Immune checkpoint inhibitor use and the incidence of hepatitis B virus reactivation or immune-related hepatitis in non-small cell lung cancer patients with chronic hepatitis B.

BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting. METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy. RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons). CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.

1,8-Dihydroxy-3-methoxy-anthraquinone inhibits tumor angiogenesis through HIF-1α downregulation.

Photorhabdus luminescens is a gram-negative bioluminescent bacterium known as an intestinal bacterium that coexists in the digestive tract of insect-pathogenic nematodes. As part of our ongoing exploration to identify bioactive compounds from diverse natural resources, the chemical analysis of the cultures of P. luminescens KACC 12254 via LC/MS and TLC-based analyses enabled the isolation and identification of a major fluorescent compound. Its chemical structure was elucidated as 1,8-dihydroxy-3-methoxyanthraquinone (DMA) using HR-ESI-MS and NMR analysis. In this study, we conducted comprehensive investigations utilizing human colorectal cancer HCT116 cells, human umbilical cord vascular endothelial cells (HUVECs), and zebrafish embryos to assess the potential benefits of DMA in suppressing tumor angiogenesis. Our results convincingly demonstrate that DMA effectively suppresses the stability of hypoxia-inducible factor-1α (HIF-1α) protein and its target genes without inducing any cytotoxic effects. Furthermore, DMA demonstrates the ability to inhibit HIF-1α transcriptional activation and mitigate the production of reactive oxygen species (ROS). In our in vitro experiments, DMA exhibits notable inhibitory effects on VEGF-mediated tube formation, migration, and invasion in HUVECs. Additionally, in vivo investigations using zebrafish embryos confirm the antiangiogenic properties of DMA. Notably, DMA does not exhibit any adverse developmental or cardiotoxic effects in the in vivo setting. Moreover, we observe DMA's capability to restrain tumor growth through the downregulation of PI3K/AKT and c-RAF/ERK pathway. Collectively, these compelling findings underscore DMA's potential as a promising therapeutic candidate for targeted intervention against HIF-1α and angiogenesis in cancer treatment.

6-Pentyl-α-Pyrone from Trichoderma gamsii Exert Antioxidant and Anti-Inflammatory Properties in Lipopolysaccharide-Stimulated Mouse Macrophages.

Filamentous fungi produce several beneficial secondary metabolites, including bioactive compounds, food additives, and biofuels. Trichoderma, which is a teleomorphic Hypocrea that falls under the taxonomic groups Ascomycota and Dikarya, is an extensively studied fungal genus. In an ongoing study that seeks to discover bioactive natural products, we investigated potential bioactive metabolites from the methanolic extract of cultured Trichoderma gamsii. Using liquid chromatography-mass spectrometry (LC-MS), one major compound was isolated and structurally identified as 6-pentyl-α-pyrone (6PP) based on nuclear magnetic resonance data and LC-MS analysis. To determine its antioxidant and anti-inflammatory activity, as well as the underlying mechanisms, we treated lipopolysaccharide (LPS)-stimulated Raw264.7 mouse macrophages with 6PP. We found that 6PP suppresses LPS-induced increase in the levels of nitric oxide, a mediator of oxidative stress and inflammation, and restores LPS-mediated depletion of total glutathione by stabilizing nuclear factor erythroid 2-related factor 2 (Nrf2), an antioxidative factor, and elevating heme oxygenase-1 levels. Furthermore, 6PP inhibited LPS-induced production of proinflammatory cytokines, which are, at least in part, regulated by heme oxygenase-1 (HO-1). 6PP suppressed proinflammatory responses by inhibiting the nuclear localization of nuclear factor kappa B (NF-κB), as well as by dephosphorylating the mitogen-activated protein kinases (MAPKs). These results indicate that 6PP can protect macrophages against oxidative stress and LPS-induced excessive inflammatory responses by activating the Nrf2/HO-1 pathway while inhibiting the proinflammatory, NF-κB, and MAPK pathways.

Tumor mutation burden in gastro-entero-pancreatic-neuroendocrine neoplasms.

Background: As rare tumors, there are limited treatment options for neuroendocrine neoplasms (NENs). Recently, microsatellite instability (MSI) and tumor mutation burden (TMB) have been emerging as potential biomarkers in various tumors. However, there is a lack of research on the use of these biomarkers in gastro-entero-pancreatic (GEP)-NENs. Methods: We analyzed 31 patients diagnosed with GEP-NEN between 2013 to 2022. The TMB and MSI analyses using next-generation sequencing (NGS) were performed for all patients. The TruSightTM Oncology 500 assay from Illumina was used as the NGS panel. Results: Out of the 31 patients analyzed, the most frequent primary origin was the pancreas (12 patients, 38.7%), followed by the stomach (4 patients, 12.9%), gallbladder (4 patients, 12.9%), rectum (7 patients, 22.6%), small bowel (2 patients, 6.5%), and bile duct (1 patient, 3.2%). Among these patients, 19 (61.3%) were diagnosed with well-differentiated neuroendocrine tumors, with grade 2 being the most common (15 patients, 48.4%), followed by grade 3 (3 patients, 9.7%) and grade 1 (1 patient, 3.2%). Neuroendocrine carcinoma was confirmed in 12 patients (38.7%). The median number of metastases was 2.0 [interquartile range (IQR), 1.0-3.0], and the liver was the most common site of metastasis (23 patients, 74.2%). The median TMB was 4.7 (IQR, 3.1-6.3) mutations/Mb, and all tumors were classified as microsatellite stability (MSS). Only one patient had a high TMB (266.4 mutations/Mb), which was a grade 3 neuroendocrine tumor originating from the pancreas. The TMB value did not vary depending on the primary tumor site or World Health Organization (WHO) grade. Conclusions: This analysis showed that, despite very low incidence, there are GEP-NENs with high TMB. For precision medicine, testing for MSI and TMB is needed for this tumor type.

Anti-osteoporosis effects of triterpenoids from the fruit of sea buckthorn (Hippophae rhamnoides) through the promotion of osteoblast differentiation in mesenchymal stem cells, C3H10T1/2.

In a previous study, we discovered that the ethanolic extract of sea buckthorn (Hippophae rhamnoides) fruits exhibited anti-osteoporosis effects both in vitro and in vivo. Through bioassay-guided fractionation, we identified the hexane fraction (HRH) as the active fraction, which was further fractionated using preparative HPLC. Among the resulting six fractions, HRHF4 showed significant activity. In the present study, we focused on the bioassay-guided isolation of bioactive compounds from the HRHF4 fraction. We successfully identified the active HRHF43 fraction, which led us to the isolation of potential bioactive compounds (1-6). The chemical structures of these compounds were determined using NMR data, LC-MS analysis, and HR-ESI-MS data as four triterpenes, ursolic acid (1), uvaol (2), oleanolic aldehyde (3), and ursolic aldehyde (4), together with two fatty acids, methyl linoleate (5) and ethyl oleate (6). To evaluate the efficacy of promoting osteoblast differentiation and the expression of mRNA biomarkers related to osteogenesis, we tested the isolated compounds in the mouse mesenchymal stem cell line, C3H10T1/2. Alkaline phosphate staining demonstrated that triterpenes (1-4) displayed osteogenic activity. Particularly noteworthy, ursolic aldehyde (4) exhibited the most potent effect, showing an 11.2-fold higher activity at a concentration of 10 µg/mL compared to the negative control. Moreover, ursolic aldehyde (4) upregulated the gene expression of bone formation-related biomarkers, including Runx2, Osterix, Alp, and Osteopontin. These findings suggest that the fruit extract of H. rhamnoides may have potential as a nutraceutical for promoting bone health, with ursolic aldehyde (4) identified as an active constituent.

Osimertinib Combined with Systemic Chemotherapy for EGFR Mutant, T790M-Negative, Non-Small Cell Lung Cancer Patients Who Develop Leptomeningeal Metastases with Extracranial Progression to Prior EGFR TKI.

Leptomeningeal metastasis (LM) is a rare but fatal clinical condition with a short survival time. The incidence of LM from epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) has increased due to the limited efficacy of first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the central nervous system (CNS). Osimertinib is a third-generation, irreversible, CNS penetrant, oral EGFR TKI that demonstrates promising efficacy in CNS metastases regardless of T790M. Herein, we report four cases of T790M-negative EGFRm NSCLC patients treated with osimertinib combined with systemic chemotherapy, who progressed on prior EGFR TKI and developed LM with extracranial lesions. The combination treatment was well tolerated, and the mean overall survival from LM diagnosis was 14.7 months (95% confidence interval, 10.4 to 19.0). These results suggest that osimertinib combined with systemic chemotherapy would be a reasonable treatment option for T790M-negative EGFRm NSCLC patients who develop LM with extracranial progression to prior EGFR TKI. A further prospective study is warranted.

Neoadjuvant Nivolumab Plus Gemcitabine/Cisplatin Chemotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder.

PURPOSE: The activity and safety of neoadjuvant nivolumab plus gemcitabine/cisplatin (N+GC) were tested in patients with muscle-invasive bladder urothelial carcinoma (MIBC). Materials and Methods: In a prospective phase II trial, patients with cT2-T4a N0 MIBC who were eligible for cisplatin and medically appropriate to undergo radical cystectomy (RC) were enrolled. Treatment with nivolumab 3 mg/kg on days 1 and 15 plus GC (cisplatin 70 mg/m2 on day 1, and gemcitabine 1,000 mg/m2 on days 1, 8, and 15) was repeated every 28 days up to 3 or 4 cycles, depending on the surgery schedules. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging (≤ ypT1), disease-free survival (DFS), and safety. RESULTS: Between September 2019 and October 2020, 51 patients were enrolled. Neoadjuvant N+GC was well tolerated. Among 49 patients who completed neoadjuvant N+GC, clinical complete response (cCR) was achieved in 59% of intent-to-treat (ITT) population. RC was performed in 34 (69%) patients. pCR was achieved in 24% (12/49) of ITT population and 35% (12/34) of RC patients. Median DFS was not reached. Over a median follow-up of 24 months, 12 patients experienced disease recurrence and were treated with palliative therapy or surgery. Although 12 patients declined surgery and were treated with concurrent chemoradiotherapy, DFS was longer in patients with cCR after neoadjuvant therapy than those without. Preoperative programmed death-ligand 1 (PD-L1) did not correlate with pCR or pathologic downstaging rates. CONCLUSION: Neoadjuvant N+GC was feasible and provided meaningful pathologic responses in patients with MIBC, regardless of baseline PD-L1 expression (ONO-4538-X41; CRIS.nih.go.kr, KCT0003804).

Estrogenic Activity of 4-Hydroxy-Benzoic Acid from Acer tegmentosum via Estrogen Receptor α-Dependent Signaling Pathways.

Acer tegmentosum, a deciduous tree belonging to Aceraceae, has been used in traditional oriental medicine for treating hepatic disorders, such as hepatitis, cirrhosis, and liver cancer. We evaluated the estrogen-like effects of A. tegmentosum using an estrogen receptor (ER)-positive breast cancer cell line, namely MCF-7, to identify potential phytoestrogens and found that an aqueous extract of A. tegmentosum promoted cell proliferation in MCF-7 cells. Five phenolic compounds (1-5) were separated and identified from the active fraction using bioassay-guided fractionation of crude A. tegmentosum extract and phytochemical analysis. The chemical structures of the compounds were characterized as vanillic acid (1), 4-hydroxy-benzoic acid (2), syringic acid (3), isoscopoletin (4), and (E)-ferulic acid (5) based on the analysis of their nuclear magnetic resonance spectra and liquid chromatography-mass spectrometry data. All five compounds were evaluated using an E-screen assay for their estrogen-like effects on MCF-7 cells. Among the tested compounds, only 4-hydroxy-benzoic acid (2) promoted the proliferation of MCF-7 cells, which was mitigated by the ER antagonist, ICI 182,780. The mechanism underlying the estrogen-like effect of 4-hydroxy-benzoic acid (2) was evaluated via western blotting analysis to determine the expression levels of extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), serine/threonine kinase (AKT), and ERα. Our results demonstrated that 4-hydroxy-benzoic acid (2) induced the increase in the protein expression levels of p-ERK, p-AKT, p-PI3K, and p-Erα, concentration dependently. Collectively, these experimental results suggest that 4-hydroxy-benzoic acid (2) is responsible for the estrogen-like effects of A. tegmentosum and may potentially aid in the control of estrogenic effects during menopause.

Long-Term Breast Cancer Outcomes of Pregnancy-Associated Breast Cancer (PABC) in a Prospective Cohort.

Background: Given that peak age of breast cancer (BC) is younger in Asians than in Western populations, relatively higher prevalence of pregnancy-associated breast cancer (PABC) has been reported. This study aimed to analyze the characteristics and clinical outcomes of PABC in Korea. Methods: We defined PABC as BC diagnosed during pregnancy or in the first postpartum year. We compared the clinicopathological characteristics and BC outcomes between patients with PABC and non-PABC patients in the prospective YBC cohort from Samsung Medical Center. Results: In total, 1492 patients were initially enrolled, and 1364 patients were included, of which 93 had PABC (6.8%). The median age of patients with PABC was 34 years. Hormone receptor expression was lower (64.6% vs 74.6%) and frequency of HER2 overexpression was higher (26.9% vs 17.6%) in patients with PABC than in non-PABC patients. The 5-year overall survival (OS) rates were 83.2% and 93.4% in patients with PABC and non-PABC patients, respectively (p < 0.001). The 5-year disease-free survival (DFS) rates were 72.2% and 83.8% in PABC and non-PABC patients. Conclusion: Compared to non-PABC patients, patients with PABC had poorer OS and DFS in this prospective cohort. Exploratory biomarker analysis for PABC is warranted.

Anti-Osteoporosis Effects of the Fruit of Sea Buckthorn (Hippophae rhamnoides) through Promotion of Osteogenic Differentiation in Ovariectomized Mice.

The fruit of Hippophae rhamnoides has been widely used for medicinal purposes because of its anti-inflammatory, antioxidant, antiplatelet, and antimicrobial effects. Since there are no clear reports on the therapeutic efficacy of H. rhamnoides in osteoporosis, this study aimed to confirm the potential use of H. rhamnoides for the treatment of osteoporosis through its osteogenic differentiation-promoting effect in ovariectomized mice. Through an in vitro study, we compared the effects of the EtOH extract of H. rhamnoides fruits (EHRF) on the differentiation of C3H10T1/2, a mouse mesenchymal stem cell line, into osteoblasts based on alkaline phosphatase (ALP) staining and the relative expression of osteogenesis-related mRNAs. The EHRF significantly stimulated the differentiation of mesenchymal stem cells into osteoblasts and showed 7.5 times (* p < 0.05) higher osteogenesis than in the untreated control. A solvent fractionation process of EHRF showed that the hexane-soluble fraction (HRH) showed 10.4 times (** p < 0.01) higher osteogenesis than in the untreated control. Among the subfractions derived from the active HRH by preparative HPLC fractionation, HRHF4 showed 7.5 times (* p < 0.05) higher osteogenesis than in the untreated naïve cells, and HRH and HRHF4 fractions showed 22.6 times (*** p < 0.001) stronger osteogenesis activity than in the negative control. Osteoporosis was induced by excision of both ovaries in 9-week-old female ICR mice for in vivo analysis, and two active fractions, HRH and HRHF4, were administered orally for three months. During the oral administration period, body weight was measured weekly, and bone mineral density (BMD) and body fat density were measured simultaneously using a DEXA machine once a month. In particular, during the in vivo study, the average BMD of the ovariectomized group decreased by 0.0009 g/cm2, whereas the average BMD of the HRH intake group increased by 0.0033 g/cm2 (* p < 0.05) and that of the HRHF4 intake group increased by 0.0059 g/cm2 (** p < 0.01). The HRH and HRHF4 intake groups significantly recovered the mRNA and protein expression of osteogenic genes, including ALP, Osteopontin, Runx2, and Osterix, in the osteoporosis mouse tibia. These findings suggest that the active fractions of H. rhamnoides fruit significantly promoted osteoblast differentiation in mesenchymal stem cells and increased osteogenic gene expression, resulting in an improvement in bone mineral density in the osteoporosis mouse model. Taken together, H. rhamnoides fruits are promising candidates for the prevention and treatment of osteoporosis.

Expression of PD-L1 as a predictive marker of sensitivity to immune checkpoint inhibitors in patients with advanced biliary tract cancer.

Background: Expression of programmed death-ligand 1 (PD-L1) has been reported to correlate with response to immune checkpoint inhibitors (ICIs) in various tumor types. However, there are few data on the role of PD-L1 expression as a predictive and prognostic biomarker of sensitivity to ICIs in patients with advanced biliary tract cancer (BTC). Objectives: We evaluated the role of PD-L1 expression as a predictive and prognostic biomarker of response to ICIs in patients with advanced BTC. Design: We retrospectively analyzed data from 83 advanced BTC patients who received ICIs as second- or third-line treatment between February 2018 and April 2021. Methods: All patient data analysis included evaluation of PD-L1 expression by the combined positive score (CPS). Results: Among 83 patients, 56 (67.5%) had PD-L1 positivity (CPS ⩾ 1). The objective response rate (ORR) to ICIs was significantly higher in advanced BTC patients with PD-L1 expression compared to those without PD-L1 expression (17.8% versus 0%, p = 0.026). However, there were no significant differences in median progression-free survival (PFS; 2.9 versus 2.6 months, p = 0.330) and median overall survival (OS; 8.1 versus 6.3 months, p = 0.289) as a response to ICIs between patients with and without PD-L1 expression. Also, there were no significant differences in ORR, PFS, and OS as a response to ICIs in conjunction with a response to a prior gemcitabine plus cisplatin regimen (p = 0.654, p = 0.278, and p = 0.302, respectively). Conclusions: The present study suggests that the expression of PD-L1 alone was not sufficient as a novel marker to select advanced BTC patients who might benefit from ICIs. Additional comprehensive studies of biomarkers that can assist in predicting BTC patient responses to pembrolizumab and/or nivolumab therapy are required.

Subsequent Systemic Therapy following Platinum and Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.

Treatment of metastatic urothelial carcinoma (mUC) after failure with platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) remains controversial. To explore the role of subsequent systemic therapy, medical records from 436 patients who were consecutively treated with chemotherapy for mUC between May 2017 and April 2021 were collected from a single-center cancer registry. The primary endpoint was overall survival (OS), and progression-free survival (PFS) and response rate (RR) were also assessed. Among the 318 patients who failed both platinum and ICIs, subsequent therapy was delivered to 166 (52%) patients: taxanes (n = 56), platinum rechallenge (n = 46), pemetrexed (n = 39), and clinical trials (n = 25). Objective responses to third-line therapy were noted in 50 patients (RR, 30%; 95% CI, 23-37%). The patients who were enrolled in clinical trials and treated with platinum rechallenge were significantly more likely to respond than those treated with taxanes or pemetrexed. The median PFS and OS were 3.5 months (95% CI, 2.9-4.2 months) and 9.5 months (95% CI, 8.1-11.0 months), respectively. Similar to RR, PFS and OS were longer for the patients who were enrolled in clinical trials. Based on multivariate analyses, good performance status and enrollment in clinical trials are associated with benefits from subsequent therapy for pretreated mUC.

Perioperative HER2 targeted treatment in early stage HER2-positive breast cancer.

Although human epidermal growth factor receptor 2 (HER2)-positive breast cancer was associated with poor prognosis, it has been changed after the development of trastuzumab. There has been great progress in perioperative HER2-targeting treatment, and investigations of several novel drugs and their combinations are ongoing. Adjuvant trastuzumab with or without pertuzumab for 1 year in combination with concomitant chemotherapy has become a standard treatment in high-risk node-negative tumors or node-positive HER2-positive early breast cancer patients without residual disease or who have not received neoadjuvant treatment. For low-risk HER2-positive early breast cancer patients, adjuvant paclitaxel and 1-year trastuzumab are possible alternatives. For residual disease after neoadjuvant treatment, adjuvant trastuzumab emtansine (T-DM1) for 14 cycles is a standard treatment. Non-anthracycline chemotherapy with dual anti-HER2 targeting of trastuzumab and pertuzumab represents one of the preferred neoadjuvant regimens to achieve higher pathologic complete response (pCR) rates and better clinical outcomes. Further research is needed to develop and validate potential biomarkers to predict pCR, which could help escalate or de-escalate anti-HER2 therapy. Trials incorporating novel agents such as T-DM1, trastuzumab deruxtecan (T-DXd), and immune checkpoint inhibitors and trying to de-escalate treatments in neoadjuvant setting are ongoing. In the future, tailored treatments such as no adjuvant therapy, various HER2-directed therapies alone with chemotherapy, combinations of various HER2-directed therapies and chemotherapy, addition of immune checkpoint inhibitors, and omission of surgery will be individualized in HER2-positive early breast cancer patients.

Recent advances in pain management based on nanoparticle technologies.

BACKGROUND: Pain is a vital sense that indicates the risk of injury at a particular body part. Successful control of pain is the principal aspect in medical treatment. In recent years, the advances of nanotechnology in pain management have been remarkable. In this review, we focus on literature and published data that reveal various applications of nanotechnology in acute and chronic pain management. METHODS: The presented content is based on information collected through pain management publications (227 articles up to April 2021) provided by Web of Science, PubMed, Scopus and Google Scholar services. RESULTS: A comprehensive study of the articles revealed that nanotechnology-based drug delivery has provided acceptable results in pain control, limiting the side effects and increasing the efficacy of analgesic drugs. Besides the ability of nanotechnology to deliver drugs, sophisticated nanosystems have been designed to enhance imaging and diagnostics, which help in rapid diagnosis of diseases and have a significant impact on controlling pain. Furthermore, with the development of various tools, nanotechnology can accurately measure pain and use these measurements to display the efficiency of different interventions. CONCLUSIONS: Nanotechnology has started a new era in the pain management and many promising results have been achieved in this regard. Nevertheless, there is still no substantial and adequate act of nanotechnology in this field. Therefore, efforts should be directed to broad investigations.

A Retrospective Study of First-Line Therapy Involving Immune Checkpoint Inhibitors in Patients With Poor Risk Metastatic Renal Cell Carcinoma.

Purpose: Patients with International Metastatic RCC Database Consortium (IMDC) poor risk metastatic renal cell carcinoma (mRCC) rarely respond to first-line tyrosine kinase inhibitors (TKIs) including sunitinib, and carries a very poor prognosis. In recent years, combination therapy involving immune checkpoint inhibitors (ICIs) have demonstrated superior efficacy to sunitinib in poor risk disease. Materials and Methods: In a retrospective study using a cancer chemotherapy registry, 206 consecutive patients with mRCC in the first-line setting were identified between Oct 2019 and Dec 2020. Sixty-one patients had a poor risk mRCC, and were treated with TKI monotherapy (n=36), nivolumab plus ipilimumab (n=16), or pembrolizumab plus axitinib (n=9). Endpoints included overall survival (OS), progression-free survival (PFS), response rate (RR), and safety. Results: Patients' median age was 61 years and the median number of risk factors was 3 (range, 3-5). During a median 23.0 months of follow-up, the median OS was 24.3 months with ICI-based combinations and 14.8 months with TKI monotherapy, and the median PFS periods were 9.3 months and 3.4 months, respectively. An objective response occurred in 60% of the patients receiving ICI-based combinations and in 19% of those receiving TKI monotherapy (P=0.001). In the multivariate regression model, number of IMDC risk factors and the ICI-based combination therapy were independent prognostic factors for PFS. All-causality grade 3 or 4 adverse events were 44% for ICI-based combinations and 50% for TKI monotherapy. Conclusions: Among patients with poor risk mRCC, first-line ICI-based therapy showed significantly longer OS and PFS, as well as a higher RR, than TKI monotherapy.

Nano-liposomal zein hydrolysate for improved apoptotic activity and therapeutic index in lung cancer treatment.

Lung cancer is one of the most common cancers in the world with a high mortality rate. Zein is a protein compound whose protein isolate is not useful and whose protein hydrolysis produces biological activity. By encapsulating this bioactive compound inside the nanoparticles (NPs), it causes itself to reach the tumor site and destroy it rapidly. In this study, the effects of zein hydrolysate (ZH) and nano-liposomal ZH (N-ZH) were investigated on the human A549 cell line. Western blotting and cell cycle analyses showed that ZH and N-ZH caused cytotoxicity. They induced apoptosis via cell cycle arrest at the G0 phase, as well as significant increases in pro-apoptotic genes, such as Bax, caspase-3, -8, -9, and p53, accompanied with significant decreases in the anti-apoptotic marker Bcl-2. Based on the results, the cytotoxic and anticancer effects of N-ZH were higher than those of free ZH. In conclusion, liposomes improved the performance of ZH and dramatically reduced the IC50 value of ZH. These findings provided the experimental evidence that N-ZH with favorable anticancer activity can be used as a therapeutic agent and strategy for lung cancer treatment in future clinical trials.

Phytochemical Investigation of Marker Compounds from Indigenous Korean Salix Species and Their Antimicrobial Effects.

Salix species, including willow trees, are distributed in the temperate regions of Asian countries, including South Korea. Willow trees are used to treat pain and inflammatory diseases. Due to the medicinal properties of willow trees, pharmacological studies of other Salix spp. have gained attention; however, only a few studies have investigated the phytochemicals of these species. As part of our ongoing natural product research to identify bioactive phytochemicals and elucidate their chemical structures from natural resources, we investigated the marker compounds from indigenous Korean Salix species, namely, Salix triandra, S. chaenomeloides, S. gracilistyla, S. koriyanagi, S. koreensis, S. pseudolasiogyne, S. caprea, and S. rorida. The ethanolic extract of each Salix sp. was investigated using high-performance liquid chromatography combined with thin-layer chromatography and liquid chromatography−mass spectrometry-based analysis, and marker compounds of each Salix sp. were isolated. The chemical structures of the marker compounds (1−8), 3-(4-hydroxyphenyl)propyl ß-D-glucopyranoside (1), 2-O-acetylsalicin (2), 1-O-p-coumaroyl glucoside (3), picein (4), isograndidentatin B (5), 2'-O-acetylsalicortin (6), dihydromyricetin (7), and salicin (8) were elucidated via nuclear magnetic resonance spectroscopy and high-resolution liquid chromatography−mass spectrometry using ultrahigh-performance liquid chromatography coupled with a G6545B Q-TOF MS system with a dual electrospray ionization source. The identified marker compounds 1−8 were examined for their antimicrobial effects against plant pathogenic fungi and bacteria. Dihydromyricetin (7) exhibited antibacterial activity against Staphylococcus aureus, inducing 32.4% inhibition at a final concentration of 125 µg/mL with an MIC50 value of 250 µg/mL. Overall, this study isolated the marker compounds of S. triandra, S. chaenomeloides, S. gracilistyla, S. koriyanagi, S. koreensis, S. pseudolasiogyne, S. caprea, and S. rorida and identified the anti-Staphylococcus aureus bacterial compound dihydromyricetin.

The Impact of Tumor Mutation Burden on the Effect of Frontline Trastuzumab Plus Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Advanced Gastric Cancers.

BACKGROUND: Trastuzumab is a HER2-trargeted humanized monoclonal antibody that has been studied as a first-line treatment for patients with HER2-positive advanced gastric cancer (AGC). The effect of anti-HER2 therapy according to tumor mutational burden (TMB) in HER2-positive AGC remains unclear. METHODS: We performed next-generation sequencing (NGS), including TMB analysis, in 31 HER2-positive AGC patients with trastuzumab plus chemotherapy as first-line therapy for recurrent (n=8) or metastatic (n=23) tumors. The TruSight Oncology 500 Assay from Illumina (San Diego, CA, USA) was used to evaluate TMB. RESULTS: Among 31 patients, 30 had tumors with immunohistochemistry (IHC) 3+, and one was IHC 2+ and silver in situ hybridization (SISH) positive. The median age was 57.0 years old (range, 35-76), and the majority had tumors with low TMB (87.1%, n=27/31). Only four (12.9%) had tumors with high TMB. Of these four, three achieved complete response (CR) or partial response (PR) to treatment, and the remaining patient was not evaluable for tumor response. Objective response rate (ORR) to trastuzumab plus chemotherapy showed a favorable trend in patients with high TMB (75.0%, n=3/4) compared to patients with low TMB (59.3%, n=16/27) (P=0.546). The median progression-free survival (PFS) was not reached in the TMB-high group but was 8.0 months (95% CI, 7.6-8.5) in the TMB-low group (P=0.019). CONCLUSION: The status of TMB could be a novel biomarker in predicting the efficacy of trastuzumab plus chemotherapy in HER2-positive AGCs.

Tumor Mutational Burden as a Biomarker for Advanced Biliary Tract Cancer.

Background: High tumor mutational burden (TMB-H) has been reported as a predictive marker to immunotherapy or prognostic marker in various tumor types. However, there has been little study of the role of TMB-H in advanced biliary tract cancer (BTC). Methods: We analyzed 119 advanced BTC patients who received Gemcitabine/Cisplatin (GP) as a first-line treatment between November 2019 and April 2021. Next-generation sequencing (NGS), including TMB analysis, as a routine clinical practice was performed in 119 patients. The TruSightTM Oncology 500 assay from Illumina was used as a cancer panel. Results: Among 119 patients, 18 (18.5%) had a tumor with high TMB (≥ 10 Muts/Mb). There were no significant differences between the status of TMB and clinical outcomes with GP, including objective response rate (ORR) (P = .126), disease control rate (DCR) (p = .454), and median progression-free survival (PFS) (p = .599). The median overall survival (OS) was not different between patients with TMB-H and no TMB-H (p = .430). In subgroup analysis of 32 patients receiving immune checkpoint inhibitor (ICIs), there were significant differences in ORR (p = .034) and median PFS (p = .025) with ICIs between patients with and without TMB-H. Conclusions: This study revealed that TMB-H in advanced BTCs did not have a prognostic or role in the standard first-line treatment. However, TMB-H might be a predictive biomarker for response to ICIs in advanced BTC.