adverse events (Common Terminology Criteria for Adverse Events greater than grade 2) occurred after 12-15% of procedures, and commonly included bowel obstruction, bleeding, and abdominal pain. Repeated PIPAC did not have a negative effect on quality of life. Using PIPAC, an objective clinical response of 62-88% was reported for patients with ovarian cancer (median survival of 11-14 months), 50-91% for gastric cancer (median survival of 8-15 months), 71-86% for colorectal cancer (median survival of 16 months), and 67-75% (median survival of 27 months) for peritoneal mesothelioma. From our findings, PIPAC has been shown to be feasible and safe. Data on objective response and quality of life were encouraging. Therefore, PIPAC can be considered as a treatment option for refractory, isolated peritoneal metastasis of various origins. However, its use in further indications needs to be validated by prospective studies.

BACKGROUND: Reduced mobility is the first sign of functional decline and can lead to dependency in elderly people. Screening for the risk of mobility limitation in this population is an important public health issue to prevent further disabilities. Despite the current lack of guidelines, primary care healthcare providers may have a central role to play in this type of screening. Multi-domain physical exercise interventions in older persons have shown some efficacy/effectiveness on frailty status, yet, to the best of our knowledge, no published study has focused on patients screened in primary care. METHOD: The PRISME-3P study is a national, interventional, multicenter, cluster randomized trial. Patients over 70 years of age will be systematically screened by their general practitioner (GP) on the basis of clinical criteria of mobility limitation. To avoid contamination bias, the unit of randomization will be the GP practice. In the intervention group, patients will consult a geriatrician and a dietician, and will receive a physical training program from a personal trainer who will demonstrate the exercises and provide follow-up coaching. The control group will receive standard care. The primary outcome will be the change in Short Physical Performance Battery (SPPB) scores between inclusion and 6-months follow-up. DISCUSSION: We expect an improvement of the SPPB between inclusion and 6 months of follow-up. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov ( NCT02847871 , 27 July 2016).

Soft law is a common feature of international governance, occupying a grey zone between the realms of politics and law. The multifaceted concept can refer to vague provisions or norms generally, but is most useful when defined as international instruments adopted in a non-binding form. Whilst the advantages and appeal of soft law have been widely studied, with its effects explored in both International Relations (IR) and International Law (IL) scholarship, states’ behaviour on commitment to soft law per se has remained underexplored. It is often assumed that its non-binding status upon adoption makes commitment to soft law a relatively inconsequential endeavor, at least in comparison to hard law. In this thesis, incorporating insights from public international law into rationalist IR approaches, I argue that soft law instruments can have important effects over time and bring substantial costs for states to bear. This is particularly the case for soft law instruments ‘hardening’ through domestic law, treaties or customary international law, increasing the sovereignty and implementation costs attached to commitment. I further argue that those potential costs of soft law are taken into account by states when making decisions on commitment. Depending on the importance and likelihood of the costs foreseen, states can craft their commitment to mitigate these costs or block them from arising. Empirical evidence for the place of the costs of soft law in states’ decision-making on commitment is offered through an in-depth case study of the UN Declaration on the Rights of Indigenous Peoples, with a focus on the opposition it faced upon adoption – an unusual occurrence for a UN declaration in the field of human rights. Recognizing the potential costs of soft law and their impact on state commitment helps to bridge theory and practice regarding the creation of non-binding instruments and sheds light on challenges raised by the use of soft law by states and non-state actors at the frontiers of international law-making.

INTRODUCTION / BACKGROUND: Among gastrointestinal (GI) tumours, pseudomyxoma peritonei (PMP) from appendiceal origin has unique clinical and morphologic features. Due to the relative paucity of patients and the absence of therapeutic consensus, evaluation and refinement of the morphologic criteria used for assessment of the disease are still difficult. As a result, a uniformly accepted classification is still lacking. In collaboration with NJ Carr, who initiated the conference consensus process, in Basingstoke, and on behalf of the French group RENA-PATH, 11 experienced GI pathologists agreed to participate to a virtual workshop, in order to assess inter-observer variability in PMP diagnosis and staging. AIMS: The goal of the study was to evaluate, for appendiceal and peritoneal mucinous neoplasms, the degree of concordance in the identification of diagnostic histological criteria by experienced pathologists, and to assess the degree of inter-individual variation in the application of WHO classification (2010) and TNM staging system (7th edition). METHODS: A single section stained with hematoxylin and eosin from 9 resected cases of mucinous neoplasms was selected by members of RENA-PATH. All digitalized at a maximum resolution (X40) using an HAMMAMATSU scanner system, to ensure that all participants evaluate exactly the same tumour areas; 1 to 16 questions were prepared for each case. On Teleslide web platform, interactive services provided by TRIBVN. All submitted cases were then reviewed by a panel of 11 pathologists with specific expertise and interest in PMP. Data were analyzed using SAS program. RESULTS: Whole slide set evaluated by all participants; no abstention or “unknown diagnosis” for any submitted case. Agreement for classification, WHO 2010: -Appendiceal mucinous neoplasms: LAMN 83 %; mucinous adenocarcinoma 92%. -Peritonei mucinous carcinoma: Low grade 91.7%; high grade 91.7%. -Disagreement on the concept of High Grade AMN defined by low power architecture of LAMN + high grade cytology. -Agreement for using pTNM classification (82%) in PMP. -Pushing Invasion (PI) and dissection by acellular mucin (DAM) in appendix wall are not reproducible criteria and need to be better defined. -Criteria need to be redefined to use HAMN according to a majority of participants. -The identification of signet ring cells is not reproducible; the lesion needs to be better defined. -Invasion of organs and pattern of invasion (broatfront invasion / classic by irregular glands or single cells with desmoplasia) are not reproducible criteria. -Improvement in staging assessment is needed

The aim of this study was to determine the nutritional effects of vitamin A and PUFA (including EPA and DHA) on sea bass larvae development. An excess of vitamin A in the diet led to malformations affecting the cephalic region linked to an increase of RARgama transcription and the loss of a vertebra when larvae were fed this diet from 8 days post hatch (dph) to 13 dph. A diet containing an excess of PUFA disrupted the development of larvae vertebral column, deformities were correlated to a decrease of RARalpha, RARgama, RXRalpha and BMP4 transcription and an additional vertebra appeared when larvae were fed this diet from 8 dph to 13 dph. A diet containing 31 mg/kg of dry matter of vitamin A and between 1.1 and 2.3% of EPA + DHA allows larvae to develop harmoniously. The period 8-13 dph is crucial for the development as sea bass larvae are very sensible to the level and the nature of nutrients during this interval of time., Le but de ce travail était de tester l'effet nutritionnel de la vitamine A et des AGPI (dont l'EPA et le DHA) sur le développement des larves de bar. Un excès de vitamine A dans l'aliment provoquait des malformations au niveau de la tête reliées à une hausse de la transcription de RARgama et la perte d'une vertèbre lorsque les larves étaient nourries avec cet aliment de J8 à J13. Un aliment contenant un excès d'AGPI perturbait le développement de la colonne vertébrale des bars, les malformations étaient corrélées à une chute de l'expression de RARalpha, RARgama, RXRalpha et BMP4 et une vertèbre surnuméraire apparaissait sur les larves nourries de J8 à J13 avec cet aliment. Un aliment contenant 31 mg/kg de matière sèche de vitamine A et entre 1.1 et 2.3% d'EPA + DHA permet un développement harmonieux des larves. Il apparaît que la période J8-J13 est cruciale pour le développement, période pendant laquelle les larves sont très sensibles à la nature et à la teneur des nutriments.

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