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Objective: This study was undertaken to study whether high-dose folic acid (>1 mg daily) use is associated with an increased risk of cancer in all women who have given birth and in women with epilepsy. High-dose folic acid supplementation during pregnancy has been linked to increased cancer risk in children born to mothers with epilepsy., Methods: We identified women with their first pregnancy in Denmark (1997-2017), Norway (2005-2017), and Sweden (2006-2017) using medical birth registers, linking individual data across nationwide health registers and statistical agencies. Exposure was defined as filled prescriptions for high-dose folic acid, considered time-varyingly. The primary outcome was the first malignant cancer diagnosis. Hazard ratios (HRs) of cancer after high-dose folic acid exposure were estimated using Cox proportional hazard models with 95% confidence intervals (CIs), adjusted for confounders including antiseizure medication (ASM) use, and stratified by maternal epilepsy diagnosis. A 6-month time lag was applied, as cancer is unlikely to develop immediately., Results: With up to 21 years of follow-up, we identified 1 465 785 women who gave birth, including 64 485 (4.4%) exposed to high-dose folic acid. In the exposed group, 755 cancer cases were observed (208 per 100 000 person-years, 95% CI = 193.8-223.5), compared with 18 702 cases in the unexposed group (164 per 100 000 person-years, 95% CI = 161.5-166.2), yielding a 20% increased cancer risk overall (adjusted HR = 1.2, 95% CI = 1.1-1.2). This risk was attenuated after the 6-month lag analysis (adjusted HR = 1.1, 95% CI = 1.04-1.2). The risk for non-Hodgkin lymphoma was increased in all analyses (n = 28, adjusted HR = 2.0, 95% CI = 1.3-2.9). The association between high-dose folic acid use and overall cancer risk was similar in those with epilepsy regardless of ASM use (adjusted HR = 1.3, 95% CI = 1.0-1.8)., Significance: High-dose folic acid use was associated with increased overall cancer risk in women who have given birth, with a consistent association with non-Hodgkin lymphoma, including those with epilepsy, regardless of ASM use., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Purposeless physiological monitoring at the end-of-life is not recommended. However, studies on how families feel regarding the death of patients with terminal cancer without continuous electrocardiographic monitoring (CEM) are lacking., Objectives: To explore the impact on the quality of care and the feelings and psychological distress experienced by families when CEM is not used during the 24 hours preceding a patient's death., Methods: In this multicenter cross-sectional, self-report questionnaires were distributed to 1087 bereaved families at Japanese specialized palliative care units in 2018., Results: Out of 671 responses, 394 valid responses were analyzed. Families of nonmonitored patients (NM-group) accounted for 79.2%, while those with bedside electrocardiogram monitoring (MB-group) and remote nurse station monitoring (MC-group) comprised 11.9% and 8.9%, respectively. In the NM-group, 85.5% expressed satisfaction without CEM, which was more than 10% lower than other groups. While 14% in the NM-group desired patient monitoring, families who received adequate explanations about CEM had lower proportions compared to the MB-group ( P = .021). Univariate analyses showed no significant differences in evaluations of the quality of care and families' psychological distress (mean scores of Overall Care Satisfaction, Care Evaluation Scale, Good Death Inventory, Brief Grief Questionnaires) across all groups., Conclusion: While the majority of NM-group were satisfied with their patient's care without CEM, the proportion of dissatisfied families was higher than in other groups. Although not using CEM is not a major hindrance to end-of-life care for patients with terminal cancer, providing sufficient explanations may be important for satisfactory care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Lifestyle factors may affect cancer risk. This study aimed to identify whether the American Heart Association ideal cardiovascular health (ICH) score and its individual variables in youth are associated with subsequent cancer incidence., Methods: This study comprised participants of the Cardiovascular Risk in Young Finns Study free of cancer at the analysis baseline in 1986 (n = 1,873). The baseline age was 12 to 24 years, and the follow-up occurred between 1986 and 2018., Results: Among 1,873 participants (mean age 17.3 ± 4.1 years; 53.4% females at baseline), 72 incident cancer cases occurred during the follow-up (mean follow-up time 31.4 ± 3.4 years). Baseline ICH score was not associated with future cancer risk (HR, 0.96; 95% confidence interval, 0.78-1.12 per 1-point increment). Of individual ICH score variables, ideal physical activity (PA) was inversely associated with cancer incidence [age- and sex-adjusted HR, 0.45 (0.23-0.88) per 1-category change (nonideal/ideal)] and remained significant in the multivariable-adjusted model, including body mass index, smoking, diet, and socioeconomic status. A continuous PA index at ages 9 to 24 years and moderate-to-vigorous PA in youth were also related to decreased cancer incidence (P < 0.05). Body mass index, smoking, diet, total cholesterol, glucose, and blood pressure were not related to cancer risk. Of the dietary components, meat consumption was associated with cancer incidence (P = 0.023)., Conclusions: These findings indicate that higher PA levels in youth are associated with a reduced subsequent cancer incidence, whereas the American Heart Association's ICH score in youth does not., Impact: This finding supports efforts to promote a healthy lifestyle and encourages PA during childhood, yielding a subsequent healthier life., (©2024 American Association for Cancer Research.)

Introduction: To investigate the occurrence of previous cancer diagnoses in women suffering from premature ovarian insufficiency (POI) and compare it with the general population, shedding light on the association between cancer, cancer treatments, and POI., Material and Methods: We conducted a nationwide case-control study based on registry data from various sources, including the Social Insurance Institution, Finnish Population Information System, and Finnish Cancer Registry spanning from 1953 to 2018. Our participants comprised all women in Finland who, between 1988 and 2017, received hormone replacement therapy reimbursement for ovarian insufficiency before the age of 40 years (n = 5221). Controls, matched in terms of age and municipality of residence, were selected from the Finnish Population Information System (n = 20 822). Our main exposure variable was a history of cancer diagnosis preceding the diagnosis of POI. We analyzed odds ratios (OR) to compare the prevalence of previous cancers in women with POI with that in controls, stratifying results based on cancer type, age at cancer diagnosis, and the time interval between cancer diagnosis and POI. We also assessed changes in OR for previous cancer diagnoses over the follow-up period., Results: Out of the women diagnosed with POI, 21.9% had previously been diagnosed with cancer, resulting in an elevated OR of 36.5 (95% confidence interval [CI] 30.9 to 43.3) compared with 0.8% of the controls. The risk of developing POI was most pronounced during the first 2 years following a cancer diagnosis, with an OR of 103 (95% CI 74.1 to 144). Importantly, this risk remained elevated even when the time interval between cancer and POI exceeded 10 years, with an OR of 5.40 (95% CI 3.54 to 8.23)., Conclusions: This study reveals that 21.9% of women with POI have a history of cancer, making the prevalence of cancer among these women 27.5 times higher than age-matched controls in the Finnish population. The risk of developing POI is most substantial in the first 2 years following a cancer diagnosis. These findings underscore the role of cancer treatments as an etiological factor for POI and emphasize the importance of recognizing the risk of POI in cancer survivors for early diagnosis and intervention., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Aim: The aim is to examine the risk of cerebral palsy, seizures/epilepsy, visual- and hearing impairments, cancer, injury/poisoning and child abuse in children with and without a congenital anomaly up to age 5 and 10 years., Methods: This is a population-based data linkage cohort study linking information from the European Surveillance of Congenital Anomalies network (EUROCAT) and birth registries to hospital discharge databases. We included 91 504 live born children with major congenital anomalies born from 1995 to 2014 from nine EUROCAT registries in five countries and 1 960 727 live born children without congenital anomalies (reference children). Prevalence and relative risk (RR) were estimated for each of the co-morbidities using Kaplan-Meier survival estimates., Results: Children with congenital anomalies had higher risks of the co-morbidities than reference children. The prevalences in the reference children were generally very low. The RR was 13.8 (95% CI 12.5-15.1) for cerebral palsy, 2.5 (95% CI 2.4-2.6) for seizures/epilepsy, 40.8 (95% CI 33.2-50.2) for visual impairments, 10.0 (95% CI 9.2-10.9) for hearing loss, 3.6 (95% CI 3.2-4.2) for cancer, 1.5 (95% CI 1.4-1.5) for injuries/poisoning and 2.4 (95% CI 1.7-3.4) for child abuse., Conclusion: Children with congenital anomalies were more likely to be diagnosed with the specified co-morbidities compared to reference children., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Environmental contamination is a global challenge that impacts every aspect of ecosystem. The contaminants from anthropogenic or industrial trash continually recirculate into the environment, agricultural land, plants, livestock, and ultimately into humans by way of the food chain. After an increase in human and farmland animal deaths from illnesses due to contaminated drinking water, toxic metal water poisoning has remained a global concern. Diverse environmental and enforcement organisations have attempted to regulate the activities that serve as precursors to these heavy metals which have been proven ineffective. These unnecessary metals have severely hampered most biological processes. The presence of hazardous metals, which are harmful at extremely high levels and have a negative effect on the health of living bodies generally degrades the nutritional value of water. In order to evaluate the heavy metals (Cu, Ni, and Fe) toxicity of groundwater in pri-urban areas, the current study was conducted that have been considered as advance solution to tackle climate change which influence coastal ecosystem. Additionally, the impacts of soil and plant (spinach and brassica) contamination from groundwater were evaluated. The heavy metals were examined in the soil and groundwater samples (Pb, Fe and Ni). While Fe concentrations in water samples were found to be high as 1.978 mg/L as compared to Ni and Cu values low. According to WHO guidelines, the mean value of Fe exceeds the limit value. Similarly, Cu had a higher mean value (0.7 mg/L) in soil samples than other metals (Ni and Fe). In comparison to Ni and Cu, the Fe concentrations in spinach and brassica plants samples are greater, at 17.2 mg/L and 3.22 mg/L, respectively. The possible effects of metal poisoning of groundwater and plants on human health have been assessed using the Hazard Quotient (HQ), Evaluated Daily Intake (EDI), and Incremental Life Time Cancer Risk formulas (ILTCR). When drinking Ni-contaminated water, humans are more at risk of developing cancer (0.0031) than Fe and Cu. Metal concentrations in water and brassica showed substantially more scattered behaviour on the plot and no meaningful relationship, although PCA and masked matrix correlation showed a fair association between Ni and Cu in brassica (r2: 0.46) and Fe and Ni in spinach (r2: 0.31). According to the study's findings, it is anticipated that special management and groundwater monitoring will be needed in the examined area to reduce the health risks related to drinking water that has been contaminated with metals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Silica nanoparticles (SNP) have gained tremendous attention in the recent decades. They have been used in many different biomedical fields including diagnosis, biosensing and drug delivery. Medical uses of SNP for anti-cancer, anti-microbial and theranostic applications are especially prominent due to their exceptional performance to deliver many different small molecules and recently biologics (mRNA, siRNA, antigens, antibodies, proteins, and peptides) at targeted sites. The physical and chemical properties of SNP such as large specific surface area, tuneable particle size and porosity, excellent biodegradability and biocompatibility make them an ideal drug delivery and diagnostic platform. Based on the available data and the pre-clinical performance of SNP, recent interest has driven these innovative materials towards clinical application with many of the formulations already in Phase I and Phase II trials. Herein, the progress of SNP in biomedical field is reviewed, and their safety aspects are analysed. Importantly, we critically evaluate the key structural characteristics of SNP to overcome different biological barriers including the blood-brain barrier (BBB), skin, tumour barrier and mucosal barrier. Future directions, potential pathways, and target areas towards rapid clinical translation of SNP are also recommended., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

An efficient nanoparticulate drug carrier intended for chemotherapy based on intravenous administration must exhibit a long enough blood circulation time, a good penetrability into the tumour volume, as well as an efficient uptake by cancer cells. Limiting factors for the therapeutic outcome in vivo are recognition of the nanoparticles as foreign objects, which triggers nanoparticle uptake by defence organs rich in macrophages, e.g. liver and spleen, on the time-scale of accumulation and uptake in/by the tumour. However, the development of nanomedicine towards efficient nanoparticle-based delivery to solid tumours is hampered by the lack of simple, reproducible, cheap, and predictive means for early identification of promising nanoparticle formulations. The surface chemistry of nanoparticles is known to be the most important determinant for the biological fate of nanoparticles, as it influences the extent of serum protein adsorption, and also the relative composition of the protein corona. Here we preliminarily evaluate an extremely simple screening method for nanoparticle surface chemistry pre-optimization based on nanoparticle uptake in vitro by PC-3 cancer cells and THP-1 macrophages. Only when both selectivity for the cancer cells as well as the extent of nanoparticle uptake are taken into consideration do the in vitro results mirror literature results obtained for small animal models. Furthermore, although not investigated here, the screening method does also lend itself to the study of actively targeted nanoparticles.

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Extracellular vesicles (EVs), including nanoscale exosomes and ectosomes, hold promise as biomarkers that provide information about the cell of origin through their cargo of nucleic acids and proteins, both on their surface and within. Here, we develop a detection method of EVs based on light-induced acceleration of specific binding between their surface and antibody-modified microparticles, using a controlled microflow with three-dimensional analysis by confocal microscopy. Our method successfully detected 10 3 -10 4 nanoscale EVs in liquid samples as small as a 500 nanoliters within 5 minutes, with the ability to distinguish multiple membrane proteins. Remarkably, we achieved the specific detection of EVs secreted from living cancer cell lines with high linearity, without the need for a time-consuming ultracentrifugation process that can take several hours. Furthermore, the detection range can be controlled by adjusting the action range of optical force using a defocused laser, consistent with the theoretical calculations. These findings demonstrate an ultrafast, sensitive, and quantitative approach for measuring biological nanoparticles, enabling innovative analyses of cell-to-cell communication and early diagnosis of various diseases, including cancer.

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries., (© 2023. Japanese Society of Hematology.)

Background: Decision-making during the end-of-life (EOL) phase for children with cancer is extremely difficult for parents. We synthesized the qualitative experiences of children with cancer, parents, and healthcare professionals (HCPs), and their social interactions during the EOL decision-making process in the pediatric oncology setting., Methods: Meta-ethnography was used to conduct a systematic review and meta-synthesis. We searched four online databases to identify original studies published in English and Japanese and examined 21 relevant studies. Two Japanese reviewers discussed the differences/relationships and included studies that synthesized the translated qualitative findings. A conceptual model of social interactions was created., Results: We identified four themes regarding children's, parents', and HCPs' experiences: hope and confrontation with the child's death, guidance and support during uncertainty, awareness of being protected and having hope, and mutual unspoken integration of values., Conclusions: These themes evince the experiences of children, parents, and HCPs during the EOL decision-making process and suggests a complex three-way social interaction model. While considering such distinctive social interactions during a child's EOL, this study revealed the sharing of prudent information and psychosocial support by HCPs. The findings indicate that hope and uncertainty are key elements for effectively understanding the experiences of children and parents and that EOL decision-making should not be rushed but should be supported by leaving room for uncertainty and acknowledging parents' emotional needs and fostering new hope. Further research into how hope can be further supported in situations that are rife with uncertainty is needed., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aim: The severity and associated mortality of coronavirus disease 2019 (COVID-19) are higher in patients with thoracic cancer than in healthy populations and those with other cancer types. Here, we investigated real-world data on the incidence of COVID-19 and false-negative cases using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing in patients with thoracic cancer., Patients and Methods: We retrospectively reviewed patients with advanced thoracic cancer at the National Cancer Center Hospital between March 2020-May 2021. Blood samples were collected and evaluated for IgM and IgG antibodies specific for nucleocapsid (N) and spike (S) protein SARS-CoV-2 before and after rRT-PCR testing. False-negative cases were assessed based on anti-SARS-CoV-2 antibody levels before and after rRT-PCR testing., Results: A total of 2,107 patients with thoracic cancer were identified between March 2020 and May 2021, 7 (0.3%) of whom developed COVID-19. Among the 218 patients who underwent at least one rRT-PCR test because of suspected COVID-19 symptoms or as a screening test at our institute, the most common diagnosis was non-COVID-19 pneumonia (34.4%), followed by tumor fever (30.7%). Furthermore, of the 218 patients, 120 paired serum samples before and after rRT-PCR testing were available. Seroconversion was identified in all three patients with positive SARS-CoV-2 rRT-PCR results but was only observed in 1 out of the 117 patients who tested negative; the rate of false-negative cases was low (0.9%)., Conclusion: COVID-19 incidence among patients with advanced thoracic cancer was low during the early phase of the pandemic in Japan., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This study investigated the knowledge, thoughts, and attitudes of oncology nurses in China regarding fertility preservation for male cancer patients of childbearing age, and for offering counseling or oncofertility services for the men in their care. Data was collected from 18 oncology nurses in Southwest China through voluntary self-report and in-depth interviews. The qualitative interview data were analyzed using a descriptive phenomenology method based on the lived experience of the nurses. The interviewees commonly reported 6 main concerns regarding fertility preservation (FP): their insufficient knowledge and inadequate nursing education; the importance of offering such services to cancer patients; legal vulnerability if FP information is withheld from patients; the role of the nurse in counseling; and barriers to discussing FP in practice. Nurses had a positive attitude toward FP, but most had no practical role in routinely informing male patients of their options, and the nurses believed that discussion of FP was outside their scope of practice. This study offers insight into the perceptions of oncology nurses in a developing country regarding the provision of FP services for adult male cancer patients. These results lead us to recommend that local fertility nurses should be given new training regarding FP. Furthermore, nurse-led clinics are desirable. Future research should focus on the effectiveness of nurse participation in FP counseling and referral, and how to improve the professional confidence of oncology nurses for addressing FP issues., (© 2021. American Association for Cancer Education.)

Education programs for certified palliative care nurses who promote advance care planning (ACP) for cancer patients are important, but not currently available in Japan. This study aimed to develop an educational program of ACP for certified palliative care nurses in Japan and evaluate its effectiveness. A program consisting of four modules was implemented for 60 certified palliative care nurses in the Kyushu, Chugoku, and Shikoku regions. Participants attended one training session, and 39 responded to a survey on changes in ACP practice and difficulties with cancer nursing 3 months after the intervention. The Wilcoxon signed-rank test was performed to compare data before and after the intervention. The results obtained showed an increase in dialogue on ACP among patients/families and healthcare professionals (mean before the intervention = 24.49, mean after the intervention = 27.59, p = 0.045), and a significant decrease in the sense of difficulty with knowledge of and skills for ACP (mean before the intervention = 4.85, mean after the intervention = 4.30, p = 0.001). More than 90% of the participants gave positive comments on the evaluation items such as understanding and satisfaction with the educational program and appropriateness of the contents. After attending the training program, participants' sense of difficulty with their knowledge of and skills for ACP decreased, and their practice of ACP increased. This program may promote the practice of ACP for cancer patients in the future., (© 2021. The Author(s).)

Cancer is one of the most lethal diseases, and limited available treatment options contribute to its high mortality rate. Exosomes are considered membrane-bound nanovesicles that include different molecules such as lipids, proteins, and nucleic acids. Virtually most cells could release exosomes via exocytosis in physiological and pathological conditions. Tumour-derived exosomes (TDEs) play essential roles in tumorigenesis, proliferation, progression, metastasis, immune escape, and chemoresistance by transferring functional biological cargos, triggering different autocrine, and paracrine signalling cascades. Due to their antigen-presenting properties, exosomes are widely used as biomarkers and drug carriers and have a prominent role in cancer immunotherapy. They offer various advantages in carrier systems (e.g. in chemotherapy, siRNA, and miRNA), delivery of diagnostic agents owing to their stability, loading of hydrophobic and hydrophilic agents, and drug targeting. Novel exosomes-based carriers can be generated as intelligent systems using various sources and crosslinking chemistry extracellular vesicles (EVs). Exosomes studded with targeting ligands, including peptides, can impart in targeted delivery of cargos to tumour cells. In this review, we comprehensively summarised the important role of tumour-derived exosomes in dictating cancer pathogenesis and resistance to therapy. We have therefore, investigated in further detail the pivotal role of tumour-derived exosomes in targeting various cancer cells and their applications, and prospects in cancer therapy and diagnosis. Additionally, we have implicated the potential utility and significance of tumour exosomes-based nanoparticles as an efficient and novel therapeutic carrier and their applications in treating advanced cancers.

Patients found to have presumed germline pathogenic variants (PGPVs) during comprehensive genomic profiling (CGP) require genetic counseling (GC) referrals. We retrospectively investigated the outcomes of patients with PGPVs. Among 159 patients who underwent CGP, we recommended GC for the 16 patients with PGPVs (3 with [FG group] and 13 without [G Group] a family/personal history of hereditary cancer) as well as for the 8 patients with no PGPVs, but a history (F group); 2 (67%), 5 (38%), and 3 (38%) patients received GC in the FG, G, and F groups, respectively. Germline testing results were positive in 1 and 2 patients of the FG and G groups, respectively. Among the patients recommended for GC, 58% did not receive GC due to lack of interest, poor performance status, or death. CGP contributes to the identification of germline variants in patients without a history of hereditary cancer. However, the proportion of patients who undergo GC should be improved., Competing Interests: No potential conflict of interest relevant to this article was reported.

Importance: Women with epilepsy are recommended high doses of folic acid before and during pregnancy owing to risk of congenital anomalies associated with antiseizure medications. Whether prenatal exposure to high-dose folic acid is associated with increases in the risk of childhood cancer is unknown., Objective: To assess whether high-dose folic acid supplementation in mothers with epilepsy is associated with childhood cancer., Design, Setting, and Participants: Observational cohort study conducted with nationwide registers in Denmark, Norway, and Sweden from 1997 to 2017. Analyses were performed during January 10, 2022, to January 31, 2022. Mother-child pairs were identified in medical birth registers and linked with information from patient, prescription, and cancer registers, as well as with sociodemographic information from statistical agencies, and were categorized by maternal diagnosis of epilepsy. The study population consisted of 3 379 171 children after exclusion of 126 711 children because of stillbirth or missing or erroneous values on important covariates., Exposures: Maternal prescription fills for high-dose folic acid tablets (≥1 mg daily) between 90 days before pregnancy start and birth., Main Outcomes and Measures: First onset of childhood cancer at younger than 20 years. Cox proportional hazards models were used to calculate adjusted hazard ratios with corresponding 95% CIs, adjusted for potential confounders. Cumulative incidence at aged 20 years was used as a measure of absolute risk., Results: The median age at the end of follow-up in the study population of 3 379 171 children was 7.3 years (IQR, 3.5-10.9 years). Among the 27 784 children (51.4% male) born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed, producing an adjusted hazard ratio of 2.7 (95% CI, 1.2-6.3), absolute risk if exposed of 1.4% (95% CI, 0.5%-3.6%), and absolute risk if unexposed of 0.6% (95% CI, 0.3%-1.1%). In children of mothers without epilepsy, 46 646 (1.4%) were exposed to high-dose folic acid (mean dose, 2.9 mg), with 69 exposed and 4927 unexposed cancer cases and an adjusted hazard ratio of 1.1 (95% CI, 0.9-1.4; absolute risk, 0.4% [95% CI, 0.3%-0.5%]). There was no association between children born to mothers with epilepsy who were prenatally exposed to antiseizure medications, but not high-dose folic acid, and an increased risk of cancer (absolute risk, 0.6%; 95% CI, 0.2%-1.3%)., Conclusions and Relevance: Prenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.

Identifying a strategy with strong efficacy against non-inflamed tumours is vital in cancer immune therapy. ERY974 is a humanized IgG4 bispecific T cell-redirecting antibody that recognizes glypican-3 and CD3. Here we examine the combination effect of ERY974 and chemotherapy (paclitaxel, cisplatin, and capecitabine) in the treatment of non-inflamed tumours in a xenograft model. ERY974 monotherapy shows a minor antitumour effect on non-inflamed NCI-H446 xenografted tumours, as infiltration of ERY974-redirected T cells is limited to the tumour-stromal boundary. However, combination therapy improves efficacy by promoting T cell infiltration into the tumour centre, and increasing ERY974 distribution in the tumour. ERY974 increases capecitabine-induced cytotoxicity by promoting capecitabine conversion to its active form by inducing thymidine phosphorylase expression in non-inflamed MKN45 tumour through ERY974-induced IFNγ and TNFα in T cells. We show that ERY974 with chemotherapy synergistically and reciprocally increases antitumour efficacy, eradicating non-inflamed tumours., (© 2022. The Author(s).)

Background: The aim was to investigate whether children born after assisted reproduction technology (ART), particularly after frozen-thawed embryo transfer (FET), are at higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception., Methods and Findings: We performed a registry-based cohort study using data from the 4 Nordic countries: Denmark, Finland, Norway, and Sweden. The study included 7,944,248 children, out of whom 171,774 children were born after use of ART (2.2%) and 7,772,474 children were born after spontaneous conception, representing all children born between the years 1994 to 2014 in Denmark, 1990 to 2014 in Finland, 1984 to 2015 in Norway, and 1985 to 2015 in Sweden. Rates for any cancer and specific cancer groups in children born after each conception method were determined by cross-linking national ART registry data with national cancer and health data registries and population registries. We used Cox proportional hazards models to estimate the risk of any cancer, with age as the time scale. After a mean follow-up of 9.9 and 12.5 years, the incidence rate (IR) of cancer before age 18 years was 19.3/100,000 person-years for children born after ART (329 cases) and 16.7/100,000 person-years for children born after spontaneous conception (16,184 cases). Adjusted hazard ratio (aHR) was 1.08, 95% confidence interval (CI) 0.96 to 1.21, p = 0.18. Adjustment was performed for sex, plurality, year of birth, country of birth, maternal age at birth, and parity. Children born after FET had a higher risk of cancer (48 cases; IR 30.1/100,000 person-years) compared to both fresh embryo transfer (IR 18.8/100,000 person-years), aHR 1.59, 95% CI 1.15 to 2.20, p = 0.005, and spontaneous conception, aHR 1.65, 95% CI 1.24 to 2.19, p = 0.001. Adjustment either for macrosomia, birth weight, or major birth defects attenuated the association marginally. Higher risks of epithelial tumors and melanoma after any assisted reproductive method and of leukemia after FET were observed. The main limitation of this study is the small number of children with cancer in the FET group., Conclusions: Children born after FET had a higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception. The results should be interpreted cautiously based on the small number of children with cancer, but the findings raise concerns considering the increasing use of FET, in particular freeze-all strategies without clear medical indications., Trial Registration: Trial registration number: ISRCTN 11780826., Competing Interests: The authors have declared that no competing interests exist.

Cellular senescence and cell competition are important tumor suppression mechanisms that restrain cells with oncogenic mutations at the initial stage of cancer development. However, the link between cellular senescence and cell competition remains unclear. Senescent cells accumulated during the in vivo aging process contribute toward age-related cancers via the development of senescence-associated secretory phenotype (SASP). Here, we report that hepatocyte growth factor (HGF), a SASP factor, inhibits apical extrusion and promotes basal protrusion of Ras-mutated cells in the cell competition assay. Additionally, cellular senescence induced by a high-fat diet promotes the survival of cells with oncogenic mutations, whereas crizotinib, an inhibitor of HGF signaling, provokes the removal of mutated cells from mouse livers and intestines. Our study provides evidence that cellular senescence inhibits cell competition-mediated elimination of oncogenic cells through HGF signaling, suggesting that it may lead to cancer incidence during aging., (© 2022. The Author(s).)

Although ropeginterferon alfa-2b has recently been clinically applied to myeloproliferative neoplasms with promising results, its antitumor mechanism has not been thoroughly investigated. Using a leukemia model developed in immunocompetent mice, we evaluated the direct cytotoxic effects and indirect effects induced by ropeginterferon alfa-2b in tumor cells. Ropeginterferon alfa-2b therapy significantly prolonged the survival of mice bearing leukemia cells and led to long-term remission in some mice. Alternatively, conventional interferon-alpha treatment slightly extended the survival and all mice died. When ropeginterferon alfa-2b was administered to interferon-alpha receptor 1-knockout mice after the development of leukemia to verify the direct effect on the tumor, the survival of these mice was slightly prolonged; nevertheless, all of them died. In vivo CD4 + or CD8 + T-cell depletion resulted in a significant loss of therapeutic efficacy in mice. These results indicate that the host adoptive immunostimulatory effect of ropeginterferon alfa-2b is the dominant mechanism through which tumor cells are suppressed. Moreover, mice in long-term remission did not develop leukemia, even after tumor rechallenge. Rejection of rechallenge tumors was canceled only when both CD4 + and CD8 + T cells were removed in vivo, which indicates that each T-cell group functions independently in immunological memory. We show that ropeginterferon alfa-2b induces excellent antitumor immunomodulation in hosts. Our finding serves in devising therapeutic strategies with ropeginterferon alfa-2b., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

STA551, a novel anti-CD137 switch antibody, binds to CD137 in an extracellular ATP concentration-dependent manner. Although STA551 is assumed to show higher target binding in tumor tissues than in normal tissues, quantitative detection of the target binding of the switch antibody in vivo is technically challenging. In this study, we investigated the target binding of STA551 in vivo using intravital imaging with two-photon microscopy. Tumor-bearing human CD137 knock-in mice were intravenously administered fluorescently labeled antibodies. Flow cytometry analysis of antibody-binding cells and intravital imaging using two-photon microscopy were conducted. Higher CD137 expression in tumor than in spleen tissues was detected by flow cytometry analysis, and T cells and NK cells were the major CD137-expressing cells. In the intravital imaging experiment, conventional and switch anti-CD137 antibodies showed binding in tumors. However, in the spleen, the fluorescence of the switch antibody was much weaker than that of the conventional anti-CD137 antibody and comparable with that of the isotype control. In conclusion, we were able to assess switch antibody biodistribution in vivo through intravital imaging with two-photon microscopy. These results suggest that the tumor-selective binding of STA551 leads to a wide therapeutic window and potent antitumor efficacy without systemic immune activation., (© 2022. The Author(s).)

Background: Patients with life-limiting illnesses frequently experience urinary difficulties, and urinary catheterization is one of the interventions for managing them. However, evidence supporting the effects of urinary catheters on the quality of death (QoD) is lacking in this population. Objectives: To investigate whether urinary catheterization affects QoD in patients with advanced cancer in palliative care units. Design: A secondary analysis of a multicenter, prospective cohort study. Setting/Subjects: The study enrolled consecutive patients with advanced cancer admitted to palliative care units in Japan between January and December 2017. Those who were not catheterized on admission and who died while in a palliative care unit were analyzed. Measurements: QoD was evaluated at death using the Good Death Scale (GDS). Results: Of 885 patients, 297 (33.6%) were catheterized during their palliative care unit stay. Females and patients with a long palliative care unit stay were more likely to be catheterized. In inverse probability-weighted propensity score analysis, patients with urinary catheterization during their palliative care unit stay had higher total GDS scores than those without catheterization (coefficient 0.410, 95% confidence interval 0.068-0.752). In subgroup analyses stratified by sex, age, and length of palliative care unit stay, urinary catheterization was associated with higher total GDS scores in patients younger than 65 years of age and those who died after a palliative care unit stay of 21 days or fewer. Conclusions: This study suggested that urinary catheterization during a palliative care unit stay may have a positive impact on overall QoD in patients with advanced cancer. This study was registered in the UMIN Clinical Trials Registry (UMIN000025457).

Background: Elevated blood pressure is a major risk factor for cardiovascular (CV) disease. But the effects of sodium intake or excretion on CV mortality are uncertain. The present study aimed to investigate the association between 24 h urinary sodium excretion, as a marker of dietary salt intake, and CV or cancer mortality in a healthy Japanese population using 24 hurine collection., Methods: The baseline study was conducted in 1980. A total of 1291 participants aged 21 to 85 years, underwent health check-ups, which included blood chemistry measurements and the collection of 24 h urine samples. Enrolled 1291 participants were followed up for 27.5 years, in whom the final follow-up rate was 95.8%. Cox proportional hazards regression models were used to assess the association between 24 h urinary sodium excretion and CV or cancer mortality., Results: The mean 24 h urinary sodium excretion was 5.80 ± 2.28 g/day. There were 631 deaths: 153 (27%) from cancer, 142 (26%) from CV disease. In the Cox proportional hazard regression model after adjustment for confounding factors, systolic and diastolic blood pressures, and uric acid were positively associated with CV mortality, and the 24 h urinary sodium and potassium excretions were inversely associated with CV mortality (p < 0.05). On the other hand, there were no association between 24 h urinary sodium excretions and cancer mortality. We divided the urinary sodium excretions levels into quartiles. After adjustment for confounding factors, the hazard ratio of CV mortality in the highest quartile of 24 h urinary sodium excretion versus the lowest was 0.46 (p < 0.05). The cumulative survival rate for CV death was significantly decreased in the lowest quartile compared with the other higher groups., Conclusions: We found that impacts of 24 h sodium excretion on CV and cancer mortalities were much different in the general population., (Copyright © 2021. Published by Elsevier Ltd.)

Objective In Japan, both medical oncologists and pulmonologists treat lung cancer patients; however, the difference in their attitude toward palliative care referral is unknown. Thus, we retrospectively investigated the difference in attitudes toward palliative care referral between medical oncologists and pulmonologists in Japan. Methods We retrospectively reviewed the charts of patients with thoracic malignancy who died at Shimane University Hospital between June 2011 and October 2015. We compared the patients' demographics and medical history according to their doctor's specialty (i.e., medical oncologist or pulmonologist). Results We identified 182 patients, among whom 90 were treated by medical oncologists and 56 by pulmonologists at the outpatient clinic. Thirty-six patients did not undergo outpatient clinic treatment. Out of 59 patients, 22 (37.3%) referred by medical oncologists, and 7 out of 36 patients (19.4%) referred by pulmonologists, were referred to palliative care specialists in the outpatient setting (p=0.107, Fisher's exact test). The median survival time after admission to PCU was 21 (95% CI: 13-32) and 9 (95% CI: 5-15) days among the patients treated by medical oncologists and pulmonologists, respectively (p=0.128). Conclusion Medical oncologists are more likely to refer their patients to palliative care in the outpatient setting, thus enabling patients to receive longer end of life care in the PCU. Bridging the research gap regarding differences between the physicians' attitudes toward palliative care referral may lead to patients receiving more quality palliative care.

Importance: Patients with cancer and health care workers (HCWs) are at high risk of SARS-CoV-2 infection. Assessing the antibody status of patients with cancer and HCWs can help understand the spread of COVID-19 in cancer care., Objective: To evaluate serum SARS-CoV-2 antibody status in patients with cancer and HCWs during the COVID-19 pandemic in Japan., Design, Setting, and Participants: Participants were enrolled for this prospective cross-sectional study between August 3 and October 30, 2020, from 2 comprehensive cancer centers in the epidemic area around Tokyo, Japan. Patients with cancer aged 16 years or older and employees were enrolled. Participants with suspected COVID-19 infection at the time of enrollment were excluded., Exposures: Cancer of any type and cancer treatment, including chemotherapy, surgery, immune checkpoint inhibitors, radiotherapy, and targeted molecular therapy., Main Outcomes and Measures: Seroprevalence and antibody levels in patients with cancer and HCWs. Seropositivity was defined as positivity to nucleocapsid IgG (N-IgG) and/or spike IgG (S-IgG). Serum levels of SARS-CoV-2 IgM and IgG antibodies against the nucleocapsid and spike proteins were measured by chemiluminescent enzyme immunoassay., Results: A total of 500 patients with cancer (median age, 62.5 years [range, 21-88 years]; 265 men [55.4%]) and 1190 HCWs (median age, 40 years [range, 20-70 years]; 382 men [25.4%]) were enrolled. In patients with cancer, 489 (97.8%) had solid tumors, and 355 (71.0%) had received anticancer treatment within 1 month. Among HCWs, 385 (32.3%) were nurses or assistant nurses, 266 (22.4%) were administrative officers, 197 (16.6%) were researchers, 179 (15.0%) were physicians, 113 (9.5%) were technicians, and 50 (4.2%) were pharmacists. The seroprevalence was 1.0% (95% CI, 0.33%-2.32%) in patients and 0.67% (95% CI, 0.29%-1.32%) in HCWs (P = .48). However, the N-IgG and S-IgG antibody levels were significantly lower in patients than in HCWs (N-IgG: β, -0.38; 95% CI, -0.55 to -0.21; P < .001; and S-IgG: β, -0.39; 95% CI, -0.54 to -0.23; P < .001). Additionally, among patients, N-IgG levels were significantly lower in those who received chemotherapy than in those who did not (median N-IgG levels, 0.1 [interquartile range (IQR), 0-0.3] vs 0.1 [IQR, 0-0.4], P = .04). In contrast, N-IgG and S-IgG levels were significantly higher in patients who received immune checkpoint inhibitors than in those who did not (median N-IgG levels: 0.2 [IQR, 0.1-0.5] vs 0.1 [IQR, 0-0.3], P = .02; S-IgG levels: 0.15 [IQR, 0-0.3] vs 0.1[IQR, 0-0.2], P = .02)., Conclusions and Relevance: In this cross-sectional study of Japanese patients with cancer and HCWs, the seroprevalence of SARS-CoV-2 antibodies did not differ between the 2 groups; however, findings suggest that comorbid cancer and treatment with systemic therapy, including chemotherapy and immune checkpoint inhibitors, may influence the immune response to SARS-CoV-2.

The emerging discipline of oncofertility advocates for the timely provision of fertility preservation (FP) to all cancer patients of childbearing age by healthcare providers. A lack of practice due to limited FP-related knowledge was found among healthcare providers. A systematic review was undertaken on the educational programs on FP for healthcare providers. An initial search was performed in MEDLINE, PsycINFO, CINAHL, Web of Science, PubMed, and Scopus databases in October 2019. This review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Among the 160 articles that were identified, five relevant articles published between 2009 and 2019 were reviewed. Of the five studies, three were quantitative nonrandomized studies, one was a randomized controlled trial, and one was a qualitative study. Three programs were relevant to oncology nurses, one was relevant to social workers as well as nurses, and one was relevant to oncology fellows and residents. The four programs significantly increased healthcare providers' knowledge about FP, but clinical practice was only improved in the Educating Nurses about Reproductive Issues in Cancer Healthcare program (P < 0.01). Nevertheless, most of the studies used a self-made questionnaire or tool to assess the effects of the training programs. The educational programs improved the FP-related knowledge of healthcare providers but lacked the high-quality randomized controlled trials needed to provide robust evidence on the effectiveness of training programs using standard tools. More training projects should be developed based on learning theories or models to improve oncofertility care in clinical practice.

Synthetic lethality is a successful strategy employed to develop selective chemotherapeutics against cancer cells. Inactivation of RAD52 is synthetically lethal to homologous recombination (HR) deficient cancer cell lines. Replication protein A (RPA) recruits RAD52 to repair sites, and the formation of this protein-protein complex is critical for RAD52 activity. To discover small molecules that inhibit the RPA:RAD52 protein-protein interaction (PPI), we screened chemical libraries with our newly developed Fluorescence-based protein-protein Interaction Assay (FluorIA). Eleven compounds were identified, including FDA-approved drugs (quinacrine, mitoxantrone, and doxorubicin). The FluorIA was used to rank the compounds by their ability to inhibit the RPA:RAD52 PPI and showed mitoxantrone and doxorubicin to be the most effective. Initial studies using the three FDA-approved drugs showed selective killing of BRCA1-mutated breast cancer cells (HCC1937), BRCA2-mutated ovarian cancer cells (PE01), and BRCA1-mutated ovarian cancer cells (UWB1.289). It was noteworthy that selective killing was seen in cells known to be resistant to PARP inhibitors (HCC1937 and UWB1 SYr13). A cell-based double-strand break (DSB) repair assay indicated that mitoxantrone significantly suppressed RAD52-dependent single-strand annealing (SSA) and mitoxantrone treatment disrupted the RPA:RAD52 PPI in cells. Furthermore, mitoxantrone reduced radiation-induced foci-formation of RAD52 with no significant activity against RAD51 foci formation. The results indicate that the RPA:RAD52 PPI could be a therapeutic target for HR-deficient cancers. These data also suggest that RAD52 is one of the targets of mitoxantrone and related compounds., Competing Interests: The authors have declared that no competing interests exist.

Background: Hyperactive delirium is known to increase family distress and the burden on health care providers. We compared the prevalence and associated factors of agitated delirium in advanced cancer patients between inpatient palliative care and palliative home care on admission and at 3 days before death., Methods: This was a post hoc exploratory analysis of two multicenter, prospective cohort studies of advanced cancer patients, which were performed at 23 palliative care units (PCUs) between Jan and Dec 2017, and on 45 palliative home care services between July and Dec 2017., Results: In total, 2998 patients were enrolled and 2829 were analyzed in this study: 1883 patients in PCUs and 947 patients in palliative home care. The prevalence of agitated delirium between PCUs and palliative home care was 5.2% (95% CI: 4.2% - 6.3%) vs. 1.4% (0.7% - 2.3%) on admission (p < 0.001) and 7.6% (6.4% - 8.9%) vs. 5.4% (4.0% - 7.0%) 3 days before death (p < 0.001). However, multivariate logistic regression analysis revealed that the place of care was not significantly associated with the prevalence of agitated delirium at 3 days before death after adjusting for prognostic factors, physical risk factors, and symptoms., Conclusions: There was no significant difference in the prevalence of agitated delirium at 3 days before death between inpatient palliative care and palliative home care after adjusting for the patient background, prognostic factors, symptoms, and treatment., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Agonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Because conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigens, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of the tumor microenvironment and highly elevated in solid tumors, as a broadly tumor-selective switch. We generated a novel anti-CD137 switch antibody, STA551, which exerts agonistic activity only in the presence of exATP. STA551 demonstrated potent and broad antitumor efficacy against all mouse and human tumors tested and a wide therapeutic window without systemic immune activation in mice. STA551 was well tolerated even at 150 mg/kg/week in cynomolgus monkeys. These results provide a strong rationale for the clinical testing of STA551 against a broad variety of cancers regardless of antigen expression, and for the further application of this novel platform to other targets in cancer therapy. SIGNIFICANCE: Reported CD137 agonists suffer from either systemic toxicity or limited efficacy against antigen-specific cancers. STA551, an antibody designed to agonize CD137 only in the presence of extracellular ATP, inhibited tumor growth in a broad variety of cancer models without any systemic toxicity or dependence on antigen expression. See related commentary by Keenan and Fong, p. 20 . This article is highlighted in the In This Issue feature, p. 1 ., (©2020 American Association for Cancer Research.)

Background: Outpatient cancer chemotherapy may lead to improved quality of life (QOL) by allowing treatment to continue without impairing the social lives of patients compared with hospitalization. However, the occurrence of serious adverse events may cause a decline in QOL. We investigated the relationship between outpatient chemotherapy-induced adverse events and QOL., Methods: A single-center retrospective descriptive study was conducted in patients who received outpatient chemotherapy at Gifu University Hospital (Gifu, Japan) between September 2017 and December 2018. The utility values of QOL, type and severity of adverse events, type of cancer, chemotherapy regimen, and other patient demographics were analyzed. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. QOL was evaluated using the Japanese version of the EuroQol 5 Dimension 5 Level (EQ-5D-5L). Associations between the EQ-5D-5L utility value and serious adverse events were assessed using adjusted (age and sex) odds ratios obtained with a proportional odds logistic regression model., Results: Data from 1008 patients who received 4695 chemotherapy cycles were analyzed. According to proportional odds logistic regression, the adverse events that significantly correlated with a decreased EQ-5D-5L utility value were malaise, edema of the limbs, peripheral neuropathy, pruritus, and dry skin. Based on the proportional odds logistic analysis, neither cancer type nor anticancer drugs were significantly correlated with the EQ-5D-5L utility value in patients who received chemotherapy. Pharmaceutical care for peripheral neuropathy significantly improved patients' EQ-5D-5L utility value from 0.747 to 0.776 (P < 0.01)., Conclusions: Adverse events (i.e., peripheral neuropathy, malaise, and edema of the limbs) are significantly correlated with a decrease in QOL, regardless of the type of cancer or anticancer drugs used. Pharmaceutical care provided by pharmacists in collaboration with physicians may improve QOL.

The incidence pattern of lichen planus (LP) and LP-related mortality are unknown. The aim of this study was to assess these factors, based on Finnish nationwide registry data including 13,378 women with LP diagnosed during 1969 to 2012. The incidence rate for LP in 2003 to 2012 was 28 per 100,000 woman-years age-adjusted to the European Standard Population. Mortality was assessed using the standardized mortality ratio (SMR) with national mortality rates as the reference. All-cause mortality was increased (SMR 1.07, 95% confidence interval (95% CI) 1.02-1.11), with excess mortality from Hodgkin lymphoma (SMR 6.73, 95% CI 1.83-17.2), non-Hodgkin lymphoma (SMR 1.68, 95% CI 1.11-2.44), cancer of the oral cavity (SMR 10.5, 95% CI 5.99-17.0), cancer of the tongue (SMR 7.25, 95% CI 3.13-14.3), infections (SMR 1.78, 95% CI 1.14-2.64), respiratory diseases (SMR 1.31, 95% CI 1.07-1.57), and diseases of the digestive system (SMR 1.39, 95% CI 1.09-1.75). In conclusion, LP is a common disease and patients seem to have an impaired long-term prognosis.

Background: Oral mucositis (OM) is a significant side effect of cancer treatment. The purpose of this study was to compare topically administered Caphosol to saline rinses in the prevention of mucositis in pediatric cancer patients., Procedure: A controlled, double-blinded, and randomized clinical crossover study recruited patients between 2 to 17.99 years of age who were diagnosed with a malignancy and were receiving either high-dose methotrexate (≥1 g/m 2 ), anthracycline, or cisplatin chemotherapy (NCT0280733). All patients received two 7-day cycles of the mouth rinses; that is, one cycle of Caphosol and one cycle of saline in a randomized order. Oral changes and symptoms were evaluated using the World Health Organisation (WHO) toxicity scale and the Children's International Mucositis Evaluation Scale (ChIMES). The primary endpoint was the frequency and severity of OM and oral symptoms., Results: A total of 56 patients were recruited to the study, of whom 45 were randomized with a median age of 6.5 years (range 2.1-17.1 years). No cases of severe OM were observed. Grade ≥ 3 oral symptoms were present at least once in six (13%) patients during the Caphosol cycle and 13 (29%) patients during the saline cycle (P = .12). The peak of symptom scores was evident at around day 4-7 after administration of the chemotherapy with no marked differences between the rinse solutions. Multivariable regression analysis did not indicate a benefit of using Caphosol over the saline solution., Conclusions: No difference in prevention of oral mucositis was observed between the use of Caphosol or saline rinses., (© 2020 Wiley Periodicals LLC.)

Background: Epigenetic reprogramming using DNA demethylating drugs is a promising approach for cancer therapy, but its efficacy is highly dependent on the dosing regimen. Low-dose treatment for a prolonged period shows a remarkable therapeutic efficacy, despite its small demethylating effect. Here, we aimed to explore the mechanisms of how such low-dose treatment shows this remarkable efficacy by focusing on epigenetic reprograming at the single-cell level., Methods: Expression profiles in HCT116 cells treated with decitabine (DAC) were analyzed by single-cell RNA-sequencing (scRNA-seq). Functional consequences and DNA demethylation at the single-cell level were analyzed using cloned HCT116 cells after DAC treatment., Results: scRNA-seq revealed that DAC-treated cells had highly diverse expression profiles at the single-cell level, and tumor-suppressor genes, endogenous retroviruses, and interferon-stimulated genes were upregulated in random fractions of cells. DNA methylation analysis of cloned HCT116 cells revealed that, while only partial reduction of DNA methylation levels was observed in bulk cells, complete demethylation of specific cancer-related genes, such as cell cycle regulation, WNT pathway, p53 pathway, and TGF-β pathway, was observed, depending upon clones. Functionally, a clone with complete demethylation of CDKN2A (p16) had a larger fraction of cells with tetraploid than parental cells, indicating induction of cellular senescence due to normalization of cell cycle regulation., Conclusions: Epigenetic reprogramming of specific cancer-related pathways at the single-cell level is likely to underlie the remarkable efficacy of low-dose DNA demethylating therapy.

Aim: The aim of this study was to assess the outcome of transcatheter aortic valve replacement (TAVR) in patients with cancer., Methods: This is a retrospective study from the nationwide FinnValve registry on 2130 consecutive patients who underwent TAVR for severe AS from January 2008 to October 2017., Results: In this cohort, 417 patients (19.6%) had history of cancer and 113 (5.3%) had an active malignancy at the time of TAVR. Patients with any malignancy had similar late mortality than patients without any malignancy (at 7 years, 65.1% vs. 59.3%, adjusted HR 1.105, 95%CI 0.892-1.369). At 7 years, cancer-related mortality was 22.5% among patients with preoperative cancer, and 11.0% in those without preoperative cancer (p < 0.0001). Among cancer patients, 18 died of the same disease (at 7 years, mortality 12.5%). Active malignancy was not associated with increased risk of all-cause mortality (adjusted HR 1.100, 95%CI 0.757-1.599). However, patients with blood malignancies had a significantly increased risk of mortality (at 4-year, 53.5% vs. 35.4%, adjusted HR 2.029, 95%CI 1.328-3.098)., Conclusions: This analysis showed that, when properly selected by the heart team and oncologists, most cancer patients undergoing TAVR can achieve a good survival and eventually die of other diseases. Blood malignancies seem to carry a poor prognosis in these patients., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03385915; https://clinicaltrials.gov/ct2/show/NCT03385915., Competing Interests: Declaration of competing interest Dr. Mikko Savontaus is proctor for Medtronic, the relationship is significant; Dr. Mika Laine is proctor for Boston Scientific, the relationship is significant. The other coauthors do not have any significant conflict of interest related to this study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: It is well known that a decline in physical activity is associated with an increase of all-cause death including cardiovascular events and cancer. Few studies have examined the association between occupational sitting time and mortality. Therefore, we investigated this issue in a general population., Methods: Physical activity and occupational sitting time were measured using the Baecke physical activity questionnaire in 1999. The questionnaire generated indices in three physical activity categories: work, sport and leisure-time. A total physical activity index was calculated by adding these three indices. The Baecke physical activity questionnaire was able to evaluate occupational sitting time. Hazard ratios and 95% confidence intervals (CIs) were calculated using Cox's proportional hazard regression models., Results: We enrolled a total of 1680 participants, who were followed up for 15.9 ± 3.8 years. The final follow-up rate was 93%. During the follow-up period, 397 subjects died. A significant inverse association ( p  < 0.0001) was found between physical activity and mortality after adjustment for age and sex. Compared with lower levels of physical activity, the adjusted hazard ratio for mortality at higher levels of physical activity was 0.85 (95% CI: 0.78-0.92). Longer occupational sitting time was also significantly associated with higher mortality ( p  < 0.01). The adjusted hazard ratio for mortality at longer occupational sitting time was 1.16 (95% CI: 1.05-1.27). These findings were observed in males, but not in females., Conclusions: Our data demonstrated that higher levels of physical activity are associated with a reduced risk of cancer and cardiovascular death. Further, longer occupational sitting time is associated with increased mortality.

Background: Dyspnea is a common distressing symptom in patients with malignant and nonmalignant diseases. Fan therapy, which uses a fan to blow air toward the patient's face, can alleviate dyspnea; however, its efficacy remains unclear., Aim: To examine the immediate efficacy of fan therapy for alleviation of dyspnea at rest., Design: Meta-analysis., Data Sources: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library, MEDLINE EBSCO, CINAHL EBSCO, and Scopus from January 1, 1987, to August 21, 2018 (PROSPERO-CRD42018108610). In addition, we hand-searched studies and used the similar articles feature on PubMed to search for articles. Randomized controlled trials comparing the effects of fan therapy with placebo or other interventions to alleviate dyspnea at rest, in which patients were aged ≥18 years, were eligible for inclusion in the review. We excluded articles on long-term intervention involving fan therapy and complex intervention (including fan therapy). The risk of bias assessment was conducted using the Cochrane tool, and the meta-analysis was performed using RevMan version 5.3., Results: We identified a total of 218 studies; 2 met our criteria for inclusion in the meta-analysis. Fan therapy significantly improved dyspnea at rest in terminally ill patients with cancer compared to control groups (mean difference: -1.31, 95% confidence interval: -1.79 to -0.83, P < .001). There were no studies that met the inclusion criteria regarding fan therapy for patients with nonmalignant disease., Conclusions: This meta-analysis demonstrated that fan therapy may be an effective intervention for dyspnea at rest in patients with terminal cancer.

Constitutional mismatch repair deficiency is a rare cancer predisposition syndrome caused by biallelic mutations in one of the four mismatch repair genes. Patients are predisposed to various tumors including hematological malignancies, brain tumors and colorectal carcinomas. Phenotypic overlap with Neurofibromatosis-1 is well known, with most patients presenting with café-au-lait macules. Other common features include axillary and/or inguinal freckling and intracranial MRI foci of high T2W/FLAIR signal intensity similar to the typical FASI seen in Neurofibromatosis-1. In this cohort of eight patients with constitutional mismatch repair deficiency we describe overlapping phenotypical features with Tuberous Sclerosis complex. In addition to "ash-leaf like" hypomelanotic macules (five patients), we detected intracranial tuber-like lesions (three patients), renal cysts (three patients) and renal angiomyolipomas (two patients). All our patients also had Neurofibromatosis-1 like features, mainly café-au-lait macules. This study suggests that features of Tuberous sclerosis especially when overlapping with those of Neurofibromatosis 1 or malignancies atypical for these syndromes should raise the possibility of constitutional mismatch repair deficiency. Correct diagnosis is essential for appropriate genetic counseling and pre-emptive cancer surveillance., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Advances in multimodality cancer treatments have increased the risk of long-term complications in early-onset cancer survivors. For female cancer survivors, these include diminished reproductive function, often resulting in a narrowed fertile window. The aim of our study was to evaluate the use of fertility treatments in cancer survivors (aged 0-39 years at diagnosis) compared to siblings. Data from Finnish registers on cancer, birth and prescribed medications were merged to identify 8,929 survivors and 9,495 siblings without previous deliveries. Fertility drug purchases from 1993 to 2012 at the age of 16-41 years were included. A Poisson regression model was used to estimate incidence rate ratios (IRRs) for the use of fertility drugs, adjusting for age and calendar time at fertility drug purchase. Fertility treatments were more common in survivors compared to siblings, as 6.1% of survivors compared to 3.8% of siblings had bought fertility drugs (IRR 1.43, 95% confidence interval [CI] 1.25-1.65). A subclassification of fertility treatments into ovulation inductions and assisted reproductive technology (ART), showed increased use of ART (IRR 2.41, 95% CI 1.97-2.96), whereas the use of ovulation induction was similar in survivors and siblings. Analyses by calendar time periods showed the use of ART to be significantly higher in the most recent decade, from 2003 onwards. We conclude that cancer survivors have an increased risk for subfertility, which is why fertility counseling is important. However, our results mirror a more active approach among clinicians towards fertility treatments in cancer survivors during the most recent years., (© 2019 UICC.)

We explored the mechanism of action of CD39 antibodies that inhibit ectoenzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinflammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action. Efficacy of anti-CD39 activity was underpinned by CD39 and P2X7 coexpression on intratumor myeloid subsets, an early signature of macrophage depletion, and active IL18 release that facilitated the significant expansion of intratumor effector T cells. More importantly, anti-CD39 facilitated infiltration into T cell-poor tumors and rescued anti-PD-1 resistance. Anti-human CD39 enhanced human T-cell proliferation and Th1 cytokine production and suppressed human B-cell lymphoma in the context of autologous Epstein-Barr virus-specific T-cell transfer. SIGNIFICANCE: Overall, these data describe a potent and novel mechanism of action of antibodies that block mouse or human CD39, triggering an eATP-P2X7-inflammasome-IL18 axis that reduces intratumor macrophage number, enhances intratumor T-cell effector function, overcomes anti-PD-1 resistance, and potentially enhances the efficacy of adoptive T-cell transfer. This article is highlighted in the In This Issue feature, p. 1631 ., (©2019 American Association for Cancer Research.)

The Consultation Support and Information Providing Committee, which is a subsidiary organization of the Kumamoto Cancer Medical Cooperation Council, created a critical path called"my medical chart,"which is used in Kumamoto prefecture jointly. The path was implemented in 2009 at designated cancer hospitals. For promoting cancer consultation support centers and nurturing cancer counselors, the Cancer Special Counselor Working Group was formed, and activities were initiated. These activities of the Committee resulted in an increased number of patients visiting the designated cancer hospitals. The number of medical cooperations using"my medical chart"exceeded 4,800. A disparity was also observed in cancer treatment, such as surgery, radiotherapy, and chemotherapy. We investigate the situation of cancer treatment and report current problems and future issues.

Previous studies have shown an elevated risk for preterm delivery among early onset cancer survivors. Whether the preterm delivery starts spontaneously, due to possible uterine damage because of cancer treatment, or is induced due to maternal conditions is unclear. Our aim was to assess pregnancy related conditions in female cancer survivors possibly underlying the elevated risk for preterm labor. Nationwide cancer and birth registries were merged to identify 1,753 first deliveries of cancer survivors (diagnosed below 40 years of age) and 5,123 first deliveries of matched female comparison subjects between January 1991 and December 2013. Conditional logistic regression models were used to estimate the risk for pregnancy related conditions adjusting for maternal age, gestational age and smoking. We found an overall increased risk for hospitalization during pregnancy (OR 1.45, 95% CI 1.25-1.68), intrahepatic cholestasis (OR 2.86, 95% CI 1.09-7.49), fear of childbirth (OR 2.25, 95% CI 1.31-3.85) and mental disorders and diseases of the nervous system complicating pregnancy and labor (OR 5.89, 95% CI 2.31-15.00). Among survivors, 129 (7.4%) delivered preterm compared to 268 (5.2%) comparisons subjects (p = 0.004). We found a statistically significant increased risk for preterm delivery among cancer survivors with vaginal bleeding (OR 1.35, 95% CI 1.07-1.71) and pre-eclampsia (1.35, 95% CI 1.06-1.72) compared to comparison subjects with the same condition. Health professionals treating these women should be aware of these risks. In general, however, our results are reassuring when it comes to pregnancies among cancer survivors., (© 2018 UICC.)

Objective: Maternal cancer may be associated with offspring mental and behavioural disorders through various biological pathways. When postnatally diagnosed, it may cause stress and changes in care, potentially influencing mental health. Prenatally diagnosed cancer could lead to maternal stress and treatment, or influence foetal neural development. This study investigates associations between prenatally or postnatally diagnosed maternal cancers and mental and behavioural disorders in children., Methods: The study composed of 2 158 430 children born in Denmark (1978-2012). Children were exposed if their mother received a cancer diagnosis prenatally (2 years prepartum, until birth) or postnatally (birth, until 18 years postpartum). Further analyses considered cancer types and diagnostic delays. Children were followed until 18 years of age or the first of the following: diagnosis of a mental or behavioural disorder, emigration, death, end of follow-up., Results: During follow-up 79 682 (3.7%) children were diagnosed with mental or behavioural disorders. There was an increased risk among offspring exposed to postnatally diagnosed cancers (HR 1.05; 95% CI, 1.00-1.11); for prenatally diagnosed cancers HR was 1.07 (0.87-1.31). The strongest associations for disorder types were for prenatal diagnoses with mood/affective disorders (HR 2.45; 1.02-5.89) and postnatal diagnoses with mood/affective disorders (HR 1.43; 1.14-1.79)., Conclusions: The results indicate a link between maternal cancer occurrence during pregnancy or early postnatal life, and mental and behavioural disorders in offspring. This association could be driven by common factors in the two periods, such as psychological stress or genetic factors. No specific foetal programming was identified., (© 2018 John Wiley & Sons, Ltd.)

Background: Placentation is characterized by extensive cell proliferation and neovascularization, which is similar to the processes observed in the development of cancer. Nonetheless, little is known about the relation between abnormal placentation, such as placental abruption, and cancer., Material and Methods: Data on women with placental abruption in a singleton pregnancy between 1971 and 2005 (n = 7804) were collected from the Finnish Hospital Discharge Registry and the Finnish Medical Birth Registry. The cohort was then linked with the Finnish Cancer Registry records until the end of 2013. Standardized incidence ratios (SIRs) were calculated for different cancers by dividing the observed numbers of cancers by those expected. The expected numbers were based on national cancer incidence rates., Results: During follow-up, 597 cancers were found among women with a history of placental abruption. The overall risk of cancer was not increased (SIR 0.95, 95% CI 0.88-1.02). However, the history of placental abruption was associated with an increased risk of lung cancer (SIR 1.51, 95% CI 1.05-2.10) and thyroid cancer (SIR 1.47, 95% CI 1.04-2.02). A decreased risk was found for breast cancer (SIR 0.85, 95% CI 0.75-0.96). The risk of rectal cancer was also decreased, although these numbers were small (SIR 0.49, 95% CI 0.20-1.01)., Conclusions: Overall, the risk of lung cancer was increased, and the risk of breast cancer decreased, in women with a history of placental abruption. These observations can be explained to some extent by risk factors or risk markers for placental abruption. The increased risk of thyroid cancer may be explained by surveillance bias.

We assessed the association of surgically verified endometriosis and risk of non-gynecological cancers according to the type of endometriosis (i.e., ovarian, peritoneal and deep infiltrating endometriosis). All diagnoses of endometriosis combined with relevant procedural codes were identified from the Finnish Hospital Discharge Register 1987-2012. Non-gynecological cancers diagnosed after the endometriosis diagnosis were obtained from the Finnish Cancer Registry. The cohort of 49,933 women with surgically verified endometriosis and the sub-cohorts of ovarian (n = 23,210), peritoneal (n = 20,187), and deep infiltrating (n = 2,372) endometriosis were analyzed separately. The endometriosis cohort contributed 838,685 person-years of follow-up and the Finnish female population served as the reference cohort. The standardized incidence ratio (SIR) and 95% confidence interval (95%CI) was calculated for each cancer separately. The follow-up ended at emigration, death or on the 31st of December 2014. The non-gynecological cancer risk was not increased among women with endometriosis (SIR 1.03, 95%CI 0.98-1.08). Endometriosis was associated with an increased risk of thyroid cancer in the entire cohort (SIR 1.43, 95%CI 1.23-1.64) and in the sub-cohorts of ovarian and peritoneal endometriosis. We found a decreased risk of mouth and pharynx cancer (SIR 0.60, 95%CI 0.41-0.80), and of pancreatic cancer (SIR 0.76, 95%CI 0.58-0.96). The incidence of basal cell carcinoma was elevated in the entire cohort (SIR 1.18, 95%CI 1.10-1.25) and in the sub-cohorts of ovarian and peritoneal endometriosis. In conclusion, women with surgically verified endometriosis have an altered risk of only few non-gynecological cancers., (© 2018 UICC.)