Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs.

BACKGROUND: Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known. METHODS: A typical von Hippel-Lindau tumor suppressor (VHL)-PROTAC 14C-A947 (BRM degrader)-was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing. Bile duct-cannulated (BDC) rats allowed the elucidation of in vivo clearance pathways. Distribution kinetics was evaluated in the tissues and tumors of mice to support PK-PD correlation. In vitro studies enabled the evaluation of cell uptake mechanisms and cell retention properties. RESULTS: Here, we show that A947 quickly distributes into rat tissues after IV dosing, where it accumulates and is retained in tissues such as the lung and liver although it undergoes fast clearance from circulation. Similar uptake/retention kinetics enable tumor growth inhibition over 2-3 weeks in a lung cancer model. A947 quickly excretes in the bile of rats. Solute carrier (SLC) transporters are involved in hepatocyte uptake of PROTACs. Sustained BRM protein degradation is seen after extensive washout that supports prolonged cell retention of A947 in NCI-H1944 cells. A947 tissue exposure and pharmacodynamics are inversely correlated in tumors. CONCLUSIONS: Plasma sampling for VHL-PROTAC does not represent the tissue concentrations necessary for efficacy. Understanding of tissue uptake and retention could enable less frequent IV administration to be used for therapeutic dosing.

Proteolysis-targeting chimeras (PROTACs) are a type of potential cancer medicine designed to target proteins primarily present in tumours. There is limited data on how it is absorbed, distributed, metabolised and excreted from tissues. Here, we studied the tissue distribution of synthetic PROTAC molecules labelled with radioactivity following intravenous injection in rodent models. We find that PROTAC can rapidly distribute to target tumour tissues and its prolonged retention within the tumour cells can contribute to prevention of further tumour growth, as demonstrated in the lung cancer model. These findings suggest the evaluation of PROTAC therapeutic effectiveness directly from tumour tissues provides more relevant assessment than sampling from blood circulation, which may have implications for a reduction in intravenous dosing.

TCL1A-expressing B cells are critical for tertiary lymphoid structure formation and the prognosis of oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a malignant tumor with a poor prognosis. Traditional treatments have limited effectiveness. Regulation of the immune response represents a promising new approach for OSCC treatment. B cells are among the most abundant immune cells in OSCC. However, the role of B cells in OSCC treatment has not been fully elucidated. METHODS: Single-cell RNA sequencing analysis of 13 tissues and 8 adjacent normal tissues from OSCC patients was performed to explore differences in B-cell gene expression between OSCC tissues and normal tissues. We further investigated the relationship between differentially expressed genes and the immune response to OSCC. We utilized tissue microarray data for 146 OSCC clinical samples and RNA sequencing data of 359 OSCC samples from The Cancer Genome Atlas (TCGA) to investigate the role of T-cell leukemia 1 A (TCL1A) in OSCC prognosis. Multiplex immunohistochemistry (mIHC) was employed to investigate the spatial distribution of TCL1A in OSCC tissues. We then investigated the effect of TCL1A on B-cell proliferation and trogocytosis. Finally, lentiviral transduction was performed to induce TCL1A overexpression in B lymphoblastoid cell lines (BLCLs) to verify the function of TCL1A. RESULTS: Our findings revealed that TCL1A was predominantly expressed in B cells and was associated with a better prognosis in OSCC patients. Additionally, we found that TCL1A-expressing B cells are located at the periphery of lymphatic follicles and are associated with tertiary lymphoid structures (TLS) formation in OSCC. Mechanistically, upregulation of TCL1A promoted the trogocytosis of B cells on dendritic cells by mediating the upregulation of CR2, thereby improving antigen-presenting ability. Moreover, the upregulation of TCL1A expression promoted the proliferation of B cells. CONCLUSION: This study revealed the role of B-cell TCL1A expression in TLS formation and its effect on OSCC prognosis. These findings highlight TCL1A as a novel target for OSCC immunotherapy.

Connecting Clinical Capacity and Intervention Sustainability in Resource-Variable Pediatric Oncology Centers in Latin America.

Clinical capacity for sustainability, or the clinical resources needed to sustain an evidence-based practice, represent proximal determinants that contribute to intervention sustainment. We examine the relationship between clinical capacity for sustainability and sustainment of PEWS, an evidence-based intervention to improve outcomes for pediatric oncology patients in resource-variable hospitals. We conducted a cross-sectional survey among Latin American pediatric oncology centers participating in Proyecto Escala de Valoración de Alerta Temprana (EVAT), an improvement collaborative to implement Pediatric Early Warning Systems (PEWS). Hospitals were eligible if they had completed PEWS implementation. Clinicians were eligible to participate if they were involved in PEWS implementation or used PEWS in clinical work. The Spanish language survey consisted of 56 close and open-ended questions about the respondent, hospital, participants' assessment of clinical capacity to sustain PEWS using the clinical sustainability assessment tool (CSAT), and perceptions about PEWS and its use as an intervention. Results were analyzed using a multi-level modeling approach to examine the relationship between individual, hospital, intervention, and clinical capacity determinants to PEWS sustainment. A total of 797 responses from 37 centers in 13 countries were included in the analysis. Eighty-seven percent of participants reported PEWS sustainment. After controlling for individual, hospital, and intervention factors, clinical capacity was significantly associated with PEWS sustainment (OR 3.27, p < .01). Marginal effects from the final model indicate that an increasing capacity score has a positive influence (11% for every additional CSAT point) of predicting PEWS sustainment. PEWS is a sustainable intervention and clinical capacity to sustain PEWS contributes meaningfully to PEWS sustainment.

The Xanthine Derivative KMUP-1 Inhibits Hypoxia-Induced TRPC1 Expression and Store-Operated Ca2+ Entry in Pulmonary Arterial Smooth Muscle Cells.

Exposure to hypoxia results in the development of pulmonary arterial hypertension (PAH). An increase in the intracellular Ca2+ concentration ([Ca2+]i) in pulmonary artery smooth muscle cells (PASMCs) is a major trigger for pulmonary vasoconstriction and proliferation. This study investigated the mechanism by which KMUP-1, a xanthine derivative with phosphodiesterase inhibitory activity, inhibits hypoxia-induced canonical transient receptor potential channel 1 (TRPC1) protein overexpression and regulates [Ca2+]i through store-operated calcium channels (SOCs). Ex vivo PASMCs were cultured from Sprague-Dawley rats in a modular incubator chamber under 1% O2/5% CO2 for 24 h to elucidate TRPC1 overexpression and observe the Ca2+ release and entry. KMUP-1 (1 µM) inhibited hypoxia-induced TRPC family protein encoded for SOC overexpression, particularly TRPC1. KMUP-1 inhibition of TRPC1 protein was restored by the protein kinase G (PKG) inhibitor KT5823 (1 µM) and the protein kinase A (PKA) inhibitor KT5720 (1 µM). KMUP-1 attenuated protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA, 1 µM)-upregulated TRPC1. We suggest that the effects of KMUP-1 on TRPC1 might involve activating the cyclic guanosine monophosphate (cGMP)/PKG and cyclic adenosine monophosphate (cAMP)/PKA pathways and inhibiting the PKC pathway. We also used Fura 2-acetoxymethyl ester (Fura 2-AM, 5 µM) to measure the stored calcium release from the sarcoplasmic reticulum (SR) and calcium entry through SOCs in hypoxic PASMCs under treatment with thapsigargin (1 µM) and nifedipine (5 µM). In hypoxic conditions, store-operated calcium entry (SOCE) activity was enhanced in PASMCs, and KMUP-1 diminished this activity. In conclusion, KMUP-1 inhibited the expression of TRPC1 protein and the activity of SOC-mediated Ca2+ entry upon SR Ca2+ depletion in hypoxic PASMCs.

Retinoblastoma Incidence in Taiwan Over a Recent 20-Year Period: A Comprehensive Nationwide Study.

Purpose: Continuous advancements in medical diagnostic technology and the growing availability of resources suggest a potential for fluctuations in the incidence rate of retinoblastoma (Rb). This study aimed to analyze incidence data of Rb patients in Taiwan from 1999 to 2018, utilizing the nationwide Taiwan Cancer Registry (TCR) database. Additionally, we investigated the treatment modalities used for these Rb patients and compared them with those observed in other countries. Patients and Methods: We conducted a retrospective cohort study utilizing data from the TCR database. The study cohort comprised individuals who were newly diagnosed with Rb between 1999 and 2018. The incidence of Rb was calculated as the number of patients with Rb per million live births, both for the entire population and for different gender groups and time periods. The trends in Rb incidence from 1999 to 2018 across various age groups and sexes were presented with the linear trend test. Results: From 1999 to 2018, a total of 248 cases of Rb were identified. The overall incidence rate over this 20-year period was 60.20 cases per million live births, corresponding to 1 case per 16,611 live births. Incidence rates for each 5-year period between 1999 and 2018 exhibited no significant differences. The study cohort was predominantly male, with 134 cases (54.03%) being males and 114 cases (45.97%) being females, resulting in an overall male-to-female sex ratio of 1.18. Females had lower relative risk than males (RR: 0.92, 95% CI: 0.72-1.19). Primary surgical intervention was the preferred treatment modality for over 75% of the cases. Conclusion: This retrospective epidemiology study, using TCR from 1999 to 2018, indicated that no discernible trend of retinoblastoma incidence in Taiwan. Nevertheless, continuous monitoring of incidence rates and exploration of treatment strategies for retinoblastoma within the Taiwanese population are important to address potential changes in developing medical practices.

Global prevalence and risk factors of emergence delirium in pediatric patients undergoing general anesthesia: A systemic review and meta-analysis.

PROBLEM: Emergence delirium (ED) in children post-general anesthesia has been persistently underestimated, impacting the well-being of children, nurses, and even parents. This study employs integrated analysis to establish a comprehensive understanding of ED, including its occurrence and related risk factors, emphasizing the imperative for enhanced awareness and comprehension among pediatric nursing care providers. ELIGIBILITY CRITERIA: A systematic review and meta-analysis were conducted using four electronic databases, namely PubMed, CINAHL via EBSCOhost, Embase via Elsevier, and ProQuest Dissertations and Theses. RESULTS: This meta-analysis included 16 studies involving 9598 children who underwent general anesthesia. The pooled prevalence of ED was 19.2% (95% confidence interval [CI] = 0.12 to 0.29), with younger patients exhibiting a higher prevalence of ED. ED research is scant in Africa and is mostly limited to the Asia Pacific region and Northern Europe. Neck and head surgery (odds ratio [OR] = 2.34, 95% CI = 1.29 to 4.27) were significantly associated with ED risk. CONCLUSIONS: ED should be monitored in children who receive general anesthesia. In this study, ED had a prevalence rate of 19.2%, and head and neck surgery were significantly associated with ED risk. Therefore, healthcare professionals should carefully manage and prevent ED in children undergoing general anesthesia. IMPLICATIONS: A comprehensive understanding of ED's prevalence and risk factors is crucial for enhancing nursing care. Adopting a family-centered care approach can empower parents with information to collaboratively care for their children, promoting a holistic approach to pediatric healthcare.

Patterns and trends of mortality from metastatic colorectal cancer in Shanghai, China from 2005 to 2021: a population-based retrospective analysis.

PURPOSE: Metastatic colorectal cancer (mCRC) is the leading cause of CRC deaths, however, the relative epidemiological research was insufficient. We aimed to analyze the patterns and trends of mortality of mCRC in Shanghai with a more complete system for monitoring the cause of death of the population and find potential methods to reduce the burden of CRC in China. METHODS: Mortality data from 2005 to 2021 of mCRC deaths were obtained from the mortality registration system in Shanghai. We analyzed the crude mortality rates, age-standardized mortality rates, and rates of years of life lost (YLL rates) of mCRC. In addition, the trends were quantified using Joinpoint Regression software. RESULTS: A total of 4,386 mCRC deaths were included, with 1,937 (44.16%) liver metastases and 1,061 (24.19%) lung metastases. The crude mortality rate and age-standardized mortality rate of mCRC were 9.09 per 105 person-years and 3.78 per 105 person-years, respectively. The YLL was 50,533.13 years, and the YLL rate was 104.67 per 105 person-years. The overall annual crude mortality rate of mCRC increased by 1.47% (95% CI 0.28-2.68%, P < 0.001) from 2005 to 2021. The crude mortality rate of mCRC increased by 3.20% per year (95% CI 1.80-4.70%, P < 0.001) from 2005 to 2013, but the trend of mortality growth remained stable from 2013 to 2021. The YLL rates remained stable between 2005 and 2021. CONCLUSIONS: Population aging was the most likely factor responsible for the increase in CRC mortality in Pudong. Physical examinations and screenings for the elderly were possible reasons for reducing the burden of CRC in fast-growing regions.

Comparative survival analysis of bladder preservation therapy versus radical cystectomy in muscle-invasive bladder cancer.

BACKGROUND: Bladder preservation therapy is an alternative to radical cystectomy in patients with muscle-invasive bladder cancer (MIBC). The purpose of this study is to compare survival outcomes between bladder preservation therapy and radical cystectomy in MIBC patients using an Asian nationwide cancer registry database. METHODS: From the Taiwan Cancer Registry database and the Taiwan National Health Insurance Research Database, we identified bladder cancer patients from 2008 to 2018. The patients with urothelial carcinoma and clinical stage T2-T4aN0-1 M0 were included. Propensity score matching by age, gender, clinical stage, cT classification, and Charlson Comorbidity Index score was used between those receiving bladder preservation therapy or radical cystectomy. Overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) were compared using the Kaplan-Meier method. Multivariate Cox regression models were used to determine the predictive factors of OS, CSS, and DFS. RESULTS: Following the propensity score matching, 393 MIBC patients were analyzed, 131 (33.3%) receiving bladder preservation therapy and 262 (66.7%) receiving radical cystectomy. After 5 years of the follow-up period the overall duration was with a median of 15.6 months. The treatment groups did not differ significantly in OS, CSS, and DFS (p = 0.2681, 0.7208, and 0.3616, respectively). In multivariable Cox regression models, bladder preservation therapy remained non-inferior to radical cystectomy in OS (adjusted hazard ratio [aHR] 1.08; 95% confidence interval [CI], 0.77-1.50; p = 0.6689), CSS (aHR, 1.06; 95% CI, 0.72-1.57; p = 0.7728), and DFS (aHR, 0.76; 95% CI, 0.46-1.27; p = 0.2929). Additionally, among patients ≥80 years, the use of bladder preservation therapy compared with radical cystectomy resulted in an equivalent OS, CSS and DSS. CONCLUSION: In Asian populations, bladder preservation therapy yielded similar survival outcomes as radical cystectomy in MIBC patients. Based on the results, it is evident that a multidisciplinary approach and shared decision-making are recommended for bladder cancer treatment.

Comparison of microbial abundance and diversity in uterine and peritoneal fluid in infertile patients with or without endometriosis.

INTRODUCTION: Endometriosis (EM) is a multifactorial disease that affects 10 - 15% of women of reproductive age. Additionally, 30-50% of women with EM suffer from infertility. The mechanism of infertility caused by EM has not yet been consistently explained. In recent years, studies have shown a link between infertility associated with EM and changes in the reproductive tract microbiota. METHODS: In this study, we involved 26 EM patients (8 cases of stage I-II and 18 cases of stage III-IV) and 31 control subjects who were tubal obstruction-related infertility (TORI). The samples from peritoneal fluid (PF) and uterine fluid (UF) were collected and sequenced by 16 S rRNA amplicon. RESULTS: In the comparison of microbial diversity, we found no significant differences in the microbial diversity of PF and UF between patients with stage I-II EM and those with TORI. However, there was a significant difference in microbial diversity among patients with stage III-IV EM compared to the previous two groups. Lactobacillus decreased in PF of EM compared to the control group, while it increased in UF. In PF, the abundance of Pseudomonas, Enterococcus, Dubosiella and Klebsiella was significantly higher in patients with stage III-IV compared to TORI patients. And in UF, the main differences existed between stage I-II EM compared to the other two groups. The abundance of pontibacter, aquabacterium, Rikenellaceae and so on at the genus level was significantly enriched in the EM patients with stage I-II. In the analysis based on KEGG database, EM may affect the receptivity related pathways of the endometrium by influencing changes in the uterine microbiota. CONCLUSION: Our results indicated that as EM progresses, the microorganisms in UF and PF keep changing. These changes in the microbiota, as well as the resulting alternations in gene functional classification, may play an important role in the infertility associated with EM.

An alleviative effect of Lonicerae japonicae flos water extract against liver fibrogenesis in vitro and in vivo.

Lonicerae japonicae (L. japonicae) flos is a medical and food homology herb. This study investigated the phenolic acid and flavonoid contents in L. japonicae flos water extract solution (LJWES) and the preventive effects of LJWES against liver fibrogenesis via FL83B cells and rats. LJWES contains many polyphenols, such as chlorogenic acid, morin, and epicatechin. LJWES increased cell viability and decreased cytotoxicity in thioacetamide (TAA)-treated FL83B cells (75 mM) (p < .05). LJWES decreased (p < .05) gene expressions of Tnf-α, Tnfr1, Bax, and cytochrome c but upregulated Bcl-2 and Bcl-xl in TAA-treated cells; meanwhile, increased protein levels of P53, cleaved caspase 3, and cleaved caspase 9 in TAA treated cells were downregulated (p < .05) by LJWES supplementation. In vivo, results indicated that TAA treatment increased serum liver damage indices (alanine aminotransferase [ALT] and alkaline phosphatase [ALP]) and cytokines (interleukin-6 and transforming growth factor-ß1) levels and impaired liver antioxidant capacities (increased thiobarbituric acid reactive substance value but decreased catalase/glutathione peroxidase activities) in rats (p < .05) while LJWES supplementation amended (p < .05) them. Liver fibrosis scores, collagen deposition, and alpha-smooth muscle actin deposition in TAA-treated rats were also decreased by LJWES supplementation (p < .05). To sum up, LJWES could be a potential hepatoprotective agent against liver fibrogenesis by enhancing antioxidant ability, downregulating inflammation in livers, and reducing apoptosis in hepatocytes.

Unplanned Emergency Department Visits Following Revision Total Joint Arthroplasty: Incidences, Risk Factors, and Mortalities.

BACKGROUND: The incidence of unplanned emergency department (ED) visits following revision total joint arthroplasty is an indicator of the quality of postoperative care. The aim of this study was to investigate the incidences, timings, and characteristics of ED visits within 90 days after revision total joint arthroplasty. METHODS: A retrospective review of 457 consecutive cases, including 254 revision total hip arthroplasty (rTHA) and 203 revision total knee arthroplasty (rTKA) cases, was conducted. Data regarding patient demographics, timings of the ED encounter, chief complaints, readmissions, and diagnoses indicating reoperation were analyzed. RESULTS: The results showed that 41 patients who had rTHA (16.1%) and 14 patients who had rTKA (6.9%) returned to the ED within 90 days postoperatively. The incidence of ED visits was significantly higher in the rTHA group than in the rTKA group (P = .003). The most common surgery-related complications were dislocation among rTHA patients and wound conditions among rTKA patients. Apart from elevated calculated comorbidity scores, peptic ulcer in rTHA patients and cerebral vascular events and chronic obstructive pulmonary disease in rTKA patients might increase chances of unplanned ED visits. Patients who had ED visits showed significantly higher mortality rates than the others in both rTHA and rTKA cohorts (P = .050 and P = .008, respectively). CONCLUSIONS: The ED visits within 90 days are more common after rTHA than after rTKA. Patients in both ED visit groups after rTHA and rTKA demonstrated worse survival. Efforts should be made to improve quality of care to prevent ED visits.

Treatment of high-risk Hodgkin lymphoma with a modified Stanford V regimen in the AHOPCA: Substituting chemotherapy agents and hampered outcomes.

BACKGROUND/OBJECTIVES: High-risk Hodgkin lymphoma (HRHL) in children is curable with combined modality therapy. The Association of Pediatric Hematology-Oncology of Central America (AHOPCA) is a consortium of cancer centers from Central America. In 2004, AHOPCA implemented a guideline with a short course of chemotherapy (mStanfordV), strict diagnostics, and radiation guidelines, aimed at reducing abandonment and improving outcomes. METHODS: Newly diagnosed children less than 18 years of age with high-risk HL (Ann Arbor stages: IIB, IIIB, IV) from AHOPCA centers were staged with chest radiography and ultrasound or computed tomography. Therapy was a modified Stanford V (mStanfordV), substituting cyclophosphamide for mechlorethamine and involved field radiation. RESULTS: Of 219 patients with HRHL, 181 patients were eligible and evaluable; 146 (81%) were boys, 22% being less than 6 years; 43 were stage IIB, 84 IIIB, and 54 IV. Thirty-one (17%) abandoned therapy, 28 (15%) progressed, 30 (17%) relapsed, and eight (4%) died of toxicity. Radiation guidelines were not followed. Five-year abandonment-sensitive event-free survival and overall survival (AS-EFS, AS-OS ± SE) for the cohort were 46% ± 4% and 56% ± 4%; 5-year AS-OS for stages IIB, IIIB, and IV was 76% ± 7%, 59% ± 7%, and 35% ± 7% (p = .0006). CONCLUSION: Despite instituting a short treatment guideline, it did not improve the abandonment rate (17%) and did not achieve the reported outcomes of Stanford V. The cyclophosphamide dose used to replace merchlorethamine was inadequate. Despite strict guidelines, the radiation therapy application was inaccurate. Weekly chemotherapy may have adversely affected abandonment of therapy by increasing the burden of travel time. Based on these results, AHOPCA established a new abandonment strategy and a new guideline.

A functional chicken-liver hydrolysate-based supplement ameliorates alcohol liver disease via regulation of antioxidation, anti-inflammation, and antiapoptosis.

Tons of broiler livers are produced yearly in Taiwan but always considered waste. Our team has successfully patented and characterized a chicken-liver hydrolysate (CLH) with several biofunctions. Chronic alcohol consumption causes hepatosteatosis or even hepatitis, cirrhosis, and cancers. This study was to investigate the hepatoprotection of CLH-based supplement (GBHP01™) against chronic alcohol consumption. Results showed that GBHP01™ could reduce (p < .05) enlarged liver size, lipid accumulation/steatosis scores, and higher serum AST, ALT, γ-GT, triglyceride, and cholesterol levels induced by an alcoholic liquid diet. GBHP01™ reduced liver inflammation and apoptosis in alcoholic liquid-diet-fed mice via decreasing TBARS, interleukin-6, interleukin-1ß, and tumor necrosis factor-α levels, increasing reduced GSH/TEAC levels and activities of SOD, CAT and GPx, as well as downregulating CYP2E1, BAX/BCL2, Cleaved CASPASE-9/Total CASPASE-9 and Active CASPASE-3/Pro-CASPASE-3 (p < .05). Furthermore, GBHP01™ elevated hepatic alcohol metabolism (ADH and ALDH activities) (p < .05). In conclusion, this study prove the hepatoprotection of GBHP01™ against alcohol consumption.

Retrospective analysis of outcomes for pediatric acute lymphoblastic leukemia in South American centers.

Introduction: Acute lymphoblastic Leukemia (ALL) is the most common pediatric malignancy. While the survival rate for childhood ALL exceeds 90% in high-income countries, the estimated survival in low-and middle-income countries ranges from 22-79%, depending on the region and local resources. Methods: This study retrospectively reviewed demographic, biological, and clinical parameters of children under 18 years of age with newly diagnosed ALL presenting between 2013-2017 across five pediatric centers in 4 countries in South America. Survival analyses were estimated using the Kaplan-Meier method. Results: Across the five centers, 752 patients were analyzed (Bolivia [N=9], Ecuador [N=221], Paraguay [N=197], Peru [N=325]) and 92.1% (n=690) patients were diagnosed with B-cell and 7.5% (n= 56) with T-cell ALL. The median age was 5.5 years old (IQR 7.29). At diagnosis, 47.8% of patients were categorized as standard and 51.9% as high risk per their institutional regimen. Advanced diagnostics availability varied between modalities. MRD was evaluated in 69.1% of patients; molecular testing was available for ETV6-RUNX, BCR-ABL1, TCF3-PBX1, and KMT2A-rearranged ALL in 75-81% of patients; however, karyotyping and evaluation for iAMP21 were only performed in 42-61% of patients. Central nervous system (CNS) involvement was evaluated at diagnosis in 57.3% (n=429) patients; of these, 93.7% (n=402) were CNS 1, 1.6% (n=7) were CNS 2, 0.7% (n=11) were CNS3, 1.9% (n=8) had cranial nerve palsy, and 2.1% (n=9) results unavailable. Chemotherapy delays >2 weeks were reported in 56.0% (n=421) patients during treatment. Delays were attributed to infection in 63.2% (n=265), drug-related toxicities in 47.3% (n=198), and resource constraints, including lack of bed availability in 23.2% (n=97) of patients. The 3-year Abandonment-sensitive EFS and OS were 61.0±1.9% and 67.2±1.8%, respectively. The 3-year EFS and OS were 71.0±1.8% and 79.6±1.7%, respectively. Discussion: This work reveals opportunities to improve survival, including addressing severe infections, treatment interruptions, and modifications due to drug shortages. In 2018, healthcare professionals across South America established the Pediatric Oncology Latin America (POLA) group in collaboration with St. Jude Children's Research Hospital. POLA collaborators developed an evidence-based, consensus-derived, adapted treatment guideline, informed by preliminary results of this evaluation, to serve as the new standard of care for pediatric ALL in participating institutions.

Sustainability determinants of an intervention to identify clinical deterioration and improve childhood cancer survival in Latin American hospitals: the INSPIRE study protocol.

BACKGROUND: More than 90% of children with cancer live in low-resourced settings, where survival is only 20%. Sustainable evidence-based (EB) interventions yielding ongoing beneficial patient outcomes are critical to improve childhood cancer survival. A better understanding of factors promoting intervention sustainability in these settings is urgently needed. The aim of this study is to provide an empirical understanding of how clinical capacity for sustainability, or the resources needed to sustain an intervention, impacts the sustainment of Pediatric Early Warning System (PEWS), an EB intervention that improves pediatric oncology outcomes in low-resource hospitals by detecting clinical deterioration and preventing the need for more intense treatment. METHODS: We will conduct a prospective, longitudinal study of approximately 100 resource-variable hospitals implementing and sustaining PEWS participating in Proyecto EVAT, a quality improvement collaborative of Latin American pediatric oncology centers. Aim 1: We will evaluate how clinical capacity for sustainability changes over time through 5 to 9 prospective measurements of capacity via survey of clinical staff using PEWS (approximately n = 13 per center) during the phases of PEWS adoption, implementation, and sustainability using the Clinical Sustainability Assessment Tool (CSAT). Aim 2: We will determine the relationship between capacity and a) PEWS sustainment and b) clinical deterioration mortality among pediatric oncology patients at centers sustaining PEWS for 2 to 10 years using chart review and an existing patient outcomes registry. Aim 3: We will develop novel strategies to promote sustainability by gaining a deeper understanding of perceived challenges to building capacity and PEWS sustainment. In combination with quantitative outcomes, we will conduct 24 focus groups with staff (doctors, nurses, and administrators) from hospitals with both high (n = 4) and low capacity (n = 4). We will then use implementation mapping to generate theoretically driven, empirically-supported sustainability strategies. DISCUSSION: This study will advance implementation science by providing a theoretically driven, foundational understanding of factors that predict sustainability among a large, diverse cohort of hospitals. We will then use this knowledge to develop sustainability evidence-informed strategies that optimize capacity and promote long-term sustainment of PEWS and improvements in patient outcomes, thus promoting equity in childhood cancer care globally.

Evaluation of factors leading to poor outcomes for pediatric acute lymphoblastic leukemia in Mexico: a multi-institutional report of 2,116 patients.

Background and aims: Pediatric acute lymphoblastic leukemia (ALL) survival rates in low- and middle-income countries are lower due to deficiencies in multilevel factors, including access to timely diagnosis, risk-stratified therapy, and comprehensive supportive care. This retrospective study aimed to analyze outcomes for pediatric ALL at 16 centers in Mexico. Methods: Patients <18 years of age with newly diagnosed B- and T-cell ALL treated between January 2011 and December 2019 were included. Clinical and biological characteristics and their association with outcomes were examined. Results: Overall, 2,116 patients with a median age of 6.3 years were included. B-cell immunophenotype was identified in 1,889 (89.3%) patients. The median white blood cells at diagnosis were 11.2.5 × 103/mm3. CNS-1 status was reported in 1,810 (85.5%), CNS-2 in 67 (3.2%), and CNS-3 in 61 (2.9%). A total of 1,488 patients (70.4%) were classified as high-risk at diagnosis. However, in 52.5% (991/1,889) of patients with B-cell ALL, the reported risk group did not match the calculated risk group allocation based on National Cancer Institute (NCI) criteria. Fluorescence in situ hybridization (FISH) and PCR tests were performed for 407 (19.2%) and 736 (34.8%) patients, respectively. Minimal residual disease (MRD) during induction was performed in 1,158 patients (54.7%). The median follow-up was 3.7 years. During induction, 191 patients died (9.1%), and 45 patients (2.1%) experienced induction failure. A total of 365 deaths (17.3%) occurred, including 174 deaths after remission. Six percent (176) of patients abandoned treatment. The 5-year event-free survival (EFS) was 58.9% ± 1.7% for B-cell ALL and 47.4% ± 5.9% for T-cell ALL, while the 5-year overall survival (OS) was 67.5% ± 1.6% for B-cell ALL and 54.3% ± 0.6% for T-cell ALL. The 5-year cumulative incidence of central nervous system (CNS) relapse was 5.5% ± 0.6%. For the whole cohort, significantly higher outcomes were seen for patients aged 1-10 years, with DNA index >0.9, with hyperdiploid ALL, and without substantial treatment modifications. In multivariable analyses, age and Day 15 MRD continued to have a significant effect on EFS. Conclusion: Outcomes in this multi-institutional cohort describe poor outcomes, influenced by incomplete and inconsistent risk stratification, early toxic death, high on-treatment mortality, and high CNS relapse rate. Adopting comprehensive risk-stratification strategies, evidence-informed de-intensification for favorable-risk patients and optimized supportive care could improve outcomes.

Risk Prediction of Chronic Rhinosinusitis with or without Nasal Polyps in Taiwanese Population Using Polygenic Risk Score for Nasal Polyps.

The association between single nucleotide polymorphisms and chronic rhinosinusitis (CRS) has been determined. However, it was not known whether the polygenic risk score (PRS) for nasal polyps (NP) could predict CRS with NP (CRSwNP) or without NP (CRSsNP). The aim of this study was to investigate the association between PRSs for NP and the risk of CRS with or without NP. Data from 535 individuals with CRS and 5350 control subjects in the Taiwan Precision Medicine Initiative project were collected. Four PRSs for NP, including PGS000933, PGS000934, PGS001848, and PGS002060 from UK Biobank, were tested in these participants. They were divided into four groups according to quartiles of PRSs. The logistic regression model was performed to evaluate CRSwNP and CRSsNP risk according to PRSs for NP. The PGS002060 had the highest area under the curve at 0.534 for CRSsNP prediction and at 0.588 for CRSwNP prediction. Compared to subjects in the lowest PRS category, the PGS002060 significantly increased the odds for CRSsNP by 1.48 at the highest quintile (p = 0.003) and by 2.32 at the highest quintile for CRSwNP (p = 0.002). In addition, the odds for CRSwNP increased by 3.01 times in female CRSwNP patients (p = 0.009) at the highest quintile compared with those in the lowest PRS category. The PRSs for NP developed from European populations could be applied to the Taiwanese population to predict CRS risk, especially for female CRSwNP.

Incidence change of postoperative delirium after implementation of processed electroencephalography monitoring during surgery: a retrospective evaluation study.

BACKGROUND: Postoperative delirium (POD) is a common complication in the elderly, which is associated with poor outcomes after surgery. Recognized as predisposing factors for POD, anesthetic exposure and burst suppression during general anesthesia can be minimized with intraoperative processed electroencephalography (pEEG) monitoring. In this study, we aimed to evaluate whether implementation of intraoperative pEEG-guided anesthesia is associated with incidence change of POD. METHODS: In this retrospective evaluation study, we analyzed intravenous patient-controlled analgesia (IVPCA) dataset from 2013 to 2017. There were 7425 patients using IVPCA after a noncardiac procedure under general anesthesia. Patients incapable of operating the device independently, such as cognitive dysfunction or prolonged sedation, were declined and not involved in the dataset. After excluding patients who opted out within three days (N = 110) and those with missing data (N = 24), 7318 eligible participants were enrolled. Intraoperative pEEG has been implemented since July 2015. Participants having surgery after this time point had intraoperative pEEG applied before induction until full recovery. All related staff had been trained in the application of pEEG-guided anesthesia and the assessment of POD. Patients were screened twice daily for POD within 3 days after surgery by staff in the pain management team. In the first part of this study, we compared the incidence of POD and its trend from 2013 January-2015 July with 2015 July-2017 December. In the second part, we estimated odds ratios of risk factors for POD using multivariable logistic regression in case-control setting. RESULTS: The incidence of POD decreased from 1.18 to 0.41% after the administration of intraoperative pEEG. For the age group ≧ 75 years, POD incidence decreased from 5.1 to 1.56%. Further analysis showed that patients with pEEG-guided anesthesia were associated with a lower odd of POD (aOR 0.33; 95% CI 0.18-0.60) than those without after adjusting for other covariates. CONCLUSIONS: Implementation of intraoperative pEEG was associated with a lower incidence of POD within 3 days after surgery, particularly in the elderly. Intraoperative pEEG might be reasonably considered as part of the strategy to prevent POD in the elder population. TRIAL REGISTRATION: Not applicable.

Dapagliflozin protects against doxorubicin-induced nephrotoxicity associated with nitric oxide pathway-A translational study.

Doxorubicin (Dox) is a potent anticancer agent, but its associated organ toxicity, including nephrotoxicity, restricts clinical applications. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor, has been shown to slow the progression of kidney disease in patients with and without diabetes. However, the effect of DAPA to counteract Dox-induced nephrotoxicity remains uncertain. Therefore, in this study, we aimed to elucidate the effects of DAPA in mitigating Dox-induced nephrotoxicity. We analyzed the Taiwan National Health Insurance Database to evaluate the incidence of renal failure among breast cancer patients receiving Dox treatment compared to those without. After adjusting for age and comorbidities, we found that the risk of renal failure was significantly higher in Dox-treated patients (incidence rate ratio, 2.45; confidence interval, 1.41-4.26; p = 0.0014). In a parallel study, we orally administered DAPA to Sprague-Dawley rats for 6 weeks, followed by Dox for 4 weeks. DAPA ameliorated Dox-induced glomerular atrophy, renal fibrosis, and dysfunction. Furthermore, DAPA effectively suppressed Dox-induced apoptosis and reactive oxygen species production. On a cellular level, DAPA in HK-2 cells mitigated Dox-mediated suppression of the endothelial NOS pathway and reduced Dox-induced activities of reactive oxygen species and apoptosis-associated proteins. DAPA improved Dox-induced apoptosis and renal dysfunction, suggesting its potential utility in preventing nephrotoxicity in patients with cancer undergoing Dox treatment.

Optimizing allocation of colorectal cancer screening hospitals in Shanghai: a geospatial analysis.

Screening programmes are important for early diagnosis and treatment of colorectal cancer (CRC) but they are not equally efficient in all locations. Depending on which hospital people belong to, they often are not willing to follow up even after a positive result, resulting in a lower-than-expected overall detection rate. Improved allocation of health resources would increase the program's efficiency and assist hospital accessibility. A target population exceeding 70,000 people and 18 local hospitals were included in the investigation of an optimization plan based on a locationallocation model. We calculated the hospital service areas and the accessibility for people in communities to CRC-screening hospitals using the Huff Model and the Two-Step Floating Catchment Area (2SFCA) approach. We found that only 28.2% of the residents with initially a positive screening result had chosen followup with colonoscopy and significant geographical differences in spatial accessibility to healthcare services indeed exist. The lowest accessibility was found in the Southeast, including the Zhangjiang, Jichang and Laogang communities with the best accessibility mainly distributed near the city centre of Lujiazui; the latter also had relatively a high level of what is called "ineffective screening" as it represents wasteful resource allocation. It is recommended that Hudong Hospital should be chosen instead of Punan Hospital as the optimization, which can improve the service population of each hospital and the populations served per colonoscope. Based on our results, changes in hospital configuration in colorectal cancer screening programme are needed to achieve adequate population coverage and equitable facility accessibility. Planning of medical services should be based on the spatial distribution trends of the population served.