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Therapeutic drug monitoring (TDM) is recommended during valproic acid (VPA) use, and total serum concentration has been widely adopted. However, the free form of VPA is responsible for its pharmacologic and toxic effects, and the total and free concentrations are highly discordant because of VPA's highly protein bound and saturable binding characteristics. Therefore, free VPA monitoring is increasingly advocated. Nevertheless, the correlation between free VPA concentration and associated adverse effects remains unknown. To determine the optimal safety range of free VPA concentration in adult patients. This prospective cohort study enrolled adult patients undergoing VPA therapy with TDM. Patient characteristics, VPA use, and adverse effects (thrombocytopenia, hyperammonemia, and hepatotoxicity) were recorded. A multivariate logistic regression model was applied to identify the predictors of adverse effects, and the receiver operating characteristic curve was applied to locate the cutoff point of free VPA concentration. A total of 98 free serum concentrations from 51 patients were included for final analysis. In total, 31 (31.6%), 27 (27.6%), and 4 (4.1%) episodes of hyperammonemia, thrombocytopenia, and hepatotoxicity were observed, respectively. Free VPA concentration was a predicting factor for thrombocytopenia but not for hyperammonemia. A free VPA concentration of >14.67 mcg/mL had the greatest discriminating power (area under the curve = 0.77) for the occurrence of thrombocytopenia. A free VPA serum concentration of 14.67 mcg/mL had the optimal discriminating power for the occurrence of thrombocytopenia. Ammonemia should be monitored even if free VPA concentration is within the safety range.

In this retrospective study, we investigated the impact of diabetes mellitus (DM) on patients with head and neck cancer (HNC) undergoing concurrent chemoradiotherapy (CCRT). We analyzed the demographic and clinical characteristics, treatment tolerance, and toxicities of patients with HNC undergoing primary or adjuvant CCRT with or without DM between 2007 and 2016. Of the 556 patients undergoing CCRT, 84 (15.1%) had DM. Compared with patients without DM, patients with DM were significantly older (56.2 ± 11.2 vs. 51.9 ± 9.5 years, P < 0.001), received lower doses of cisplatin (adjuvant CCRT: 175.30 ± 84.03 vs. 214.88 ± 68.25, P = 0.014; primary CCRT: 142.84 ± 79.49 vs. 187.83 ± 76.19, P < 0.001), and experienced higher rates of infection (adjuvant CCRT: 52% vs. 30.5%, P = 0.042; primary CCRT: 45.8% vs. 22.9%, P < 0.001). Among patients undergoing primary CCRT, compared with those without DM, the patients with DM experienced significantly higher rates of hematologic toxicity (65.7% vs. 39.3%, P = 0.004) and treatment-related deaths (10.2% vs. 3.5%, P = 0.051); and a greater weight loss (−6.17 ± 9.27% vs. −4.49 ± 6.84, P = 0.078). Patients with HNC and DM undergoing CCRT, compared with patients without DM, experienced higher rates of infection and hematotoxicity, loss of body weight, and higher treatment-related mortality.

Long-chain fatty acids induce apolipoprotein A4 (APOA4) production in the small intestine and activate brown adipose tissue (BAT) thermogenesis. The increase in BAT thermogenesis enhances triglyceride clearance and insulin sensitivity. Acute administration of recombinant APOA4 protein elevates BAT thermogenesis in chow-fed mice. However, the physiological role of continuous infusion of recombinant APOA4 protein in regulating sympathetic activity, thermogenesis, and lipid and glucose metabolism in low-fat-diet (LFD)-fed mice remained elusive. The hypothesis of this study was that continuous infusion of mouse APOA4 protein would increase sympathetic activity and thermogenesis in BAT and subcutaneous inguinal white adipose tissue (IWAT), attenuate plasma lipid levels, and improve glucose tolerance. To test this hypothesis, sympathetic activity, BAT temperature, energy expenditure, body weight, fat mass, caloric intake, glucose tolerance, and levels of BAT and IWAT thermogenic and lipolytic proteins, plasma lipids, and markers of fatty acid oxidation in the liver in mice with APOA4 or saline treatment were measured. Plasma APOA4 levels were elevated, BAT temperature and thermogenesis were upregulated, and plasma triglyceride (TG) levels were reduced, while body weight, fat mass, caloric intake, energy expenditure, and plasma cholesterol and leptin levels were comparable between APOA4- and saline-treated mice. Additionally, APOA4 infusion stimulated sympathetic activity in BAT and liver but not in IWAT. APOA4-treated mice had greater fatty acid oxidation but less TG content in the liver than saline-treated mice had. Plasma insulin in APOA4-treated mice was lower than that in saline-treated mice after a glucose challenge. In conclusion, continuous infusion of mouse APOA4 protein stimulated sympathetic activity in BAT and the liver, elevated BAT thermogenesis and hepatic fatty acid oxidation, and consequently attenuated levels of plasma and hepatic TG and plasma insulin without altering caloric intake, body weight gain and fat mass.

Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) mice. In light of these observations, we sought to determine whether steady production of APOA4 could keep BAT thermogenesis elevated, even in the presence of HFD consumption, with an aim toward eventual reduction of body weight, fat mass and plasma lipid levels. Transgenic mice with overexpression of mouse APOA4 in the small intestine (APOA4-Tg mice) produce greater plasma APOA4 than their WT controls, even when fed an atherogenic diet. Thus, we used these mice to investigate the correlation of levels of APOA4 and BAT thermogenesis during HFD consumption. The hypothesis of this study was that overexpression of mouse APOA4 in the small intestine and increased plasma APOA4 production would increase BAT thermogenesis and consequently reduce fat mass and plasma lipids of HFD-fed obese mice. To test this hypothesis, BAT thermogenic proteins, body weight, fat mass, caloric intake, and plasma lipids in male APOA4-Tg mice and WT mice fed either a chow diet or a HFD were measured. When fed a chow diet, APOA4 levels were elevated, plasma triglyceride (TG) levels were reduced, and BAT levels of UCP1 trended upward, while body weight, fat mass, caloric intake, and plasma lipids were comparable between APOA4-Tg and WT mice. After a four-week feeding of HFD, APOA4-Tg mice maintained elevated plasma APOA4 and reduced plasma TG, but UCP1 levels in BAT were significantly elevated in comparison to WT controls; body weight, fat mass and caloric intake were still comparable. After 10-week consumption of HFD, however, while APOA4-Tg mice still exhibited increased plasma APOA4, UCP1 levels and reduced TG levels, a reduction in body weight, fat mass and levels of plasma lipids and leptin were finally observed in comparison to their WT controls and independent of caloric intake. Additionally, APOA4-Tg mice exhibited increased energy expenditure at several time points when measured during the 10-week HFD feeding. Thus, overexpression of APOA4 in the small intestine and maintenance of elevated levels of plasma APOA4 appear to correlate with elevation of UCP1-dependent BAT thermogenesis and subsequent protection against HFD-induced obesity in mice.

Cancer mortality is closely linked to recurrence and distant metastasis, posing challenges in real-time tracking due to the invasiveness of current methods. Circulating tumor cells (CTCs) show promise as potential tools; however, their scarcity remains a significant obstacle. In this prospective study, we validated a simple culture protocol and investigated the correlation between clinical response and CTC growth status. Following negative selection, the isolated cells were subjected to ex vivo cultivation in a two-dimensional environment supplemented with cytokines for up to 21 days, followed by immunofluorescence staining for analysis. Among 37 participants with solid tumors and distant metastasis (34.8% head and neck cancer), 47 samples were collected, from which CTCs were detected. The percentages of CTCs, atypical CTCs, and white blood cells during cultivation from days 7-21 were significantly different (p < 0.001, p < 0.001, and p = 0.330, respectively). Patients were further categorized into progressive disease (PD) and non-PD groups based on disease status, revealing significant differences in CTC growth rates, which increases from Days 7-21 between groups (5.5x vs. 2.8x growth, respectively; p < 0.001). With the proposed protocols, we cultured CTCs from patients with various cancers for 21 days and identified a tool for predicting cancer response. The actual cancer status (PD or non-PD) at CTC isolation correlates to CTC growth rate, guiding the required observation time and parameters for culture.

Background: This study aimed to investigate the role of circulating tumor cells (CTCs) and circulating cancer stem-like cells (cCSCs) before and after one cycle of chemotherapy and assessed the effects of early changes in CTCs and cCSCs on the outcomes of patients with metastatic breast cancer. Methods: Patients with stage IV invasive ductal carcinoma of the breast who received first-line chemotherapy between April 2014 and January 2016 were enrolled. CTCs and cCSCs were measured before the first cycle of chemotherapy (baseline) and on day 21, before the second cycle of chemotherapy commenced; a negative selection strategy and flow cytometry protocol were employed. Results: CTC and cCSC counts declined in 68.8 and 45.5% of patients, respectively. Declines in CTCs and cCSCs following the first chemotherapy cycle were associated with superior chemotherapy responses, longer progression-free survival (PFS), and longer overall survival (OS). An early decline in cCSCs remained an independent prognostic indicator for OS and PFS in multivariate analysis. Conclusions: A cCSC decline after one cycle of chemotherapy for metastatic breast cancer is predictive of a superior chemotherapy response and longer PFS and OS, implying that cCSC dynamic monitoring may be helpful in early prediction of treatment response and prognosis.

Background: The Glasgow Prognostic Score and circulating cytokine levels are related to the prognosis of colorectal cancer and the severity of chronic inflammation. The association between the Glasgow Prognostic Score and circulating cytokines in colorectal cancer remains unclear. Methods: The levels of 10 circulating cytokines (TNF-α, TGF-β, IFN-γ, IL-1β, IL-4, IL-6, IL-10, IL-12, IL-13, and IL-23) were measured in 128 patients with colorectal cancer. The relationship between the Glasgow Prognostic Score, clinicopathologic variables, and cytokine levels was assessed by univariate and multivariate logistic regression analyses. The correlation among cytokines was also examined. Results: Patients with advanced stage colorectal cancer had lower levels of albumin (P = 0.003), higher levels of C-reactive protein (CRP; P < 0.001), carcinoembryonic antigen (CEA; P < 0.001), interferon (IFN)-γ (P < 0.001), and interleukin (IL)-10 (P = 0.006), and shorter survival outcomes (P < 0.001). Patients with a high Glasgow Prognostic Score (1 or 2) had lower 5-year progression-free survival and poor overall survival (log-rank P < 0.001). A high Glasgow Prognostic Score was significantly correlated with abnormal CEA levels (CEA > 5 ng/mL, P = 0.033), and higher levels of tumor necrosis factor (TNF)-α (TNF-α ⩾ 53.9 pg/mL, P = 0.035) and IL-10 (IL-10 ⩾ 75.95 pg/mL, P = 0.008). TNF-α, IFN-γ, IL-1β, IL-4, IL-6, IL-10, IL-13, and IL-23 were significantly correlated with each other (all P < 0.05). Only IL-10 was correlated with abnormal CEA levels (P < 0.001). Conclusion: The Glasgow Prognostic Score and level of circulating cytokines have an intergroup correlation, and there is a close association among cytokines in colorectal cancer.

PURPOSE: This study assessed the impact of the navify Tumor Board digital tool on multidisciplinary team tumor boards’ (MDTs) efficiency, comparing its streamlined workflow and preparation to conventional, time-consuming methods. METHODS: This prospective observational study (January–June 2021) compared MDT phase durations (preparation, discussion, follow-up) using the navify Tumor Board platform versus conventional methods for integrated patient data management and decision-making. RESULTS: The navify Tumor Board significantly improved MDT efficiency across all phases compared to conventional methods. In the preparation phase, it reduced the time needed for cancer staging imaging checks and sending meeting materials by 8.62% (p < 0.001). During the discussion phase, it decreased the time required for presenting patient history, reviewing pathology/immunohistochemistry results, and gathering expert opinions, leading to a 21.26% overall reduction in discussion time (p < 0.001). For post-discussion follow-up, it saved 76.54% of the time required recording MDT comments (p < 0.001) and 33.43% of the time needed to schedule second discussions (p = 0.011). Overall, the Navify Tumor Board reduced the total MDT process time by 35.37% (p < 0.001), demonstrating its potential to streamline multidisciplinary cancer care decision-making. CONCLUSIONS: This study showed that the navify Tumor Board tool can significantly improve the efficiency of MDT workflows in Taiwan.

Current tools are insufficient for distinguishing patients with ovarian cancer from those with benign ovarian lesions before extensive surgery. The present study utilized a readily accessible platform employing a negative selection strategy, followed by flow cytometry, to enumerate circulating tumor cells (CTCs) in patients with ovarian cancer. These counts were compared with those from patients with benign ovarian lesions. CTC counts at baseline, before and after anticancer therapy, and across various clinical scenarios involving ovarian lesions were assessed. A negative-selection protocol we proposed was applied to patients with suspected ovarian cancer and prospectively utilized in those subsequently confirmed to have malignancy. The protocol was implemented before anticancer therapy and at months 3, 6, 9 and 12 post-treatment. A cut-off value for CTC number at 4.75 cells/ml was established to distinguish ovarian malignancy from benign lesions, with an area under the curve of 0.900 (P<0.001). In patients with ovarian cancer, multivariate Cox regression analysis revealed that baseline CTC counts and the decline in CTCs within the first three months post-therapy were significant predictors of prolonged progression-free survival. Additionally, baseline CTC counts independently prognosticated overall survival. CTC counts obtained with the proposed platform, used in the present study, suggest that pre-operative CTC testing may be able to differentiate between malignant and benign tumors. Moreover, CTC counts may indicate oncologic outcomes in patients with ovarian cancer who have undergone cancer therapies.

Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear. In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns. One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all < 0.001) and, similarly, after excluding progressive disease ( = 0.014, = 0.002, < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin ( 0.003) and AST ( = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses. Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.