Cancer data quality and harmonization in Europe: the experience of the BENCHISTA Project – international benchmarking of childhood cancer survival by stage

Introduction: Variation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers. Methods: PBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created. Results: 67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)]. Conclusion: Differences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans

Revealing the mid-infrared emission structure of IRAS 16594-4656 and IRAS 07027-7934

TIMMI2 diffraction-limited mid-infrared images of a multipolar proto-planetary nebula IRAS 16594-4656 and a young [WC] elliptical planetary nebula IRAS 07027-7934 are presented. Their dust shells are for the first time resolved (only marginally in the case of IRAS 07027-7934) by applying the Lucy-Richardson deconvolution algorithm to the data, taken under exceptionally good seeing conditions (<0.5"). IRAS 16594-4656 exhibits a two-peaked morphology at 8.6, 11.5 and 11.7 microns which is mainly attributed to emission from PAHs. Our observations suggest that the central star is surrounded by a toroidal structure observed edge-on with a radius of 0.4" (~640 AU at an assumed distance of 1.6 kpc) with its polar axis at P.A.~80 degrees, coincident with the orientation defined by only one of the bipolar outflows identified in the HST optical images. We suggest that the material expelled from the central source is currently being collimated in this direction and that the multiple outflow formation has not been coeval. IRAS 07027-7934 shows a bright, marginally extended emission (FWHM=0.3") in the mid-infrared with a slightly elongated shape along the N-S direction, consistent with the morphology detected by HST in the near-infrared. The mid-infrared emission is interpreted as the result of the combined contribution of small, highly ionized PAHs and relatively hot dust continuum. We propose that IRAS 07027-7934 may have recently experienced a thermal pulse (likely at the end of the AGB) which has produced a radical change in the chemistry of its central star.Comment: 35 pages, 8 figures (figures 1, 2, 4 and 6 are in low resolution) accepted for publication in Ap

Psychometric properties of the Spanish version of the Clinical Outcomes in Routine Evaluation Outcome Measure

Objective: The objective of this paper is to assess the reliability and validity of the Spanish translation of the Clinical Outcomes in Routine Evaluation – Outcome Measure, a 34-item selfreport questionnaire that measures the client’s status in the domains of Subjective well-being, Problems/Symptoms, Life functioning, and Risk. Method: Six hundred and forty-four adult participants were included in two samples: the clinical sample (n=192) from different mental health and primary care centers; and the nonclinical sample (n=452), which included a student and a community sample. Results: The questionnaire showed good acceptability and internal consistency, appropriate test–retest reliability, and acceptable convergent validity. Strong differentiation between clinical and nonclinical samples was found. As expected, the Risk domain had different characteristics than other domains, but all findings were comparable with the UK referential data. Cutoff scores were calculated for clinical significant change assessment. Conclusion: The Spanish version of the Clinical Outcomes in Routine Evaluation – Outcome Measure showed acceptable psychometric properties, providing support for using the questionnaire for monitoring the progress of Spanish-speaking psychotherapy clients

Mass measurements towards doubly magic Ni-78 : Hydrodynamics versus nuclear mass contribution in core-collapse supernovae

We report the first high-precision mass measurements of the neutron-rich nuclei Ni-74,Ni-75 and the clearly identified ground state of Cu-76, along with a more precise mass-excess value of Cu-78, performed with the double Penning trap JYFLTRAP at the Ion Guide Isotope Separator On-Line (IGISOL) facility. These new results lead to a quantitative estimation of the quenching for the N = 50 neutron shell gap. The impact of this shell quenching on core-collapse supernova dynamics is specifically tested using a dedicated statistical equilibrium approach that allows a variation of the mass model independent of the other microphysical inputs. We conclude that the impact of nuclear masses is strong when implemented using a fixed trajectory as in the previous studies, but the effect is substantially reduced when implemented self-consistently in the simulation. (C) 2022 The Authors. Published by Elsevier B.V.Peer reviewe

Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)

Background: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). // Patients and methods: The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. // Results: In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan–Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. // Conclusions: The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755)

New constraints on the Al 25 (p,γ) reaction and its influence on the flux of cosmic γ rays from classical nova explosions

The astrophysical Al25(p,γ)Si26 reaction represents one of the key remaining uncertainties in accurately modeling the abundance of radiogenic Al26 ejected from classical novae. Specifically, the strengths of key proton-unbound resonances in Si26, that govern the rate of the Al25(p,γ) reaction under explosive astrophysical conditions, remain unsettled. Here, we present a detailed spectroscopy study of the Si26 mirror nucleus Mg26. We have measured the lifetime of the 3+, 6.125-MeV state in Mg26 to be 19(3)fs and provide compelling evidence for the existence of a 1- state in the T=1,A=26 system, indicating a previously unaccounted for=1 resonance in the Al25(p,γ) reaction. Using the presently measured lifetime, together with the assumption that the likely 1- state corresponds to a resonance in the Al25+p system at 435.7(53) keV, we find considerable differences in the Al25(p,γ) reaction rate compared to previous works. Based on current nova models, we estimate that classical novae may be responsible for up to ≈15% of the observed galactic abundance of Al26.This work was supported by the U.S. Department of Energy, Office of Science, Office of Nuclear Physics, under Contract No. DEAC02-06CH11357 and Grants No. DEFG02-94-ER40834, No. DEFG02-97-ER41041, No. DEFG02-97-ER41043, and No. DE-FG02-93ER4077. U.K. personnel were supported by the Science and Technologies Facilities Council (STFC). This work was partially supported by the Spanish MINECO Grant No. AYA2017-86274-P, by the E.U. FEDER funds, and by the AGAUR/Generalitat de Catalunya Grant No. SGR-661/2017. This article benefited from discussions within the “ChETEC” COST Action (Grant No. CA16117). This research used resources of ANL's ATLAS facility, which is a DOE Office of Science User facility

Extrafollicular plasmablast present in the acute phase of infections express high levels of PD-L1 and are able to limit T cell respose

During infections with protozoan parasites or some viruses, T cell immunosuppression is generated simultaneously with a high B cell activation. It has been described that, as well as producing antibodies, plasmablasts, the differentiation product of activated B cells, can condition the development of protective immunity in infections. Here, we show that, in T. cruzi infection, all the plasmablasts detected during the acute phase of the infection had higher surface expression of PD-L1 than other mononuclear cells. PD-L1hi plasmablasts were induced in vivo in a BCR-specific manner and required help from Bcl-6+CD4+T cells. PD-L1hi expression was not a characteristic of all antibody-secreting cells since plasma cells found during the chronic phase of infection expressed PD-L1 but at lower levels. PD-L1hi plasmablasts were also present in mice infected with Plasmodium or with lymphocytic choriomeningitis virus, but not in mice with autoimmune disorders or immunized with T cell-dependent antigens. In vitro experiments showed that PD-L1hi plasmablasts suppressed the T cell response, partially via PD-L1. Thus, this study reveals that extrafollicular PD-L1hi plasmablasts, whose peaks of response precede the peak of germinal center response, may have a modulatory function in infections, thus influencing T cell response.Fil: Gorosito Serran, Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Fiocca Vernengo, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Almada, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Beccaria, Cristian Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gazzoni, Yamila Natali. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Canete, Pablo F.. Australian National University; ArubaFil: Roco, Jonathan A.. Australian National University; ArubaFil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Ramello, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Wehrens, Ellen. University of California; Estados UnidosFil: Cai, Yeping. Australian National University; ArubaFil: Zuniga, Elina Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Cockburn, Ian A.. Australian National University; ArubaFil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Vinuesa, Carola G.. Australian National University; ArubaFil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin

Confirmation of a new resonance in 26Si and contribution of classical novae to the galactic abundance of 26Al

© 2023 The Author(s). Published by the American Physical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/The 25Al(p ,γ ) reaction has long been highlighted as a possible means to bypass the production of 26Al cosmic γ rays in classical nova explosions. However, uncertainties in the properties of key resonant states in 26Si have hindered our ability to accurately model the influence of this reaction in such environments. We report on a detailed γ -ray spectroscopy study of 26Si and present evidence for the existence of a new, likely ℓ =1 , resonance in the 25Al + p system at Er=153.9 (15 ) keV. This state is now expected to provide the dominant contribution to the 25Al(p ,γ ) stellar reaction rate over the temperature range, T ≈0.1 −0.2 GK. Despite a significant increase in the rate at low temperatures, we find that the final ejected abundance of 26Al from classical novae remains largely unaffected even if the reaction rate is artificially increased by a factor of 10. Based on new, galactic chemical evolution calculations, we estimate that the maximum contribution of novae to the observed galactic abundance of 26Al is ≈0.2 M⊙ . Finally, we briefly highlight the important role that super-asymptotic giant branch stars may play in the production of 26Al.Peer reviewe

What do we have to know about PD-L1 expression in prostate cancer? A systematic literature review. part 4: Experimental treatments in pre-clinical studies (cell lines and mouse models)

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapyresistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ Tcells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223)

What do we have to know about PD-L1 expression in prostate cancer? A systematic literature review. Part 3: PD-L1, intracellular signaling pathways and tumor microenvironment

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells