Incidence and Characteristics of Multiple Primary Cancers: A 20-Year Retrospective Study of a Single Cancer Center in Korea.

Rising cancer survival rates have led to an increased risk of multiple primary cancers (MPCs). Data on MPCs in South Korea are limited. This study aimed to address incidence and clinical characteristics of MPCs in a single cancer center in Korea during a 20-year period. We retrospectively analyzed 96,174 cancer patients at the Korea Cancer Center Hospital between 2003 and 2022, identifying 2167 patients with metachronous MPCs based on Surveillance, Epidemiology, and End Results SEER criteria. We categorized patients by cancer type (15 major solid cancer groups and 3 major hematologic cancer groups), including pathological diagnosis, assessed latency periods, and relative risks (RRs) for developing MPCs. The overall MPC incidence was 2.3%. Breast cancer (15.7%) was the most common primary cancer, and lung cancer (15.2%) was the most frequent second primary cancer. The median latency period for second primary cancers was 4.1 years. Decreasing latency periods for third and fourth primary cancers were observed (2.1 years and 1.6 years, respectively). Most cancers maintained their dominant pathological type despite notable changes in the prevalence of specific pathologies for certain types of second primaries. Lymphoma showed the highest RR (2.1) for developing MPCs. Significant associations were found between specific primary and subsequent cancers, including breast-ovary, thyroid-breast, stomach-pancreas, colorectal-head and neck, lung-prostate, and lymphoma-myeloid neoplasms. These findings contribute to a better understanding of MPC occurrence. They can inform future research on their etiology and development of improved management strategies.

JNC-1043, a Novel Podophyllotoxin Derivative, Exerts Anticancer Drug and Radiosensitizer Effects in Colorectal Cancer Cells.

The objective of this study was to determine whether (5S)-5-(4-benzyloxy-3,5-dimethoxy-phenyl)-5,9-dihydro-8H-furo [3',4':6,7] naphtho [2,3-d] [1,3]dioxol-6-one (JNC-1043), which is a novel chemical derivative of ß-apopicropodophyllin, acts as a novel potential anticancer reagent and radiosensitizer in colorectal cancer (CRC) cells. Firstly, we used MTT assays to assess whether JNC-1043 could inhibit the cell proliferation of HCT116 and DLD-1 cells. The IC50 values of these cell lines were calculated as 114.5 and 157 nM, respectively, at 72 h of treatment. Using doses approximating the IC50 values, we tested whether JNC-1043 had a radiosensitizing effect in the CRC cell lines. Clonogenic assays revealed that the dose-enhancement ratios (DER) of HCT116 and DLD-1 cells were 1.53 and 1.25, respectively. Cell-counting assays showed that the combination of JNC-1043 and γ-ionizing radiation (IR) enhanced cell death. Treatment with JNC-1043 or IR alone induced cell death by 50~60%, whereas the combination of JNC-1043 and IR increased this cell death by more than 20~30%. Annexin V-propidium iodide assays showed that the combination of JNC-1043 and IR increased apoptosis by more 30~40% compared to that induced by JNC-1043 or IR alone. DCFDA- and MitoSOX-based assays revealed that mitochondrial ROS production was enhanced by the combination of JNC-1043 and IR. Finally, we found that suppression of ROS by N-acetylcysteine (NAC) blocked the apoptotic cell death induced by the combination of JNC-1043 and IR. The xenograft model also indicated that the combination of JNC-1043 and IR increased apoptotic cell death in tumor mass. These results collectively suggest that JNC-1043 acts as a radiosensitizer and exerts anticancer effects against CRC cells by promoting apoptosis mediated by mitochondrial ROS.

Comparative Pharmacodynamics of Three Different Botulinum Toxin Type A Preparations following Repeated Intramuscular Administration in Mice.

Botulinum neurotoxin type A (BoNT/A) causes muscle paralysis by blocking cholinergic signaling at neuromuscular junctions and is widely used to temporarily correct spasticity-related disorders and deformities. The paralytic effects of BoNT/A are time-limited and require repeated injections at regular intervals to achieve long-term therapeutic benefits. Differences in the level and duration of effectivity among various BoNT/A products can be attributed to their unique manufacturing processes, formulation, and noninterchangeable potency units. Herein, we compared the pharmacodynamics of three BoNT/A formulations, i.e., Botox® (onabotulinumtoxinA), Xeomin® (incobotulinumtoxinA), and Coretox®, following repeated intramuscular (IM) injections in mice. Three IM injections of BoNT/A formulations (12 U/kg per dose), 12-weeks apart, were administered at the right gastrocnemius. Local paresis and chemodenervation efficacy were evaluated over 36 weeks using the digit abduction score (DAS) and compound muscle action potential (CMAP), respectively. One week after administration, all three BoNT/A formulations induced peak DAS and maximal reduction of CMAP amplitudes. Among the three BoNT/A formulations, only Coretox® afforded a significant increase in paretic effects and chemodenervation with a prolonged duration of action after repeated injections. These findings suggest that Coretox® may offer a better overall therapeutic performance in clinical settings.

Radiosensitizer Effect of ß-Apopicropodophyllin against Colorectal Cancer via Induction of Reactive Oxygen Species and Apoptosis.

ß-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an anti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP exerted an anti-cancer effect against the CRC cell lines HCT116, DLD-1, SW480, and COLO320DM, with IC50 values of 7.88 nM, 8.22 nM, 9.84 nM, and 7.757 nM, respectively, for the induction of DNA damage. Clonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either treatment alone, suggesting that APP sensitized CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in the in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

Comparative Analysis of Hyaluronidase-Mediated Degradation Among Seven Hyaluronic Acid Fillers in Hairless Mice.

PURPOSE: Hyaluronic acid (HA) is the most common injectable dermal filler used for soft-tissue augmentation, and can be removed non-surgically by directly injecting hyaluronidase. In this study, the hyaluronidase-mediated degradation of different types of HA fillers implanted subcutaneously at the back of hairless mice having filler residence time of four days or three months were compared. METHODS: Two sites at the back of female hairless mice were subcutaneously implanted with 0.1-mL of one of the seven HA fillers (NLL, NL, NDL, NVL, and ND, JUVX+, and RESLYFT) and injected with 30 IU or 60 IU hyaluronidase per 0.1-mL filler after reaching a filler residence time of 4 or 91 days, respectively. Filler bolus projection was measured using three-dimensional optical imaging over a 72 h period, and the implantation sites were histologically examined 2 weeks after hyaluronidase injection. RESULTS: Following hyaluronidase injection, all seven HA fillers showed a rapid decrease of filler volume within 24 h, and complete degradation was confirmed by histological examination after 2 weeks. There was no significant difference in filler volume reduction rate among the seven HA fillers, and no evidence of macroscopic or microscopic adverse effects were observed at the implantation sites. CONCLUSION: All seven HA fillers show comparable susceptibility to hyaluronidase-mediated degradation. HA fillers with prolonged filler residence time may require a higher dose of hyaluronidase to achieve efficient degradation owing to tissue integration.

Radiation-induced IL-1ß expression and secretion promote cancer cell migration/invasion via activation of the NF-κB-RIP1 pathway.

Here, we demonstrate that interleukin-1ß (IL-1ß) contributes to the γ-ionizing radiation (IR)-induced increase of migration/invasion in A549 lung cancer cells, and that this occurs via RIP1 upregulation. We initially observed that the protein expression and secreted concentration of IL-1ß were increased upon exposure of A549 cells to IR. We then demonstrated that IR-induced IL-1ß is located downstream of the NF-κB-RIP1 signaling pathway. Treatments with siRNA and specific pharmaceutical inhibitors of RIP1 and NF-κB suppressed the IR-induced increases in the protein expression and secreted concentration of IL-1ß. IL-1Ra, an antagonist of IL-1ß, treatment suppressed the IR-induced epithelial-mesenchymal transition (EMT) and IR-induced invasion/migration in vitro. These results suggest that IL-1ß could regulate IR-induced EMT. We also found that IR could induce the expression of IL-1ß expression in vivo and that of IL-1 receptor (R) I/II in vitro and in vivo. The IR-induced increases in the protein levels of IL-1 RI/II and IL-1ß suggest that an autocrine loop between IL-1ß and IL-1 RI/II might play important roles in IR-induced EMT and migration/invasion. Based on these collective results, we propose that IR concomitantly activates NF-κB and RIP1 to trigger the NF-κB-RIP1-IL-1ß-IL-1RI/II-EMT pathway, ultimately promoting metastasis.