Mass drug administration to reduce malaria incidence in a low-to-moderate endemic setting: short-term impact results from a cluster randomised controlled trial in Senegal.

Background: In Africa, the scale-up of malaria control interventions, including seasonal malaria chemoprevention (SMC), has dramatically reduced malaria burden, but progress toward malaria elimination has stalled. We evaluated mass drug administration (MDA) as a strategy to accelerate reductions in malaria incidence in Senegal. Methods: We conducted an open-label, cluster-randomised controlled trial in a low-to-moderate transmission setting of Tambacounda, Senegal. Eligible villages had a population size between 200-800. All villages received pyrethroid-piperonyl butoxide bednets and proactive community case management of malaria at baseline. Sixty villages were randomised 1:1 to either three cycles of MDA with dihydroartemisinin-piperaquine+single-low dose primaquine administered to individuals aged ≥3 months, six-weeks apart starting the third week of June (intervention), or standard-of-care, which included three monthly cycles of SMC with sulfadoxine-pyrimethamine+amodiaquine administered to children aged 3-120 months starting end of July (control). MDA and SMC were delivered door-to-door. The primary outcome was clinical malaria incidence in all ages assessed during the peak transmission season (July-December), the year after intervention. Here, we report safety, coverage, and impact outcomes during the intervention year. The trial is registered at ClinicalTrials.Gov (NCT04864444). Findings: Between June 21, 2021 and October 3, 2021, 6505, 7125, and 7250 participants were administered MDA and 3202, 3174, and 3146 participants were administered SMC across cycles. Coverage of ≥1 dose of MDA drugs was 79%, 82%, and 83% across cycles. During the transmission season of the intervention year, MDA was associated with a 55% [95% CI: 28%-72%] lower incidence of malaria compared to control (MDA: 93 cases/1000 population; control: 173 cases/1000 population). No serious adverse events were reported in either arm. Interpretation: In low-to-moderate malaria transmission settings with scaled-up malaria control interventions, MDA with dihydroartemisinin-piperaquine+single-low dose primaquine is effective and well-tolerated for reducing malaria incidence. Further analyses will focus on the sustainability of this reduction. Funding: United States President's Malaria Initiative.

Two decades of molecular surveillance in Senegal reveal rapid changes in known drug resistance mutations over time.

BACKGROUND: Drug resistance in Plasmodium falciparum is a major threat to malaria control efforts. Pathogen genomic surveillance could be invaluable for monitoring current and emerging parasite drug resistance. METHODS: Data from two decades (2000-2020) of continuous molecular surveillance of P. falciparum parasites from Senegal were retrospectively examined to assess historical changes in malaria drug resistance mutations. Several known drug resistance markers and their surrounding haplotypes were profiled using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole genome sequence based population genomics. RESULTS: This dataset was used to track temporal changes in drug resistance markers whose timing correspond to historically significant events such as the withdrawal of chloroquine (CQ) and the introduction of sulfadoxine-pyrimethamine (SP) in 2003. Changes in the mutation frequency at Pfcrt K76T and Pfdhps A437G coinciding with the 2014 introduction of seasonal malaria chemoprevention (SMC) in Senegal were observed. In 2014, the frequency of Pfcrt K76T increased while the frequency of Pfdhps A437G declined. Haplotype-based analyses of Pfcrt K76T showed that this rapid increase was due to a recent selective sweep that started after 2014. DISCUSSION (CONCLUSION): The rapid increase in Pfcrt K76T is troubling and could be a sign of emerging amodiaquine (AQ) resistance in Senegal. Emerging AQ resistance may threaten the future clinical efficacy of artesunate-amodiaquine (ASAQ) and AQ-dependent SMC chemoprevention. These results highlight the potential of molecular surveillance for detecting rapid changes in parasite populations and stress the need to monitor the effectiveness of AQ as a partner drug for artemisinin-based combination therapy (ACT) and for chemoprevention.

LymphoDose: a lymphocyte dose estimation framework-application to brain radiotherapy.

Objective. Severe radiation-induced lymphopenia occurs in 40% of patients treated for primary brain tumors and is an independent risk factor of poor survival outcomes. We developed anin-silicoframework that estimates the radiation doses received by lymphocytes during volumetric modulated arc therapy brain irradiation.Approach. We implemented a simulation consisting of two interconnected compartmental models describing the slow recirculation of lymphocytes between lymphoid organs (M1) and the bloodstream (M2). We used dosimetry data from 33 patients treated with chemo-radiation for glioblastoma to compare three cases of the model, corresponding to different physical and biological scenarios: (H1) lymphocytes circulation only in the bloodstream i.e. circulation inM2only; (H2) lymphocytes recirculation between lymphoid organs i.e. circulation inM1andM2interconnected; (H3) lymphocytes recirculation between lymphoid organs and deep-learning computed out-of-field (OOF) dose to head and neck (H&N) lymphoid structures. A sensitivity analysis of the model's parameters was also performed.Main results. For H1, H2 and H3 cases respectively, the irradiated fraction of lymphocytes was 99.8 ± 0.7%, 40.4 ± 10.2% et 97.6 ± 2.5%, and the average dose to irradiated pool was 309.9 ± 74.7 mGy, 52.6 ± 21.1 mGy and 265.6 ± 48.5 mGy. The recirculation process considered in the H2 case implied that irradiated lymphocytes were irradiated in the field only 1.58 ± 0.91 times on average after treatment. The OOF irradiation of H&N lymphoid structures considered in H3 was an important contribution to lymphocytes dose. In all cases, the estimated doses are low compared with lymphocytes radiosensitivity, and other mechanisms could explain high prevalence of RIL in patients with brain tumors.Significance. Our framework is the first to take into account OOF doses and recirculation in lymphocyte dose assessment during brain irradiation. Our results demonstrate the need to clarify the indirect effects of irradiation on lymphopenia, in order to potentiate the combination of radio-immunotherapy or the abscopal effect.

Radiation Doses Received by Major Organs at Risk in Children and Young Adolescents Treated for Cancer with External Beam Radiation Therapy: A Large-scale Study from 12 European Countries.

PURPOSE: Childhood cancer survivors, in particular those treated with radiation therapy, are at high risk of long-term iatrogenic events. The prediction of risk of such events is mainly based on the knowledge of the radiation dose received to healthy organs and tissues during treatment of childhood cancer diagnosed decades ago. We aimed to set up a standardized organ dose table to help former patients and clinicians in charge of long-term follow-up clinics. METHODS AND MATERIALS: We performed whole body dosimetric reconstruction for 2646 patients from 12 European countries treated between 1941 and 2006 (median, 1976). Most plannings were 2- or 3-dimensional. A total of 46% of patients were treated using Cobalt 60, and 41%, using a linear accelerator. The median prescribed dose was 27.2 Gy (IQ1-IQ3, 17.6-40.0 Gy). A patient-specific voxel-based anthropomorphic phantom with more than 200 anatomic structures or substructures delineated as a surrogate of each subject's anatomy was used. The radiation therapy was simulated with a treatment planning system based on available treatment information. The radiation dose received by any organ of the body was estimated by extending the treatment planning system dose calculation to the whole body, by type and localization of childhood cancer. RESULTS: The integral dose and normal tissue doses to most of the 23 considered organs increased between the 1950s and 1970s and decreased or plateaued thereafter. Whatever the organ considered, the type of childhood cancer explained most of the variability in organ dose. The country of treatment explained only a small part of the variability. CONCLUSIONS: The detailed dose estimates provide very useful information for former patients or clinicians who have only limited knowledge about radiation therapy protocols or techniques, but who know the type and site of childhood cancer, sex, age, and year of treatment. This will allow better prediction of the long-term risk of iatrogenic events and better referral to long-term follow-up clinics.

Deep-Learning for Rapid Estimation of the Out-of-Field Dose in External Beam Photon Radiation Therapy - A Proof of Concept.

PURPOSE: The dose deposited outside of the treatment field during external photon beam radiation therapy treatment, also known as out-of-field dose, is the subject of extensive study as it may be associated with a higher risk of developing a second cancer and could have deleterious effects on the immune system that compromise the efficiency of combined radio-immunotherapy treatments. Out-of-field dose estimation tools developed today in research, including Monte Carlo simulations and analytical methods, are not suited to the requirements of clinical implementation because of their lack of versatility and their cumbersome application. We propose a proof of concept based on deep learning for out-of-field dose map estimation that addresses these limitations. METHODS AND MATERIALS: For this purpose, a 3D U-Net, considering as inputs the in-field dose, as computed by the treatment planning system, and the patient's anatomy, was trained to predict out-of-field dose maps. The cohort used for learning and performance evaluation included 3151 pediatric patients from the FCCSS database, treated in 5 clinical centers, whose whole-body dose maps were previously estimated with an empirical analytical method. The test set, composed of 433 patients, was split into 5 subdata sets, each containing patients treated with devices unseen during the training phase. Root mean square deviation evaluated only on nonzero voxels located in the out-of-field areas was computed as performance metric. RESULTS: Root mean square deviations of 0.28 and 0.41 cGy/Gy were obtained for the training and validation data sets, respectively. Values of 0.27, 0.26, 0.28, 0.30, and 0.45 cGy/Gy were achieved for the 6 MV linear accelerator, 16 MV linear accelerator, Alcyon cobalt irradiator, Mobiletron cobalt irradiator, and betatron device test sets, respectively. CONCLUSIONS: This proof-of-concept approach using a convolutional neural network has demonstrated unprecedented generalizability for this task, although it remains limited, and brings us closer to an implementation compatible with clinical routine.

Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study.

PURPOSE: Childhood cancer survivors are at the risk of developing subsequent colorectal cancers (CRCs), but the absolute risks by treatment modality are uncertain. We quantified the absolute risks by radiotherapy treatment characteristics using clinically accessible data from a Pan-European wide case-control study nested within a large cohort of childhood cancer survivors: the PanCareSurFup Study. METHODS: Odds ratios (ORs) from a case-control study comprising 143 CRC cases and 143 controls nested within a cohort of 69,460 survivors were calculated. These, together with standardized incidence ratios for CRC for this cohort and European general population CRC incidence rates and survivors' mortality rates, were used to estimate cumulative absolute risks (CARs) by attained age for different categories of radiation to the abdominopelvic area. RESULTS: Overall, survivors treated with abdominopelvic radiotherapy treatment (ART) were three times more likely to develop a subsequent CRC than those who did not receive ART (OR, 3.1 [95% CI, 1.4 to 6.6]). For male survivors treated with ART, the CAR was 0.27% (95% CI, 0.17 to 0.59) by age 40 years, 1.08% (95% CI, 0.69 to 2.34) by age 50 years (0.27% expected in the general population), and 3.7% (95% CI, 2.36 to 7.80) by age 60 years (0.95% expected). For female survivors treated with ART, the CAR was 0.29% (95% CI, 0.18 to 0.62) by age 40 years, 1.03% (95% CI, 0.65 to 2.22) by age 50 years (0.27% expected), and 3.0% (95% CI, 1.91 to 6.37) by age 60 years (0.82% expected). CONCLUSION: We demonstrated that by age 40 years survivors of childhood cancer treated with ART already have a similar risk of CRC as those age 50 years in the general population for whom population-based CRC screening begins in many countries. This information should be used in the development of survivorship guidelines for the risk stratification of survivors concerning CRC risk.

A spinal cord compression syndrome revealing neurofibromatosis type 1: A case report.

Neurofibromatosis type 1 (NF1), formerly known as von Recklinghausen disease is an autosomal dominant disease with multisystem involvement. In the peripheral nervous system, it leads to the development of benign tumors from the tissue of the spinal or cranial nerve sheaths, known as "neurofibromas." We report the case of a 40-year-old patient with spinal cord compression syndrome in whom spinal MRI revealed cervical, dorsal and lumbosacral neurofibromas revealing neurofibromatosis type 1.

Dosiomics-Based Prediction of Radiation-Induced Valvulopathy after Childhood Cancer.

Valvular Heart Disease (VHD) is a known late complication of radiotherapy for childhood cancer (CC), and identifying high-risk survivors correctly remains a challenge. This paper focuses on the distribution of the radiation dose absorbed by heart tissues. We propose that a dosiomics signature could provide insight into the spatial characteristics of the heart dose associated with a VHD, beyond the already-established risk induced by high doses. We analyzed data from the 7670 survivors of the French Childhood Cancer Survivors' Study (FCCSS), 3902 of whom were treated with radiotherapy. In all, 63 (1.6%) survivors that had been treated with radiotherapy experienced a VHD, and 57 of them had heterogeneous heart doses. From the heart-dose distribution of each survivor, we extracted 93 first-order and spatial dosiomics features. We trained random forest algorithms adapted for imbalanced classification and evaluated their predictive performance compared to the performance of standard mean heart dose (MHD)-based models. Sensitivity analyses were also conducted for sub-populations of survivors with spatially heterogeneous heart doses. Our results suggest that MHD and dosiomics-based models performed equally well globally in our cohort and that, when considering the sub-population having received a spatially heterogeneous dose distribution, the predictive capability of the models is significantly improved by the use of the dosiomics features. If these findings are further validated, the dosiomics signature may be incorporated into machine learning algorithms for radiation-induced VHD risk assessment and, in turn, into the personalized refinement of follow-up guidelines.

Risk factors for obesity in adulthood among survivors of childhood cancer.

OBJECTIVE: The aim of this study was to identify risk factors for obesity in childhood cancer survivors (CCSs). METHODS: The study included 3199 patients of the French Childhood Cancer Survivor Study cohort, with 303 patients with obesity who had returned the self-questionnaire. Analyses were adjusted for social deprivation index and sex. RESULTS: CCSs were less likely to have obesity (9.5%; 95% CI: 8.5%-10.5%) than expected from the general French population rates (12.5%; p = 0.0001). Nevertheless, brain tumor survivors were significantly more likely to develop obesity than the general French population (p = 0.0001). Compared with patients who did not receive radiotherapy to the pituitary gland, those who received a dose >5 Gy had an increased risk of obesity: relative risk 1.9 (95% CI: 1.2-3.1), 2.5 (95% CI: 1.7-3.7), and 2.6 (95% CI: 1.6-4.3), respectively, for participants with 6 to 20 Gy, 20 to 40 Gy, and ≥40 Gy of radiation. Etoposide administration significantly increased the risk of obesity (relative risk 1.7; 95% CI: 1.1-2.6). High social deprivation index was also a risk factor, just like BMI at diagnosis. CONCLUSIONS: Long-term follow-up of CCSs should include weight follow-up during adulthood.

Two decades of molecular surveillance in Senegal reveal changes in known drug resistance mutations associated with historical drug use and seasonal malaria chemoprevention.

Drug resistance in Plasmodium falciparum is a major threat to malaria control efforts. We analyzed data from two decades (2000-2020) of continuous molecular surveillance of P. falciparum parasite strains in Senegal to determine how historical changes in drug administration policy may have affected parasite evolution. We profiled several known drug resistance markers and their surrounding haplotypes using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole-genome sequence (WGS) based population genomics. We observed rapid changes in drug resistance markers associated with the withdrawal of chloroquine and introduction of sulfadoxine-pyrimethamine in 2003. We also observed a rapid increase in Pfcrt K76T and decline in Pfdhps A437G starting in 2014, which we hypothesize may reflect changes in resistance or fitness caused by seasonal malaria chemoprevention (SMC). Parasite populations evolve rapidly in response to drug use, and SMC preventive efficacy should be closely monitored.

Analytical models for external photon beam radiotherapy out-of-field dose calculation: a scoping review.

A growing body of scientific evidence indicates that exposure to low dose ionizing radiation (< 2 Gy) is associated with a higher risk of developing radio-induced cancer. Additionally, it has been shown to have significant impacts on both innate and adaptive immune responses. As a result, the evaluation of the low doses inevitably delivered outside the treatment fields (out-of-field dose) in photon radiotherapy is a topic that is regaining interest at a pivotal moment in radiotherapy. In this work, we proposed a scoping review in order to identify evidence of strengths and limitations of available analytical models for out-of-field dose calculation in external photon beam radiotherapy for the purpose of implementation in clinical routine. Papers published between 1988 and 2022 proposing a novel analytical model that estimated at least one component of the out-of-field dose for photon external radiotherapy were included. Models focusing on electrons, protons and Monte-Carlo methods were excluded. The methodological quality and potential limitations of each model were analyzed to assess their generalizability. Twenty-one published papers were selected for analysis, of which 14 proposed multi-compartment models, demonstrating that research efforts are directed towards an increasingly detailed description of the underlying physical phenomena. Our synthesis revealed great inhomogeneities in practices, in particular in the acquisition of experimental data and the standardization of measurements, in the choice of metrics used for the evaluation of model performance and even in the definition of regions considered out-of-the-field, which makes quantitative comparisons impossible. We therefore propose to clarify some key concepts. The analytical methods do not seem to be easily suitable for massive use in clinical routine, due to the inevitable cumbersome nature of their implementation. Currently, there is no consensus on a mathematical formalism that comprehensively describes the out-of-field dose in external photon radiotherapy, partly due to the complex interactions between a large number of influencing factors. Out-of-field dose calculation models based on neural networks could be promising tools to overcome these limitations and thus favor a transfer to the clinic, but the lack of sufficiently large and heterogeneous data sets is the main obstacle.

The risk of valvular heart disease in the French Childhood Cancer Survivors' Study: Contribution of dose-volume histogram parameters.

BACKGROUND AND PURPOSE: Valvular Heart Disease (VHD) is a known complication of childhood cancer after radiotherapy treatment. However, the dose-volume-effect relationships have not been fully explored. MATERIALS AND METHODS: We obtained individual heart Dose Volume Histograms (DVH) for survivors of the French Childhood Cancer Survivors Study (FCCSS) who had received radiotherapy. We calculated the Mean Dose to the Heart (MHD) in Gy, as well as the heart DVH parameters (Vd Gy, which represents the percentage of heart volume receiving at least d Gy), fixing the thresholds to 0.1 Gy, 5 Gy, 20 Gy, and 40 Gy. We analyzed them furtherly in the subpopulation of the cohort that was treated with a dose lower than 5 Gy (V0.1Gy|V5Gy=0%), 20 Gy (V5Gy|V20Gy=0%), and 40 Gy (V20Gy|V40Gy=0%), respectively. We investigated their role in the occurrence of a VHD in this population-based observational cohort study using the Cox proportional hazard model, adjusting for age at cancer diagnosis and chemotherapy exposure. RESULTS: Median follow-up was 30.6 years. Eighty-one patients out of the 7462 (1 %) with complete data experienced a severe VHD (grade ≥ 3). The risk of VHD increased along with the MHD, and it was associated with high doses to the heart (V40Gy < 50 %, hazard ratio (HR) = 7.96, 95 % CI: 4.26-14.88 and V20Gy|V40Gy=0% >50 %, HR = 5.03, 95 % CI: [2.35-10.76]). Doses 5-20 Gy to more than 50 % (V5Gy|V20Gy=0% >50 %) of the heart induced a marginally non-significant estimated risk. We also observed a remarkable risk increase with attained age. CONCLUSIONS: Our results provide new insight into the VHD risk that may impact current treatments and long-term follow-up of childhood cancer survivors.

Risk of Renal or Urinary Related Hospitalization in Survivors of Childhood Cancer: Results from the French Childhood Cancer Survivor Study.

BACKGROUND: Hospitalization rates can be used as an indirect indicator of the burden and severity of adverse health outcomes in childhood cancer survivors (CCS). We aimed to determine the long-term risks of hospitalization related to renal and urinary diseases among 5-year CCS. METHODS: The French Childhood Cancer Survivor Study cohort was linked with data from the French National Healthcare System database, which enabled the identification of hospitalizations related to renal or urinary diseases. Clinical and detailed treatment data were collected from medical records. Dose-volume histograms were estimated for all patients treated with radiotherapy. Standardized Hospitalization Ratios and absolute excess risks (AER) were calculated. Relative risks were estimated using Poisson regression. RESULTS: A total of 5,498 survivors were followed for 42,118 person-years (PY). Survivors experience 2.9 times more renal hospitalizations than expected in the general population, with an AER of 21.2/10,000 PY. Exposing more than 10% of the kidneys' volume to at least 20 Gray increases the risk of being hospitalized for renal causes by 2.2 (95% confidence interval, 1.3-3.6). Nephrectomized survivors treated with high doses of ifosfamide (>60 g/m²) have an extremely high risk of hospitalization for renal causes. Patients with comorbidities have about a 3-fold higher risk, and nephrectomized patients a 2-fold higher risk of being hospitalized for renal causes compared with other subjects. In the case of hospitalization for urinary causes, treatment by anthracycline administration was found to be associated with an almost 2-fold higher risk of hospitalization compared with the general population. CONCLUSIONS: These results support the need for careful monitoring of long-term renal diseases in survivors who have undergone nephrectomy, those treated with high doses of radiation (≥20 Gy) even to small volumes of the kidneys, and those with predisposing risk factors. IMPACT: This study provides new evidence with potential impact on surveillance guidelines related to dose-volume indicators associated with renal toxicity.

Risk Factors for Heart Failure Among Pan-European Childhood Cancer Survivors: A PanCareSurFup and ProCardio Cohort and Nested Case-Control Study.

PURPOSE: Heart failure (HF) is a potentially life-threatening complication of treatment for childhood cancer. We evaluated the risk and risk factors for HF in a large European study of long-term survivors. Little is known of the effects of low doses of treatment, which is needed to improve current treatment protocols and surveillance guidelines. METHODS: This study includes the PanCareSurFup and ProCardio cohort of ≥ 5-year childhood cancer survivors diagnosed between 1940 and 2009 in seven European countries (N = 42,361). We calculated the cumulative incidence of HF and conducted a nested case-control study to evaluate detailed treatment-related risk factors. RESULTS: The cumulative incidence of HF was 2% (95% CI, 1.7 to 2.2) by age 50 years. The case-control study (n = 1,000) showed that survivors who received a mean heart radiation therapy (RT) dose of 5 to < 15 Gy have an increased risk of HF (odds ratio, 5.5; 95% CI, 2.5 to 12.3), when compared with no heart RT. The risk associated with doses 5 to < 15 Gy increased with exposure of a larger heart volume. In addition, the HF risk increased in a linear fashion with higher mean heart RT doses. Regarding total cumulative anthracycline dose, survivors who received ≥ 100 mg/m2 had a substantially increased risk of HF and survivors treated with a lower dose showed no significantly increased risk of HF. The dose-response relationship appeared quadratic with higher anthracycline doses. CONCLUSION: Survivors who received a mean heart RT dose of ≥ 5 Gy have an increased risk of HF. The risk associated with RT increases with larger volumes exposed. Survivors treated with < 100 mg/m2 total cumulative anthracycline dose have no significantly increased risk of HF. These new findings might have consequences for new treatment protocols for children with cancer and for cardiomyopathy surveillance guidelines.

Increased Cardiac Risk After a Second Malignant Neoplasm Among Childhood Cancer Survivors: A FCCSS Study.

Background: Childhood cancer survivors (CCS) are at an elevated risk of developing both a second malignant neoplasm (SMN) and cardiac disease. Objectives: This study sought to assess the excess of occurrence of cardiac disease after a SMN among CCS. Methods: Analyses included 7,670 CCS from the French Childhood Cancer Survivors Study cohort diagnosed between 1945 and 2000. To account for the time dependence of the occurrence of a SMN, we employed a landmark approach, considering an additive regression model for the cumulative incidence of cardiac disease. We estimated the effect of a SMN on the instantaneous risk of cardiac disease using a proportional cause-specific hazard model, considering a SMN as a time-dependent exposure. In both models, we adjusted for demographic and treatment information and considered death as a competing event. Results: In 7,670 CCS over a median follow-up of 30 years (IQR: 22-38 years), there were 378 cases of cardiac disease identified, of which 49 patients experienced a SMN. Patients who survived 25 years after their childhood cancer diagnosis and had a SMN in that time frame had a significantly increased cumulative incidence of cardiac disease, which was 3.8% (95% CI: 0.5% to 7.1%) higher compared with those without a SMN during this period. No SMN-induced excess of cardiac disease was observed at subsequent landmark times. SMNs were associated with a 2-fold increase (cause-specific HR: 2.0; 95% CI: 1.4-2.8) of cardiac disease. Conclusions: The occurrence of a SMN among CCS is associated with an increased risk of cardiac disease occurrence and risk at younger ages.

Cohort profile: Risk and risk factors for female breast cancer after treatment for childhood and adolescent cancer: an internationally pooled cohort.

PURPOSE: The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast cancer subsequent to childhood/adolescent cancer by pooling individual patient data from seven cohorts. Initially, the pooled cohort will focus on three clinically relevant questions regarding treatment-related subsequent breast cancer risk in female survivors, which are the risk related to low-dose radiotherapy exposure to the chest, specific chemotherapy agents and attained age. PARTICIPANTS: The consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at <21 years of age, and survival ≥5 years from diagnosis. FINDINGS TO DATE: This is a newly established pooled study. The cohort profile summarised the data collected from each included cohort, including childhood cancer diagnosis information and treatment details (ie, radiotherapy fields and cumulative doses, and chemotherapy agents and cumulative doses for each agent). Included cohorts' follow-up started 1951-1981 and ended 2013-2021, respectively, for a median follow-up duration of 24.3 (IQR 18.0-32.8) years since primary cancer diagnosis. The median age at primary cancer diagnosis was 5.4 (IQR 2.5-11.9) years. And the median attained age at last follow-up was 32.2 (IQR 24.0-40.4) years. In all, 4240 (19.4%) survivors were treated with radiotherapy to the chest and 9308 (42.5%) with anthracyclines. At the end of the follow-up, 835 females developed a first subsequent breast cancer, including 635 invasive breast cancer only, 184 carcinomas in situ only (172 ductal carcinomas in situ and 12 lobular carcinomas in situ), and 16 with both an invasive and in situ diagnosis at the same moment. The cumulative incidences of subsequent breast cancer (both invasive and in situ) 25 and 35 years after primary cancer diagnosis were 2.2% and 6.2%, respectively. FUTURE PLANS: The consortium is intended to serve as a model and robust source of childhood/adolescent cancer survivor data for elucidating other knowledge gaps on subsequent breast cancer risk, and risk of other subsequent malignancies (including data on males) in the future.

Isolated esophageal tuberculosis: A case report.

BACKGROUND: Tuberculosis is endemic in Senegal. While its extra-pulmonary localization is rare, esophageal tuberculosis, particularly the isolated form, is exceptional. We report here a case of isolated esophageal tuberculosis in an immunocompetent patient. CASE SUMMARY: A 58-year-old man underwent consultation for mechanical dysphagia that had developed over 3 mo with non-quantified weight loss, anorexia, and fever. Upper digestive endoscopy showed extensive ulcerated lesions, suggesting neoplasia. The diagnosis was confirmed by histopathology, which showed gigantocellular epithelioid granuloma surrounding a caseous necrosis. Thoracoabdominal computed tomography scan did not show another localization of the tuberculosis. The outcome was favorable with treatment. CONCLUSION: Esophageal tuberculosis should be considered when dysphagia is associated with atypical ulcerated lesions of the esophageal mucosa, in an endemic area.

Breast cancer risk among thyroid cancer survivors and the role of I-131 treatment.

BACKGROUND: Female thyroid cancer survivors are more likely to have a higher risk of breast cancer compared to the general population, and the underlying causes are yet to be understood. The potential role of I-131 treatment on this association remains controversial. METHODS: We pooled individual data of women who were treated for differentiated thyroid cancer from 1934 to 2005 in France, Italy and Sweden. Standardized incidence ratios (SIRs) for breast cancer were estimated by comparison with age, sex and calendar-year expected values of the general population in each country. We estimated breast cancer risk in relation to I-131 treatment using time-dependent Poisson models. RESULTS: Of 8475 women (mean age at diagnosis: 45 years, range 2-90 years), 335 were diagnosed with breast cancer [SIR = 1.52, 95% confidence interval (CI): 1.36-1.69] during a median follow-up time of 12.7 years since diagnosis. Overall, breast cancer risk did not differ between women treated or not with I-131 (relative risk=1.07, 95% CI 0.84-1.35). However, breast cancer risk increased with increasing cumulative I-131 activity, without significant departure from linearity (excess relative risk per 100 mCi=17%, 95% CI: 2% to 38%). The higher risk associated with a cumulative I-131 activity of ≥100 mCi and ≥400 mCi was translated into 4 (95% CI -4 to 13) and 42 (95% CI -8 to 93) excess breast cancer cases per 10,000 person-years, respectively. CONCLUSIONS: An elevated risk was observed for the highest cumulative administered activity (>=400 mCi), and a significant dose-dependent association was observed among thyroid cancer survivors who were treated with I-131. However, overall, I-131 treatment might only explain partly the increase in breast cancer risk among female thyroid cancer survivors.

Pooled Analysis of Meningioma Risk Following Treatment for Childhood Cancer.

Importance: Meningioma is the most common subsequent neoplasm following cranial irradiation among survivors of childhood cancer, but there are still uncertainties regarding the magnitude of the radiation dose-response association, potential modifiers of radiation risks, and the role of chemotherapy. Objective: To evaluate meningioma risk in survivors of childhood cancer following radiotherapy and chemotherapy and identify possible modifying factors of radiation-associated risk. Design, Setting, and Participants: This international case-control study pooled data from 4 nested case-control studies of survivors of childhood cancer diagnosed between 1942 and 2000, followed through 2016. Cases were defined as participants diagnosed with a subsequent meningioma. Controls were matched to cases based on sex, age at first cancer diagnosis, and duration of follow-up. Data were analyzed from July 2019 to June 2022. Exposures: Radiation dose (Gy) to the meningioma site and cumulative chemotherapy doses, including intrathecal and systemic methotrexate doses. Main Outcomes and Measures: The main outcome was subsequent meningioma, assessed using odds ratios (ORs) and excess odds ratios per gray (EOR/Gy). Results: The analysis included 273 survivors of childhood cancer who developed meningioma (cases) and 738 survivors who did not (controls), with a total of 1011 individuals (median [IQR] age at first cancer diagnosis 5.0 [3.0-9.2] years; 599 [59.2%] female). Median (IQR) time since first cancer was 21.5 (15.0-27.0) years. Increasing radiation dose was associated with increased risk of meningioma (EOR/Gy, 1.44; 95% CI, 0.62-3.61), and there was no evidence of departure from linearity (P = .90). Compared with survivors who were not exposed to radiation therapy, those who received doses of 24 Gy or more had more than 30-fold higher odds of meningioma (OR, 33.66; 95% CI, 14.10-80.31). The radiation dose-response association was significantly lower among patients treated at age 10 years or older compared with those treated before age 10 years (EOR/Gy, 0.57; 95% CI, 0.18-1.91 vs 2.20; 95% CI, 0.87-6.31; P for heterogeneity = .03). Risk associated with radiation remained significantly elevated 30 years after exposure (EOR/Gy, 3.76; 95% CI, 0.77-29.15). We found an increased risk of meningioma among children who had received methotrexate (OR, 3.43; 95% CI, 1.56-7.57), but no evidence of a dose-response association or interaction with radiation dose. Conclusions and Relevance: These findings suggest that the meninges are highly radiosensitive, especially for children treated before age 10 years. These results support the reduction in whole-brain irradiation over recent decades and the prioritization of approaches that limit radiation exposure in healthy tissue for children. The persistence of elevated risks of meningiomas for 30 years after cranial radiotherapy could help inform surveillance guidelines.

Radiotherapy-Related Dose and Irradiated Volume Effects on Breast Cancer Risk Among Hodgkin Lymphoma Survivors.

BACKGROUND: Breast cancer (BC) risk is increased among Hodgkin lymphoma (HL) survivors treated with chest radiotherapy. Case-control studies showed a linear radiation dose-response relationship for estimated dose to the breast tumor location. However, these relative risks cannot be used for absolute risk prediction of BC anywhere in the breasts. Furthermore, the independent and joint effects of radiation dose and irradiated volumes are unclear. Therefore, we examined the effects of mean breast dose and various dose-volume parameters on BC risk in HL patients. METHODS: We conducted a nested case-control study of BC among 5-year HL survivors (173 case patients, 464 matched control patients). Dose-volume histograms were obtained from reconstructed voxel-based 3-dimensional dose distributions. Summary parameters of dose-volume histograms were studied next to mean and median breast dose, Gini index, and the new dose metric mean absolute difference of dose, using categorical and linear excess odds ratio (EOR) models. Interactions between dose-volume parameters and mean dose were also examined. RESULTS: Statistically significant linear dose-response relationships were observed for mean breast dose (EOR per Gy = 0.19, 95% confidence interval [CI] = 0.05 to 1.06) and median dose (EOR/Gy = 0.06, 95% CI = 0.02 to 0.19), with no statistically significant curvature. All metrics except Gini and mean absolute difference were positively correlated with each other. These metrics all showed similar patterns of dose-response that were no longer statistically significant when adjusting for mean dose. No statistically significant modification of the effect of mean dose was observed. CONCLUSION: Mean breast dose predicts subsequent BC risk in long-term HL survivors.