Biological sample collection to advance research and treatment: a Fight Osteosarcoma Through European Research (FOSTER) and Euro Ewing Consortium (EEC) statement.

Osteosarcoma and Ewing sarcoma are bone tumours mostly diagnosed in children, adolescents and young adults. Despite multi-modal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been ground-breaking. Better understanding of biological subgroups, the role of the tumour immune microenvironment, factors that promote metastasis and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic and clinically linked biological analysis of patient samples but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage and analysis of patient samples. Two international panels of scientists, clinicians and patient and parent advocates have formed the Fight Osteosarcoma Through European Research (FOSTER) consortium and the Euro Ewing Consortium (EEC). The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, liquid biopsy tubes), handling and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonisation with practical, legal and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration and improve outcomes.

Successful treatment of paediatric refractory Hodgkin lymphoma with immunotherapy - A case report and literature review.

AIM: To describe a rare case of primary refractory Hodgkin lymphoma nodular sclerosis syncytial variant in a child and review immunotherapy in relapsed/refractory Hodgkin lymphoma. METHODS: We described the treatment course of a child with primary refractory classic Hodgkin lymphoma and discussed different options for salvage therapy, with an emphasis on immunotherapy. We searched PubMed for all published clinical trials investigating immunotherapy in classic Hodgkin lymphoma written in English until 31 June, 2023. The reference list of each identified paper was searched for additional publications. RESULTS: Our patient was salvaged with anti-programmed cell death 1 (PD-1) antibody therapy followed by high-dose chemotherapy with autologous stem cell rescue. Radiotherapy was avoided. We identified five one-armed phase II trials investigating anti-PD-1 therapy in first relapse/refractory disease in a total of 254 patients aged 9-71 years, of which one included 31 children. The complete remission rate before high-dose chemotherapy was 59%-95% overall and 67%-89% among those with refractory disease. CONCLUSION: Although it remains to be proven in randomised trials, anti-PD-1 therapy may provide higher complete response rates than traditional chemotherapy. Anti-PD-1 therapy has the potential to increase the chance of cure while decreasing the risk of late effects from chemotherapy and radiotherapy.

Familial Co-Aggregation of Idiopathic Inflammatory Myopathies and Cancer: A Swedish Population-Based Study.

OBJECTIVE: To examine if idiopathic inflammatory myopathies (IIMs) share familial susceptibility with cancer, we estimated the familial co-aggregation of these diseases. METHODS: This Swedish population-based family study with data from national registers included 8,460 first-degree relatives of patients with IIM and 41,127 relatives of matched individuals without IIM. We modeled the adjusted odds ratios (ORs) of familial co-aggregation of IIM and cancer using conditional logistic regressions and adjusted for sex and birth year of index individuals and their first-degree relatives. We examined the associations for cancer overall and stratified by several factors of interest. We also performed exploratory analyses for specific cancer types. RESULTS: We observed no statistically significant familial associations between IIM and cancer overall. However, there was a familial association in male relative pairs of patients with dermatomyositis (adjusted OR for familial association 1.39 [95% confidence interval (95% CI) 1.15-1.68]). The association remained statistically significant after controlling for multiple testing. Moreover, this finding was consistent between kinships. Familial co-aggregation of IIM and cancer diagnosed before 50 years of age was only observed in offspring. In exploratory analyses, only the familial associations for myeloid malignancies (adjusted OR 2.27 [95% CI 1.43-3.60]) and liver cancer (adjusted OR 2.01 [95% CI 1.21-3.33]) in male relative pairs remained significant after controlling for multiple testing. CONCLUSION: We found little evidence of shared familial susceptibility as a major pathologic mechanism contributing to the co-occurrence of IIM and cancer overall. There could be subsets of patients and cancer types for which familial factors including genetics and shared environments are of more importance, but these findings need replication.

Long-term diagnosis-specific sickness absence, disability pension, and healthcare use in 1305 young adult childhood cancer survivors and in 6430 references; a Swedish ten-year prospective cohort study.

BACKGROUND: Childhood cancer survivors (CCS) are at high risk of chronic health conditions. We aimed to explore young adult CCS' and matched references' future diagnoses-specific healthcare use, sickness absence (SA), and disability pension (DP). METHODS: We performed a prospective cohort study with microdata from seven nationwide Swedish registers. We included 1305 young adult CCS born 1983-1988 and living in Sweden in 2008 and 6430 matched references and followed them for ten years (2009-2018) regarding mean annual specialized outpatient visits, inpatient days, and SA (spells >14 days) and/or DP (SADP) days, overall and by eight diagnostic groups. Risk factors for >90 SADP days in 2018 were explored as odds ratios (OR) with 95% confidence intervals (CI) by adjusted logistic regression. RESULTS: Approximately 80% of CCS and 90% of references did not have SADP in the ten-year follow-up. Mean SADP days/year was higher among CCS (40-50 days/year), particularly in CNS tumor survivors (76-83 days/year), compared to references (12-18 days/year). Most SADP days were DP days. CCS had more mean outpatient visits (1.6-1.8 visits/year) and inpatient days (0.8-1.7 days/year) than references (0.8-1.2 visits/year and 0.6-0.75 days/year, respectively). The main healthcare use and SADP diagnoses were neoplasms and psychiatric disorders among all CCS, along with nervous system and endocrine conditions among CNS tumor survivors. The risk of SADP >90 days in 2018 was higher among female compared to male CCS (OR = 2.34, 95% CI 1.67-3.32), those with elementary schooling compared to high school/university education (OR = 6.52, 95% CI 4.49-9.49), and survivors of CNS tumors compared to other malignancies (OR hematological versus CNS = 2.88, 95% CI 1.95-4.28; OR hematological versus non-CNS solid tumors = 0.71, 95% CI 0.45-1.09). CONCLUSIONS: Most CCS did not have SADP as young adults; nevertheless, their risk of SADP was higher than among matched references. CNS tumor survivors were at particularly high risk of SADP.

Sickness absence and disability pension trajectories in childhood cancer survivors and references- a Swedish prospective cohort study.

BACKGROUND: Childhood cancer survivors are at high risk of chronic health conditions. We aimed to explore future long-term sickness absence and disability pension in young adult childhood cancer survivors and matched references. METHODS: We performed a prospective cohort study using microdata from five Swedish nationwide registers. Among all individuals born 1976-1998 and living in Sweden, we included 3632 childhood cancer survivors and 17,468 matched references that could be followed-up for 15, 10, or 5 years, respectively. A group-based trajectory model was applied to identify trajectories of mean annual sickness absence and/or disability pension days (SADP) in each sub-cohort, with 95% confidence intervals (CI). Potential risk factors for trajectory belonging were explored using χ2 test and multinomial logistic regression. RESULTS: Most young adult childhood cancer survivors (90.2-96.5%) and references (97.4-98.8%) followed a No SADP trajectory. A larger proportion of childhood cancer survivors than references followed a Moderate (33-102 days/year) or High (115-260 days/year) SADP trajectory (15-year follow-up cohorts: Moderate 4.6% versus 1.2%; High 5.1% versus 1.5%). Childhood cancer survivors of central nervous system (CNS) tumors were at higher risk of the High SADP trajectory than childhood cancer survivors of hematological or non-CNS solid tumors (hematological versus CNS: odds ratio = 2.30, 95% CI 1.23-4.30; hematological versus non-CNS: odds ratio = 0.32, 95% CI 0.13-0.79). CONCLUSIONS: Although most young adult childhood cancer survivors had no SADP during follow-up, 9.7% experienced moderate or high numbers of SADP days/year throughout the 15-year follow-up; compared to 2.7% among references. CNS tumor survivors were at particular risk of SADP long-term and need extra attention in their future work prospect.

Is primary hepatic angiosarcoma in children an indication for liver transplantation?-A single-centre experience and review of the literature.

PHA in the paediatric population is an extremely rare and aggressive malignant soft tissue neoplasm, with less than 50 cases published worldwide. The prognosis is dismal. If the tumour is unresectable, one treatment option is LT. In this article, the current available literature is reviewed and additionally, three cases of paediatric patients with PHA who underwent LT at Karolinska University Hospital, Sweden, are presented. Based on the literature and our own experience, there is undoubtedly possible good outcome of LT due to PHA. On the contrary, no patients have survived PHA without LT. PHA in paediatric patients should be recommended to LT in selected patients. Effect of modern adjuvant chemo and RT should be evaluated further based on international registry for such rare cases of PHA.

Concordance in survival among first-degree relatives diagnosed with indolent lymphoid malignancies including chronic lymphocytic leukemia.

OBJECTIVES: To investigate concordance in survival time among first-degree relatives with lymphoid malignancies. METHODS: By linkage of national Swedish registers, we identified 66 430 patients diagnosed with a lymphoid malignancy 1958-2016 with information on first-degree relationships and follow-up until 2017. Among these, we identified pairs of first-degree relatives with any (N = 3326) or a similar (N = 690) lymphoid malignancy subtype. We defined survival in the first-degree relative as good, expected, or poor based on tertiles of deviance residuals from a multivariable Cox regression model. Next, we used Cox regression to estimate hazard ratios (HR) of death with 95% confidence intervals (CI) among patients, using the survival of their first-degree relative as exposure and adjusting for confounders. RESULTS: There was no concordance in survival among first-degree relatives with any lymphoid malignancy (HRgood  = 1.00 (reference), HRExpected  = 1.02, 95% CI: 0.89-1.17, HRPoor  = 1.12, 95% CI: 0.98-1.27, Ptrend  = .08). Among first-degree relatives with indolent lymphoma, including chronic lymphocytic leukemia, those with a first-degree relative to an expected or poor survival had worse outcome compared to those with a first-degree relative with good survival (HRExpected  = 1.44, 95% CI: 0.82-2.53, HRPoor  = 1.79, 95% CI: 1.07-3.00, Ptrend  = .03). CONCLUSION: Our results support a role of inherited factors in the outcome of indolent lymphoma, including chronic lymphocytic leukemia.

Possible Interaction Between Cigarette Smoking and HLA-DRB1 Variation in the Risk of Follicular Lymphoma.

Follicular lymphoma (FL) risk is strongly associated with germline genetic variation in human leukocyte antigen (HLA) class II. Cigarette smoking has been suggested to increase FL risk, primarily among women. We hypothesized that amino acids in HLA-antigen D-related ß1 subunit (DRB1) interact with smoking in FL risk, as shown for rheumatoid arthritis. We analyzed 373 patients with FL and 818 controls from 2 population-based case-control studies in Sweden and Denmark (1999-2003). Haplotypes in HLA-DRB1 were imputed at amino acid positions 11, 13, 28, 30, and 70-74 (shared epitope). We estimated the relative risk of FL as odds ratios with 95% confidence intervals for different smoking status/haplotype combinations. Interaction was defined as departure from additivity of effects and quantified by the attributable proportion (AP). Relative to never-smokers carrying no shared epitope alleles, smoking was associated with the risk of FL among all subjects (for former smokers, odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.10, 4.41; ORcurrent = 3.56, 95% CI: 1.60, 7.92) and women (ORformer = 2.95, 95% CI: 1.18, 7.37; ORcurrent = 5.63, 95% CI: 2.07, 15.3) carrying 2 shared epitope alleles but not among those carrying zero or 1 shared epitope allele. Smoking and shared epitope status interacted significantly as measured by AP (overall, AP = 0.6, 95% CI: 0.15, 1.0; for women, AP = 0.5, 95% CI: 0.005, 1.0). These results suggest a possible interaction between smoking and HLA-DRB1-associated antigen presentation in FL risk and provide a model to further unravel FL etiology.

A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival.

BACKGROUND: Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed. METHODS: We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999-2002 and in the United States 2001-2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model. RESULTS: In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0 ×10(-8)). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 5.24 ×10(-8)). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival. CONCLUSIONS: The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.

Lifestyle factors, autoimmune disease and family history in prognosis of non-hodgkin lymphoma overall and subtypes.

Lifestyle factors and medical history are known to influence risk of non-Hodgkin lymphoma (NHL). Whether these factors affect the prognosis of NHL, especially its subtypes, is unclear. To investigate this, the association between these factors and all-cause and lymphoma-related mortality was assessed in a population-based cohort of 1,523 Swedish NHL patients included in the Scandinavian Lymphoma Etiology study in 1999-2002. Participants contributed time from NHL diagnosis until death or October 1, 2010, with virtually complete follow-up through linkage to the Swedish Cause of Death Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using stratified and multivariable-adjusted Cox regression models. During a median follow-up of 8.8 years, 670 patients (44%) died, with the majority of deaths attributed to lymphoma (86%). Current versus never smoking at diagnosis was associated with increased rate of all-cause death for all NHL (HR = 1.5, 1.2-1.8) and diffuse large B-cell lymphoma (HR = 1.8, 1.2-2.7). Low educational level (HR = 1.3, 1.1-1.7, <9 vs. >12 years) and NHL risk-associated autoimmune disease (HR = 1.4, 1.0-1.8) were associated with death for all NHL combined. However, evidence of an association with lymphoma-related death was limited. Body mass index, recent sunbathing and family history of hematopoietic malignancy were not consistently associated with death after NHL or its specific subtypes. These results add to the evidence that cigarette smoking, socioeconomic status and certain autoimmune diseases affect survival after NHL. Further investigations are needed to determine how these factors should be incorporated into clinical prognostic assessment.