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The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first-or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplanta-tion and be definitive therapy versus those in whom it provides a more effective bridge to hae-matopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully huma-nised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prior-itisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary medi-astinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this pop-ulation. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials.CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell ther-apies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success.The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies.Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regu-latory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially impor-tant as these are very expensive therapies.The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Clinicians assessing cardiac risk as part of a comprehensive consultation before surgery can use an expanding set of tools, including predictive risk calculators, cardiac stress tests and measuring serum natriuretic peptides. The optimal assessment strategy is unclear, with conflicting international guidelines. We investigated the prognostic accuracy of the Revised Cardiac Risk Index for risk stratification and cardiac outcomes in patients undergoing elective non-cardiac surgery in a contemporary Australian cohort. We audited the records for 1465 consecutive patients 45 years and older presenting to the perioperative clinic for elective non-cardiac surgery in our tertiary hospital. We calculated individual Revised Cardiac Risk Index scores and documented any use of preoperative cardiac tests. The primary outcome was any major adverse cardiac events within 30 days of surgery, including myocardial infarction, pulmonary oedema, complete heart block or cardiac death. Myocardial perfusion imaging was the most common preoperative stress test (4.2%, 61/1465). There was no routine investigation of natriuretic peptide levels for cardiac risk assessment before surgery. Major adverse cardiac events occurred in 1.3% (18/1366) of patients who had surgery. The Revised Cardiac Risk Index score had modest prognostic accuracy for major cardiac complications, area under receiver operator curve 0.73, 95% confidence interval 0.60 to 0.86. Stratifying major adverse cardiac events by the Revised Cardiac Risk Index scores 0, 1, 2 and 3 or greater corresponded to event rates of 0.6% (4/683), 0.8% (4/488), 4.1% (6/145) and 8.0% (4/50), respectively. The Revised Cardiac Risk Index had only modest predictive value in our single-centre experience. Patients with a revised cardiac risk index score of 2 or more had an elevated risk of early cardiac complications after elective non-cardiac surgery.

Migration—whether international or internal, forced or voluntary—intertwines with digital media, especially for sexual minorities and trans people who seek out platforms catering to lesbian, gay, bisexual, trans, and queer (LGBTQ) people. Online networks foster transnational flows of ideas and information, which can enable international travel. The ways that queer people interact on digital media in the 21st century have emerged not only from decades of online subcultures—such as 1990s chatrooms and profile sites—but also from predigital media cultures, such as printed personal ads in gay and lesbian journals. The internet accelerated the growth of media platforms and queer international networks, both of which continued to develop with the advent of mobile phone apps and the proliferation of social media. Online media—from blogs to hashtags to “hook-up” apps—can relate to all aspects of the migration process. Before, during, and after a move, queer migrants access online media for information about LGBTQ laws and norms or for help with the logistics of migration. When in a new country, queer migrants use online media to try to connect with locals. During these interactions, migrants might encounter forms of xenophobia, racism, and exclusion. In spite or because of these experiences, queer migrants utilize digital media to build new networks, such as queer diasporic communities aimed at social or political activities.

ENGLISH BELOW:De 1965 à 1975, des travailleurs immigrés venus seuls – la plupart originaires de Turquie, du Maroc et de l’Europe du Sud – ont participé aux transformations des cultures sexuelles et de genre de l’Europe du Nord. Cependant, à partir du milieu des années 1970, l’arrivée des épouses et enfants venus de leur pays d’origine conduit à un changement d’attitude à l’égard de la liberté sexuelle. Cet article explore, dans le cas des Pays-Bas, ce tournant conservateur chez les travailleurs immigrés lié au regroupement familial. Il propose l’utilisation du fonds de collections photographiques déposées par des immigrant.es à l’Institut d’histoire sociale d’Amsterdam et montre l’intérêt de ces archives personnelles pour écrire une histoire de la sexualité et de l’immigration.From the mid-1960s through the mid-1970s, solo male guest-workers – often from Turkey, Morocco, and southern Europe – participated in the radicalizing gender and sexual cultures of northwest Europe. From the mid-1970s onward, however, with the arrival of wives and children from their countries of origin, these men’s attitudes toward sexual liberty changed. This article explores this conservative turn during the guest-worker family reunification years in the Netherlands, using photographs from the Historical Image Archive of Migrants (International Institute of Social History, the Netherlands) to show how personal photo collections can contribute to histories of sexuality and immigration.

10002 Background: The BEACON phase II trial (NCT02308527) addressed a number of questions in children with relapsed/refractory high-risk neuroblastoma (RR-HRNB). Here we report the chemo-immunotherapy randomisation, assessing if anti-GD2 (dB) demonstrates activity when added to chemotherapy. Methods: Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomised in a 1:2 ratio to receive chemotherapy alone or with dB, given concurrently as a 7 day continuous infusion (10 mg/m2/24hr). As the trial had a factorial design, some patients were also randomised between chemotherapy regimens (temozolomide (T) versus Temozolomide-Topotecan (TTo); this randomisation closed soon after the dB randomisation opened and all patients subsequently received TTo chemotherapy. Cross-over to dB with topotecan and cyclophosphamide was allowed for patients randomised to chemotherapy alone who experienced disease progression. The primary outcome measure was best response (complete or partial) at any point during the first 6 courses of treatment, by RECIST or International Neuroblastoma Response Criteria for patients with measurable and evaluable disease respectively. Progression free and overall survival (PFS & OS) and safety were secondary outcomes. The success criterion for proceeding to a Phase 3 trial was a one-sided p-value (1p) less than 0.23 for Objective Response Rate (ORR). Results: From Aug 2019 to Feb 2021, 65 patients were randomised to chemotherapy alone (3 T, 19 TTo) or with dB (6 dBT, 37 dBTTo). Median age was 4 years; 48 and 17 had measurable and evaluable disease respectively; 29 and 36 had refractory and relapsed disease respectively; 19 had MYCN amplification. Baseline characteristics were balanced between arms. Response was assessable in all patients. The ORR was 18% with chemotherapy alone and 35% for patients receiving chemotherapy with dB (risk ratio 1.66, 80% confidence interval (CI) 0.9 to 3.06, 1p = 0.19). 1-year PFS was 27% for chemotherapy alone, and 57% for those receiving chemotherapy +dB (HR 0.63, 95% CI 0.32 to 1.25, p = 0.19). Twelve patients in the chemotherapy only arm crossed over to receive dB at progression. OS did not differ between the arms: HR = 0.99, 95% CI 0.42 to 2.36, p = 0.99. Nine (41%) patients receiving chemotherapy alone and 13 (30%) receiving chemotherapy plus dB had grade ≥3 toxicities (CTCAE v4.0). Neurotoxicities were more common in patients receiving dB compared to chemotherapy alone (Grade 1-2: 67.4% vs 13.6%, Grade 3: 9.3 vs 0%). Other toxicities were similar with and without dB. Conclusions: The Phase 2 success criterion for ORR was met and PFS is also encouraging. The addition of dB to temozolomide-based chemotherapy shows promising activity in patients with RR-HR-NB. Clinical trial information: NCT02308527.

e22015 Background: GSK-3β overexpression is associated with aggressive malignancies, treatment resistance and poor prognosis. The GSK-3β inhibitor Elraglusib induces apoptosis via NFΚB and p53 pathways and has potent anti-fibrotic and immunomodulatory activity. Adult studies of elraglusib demonstrate clinical activity in pancreatic cancer, melanoma, lymphoma and sarcoma as a single agent or in combination with cytotoxic chemotherapy. Elraglusib is active in in vivo models of neuroblastoma (NBL) and malignant glioma. This first-in-pediatrics study (NCT04239092) is evaluating the safety, pharmacokinetics (PK), and efficacy of elraglusib monotherapy and in combination with chemotherapy in patients with refractory malignancies. Methods: Elraglusib is given intravenously (IV) twice-weekly at 3 dose levels (DL) (9.3, 12.4 and 15 mg/kg) as a single agent or in combination with irinotecan, cyclophosphamide/topotecan or temozolomide/irinotecan in 21-day cycles. A cohort of pts with refractory NBL will be treated at the recommended phase 2 dose (RP2D) of elraglusib with temozolomide/irinotecan. Results: As of January 2022, 23 pts (n = 7 female, median age 14.2 years) have received at least one dose of elraglusib. Tumor types: 5 NBL, 3 diffuse midline glioma (DMG), 3 osteosarcoma (OS), 3 ependymoma (EP), 2 alveolar rhabdomyosarcoma (aRMS), 1 angiosarcoma (AS), 1 Ewing sarcoma (ES), 1 glioblastoma (GBM), 1 hepatoblastoma (HB), 1 embryonal CNS tumor NOS, 1 NUT midline carcinoma, 1 pineoblastoma (PB). Median time from diagnosis is 26 months (range: 6.7 – 156.3) and median number of lines of prior systemic therapy is 2 (range 0-14). Two DLs of single agent (6 pts) have been completed (9.3 and 12.4 mg/kg) without elraglusib-attributable severe adverse events (SAEs). Of the 15 patients on the combination arm with irinotecan or cyclophosphamide/topotecan, a single adverse event (Grade 4 hypotension/infusion reaction) was reported. Grade 1/2 elraglusib attributable-AEs include: transient visual change (n = 10), nausea (n = 7), vomiting (n = 6), fatigue (n = 2), hypotension (n = 2) and infusion reaction (n = 1). One pt with recurrent ES had a radiographic and pathologic CR after 3 cycles of elraglusib/cyclophosphamide/topotecan. 6 pts (26.1%) had SD (2 NBL, 1 aRMS, 1 EP, 1 OS, 1 GBM). 8 pts (35%) remained on study treatment ≥ 3 months (2 NBL, 2 EP, 1 OS, 1 aRMS, 1 ES, 1 PB). Median treatment duration was 40 days (range 1 - 126). 4 pts remain on therapy. Conclusions: Elraglusib is well tolerated as a single agent and with several chemotherapy regimens in this heavily pretreated pediatric population with refractory cancers. It has encouraging antitumor activity, with 1 CR in a patient with recurrent ES. Enrollment is ongoing; a RPD2 has not been reached. Clinical trial information: NCT04239092.

During the late 1960s and early 1970s, Denmark received about 15,000 foreign workers from Turkey, Yugoslavia, Pakistan, the Middle East and North Africa during a unique period of women’s and sexual liberation. As foreign men visited discos—sometimes in search of sexual relationships with Danish women—a segment of Danish men accused foreigners of taking not only ‘their’ jobs but also ‘their’ women, and depicted foreign men as hypersexual or sexually violent (e.g. in union newspapers, men’s magazines). These ‘sexotic’ depictions of foreign men had immediate and negative effects on immigrants’ lived experiences in Denmark. In gay male subcultures, ‘sexotic’ depictions of men of color served mainly to entertain white fantasies, which also affected the experiences especially of gay men of color in Denmark. Overall, sexualized stereotypes about the male Other were central to broader political discussions in Denmark in the long 1970s, including debates about Danish wage suppression, immigrant ghetto formation, and the definition of sexual liberation.

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner. (C) 2020 The Authors. Published by Elsevier Ltd.

Objective. To summarise the evidence for use of intravenous magnesium for analgesic effect in caesarean section patients. Background. Postcaesarean pain requires effective analgesia. Magnesium, an N-methyl-D-aspartate receptor antagonist and calcium-channel blocker, has previously been investigated for its analgesic properties. Methods. A systematic search was conducted of PubMed, Scopus, MEDLINE, Cochrane Library, and Google Scholar databases for randomised-control trials comparing intravenous magnesium to placebo with analgesic outcomes in caesarean patients. Results. Ten trials met inclusion criteria. Seven were qualitatively compared after exclusion of three for unclear bias risk. Four trials were conducted with general anaesthesia, while three utilised neuraxial anaesthesia. Five of seven trials resulted in decreased analgesic requirement postoperatively and four of seven resulted in lower serial visual analogue scale scores. Conclusions. Adjunct analgesic agents are utilised to improve analgesic outcomes and minimise opioid side effects. Preoperative intravenous magnesium may decrease total postcaesarean rescue analgesia consumption with few side effects; however, small sample size and heterogeneity of methodology in included trials restricts the ability to draw strong conclusions. Therefore, given the apparent safety and efficacy of magnesium, its role as an adjunct analgesic in caesarean section patients should be further investigated with the most current anaesthetic techniques.