Cancer Risks of Patients with Graves' Disease Who Received Antithyroid Drugs as Initial Treatment: A Nationwide Population-Based Analysis.

Background: Population-based studies that examine the associations between hyperthyroidism and cancer risk have yielded inconsistent results. It remains unclear whether the risks of different cancers increase in patients with Graves' disease (GD) who received antithyroid drugs (ATDs) as initial treatment. We aimed to determine whether cancer risk increases in patients with GD, compared with controls. Methods: This nationwide retrospective cohort study utilized data from the National Health Information Database of South Korea. We included 29,502 patients aged >20 years with GD, who received ATDs as initial treatment, and 57,173 age- and sex-matched controls. The primary outcome was the incidence of various types of cancers. Hazard ratios (HRs) with confidence intervals (CIs) for cancer risk were estimated using Cox proportional hazards models. We also analyzed HR by follow-up period since the diagnosis of GD, accounting for surveillance effect. Results: The risk of biliary tract and pancreatic cancers (HR: 1.41, CI: 1.24-1.60), thyroid cancer (HR: 15.51, CI: 12.29-19.57), prostate cancer (HR: 1.48, CI: 1.28-1.71), and ovarian cancer (HR: 1.31, CI: 1.13-1.52) was elevated in the GD group than in the control group even after the first year of follow-up was excluded. The increased risk of these cancers persisted after a follow-up period of more than 5 years. The risk of thyroid cancer in patients with GD was higher during the initial follow-up period (1 to <2 years) (HR: 19.35, CI: 7.66-48.87) compared with that in the follow-up period exceeding 2 years. The cancer risk estimates remained significant after excluding patients with GD who underwent subsequent radioactive iodine therapy. Conclusion: In this large-scale population-based study, GD was associated with increased risks of biliary tract and pancreatic, prostate, ovarian, and thyroid cancers. The increased risk of thyroid cancer, particularly during the initial follow-up period, may be a surveillance effect.

Macrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review.

Primary central nervous system (CNS) tumors affect tens of thousands of patients each year, and there is a significant need for new treatments. Macrophage migration inhibitory factor (MIF) is a cytokine implicated in multiple tumorigenic processes such as cell proliferation, vascularization, and immune evasion and is therefore a promising therapeutic target in primary CNS tumors. There are several MIF-directed treatments available, including small-molecule inhibitors, peptide drugs, and monoclonal antibodies. However, only a small number of these drugs have been tested in preclinical models of primary CNS tumors, and even fewer have been studied in patients. Moreover, the brain has unique therapeutic requirements that further make effective targeting challenging. In this review, we summarize the latest functions of MIF in primary CNS tumor initiation and progression. We also discuss advances in MIF therapeutic development and ongoing preclinical studies and clinical trials. Finally, we discuss potential future MIF therapies and the strategies required for successful clinical translation.

Comprehensive analysis of nationwide anticancer drug-related complications in Korea: incidence, types, and cancer-specific considerations in contemporary oncology.

Background: The rising global incidence of cancer has increased the demand for chemotherapy, which is a crucial treatment modality. Recent advancements in cancer treatment, including targeted agents and immunotherapy, have introduced complications owing to their specific mechanisms. However, comprehensive studies of the combined complications of these approaches are lacking. Objectives: This study aimed to comprehensively assess and analyze the overall incidence of anticancer drug-related complications in a nationwide patient cohort, utilizing a customized National Health Insurance Sharing Service database in Korea. Design: Retrospective cohort study. Methods: We included patients who were prescribed anticancer drugs (excluding endocrine agents) and diagnosed with cancer. For the type of cancer classification, the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) was used and anticancer drugs were classified based on the Anatomical Therapeutic Chemical code. We classified cancer into 18 types based on the ICD-10 code and delineated cancer-related complications into 12 categories. Complications included hematological, gastrointestinal, infectious, cardiovascular, major bleeding, endocrine, neurotoxic, nephrotoxic, dermatological, pulmonary, musculoskeletal, and hepatotoxic effects. Result: We included 294,544 patients diagnosed with cancer and administered anticancer drugs between 2016 and 2018, with follow-up continuing until 2021. We identified 486,929 anticancer drug-related complications, with an incidence of 1843.6 per 1000 person-years (PY). Anemia was the most common complication, with a rate of 763.7 per 1000 PY, followed by febrile neutropenia (295.7) and nausea/vomiting (246.9). Several complications peaked during the first months following the initiation of anticancer drug therapy; however, herpes, skin infection, heart failure, and peripheral neuropathy peaked at 6-12 months. Among major cancers, breast cancer had the lowest overall incidence of complications. Targeted therapies revealed lower complication rates than cytotoxic chemotherapy; however, they also required careful monitoring of rash. Conclusion: This study highlights the importance of the proactive management of anticancer drug-related complications for patient care improvement.

Sex-dependent niche responses modulate steady-state and regenerative hematopoiesis.

Hematopoietic stem cells (HSCs) adapt to organismal blood production needs by balancing self-renewal and differentiation, adjusting to physiological demands and external stimuli. Although sex differences have been implicated in differential hematopoietic function in males versus females, the mediators responsible for these effects require further study. Here, we characterized hematopoiesis at a steady state and during regeneration following hematopoietic stem cell transplantation (HST). RNA sequencing of lineage(-) bone marrow cells from C57/Bl6 mice revealed a broad transcriptional similarity between the sexes. However, we identified distinct sex differences in key biological pathways, with female cells showing reduced expression of signatures involved in inflammation and enrichment of genes related to glycolysis, hypoxia, and cell cycle regulation, suggesting a more quiescent and less inflammatory profile compared with male cells. To determine the functional impacts of the observed transcriptomic differences, we performed sex-matched and mismatched transplantation studies of lineage(-) donor cells. During short-term 56-day HST recovery, we found a male donor cell proliferative advantage, coinciding with elevated serum TNF-α, and a male recipient engraftment advantage, coinciding with increased serum CXCL12. Together, we show that sex-specific cell responses, marked by differing expression of pathways regulating metabolism, hypoxia, and inflammation, shape normal and regenerative hematopoiesis, with implications for the clinical understanding of hematopoietic function.

Androgen loss weakens anti-tumor immunity and accelerates brain tumor growth.

Many cancers, including glioblastoma (GBM), have a male-biased sex difference in incidence and outcome. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further amplified by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity. Here, we show that androgens drive anti-tumor immunity in brain tumors, in contrast to its effect in other tumor types. Upon castration, tumor growth was accelerated with attenuated T cell function in GBM and brain tumor models, but the opposite was observed when tumors were located outside the brain. Activity of the hypothalamus-pituitary-adrenal gland (HPA) axis was increased in castrated mice, particularly in those with brain tumors. Blockade of glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that the effect of castration was mediated by elevated glucocorticoid signaling. Furthermore, this mechanism was not GBM specific, but brain specific, as hyperactivation of the HPA axis was observed with intracranial implantation of non-GBM tumors in the brain. Together, our findings establish that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.

Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications.

Sex differences are present across multiple non-reproductive organ cancers, with male individuals generally experiencing higher incidence of cancer with poorer outcomes. Although some mechanisms underlying these differences are emerging, the immunological basis is not well understood. Observations from clinical trials also suggest a sex bias in conventional immunotherapies with male individuals experiencing a more favourable response and female individuals experiencing more severe adverse events to immune checkpoint blockade. In this Perspective article, we summarize the major biological hallmarks underlying sex bias in immuno-oncology. We focus on signalling from sex hormones and chromosome-encoded gene products, along with sex hormone-independent and chromosome-independent epigenetic mechanisms in tumour and immune cells such as myeloid cells and T cells. Finally, we highlight opportunities for future studies on sex differences that integrate sex hormones and chromosomes and other emerging cancer hallmarks such as ageing and the microbiome to provide a more comprehensive view of how sex differences underlie the response in cancer that can be leveraged for more effective immuno-oncology approaches.

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma.

Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown. Methods: We leveraged previously published paired miRNA and mRNA sequencing of 39 GBM patients (22 male, 17 female) to identify sex-biased miRNAs. We further interrogated a separate single-cell RNA sequencing dataset of 110 GBM patients to examine whether differences in miRNA target gene expression were tumor cell intrinsic or tumor cell extrinsic. Results were validated in a panel of patient-derived cell models. Results: We identified 10 sex-biased miRNAs (adjusted < 0.1), of which 3 were more highly expressed in males and 7 more highly expressed in females. Of these, miR-644a was higher in females, and increased expression of miR-644a target genes was significantly associated with decreased overall survival (HR 1.3, p = 0.02). Furthermore, analysis of an independent single-cell RNA sequencing dataset confirmed sex-specific expression of miR-644a target genes in tumor cells (p < 10-15). Among patient derived models, miR-644a was expressed a median of 4.8-fold higher in females compared to males. Conclusions: Our findings implicate miR-644a as a candidate tumor cell-intrinsic regulator of sex-biased gene expression in GBM.

Development of a multidisciplinary medication management program in nursing homes: protocol for a randomized controlled trial : Multidisciplinary medication management in nursing homes.

BACKGROUND: Polypharmacy and the use of potentially inappropriate medications are common among nursing home residents and are associated with negative outcomes. Although deprescribing has been proposed as a way to curtail these problems, the best way to implement multidisciplinary comprehensive medication review and deprescribing and its real impact in specific high-risk populations, such as nursing home residents, is still unclear. This multicenter randomized controlled clinical trial aims to assess the effects of a multidisciplinary mediation management program on medication use and health problems. METHODS: A total of 1,672 residents aged ≥ 65 years from 22 nursing homes in South Korea who meet the targeted criteria, such as the use of ≥ 10 medications, are eligible to participate. The experimental group will receive a comprehensive medication review, deprescription, and multidisciplinary case conference with the help of platform. Outcomes will be measured at baseline, at the end of the intervention, as well as at 3, 6, 9, and 12 months after the end of the intervention. The primary endpoints will be the rate of adverse drug events, number of potentially inappropriate medications/potentially inappropriate medication users/two or more central nervous system drug/ central nervous system drug users, delirium, emergency department visits, hospitalization, and falls. The secondary endpoint will be the number of medications taken and polypharmacy users. DISCUSSION: Our trial design is unique in that it aims to introduce a structured operationalized clinical program focused on reducing polypharmacy and potentially inappropriate medications in a nursing home setting with large samples. TRIAL REGISTRATION: Ethical approval was granted by the public institutional review board of the Ministry of Health and Welfare (2022-1092-009). The study is also registered with the Clinical Research Information Service (Identifier: KCT0008157, Development and evaluation of a multidisciplinary medication management program in long-term care facility residents Status: Approved First Submitted Date: 2023/01/18 Registered Date: 2023/02/03 Last Updated Date: 2023/01/18 (nih.go.kr) https://cris.nih.go.kr/ ), which includes all items from the World Health Organization Trial Registration Dataset.

Real-world incidence and risk factors of bortezomib-related cardiovascular adverse events in patients with multiple myeloma.

BACKGROUND: Although most studies on the cardiovascular toxicity of proteasome inhibitors have focused on carfilzomib, the risk of cardiotoxicity associated with bortezomib remains controversial. This study aimed to evaluate the incidence and risk factors of cardiovascular adverse events (CVAEs) associated with bortezomib in patients with multiple myeloma in a real-world setting. METHODS: This cross-sectional study included patients who were treated with bortezomib at a tertiary hospital in South Korea. CVAEs, defined as hypertension, arrhythmia, heart failure, myocardial infarction, pulmonary arterial hypertension, angina, and venous thromboembolism, were detected using cardiac markers, ECG, echocardiography, medications, or documentation by clinicians. The patients were observed for at least 6 months and up to 2 years after starting bortezomib administration. RESULTS: Among the 395 patients, 20.8% experienced CVAEs of any grade, and 14.7% experienced severe adverse events. The median onset time for any CVAE was 101.5 days (IQR, 42-182 days), and new-onset/worsened hypertension was the most prevalent CVAE. The risk of CVAEs increased in patients with a body mass index lower than 18.5 (adjusted HR (aHR) 3.50, 95% confidence interval (CI) 1.05-11.72), light chain (1.80, 1.04-3.13), and IgD (4.63, 1.06-20.20) as the multiple myeloma subtype, baseline stroke (4.52, 1.59-12.80), and hypertension (1.99, 1.23-3.23). However, CVAEs did not significantly affect the 2-year overall survival and progression-free survival. CONCLUSION: Approximately 15% of the Korean patients treated with bortezomib experienced severe CVAEs. Thus, patients, especially those with identified risk factors, should be closely monitored for CVAE symptoms during bortezomib treatment.

Inconsistency in steroid use as antiemetics in clinical trial protocols involving immune checkpoint inhibitors combined with chemotherapy.

OBJECTIVES: This study aims to investigate the use of steroids as antiemetics in clinical trials involving immune checkpoint inhibitors with chemotherapy. METHODS: Focusing on phase III trials registered before August 2023, it evaluated the consistency of steroid use guidelines. RESULTS: Out of 3452 trials screened, 44 were selected for in-depth review. The findings indicate a considerable variation: 13 trials did not specify the use of antiemetics, while 31 provided criteria for antiemetics, with 13 conforming to local standards, six to international guidelines, and five allowing either. Seven trials recommended effective antiemetics without detailed criteria. This inconsistency led to a range of steroid dosages, with only 11 trials advocating for minimizing or avoiding steroids for antiemetic purposes. CONCLUSION: The research highlights the lack of uniformity in antiemetic steroid use in trials, reflecting diverse clinical practices and underscoring the need for further research to understand the implications on treatment outcomes.

Development of a claims-based risk-scoring model to predict emergency department visits in older patients receiving anti-neoplastic therapy.

This study developed and validated a risk-scoring model, with a particular emphasis on medication-related factors, to predict emergency department (ED) visits among older Korean adults (aged 65 and older) undergoing anti-neoplastic therapy. Utilizing national claims data, we constructed two cohorts: the development cohort (2016-2018) with 34,642 patients and validation cohort (2019) with 10,902 patients. The model included a comprehensive set of predictors: demographics, cancer type, comorbid conditions, ED visit history, and medication use variables. We employed the least absolute shrinkage and selection operator (LASSO) regression to refine and select the most relevant predictors. Out of 120 predictor variables, 12 were integral to the final model, including seven related to medication use. The model demonstrated acceptable predictive performance in the validation cohort with a C-statistic of 0.76 (95% CI 0.74-0.77), indicating reasonable calibration. This risk-scoring model, after further clinical validation, has the potential to assist healthcare providers in the effective management and care of older patients receiving anti-neoplastic therapy.

Contemporary Patterns and Underlying Causes of Vitrectomy in Pediatric and Adolescent Patients: A Nationwide, Population-Based Analysis.

PURPOSE: We determined the incidence, etiology, and longitudinal trends of vitreoretinal diseases necessitating pars plana vitrectomy (PPV) in the pediatric and adolescent population. DESIGN: Nationwide, population-based cohort study. METHODS: This study utilized data extracted from the Korean National Health Claims database spanning from 2009 to 2020. All pediatric and adolescent patients (under 20 years of age) who underwent PPV across the Korean population were included. The cumulative incidence of PPV was estimated from 2009 to 2020, with 2009 to 2011 as the washout period. The annual trends of PPV incidence, the proportion of each etiology, and comorbidity were estimated based on sex and specific age groups. RESULTS: In total, 1913 patients, including 83 infants, 746 pediatric patients, and 1084 adolescents, were newly identified as having undergone PPV surgery. The cumulative incidence of PPV surgery per 100,000 individuals was 21.42 (95% CI, 21.41-21.43). The rate of PPV was 2.4 times higher for males than females, and the rate of trauma as a comorbidity was also higher for males than females (13.1% vs 4.8%). Among males aged 5 years and older, the incidence of PPV nearly halved from 2011 to 2020. Among the primary etiologies, ROP had the highest rate (72%) in infants (under 1 year), while RD was most common (63%) in individuals aged 5 to 19 years. Myopia was present in 30.3% of patients, and atopic dermatitis was present in 31.8% of all patients. CONCLUSION: The primary etiologies underlying the need for PPV in the pediatric and adolescent populations vary by sex and age group. The incidence of PPV continues to decline in the adolescent population. Therefore, tailored patient education and age-specific etiological examination are recommended.

Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses.

Background: Glioblastoma (GBM) displays alterations in iron that drive proliferation and tumor growth. Iron regulation is complex and involves many regulatory mechanisms, including the homeostatic iron regulator (HFE) gene, which encodes the homeostatic iron regulatory protein. While HFE is upregulated in GBM and correlates with poor survival outcomes, the function of HFE in GBM remains unclear. Methods: We interrogated the impact of cell-intrinsic Hfe expression on proliferation and survival of intracranially implanted animals through genetic gain- and loss-of-function approaches in syngeneic mouse glioma models, along with in vivo immune assessments. We also determined the expression of iron-associated genes and their relationship to survival in GBM using public data sets and used transcriptional profiling to identify differentially expressed pathways in control compared to Hfe-knockdown cells. Results: Overexpression of Hfe accelerated GBM proliferation and reduced animal survival, whereas suppression of Hfe induced apoptotic cell death and extended survival, which was more pronounced in females and associated with attenuation of natural killer cells and CD8+ T cell activity. Analysis of iron gene signatures in Hfe-knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Further analysis of differentially expressed pathways revealed oxidative stress as the top pathway upregulated following Hfe loss. Hfe knockdown indeed resulted in enhanced 55Fe uptake and generation of reactive oxygen species. Conclusions: These findings reveal an essential function for HFE in GBM cell growth and survival, as well as a sex-specific interaction with the immune response.

Increased Risk of Optic Neuritis in Patients With Fibromyalgia: Nationwide Population-Based Cohort Study in South Korea.

PURPOSE: To estimate the risk of incidence of optic neuritis and identify the high-risk group among patients with fibromyalgia (FM). DESIGN: Population-based cohort study. METHODS: A nationwide, population-based study was conducted using data from the Korean National Health Claims database from 2012 to 2021. This study included all the patients with FM from the entire South Korean population aged 20-79 years (FM group). Moreover, those with pain but not diagnosed with FM were considered as the non-FM group. A cohort was established by classifying it into the FM and non-FM groups during the recruitment period. A log-rank analysis was used to compare the risk of optic neuritis incidence between the FM group and non-FM group. Cox proportional hazards regression analysis was performed to calculate the adjusted hazard ratio (HR). The cohort was analyzed by stratifying according to age and sex. RESULTS: The FM and non-FM groups included 479,892 and 479,892 participants, respectively. The incidence rate of optic neuritis was 35.65/100,000 person-years in the FM group; the HR was significantly higher in the FM group than in the non-FM group (HR 2.11, 95% CI 1.84-2.41; P < .001). The mean interval between the onset of FM and incident optic neuritis was 2.4 ± 1.8 years. The risk increased significantly in men aged 60-79 years (HR 3.37, 95% CI 2.54-4.48) and in women aged 20-39 years (HR 2.07, 95% CI 1.38-3.22). CONCLUSION: We quantified the risk of optic neuritis through a long-term follow-up, which could contribute to understanding the pathophysiology and estimating the general health care burden associated with FM in a practical setting. Great attention should be paid to its risk in older men and younger women.

Consultation-Based Deprescribing Service to Optimize Palliative Care for Terminal Cancer Patients.

(1) Background: A pharmacist-led deprescribing service previously developed within the Consultation-Based Palliative Care Team (CB-PCT) was implemented for terminal cancer patients. (2) Objective: To evaluate the clinical outcomes of the developed deprescribing service for terminal cancer patients in CB-PCT. (3) Methods: A retrospective analysis compared the active care (AC) group to the historical usual care (UC) group. The clinical outcomes included the deprescribing rate of preventive medications, the proportion of patients with one or more medication-related problems (MRPs) resolved upon discharge, and the clinical significance. The implementability of the service was also gauged by the acceptance rates of pharmacists' interventions. (4) Results: Preventive medications included lipid-lowering agents, gastroprotective agents, vitamins, antihypertensives, and antidiabetic agents. The AC group revealed a higher deprescribing rate (10.4% in the UC group vs. 29.6% in the AC group, p < 0.001). At discharge, more AC patients had one or more MRPs deprescribed (39.7% vs. 2.97% in UC, p < 0.001). The clinical significance consistently had a very significant rating (mean score of 2.96 out of 4). Acceptance rates were notably higher in the AC group (30.0% vs. 78.0%. p = 0.003). (5) Conclusions: The collaborative deprescribing service in CB-PCT effectively identified and deprescribed MRPs that are clinically significant and implementable in practice.

Machine learning-based prediction model for emergency department visits using prescription information in community-dwelling non-cancer older adults.

Older adults are more likely to require emergency department (ED) visits than others, which might be attributed to their medication use. Being able to predict the likelihood of an ED visit using prescription information and readily available data would be useful for primary care. This study aimed to predict the likelihood of ED visits using extensive medication variables generated according to explicit clinical criteria for elderly people and high-risk medication categories by applying machine learning (ML) methods. Patients aged ≥ 65 years were included, and ED visits were predicted with 146 variables, including demographic and comprehensive medication-related factors, using nationwide claims data. Among the eight ML models, the final model was developed using LightGBM, which showed the best performance. The final model incorporated 93 predictors, including six sociodemographic, 28 comorbidity, and 59 medication-related variables. The final model had an area under the receiver operating characteristic curve of 0.689 in the validation cohort. Approximately half of the top 20 strong predictors were medication-related variables. Here, an ED visit risk prediction model for older people was developed and validated using administrative data that can be easily applied in clinical settings to screen patients who are likely to visit an ED.

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.

The one-two punch: TIM-3 blockade targets immune and tumor cells to knock out pediatric brain tumors.

Diffuse midline gliomas (DMGs) pose treatment challenges due to their location within the brainstem and invasive nature. Although classical immune checkpoint inhibitors have demonstrated limited success in clinical trials, Ausejo-Mauleon et al. demonstrate TIM-3 is an effective DMG strategy, targeting both immune and tumor cells for dual therapeutic benefit.

Let the Guard Down: cAMP Activators Can Improve Immunotherapy in GBM.

Enhancing T-cell infiltration into glioblastoma (GBM) tumors has proven challenging yet remains crucial for improving the efficacy of immunotherapy for patients with this deadly cancer. In this issue, Qin, Huang, Li, and colleagues find that inhibiting vasculature formation driven by cancer stem cells is a promising target to enhance immunotherapy in GBM. See related article by Qin, Huang, Li, et al., p. 1351 (2).