Outcome of Stage IV Completely Necrotic Wilms Tumour and Local Stage III Treated According to the SIOP 2001 Protocol

Objective: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the SIOP 2001 protocol, the SIOP– Renal Tumour Study Group (SIOP–RTSG) has omitted radiotherapy for such patients with low-risk, local stage III in an attempt to reduce treatment burden. However, for metastatic patients with local stage III, completely necrotic WT, the recommendations led to ambiguous use. The purpose of this descriptive study is to demonstrate the outcomes of patients with metastatic, completely necrotic and local stage III WT in relation to the application of radiotherapy or not. Methods and materials: all metastatic patients with local stage III, completely necrotic WT after 6 weeks of preoperative chemotherapy who were registered in the SIOP 2001 study were included in this analysis. The pattern of recurrence according to the usage of radiation treatment and 5 year event-free survival (EFS) and overall survival (OS) was analysed. Results: seven hundred and three metastatic WT patients were registered in the SIOP 2001 database. Of them, 47 patients had a completely necrotic, local stage III WT: 45 lung metastases (11 combined localisations), 1 liver/peritoneal, and 1 tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial embolism. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal irradiation and 9 combined with lung irradiation). Eighteen patients did not receive radiotherapy. Median follow-up was 6.6 years (range 1–151 months). Two of the 47 patients (4%) developed disease recurrence in the lung (one combined with abdominal relapse) and eventually died of the disease. Both patients had received abdominal radiotherapy, one of them combined with lung irradiation. Five-year EFS and OS were 95% and 95%, respectively. Conclusions: the outcome of patients with stage IV, local stage III, completely necrotic Wilms tumours is excellent. Our results suggest that abdominal irradiation in this patient category may not be of added value in first-line treatment, consistent with the current recommendation in the SIOP–RTSG 2016 UMBRELLA protocol

Unforeseen plant phenotypic diversity in a dry and grazed world

23 páginas..- 4 figuras y 7 figuras.- 50 referencias y 90 referenciasEarth harbours an extraordinary plant phenotypic diversity1 that is at risk from ongoing global changes2,3. However, it remains unknown how increasing aridity and livestock grazing pressure—two major drivers of global change4,5,6—shape the trait covariation that underlies plant phenotypic diversity1,7. Here we assessed how covariation among 20 chemical and morphological traits responds to aridity and grazing pressure within global drylands. Our analysis involved 133,769 trait measurements spanning 1,347 observations of 301 perennial plant species surveyed across 326 plots from 6 continents. Crossing an aridity threshold of approximately 0.7 (close to the transition between semi-arid and arid zones) led to an unexpected 88% increase in trait diversity. This threshold appeared in the presence of grazers, and moved toward lower aridity levels with increasing grazing pressure. Moreover, 57% of observed trait diversity occurred only in the most arid and grazed drylands, highlighting the phenotypic uniqueness of these extreme environments. Our work indicates that drylands act as a global reservoir of plant phenotypic diversity and challenge the pervasive view that harsh environmental conditions reduce plant trait diversity8,9,10. They also highlight that many alternative strategies may enable plants to cope with increases in environmental stress induced by climate change and land-use intensification.This research was funded by the European Research Council (ERC Grant agreement 647038 1004 [BIODESERT]) and Generalitat Valenciana (CIDEGENT/2018/041). N.G. was supported by CAP 20–25 (16-IDEX-0001) and the AgreenSkills+ fellowship programme which has received funding from the European Union’s Seventh Framework Programme under grant agreement FP7-609398 (AgreenSkills+ contract). F.T.M. acknowledges support from the King Abdullah University of Science and Technology (KAUST), the KAUST Climate and Livability Initiative, the University of Alicante (UADIF22-74 and VIGROB22-350), the Spanish Ministry of Science and Innovation (PID2020-116578RB-I00), and the Synthesis Center (sDiv) of the German Centre for Integrative Biodiversity Research Halle–Jena–Leipzig (iDiv). Y.L.B.-P. was supported by a Marie Sklodowska-Curie Actions Individual Fellowship (MSCA-1018 IF) within the European Program Horizon 2020 (DRYFUN Project 656035). H.S. is supported by a María Zambrano fellowship funded by the Ministry of Universities and European Union-Next Generation plan. L.W. acknowledges support from the US National Science Foundation (EAR 1554894). G.M.W. acknowledges support from the Australian Research Council (DP210102593) and TERN. M.B is supported by a Ramón y Cajal grant from Spanish Ministry of Science (RYC2021-031797-I). L.v.d.B. and K.T. were supported by the German Research Foundation (DFG) Priority Program SPP-1803 (TI388/14-1). A.F. acknowledges the financial support from ANID PIA/BASAL FB210006 and Millenium Science Initiative Program NCN2021-050. A.J. was supported by the Bavarian Research Alliance for travel and field work (BayIntAn UBT 2017 61). A.L. and L.K. acknowledge support from the German Research Foundation, DFG (grant CRC TRR228) and German Federal Government for Science and Education, BMBF (grants 01LL1802C and 01LC1821A). B.B. and S.U. were supported by the Taylor Family-Asia Foundation Endowed Chair in Ecology and Conservation Biology. P.J.R. and A.J.M. acknowledge support from Fondo Europeo de Desarrollo Regional through the FEDER Andalucía operative programme, FEDER-UJA 1261180 project. E.M.-J. and C.P. acknowledge support from the Spanish Ministry of Science and Innovation (PID2020-116578RB-I00). D.J.E. was supported by the Hermon Slade Foundation. J.D. and A.Rodríguez acknowledge support from the FCT (2020.03670.CEECIND and SFRH/BDP/108913/2015, respectively), as well as from the MCTES, FSE, UE and the CFE (UIDB/04004/2021) research unit financed by FCT/MCTES through national funds (PIDDAC). S.C.R. acknowledges support from the US Department of Energy (DE-SC-0008168), US Department of Defense (RC18-1322), and the US Geological Survey Ecosystems Mission Area. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the US government. E.H.-S. acknowledges support from Mexican National Science and Technology Council (CONACYT PN 5036 and 319059). A.N. and C. Branquinho. acknowledge the support from FCT—Fundação para a Ciência e a Tecnologia (CEECIND/02453/2018/CP1534/CT0001, PTDC/ASP-SIL/7743/ 2020, UIDB/00329/2020), from AdaptForGrazing project (PRR-C05-i03-I-000035) and from LTsER Montado platform (LTER_EU_PT_001). Field work of G.P. and J.M.Z. was supported by UNRN (PI 40-C-873).Peer reviewe

Hotspots of biogeochemical activity linked to aridity and plant traits across global drylands

14 páginas.- 4 figuras.- 67 referencias.- The online version contains supplementary material available at https://doi.org/10.1038/s41477-024-01670-7Perennial plants create productive and biodiverse hotspots, known as fertile islands, beneath their canopies. These hotspots largely determine the structure and functioning of drylands worldwide. Despite their ubiquity, the factors controlling fertile islands under conditions of contrasting grazing by livestock, the most prevalent land use in drylands, remain virtually unknown. Here we evaluated the relative importance of grazing pressure and herbivore type, climate and plant functional traits on 24 soil physical and chemical attributes that represent proxies of key ecosystem services related to decomposition, soil fertility, and soil and water conservation. To do this, we conducted a standardized global survey of 288 plots at 88 sites in 25 countries worldwide. We show that aridity and plant traits are the major factors associated with the magnitude of plant effects on fertile islands in grazed drylands worldwide. Grazing pressure had little influence on the capacity of plants to support fertile islands. Taller and wider shrubs and grasses supported stronger island effects. Stable and functional soils tended to be linked to species-rich sites with taller plants. Together, our findings dispel the notion that grazing pressure or herbivore type are linked to the formation or intensification of fertile islands in drylands. Rather, our study suggests that changes in aridity, and processes that alter island identity and therefore plant traits, will have marked effects on how perennial plants support and maintain the functioning of drylands in a more arid and grazed world.This research was supported by the European Research Council (ERC grant 647038 (BIODESERT) awarded to F.T.M.) and Generalitat Valenciana (CIDEGENT/2018/041). D.J.E. was supported by the Hermon Slade Foundation (HSF21040). J. Ding was supported by the National Natural Science Foundation of China Project (41991232) and the Fundamental Research Funds for the Central Universities of China. M.D.-B. acknowledges support from TED2021-130908B-C41/AEI/10.13039/501100011033/Unión Europea Next Generation EU/PRTR and the Spanish Ministry of Science and Innovation for the I + D + i project PID2020-115813RA-I00 funded by MCIN/AEI/10.13039/501100011033. O.S. was supported by US National Science Foundation (Grants DEB 1754106, 20-25166), and Y.L.B.-P. by a Marie Sklodowska-Curie Actions Individual Fellowship (MSCA-1018 IF) within the European Program Horizon 2020 (DRYFUN Project 656035). K.G. and N.B. acknowledge support from the German Federal Ministry of Education and Research (BMBF) SPACES projects OPTIMASS (FKZ: 01LL1302A) and ORYCS (FKZ: FKZ01LL1804A). B.B. was supported by the Taylor Family-Asia Foundation Endowed Chair in Ecology and Conservation Biology, and M. Bowker by funding from the School of Forestry, Northern Arizona University. C.B. acknowledges funding from the National Natural Science Foundation of China (41971131). D.B. acknowledges support from the Hungarian Research, Development and Innovation Office (NKFI KKP 144096), and A. Fajardo support from ANID PIA/BASAL FB 210006 and the Millennium Science Initiative Program NCN2021-050. M.F. and H.E. received funding from Ferdowsi University of Mashhad (grant 39843). A.N. and M.K. acknowledge support from FCT (CEECIND/02453/2018/CP1534/CT0001, SFRH/BD/130274/2017, PTDC/ASP-SIL/7743/2020, UIDB/00329/2020), EEA (10/CALL#5), AdaptForGrazing (PRR-C05-i03-I-000035) and LTsER Montado platform (LTER_EU_PT_001) grants. O.V. acknowledges support from the Hungarian Research, Development and Innovation Office (NKFI KKP 144096). L.W. was supported by the US National Science Foundation (EAR 1554894). Y.Z. and X.Z. were supported by the National Natural Science Foundation of China (U2003214). H.S. is supported by a María Zambrano fellowship funded by the Ministry of Universities and European Union-Next Generation plan. The use of any trade, firm or product names does not imply endorsement by any agency, institution or government. Finally, we thank the many people who assisted with field work and the landowners, corporations and national bodies that allowed us access to their land.Peer reviewe

Rhabdomyosarcoma

Rhabdomyosarcoma is a heterogeneous disease both in presentation and histology. Improvements in a multimodality therapy resulted in the improved overall survival for patients with a low‐risk and intermediate‐risk disease but not for patients with a metastatic disease. We reviewed and contrasted the North American and European practice patterns, though ultimately the principles of staging, surgery, radiation therapy, and chemotherapy are similar in both Children's Oncology Group and International Society of Paediatric Oncology treatment approaches. Efforts are underway to investigate improved local control rates in higher risk patients using radiation dose escalation strategies, and delayed primary excision in select cases. The prognostic significance of imaging‐based chemotherapy response, proton therapy, novel biomarkers, and targeted drugs will be determined in upcoming clinical trials

Rhabdomyosarcoma

Rhabdomyosarcoma is a heterogeneous disease both in presentation and histology. Improvements in a multimodality therapy resulted in the improved overall survival for patients with a low-risk and intermediate-risk disease but not for patients with a metastatic disease. We reviewed and contrasted the North American and European practice patterns, though ultimately the principles of staging, surgery, radiation therapy, and chemotherapy are similar in both Children's Oncology Group and International Society of Paediatric Oncology treatment approaches. Efforts are underway to investigate improved local control rates in higher risk patients using radiation dose escalation strategies, and delayed primary excision in select cases. The prognostic significance of imaging-based chemotherapy response, proton therapy, novel biomarkers, and targeted drugs will be determined in upcoming clinical trials

Locoregional Control Using Highly Conformal Flank Target Volumes and Volumetric-Modulated Arc Therapy in Pediatric Renal Tumors: Results from the Dutch National Cohort

Background and Aims: In pediatric renal tumors, conventional two opposing photon beams have been used to cover the postoperative flank target volume for decades. This single center study describes the locoregional outcome using highly conformal flank target volumes adjusted for postoperative changes and intra-fraction motion combined with Volumetric-Modulated Arc Therapy (VMAT). Methods: Between 01-2015 and 12-2019, 36/161 newly diagnosed patients with renal tumors underwent flank only irradiation (n=30) or flank+whole lung irradiation (n=6) using highly conformal target volumes in line with the SIOP-RTSG consensus statement. VMAT consisted of full-arc 10MV photon beams optimized for constraints of the organs at risk. In case of locoregional relapses, image co-registration and dose reconstruction was performed. Each relapse was classified as either ‘infield’ (V95%relapse: ≥99.0%), ‘marginal’ (V95%relapse: 20.0%-98.9%) or ‘outfield’ (V95%relapse: 0%-19.9%). Results: At a median follow-up from diagnosis of 3.1 years (range:0.4-5.7), the estimated 2-year Locoregional Control Rate, Disease-Free Interval and Overall Survival were 94%, 91% and 94%, respectively. Locoregional relapse was observed in two patients. One patient had a combined tumor bed and regional recurrence, classified as infield (V95%relapse: 100%) and outfield (V95%relapse: 1.2%). The second patient had a regional relapse in the inferior vena cava classified as marginal recurrence (V95%relapse: 93%). Relapses would not have been adequately covered by conventional beams. Conclusions: This single center analysis provides encouraging evidence that excellent locoregional control can be obtained by using highly conformal flank target volumes with VMAT in pediatric renal tumors. The safety of this approach will be validated in a prospective multicenter study

Hearing loss in survivors of childhood head and neck rhabdomyosarcoma: a long-term follow-up study

To determine the hearing status of survivors treated for head and neck rhabdomyosarcoma (HNRMS) at long-term follow-up. Cross-sectional long-term follow-up study. Tertiary comprehensive cancer centre. Survivors treated for HNRMS during childhood in two concurrent cohorts; survivors in London had been treated with external beam radiotherapy (EBRT-based local therapy); survivors in Amsterdam were treated with AMORE (Ablative surgery, MOuld technique afterloading brachytherapy and surgical REconstruction) if feasible, otherwise EBRT (AMORE-based local therapy). We assessed hearing status of HNRMS survivors at long-term follow-up. Hearing thresholds were obtained by pure-tone audiometry. We assessed the hearing thresholds, the number of patients with clinically relevant hearing loss and hearing impairment graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4) and Boston criteria. Furthermore, we compared hearing loss between survivors treated with EBRT-based local therapy (London) and AMORE-based local therapy (Amsterdam). Seventy-three survivors were included (median follow-up 11 years). We found clinically relevant hearing loss at speech frequencies in 19% of survivors. Multivariable analysis showed that survivors treated with EBRT-based treatment and those with parameningeal tumours had significantly more hearing impairment, compared to survivors treated with AMORE-based treatment and non-parameningeal tumours. One in five survivors of HNRMS developed clinically relevant hearing loss. AMORE-based treatment resulted in less hearing loss compared to EBRT-based treatment. As hearing loss was highly prevalent and also occurred in survivors with orbital primaries, we recommend systematic audiological follow-up in all HNRMS survivor

Endocrine disorders among long-term survivors of childhood head and neck rhabdomyosarcoma

Head and neck rhabdomyosarcoma (HNRMS) survivors are at increased risk of developing pituitary dysfunction as an adverse event of radiotherapy. Our aim was to investigate the frequency and risk factors for pituitary dysfunction in these survivors. Secondly, we aimed to compare the prevalence of pituitary dysfunction between survivors treated with external beam radiation therapy (EBRT) and survivors treated with the ablative surgery, moulage technique after loading brachytherapy, and surgical reconstruction (AMORE) procedure. Eighty HNRMS survivors treated in London (EBRT based) and Amsterdam (AMORE based: AMORE if feasible, otherwise EBRT) in the period 1990-2010 and alive ≥ 2 years post-treatment were evaluated. Survivors were evaluated in multidisciplinary late-effects clinics, with measurement of linear growth, determination of thyroid function, and growth hormone parameters. Additional data, such as baseline characteristics, anthropometrics, pubertal stage, and the results of additional laboratory investigations, were retrieved from patient charts. Pituitary dysfunction was diagnosed in 24 in 80 (30%) survivors, after a median follow-up time of 11 years. Median time to develop pituitary dysfunction after HNRMS diagnosis was 3.0 years. Risk factors were EBRT-based therapy (odds ratio [OR] 2.06; 95% confidence interval [CI] 1.79-2.46), parameningeal tumour site (OR 1.83; 95% CI 1.60-2.17) and embryonal RMS histology (OR 1.49; 95% CI 1.19-1.90). Radiotherapy used for the treatment of HNRMS confers a significant risk of the development of pituitary dysfunction. AMORE-based treatment in children with HNRMS resulted in less pituitary dysfunction than treatment with conventional EBRT. Our findings underscore the importance of routine early endocrine follow-up in this specific populatio

Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group

Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (<6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy