Olaparib enhances sensitization of BRCA-proficient breast cancer cells to x-rays and protons.

PURPOSE: This study aimed to compare the radiosensitizing effect of the PARP inhibitor, Olaparib, between proton and X-rays irradiations in BRCA-proficient breast cancer (BC) cells. METHODS: Two BRCA-proficient BC cell lines, MDA-MB-231 and T47D BC, were used. Cell proliferation was assessed using the CCK-8 assay, and radiosensitivity was determined through the clonogenic survival assay. Flow cytometry was employed to analyze cell cycle distribution and apoptosis. The kinetics of DNA damage repair were evaluated using γH2AX immunofluorescence imaging and the comet assay. Tumor spheroid assays were conducted to test radiosensitivity in a three-dimensional culture condition. RESULTS: Olaparib sensitized both MDA-MB-231 and T47D cells to proton and X-ray irradiation in the clonogenic assay. MDA-MB-231 cells exhibited a higher dose enhancement factor for Olaparib than T47D cells. Olaparib increased radiation-induced G2/M cell cycle arrest and apoptosis specifically in MDA-MB-231 cells. γH2AX immunostaining and the comet assay showed Olaparib augmented radiation-induced DNA damage and apoptosis. The enhancement effect of Olaparib was more pronounced in proton irradiation than in X-ray irradiation, particularly in MDA-MB-231 cells than T47D cells. Both radiation and Olaparib dose-dependently inhibited spheroid growth in both cell lines. The synergy scores demonstrated that Olaparib interacted more strongly with protons than X-rays. The addition of an ATR inhibitor further enhanced Olaparib-induced proton radiosensitization in MDA-MB-231 cells. CONCLUSION: This study found that Olaparib enhanced radiation efficacy in BRCA-proficient breast cancer cells, with a more pronounced effect observed with proton irradiation compared to X-ray irradiation. Combining Olaparib with an ATR inhibitor increased the radiosensitizing effect of protons.

Quantitative assessment of breast volume changes after whole-breast irradiation for breast cancer using breast auto-segmentation.

PURPOSE: This study aimed to quantitatively estimate the changes in breast volume associated with radiotherapy in patients undergoing breast-conserving surgery and whole-breast irradiation (WBI). METHODS: Pre-WBI simulation computed tomography (CT) scans and post-WBI follow-up chest CT scans from a total of 1,151 breast cancer patients were analyzed using a deep-learning-driven auto-segmentation approach. The CT-based asymmetry index (CTAI) was calculated by dividing the volume of the irradiated breast by the volume of the contralateral breast. Significant breast shrinkage was defined as a CTAI < 0.85. To quantify changes in CTAI over the follow-up period, the CTAI ratio was determined as the post-WBI CTAI divided by the pre-WBI CTAI. A multivariate logistic regression analysis was conducted to identify potential variables associated with post-WBI significant breast shrinkage. RESULTS: The median CTAI values for pre- and post-WBI CT scans were 0.973 (interquartile range: 0.887-1.069) and 0.866 (interquartile range: 0.773-0.967), respectively. The difference between them was statistically significant (p < 0.001). Following WBI, there was an increase in the rate of significant breast shrinkage from 16.3 to 44.8%. The CTAI ratio showed a negative association with the time interval (p < 0.001, Pearson r = - 0.310). In the multivariate logistic regression analysis, lower pre-WBI CTAI, younger age, and longer interval between CT scans were found to be significantly associated with a higher occurrence of post-WBI significant breast shrinkage. CONCLUSION: Breast volume decreases following WBI, and this decrease is correlated with an increased duration after WBI. These findings highlight the long-term consequences of WBI on breast asymmetry.

Risk Factors Affecting Clinical Outcomes of Low-risk Early-stage Human Papillomavirus-Associated Endocervical Adenocarcinoma Treated by Surgery Alone: Application of Silva Pattern.

This study aimed to report the clinical outcomes and risk factors for survival of patients with low-risk early-stage human papillomavirus-associated (HPVA) endocervical adenocarcinoma (EAC) treated with surgery alone. This retrospective study obtained the clinicopathological data of patients with early-stage HPVA EAC who underwent surgery between 2012 and 2018. The Silva pattern of invasion was determined by reviewing pathology slides. Locoregional recurrence-free survival (RFS), RFS, and overall survival were calculated, and the risk factors for survival were analyzed. One hundred seventeen patients with a median follow-up of 5.2 years (0.5-9.7 yr) were included. The most common histologic type was usual (94/117, 80.3%). The Silva pattern was A in 79 patients (67.5%), B in 30 (25.6%), and C in 8 (6.8%). The 5-year locoregional RFS, RFS, and overall survival rates were 92.4%, 87.8%, and 97.2%, respectively. The presence of intermediate-risk factors and Silva pattern C were significantly associated with worse survival. Based on these findings, patients were categorized into 2 groups: Group 1 (Silva pattern A or Silva pattern B without intermediate-risk factors) and Group 2 (Silva pattern B with intermediate-risk factors or Silva pattern C ). Group 2 showed significantly worse outcomes than Group 1, including the 5-year locoregional RFS (98.6% vs 68.0%), RFS (96.4% vs 54.6%), and overall survival (100.0% vs 86.5%). In conclusion, surgery alone for early-stage HPVA EAC resulted in favorable outcomes. Consideration of the Silva pattern, in addition to well-known risk factors, could help in precise risk group stratification of low-risk, early-stage HPVA EAC.

Chalazion-mimicked eyelid angiosarcoma in a young Asian with good prognosis: a case report.

BACKGROUND: Angiosarcoma is an extremely rare malignant tumor. So far, only about 42 cases of angiosarcoma involving the eyelids have been reported. Eyelid angiosarcoma occurs more frequently in elderly Caucasian males and is prone to misdiagnosis. We present a case report in a young Asian male patient with eyelid angiosarcoma that was misdiagnosed as a chalazion. CASE PRESENTATION: A 46-year-old South Korean male with no underlying disease had a right lower lid mass. The lesion was initially misdiagnosed as a chalazion at a local clinic, but a diagnosis of eyelid angiosarcoma was made after the first biopsy trial. PET-CT was performed to ensure that there was no metastasis in the whole body. Surgical excision with enough surgical margin was used alone for treatment and reconstruction was performed with a tarsoconjunctival advancement flap (modified Hughes procedure), which helped ensure good cosmesis. No recurrence was observed 4 years and 5 months after the surgery. CONCLUSIONS: The current study presents the first case of chalazion-mimicked eyelid angiosarcoma in a young Asian male aged under 50 years. This case shows that even if a benign eyelid disease is suspected in a young patient, an incisional biopsy must be performed to confirm whether the lesion is malignant. Since the prognosis is good for the case of eyelid angiosarcoma, if there is no clear evidence of distal metastasis, surgical resection should be performed with an enough safety margin.

Inhibition of the H3K27 demethylase UTX enhances the epigenetic silencing of HIV proviruses and induces HIV-1 DNA hypermethylation but fails to permanently block HIV reactivation.

One strategy for a functional cure of HIV-1 is "block and lock", which seeks to permanently suppress the rebound of quiescent HIV-1 by epigenetic silencing. For the bivalent promoter in the HIV LTR, both histone 3 lysine 27 tri-methylation (H3K27me3) and DNA methylation are associated with viral suppression, while H3K4 tri-methylation (H3K4me3) is correlated with viral expression. However, H3K27me3 is readily reversed upon activation of T-cells through the T-cell receptor. In an attempt to suppress latent HIV-1 in a stable fashion, we knocked down the expression or inhibited the activity of UTX/KDM6A, the major H3K27 demethylase, and investigated its impact on latent HIV-1 reactivation in T cells. Inhibition of UTX dramatically enhanced H3K27me3 levels at the HIV LTR and was associated with increased DNA methylation. In latently infected cells from patients, GSK-J4, which is a potent dual inhibitor of the H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A, effectively suppressed the reactivation of latent HIV-1 and also induced DNA methylation at specific sites in the 5'LTR of latent HIV-1 by the enhanced recruitment of DNMT3A to HIV-1. Nonetheless, suppression of HIV-1 through epigenetic silencing required the continued treatment with GSK-J4 and was rapidly reversed after removal of the drug. DNA methylation was also rapidly lost after removal of drug, suggesting active and rapid DNA-demethylation of the HIV LTR. Thus, induction of epigenetic silencing by histone and DNA methylation appears to be insufficient to permanently silence HIV-1 proviral transcription.

Non-immune and immune functions of interleukin-36γ suppress epithelial repair at the ocular surface.

Regulation of innate inflammation is critical for maintaining tissue homeostasis and barrier function, especially in those interfacing the external environments such as the skin and cornea. Expression of pro-inflammatory cytokines by injured tissues has been shown to exacerbate the inflammatory cascade, causing tissue damage. Interleukin 36, a subfamily of the IL-1 superfamily, consists of three pro-inflammatory agonists-IL36α, IL36ß, and IL36γ and an IL36 receptor antagonist (IL36Ra). The current investigation, for the first time, reports that IL36γ is the primary agonist expressed by the corneal epithelium, which is significantly upregulated following corneal injury. The function of IL36γ on non-immune cells, in addition to innate inflammatory cells, in regulating tissue homeostasis has not been well investigated. Using a loss-of-function approach via neutralizing antibody treatment, our data demonstrate that blocking endogenously expressed IL36γ in epithelial cells promotes rapid re-epithelialization in in vitro wound closure assay. Finally, by utilizing a naturally occurring antagonist IL36Ra in a well-established murine model of ocular injury, our study demonstrates that inhibition of IL36γ accelerates epithelial regeneration and suppresses tissue inflammation. Given rapid wound healing is critical for re-establishing normal tissue structure and function, our investigation on the function of IL36γ provides evidence for the development of novel IL36γ-targeting strategies to promote tissue repair.

Patterns of regional recurrence according to molecular subtype in patients with pN2 breast cancer treated with limited field regional irradiation.

OBJECTIVE: There is little evidence regarding the radiotherapy modification based on molecular subtypes in breast cancer. This study aimed to identify the risk and patterns of regional recurrence according to molecular subtype in patients with pN2 breast cancer. METHODS: We identified 454 patients who underwent radical surgery for breast cancer with 4-9 axillary lymph node metastases. All patients underwent axillary lymph node dissection, adjuvant chemotherapy and limited-field regional nodal irradiation. The rates and patterns of regional recurrence were compared between the following three subgroups: luminal type (estrogen receptor- and/or progesterone receptor-positive), HER2-type (estrogen receptor- and progesterone receptor-negative and HER2-positive) and triple-negative type (estrogen receptor-, progesterone receptor- and HER2-negative). RESULTS: Regional recurrence occurred in 18/454 patients (4%). The risk of regional recurrence was higher in the triple-negative (hazard ratio 7.641) and HER2-type (hazard ratio 4.032) subtypes than in the luminal subtype. The predominant pattern of regional recurrence was inside the radiotherapy field in triple-negative breast cancer and outside the radiotherapy field in HER2-type and luminal-type cancers. CONCLUSIONS: In patients with pN2 breast cancer, the risk of regional recurrence was higher in the triple-negative and HER2-type than in the luminal type. In-field recurrence was predominant in triple-negative cancer, while out-field recurrence was frequent in luminal and HER2-type breast cancers.

Role of salvage radiotherapy for recurrent ovarian cancer.

OBJECTIVE: This study aimed to report clinical outcomes of salvage radiotherapy for recurrent ovarian cancer and identify predictors of clinical outcomes. METHODS: We retrospectively reviewed data of patients who received salvage radiotherapy for recurrent ovarian cancer between January 2011 and June 2021. Stereotactic body radiotherapy, involved-field radiotherapy with conventional fractionation, and non-involved-field radiotherapy with conventional fractionation were included in this study. Local failure-free survival, progression-free survival, chemotherapy-free survival, and overall survival were assessed. Additionally, potential prognostic factors for survival were analyzed. RESULTS: A total of 79 patients were included with 114 recurrent lesions. The median follow-up was 18.3 months (range 1.7-83). The 2-year local failure-free survival, progression-free survival, chemotherapy-free survival, and overall survival rates were 80.7%, 10.6%, 21.2%, and 74.7%, respectively. Pre-radiotherapy platinum resistance (hazard ratio (HR) 3.326, p<0.001) and short pre-radiotherapy CA-125 doubling time (HR 3.664, p<0.001) were associated with poor chemotherapy-free survival. The 1-year chemotherapy-free survival rates of patients with both risk factors, a single risk factor, and no risk factor were 0%, 20.4%, and 53.5%, respectively. The difference between risk groups was statistically significant: low risk versus intermediate risk (p<0.001) and intermediate risk versus high risk (p<0.001). CONCLUSIONS: Salvage radiotherapy for recurrent ovarian cancer resulted in local control with improved chemotherapy-free survival in carefully selected patients. Our results suggest that the consideration of pre-radiotherapy platinum resistance and pre-radiotherapy CA-125 doubling time could help with patient selection.

Anti-Atopic Effect of Isatidis Folium Water Extract in TNF-α/IFN-γ-Induced HaCaT Cells and DNCB-Induced Atopic Dermatitis Mouse Model.

Isatidis folium or Isatis tinctoria L. is a flowering plant of the Brassicaceae family, commonly known as woad, with an ancient and well-documented history as an indigo dye and medicinal plant. This study aimed to evaluate the anti-atopic dermatitis (AD) effects of Isatidis folium water extract (WIF) using a 2,4-dinitrochlorobenzene (DNCB)-induced AD-like mouse model and to investigate the underlying mechanism using tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)-activated HaCaT cells. Oral administration of WIF reduced spleen weight, decreased serum IgE and TNF-α levels, reduced epidermal and dermal thickness, and inhibited eosinophil and mast cell recruitment to the dermis compared to DNCB-induced control groups. Furthermore, oral WIF administration suppressed extracellular signal-regulated kinase and p38 mitogen-activated protein kinase protein expression levels, p65 translocation from the cytoplasm to the nucleus, and mRNA expression of TNF-α, IFN-γ, interleukin (IL)-6, and IL-13 in skin lesion tissues. In HaCaT cells, WIF suppressed the production of regulated upon activation, normal T cell expressed and secreted (RANTES), thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), MCP-1, and MIP-3a, which are inflammatory cytokines and chemokines related to AD, and inhibited the mRNA expression of RANTES, TARC, and MDC in TNF-α/IFN-γ-stimulated HaCaT cells. Overall, the results revealed that WIF ameliorated AD-like skin inflammation by suppressing proinflammatory cytokine and chemokine production via nuclear factor-κB pathway inhibition, suggesting WIF as a potential candidate for AD treatment.

Immediate breast reconstruction has no impact on the oncologic outcomes of patients treated with post-mastectomy radiation therapy: a comparative analysis based on propensity score matching.

PURPOSE: To investigate the impact of immediate breast reconstruction (iBR) on patients treated with post-mastectomy radiation therapy (PMRT) using propensity score matching (PSM). METHODS: After a retrospective review of patients treated with PMRT between 2008 and 2017, we included 153 patients who underwent iBR and 872 patients who did not undergo iBR. Among the 153 patients who underwent iBR, 34 received one-stage iBR with autologous tissue and 119 received two-stage iBR. Conventional fractionated PMRT with a total dose of 50-50.4 Gy in 25-28 fractions was performed in all patients. Propensity scores were calculated via logistic regression. RESULTS: Patients who underwent iBR were younger, had early stage disease, and had more frequent hormone receptor-positive tumor than those who did not undergo iBR. After PSM, 127 patients from each group with well-balanced characteristics were selected. With a median follow-up of 67.5 months, iBR led to better 6-year disease-free survival rates compared to no iBR before PSM (84.8% vs. 71.4%, p = 0.003); after PSM, there was no significant difference (84.8% vs. 75.5%, p = 0.130). On multivariable analysis in the matched cohort, iBR was not associated with inferior disease-free survival (hazard ratio, 0.67; p = 0.175). In the sensitivity analysis, iBR was not associated with a lower disease-free survival across all prognostic groups. The 5-year cumulative incidence of iBR failure was 15.0%. CONCLUSION: In patients with adverse pathologic factors planning to receive PMRT, iBR did not compromise oncologic outcomes. In addition, iBR can be considered in patients treated with PMRT with several clinicopathologic risk factors.

Patterns and risk factors of recurrence in low-risk early-stage cervical adenocarcinoma treated with surgery alone: implications on risk group stratification.

OBJECTIVE: Cervical adenocarcinoma has poorer outcomes compared with squamous cell carcinoma; however, treatment is identical irrespective of histologic sub-types. This study aimed to investigate the patterns and risk factors of recurrence following surgery alone for low-risk early-stage cervical adenocarcinoma. METHODS: We retrospectively reviewed patients who underwent surgery alone for low-risk early-stage cervical adenocarcinoma between January 2001 and December 2018 in a single institution. Baseline clinicopathological characteristics were collected to identify the factors associated with recurrence-free survival. RESULTS: A total of 252 patients met the inclusion criteria. Most patients underwent radical hysterectomy (218 patients, 86.5%) and had usual type endocervical adenocarcinoma (190 patients, 75.4%). The International Federation of Gynecology and Obstetrics 2018 stage was IA1 in 72 patients (27.4%), IA2 in 58 (22.1%), IB1 in 51 (19.4%), and IB2 in 71 patients (27.0%). With a median follow-up of 70.4 months (range 6.2-252.5 months), 5-year survival rates were as follows: locoregional recurrence-free survival, 93.0%; recurrence-free survival, 89.6%; overall survival, 94.7%. The recurrence patterns were local in nine patients (32.1%), regional in five patients (17.8%), distant in 10 patients (35.7%), local and distant in one patient (3.6%), regional and distant in two patients (7.2%), and locoregional and distant in one patient (3.6%). In multivariable analysis, negative human papillomavirus (HPV) status (HR 7.314; p<0.001) and deep cervical stromal invasion (HR 5.110; p=0.003) were associated with poor locoregional recurrence-free survival. Patients were stratified based on the number of risk factors and a statistically significant difference in locoregional recurrence-free survival was observed: 5-year survival rates of 99.0%, 84.2%, and 50.0% for patients with 0, 1, and 2 risk factors (0 vs 1, p=0.001; 1 vs 2, p=0.011). CONCLUSION: Surgery alone for low-risk early-stage cervical adenocarcinoma was associated with favorable outcomes over a long follow-up period. Patients with the highest risk of recurrence were those with a negative HPV status and deep cervical stromal invasion. Additional management following surgery may be considered in patients with these risk factors.

Clinical Features and Outcomes of Patients with Orbital Schwannoma.

PURPOSE: To report the clinical features, treatment, and outcome of 11 patients with orbital schwannoma in Korean patients. METHODS: The medical records of 11 orbital schwannoma patients treated between April 2007 and April 2021 were retrospectively reviewed. The demographic data, clinical characteristics, radiological features, and outcomes were reviewed. RESULTS: The mean age at the time of diagnosis was 49.00 ± 14.45 years. The most common initial symptom was ocular protrusion (n = 7), and other symptoms were decreased visual acuity ( n = 5), restriction of eye movement ( n = 4), swelling ( n = 3), and pain ( n = 2). Locations of tumors were superomedial; followed by the orbital apex and inferolateral. The most common shape seen in our patients was beads like multilobulated appearance; followed by a round, oval, fusiform, and dumbbell shape. MRI of T1-weighted revealed isointense or hypointense, whereas the T2-weighted indicated hyper or isointense lesion. Five patients had optic neuropathy at presentation, and 1 of them showed improved vision after surgery. Complete or incomplete excision was performed for all. Surgical complications include decreased vision and paraesthesia. There has been no recurrence to date. CONCLUSIONS: Orbital schwannoma is a rare disease and it is difficult to distinguish it from other orbital tumors because the initial symptoms are nonspecific. Differential diagnosis by combining the shape, location, and contrast enhancement findings seen on computed tomography and magnetic resonance imaging can be helpful in surgical treatment. Complete excision gives the best results without recurrence, but if the patient is in an inaccessible location, only surgery to reduce the volume can satisfy the patient without recurrence.

Antiviral Effect of Isoquercitrin against Influenza A Viral Infection via Modulating Hemagglutinin and Neuraminidase.

Isoquercitrin (IQC) is a component abundantly present in many plants and is known to have an anti-viral effect against various viruses. In this study, we demonstrate that IQC exhibits strong anti-influenza A virus infection, and its effect is closely related to the suppression of hemagglutinin (HA) and neuraminidase (NA) activities. We used green fluorescent protein-tagged Influenza A/PR/8/34 (H1N1), A/PR/8/34 (H1N1), and HBPV-VR-32 (H3N2) to evaluate the anti-IAV effect of IQC. The fluorescence microscopy and fluorescence-activated cell sorting analysis showed that IQC significantly decreases the levels of GFP expressed by IAV infection, dose-dependently. Consistent with that, IQC inhibited cytopathic effects by H1N1 or H3N2 IAV infection. Immunofluorescence analysis confirmed that IQC represses the IAV protein expression. Time-of-addition assay showed that IQC inhibits viral attachment and entry and exerts a strong virucidal effect during IAV infection. Hemagglutination assay confirmed that IQC affects IAV HA. Further, IQC potently reduced the NA activities of H1N1 and H3N2 IAV. Collectively, IQC prevents IAV infection at multi-stages via virucidal effects, inhibiting attachment, entry and viral release. Our results indicate that IQC could be developed as a potent antiviral drug to protect against influenza viral infection.

Therapeutic Effects of Acer palmatum Thumb. Leaf Extract (KIOM-2015E) on Benzalkonium Chloride-Induced Dry Eye in a Mouse Model.

We determined the effects of two extracts from Acer palmatum Thumb. leaves (hot water extract KIOM-2015EW and 25% ethanol extract KIOM-2015EE) in a benzalkonium chloride (BAC)-induced dry eye mouse model. Dry eye was induced by 0.2% BAC for 2 weeks, followed by treatment three times (eye drop) or once (oral administration) daily with KIOM-2015E for 2 weeks. Treatment with both KIOM-2015EE and KIOM-2015EW resulted in a marked increase in tear volume production for the 4 days of treatment. The Lissamine Green staining score, TUNEL-positive cells, and inflammatory index were significantly decreased after 2 weeks. Topical KIOM-2015EE administration exhibited a greater improvement in decreasing the ocular surface staining scores, inflammation, dead cells, and increasing tear production in a dose-dependent manner compared with the other groups. Furthermore, KIOM-2015E significantly reduced the phosphorylation of NF-κB, which was activated in the BAC-treated cornea. Topical administration was much more effective than oral administration for KIOM-2015E and KIOM-2015EE was more effective than KIOM-2015EW. Application of KIOM-2015E resulted in clinical improvement, inhibited the inflammatory response, and alleviated signs of dry eye. These results indicate that KIOM-2015E has potential as a therapeutic agent for the clinical treatment of dry eye.

Indigo Pulverata Levis (Chung-Dae, Persicaria tinctoria) Alleviates Atopic Dermatitis-like Inflammatory Responses In Vivo and In Vitro.

Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with a type 2 T helper cell (Th2) immune response. The IndigoPulverata Levis extract (CHD) is used in traditional Southeast Asian medicine; however, its beneficial effects on AD remain uninvestigated. Therefore, we investigated the therapeutic effects of CHD in 2,4-dinitrochlorobenzene (DNCB)-induced BALB/c mice and tumor necrosis factor (TNF)-α- and interferon gamma (IFN)-γ-stimulated HaCaT cells. We evaluated immune cell infiltration, skin thickness, and the serum IgE and TNF-α levels in DNCB-induced AD mice. Moreover, we measured the expression levels of pro-inflammatory cytokines, mitogen-activated protein kinase (MAPK), and the nuclear factor-kappa B (NF-κB) in the mice dorsal skin. We also studied the effect of CHD on the translocation of NF-κB p65 and inflammatory chemokines in HaCaT cells. Our in vivo results revealed that CHD reduced the dermis and epidermis thicknesses and inhibited immune cell infiltration. Furthermore, it suppressed the proinflammatory cytokine expression and MAPK and NF-κB phosphorylations in the skin tissue and decreased serum IgE and TNF-α levels. In vitro results indicated that CHD downregulated inflammatory chemokines and blocked NF-κB p65 translocation. Thus, we deduced that CHD is a potential drug candidate for AD treatment.

Dynamics of circulating tumor DNA during postoperative radiotherapy in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy: a prospective observational study.

BACKGROUND: This study was performed to evaluate circulating tumor DNA (ctDNA) kinetics during postoperative radiotherapy (PORT) in patients with residual triple-negative breast cancer (TNBC) at surgery following neoadjuvant chemotherapy (NAC). METHODS: Stage II/III patients with post-NAC residual TNBC who required PORT were prospectively included in this study between March 2019 and July 2020. For 11 TNBC patients, next-generation sequencing targeting 38 genes was conducted in 55 samples, including tumor tissue, three plasma samples, and leukocytes from each patient. The plasma samples were collected at three-time points; pre-PORT (T0), after 3 weeks of PORT (T1), and 1 month after PORT (T2). Serial changes in ctDNA variant allele frequency (VAF) were analyzed. RESULTS: Somatic variants were found in the tumor specimens in 9 out of 11 (81.8%) patients. Mutated genes included TP53 (n = 7); PIK3CA (n = 2); and AKT1, APC, CSMD3, MYC, PTEN, and RB1 (n = 1). These tumor mutations were not found in plasma samples. Plasma ctDNA variants were detected in three (27.3%) patients at T0. Mutations in EGFR (n = 1), CTNNB1 (n = 1), and MAP2K (n = 1) was identified with ctDNA analysis. In two (18.2%) patients, the ctDNA VAF decreased through T1 and T2 while increasing at T2 in one (9.1%) patient. After a median follow-up of 22 months, no patient showed cancer recurrence. CONCLUSION: Among patients with post-NAC residual TNBC, more than a quarter exhibited a detectable amount of ctDNA after curative surgery. The ctDNA VAF changed variably during the course of PORT. Therefore, ctDNA kinetics can serve as a biomarker for optimizing adjuvant treatment.

Effect of multiple comorbidities on mortality in chronic obstructive pulmonary disease among Korean population: a nationwide cohort study.

BACKGROUND: The effects of comorbidities on chronic obstructive pulmonary disease (COPD) have been usually studied individually in the past. In this study, we aimed to investigate the comorbidities associated with mortality, the effect of multimorbidity on mortality and other factors associated with mortality among Korean COPD population. METHODS: The Korean National Health Insurance Service-National Sample Cohort version 2.0, collected between 2002 and 2015, was used. Among COPD patients [entire cohort (EC), N = 12,779], 44% of the participants underwent additional health examination, and they were analysed separately [health-screening cohort (HSC), N = 5624]. Fifteen comorbidities previously reported as risk factors for mortality were studied using Cox proportional hazards regression models. RESULTS: Total mortality rates were 38.6 per 1000 person-years (95% CI 37.32-40.01) and 27.4 per 1000 person-years (95% CI 25.68-29.22) in EC and HSC, respectively. The most common causes of death were disease progression, lung cancer, and pneumonia. Only some of the comorbidities had a direct impact on mortality. Multimorbidity, assessed by the number of comorbid diseases, was an independent risk factor of all-cause mortality in both cohorts and was a risk factor of respiratory mortality only in HSC. The Kaplan-Meier analysis showed significant differences in survival trajectories according to the number of comorbidities in all-cause mortality but not in respiratory mortality. Low BMI, old age and male sex were independent risk factors for both mortalities in both cohorts. CONCLUSIONS: The number of comorbidities might be an independent risk factor of COPD mortality. Multimorbidity contributes to all-cause mortality in COPD, but the effect of multimorbidity is less evident on respiratory mortality.

Exploring the impact of number and type of comorbidities on the risk of severe COPD exacerbations in Korean Population: a Nationwide Cohort Study.

BACKGROUND: It is difficult to assess the impact of multiple comorbidities on clinical outcomes in chronic obstructive pulmonary disease (COPD). In this study, we aimed to investigate exacerbation-associated comorbidities, determine whether the number of comorbidities is an independent risk factor for exacerbation, and identify other exacerbation-associated factors in a Korean COPD population using a nationwide population-based cohort. This study focused on severe exacerbations that required hospitalisation or emergency room visits. METHODS: The National Health Insurance Service-National Sample Cohort, version 2.0, data sampled between 2002 and 2015 were analysed. Data from two years after the diagnosis of COPD were analysed for each participant (N = 12,554, entire cohort). Moreover, 42% of the participants underwent additional health examinations (N = 5306, health-screening cohort). Fifteen comorbidities that were previously reported as risk factors for exacerbations were examined. A logistic regression model was used to analyse association with exacerbations. RESULTS: Asthma (1.57 [1.39-1.76] and 1.24 [1.06-1.44]), lung cancer (1.84 [1.30-2.59] and 2.28 [1.54-3.37]), and heart failure (1.39 [1.16-1.67] and 1.52 [1.18-1.97]) were associated with exacerbation in both cohorts (odds ratio [95% confidence interval] in the entire cohort and health-screening cohort, respectively). The number of comorbidities was an independent risk factor, and old age, male sex, low body mass index, and current smoking were also independent risk factors. High cholesterol levels and body mass index exerted protective effects against exacerbation. CONCLUSIONS: The number of comorbidities, certain comorbidities such as asthma, lung cancer and heart failure, and low BMI were associated with an increased risk of severe exacerbation in COPD patients.

Chronological Skin Changes Through Postmastectomy Radiotherapy Based on Radiotherapy Techniques: Using Quantitative Dermatological Measurements.

BACKGROUND: There has been few research on how to measure skin status quantitatively throughout the course of radiotherapy (RT). We evaluated the changes in the skin induced by 2 different RT techniques using objective measurements in breast cancer patients. METHODS: In this prospective study, between August 2015 and March 2019, serial measurements of the dermatological factors during and after postmastectomy radiotherapy (PMRT) were made in 40 breast cancer patients. PMRT was performed using the conventional photon tangential technique (PTT) or patient-tailored bolus technique (PTB). We analyzed these measurements using a mixed effect model and compared the clinically evaluated radiation dermatitis and patient-reported outcomes (PROs). RESULTS: The trend of changes in melanin and erythema was significantly different between the PTB and PTT groups (p = 0.045 and 0.016, respectively). At the 3-month follow-up erythema intensity and melanin were higher in the PTB group than in PTT group (both p < 0.001). Eight patients (40% in the PTB group) reported grade 2 radiation dermatitis and 1 patient (5% in the PTB group) reported grade 3 radiation dermatitis. No grade 2 or higher radiation dermatitis was found in the PTT group. Ten patients (50%) in the PTB group and 3 patients (15%) in the PTT group reported severe erythema likely due to questionable clinical evaluation, but hyperpigmentation was rarely reported at the follow-up visits. CONCLUSION: The PTB group showed higher intensity of erythema at the end of RT than the PTT group and the increase in melanin lasted until the 3-month follow-up visits in the PTB group. Moreover, patients subjectively appealed more severe symptoms following PTB in PROs.

Isolation and Characterization of Compounds from Glycyrrhiza uralensis as Therapeutic Agents for the Muscle Disorders.

Skeletal muscle is the most abundant tissue and constitutes about 40% of total body mass. Herein, we report that crude water extract (CWE) of G. uralensis enhanced myoblast proliferation and differentiation. Pretreatment of mice with the CWE of G. uralensis prior to cardiotoxin-induced muscle injury was found to enhance muscle regeneration by inducing myogenic gene expression and downregulating myostatin expression. Furthermore, this extract reduced nitrotyrosine protein levels and atrophy-related gene expression. Of the five different fractions of the CWE of G. uralensis obtained, the ethyl acetate (EtOAc) fraction more significantly enhanced myoblast proliferation and differentiation than the other fractions. Ten bioactive compounds were isolated from the EtOAc fraction and characterized by GC-MS and NMR. Of these compounds (4-hydroxybenzoic acid, liquiritigenin, (R)-(-)-vestitol, isoliquiritigenin, medicarpin, tetrahydroxymethoxychalcone, licochalcone B, liquiritin, liquiritinapioside, and ononin), liquiritigenin, tetrahydroxymethoxychalcone, and licochalcone B were found to enhance myoblast proliferation and differentiation, and myofiber diameters in injured muscles were wider with the liquiritigenin than the non-treated one. Computational analysis showed these compounds are non-toxic and possess good drug-likeness properties. These findings suggest that G. uralensis-extracted components might be useful therapeutic agents for the management of muscle-associated diseases.