About half of the human genome is composed of repeated sequences derived from mobile elements, mainly retrotransposons, generally without pathogenic effect. Familial forms of retinoblastoma are ...caused by germline pathogenic variants in
gene. Here, we describe a family with retinoblastoma affecting a father and his son. No pathogenic variant was identified after DNA analysis of
gene coding sequence and exon-intron junctions. However,
mRNA analysis showed a chimeric transcript with insertion of 114 nucleotides from
gene inside
gene. This chimeric transcript led to an insertion of 38 amino acids in functional domain of retinoblastoma protein. Subsequent DNA analysis in
intron 17 revealed the presence of a full-length
retrogene insertion in opposite orientation. Functional assay shows that this insertion has a deleterious impact on retinoblastoma protein function. This is the first report of a full-length retrogene insertion involved in human Mendelian disease leading to a chimeric transcript and a non-functional chimeric protein. Some retrogene insertions may be missed by standard diagnostic genetic testing, so contribution of retrogene insertions to human disease may be underestimated. The increasing use of whole genome sequencing in diagnostic settings will help to get a more comprehensive view of retrogenes.
Although survival from childhood cancer has increased, little is known on the long-term impact of treatment late effects on occupational attainment or work ability.
A total of 3512 five-year ...survivors treated before the age of 19 years in 10 French cancer centres between 1948 and 2000 were identified. Educational level, employment status and occupational class of survivors were assessed by a self-reported questionnaire. These outcome measures were compared with sex-age rates recorded in the French population, using indirect standardisation. Paternal occupational class was also considered to control for the role of survivors' socioeconomic background on their achievement. Multivariable analyses were conducted to explore clinical characteristics associated with the outcomes.
A total of 2406 survivors responded to the questionnaire and survivors aged below 25 years were included in the current analysis. Compared with national statistics adjusted on age and sex, male survivors were more likely to be college graduates (39.2% vs 30.9% expected; P<0.001). This higher achievement was not observed either for leukaemia or central nervous system (CNS) tumour survivors. Health-related unemployment was higher for survivors of CNS tumour (28.1% vs 4.3%; P<0.001) but not for survivors of other diagnoses. Survivors of non-CNS childhood cancer had a similar or a higher occupational class than expected.
Survivors treated for CNS tumour or leukaemia, especially when treatment included cranial irradiation, might need support throughout their lifespan.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary
In children, lymphoblastic lymphomas represent 30% of Non‐Hodgkin lymphomas (NHL), and approximately 15% are precursor B‐cell lymphomas (PBLL). Our study evaluated their main clinical ...characteristics, evolution, and prognosis in three trials. From 1989 to 2008, 53 children with PBLL (median age 7·75 years) were included in three protocols: Malignant Lymphoma Therapy (LMT) 96, European Organization for Research and Treatment of Cancer (EORTC) 58881, and EORTC 58951 using Berlin‐Frankfürt‐Münster‐derived acute lymphoblastic leukaemia (ALL) therapy. There were 10 stage I disease, 9 stage II, 9 stage III and 25 stage IV. Clinical presentation was heterogeneous with a majority of bone lesions and cutaneous or subcutaneous manifestations. At diagnosis 23 patients had bone marrow involvement, and only three had central nervous system involvement. The median follow‐up was 74 months. At last follow‐up, 45 patients were in continuous complete remission, whereas eight had progressed or had relapsed (7 Stages IV and 1 Stage III) and died. Two patients had a secondary neoplasia, and are still alive. Disease stage was a major prognostic factor, with better overall survival (OS) and event‐free survival (EFS) (P < 0·05) rates observed in patients with Stage I to III as compared to those with Stage IV. Treatment with protocols derived from ALL therapy are efficient with an 82% EFS and an 85% OS at 5 years.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The role of high-dose chemotherapy in relapsing osteosarcomas has not been established. We evaluated the efficacy and tolerance of high-dose thiotepa (HDTp) after standard chemotherapy (SCT) in ...patients with relapsed osteosarcoma.
This randomised open-label phase II study enrolled patients 1–50 years, with local or metastatic relapse of a high-grade osteosarcoma, not progressive after two cycles of SCT, for whom a complete surgery can be achievable following treatment. The trial assigned enrolled patients in a 1:1 ratio to receive two additional courses of SCT + HDTp and autologous transplantation (Arm A), or SCT alone (Arm B). Surgery for complete resection was scheduled as soon as feasible. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS) and safety.
From September 2009 to November 2016, 44 patients were randomised (A:22; B:22). In total, 54.5% were males, and the median age was 16 years (9-32years). The two-year OS rate was 66.7% (95% CI 42.5–82.5) (SCT + HDTp, Arm A) versus 50.0% (95% CI 28.2–68.4) for SCT alone (Arm B). Median OS was 27.4 and 24.8 months, respectively (hazard ratio HR 0.826, 95% CI 0.393–1.734; p = 0.6123). Median PFS was 15.6 (8.9–24.9) months in Arm A versus 7.2 (4.8–33.3) months in Arm B, p = 0.3845. Among the 22 patients treated with SCT + HDTp, 16 (72.7%) experienced at least one grade ≥3 adverse events versus 18/22 (81.8%) patients treated with SCT. No toxic death occurred.
Adjuvant HDTp failed to significantly improve OS and PFS in resectable relapsed osteosarcomas. Despite a trend of prolonged survival and an acceptable toxicity, thiotepa cannot be recommended.
HDTp and autologous transplantation added to SCT did not improve OS and PFS in patients with resectable relapsed osteosarcomas. Despite a trend of prolonged survival, thiotepa cannot be recommended.
•NCT 00978471 is a randomised phase II study of 44 patients with relapsed osteosarcoma.•Arm A: chemotherapy + thiotepa and autologous transplantation; Arm B: chemotherapy.•Added high-dose thiotepa and autologous transplantation did not improve OS and PFS.•Experienced ≥1 Grade ≥ 3 adverse event: Arm A (72.7%) versus Arm B 81.8%.•Despite acceptable toxicity, thiotepa is not recommended out of clinical trial.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide ...alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor–relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance–specific relapse.
•Genome-wide CRISPR activation and knockout screens identify genes involved in modulating sensitivity to crizotinib in NPM1-ALK+ ALCL.•In an autocrine loop, the interleukin-10 receptor activates STAT3, bypassing NPM1-ALK, to bind to the promoters of IL10, IL10RA, and IL10RB.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction
The role of percutaneous thermal ablation as a minimally-invasive treatment has not been evaluated in children under 18 years of age with pulmonary osteosarcoma metastases.
Methods
This ...was a retrospective review of children treated with percutaneous thermal ablation for pulmonary osteosarcoma metastasis after prior surgical metastasectomy and chemotherapy. Selection criteria included number of pulmonary nodules <5 and nodule size smaller than 2 cm. Indications were discussed at multidisciplinary meetings. The goal was to achieve complete remission using percutaneous thermal ablation, thereby avoiding additional thoracotomies.
Results
A total of 26 pulmonary nodules (mean size 6.7 mm, range 2–16 mm) were successfully treated by percutaneous computed tomography (CT)-guided thermal ablation in 11 children with osteosarcoma between the ages of 7 and 17 years (median 12.5). Patients denied post-procedure pain. Complications were limited to three pneumothoraxes (two minor, one major), and median hospitalization duration was 2.0 days. One patient died of rapidly progressive lumbar metastasis discovered 20 days post-ablation. Of the remaining 10 patients, local control at the ablation site was achieved, with median follow up of 16.7 months (range 4.1–41.8). Five patients remained in complete remission after median follow-up of 37.5 months, and five patients developed new metastases (one osseous, four pulmonary), of which two are in remission after subsequent treatment.
Conclusion
Percutaneous thermal ablation is a safe and effective minimally-invasive curative local treatment alternative for children with oligometastatic pulmonary osteosarcoma in whom surgical intervention is clinically contraindicated or unappealing.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cancers of the digestive system constitute a major risk for childhood cancer survivors treated with radiotherapy once they reach adulthood. The aim of this study was to determine therapy-related risk ...factors for the development of a second malignancy in the digestive organs (SMDO) after a childhood cancer.
Among 4,568 2-year survivors of a childhood solid cancer diagnosed before 17 years of age at eight French and British centers, and among 25,120 patients diagnosed as having a malignant neoplasm before the age of 20 years, whose data were extracted from the Nordic Cancer Registries, we matched 58 case patients (41 men and 17 women) of SMDO and 167 controls, in their respective cohort, for sex, age at first cancer, calendar year of occurrence of the first cancer, and duration of follow-up. The radiation dose received at the site of each second malignancy and at the corresponding site of its matched control was estimated.
The risk of developing a SMDO was 9.7-fold higher in relation to the general populations in France and the United Kingdom. In the case-control study, a strong dose-response relationship was estimated, compared with that in survivors who had not received radiotherapy; the odds ratio was 5.2 (95% CI, 1.7-16.0) for local radiation doses between 10 and 29 Gy and 9.6 (95% CI, 2.6-35.2) for doses equal to or greater than 30 Gy. Chemotherapy was also found to increase the risk of developing SMDO.
This study confirms that childhood cancer treatments strongly increase the risk of SMDO, which occur only after a very long latency period.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Between 10% and 20% of childhood cancer survivors (CCS) experience impaired growth, leading to small adult height (SAH). Our study aimed to quantify risk factors for SAH or growth hormone deficiency ...among CCS.
The French CCS Study holds data on 7,670 cancer survivors treated before 2001. We analyzed self-administered questionnaire data from 2,965 CCS with clinical, chemo/radiotherapy data from medical records. SAH was defined as an adult height ≤ 2 standard deviation scores of control values obtained from a French population health study.
After exclusion of 189 CCS treated with growth hormone, 9.2% (254 of 2,776) had a SAH. Being young at the time of cancer treatment (relative risk RR, 0.91 95% CI, 0.88 to 0.95 by year of age), small height at diagnosis (≤ 2 standard deviation scores; RR, 6.74 95% CI, 4.61 to 9.86), pituitary irradiation (5-20 Gy: RR, 4.24 95% CI, 1.98 to 9.06; 20-40 Gy: RR, 10.16 95% CI, 5.18 to 19.94; and ≥ 40 Gy: RR, 19.48 95% CI, 8.73 to 43.48), having received busulfan (RR, 4.53 95% CI, 2.10 to 9.77), or > 300 mg/m
of lomustine (300-600 mg/m
: RR, 4.21 95% CI, 1.61 to 11.01 and ≥ 600 mg/m
: RR, 9.12 95% CI, 2.75 to 30.24) were all independent risk factors for SAH. Irradiation of ≥ 7 vertebrae (≥ 15 Gy on ≥ 90% of their volume) without pituitary irradiation increased the RR of SAH by 4.62 (95% CI, 2.77 to 7.72). If patients had also received pituitary irradiation, this increased the RR by an additional factor of 1.3 to 2.4.
CCS are at a high risk of SAH. CCS treated with radiotherapy, busulfan, or lomustine should be closely monitored for growth, puberty onset, and potential pituitary deficiency.
STUDY QUESTION
Is the age at menopause in a cohort of childhood cancer survivors earlier and what are the risk factors associated with earlier age at menopause?
SUMMARY ANSWER
Menopause occurred at a ...median age of 44 years in this cohort which is earlier than in the general population, but premature menopause was uncommon. Main risk factors for non-surgical menopause were exposure to and dose of alkylating agents, especially during adolescence, radiation dose to the ovaries and oophorectomy.
WHAT IS KNOWN ALREADY
While survivors of childhood cancer are known to be at increased risk for developing premature menopause, data on its risk factors are limited.
STUDY DESIGN
A cohort study of 1109 still-living female survivors of childhood solid cancer treated between 1945 and 1985, of whom 863 (78%) returned a follow-up questionnaire. Of them, 157 were excluded.
PARTICIPANTS AND METHODS
Seven hundred and six women, among whom 32% have attained 40 years of age, were included in this study. A Cox regression model was used to determine risk factors influencing the age at menopause.
MAIN RESULTS
Ninety seven women have reached menopause at a median age of 44 years. Menopause has been surgically induced in 36% of women. In multivariate analysis, risk factors for non-surgical menopause included exposure to alkylating agents, increasing radiation dose to the ovaries, procarbazine dose, cyclophosphamide dose and unilateral oophorectomy. The highest risk ratio for non-surgical menopause was observed for women treated after the onset of puberty with alkylating agents, either alone (RR = 9, 95% CI: 2.7–28, P = 0.0003) or associated with even a low dose of radiation to the ovaries (RR = 29, 95% CI: 8–108, P < 0.0001). Exposure to unilateral oophorectomy is associated with a 7-year earlier age at menopause. By the age of 40, only 2.1% had non-surgical premature menopause and its main risk factors were age at diagnosis, cyclophosphamide dose, exposure to melphalan and radiation dose to the ovaries.
LIMITATIONS
The information on menopause was based on self-reported data without confirmation by FSH levels. Participants to this study have been treated for cancer from 1945 to 1985 and one can expect an increase in premature menopause incidence with more recent protocols using high-dose alkylating agents.
WIDER IMPLICATIONS OF THE FINDINGS
This study provides data on risk factors for a reduced fertility window in order to inform survivors at risk and help oncologists to design new therapeutic protocols avoiding this risk. This study does not confirm the high rate of premature menopause reported by the Childhood Cancer Survivor Study, but this population differs from theirs (no leukemia and a lower percentage of lymphoma).
STUDY FUNDING
EDF, Ligue Nationale contre le cancer, IRESP, PHRC, AFSSAPS, Fondation Pfizer. No conflict of interest.
•Knowledge is lacking on the role of maternal pesticides use on childhood lymphoma.•We pooled data from two French nationwide population-based case-control studies.•Maternal insecticides use in ...pregnancy was associated with both NHL and HL.•Associations were slightly stronger for Burkitt lymphoma and mixed cellularity HL.
Few studies have assessed the relation between maternal prenatal pesticides use and childhood lymphoma risk, some reporting a positive association with non-Hodgkin lymphoma (NHL). We investigated the association between maternal exposure to pesticides during pregnancy and childhood Hodgkin (HL) and non-Hodgkin lymphoma.
We pooled data from the two French national population-based case-control studies ESCALE (2003-2004) and ESTELLE (2010-2011). Data on domestic and occupational exposures to pesticides during pregnancy were obtained through standardised maternal interviews. Logistic regression models were used to compute odds ratios (OR) and 95% confidence intervals (CI) for HL and NHL, by pesticide category adjusted for potential confounders. Analyses by histological subtypes were also performed.
We included 328 H L, 305 non-Hodgkin NHL and 2,415 controls. Around 40% of control mothers reported having used pesticides during index pregnancy, of whom 95% reported insecticides use. Maternal use of herbicides and fungicides occurred mostly in combination with insecticides. Insecticides use was more frequently reported in cases than controls (ORNHL = 1.6 95%CI 1.3–2.1, p = 0.0001; ORHL = 1.3 95%CI 1.0–1.7, p = 0.03). This association appeared more marked for Burkitt lymphoma and mixed cellularity classical HL. No obvious association was observed with occupational pesticides exposure during pregnancy.
These results suggest that maternal domestic use of insecticides during pregnancy might be related to both childhood NHL and HL. Further larger studies are urgently needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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