Nationwide precision oncology pilot study: KOrean Precision Medicine Networking Group Study of MOlecular profiling-guided therapy based on genomic alterations in advanced solid tumors (KOSMOS) KCSG AL-20-05.

BACKGROUND: Next-generation sequencing (NGS) has become widely available but molecular profiling-guided therapy (MGT) had not been well established in the real world due to lack of available therapies and expertise to match treatment. Our study was designed to test the feasibility of a nationwide platform of NGS-guided MGT recommended by a central molecular tumor board (cMTB) for metastatic solid tumors. PATIENTS AND METHODS: Patients with advanced or metastatic solid tumors with available NGS results and without standard treatment were enrolled. The cMTB interpreted the patients' NGS reports and recommended the following: (i) investigational medicinal products (IMPs) approved in other indications; (ii) alternative treatments; (iii) clinical trials. The primary variables were the proportion of patients with actionable genomic alterations and those receiving MGT as per cMTB recommendations. Others included treatment duration (TD), overall response rate (ORR), disease control rate (DCR), and safety. RESULTS: From February 2021 to February 2022, 193 cases [99 (51.3%) men; median age 58 years (range 24-88 years); median line of previous treatment 3 (range 0-9)] from 29 sites were enrolled for 60 cMTB sessions. The median time from case submission to cMTB discussion was 7 days (range 2-20 days), and to IMP treatment initiation was 28 days (range 14-90 days). Actionable genetic alterations were found in 145 patients (75.1%). A total of 89 (46.1%) patients received actual dosing of IMPs, and 10 (5.2%) were enrolled in cMTB-recommended clinical trials, achieving an MGT rate of 51.3%. ORR and DCR of IMPs were 10.1% and 72.5%, respectively. The median TD was 3.5 months [95% confidence interval (CI) 2.8-5.5 months], and the 4-month TD rate was 44.9%. The median overall survival of patients who received IMPs was 6.9 months (95% CI 5.2-10.0 months). CONCLUSION: KOSMOS confirmed the feasibility of MGT recommended by the cMTB, achieving a high MGT match rate and promising effectiveness in heavily pretreated advanced cancer patients.

Dacomitinib in EGFR-mutant non-small-cell lung cancer with brain metastasis: a single-arm, phase II study.

INTRODUCTION: Dacomitinib showed superior progression-free survival (PFS) and overall survival compared to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations in the ARCHER1050 study. However, because that study did not include patients with brain metastases, the efficacy of dacomitinib in patients with brain metastases has not been clarified. PATIENTS AND METHODS: This single-arm phase II study enrolled 30 patients with treatment-naïve advanced NSCLC harboring activating EGFR mutations from January 2021 to June 2021 and started them on dacomitinib (45 mg/day). All patients had non-irradiated brain metastases with a diameter of ≥5 mm. The primary endpoint was confirmed intracranial objective response rate (iORR). RESULTS: Patients had exon 19 deletions (46.7%) and L858R mutations in exon 21 (55.3%). The confirmed iORR was 96.7% (29/30), with an intracranial complete response of 63.3%. Median intracranial PFS (iPFS) was not reached, with 12- and 18-month iPFS rates of 78.6% [95% confidence interval (CI) 64.8% to 95.4%] and 70.4% (95% CI 54.9% to 90.1%), respectively. In the competing risk analysis, the 12-month cumulative incidence of intracranial progression was 16.7%. Regarding the overall efficacy for intracranial and extracranial lesions, the overall ORR was 96.7%, and the median PFS was 17.5 months (95% CI 15.2 months-not reached). Grade 3 or higher treatment-related adverse events were reported in 16.7% of patients, and 83.3% required a reduced dacomitinib dose to manage adverse events. However, none permanently discontinued dacomitinib treatment due to treatment-related adverse events. CONCLUSIONS: Dacomitinib has outstanding intracranial efficacy in patients with EGFR-mutant NSCLC with brain metastases.

HLA-corrected tumor mutation burden and homologous recombination deficiency for the prediction of response to PD-(L)1 blockade in advanced non-small-cell lung cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited response to ICIs remain unclear. PATIENTS AND METHODS: We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients. RESULTS: Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved. CONCLUSION: HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.

In vitro antidiabetic potential of the fruits of Crataegus pinnatifida.

In an attempt to develop alternative medicine for the treatment of diabetes and related complications, the antidiabetic potential of the fruits of Crataegus pinnatifida was evaluated. The antidiabetic potential of the methanol (MeOH) extract as well as different solvent soluble fractions of the fruits of C. pinnatifida was evaluated via α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), rat lens aldose reductase (RLAR), and advanced glycation end products (AGEs) formation inhibitory assays. The MeOH extract showed potent inhibitory activity against α-glucosidase, PTP1B, and AGEs formation with IC50 values of 122.11, 3.66 and 65.83 µg/ml respectively, while it showed moderate inhibitory activity against RLAR with the IC50 value of 160.54 µg/ml. Among different fractions, the ethyl acetate (EtOAc) and the dichloromethane (CH2Cl2) fractions were found as active fractions exhibiting potential α-glucosidase, PTP1B, RLAR inhibitory, and AGEs formation inhibitory activities. Seven compounds including hyperoside, chlorogenic acid, ursolic acid, oleanolic acid, 3-epicorosolic acid, ß-sitosterol, ß-sitosterol glucoside were isolated from these two fractions. 3-Epicorosolic acid showed both potent α-glucosidase and PTP1B inhibitory activities with IC50 values of 30.18 and 4.08 µg/ml respectively. Moreover, kinetic study revealed that 3-epicorosolic acid showed mixed type inhibition against PTP1B, while it showed uncompetitive inhibition against α-glucosidase. Therefore, these results suggest that the fruits of C. pinnatifida and its constituents have potential antidiabetic activity which might be used as a functional food for the treatment of diabetes and associated complications.

Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) who received taxane plus trastuzumab treatment.

BACKGROUND: The aim of this study was to investigate the role of human epidermal growth factor receptor (HER3) and PTEN expression in patients with HER2-overexpressing metastatic breast cancer (MBC). METHODS: One hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as first-line therapy were included in this analysis. Immunohistochemical (IHC) staining with HER3 and PTEN antibodies were conducted retrospectively. RESULTS: Patients who had negative HER3 staining (62.4%) had a better progression-free survival (PFS) than did those who had positive HER3 staining (P=0.001; median PFS, 21 vs 11 months). Patients who had a PTEN score >20 (78.1%) showed longer PFS than did those with a PTEN score ≤20 (P=0.006; median PFS, 13 vs 9 months). Patients who had a PTEN score >20 exhibited a longer overall survival (OS) than did those with a PTEN score ≤20 (P=0.005; median OS, 48 vs 25 months). HER3 negativity and PTEN loss were identified as independent risk factors for PFS. PTEN loss was identified as an independent risk factor for OS. CONCLUSION: HER3 and PTEN expressions may be predictive markers, and PTEN expression may be a predictive and prognostic biomarker for trastuzumab treatment in HER2-positive MBCs.

Clinical significance of upper-arm cephalic vein patency in autogenous radial-cephalic wrist fistulas for hemodialysis.

OBJECTIVES: To investigate the significance of upper-arm cephalic veins (UACVs) in radial-cephalic arteriovenous fistulas (RCAVFs), the medical records of 183 patients who had undergone RCAVF creation were reviewed retrospectively. METHODS: The patients were divided into two groups according to the status of the UACV upon preoperative venography: group A of 153 cases (83.6%) with a patent UACV and group B of 30 cases (16.3%) with a stenosed or occluded UACV. The clinical outcomes were compared. RESULT: RCAVFs in group B had a significantly higher maturation failure rate (26.7% vs. 9.8%, p = 0.009) and lower primary/secondary patency rates (log-rank test, p < 0.0001) than those in the group A. The patients in group B required more frequent endovascular intervention to maintain access function (p = 0.002). The most common stenosis site was a draining vein in group B, in comparison to juxta-anastomosis in group A. In the multivariate analyses, the status of the UACV was an independent predictor of the primary and secondary patency rates of RCAVFs (p < 0.005). CONCLUSION: UACV patency has a significant impact on clinical outcome for RCAVFs. When planning an RCAVF placement, venous status including the UACV should be considered.

Magnetic resonance imaging of the bone marrow after bone marrow transplantation or immunosuppressive therapy in aplastic anemia.

To compare magnetic resonance (MR) images of the bone marrow (BM) after bone marrow transplantation or immunosuppressive therapy in patients with aplastic anemia (AA), MR imaging of BM was reviewed retrospectively in 16 patients (13 males and 3 females, mean age 26 yr) with AA who completely responded clinically after transplantation or immunosuppressive therapy. The signal intensity (SI) of BM was classified into four patterns according to the increasing amount of cellular marrow, i.e., pattern I to IV. SI of MR imaging of BM exhibited an increase of cellular marrows following both transplantation and immunosuppressive therapy. Of the eight patients on transplantation, the SI of the lumbar spinal BM was pattern III in two patients and IV in six on T1-weighted and short tau inversion recovery (STIR) images. In the eight patients with immunosuppressive therapy, the SI of the lumbar spinal BM was pattern II in one, III in five, and IV in two on T1-weighted images and pattern II in one, III in four, and IV in three on STIR images. SI on MR imaging of the lumbar spinal BM showed a more cellular pattern in patients on transplantation than in those on immunosuppressive therapy.

A new cyclic phenyllactamide from Salvia miltiorrhiza.

From the rhizome of Salvia miltiorrhiza, a new cyclic phenyllactamide was isolated and characterized as 2,10,11-trihydroxy-8-methoxy-1,6,7,8-tetrahydro-2H-benzo[e]azecine-3,5-dione (1) from spectroscopic evidence. The new compound was found to be a scavenger of 1,1-diphenyl-2-picrylhydrazyl radical.

Comparative evaluation of antioxidant potential of alaternin (2-hydroxyemodin) and emodin.

The antioxidant activities of alaternin (2-hydroxyemodin) and emodin were compared for their respective potentials to inhibit lipid peroxidation in the linoleic acid system by the thiocyanate method, to inhibit total reactive oxygen species generation in kidney homogenates using 2',7'-dichlorodihydrofluorescein diacetate, to inhibit peroxynitrite formation by the 3-morpholinosydnonimine system, which generates superoxide radical and nitrogen monooxide, and to scavenge authentic peroxynitrites. Both alaternin and emodin were found to inhibit the peroxidation of linoleic acid by the thiocyanate method in a dose-dependent manner. Whereas the former shows inhibitory activities in reactive oxygen- and nitogen-mediated reactions, the latter does not. These results indicate that alaternin is a potentially effective and versatile antioxidant and can be used to protect biological systems and functions against various oxidative stresses.

A cyclohexanonyl bromophenol from the red alga Symphyocladia latiuscula.

From an extract of the red alga Symphyocladia latiuscula, a bromophenol (1) was isolated and characterized as (2R)-2-(2,3, 6-tribromo-4,5-dihydroxybenzyl)-cyclohexanone based on the spectroscopic evidence. The bromophenol was found to be a scavenger of 1,1-diphenyl-2-picrylhydrazyl radical.

Antioxidant flavonoids and chlorogenic acid from the leaves of Eriobotrya japonica.

The antioxidant activity of Eriobotrya japonica was determined by measuring the radical scavenging effect on DPPH (1,1-diphenyl-2-picrylhydrazyl) radical and lipid peroxidation produced when mouse liver homogenate was exposed to the air at 37 degrees C, using 2-thiobarbituric acid (TBA). The methanol extract and its fractions of Eriobotrya japonica leaves showed strong antioxidant activity. The antioxidant activity of EtOAc and n-BuOH soluble fractions were stronger than the others, and were further purified by repeated silica gel, MCl gel CHP-20P, and Sephadex LH-20 column chromatography. Antioxidant chlorogenic acid, quercetin-3-sambubioside from n-BuOH fraction, and methyl chlorogenate, kaempferol- and quercetin-3-rhamnosides, together with the inactive ursolic acid and 2 alpha-hydroxyursolic acid from EtOAc fraction were isolated. Antioxidant flavonoids and chlorogenic acid also showed prominent inhibitory activity against free radical generation in dichlorofluorescein (DCF) method.

Chlorogenic acid, an antioxidant principle from the aerial parts ofArtemisia iwayomogi that acts on 1,1-diphenyl-2-picrylhydrazyl radical.

The antioxidant activity ofArtemisia iwayomogi was determined by measuring the radical scavenging effect on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical The methanol extract ofA. iwayomogi showed strong antioxidant activity, and thus fractionated with several solvents. The antioxidant activity potential of the individual fraction was in the order of ethyl acetate>n-butanol>water>chloroform>n-hexane fraction. The ethyl acetate andn-butanol soluble fractions exhibiting strong antioxidant activity were further purified by repeated silica gel and Sephadex LH-20 column chromatography. Antioxidant chlorogenic acid was isolated as one of the active principles from then-butanol fraction, together with the inactive components, 1-octacosanol, scopoletin, scopolin, apigenin 7,4'-di-O-methylether luteolin 6,3'-di-O-methylether (jaceosidin), apigenin 7-methylether (genkwanin), 2,4-dihydroxy-6-methoxyacetophenone 4-O-beta-D-glucopyranoside and quebrachitol. The antioxidant activity of chlorogenic acid was comparable to that of L-ascorbic acid, which is a well known antioxidant.