The Effect of Sex on the Remimazolam Dosage Required for Successful i-gel Supraglottic Airway Insertion with Remifentanil in Non-Paralyzed Patients: An Up-and-Down Sequential Allocation Trial.

(1) Background: The physiological and pharmacological variations between men and women are known to influence drug efficacy. The objective of this study was to determine the 50% and 95% effective doses (ED50 and ED95) of remimazolam required for i-gel supraglottic airway (ISA) insertion under remifentanil infusion without neuromuscular blocking agents (NMBAs) in both males and females. (2) Methods: Patients aged 19-65 years, scheduled for general anesthesia using ISA, were enrolled in this study. Patients were divided into two groups based on their sex. The anesthesia process began with a remifentanil infusion targeting an effect-site concentration of 3.0 ng/mL, accompanied by a remimazolam injection. The initial remimazolam dose was 0.25 mg/kg, and it was adjusted with a step size of 0.05 mg/kg based on the outcome of ISA insertion in the preceding patient. (3) Results: The ED50 of remimazolam (mean ± standard error) was 0.28 ± 0.02 mg/kg in the male group and 0.18 ± 0.02 mg/kg in the female group (p < 0.001). Additionally, ED95, which was calculated using the isotonic regression method, was significantly comparable between the male and female groups (male: 0.35 mg/kg, 95% confidence interval [CI] = 0.34-0.35; female: 0.29 mg/kg, 95% CI = 0.25-0.30). (4) Conclusions: This study showed that both the ED50 and the ED95 of remimazolam for successful ISA insertion was higher for men than that for women. Therefore, while using remimazolam alongside remifentanil infusion without NMBAs for ISA insertion, one should consider the patient's sex for appropriate dosing.

Endoscopic submucosal dissection for papillary early gastric carcinoma: Insights from a large-scale analysis of post-gastrectomy pathology specimens.

Gastric papillary adenocarcinoma is considered a differentiated adenocarcinoma in the current endoscopic submucosal dissection indication guidelines. However, the safety of endoscopic submucosal dissection remains controversial. Currently, data regarding which papillary early gastric cancer should be considered for endoscopic submucosal dissection are unavailable. Thus, the aim of this study was to investigate lymph node metastasis and the safety of endoscopic submucosal dissection in patients with papillary early gastric cancer. This observational study recruited 4264 consecutive patients with early gastric cancer who underwent curative gastrectomy between October 2000 and December 2017 at the National Cancer Center, Korea. Of these, 45 had pathologically confirmed papillary early gastric cancer, 2106 had differentiated non-papillary early gastric cancer, and 2113 had undifferentiated early gastric cancer. Logistic regression analysis was performed to identify risk factors for lymph node metastasis. Mucosal tumors were less common in papillary early gastric cancer (37.9%) than in differentiated non-papillary early gastric cancer (48.8%) and undifferentiated early gastric cancer (60.4%) (both P < .001). Lymph node metastasis was more common in papillary early gastric cancer (20.0%) than in differentiated non-papillary early gastric cancer (9.2%) and undifferentiated early gastric cancer (11.7%; both P < .001). In multivariate analysis, non-mixed-type papillary early gastric cancer showed marginally increased odds of lymph node metastasis than differentiated early gastric cancer (odds ratio [OR]: 2.5, 95% confidence interval [CI]: 1.0-6.3). Rates of lymph node metastasis (1/10, 10%) and angiolymphatic invasion (2/10, 20%) for papillary early gastric cancer meeting expanded criteria were higher than those for other histology types meeting endoscopic submucosal dissection absolute or expanded criteria (P = .03 and P < .001, respectively). Endoscopic submucosal dissection should be considered carefully for papillary early gastric cancer, especially if it meets expanded endoscopic submucosal dissection indications since it is associated with high rates of submucosal invasion and lymph node metastasis.

The risk of colorectal neoplasm in ex- and never-smokers according to urinary cotinine level.

ABSTRACT: To investigate the relationship between urinary cotinine and colorectal neoplasm (CRN).The participants in the health screening cohort of the National Cancer Center who underwent screening colonoscopy between June 2007 and December 2009 were included. A total of 8121 subjects who underwent urinary cotinine measurement within 14 days from the index colonoscopy were included. Cotinine positivity was defined as having a urinary cotinine level ≥50 ng/mL. Follow-up colonoscopy data were collected by reviewing the patients' medical records.Patients were classified according to their urinary cotinine level and self-reported smoking status, and the number of patients with cotinine positivity was 1960 (24.1%). There was no significant difference in the cumulative CRN and advanced CRN (ACRN) risks according to the self-reported smoking status. However, cotinine positivity at the time of index colonoscopy was an independent risk factor for CRN (hazard ratio [HR]= 1.23, P = .006) in follow-up colonoscopy. Moreover, in never- and ex-smokers, cotinine positivity was an independent risk factor for CRN (HR = 1.95, P = .019; HR = 2.12, P = .003, respectively) and ACRN (HR = 8.89, P < .001; HR = 5.03, P = .003) during follow-up colonoscopy. The cumulative incidence of CRN and ACRN was higher in the cotinine-positive never- and ex-smokers than in the cotinine-negative never- and ex-smokers (P < .001 and P = .008, respectively).CRN or ACRN is more likely to occur at follow-up colonoscopy in the urinary cotinine-positive never- and ex-smokers than in the urinary cotinine-negative group. Therefore, urinary cotinine measurements may provide useful information on never- or ex-smokers undergoing screening colonoscopy.

Tumor-Treating Fields Inhibit the Metastatic Potential of Osteosarcoma Cells.

The prognosis of metastatic osteosarcoma (OS) remains poor with a <20% survival rate, particularly in cases of distant (non-lung) metastases. Tumor-treating field (TTF) therapy is a novel electric field-based treatment that causes metaphase arrest and tumor cell death, with the advantage of reduced side effects compared to radiation and chemotherapy. TTF shows promise in glioblastoma and other solid tumors; however, few studies have examined its potential in the treatment of osteosarcoma. Therefore, we explored the mechanism of TTF-induced metastasis inhibition and cell death using in vitro models. TTF (1.5 V/cm, 150 kHz) was applied to U2OS and KHOS/NP OS cell lines. In addition, a 3-dimensional culture system was established using these OS cell lines. Cell migration and invasion (i.e., metastatic potential) were examined using a wound-healing scratch assay and transwell assay, respectively. Western blotting of metastasis- and angiogenesis-related proteins was performed. TTF suppressed the migration of and invasion by OS cells and inhibited the expression of epithelial markers, thereby preventing epithelial-mesenchymal transition (EMT), a hallmark of metastasis. Moreover, TTF prevented angiogenesis in human tumor endothelial cells and downregulated matrix metalloproteinase-2 (MMP2) and vascular endothelial growth factor (VEGF) expression. Therefore, TTF shows potential as an improved treatment for osteosarcoma, warranting further preclinical studies in animal models to support clinical trials.

Correction: Oh, J.Y., et al. Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells, Cancers 2019, 11, 1812.

The authors wish to make the following corrections to this paper [...].

The Unfolded Protein Response: Neutron-Induced Therapy Autophagy as a Promising Treatment Option for Osteosarcoma.

Radiotherapy using high linear energy transfer (LET) radiation results in effectively killing tumor cells while minimizing dose (biological effective) to normal tissues to block toxicity. It is well known that high LET radiation leads to lower cell survival per absorbed dose than low LET radiation. High-linear energy transfer (LET) neutron treatment induces autophagy in tumor cells, but its precise mechanisms in osteosarcoma are unknown. Here, we investigated this mechanism and the underlying signaling pathways. Autophagy induction was examined in gamma-ray-treated KHOS/NP and MG63 osteosarcoma cells along with exposure to high-LET neutrons. The relationship between radiosensitivity and autophagy was assessed by plotting the cell surviving fractions against autophagy levels. Neutron treatment increased autophagy rates in irradiated KHOS/NP and MG63 cells; neutrons with high-LETs showed more effective inhibition than those with lower LET gamma-rays. To determine whether the unfolded protein response and Akt-mTOR pathways triggered autophagy, phosphorylated eIF2α and JNK levels, and phospho-Akt, phosphor-mTOR, and phospho-p70S6 levels were, respectively, investigated. High-LET neutron exposure inhibited Akt phosphorylation and increased Beclin 1 expression during the unfolded protein response, thereby enhancing autophagy. The therapeutic efficacy of high-LET neutron radiation was also assessed in vivo using an orthotopic mouse model. Neutron-irradiated mice showed reduced tumor growth without toxicity relative to gamma-ray-treated mice. The effect of high-LET neutron exposure on the expression of signaling proteins LC3, p-elF2a, and p-JNK was investigated by immunohistochemistry. Tumors in high-LET-neutron radiation-treated mice showed higher apoptosis rates, and neutron exposure significantly elevated LC3 expression, and increased p-elF2a and p-JNK expression levels. Overall, these results demonstrate that autophagy is important in radiosensitivity, cell survival, and cellular resistance against high-LET neutron radiation. This correlation between cellular radiosensitivity and autophagy may be used to predict radiosensitivity in osteosarcoma.

The Biofunctional Effects of Mesima as a Radiosensitizer for Hepatocellular Carcinoma.

The tropical basidiomycete fungus Phellinus linteus (Mesima) exhibits anti-tumor, anti-angiogenic, and immunomodulatory properties in various cancers including prostate, colon, and lung cancer along with melanoma by, for example, inducing apoptosis or cell cycle arrest. However, whether medina also facilitates treatment of hepatocellular carcinoma (HCC), the third global cause of cancer deaths, remains unknown. Here, we examined its potential as a radiosensitizer in HCC radiotherapy using human HCC Hep3B and HepG2 cell lines and xenograft tumors. Mesima pretreatment significantly enhanced HCC cell radiosensitivity in vitro and the combination of mesima + radiation treatment significantly reduced xenograft tumor growth and size in vivo compared to those with single treatments. Mechanistically, mesima significantly enhanced radiotherapy efficiency by inhibiting tumor cell survival through inducing apoptosis (assessed via annexin V), impairing cell cycle regulation (shown by flow cytometry), and reducing radiation-induced DNA damage repair (measured via γ-H2AX foci). Combination treatment also facilitated autophagic cell death beyond that from single treatments (assessed by quantifying stained acidic vesicular organelles), and diminished tumor cell metastatic potentials (shown by wound and Transwell assays). These findings support the synergistic anti-tumor effects of mesima combined with radiation and suggest scientific evidence for mesima as a radiosensitizer in HCC.

5-Fluorouracil as a Tumor-Treating Field-Sensitizer in Colon Cancer Therapy.

Colorectal cancer (CRC) is a major cause of mortality that can be treated effectively with chemotherapy and radiotherapy, although resistance to these therapeutic modalities often occurs. Tumor-treating fields (TTFields) can block tumor growth by selectively impairing tumor cell division. In this study, we investigated the mechanism by which 5-fluorouracil (5-FU) sensitizes tumor cells to TTFields. Human HCT116 and SW480 CRC cells were treated with 5-FU and/or TTFields, and characterized in vitro in terms of cell viability, apoptosis through reactive oxygen species production, autophagy, and metastatic potentials. The biological effects of 5-FU and/or TTFields were studied via positron emission tomography and computed tomography on xenograft tumor growth and were confirmed with organoid models of patients. Our results revealed that combination treatment with 5-FU and TTFields increased the efficiency of TTFields therapy in colon cancer cells by downregulating signaling pathways associated with cell proliferation, survival, cell invasion, and migration while upregulating pathways mediating apoptosis and autophagic cell death. The novel mechanistic insights gleaned in this study suggest that combination therapy with TTFields and 5-FU may be effective in treating CRC, although safety and efficacy testing in patients with CRC will need to be performed before this strategy can be implemented clinically for TTF-sensitization.

Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells.

Osteosarcoma (OS) originates from osteoid bone tissues and is prone to metastasis, resulting in a high mortality rate. Although several treatments are available for OS, an effective cure does not exist for most patients with advanced OS. Zoledronic acid (ZOL) is a third-generation bisphosphonate that inhibits osteoclast-mediated bone resorption and has shown efficacy in treating bone metastases in patients with various types of solid tumors. Here, we sought to clarify the mechanisms through which ZOL inhibits OS cell proliferation. ZOL treatment inhibited OS cell proliferation, viability, and colony formation. Autophagy inhibition by RNA interference against Beclin-1 or ATG5 inhibited ZOL-induced OS cell death. ZOL induced autophagy by repressing the protein kinase B/mammalian target of rapamycin/p70S6 kinase pathway and extracellular signal-regulated kinase signaling-dependent autophagy in OS cell lines and patient-derived OS cells. Microarrays of miRNA showed that ZOL increased the levels of miR-212-3p, which is known to play an important role in autophagy, in OS in vitro and in vivo systems. Collectively, our data provided mechanistic insight into how increased miR-212-3p through ZOL treatment induces autophagy synergistically in OS cells, providing a preclinical rationale for conducting a broad-scale clinical evaluation of ZOL + miR-212-3p in treating OS.

Temporal distance and blood donation intention.

This study tested Construal Level Theory and examined social desirability and cultural differences as factors affecting blood donation intention across different time frames. Findings showed that individuals indicated stronger intentions for the distant future (one-year and no-time indication frames) than for the near future (one-week and three-month frames). The relationship between social desirability rating of blood donation and intention was positive and significant for the no-time indication frame, but it was not significant for the one-week time frame and the three-month time frame. Koreans and Americans did not differ in the relationship between social desirability and intentions across different time frames.