Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation ...doses below 10 Gy and the dose-response relationship for specific types of chemotherapy.
Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship.
The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (
< .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m
, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer.
To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m
increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.
•SPC risks increased with extended fields for Hodgkin lymphoma or childhood cancers.•No included studies estimated normal tissue dose–volume distribution.•Current clinical evidence on possible volume ...effects on SPC risks is very limited.•Biological mechanisms underlying volume effects on SPC risks are plausible.
As modern radiotherapy, including intensity-modulated techniques, is associated with high dose gradients to normal tissues and large low-to-moderate dose volumes, the assessment of second primary cancer (SPC) risks requires quantification of dose–volume effects. We conducted a systematic review of clinical and epidemiological studies investigating the effect of the irradiated volume or dose–volume distribution to the remaining volume at risk (RVR) on SPC incidence. We identified eighteen studies comparing SPC risks according to the irradiated volume (i.e., in most studies, the size or number of fields used), and four studies reporting risk estimates according to the dose distribution to the RVR (after whole-body dose reconstruction). An increased risk of SPCs (mainly breast and lung cancers) with extended radiotherapy was observed among patients treated for Hodgkin lymphoma or childhood cancers. However, normal tissue dose distribution was not estimated, limiting the interpretation of those results in terms of volume effects on organs at risk. Studies considering whole-body exposures quantified dose–response relationships for point dose estimates, without accounting for dose–volume distributions. Therefore, they disregarded possible tissue effects (e.g. bystander and abscopal effects, stem cell repopulation) which may play a role in the induction of SPCs. Currently, there is no clinical or epidemiological information about a possible role of high dose gradients in surrounding organs, or increasing volumes of distant tissues exposed to low doses, in the risk of SPCs. Opportunities for future research nevertheless now exist, since methods and tools for estimating individual whole-body dose–volume distributions in large patient populations have been developed.
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.
Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete.
This retrospective multicenter study included patients with any-stage RET positive (RET+) ...NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated.
For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo 37.7–72.1 versus 16.3 mo 12.7–28.8, p < 0.0001).
Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.
Introduction: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete.Methods: This retrospective multicenter study included patients with any-stage ...RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated.Results: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo 37.7–72.1 versus 16.3 mo 12.7–28.8, p < 0.0001).Conclusions: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.
•A few study assessed glucose control in adolescents and young adults with type 1 diabetes during lockdown.•Our study showed a significant improvement of self-monitoring and glucose control in young ...patients, through this period.•The results were even better in patients who received telemedicine support.
There has been little data published related to glucose control in adolescents and young adults with type 1 diabetes (T1D) during lockdown, but rarely focusing on telemedicine’s role. During this unpreceded period, glucose control and self-monitoring improved in our young patients, with better results associated with telemedicine.
Abstract
Long-term sequelae are major limitations of radiation therapy use, especially for childhood brain tumour. Circle of Willis irradiation strongly increases the long-term risk of stroke, but to ...establish dose-response relationship, anticipating long-term effects of new techniques, requires to perform accurate and reproducible dosimetric estimations in large cohorts of patients having received radiotherapy decades ago. For the accuracy of retrospective dose reconstruction, the topographic variability of the Circle of Willis arteries is crucial. In order to improve retrospective dosimetric studies and dose-volume estimates to the typical Circle of Willis arteries, we aim to study the inter-individual topographic variability of these structures. Thirty-eight time of flight MRI sequences of children aged 2–17 years in both genders were investigated. A region growth algorithm was used for the segmentation of the cerebral arteries. A rigid registration in a common skull was performed following the anatomy of skull base foramina. The Posterior clinoid processes of the sella turcica were used as reference landmark (R0), and 5 key landmarks were chosen in each segmented Circle of Willis, then distances between the 5 landmarks and R0 were calculated for each of the 38 subjects. The distance between R0 and each landmark of the Circle of Willis followed a normal distribution, the average values ranging from 13.6 to 17.0 mm, and the standard deviations ranged from 2.6 to 3.0 mm, i.e. less than a fifth of the average value. The perimeter of the Circle of Willis was longer in older subjects, this increase being isotropic. Our study shows a remarkably low topographic variability of the typical Circle of Willis. An important result, allowing reliable anthropomorphic phantoms-based retrospective estimations of the radiation doses delivered to these arterial structures during radiotherapy treatment.
Zrafi et al. report inter-individual topographic variability in the Circle of Willis structure in a paediatric population. Their work shows a remarkably low variability of the typical Circle of Willis and provide data that have potential benefit for retrospective dosimetric studies in children developing cerebrovascular diseases after radiotherapy.
Graphical Abstract
Graphical Abstract
Abstract Long-term sequelae are major limitations of radiation therapy use, especially for childhood brain tumour. Circle of Willis irradiation strongly increases the long-term risk of stroke, but to ...establish dose-response relationship, anticipating long-term effects of new techniques, requires to perform accurate and reproducible dosimetric estimations in large cohorts of patients having received radiotherapy decades ago. For the accuracy of retrospective dose reconstruction, the topographic variability of the Circle of Willis arteries is crucial. In order to improve retrospective dosimetric studies and dose-volume estimates to the typical Circle of Willis arteries, we aim to study the inter-individual topographic variability of these structures. Thirty-eight time of flight MRI sequences of children aged 2–17 years in both genders were investigated. A region growth algorithm was used for the segmentation of the cerebral arteries. A rigid registration in a common skull was performed following the anatomy of skull base foramina. The Posterior clinoid processes of the sella turcica were used as reference landmark (R0), and 5 key landmarks were chosen in each segmented Circle of Willis, then distances between the 5 landmarks and R0 were calculated for each of the 38 subjects. The distance between R0 and each landmark of the Circle of Willis followed a normal distribution, the average values ranging from 13.6 to 17.0 mm, and the standard deviations ranged from 2.6 to 3.0 mm, i.e. less than a fifth of the average value. The perimeter of the Circle of Willis was longer in older subjects, this increase being isotropic. Our study shows a remarkably low topographic variability of the typical Circle of Willis. An important result, allowing reliable anthropomorphic phantoms-based retrospective estimations of the radiation doses delivered to these arterial structures during radiotherapy treatment.
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