Major clinical research advances in gynecologic cancer in 2023: a tumultuous year for endometrial cancer.

In the 2023 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Endometrial cancer: immune checkpoint inhibitor, antibody drug conjugates (ADCs), selective inhibitor of nuclear export, CDK4/6 inhibitors WEE1 inhibitor, poly (ADP-ribose) polymerase (PARP) inhibitors. 2) Cervical cancer: surgery in low-risk early-stage cervical cancer, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Ovarian cancer: immunotherapy, triplet therapies using immune checkpoint inhibitors along with antiangiogenic agents and PARP inhibitors, and ADCs. In 2023, the field of endometrial cancer treatment witnessed a landmark year, marked by several practice-changing outcomes with immune checkpoint inhibitors and the reliable efficacy of PARP inhibitors and ADCs.

Clinical implications of histologic subtypes on survival outcomes in primary mucinous ovarian carcinoma.

OBJECTIVE: In 2014, the World Health Organization introduced a new histologic classification by dividing primary mucinous ovarian carcinoma (PMOC) into two: expansile (ES) or infiltrative subtypes (IS). This study investigated the clinical implications of these histological subtypes on survival outcomes. METHODS: Data from 131 patients with PMOC who underwent primary surgery between 2003 and 2021 were analyzed. The patients baseline characteristics, surgical and pathological information were collected. Survival outcomes were calculated, while factors affecting them were also investigated. RESULTS: During 55.9 months of median follow-up, 27 (20.6%) patients experienced recurrence and 20 (15.3%) died. Among 131 patients, 113 patients were classified into 87 (77%) ES and 26 (23%) IS after a slide review. Advanced stage, lymph node involvement, and residual tumors after surgery were more common in the IS, showing poorer prognosis. In multivariate analyses, advanced stage and residual tumors after surgery were associated with worse survival, while the IS showed no statistical significance. In subgroup analysis for stage I disease, survival did not vary between subtypes. Nevertheless, patients in the IS group who underwent fertility-sparing surgeries demonstrated a 5-year progression-free survival (PFS) rate of 83.3%, significantly lower than patients without fertility preservation, irrespective of histologic subtypes (5-year PFS rate: 97.9%; P = 0.002 for the ES, 5-year PFS rate: 100%; P = 0.001 for the IS). CONCLUSIONS: The IS of PMOC had poorer survival outcomes and a higher proportion of advanced-stage tumors. Although its independent prognostic significance remains uncertain, adjuvant chemotherapy should be considered for patients with fertility preservation in the IS group.

Tissue Expression and Prognostic Role of CXCL12 and CXCR4 in High-grade Serous Ovarian Carcinoma.

BACKGROUND/AIM: The complex of C-X-C motif chemokine receptor 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), plays an essential role in cancer cell proliferation, invasion, and metastasis. These are emerging therapeutic targets, and recent studies have reported that inhibition of CXCL12-CXCR4 signaling pathway enhances the effects of immune checkpoint inhibitors. Thus, we aimed to investigate tissue expression of CXCL12 and CXCR4 in high-grade serous ovarian carcinoma (HGSOC) and to determine their potential as prognostic markers. PATIENTS AND METHODS: We used chemotherapy-naïve, formalin-fixed paraffin-embedded primary ovarian cancer tissues obtained from patients with advanced-stage HGSOC at the time of primary cytoreductive surgery. After histological reassessment, we constructed a tissue microarray and performed immunohistochemical staining for CXCL12 and CXCR4. Thereafter, clinicopathological characteristics and survival outcomes were compared between the high- and low-expression groups. RESULTS: A total of 97 patients with FIGO stage IIIC-IV HGSOC were included: 15 (15.5%), 66 (68.0%), and 13 (13.4%) patients showed high expression of CXCL12, CXCR4, and both, respectively. The expression level of each protein was not associated with germline BRCA1/2 mutational status, FIGO stage, or residual tumor after primary cytoreductive surgery. In multivariate analysis adjusted for confounders, high CXCL12 expression was identified as an independent poor prognostic biomarker for progression-free survival (adjusted hazards ratio, 1.990; 95% confidence interval=1.090-3.633; p=0.025). However, CXCR4 expression was not associated with patient survival outcomes. CONCLUSION: The CXCL12 expression level may represent a prognostic biomarker for HGSOC. Proteins related to the CXCL12/CXCR4 complex may serve as therapeutic targets in HGSOC treatment.

Reversible sulfur dioxide capture by amino acids containing a single amino group at low sulfur dioxide concentrations.

SO2, an air pollutant, is harmful to human health and causes air pollution; therefore, numerous studies have focused on the development of SO2 control technologies. Although limestone- and ammonia-based absorbents have been widely used in wet desulfurization, they are difficult to regenerate and do not enable the recycling of SO2, which is a useful resource. Recently, amino acids have attracted attention as reversible SO2 absorbents because they are eco-friendly and have excellent reactivity with SO2, as well as high regeneration performance. Glycine, L-alanine, ß-alanine, 4-aminobutyric acid, 5-aminovaleric acid, and 6-aminohexanoic acid were analyzed to investigate the relationship between SO2 absorption and the amino acid molecular structure using the simulated actual flue gas (200 ppmv SO2 + 13% CO2 in N2 balance). The SO2 absorption of amino acids (with the molecular structure of glycine and alkyl chains of various lengths) improved as the alkyl chain length increased, possibly owing to a decrease in the inductive effect in the molecular structure of the amino acid. Furthermore, 13C-nuclear magnetic resonance spectroscopy was conducted to analyze the SO2 absorption reaction mechanism (including the possible generation of irreversible species), and experiments involving a number of consecutive absorption-desorption cycles were used to confirm the reusability of the amino acids. The tested amino acids exhibited higher cyclic capacities compared to those of deep eutectic solvents and ionic liquids reported in the literature, thereby exhibiting excellent potential as SO2 absorbents. Thus, this study can guide the future design and development of eco-friendly SO2 absorbents.

A preoperative scoring system to predict lymph node metastasis in intrahepatic cholangiocarcinoma.

BACKGROUND: The abnormality of imaging finding of lymph node (LN) has demonstrated unsatisfactory diagnostic accuracy for pathologic lymph node metastasis (LNM). We aimed to develop and validate a simple scoring system predicting LNM in patients with intrahepatic cholangiocarcinoma (iCCA) prior to surgery based on MRI and clinical findings. METHODS: We retrospectively enrolled consecutive patients who underwent surgical resection for treatment-naïve iCCA from six institutions between January 2009 and December 2015. Patients who underwent lymph node dissection (LND) were randomly assigned to the training and validation cohorts at a 2:1 ratio, an¹ìd pathologic LN status was evaluated. Patients who did not undergo LND were assigned to the test cohort, and clinical LN status was evaluated. Using MRI and clinical findings, a preoperative LNM score was developed in the training cohort and validated in the validation and test cohorts. RESULTS: The training, validation, and test cohorts included 102, 53, and 118 patients, respectively. The preoperative LNM score consisted of serum carcinoembryonic antigen and two MRI findings (suspicious LN and bile duct invasion). The preoperative LNM score was associated with pathologic LNM in training (p < 0.001) and validation (p = 0.010) cohorts and clinical LNM in test cohort (p < 0.001). The preoperative LNM score outperformed MRI-suspicious LN alone in predicting pathologic LNM (area under the curve, 0.703 vs. 0.604, p = 0.004). The preoperative LNM score was also associated with overall survival in all cohorts (p < 0.001). CONCLUSIONS: Our preoperative LNM score was significantly associated with pathologic or clinical LNM and outperformed MRI-suspicious LN alone.

Effect of BRCA1/2 Mutational Status on Survival Outcomes According to Secondary Cytoreductive Surgery and Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer: A Real-World Evidence Study.

PURPOSE: This study aimed to investigate the impact of BRCA1/2 mutational status on survival outcomes in patients with platinum-sensitive relapsed (PSR) epithelial ovarian cancer (EOC). MATERIALS AND METHODS: We retrospectively identified patients who received secondary treatment for PSR EOC at our institution between January 2007 and June 2021 and who underwent BRCA1/2 gene testing by either germline or somatic methods. The association between BRCA1/2 mutational status and survival outcomes was evaluated. Both secondary cytoreductive surgery (CRS) and maintenance therapy were stratified considering real-world clinical practice. RESULTS: Of 262 patients, 91 (34.7%) and 171 (65.3%) were assigned to BRCA1/2 mutation and wild-type groups, respectively. The two groups had similar proportions of patients undergoing secondary CRS (26.4% vs. 32.7%, p=0.286) and maintenance therapy (54.9% vs. 46.2%, p=0.178). Overall, no differences in progression-free survival (PFS; median, 19.7 vs. 15.1 months, p=0.120) and overall survival (OS; p=0.400) were observed between the two groups. In multivariate analyses, BRCA1/2 mutational status was not associated with PFS (adjusted hazard ratio, 0.816; 95% confidence interval, 0.596 to 1.119; p=0.207). BRCA1/2 mutational status did not affect PFS among patients who underwent secondary CRS (n=80) and among those who did not (n=182) (p=0.074 and p=0.222, respectively). PFS did not differ in the BRCA1/2 mutational status among the patients who received bevacizumab maintenance (n=90, p=0.992). CONCLUSION: In this real-world evidence study, BRCA1/2 mutational status itself was not associated with PFS and OS in PSR EOC, which was consistent with whether secondary CRS or not and with bevacizumab maintenance.

Effect and safety of diluted vasopressin injection on bleeding during robot-assisted laparoscopic myomectomy: a protocol for a randomised controlled pilot trial.

INTRODUCTION: Even though the injection of diluted vasopressin into the uterus is expected to reduce intraoperative bleeding with decreased adverse effects during robot-assisted laparoscopic myomectomy (RALM), there is a lack of relevant trials to show its effect and safety. Thus, this study was designed to compare the effect and safety of vasopressin injection on bleedings based on dilution levels of vasopressin with constant volumes during RALM. METHODS AND ANALYSIS: This is a randomised controlled pilot trial, where a total of 39 patients will be randomly divided into three experimental groups in a 1:1:1 ratio. All patients will be classified into the three groups based on the dilution level of vasopressin: group 1-a solution prepared by mixing 20 units of vasopressin with 100 mL of normal saline to make a total of 100 mL; group 2-a solution prepared by mixing 20 units of vasopressin with 200 mL of normal saline to make a total of 100 mL and group 3-a solution prepared by mixing 20 units of vasopressin with 400 mL of normal saline to make a total of 100 mL. During RALM, we will inject diluted vasopressin at different concentrations with a total of 100 mL. As the primary endpoint, estimated blood loss would be compared. As secondary endpoints, we will check the level of haemoglobin and haematocrit, operation time, amount of transfusion, and the period of hospitalisation. In addition, we will check other complications related to vasopressin injection. ETHICS AND DISSEMINATION: This pilot study has been approved by the Institutional Review Board of the Seoul National University Hospital (No. H-2011-107-1174). All potential subjects will be provided written informed consent. The results of this study will be published in peer-reviewed journals and be presented at academic conferences. TRIAL REGISTRATION NUMBERS: NCT04874246 and CKCT0006225.

Establishment of a piglet model for peritoneal metastasis of ovarian cancer.

BACKGROUND: A piglet model for peritoneal metastasis (PM) of ovarian cancer was developed. It will contribute to establishing innovative chemotherapeutical and surgical strategies without any limitation on rodent models. METHODS: A total of 12 four- to five-week-old piglets of 7 to 8 kg were used. Two phases of ovarian cancer cell injections were performed with laparoscopic surgery. In phase I trial, 5.0 × 106 SK-OV-3 cells in 0.1 ml suspension were inoculated into the omentum, peritoneum, and uterine horns of two piglets twice with a one-week interval. In the phase II trial, 5.0 × 106 SNU-008 cells in 0.1 ml suspension were injected only into uterine horns within the same time frame because tumor implantation after inoculation of SK-OV-3 cells was not observed at the omentum or peritoneum in the phase I trial. Modified peritoneal cancer index (PCI) score was used to monitor tumorigenesis up to 4 weeks after inoculation. Tumor tissues disseminated in the peritoneum 4 weeks after injection were used for histological examination with hematoxylin and eosin (H&E) and paired-box gene 8 (PAX-8) staining. RESULTS: In the phase I trial, two piglets showed PM with modified PCI scores of 5 and 4 at 3 weeks after the first inoculation, which increased to 14 and 15 after 4 weeks, respectively. In the phase II trial, PM was detected in eight of ten piglets, which showed modified PCI scores of 6 to 12 at 4 weeks after the first inoculation. The overall incidence of PM from the total of 12 piglets after inoculation was 75%. Immunohistochemical H&E and PAX-8 staining confirmed metastatic tumors. CONCLUSIONS: This study provides strong evidence that piglets can be employed as a model for PM by inoculating ovarian cancer cell lines from humans. Using two cell lines, the PM rate is 75%.

Clinical implications of neoadjuvant chemotherapy in advanced endometrial cancer: a multi-center retrospective cohort study.

BACKGROUND: The mainstay of endometrial cancer treatment is surgical resection of tumors and postoperative adjuvant treatment is recommended if necessary. However, there is no consensus on the management of unresectable metastatic endometrial cancer. This study aimed to assess the feasibility and effectiveness of neoadjuvant chemotherapy followed by interval debulking surgery (NAC-IDS) in unresectable, metastatic endometrial cancer. METHODS: From the endometrial cancer cohorts of four institutions in Korea, we identified patients with International Federation of Gynecology and Obstetrics stages IIIC-IVB endometrial cancer who received NAC-IDS between January 2008 and December 2020. Through a medical record review, we collected patients' clinicopathological data. Progression-free survival (PFS), overall survival (OS), and the factors affecting survival outcomes were analyzed. RESULTS: Overall, 32 patients were included with endometrioid (n = 18), serous (n = 5), carcinosarcoma (n = 6), and other histological types (n = 3). Among them, 28 (87.5%) patients had stage IVB disease. The most common neoadjuvant chemotherapy (NAC) regimen was paclitaxel-carboplatin (n = 25, 78.1%), which was administered for a median of six cycles. While 26 (81.3%) patients showed an objective response, two (6.3%) progressed despite NAC. At the time of interval debulking surgery (IDS), 23 (71.9%) patients achieved complete cytoreduction. During 31.0 months of the median follow-up, there were 23 recurrences and 11 deaths, corresponding to a median PFS of 19.7 months and a 3-year OS rate of 69.7%. In multivariate analyses, non-endometrioid histology and residual tumor after IDS were identified as independent poor prognostic factors for PFS (adjusted hazard ratio [HR], 7.322; P < 0.001 and 5.934; P = 0.001, respectively). Multivariate analysis for OS could not be conducted because of the small number of events, although non-endometrioid histology was the only factor associated with worse OS in univariate analysis (adjusted HR, 4.523; P = 0.032). CONCLUSIONS: NAC-IDS may be a treatment option for unresectable metastatic endometrial cancer. Tumor histology and the possibility of complete cytoreduction are the primary considerations for NAC-IDS.

Impact of no residual disease on postoperative computed tomography on survival in patients with optimally debulked advanced high-grade serous ovarian cancer during upfront surgery.

OBJECTIVE: We sought to investigate the impact of size of residual tumors as determined by postoperative computed tomography (CT) on survival of patients with advanced, high-grade serous ovarian carcinoma (HGSC) who achieved residual disease less than 1 cm after primary debulking surgery (PDS). METHODS: We collected data of patients with stage III HGSC who had residual tumor less than 1 cm after PDS between 2013 and 2018. Surgeon-assessed residual disease during surgery was defined as sR0 (no gross residual) or sR1 (gross residual <1 cm), and radiologist-assessed residual disease on postoperative CT was defined as rR0 (no evidence of disease) or rRany (existing residual disease). All patients were classified into the following groups: sR0/rR0, sR1/rR0, sR0/rRany, and sR1/rRany. RESULTS: A total of 436 patients was placed into the sR0/rR0 (n = 187, 42.9%), sR1/rR0 (n = 59, 13.5%), sR0/rRany (n = 79, 18.1%), or sR1/rRany group (n = 111, 25.5%). Discrepancies between surgical and radiological assessments were recorded for 176 patients (40.4%) including 38 cases of sR1/rRany group with discordant residual tumor location indicated between two methods. During multivariate analysis, patients with ascites on preoperative CT, sR0/rRany group inclusion, and sR1/rRany group inclusion showed unfavorable progression-free and overall survival. CONCLUSIONS: The incorporation of surgical and radiological evaluations for determining the size of residual tumors was more accurate than surgical evaluation only for predicting survival among patients with advanced ovarian cancer who underwent PDS to residual disease less than 1 cm.

Uptake Rate of Risk-Reducing Salpingo-Oophorectomy and Surgical Outcomes of Female Germline BRCA1/2 Mutation Carriers: A Retrospective Cohort Study.

PURPOSE: This study investigated the uptake rate of risk-reducing salpingo-oophorectomy (RRSO) and surgical outcomes of germline BRCA1/2 mutation carriers at Seoul National University Hospital (SNUH). MATERIALS AND METHODS: We examined the records of 824 women who underwent germline BRCA1/2 gene testing at SNUH between 2005 and 2020. Among them, we identified women with a pathogenic mutation on either the BRCA1 or the BRCA2 gene, and excluded ovarian cancer patients. Characteristics of participants who underwent RRSO (RRSO group) were compared to those who did not (non-RRSO group). Surgical outcomes and pathologic results were investigated in the RRSO group. RESULTS: There were 117 BRCA1/2 mutation carriers included in the analysis. The uptake rate of RRSO was 70.1% (82/117). Older age (mean: 48.8 years vs. 42.1 years; p=0.002) and higher employment rate (65.9% vs. 14.3%; p<0.001) were observed in the RRSO group compared to the non-RRSO group. However, no differences in other factors, such as personal and family history of breast cancer, were observed between the two groups. In the RRSO group, the median time interval between the genetic test and RRSO was 10.0 months, and there were three (3.7%) incidental cases of high-grade serous carcinoma. However, one patient in the non-RRSO group developed primary peritoneal cancer after 103.8 months of surveillance. CONCLUSION: The uptake rate of RRSO in BRCA1/2 mutation carriers was about 70%. Considering incidental cancer cases in women without abnormal findings on preoperative evaluation, BRCA1/2-mutated women might refrain from the delayed implementation of RRSO after the genetic test.

SERPINB11 Expression Is Associated With Prognosis of High-grade Serous and Clear Cell Carcinoma of the Ovary.

BACKGROUND/AIM: To evaluate the role of serine protease inhibitor B11 (SERPINB11) expression as a prognostic biomarker in high-grade serous carcinoma (HGSC) and clear cell carcinoma of the ovary (CCC). MATERIALS AND METHODS: We obtained tumor tissues from patients with HGSC (n=145) and CCC (n=59). We evaluated immunohistochemically the expression of SERPINB11 and investigated whether SERPINB11 expression affects platinum-resistance and the prognosis of HGSC and CCC. RESULTS: High expression of SERPINB11 was more common in CCC than in HGSC (57.6% vs. 28.3%; p<0.01), and SEPRINB11 expression did not correlate with platinum-resistance of HGSC and CCC. High expression of SERPINB11 was associated with worse progression-free survival and overall survival with marginal significance in HGSC; no relation between SERPINB11 expression and the prognosis of CCC was found. CONCLUSION: SERPINB11 expression maybe a prognostic biomarker for HGSC.

Preservation of the ovarian reserve and hemostasis during laparoscopic ovarian cystectomy by a hemostatic agent versus suturing for patients with ovarian endometriosis: study protocol for randomized controlled, non-inferiority trial (PRAHA-2 trial).

BACKGROUND: Endometriosis (EMS) can be implanted everywhere, especially in pelvic organs. EMS can be asymptomatic, but it can result in pelvic pain and infertility by inducing local inflammation and pelvic adhesion. The prevalence of EMS is about 10% in reproductive-age women and higher in women with pelvic pain or infertility. For young patients with ovarian EMS, laparoscopic ovarian cystectomy is effective in relieving pelvic pain and preventing local recurrence. However, there is a concern that the ovarian reserve would decrease after the operation because of the removal of a part of the normal ovarian tissue and thermal damage during hemostasis, which depends on the types of hemostasis such as bipolar electrocoagulation, suturing, and the use of a hemostatic agent. In this study, we aim to evaluate the protective effect for the ovarian reserve and hemostasis between a hemostatic agent and suturing during laparoscopic ovarian cystectomy for patients with ovarian EMS. METHODS: This study is a randomized controlled, non-inferiority trial, where a total of 90 patients with ovarian EMS will be randomly assigned to the experimental (hemostatic agent) and control (suturing) groups. In the control group, a barbed suture will be applied for hemostasis, whereas a hemostatic agent will be applied in the experimental group. If two methods are insufficient, bipolar electrocoagulation will be applied for complete hemostasis. As the primary endpoint, the reduction rate of serum anti- Müllerian hormone (AMH) levels reflecting the ovarian reserve will be compared between the two groups 12 weeks after surgery. As secondary endpoints, we will compare the reduction rate of AMH level 48 weeks after surgery, the time required to complete hemostasis, the success rate of hemostasis within 10 min, and adverse events associated with operation. DISCUSSION: We expect that the protective effect for the ovarian reserve and hemostasis may be comparable between the two methods, suggesting that a hemostatic agent may be preferred considering that it is easy to use during laparoscopic ovarian cystectomy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04643106 . Registered on 22 November 2020.

Whole Cigarette Smoke Condensates Induce Accumulation of Amyloid Beta Precursor Protein with Oxidative Stress in Murine Astrocytes.

Although cigarette smoking has been postulated to be a potential risk factor for Alzheimer's disease (AD), the toxic mechanism is still unclear. Additionally, astrocytes have been identified as a potential target, given they play multiple roles in maintaining normal brain function. In this study, we explored the toxic mechanism of whole cigarette smoke condensates (WCSC) using murine astrocytes. Cell proliferation, the percentage of cells in the G2/M phase, and LDH concentrations in the cell supernatants were all reduced in WCSC-treated cells. In addition, oxidative stress was induced, together with shortening of processes, structural damage of organelles, disturbances in mitochondrial function, blockage of autophagic signals, accumulation of amyloid ß precursor protein, and loss of chemotactic functions. Based on these results, we hypothesize that dysfunction of astrocytes may contribute to the occurrence of cigarette-smoking-induced AD.

Development of rotational intraperitoneal pressurized aerosol chemotherapy to enhance drug delivery into the peritoneum.

This study aims to evaluate the drug distribution, tissue concentrations, penetration depth, pharmacokinetic properties, and toxicities after rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs. Because relevant medical devices have not been introduced, we developed our prototype of pressurized intraperitoneal aerosol chemotherapy (PIPAC) and RIPAC by adding a conical pendulum motion device for rotating the nozzle. RIPAC and PIPAC were conducted using 150 ml of 1% methylene blue to evaluate the drug distribution and 3.5 mg of doxorubicin in 50 ml of 0.9% NaCl to evaluate the tissue concentrations and penetration depth, pharmacokinetic properties, and toxicities. All agents were sprayed as aerosols via the nozzle, DreamPen® (Dalim Biotech, Gangwon, South Korea), with a velocity of 5 km/h at a flow rate of 30 ml/min under a pressure of 7 bars, and capnoperitoneum of 12 mmHg was maintained for 30 min. As a result, RIPAC showed a wider distribution and stronger intensity than PIPAC. Compared with PIPAC, RIPAC demonstrated high values of the tissue concentration in the central, right upper, epigastrium, left upper, left lower, right lower, and right flank regions (median, 375.5-2124.9 vs. 161.7-1240 ng/ml; p ≤ .05), and higher values of the depth of concentrated diffusion and depth of maximal diffusion (median, 232.5-392.7 vs. 116.9-240.1 µm; 291.2-551.2 vs. 250.5-362.4 µm; p ≤ .05) in all regions except for bowels. In RIPAC, the pharmacokinetic properties reflected hemodynamic changes during capnoperitoneum, and there were no related toxicities. Conclusively, RIPAC may have the potential to enhance drug delivery into the peritoneum compared to PIPAC.

Repeated intratracheal instillation of zinc oxide nanoparticles induced pulmonary damage and a systemic inflammatory response in cynomolgus monkeys.

Recently, some researchers have demonstrated that inhaled zinc oxide nanoparticles (ZnONPs) induce an acute systemic inflammatory response in workers. Considering nonhuman primates are preferably considered an animal model for translational research due to their proven similarity with humans in terms of genetics and physiology, we intratracheally instilled ZnONPs to cynomolgus monkey for 14 days and identified the toxic mechanism and bioaccumulation. ZnONPs were rapidly ionized or aggregated in a simulated pulmonary fluid, and they attracted neutrophils to the lungs and increased the pulmonary level of inflammatory mediators. Additionally, thickened alveolar walls, fibrin clots, and hemorrhages were observed in the lungs of the monkeys instilled with the higher dose accompanied by cell debris in the alveolar ducts and alveoli. Dark-field microscopy images revealed translocation of ZnONPs into other tissues accompanied by an increase in the relative weight of livers to body weight. In addition, when instilled at the higher dose, the albumin/globulin ratio notably decreased compared to the control, whereas the C-reactive protein (CRP) level was significantly elevated. ZnONPs also clearly induced apoptotic cell death in a 24 h exposure to alveolar macrophages. Taken together, part of inhaled ZnONPs may be ionized in the lung, resulting in acute toxic effects, including cell death and tissue damage, and the rest may move to other tissues in the form of particles, causing a systemic inflammatory response. Based on the proven evidence among workers, we also suggest that the CRP level can be recommended as a biomarker for ZnONPs-induced adverse health effects.

Detection of intracellular lamellar bodies as a screening marker for fibrotic lesions.

With the rapid increase in application of disinfectants worldwide as a method to block the spread of coronavirus, many new products are being introduced into the market without thorough verification of their impacts on human health and the environment. In the present study, we aimed to propose a screening marker for materials that can induce fibrotic lung disease using disinfectants, which had been demonstrated as causative materials of chronic inflammation and interstitial fibrosis. We first calculated the corresponding LC50 level based on results from cell viability test and exposed the LC50 level of disinfectants to human bronchial epithelial cells for 24 h. Formation of lamellar body-like structures, cleavage of the nuclear matrix, structural damage of mitochondria were found in the cytosol of the treated cells. We also dosed disinfectants by pharyngeal aspiration to mice to determine the LD0 level. The mice were sacrificed on Day 14 after a single dosing, and lamellar body-like structures were observed in the lung tissue of mice. Herein, we hypothesize that DNA damage and metabolic disturbance may play central roles in disinfectant-induced adverse health effects. Additionally, we propose that formation of lamellar bodies can be a screening marker for interstitial fibrosis.

Thermal and Spectroscopic Analyses of Human Adipose Tissue-Derived Extracellular Matrix.

In this study, nanofibrous extracellular matrix (ECM) was prepared from human adipose tissue, and the stepwise products were analyzed using differential thermal analysis (DTA)/thermogravimetric analysis (TGA) and Fourier-transform infrared (FTIR)/Raman spectroscopy. Human adipose tissue was liposuctioned (sample 1), centrifuged (sample 2), pulverized, centrifuged again (sample 3), and finally freeze-dried (sample 4). Each sample was subjected to DTA/TGA and FTIR/Raman analyses. In the DTA curve of sample 1, the major peak was observed at approximately 60 °C. However, relatively flat DTA curves were detected in samples 2 and 4. In the TGA results, sample 1 showed a more rapid weight loss pattern than the other samples. Samples 1, 2, and 3 showed similar FTIR spectra with a strong, broad absorption feature at ~3400 cm-1. Amide I, II, and III bands were clearly observed in the FTIR spectrum of sample 4. Samples 1 and 2 showed typical adipose tissue Raman spectra. However, in samples 3 and 4, the Raman signal was low. Scanning electron microscopic analysis of the freeze-dried ECM (sample 4) confimed its three-dimensional porous nanofibrous structure. These findings suggest that human adipose tissue, intermediate products, and human adipose tissue-derived ECM can be easily and effectively characterized with thermal and spectroscopic analyses. These efficient analyses can aid in the preparation of ECM and in clinical applications for regenerative medicine.

Drug resistance-free cytotoxic nanodrugs in composites for cancer therapy.

Drug resistance is a major cause of treatment failure for small-molecule cancer chemotherapies, despite the advances in combination therapies, drug delivery systems, epigenetic drugs, and proteolysis-targeting chimeras. Herein, we report the use of a drug resistance-free cytotoxic nanodrug as an alternative to small-molecule drugs. The present nanodrugs comprise 2 nm core gold nanoparticles (AuNPs) covered completely with multivalent hydrocarbon chains to a final diameter of ∼10 nm as single drug molecules. This hydrophobic drug-platform was delivered in composite form (∼35 nm) with block-copolymer like other small-molecular drugs. Upon uptake by cells, the nanodrugs enhanced the intracellular levels of reactive oxygen species and induced apoptosis, presumably reflecting multivalent interactions between aliphatic chains and intracellular biomolecules. No resistance to our novel nanodrug was observed following multiple treatment passages and the potential for use in cancer therapy was verified in a breast cancer patient-derived xenograft mouse model. These findings provide insight into the use of nano-scaled compounds as agents that evade drug resistance to cancer therapy.

A Case Report of Cholangiocarcinoma Arising from a Biliary Adenofibroma: Radiologic Findings and Review of Literature.

Biliary adenofibromas are rare biliary epithelial tumors that are classified as benign. Nevertheless, some cases have been reported to show malignant transformations. The radiologic findings of biliary adenofibromas and their malignant transformation are not well-established because of their rarity. We present a case of a cholangiocarcinoma arising from a biliary adenofibroma assessed using ultrasonography, CT, and MRI. The differential diagnoses include other hepatic tumors.