Methodological approaches to the study of cancer risk in the vicinity of pollution sources: the experience of a population-based case–control study of childhood cancer

Background: Environmental exposures are related to the risk of some types of cancer, and children are the most vulnerable group of people. This study seeks to present the methodological approaches used in the papers of our group about risk of childhood cancers in the vicinity of pollution sources (industrial and urban sites). A populationbased case–control study of incident childhood cancers in Spain and their relationship with residential proximity to industrial and urban areas was designed. Two methodological approaches using mixed multiple unconditional logistic regression models to estimate odds ratios (ORs) and 95% confdence intervals (95% CIs) were developed: (a) “near vs. far” analysis, where possible excess risks of cancers in children living near (“near”) versus those living far (“far”) from industrial and urban areas were assessed; and (b) “risk gradient” analysis, where the risk gradient in the vicinity of industries was assessed. For each one of the two approaches, three strategies of analysis were implemented: “joint”, “stratifed”, and “individualized” analysis. Incident cases were obtained from the Spanish Registry of Childhood Cancer (between 1996 and 2011). Results: Applying this methodology, associations between proximity (≤2 km) to specifc industrial and urban zones and risk (OR; 95% CI) of leukemias (1.31; 1.04–1.65 for industrial areas, and 1.28; 1.00–1.53 for urban areas), neuroblastoma (2.12; 1.18–3.83 for both industrial and urban areas), and renal (2.02; 1.16–3.52 for industrial areas) and bone (4.02; 1.73–9.34 for urban areas) tumors have been suggested. Conclusions: The two methodological approaches were used as a very useful and fexible tool to analyze the excess risk of childhood cancers in the vicinity of industrial and urban areas, which can be extrapolated and generalized to other cancers and chronic diseases, and adapted to other types of pollution sources

Somatic and germline analysis of a familial Rothmund-Thomson syndrome in two siblings with osteosarcoma

Rothmund–Thomson syndrome (RTS) is characterized by a rash that begins in the first few months of life and eventually develops into poikiloderma. Associated symptoms are alterations in the teeth, sparse hair, thin eyebrows, lack of eyelashes, low stature, bone abnormalities, hematological illnesses, gastrointestinal disease, malnutrition, cataracts, and predisposition to cancer, principally to bone tumors and skin cancer. Diagnostic certitude is provided by a genetic study involving detection of pathogenic variants of the RECQL4 gene. We hereby present a familiar case of RTS in two siblings from a Portuguese family, both diagnosed with osteosarcoma. Genomic analysis (203 genes) of both tumors as well as germline analysis of the RECQL4 gene, thus confirming the syndrome in the family, have been performed. The relevance of clinical recognition of the hallmarks of the disease and thus early diagnosis with early intervention is highlighted

Inflammation and immunity in ovarian cancer

The standard first-line therapy for ovarian cancer is a combination of surgery and carboplatin/paclitaxel-based chemotherapy. Patients with longer survival and improved response to chemotherapy usually present T-cell inflamed tumours. The presence of tumour-infiltrating T cells (TILs) notably varies among the different subtypes of ovarian tumours, being highest in high-grade serous ovarian carcinoma, intermediate in endometrioid tumours, and lowest in low-grade serous, mucinous and clear cell tumours. Interestingly, the presence of TILs is often accompanied by a strong immunosuppressive tumour environment. A better understanding of the immune response against ovarian cancer and the tumour immune evasion mechanisms will enable improved prognostication, response prediction and immunotherapy of this disease. This article provides an overview of some ovarian cancer cell features relevant for antitumour response, such as tumour-associated antigens, including neoantigens, expression of inhibitory molecules, and other mechanisms of immune evasion. Moreover, we describe relevant immune cell types found in epithelial ovarian tumours, including T and B lymphocytes, regulatory T cells, natural killer cells, tumour-associated macrophages, myeloid-derived suppressor cells and neutrophils. We focus on how these components influence the burden of the tumour and the clinical outcome

Inflammation and immunity in ovarian cancer

The standard first-line therapy for ovarian cancer is a combination of surgery and carboplatin/paclitaxel-based chemotherapy. Patients with longer survival and improved response to chemotherapy usually present T-cell inflamed tumours. The presence of tumour-infiltrating T cells (TILs) notably varies among the different subtypes of ovarian tumours, being highest in high-grade serous ovarian carcinoma, intermediate in endometrioid tumours, and lowest in low-grade serous, mucinous and clear cell tumours. Interestingly, the presence of TILs is often accompanied by a strong immunosuppressive tumour environment. A better understanding of the immune response against ovarian cancer and the tumour immune evasion mechanisms will enable improved prognostication, response prediction and immunotherapy of this disease. This article provides an overview of some ovarian cancer cell features relevant for antitumour response, such as tumour-associated antigens, including neoantigens, expression of inhibitory molecules, and other mechanisms of immune evasion. Moreover, we describe relevant immune cell types found in epithelial ovarian tumours, including T and B lymphocytes, regulatory T cells, natural killer cells, tumour-associated macrophages, myeloid-derived suppressor cells and neutrophils. We focus on how these components influence the burden of the tumour and the clinical outcome

Oral anticoagulation with vitamin K inhibitors and determinants of successful self-management in primary care

Background: Self-management may be an option to monitor oral anticoagulant therapy in health systems, but before recommending it, we need to assess patients’ ability to take on this task. The purpose of the study was to describe patients’ ability to self-manage and associated factors. Methods: This was a 3-year prospective quasi-experimental study with a control group. Overall, 333 patients on anticoagulant therapy from seven primary care health centres of the Basque Health Service were included in the intervention group and followed up for 6 months after the intervention, assessing their ability to self-test and self-manage. The intervention consisted of a patient training programme, providing detailed information on their condition and its treatment, and practical training in how to use a portable blood coagulation monitor and adjust their anticoagulant dose. Comparisons were made with a control group (333 patients receiving OAT under usual care from the same seven health centres). Outcome variables were ability to self-manage, quality of the outcome (in terms of time in therapeutic range), and quality of life in the intervention group, and general patient characteristics (age and sex), clinical variables (reason for OAT, INR range), and quality of the outcome (in terms of percentage of INR measurements in range and complications) in both groups. Results: Overall, 26.13 % of patients invited to participate in the intervention agreed. Of these, 99 % successfully learned to self-manage their OAT. Just 4.2 % did not complete the follow-up, in all cases for reasons unrelated to self-management, and 4.5 % required additional learning support. Outcomes were better than under usual care in terms of percentage of INR measurements in range (12 %), rate of complications (4 %) and quality of life (9.2 %). Limitations: Patients were only followed-up period for 6 months and the study was conducted in a single health organization. Though patients eligible to participate were selected randomly, they were not randomly allocated to the groups. This is a potential source of selection bias. Data needed to calculate in-range time were not collected from controls; rather the results for the self-management group were compared with external data from other studies. Conclusions: Almost all participants achieved competency in self-management, with no differences by age, sex, concurrent illnesses, polypharmacy or educational level. The greatest barrier to self-management was the attitude of patients themselves and those around them. Self-management in primary care is a good alternative to usual care, patients having longer times in therapeutic range and fewer complications, and improving their quality of life. Remote management is a good support tool

Somatic and germline analysis of a familial Rothmund-Thomson syndrome in two siblings with osteosarcoma

Rothmund–Thomson syndrome (RTS) is characterized by a rash that begins in the first few months of life and eventually develops into poikiloderma. Associated symptoms are alterations in the teeth, sparse hair, thin eyebrows, lack of eyelashes, low stature, bone abnormalities, hematological illnesses, gastrointestinal disease, malnutrition, cataracts, and predisposition to cancer, principally to bone tumors and skin cancer. Diagnostic certitude is provided by a genetic study involving detection of pathogenic variants of the RECQL4 gene. We hereby present a familiar case of RTS in two siblings from a Portuguese family, both diagnosed with osteosarcoma. Genomic analysis (203 genes) of both tumors as well as germline analysis of the RECQL4 gene, thus confirming the syndrome in the family, have been performed. The relevance of clinical recognition of the hallmarks of the disease and thus early diagnosis with early intervention is highlighted

Identification of HLA class I-restricted immunogenic neoantigens in triple negative breast cancer

Immune checkpoint inhibitor (ICI)-based immunotherapy in triple negative breast cancer (TNBC) is achieving limited therapeutic results, requiring the development of more potent strategies. Combination of ICI with vaccination strategies would enhance antitumor immunity and response rates to ICI in patients having poorly infiltrated tumors. In heavily mutated tumors, neoantigens (neoAgs) resulting from tumor mutations have induced potent responses when used as vaccines. Thus, our aim was the identification of immunogenic neoAgs suitable as vaccines in TNBC patients. By using whole exome sequencing, RNAseq and HLA binding algorithms of tumor samples from a cohort of eight TNBC patients, we identified a median of 60 mutations/patient, which originated a putative median number of 98 HLA class I-restricted neoAgs. Considering a group of 27 predicted neoAgs presented by HLA-A*02:01 allele in two patients, peptide binding to HLA was experimentally confirmed in 63% of them, whereas 55% were immunogenic in vivo in HLA-A*02:01+ transgenic mice, inducing T-cells against the mutated but not the wild-type peptide sequence. Vaccination with peptide pools or DNA plasmids expressing these neoAgs induced polyepitopic T-cell responses, which recognized neoAg-expressing tumor cells. These results suggest that TNBC tumors harbor neoAgs potentially useful in therapeutic vaccines, opening the way for new combined immunotherapies

Prenatal exposure to a wide range of environmental chemicals and child behaviour between 3 and 7 years of age – An exposome-based approach in 5 European cohorts

Background: Studies looking at associations between environmental chemicals and child behaviour usually consider only one exposure or family of exposures. Objective: This study explores associations between prenatal exposure to a wide range of environmental chemicals and child behaviour. Methods: We studied 708 mother-child pairs from five European cohorts recruited in 2003-2009. We assessed 47 exposure biomarkers from eight chemical exposure families in maternal blood or urine collected during pregnancy. We used the Strengths and Difficulties Questionnaire (SDQ) to evaluate child behaviour between three and seven years of age. We assessed associations of SDQ scores with exposures using an adjusted least absolute shrinkage and selection operator (LASSO) considering all exposures simultaneously and an adjusted exposome-wide association study (ExWAS) considering each exposure independently. Results: LASSO selected only copper (Cu) as associated with externalizing behaviour. In the ExWAS, bisphenol A [BPA, incidence rate ratio (IRR): 1.06, 95% confidence interval (95%CI): 1.01;1.12] and mono-n-butyl phthalate (MnBP, IRR: 1.06, 95%CI: 1.00;1.13) were associated with greater risk of externalizing behaviour problems. Cu (IRR: 0.90, 95%CI: 0.82;0.98), perfluoroundecanoate (PFUnDA, IRR: 0.92, 95%CI: 0.84;0.99) and organochlorine compounds (OCs) were associated with lower risk of externalizing behaviour problems, however the associations with OCs were mainly seen among women with insufficient weight gain during pregnancy. Internalizing score worsen in association with exposure to diethyl thiophosphate (DETP, IRR: 1.11, 95%CI: 1.00;1.24) but the effect was driven by the smallest cohort. Internalizing score improved with increased concentration of perfluorooctane sulfonate (PFOS, IRR: 0.92, 95%CI: 0.85;1.00), however the association was driven by the two smallest cohorts with the lowest PFOS concentrations. Discussion: This study added evidence on deleterious effects of prenatal exposure to BPA and MnBP on child behaviour. Other associations should be interpreted cautiously since they were not consistent with previous studies or they have not been studied extensively

Microglia and astrocyte activation is region-dependent in the alfa-synuclein mouse model of Parkinson's disease

Inflammation is a common feature in neurodegenerative diseases that contributes to neuronal loss. Previously, we demonstrated that the basal inflammatory tone differed between brain regions and, consequently, the reaction generated to a pro-inflammatory stimulus was different. In this study, we assessed the innate immune reaction in the midbrain and in the striatum using an experimental model of Parkinson's disease. An adeno-associated virus serotype 9 expressing the α-synuclein and mCherry genes or the mCherry gene was administered into the substantia nigra. Myeloid cells (CD11b+ ) and astrocytes (ACSA2+ ) were purified from the midbrain and striatum for bulk RNA sequencing. In the parkinsonian midbrain, CD11b+ cells presented a unique anti-inflammatory transcriptomic profile that differed from degenerative microglia signatures described in experimental models for other neurodegenerative conditions. By contrast, striatal CD11b+ cells showed a pro-inflammatory state and were similar to disease-associated microglia. In the midbrain, a prominent increase of infiltrated monocytes/macrophages was observed and, together with microglia, participated actively in the phagocytosis of dopaminergic neuronal bodies. Although striatal microglia presented a phagocytic transcriptomic profile, morphology and cell density was preserved and no active phagocytosis was detected. Interestingly, astrocytes presented a pro-inflammatory fingerprint in the midbrain and a low number of differentially displayed transcripts in the striatum. During α-synuclein-dependent degeneration, microglia and astrocytes experience context-dependent activation states with a different contribution to the inflammatory reaction. Our results point towards the relevance of selecting appropriate cell targets to design neuroprotective strategies aimed to modulate the innate immune system during the active phase of dopaminergic degeneration