Variability in gene expression underlies incomplete penetrance

The phenotypic differences between individual organisms can often be ascribed to underlying genetic and environmental variation. However, even genetically identical organisms in homogeneous environments vary, indicating that randomness in developmental processes such as gene expression may also generate diversity. To examine the consequences of gene expression variability in multicellular organisms, we studied intestinal specification in the nematode Caenorhabditis elegans in which wild-type cell fate is invariant and controlled by a small transcriptional network. Mutations in elements of this network can have indeterminate effects: some mutant embryos fail to develop intestinal cells, whereas others produce intestinal precursors. By counting transcripts of the genes in this network in individual embryos, we show that the expression of an otherwise redundant gene becomes highly variable in the mutants and that this variation is subjected to a threshold, producing an ON/OFF expression pattern of the master regulatory gene of intestinal differentiation. Our results demonstrate that mutations in developmental networks can expose otherwise buffered stochastic variability in gene expression, leading to pronounced phenotypic variation.National Institutes of Health (U.S.). Pioneer AwardMathematical Sciences Postdoctoral Research Fellowships (DMS-0603392)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (5F32GM080966

Deep learning prediction of proton and photon dose distributions for paediatric abdominal tumours

OBJECTIVE: Dose prediction using deep-learning networks prior to radiotherapy might lead to more efficient modality selections. The study goal was to predict proton and photon dose distributions based on the patient-specific anatomy and to assess their clinical usage for paediatric abdominal tumours. MATERIAL &METHODS: Data from 80 patients with neuroblastoma or Wilms' tumour was included. Pencil beam scanning (PBS) (5mm/3%) and volumetric-modulated arc therapy (VMAT) plans (5mm) were robustly optimized on the internal target volume (ITV). Separate 3-dimensional patch-based U-net networks were trained to predict PBS and VMAT dose distributions. Doses, planning-computed tomography images and relevant optimization masks (ITV, vertebra and organs-at-risk) of 60 patients were used for training with a 5-fold cross validation. The networks' performance was evaluated by computing the relative error between planned and predicted dose-volume histogram (DVH) parameters for 20 inference patients. In addition, the organs-at-risk mean dose difference between modalities was calculated using planned and predicted dose distributions (ΔDmean= DVMAT-DPBS). Two radiation oncologists performed a blind PBS/VMAT modality selection based on either planned or predicted ΔDmean. RESULTS: Average DVH differences between planned and predicted dose distributions were ≤|6%|for both modalities. The networks classified the organs-at-risk difference as a gain (ΔDmean>0) with 98% precision. An identical modality selection based on planned compared to predicted ΔDmean was made for 18/20 patients. CONCLUSION: Deep-learning networks for accurate prediction of proton and photon dose distributions for abdominal paediatric tumours were established. These networks allowing fast dose visualization might aid in identifying the optimal radiotherapy technique when experience and/or resources are unavailable

Independencia de la concepción : “mas de una fuerza actuando sobre un cuerpo en caída libre”

La presente investigación estudió el nivel de independencia de la concepción en base a las siguientes características mención del titulo de bachiller, edad, sexo, índice académico, tipo de liceo donde curso el bachillerato, para lo cual se hizo uso del concepto de independencia estadística desde la perspectiva de la teoría de probabilidades y la estadística inferencial haciendo uso de la prueba Chi-cuadrado. Para el logro de este objetivo se utilizo un cuestionario con ítems cerrados auto administrado, todo esto en el contexto de una investigación de campo. La población en estudio estuvo conformada por un total de 45 sujetos los cuales en su totalidad conformaron la muestra en estudio. Como resultado del presente trabajo se pudo determinar que solo resulto significativa la característica “tipo de liceo”, la cual resulto significativa con un nivel de confianza de 0. 90

Independencia de la concepción : "mas de una fuerza actuando sobre un cuerpo en caída libre"

La presente investigación estudió el nivel de independencia de la concepción en base a las siguientes características mención del titulo de bachiller, edad, sexo, índice académico, tipo de liceo donde curso el bachillerato, para lo cual se hizo uso del concepto de independencia estadística desde la perspectiva de la teoría de probabilidades y la estadística inferencial haciendo uso de la prueba Chi-cuadrado. Para el logro de este objetivo se utilizo un cuestionario con ítems cerrados auto administrado, todo esto en el contexto de una investigación de campo. La población en estudio estuvo conformada por un total de 45 sujetos los cuales en su totalidad conformaron la muestra en estudio. Como resultado del presente trabajo se pudo determinar que solo resulto significativa la característica "tipo de liceo", la cual resulto significativa con un nivel de confianza de 0.90

Risk communication in a patient decision aid for radiotherapy in breast cancer:How to deal with uncertainty?

Background and aim: Patient decision aids for oncological treatment options, provide information on the effect on recurrence rates and/or survival benefit, and on side-effects and/or burden of different treatment options. However, often uncertainty exists around the probability estimates for recurrence/survival and side-effects which is too relevant to be ignored. Evidence is lacking on the best way to communicate these uncertainties. The aim of this study is to develop a method to incorporate uncertainties in a patient decision aid for breast cancer patients to support their decision on radiotherapy. Methods: Firstly, qualitative interviews were held with patients and health care professionals. Secondly, in the development phase, thinking aloud sessions were organized with four patients and 12 health care professionals, individual and group-wise. Results: Consensus was reached on a pictograph illustrating the whole range of uncertainty for local recurrence risks, in combination with textual explanation that a more exact personalized risk would be given by their own physician. The pictograph consisted of 100 female icons in a 10 x 10 array. Icons with a stepwise gradient color indicated the uncertainty margin. The prevalence and severity of possible sideeffects were explained using verbal labels. Conclusions: We developed a novel way of visualizing uncertainties in recurrence rates in a patient decision aid. The effect of this way of communicating risk uncertainty is currently being tested in the BRASA study (NCT03375801)

The added value of immediate breast reconstruction to health-related quality of life of breast cancer patients

Background: Postmastectomy immediate breast reconstruction (IBR) may improve the quality of life (QoL) of breast cancer patients. Guidelines recommend to discuss the option IBR with all patients undergoing mastectomy. However, substantial hospital variation in IBR-rates was previously observed in the Netherlands, influenced by patient, tumour and hospital factors and clinicians’ believes. Information provision about IBR may have a positive effect on receiving IBR and therefore QoL. This study investigated patient-reported QoL of patients treated with mastectomy with and without IBR. Methods: An online survey, encompassing the validated BREAST-Q questionnaire, was distributed to a representative sample of 1218 breast cancer patients treated with mastectomy. BREAST-Q scores were compared between patients who had undergone mastectomy either with or without IBR. Results: A total of 445 patients were included for analyses: 281 patients with and 164 without IBR. Patients who had received IBR showed significantly higher BREAST-Q scores on “psychosocial well-being” (75 versus 67, p < 0.001), “sexual well-being” (62 versus 52, p < 0.001) and “physical well-being” (77 versus 74, p = 0.021) compared to patients without IBR. No statistically significant difference was found for “satisfaction with breasts” (64 versus 62, p = 0.21). Similar results were found after multivariate regression analyses, revealing IBR to be an independent factor for a better patient-reported QoL. Conclusions: Patients diagnosed with breast cancer with IBR following mastectomy report a better QoL on important psychosocial, sexual and physical well-being domains. This further supports the recommendation to discuss the option of IBR with all patients with an indication for mastectomy and to enable shared decision-making

Review - Late toxicity of abdominal and pelvic radiotherapy for childhood cancer

As survival improves in childhood cancer, prevention of late treatment-related toxicity in survivors becomes increasingly relevant. Radiotherapy is an important contributor to late toxicity. Therefore, minimizing radiation exposure to normal tissues is an important step towards improving the long-term therapeutic window of childhood cancer treatment. Since children are growing and developing, they are particularly vulnerable to radiation exposure. This makes the 'as low as reasonably achievable (ALARA)' principle even more important. In order to guide and achieve clinically meaningful dose reductions through advanced and emerging radiation techniques, it is important to investigate age-dependent relationships between radiation exposure to healthy tissues and late radiation-induced toxicity. In this review, we provide an overview of literature on the association between radiotherapy dose and late toxicity after abdominal and pelvic irradiation in childhood cancer. With this information, we aim to aid in decision-making regarding radiotherapy for childhood cancer. (c) 2022 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 170 (2022) 27-36 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Long-term survivors of early breast cancer treated with chemotherapy are characterized by a pro-inflammatory biomarker profile compared to matched controls

Background: Chemo- and radiotherapy for breast cancer (BC) can lead to cardiotoxicity even years after the initial treatment. The pathophysiology behind these late cardiac effects is poorly understood. Therefore, we studied a large panel of biomarkers from different pathophysiological domains in long-term BC survivors, and compared these to matched controls. Methods and results: In total 91 biomarkers were measured in 688 subjects: 342 BC survivors stratified either to treatment with chemotherapy ± radiotherapy (n = 170) or radiotherapy alone (n = 172) and matched controls. Mean age was 59 ± 9 years and 65 ± 8 years for women treated with chemotherapy ± radiotherapy and radiotherapy alone, respectively, with a mean time since treatment of 11 ± 5.5 years. No biomarkers were differentially expressed in survivors treated with radiotherapy alone vs. controls (P for all >0.1). In sharp contrast, a total of 19 biomarkers were elevated, relative to controls, in BC survivors treated with chemotherapy ± radiotherapy after correction for multiple comparisons (P <0.05 for all). Network analysis revealed upregulation of pathways relating to collagen degradation and activation of matrix metalloproteinases. Furthermore, several inflammatory biomarkers including growth differentiation factor 15, monocyte chemoattractant protein 1, chemokine (C-X-C motif) ligand 16, tumour necrosis factor super family member 13b and proprotein convertase subtilisin/kexin type 9, elevated in survivors treated with chemotherapy, showed an independent association with lower left ventricular ejection fraction. Conclusion: Breast cancer survivors treated with chemotherapy ± radiotherapy show a distinct biomarker profile associated with mild cardiac dysfunction even 10 years after treatment. These results suggest that an ongoing pro-inflammatory state and activation of matrix metalloproteinases following initial treatment with chemotherapy might play a role in the observed cardiac dysfunction in late BC survivors

Assessment of Bone Lesions with F-18-FDG PET Compared with Tc-99m Bone Scintigraphy Leads to Clinically Relevant Differences in Metastatic Breast Cancer Management

It is unknown whether assessment of potential bone lesions in metastatic breast cancer (MBC) by F-18-FDG PET instead of Tc-99m bone scintigraphy (BS) supports clinically relevant changes in MBC management. Therefore, we retrospectively compared management recommendations based on bone lesion assessment by (18)FFDG PET plus contrast-enhanced CT (ceCT) or BS plus ceCT, for patients with newly diagnosed MBC. Methods: Baseline ceCT, BS, and F-18-FDG PET for all patients included in the IMPACT-MBC study (NCT01957332) at the University Medical Center Groningen were reviewed for bone lesions. If bone lesions were found by any imaging modality, virtual MBC management recommendations were made by a multidisciplinary expert panel, based on either F-18-FDG PET plus ceCT or BS plus ceCT. The panel had access to standard clinicopathologic information and baseline imaging findings outside the skeleton. Clinically relevant management differences between the 2 recommendations were defined either as different treatment intent (curative, noncurative, or unable to determine) or as different systemic or local treatment. If no bone lesions were found by any imaging modality, the patients were included in the analyses without expert review. Results: In total, 3,473 unequivocal bone lesions were identified in 10(2) evaluated patients (39% by ceCT, 26% by BS, and 87% by F-18-FDG PET). Additional bone lesions on F-18-FDG PET plus ceCT compared with BS plus ceCT led to change in MBC management recommendations in 16% of patients (95% CI, 10%-24%). BS also changed management compared with F-18-FDG PET in 1 patient (1%; 95% CI, 0%-5%). In 26% (95% CI, 19%-36%) of patients, an additional F-18-FDG PET exam was requested, because BS provided insufficient information. Conclusion: In this exploratory analysis of newly diagnosed MBC patients, F-18-FDG PET versus BS to assess bone lesions resulted in clinically relevant management differences in 16% of patients. BS delivered insufficient information in over one fourth of patients, resulting in an additional request for F-18-FDG PET. On the basis of these data, F-18-FDG PET should be considered a primary imaging modality for assessment of bone lesions in newly diagnosed MBC

Model-Based Selection for Proton Therapy in Breast Cancer:Development of the National Indication Protocol for Proton Therapy and First Clinical Experiences

Aims: Proton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences. Materials and methods: A national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy. Results: The model of Darby et al. (N Engl J Med 2013; 368:987–82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021. Conclusion: The NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands