Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand ...1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy.
In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406.
50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 52% of 25 group A patients and 11 44% of 25 group B patients) and 26 patients with previous ICI (12 48% of 25 group A patients and 14 56% of 25 group B patients). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1–26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82–100) had an objective response, including nine (41% 95% CI 21–63) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15–52) had an objective response and four (15% 5–36) had a complete response. No significant differences in ORR were observed between groups A (18 72% of 25 patients) and B (12 52% of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B.
First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma.
Bristol Myers Squibb Rare Population Malignancy Program.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Post-operative pain and bleeding are the main complications following hemorrhoidal surgery. This study aimed to investigate whether an absorbable gelatin sponge is a superior hemostatic and analgesic ...agent compared to gauze soaked in epinephrine for post-hemorrhoidal surgery care. A retrospective study was conducted using data from a single institute. Data were collected from the electronic medical record database and outpatient patient questionnaire archive. The study encompassed 143 patients who received gauze soaked in epinephrine as the hemostatic agent after hemorrhoidal surgery and 148 patients who received an absorbable gelatin sponge. Most patients underwent stapled hemorrhoidopexy, with 119 (83.2%) in epinephrine group and 118 (79.7%) in gelatin sponge group. The primary outcome measurements were postoperative pain score, oral analgesic dosage and complications. Patients in the absorbable gelatin sponge group reported significantly lower pain scores from 8 h after their hemorrhoidal surgery (postoperative day 0) through postoperative day 2. The average pain scores in the absorbable gelatin sponge group and gauze soaked in epinephrine group were 5.3 ± 3.2 and 6.2 ± 3.2 (p = 0.03) on postoperative 8 h; 4.7 ± 3.0 and 5.8 ± 2.9 (p ≤ 0.01) on postoperative day one; and 4.4 ± 2.8 and 5.3 ± 2.9 (p = 0.01) on postoperative day two, respectively. There were no significant differences in postoperative recovery or complication rates between the two groups. Our study revealed that absorbable gelatin sponges provide more effective pain relief to patients during the initial postoperative days after hemorrhoidal surgery, without any adverse impact on patient outcomes. Consequently, absorbable gelatin sponges are recommended as a replacement for gauze soaked in epinephrine following hemorrhoidal surgery.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The primary objective of this study is to enhance the prediction accuracy of intradialytic hypotension in patients undergoing hemodialysis. A significant challenge in this context arises from the ...nature of the data derived from the monitoring devices and exhibits an extreme class imbalance problem. Traditional predictive models often display a bias towards the majority class, compromising the accuracy of minority class predictions. Therefore, we introduce a method called UnderXGBoost. This novel methodology combines the under-sampling, bagging, and XGBoost techniques to balance the dataset and improve predictive accuracy for the minority class. This method is characterized by its straightforward implementation and training efficiency. Empirical validation in a real-world dataset confirms the superior performance of UnderXGBoost compared to existing models in predicting intradialytic hypotension. Furthermore, our approach demonstrates versatility, allowing XGBoost to be substituted with other classifiers and still producing promising results. Sensitivity analysis was performed to assess the model’s robustness, reinforce its reliability, and indicate its applicability to a broader range of medical scenarios facing similar challenges of data imbalance. Our model aims to enable medical professionals to provide preemptive treatments more effectively, thereby improving patient care and prognosis. This study contributes a novel and effective solution to a critical issue in medical prediction, thus broadening the application spectrum of predictive modeling in the healthcare domain.
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•Enhanced prediction of intradialytic hypotension improves pre-emptive treatment in hemodialysis.•UnderXGBoost method addresses extreme dataset imbalance in medical prediction models.•Validation shows that UnderXGBoost outperforms alternatives in predicting hypotension events.•Sensitivity analysis confirms the robustness of UnderXGBoost for clinical applications.•The proposed method offers a new solution to various medical problems with imbalanced data.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Non-small cell lung cancer is the predominant type of lung cancer, resulting in high mortality worldwide. Digoxin, a cardiac glycoside, has recently been suggested to be a novel chemotherapeutic ...agent. Src is an oncogene that plays an important role in cancer progression and is therefore a potential target for cancer therapy. Here, we investigated whether digoxin could suppress lung cancer progression through the inhibition of Src activity. The effects of digoxin on lung cancer cell functions were investigated using colony formation, migration and invasion assays. Western blotting and qPCR assays were used to analyze the mRNA and protein expression levels of Src and its downstream proteins, and a cell viability assay was used to measure cellular cytotoxicity effects. The results of the cell function assays revealed that digoxin inhibited the proliferation, invasion, migration, and colony formation of A549 lung cancer cells. Similar effects of digoxin were also observed in other lung cancer cell lines. Furthermore, we found that digoxin significantly suppressed Src activity and its protein expression in a dose- and time-dependent manner as well as reduced EGFR and STAT3 activity. Our data suggest that digoxin is a potential anticancer agent that may suppress lung cancer progression through inhibiting Src and the activity of related proteins.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gastric cancer is one of the global health concerns. A series of studies on the stomach have confirmed the role of the microbiome in shaping gastrointestinal diseases. Delineation of microbiome ...signatures to distinguish chronic gastritis from gastric cancer will provide a non-invasive preventative and treatment strategy. In this study, we performed whole metagenome shotgun sequencing of fecal samples to enhance the detection of rare bacterial species and increase genome sequence coverage. Additionally, we employed multiple bioinformatics approaches to investigate the potential targets of the microbiome as an indicator of differentiating gastric cancer from chronic gastritis.
A total of 65 patients were enrolled, comprising 33 individuals with chronic gastritis and 32 with gastric cancer. Within each group, the chronic gastritis group was sub-grouped into intestinal metaplasia (n = 15) and non-intestinal metaplasia (n = 18); the gastric cancer group, early stage (stages 1 and 2, n = 13) and late stage (stages 3 and 4, n = 19) cancer. No significant differences in alpha and beta diversities were detected among the patient groups. However, in a two-group univariate comparison, higher Fusobacteria abundance was identified in phylum; Fusobacteria presented higher abundance in gastric cancer (LDA scored 4.27, q = 0.041 in LEfSe). Age and sex-adjusted MaAsLin and Random Forest variable of importance (VIMP) analysis in species provided meaningful features; Bacteria_caccae was the most contributing species toward gastric cancer and late-stage cancer (beta:2.43, se:0.891, p:0.008, VIMP score:2.543). In contrast, Bifidobacterium_longum significantly contributed to chronic gastritis (beta:-1.8, se:0.699, p:0.009, VIMP score:1.988). Age, sex, and BMI-adjusted MasAsLin on metabolic pathway analysis showed that GLCMANNANAUT-PWY degradation was higher in gastric cancer and one of the contributing species was Fusobacterium_varium.
Microbiomes belonging to the pathogenic phylum Fusobacteria and species Bacteroides_caccae and Streptococcus_anginosus can be significant targets for monitoring the progression of gastric cancer. Whereas Bifidobacterium_longum and Lachnospiraceae_bacterium_5_1_63FAA might be protection biomarkers against gastric cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Brown rice consumption is known to have numerous therapeutic benefits. This study aimed to examine the bioactive components of black-pigmented (BRW) and non-pigmented (TK9W) brown rice and their ...comparative effects on hypolipidemic activity in high-fat diet (HFD)-induced hamsters. The results showed that besides total flavonoids and dietary fibers, BRW displayed higher total phenol and anthocyanin contents than TK9W. At 100 mg/kg/BW, although both BRW and TK9W significantly decreased the levels of serum and hepatic total cholesterols (TC) and triglycerides (TG), and increased the levels of serum high-density lipoprotein cholesterol (HDL-C) and fecal TC in HFD-induced hamsters, BRW was more effective than TK9W in lowering serum low-density lipoprotein cholesterol (LDL-C) and hepatic TG. BRW and TK9W also effectively down-regulated fatty acid synthase and PPARγ, and up-regulated lipoprotein lipase and PPARα expression in liver tissues at this dose level. This study demonstrates that, although BRW appears to have better hypolipidemic activity than TK9W, brown rice of different pigmentation effectively decreased the levels of serum and hepatic TG and TC, increased the serum HDL-C and fecal TC, as well as modulated the lipid metabolism-related protein expression in liver tissues.
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•Hypolipidemic activity of black- (BRW) and non- (TK9W) pigmented brown rice.•BRW displayed higher total phenol and anthocyanin contents than TK9W.•BRW and TK9W significantly improved serum and hepatic lipid profiles.•BRW was more effective than TK9W in lowering serum LDL and triglyceride levels.•BRW possesses stronger hypolipidemic activity than TK9W.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this study, Polyvinyl alcohol (PVA) blended with Polyethylene glycol (PEG), Monosodium glutamate (MSG) and Glutamic acid (GA) was cast on a reverse osmosis membrane to form a composite membrane. ...It is expected that the ether group can increase the CO2 affinity of the membrane. Sodium tetraborate (Borax) as a crosslinker can increase membrane basicity and glutamic acid (salt) can provide an enhanced transport mechanism, thereby improving the permeability and selectivity of carbon dioxide. FTIR spectra show that the thickness of coating is sufficiently low, while SEM results show that PVA-PEG series have a dense surface, and particles are observed on the surface of MSG/GA series. The gas permeance and separation performance of the composite membrane was tested using a single gas. Results showed that CO2 had higher permeance (GPU) at lower pressure differential. PEG with an ether group had the greatest effect on improving CO2 permeance and selectivity. However, MSG and GA with amine groups could not effectively improve CO2 selectivity due to solubility. The best coating solution was provided by PVA-PEG-1.2. The CO2 selectivity of the composite membrane was 10.05 with a pressure differential of 1.00 bar in a humid environment and no obvious deterioration was observed over a 10-day period. Borax can improve selectivity, water absorption, and thermal stability while avoiding the need for high temperature and long crosslinking time of aldehydes, which makes it possible to be used in a PVA carbon dioxide separation membrane.
Numerous factors can influence bowel movement recovery and anastomotic healing in colorectal surgery, and poor healing can lead to severe complications and increased medical expenses. Collagen patch ...cover (CPC) is a promising biomaterial that has been demonstrated to be safe in animal models and has been successfully applied in various surgical procedures in humans. This study.
A retrospective review of medical records from July 2020 to June 2022 was conducted to identify consecutive patients who underwent laparoscopic colectomy. Patients who received CPC at the anastomotic site were assigned to the collagen group, whereas those who did not receive CPC were assigned to the control group.
Data from 241 patients (collagen group, 109; control group, 132) were analyzed. Relative to the control group, the collagen group exhibited a faster recovery of bowel function, including an earlier onset of first flatus (2.93 days vs. 3.43 days, p < 0.01), first defecation (3.73 days vs. 4.18 days, p = 0.01), and oral intake (4.30 days vs. 4.68 days, p = 0.04). CPC use was also associated with lower use of postoperative intravenous analgesics. The complication rates in the two groups did not differ significantly.
CPCs can be safely and easily applied to the anastomotic site during laparoscopic colectomy, and can accelerate bowel movement recovery. Further studies on the effectiveness of CPCs in colorectal surgery involving larger sample sizes are required.
ClinicalTrials.gov registration number: NCT05831956 (26/04/2023).
Highlights • We employed two SHP-1 agonists, sorafenib and SC-43, for HCC treatment. • The synergistic action of sorafenib and SC-43 further enhanced HCC apoptosis. • Diminished STAT3-related signals ...and increased cell death were observed. • The add-on strategy resulted in smaller tumor size in the subcutaneous model. • The novel combination contributed to 100% survival in the orthotopic HCC model.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Regarding dihydrogen as a clean and renewable energy source, ammonia borane (NH3BH3, AB) was considered as a chemical H2-storage and H2-delivery material due to its high storage capacity of ...dihydrogen (19.6 wt %) and stability at room temperature. To advance the development of efficient and recyclable catalysts for hydrolytic dehydrogenation of AB with parallel insight into the reaction mechanism, herein, ZIF-67-derived fcc-Co@porous carbon nano/microparticles (cZIF-67_nm/cZIF-67_μm) were explored to promote catalytic dehydrogenation of AB and generation of H2(g). According to kinetic and computational studies, zero-order dependence on the concentration of AB, first-order dependence on the concentration of cZIF-67_nm (or cZIF-67_μm), and a kinetic isotope effect value of 2.45 (or 2.64) for H2O/D2O identify the Co-catalyzed cleavage of the H–OH bond, instead of the H–BH2NH3 bond, as the rate-determining step in the hydrolytic dehydrogenation of AB. Despite the absent evolution of H2(g) in the reaction of cZIF-67 and AB in the organic solvents (i.e., THF or CH3OH) or in the reaction of cZIF-67 and water, Co-mediated activation of AB and formation of a Co-H intermediate were evidenced by theoretical calculation, infrared spectroscopy in combination with an isotope-labeling experiment, and reactivity study toward CO2-to-formate/H2O-to-H2 conversion. Moreover, the computational study discovers a synergistic interaction between AB and the water cluster (H2O)9 on fcc-Co, which shifts the splitting of water into an exergonic process and lowers the thermodynamic barrier for the generation and desorption of H2(g) from the Co-H intermediates. With the kinetic and mechanistic study of ZIF-67-derived Co@porous carbon for catalytic hydrolysis of AB, the spatiotemporal control on the generation of H2(g) for the treatment of inflammatory diseases will be further investigated in the near future.
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IJS, KILJ, NUK, PNG, UL, UM
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