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Purpose: We report a case of primary mucinous adenocarcinoma diagnosed in a patient presenting with a mass of the lower eyelid.Case summary: A 60-year-old man presenting with a mass on the left lower eyelid that had increased in size for 3 years was referred to our center after being diagnosed as mucinous adenocarcinoma. The mass was limited to the dermis and subcutaneous fat layer. The extent of the lesion was confirmed through frozen section examination, and tumor removal was performed. In immunohistochemistry, estrogen receptor, progesterone receptor, and cytokeratin-7 were positive, and cytokeratin-20 was negative. No metastasis was found, so it was diagnosed as primary mucinous adenocarcinoma of the eyelid. After surgery, adjuvant radiotherapy was administered to the tissues surrounding the lesion, and it did not recur during 12 months of follow-up period.Conclusions: Primary mucinous adenocarcinoma of the skin, especially of the eyelid, is rare, and it is important to differentiate it from metastatic mucinous adenocarcinoma of other organs. The authors diagnosed primary mucinous adenocarcinoma using immunohistochemistry, and we report how it was successfully treated through surgical excision and reconstruction of the eyelid.

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.

Objective: This study aimed to evaluate the effect of waiting time from diagnosis to initiation of definitive concurrent chemoradiation (CCRT) on overall survival in patients with cervical cancer. Methods: Patients with cervical cancer who had definitive CCRT between 2000 and 2017 were retrospectively reviewed. Time from pathological diagnosis to definitive CCRT was analyzed both as a continuous variable (per day) and as a categorical variable in 2 groups (Group 1 median, Group 2 > median). Patients with waiting time more than 60 days were excluded. Associations between waiting time, patients baseline characteristics, and survivals were analyzed using the Cox proportional-hazards model. Results: The median waiting time was 14 days (0-60). There were differences between Group 1 and Group 2 in age and type of chemotherapy. However, no significant difference was found in the FIGO stage, cell type, and the number of cycles of chemotherapy received during CCRT. Longer waiting time was associated with poorer overall survival on the Kaplan-Meir curve (Group 1 vs. Group 2, P = .042). On multivariate analysis, intervals as either a continuous variable (HR; 1. 023, 95% CI; 1.0061.040, P = .007) or a categorical variable (HR; 1.513, 95% CI; 1.0732.134, P = .018), FIGO stage, cell type, and the number of cycles of chemotherapy received during CCRT were significant independent prognostic factors for overall survival. Conclusion: Longer waiting time from pathological diagnosis to definitive CCRT was associated with worse overall survival. Our findings suggest that stakeholders in healthcare, including physicians and policymakers, should make an effort to minimize waiting time by rethinking factors involved in waiting time, such as referral time and time from decision making to treatment.

A choristoma is defined as a growth of histologically normal tissue in an abnormal location. Epibulbar osseous choristoma is the rarest type among all ocular choristoma with less than 100 cases reported. Here, we report a case of epibulbar osseous choristoma combined with dermolipoma and a literature review.A 15-year-old female patient presented with an accidentally found subconjunctival mass in her left eye. Slit lamp examination revealed a 10 × 10 mm elevated, sigmoid-shaped mass in the supratemporal quadrant of the bulbar conjunctiva. We performed a debulking excisional biopsy of the mass.The pathology confirmed osseous tissue surrounded by mature adipose tissue. At 1 week after the operation, the wound was clear and the patient was satisfied with the treatment. A systematic literature review of 14 previously published cases taken from PubMed dating back to 1987 along with ours was undertaken. The average age at presentation was 11.6 years and there was a female preponderance with 10 cases being female and the other 5 cases being male. Supratemporal conjunctiva was the most common site of presentation. There was no systemic disease associated with any of the cases. Since it is a benign tumor, it can be managed by observation, but if necessary, it can be treated by surgical removal.In pediatric subconjunctival mass, particularly located in supratemporal quadrant of bulbar conjunctiva, osseous choristoma should be considered in the differential diagnosis. Pre-operative CT scans will helpful to not also reduce complication with surgical excision but also helpful in prediction of diagnosis and prognosis.

Background It is important to continually reevaluate the risk/benefit calculus of internal mammary node irradiation (IMNI) in the era of modern systemic therapy. We aimed to investigate the effect of IMNI on survival in node-positive breast cancer treated with mastectomy and anthracycline plus taxane-based chemotherapy. Methods We analyzed 348 patients who underwent mastectomy and anthracycline plus taxane-based chemotherapy for node-positive breast cancer between January 2006 and December 2011. All patients received postoperative radiation therapy (RT) with IMNI (n = 105, 30.2%) or without IMNI (n = 243, 69.8%). The benefit of IMNI for disease-free survival (DFS) and overall survival (OS) was evaluated using multivariate analysis and inverse probability of treatment weighting (IPTW) to adjust for unbalanced covariates between the groups. Results After a median follow-up of 95 months, the 10-year locoregional recurrence-free survival rate, DFS, and OS in all patients were 94.8%, 77.4%, and 86.2%, respectively. The IPTW-adjusted hazard ratio (HR) for the association of IMNI (vs. no IMNI) with DFS and OS was 0.208 (95% confidence intervals (CI) 0.045–0.966) and 0.460 (95% CI, 0.220–0.962), respectively. In multivariate analysis, IMNI was a favorable factor for DFS (HR, 0.458; P = 0.021) and OS (HR 0.233, P = 0.018). Conclusions IMNI was associated with improved DFS and OS in node-positive patients treated with mastectomy, post-mastectomy RT, and taxane-based chemotherapy, although the rate of locoregional recurrence was low., Highlights • We evaluated the benefit of IMNI in modern era. • In taxane-based chemotherapy era, locoregional recurrence was very low (5.2%) in node-positive breast cancer. • IMNI was associated with improved survival.

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.

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.

Background Excessive skeletal muscle loss during neoadjuvant concurrent chemoradiotherapy (NACRT) is significantly related to survival outcomes of oesophageal cancer. However, the conventional method for measuring skeletal muscle mass requires computed tomography (CT) images, and the calculation process is labour‐intensive. In this study, we built machine‐learning models to predict excessive skeletal muscle loss, using only body mass index data and blood laboratory test results. Methods We randomly split the data of 232 male patients treated with NACRT for oesophageal cancer into the training (70%) and test (30%) sets for 1000 iterations. The naive random over sampling method was applied to each training set to adjust for class imbalance, and we used seven different machine‐learning algorithms to predict excessive skeletal muscle loss. We used five input variables, namely, relative change percentage in body mass index, albumin, prognostic nutritional index, neutrophil‐to‐lymphocyte ratio, and platelet‐to‐lymphocyte ratio over 50 days. According to our previous study results, which used the maximal χ 2 method, 10.0% decrease of skeletal muscle index over 50 days was determined as the cut‐off value to define the excessive skeletal muscle loss. Results The five input variables were significantly different between the excessive and the non‐excessive muscle loss group (all P

Background: Morbidity and mortality as a result of influenza is an ongoing global health issue. Macrophages are part of the immune defense mechanism, as they play a role in the inflammatory response that blocks viral replication. Thuja orientalis Folium (TOF) has been prescribed traditionally as an expectorant for inflammatory airway disease. In this investigation, we have assessed the anti-viral properties of TOF water extract on the infectivity of the influenza A (H1N1) virus in RAW 264.7 macrophages.Method: We assessed the ability of GFP-tagged influenza A virus (A/PR/8/34-GFP) to infect murine macrophages. To determine the potential of antiviral activity using Fluorescence-activated cell sorting (FACS), fluorescent microscopy with green fluorescent protein (GFP)-tagged Influenza A/PR/8/34 virus. Hemagglutination inhibition assay, Western blotting, and Immunofluorescence analyses were performed to find the target protein. To investigate which stage of viral infection is associated with the TOF antiviral impact, we evaluated viral infection at three stages: attachment, entry, and virucidal in the presence of TOF.Results: FACS and immunofluorescence analyses results showed that TOF significantly inhibited viral infection and 100 μg/mL of TOF repressed that up to 98% of untreated control. Consistently, Western blot and immunofluorescence analyses against the influenza viral protein confirmed the TOF extract reduced the influenza viral protein expression in a dose-dependent manner. Time of addition and hemagglutination assays elucidated that TOF suppresses influenza A viral infection at early stages and interfere with HA protein.Conclusion: The TOF extract was thus found to exhibit inhibitory effects on influenza virus infection by inhibiting hemagglutination, blocking viral attachment and entry, and through virucidal effects. Based on our results, TOF may be a potential natural resource that could be utilized to develop an antiviral reagent.

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.

Regulation of innate inflammation is critical for maintaining tissue homeostasis and barrier function, especially in those interfacing the external environment 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 cytokine, a subfamily of the IL-1 superfamily, consists of three pro-inflammatory agonists IL36α, IL36β, and IL36γ and an IL36 receptor antagonist (IL36Ra). The current investigation, for the first time, reports that IL36γ is the primary isoform 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 repithelialization 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 suppress 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.

Broccoli (Brassica oleracea L. var. Italica) leaves are a byproduct of broccoli and could be used as a food source. The study aimed to evaluate the effect of broccoli leaves on influenza A virus (IAV) infection. We investigated the effect of ethanol extract of Broccoli leaves (EBL) on IAV infection using green fluorescent protein (GFP)–tagged Influenza A/PR/8/34 virus (PR8-GFP IAV). When EBL and PR8-GFP IAV were cotreated to RAW 264.7 cells, the fluorescence microscopy and fluorescence-activated cell sorting (FACS) analysis showed that EBL significantly reduced the levels of GFP expression by influenza viral infection dose-dependently. Immunofluorescence (IF) analysis confirmed that EBL decreased the expression of IAV proteins. EBL exhibited a strong inhibitory effect of IAV binding on the cells and moderate virucidal impact. Consistently, EBL potently suppressed the hemagglutination by IAV infection. These results indicate that EBL prevents IAV attachment via the inhibition of HA upon viral infection. Finally, EBL as an HA inhibitor of IAV could be used as the natural antiviral source to protect against influenza viral infection.

Background The Korean Radiation Oncology Group (KROG) 19 − 09 prospective cohort study aims to determine the effect of regional nodal irradiation on regional recurrence rates in ypN0 breast cancer patients. Dosimetric variations between radiotherapy (RT) plans of participating institutions may affect the clinical outcome of the study. We performed this study to assess inter-institutional dosimetric variations by dummy run. Methods Twelve participating institutions created RT plans for four clinical scenarios using computed tomography images of two dummy cases. Based on a reference structure set, we analyzed dose-volume histograms after collecting the RT plans. Results We found variations in dose distribution between institutions, especially in the regional nodal areas. Whole breast and regional nodal irradiation (WBI + RNI) plans had lower inter-institutional agreement and similarity for 95% isodose lines than WBI plans. Fleiss’s kappa values, which were used to measure inter-institutional agreement for the 95% isodose lines, were 0.830 and 0.767 for the large and medium breast WBI plans, respectively, and 0.731 and 0.679 for the large and medium breast WBI + RNI plans, respectively. There were outliers in minimum dose delivered to 95% of the structure (D95%) of axillary level 1 among WBI plans and in D95% of the interpectoral region and axillary level 4 among WBI + RNI plans. Conclusion We found inter-institutional and inter-case variations in radiation dose delivered to target volumes and organs at risk. As KROG 19 − 09 is a prospective cohort study, we accepted the dosimetric variation among the different institutions. Actual patient RT plan data should be collected to achieve reliable KROG 19 − 09 study results.

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.

Purpose This study aimed to identify the prognostic value of early metabolic response assessed using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) during radiation therapy (RT) for cervical cancer.Materials and Methods We identified 116 patients treated with definitive RT, including FDG-PET/CT–guided intracavitary brachytherapy, between 2009 and 2018. We calculated parameters including maximum (SUVmax) and mean standardized uptake values (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for baseline FDG-PET/CT (PETbase) and image-guided brachytherapy planning FDG-PET/CT (PETIGBT). Multivariable analyses of disease-free survival (DFS) and overall survival (OS) were performed.Results We observed a time-dependent decrease in PET parameters between PETbase and PETIGBT; ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG were 65%, 61%, 78%, and 93%, respectively. With a median follow-up of 59.5 months, the 5-year DFS and OS rates were 66% and 79%, respectively. Multivariable analysis demonstrated that ΔSUVmax ≥ 50% was associated with favorable DFS (hazard ratio [HR], 2.56; 95% confidence interval [CI], 1.14 to 5.77) and OS (HR, 5.14; 95% CI, 1.55 to 17.01). Patients with ΔSUVmax ≥ 50% (n=87) showed better DFS and OS than those with ΔSUVmax < 50% (n=29) (DFS, 76% vs. 35%, p < 0.001; OS, 90% vs. 41%, p < 0.001, respectively). Adenocarcinoma was frequently observed in ΔSUVmax < 50% compared to ΔSUVmax ≥ 50% (27.6% vs. 10.3%, p=0.003). In addition, models incorporating metabolic parameters showed improved accuracy for predicting DFS (p=0.012) and OS (p=0.004) than models with clinicopathologic factors.Conclusion Changes in metabolic parameters, especially those in SUVmax by > 50%, can help improve survival outcome predictions for patients with cervical cancer treated with definitive RT.

Purpose To analyze the relationship between body mass index change and bone age progression during gonadotropin-releasing hormone agonist(GnRHa) treatment in girls with idiopathic central precocious puberty Methods: 65 girls with idiopathic central precocious puberty who are treated with GnRHa more than 2 years were retrospectively reviewed. Height, weight, Tanner stage, bone age were measured every 6 months from the start of treatment. The degree of obesity was evaluated using the body mass index (BMI) standard deviation score (SDS), and the relationship between the change in obesity and the progression of bone age was analyzed. Overweight was defined as a BMI greater than or equal to the 85th percentile. The chronological age at the start and the end of treatment was 7. 00±0. 00 years and 10.63±0.50 years in the overweight group (16 patients), and 6.86±0.35 years and 10.71±0.54 years in the other group (49 patients), respectively. Results There was no difference in bone age between the normal weight group and the overweight group at the start of treatment (9.85±0.57 years vs 10. 04±0.73 years, P=0.263). Bone age was higher in the overweight group, but after 1 year of treatment, 2 years of treatment, and at the end of treatment, the overweight group had a higher bone age than the normal weight group (10.47±0.56 years vs 10.87±0.57 years, P=0. 02; 11. 06±0.47 years vs 11.46±0.51 years, P=0. 004; 11.70±0.46 years vs 12. 01±0.52 years, P=0. 03). Bone age at the end of treatment was related to overweight at the start of treatment (r=0.265, P=0. 03) and the increase in BMI SDS from normal to overweight during treatment (r=0.285, P=0. 02). There were 11 children (17%) whose BMI SDS increased from normal to overweight during treatment, compared with the other patients, there was no difference in bone age during 2 years of treatment, but bone age at the end of treatment was higher (12. 09±0.60 years vs 11.71±0.47 years, P=0. 02), and the difference in bone age before and after treatment was also greater (2.31±0.68 years vs 1.79±0.52 years, P=0. 01). Linear regression analysis demonstrated that the increase in BMI SDS from normal to overweight during treatment had a positive correlation with bone age at the end of treatment (β=0.31, R2=0. 07, P=0. 03). Conclusion In girls with central precocious puberty, an increase in obesity from normal to overweight during GnRHa treatment does not affect bone age progression until 2 years from the start of treatment, but might be a risk factor for bone age progression at the end of treatment. Presentation: No date and time listed

A systematic search for eyelid angiosarcoma was performed from inception to December 2020 in Medline, EMBASE, and the Cochrane databases. Forty two eyelid angiosarcoma cases in 32 articles were analyzed. Eyelid angiosarcomas showed an incidence peak in the eighth decade of life, and was reported more frequently in Caucasian males. Eyelid angiosarcomas were associated with a mortality rate of 26.2%, a recurrence rate of 14.3%, and a cure rate of 45.2%. Four years event-free survival (EFS) rate was 36.0%, with median EFS of 36 months. Eyelid angiosarcomas with bilateral involvement or metastasis showed higher mortality and recurrence rates than unilateral eyelid invasion cases. In the prognosis analysis according to treatment modalities, the mortality and recurrence rates were the lowest in patients who underwent surgical excision. The 4-year EFS probability in a group with surgical excision was 60.6%, but in a group without surgical excision it was 30.3%. A total of 45.2% of the cases was misdiagnosed and 21.4% of the cases could not be correctly diagnosed with the first biopsy trial. The prognosis for eyelid angiosarcomas was better than that of angiosarcomas invading the face and scalp. Surgical excision was the most important treatment modality; thus, should be considered as the first treatment of choice.

The postoperative hypofractionated intensity-modulated radiation therapy (POHIM-RT) trial is a phase II study to evaluate toxicity following hypofractionated intensity modulated radiation therapy (IMRT) for cervical cancer. This study describes the results of a benchmark procedure for RT quality assurance of the POHIM-RT trial. Six participating institutions were provided computed tomography for RT planning and an IMRT plan for a sample and were instructed to delineate volumes, create a treatment plan and quality assurance (QA) plan, and submit the results of all procedures. The inter-institutional agreements on RT volume and plan results were evaluated using the kappa value and dice similarity coefficients. The simultaneous truth and performance level estimation (STAPLE) method was employed to generate a consensus target volume. The treatment volumes, organs-at-risk volumes, and results of the RT plan and QA reported by the institutions were acceptable and adhered well to the protocol. In terms of clinical target volume (CTV) delineation, there were differences between the institutions, particularly in vaginal cuff and paracolpium subsites. Consensus CTV was generated from the collected CTVs with the STAPLE method. The participating institutions showed considerable agreement regarding volume, dose and QA results. To improve CTV agreement in CTV, we provided feedback with images of the consensus target volume and detailed written guidelines for specific subsites that were the most heterogeneous.

Purpose The present study aimed to determine whether the administration of Acer palmatum thumb. leaf extract (KIOM-2015E) protects against the degeneration of rat retinal ganglion cells after ischemia/reperfusion (I/R) induced by midbrain cerebral artery occlusion (MCAO). Methods Sprague–Dawley rats were subjected to 90 min of MCAO, which produces transient ischemia in both the retina and brain due to the use of an intraluminal filament that blocks the ophthalmic and middle cerebral arteries. This was followed by reperfusion under anesthesia with isoflurane. The day after surgery, the eyes were treated three times (eye drop) or one time (oral administration) daily with KIOM-2015E for five days. Retinal histology was assessed in flat mounts and vertical sections to determine the effect of KIOM-2015E on I/R injury. Results A significant loss of brain-specific homeobox/POU domain protein 3A (Brn3a) and neuron-specific class III beta-tubulin (Tuj-1) fluorescence and a marked increase in glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) expression were observed after five days in the PBS-treated MCAO group compared to the sham-operated control group. However, KIOM-2015E treatment reduced (1) MCAO-induced upregulation of GFAP and GS, (2) retinal ganglion cell loss, (3) nerve fiber degeneration, and (4) the number of TUNEL-positive cells. KIOM-2015E application also increased staining for parvalbumin (a marker of horizontal cell associated calcium-binding protein and amacrine cells) and recoverin (a marker of photoreceptor expression) in rats subjected to MCAO-induced retinal damage. Conclusions Our findings indicated that KIOM-2015E treatment exerted protective effects against retinal damage following MCAO injury and that this extract may aid in the development of novel therapeutic strategies for retinal diseases, such as glaucoma and age-related macular disease.

PurposeThe purpose of this study was to investigate the role of carcinoembryonic antigen (CEA) levels in improving the performance of magnetic resonance imaging (MRI) for the prediction of pathologic response after the neoadjuvant chemoradiation (NCRT) for patients with rectalcancer.Materials and MethodsWe retrospectively reviewed the medical records of 524 rectal cancer patients who underwent NCRT and total mesorectal excision between January 2009 and December 2014. The performances of MRI with or without CEA parameters (initial CEA and CEA dynamics) for prediction of pathologic tumor response grade (pTRG) were compared by receiver-operating characteristic analysis with DeLong’s method. Cox regression was used to identify the independent factors associated to pTRG and disease-free survival (DFS) after NCRT.ResultsThe median follow-up was 64.0 months (range, 3.0 to 113.0 months). On multivariate analysis, poor tumor regression grade on MRI (mrTRG; p < 0.001), initial CEA (p < 0.001) and the mesorectal fascia involvement on MRI before NCRT (mrMFI; p=0.054) showed association with poor pTRG. The mrTRG plus CEA parameters showed significantly improved performances in the prediction of pTRG than mrTRG alone. All of mrTRG, mrMFI, and initial CEA were also identified as independent factors associated with DFS. The initial CEA further discriminated DFS in the subgroups with good mrTRG or that without mrMFI.ConclusionThe CEA parameters significantly improved the performance of MRI in the prediction of pTRG after NCRT for patients with rectal cancer. The DFS was further discriminated by initial CEA level in the groups with favorable MRI parameters.

This study was performed to identify risk factors for pelvic nodal failure (PNF) after definitive concurrent chemo-radiotherapy (CCRT) in patients with metastatic pelvic lymph nodes (mPLNs) from squamous cell carcinoma (SCC) of the cervix. We retrospectively reviewed data on 80 patients who received definitive CCRT between 2005 and 2014 at our hospital. All patients underwent brachytherapy and whole-pelvic radiotherapy (WPRT) without nodal boost. mPLNs was diagnosed by magnetic resonance imaging and positron emission tomography. The rate of PNF and factors affecting PNF were analysed. A total of 156 mPLNs were found. The median number of mPLNs was 2 per patient (range 1–6); the median short diameter was 1.7 cm (range 1.0–4.2 cm). After a median follow-up of 64 months, 10 (6.4%) mPLNs failed in 13 (16.3%) patients. The 5-year PNF-free survival (PNFFS), disease-free survival and overall survival rates were 83.4, 62.7 and 74.7%, respectively. The mPLN size was not associated with the risk of PNF. However, pre-radiotherapy SCC antigen (SCC-Ag) >6.8 ng/mL and number of mPLNs >2 were significant risk factors for PNF. Using the two risk factors, we categorized the patients into three risk groups. The 5-year PNFFS rates in patients with 0, 1 and 2 risk factors were 100.0, 78.3 and 44.4%, respectively (P

BackgroundIsatis tinctoria L(PLG) is a medicinal herb from the roots ofIsatis indigotica Fort(Family Cruciferae). Previous studies have shown that PLG has anti-inflammatory and therapeutic effects against conditions such as acute and chronic hepatitis, various respiratory inflammations, and cancer. The purpose of this study was to define the pharmacological effects of PLG on inflammatory reactions and skin hyperkeratosis, which are the main symptoms of atopic dermatitis (AD), in vivo and in vitro.MethodsFor the AD in vivo experiment, 2,4-dinitrochlorobenzene (DNCB) induction and oral administration of PLG were performed on male BALB/c mice for four weeks. For in vitro experiments, keratinocytes were activated using TNF-α/IFN-γ in cultured human keratinocyte (HaCaT) cells. PLG inhibited inflammatory chemokine production and blocked the nuclear translocation of NF-κB p65 in activated keratinocytes.ResultsAs a result of oral administration of PLG, dermis and epidermis thickening, as well as eosinophil and mast cell infiltration, were attenuated in AD skin lesions. In addition, the levels of immunoglobulin E (IgE), pro-inflammatory cytokines, and the MAPK/NF-κB signaling pathway were decreased in serum and dorsal skin tissues. Furthermore, PLG inhibited inflammatory chemokine production and blocked the nuclear translocation of NF-κB p65 in activated keratinocytes. In addition, epigoitrin and adenosine, the standard compounds of PLG, were identified as candidate AD compounds.ConclusionsThese results indicate that PLG is a potent therapeutic agent for attenuating symptoms of AD.

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.

The recently updated World Health Organization classification divides endocervical adenocarcinomas (ADCs) into human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) ADCs. This study aimed to investigate the differences in the clinical features and treatment outcomes between patients with HPVA and HPVI.We retrospectively reviewed the electronic medical records and pathology slides of 123 patients with endocervical ADC who underwent radical hysterectomy and adjuvant radiation therapy. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs.Eighty-one (65.9%) and 42 (34.1%) patients were diagnosed with HPVA and HPVI ADCs, respectively. HPVI ADC showed more frequent positive vaginal resection margin (VRM) and peritoneal seeding than HPVA ADC. After a median follow-up of 58.1 months, local recurrence and distant metastasis were more frequently observed in HPVI ADC than in HPVA ADC. Both local recurrence-free survival (77.3% vs. 91.8%) and distant metastasis-free survival (50.1% vs. 73.7%) rates of HPVI ADC were lower than those of HPVA ADC. Disease-free survival was not significantly different between HPVI and HPVA ADCs.We demonstrated that HPVI ADC exhibited higher rates of VRM involvement and peritoneal seeding than those of HPVA ADC, resulting in higher rates of local recurrence and distant metastasis. Further studies with larger populations are warranted to explore optimal treatment strategies based on the histological subtypes of endocervical ADC.

This study aimed to evaluate the oncologic outcomes according to disease burden in uterine cervical cancer patients with metachronous distant metastases.Between 2005 and 2015, 163 patients with metachronous distant metastases from uterine cervical cancer after receiving a definitive therapy were evaluated at seven institutions in Korea. Low metastatic burden was defined as less than 5 metastatic sites, whereas high metastatic burden was others. Each metastasis site was divided based on the lymph node (LN) and organs affected. The overall survival (OS) and progression-free survival (PFS) were assessed. Cox proportional hazards models, including other clinical variables, were used to evaluate the survival outcomes.The median follow-up duration was 22.2 months (range: 0.3-174.8 months). Para-aortic LNs (56.4%), lungs (26.4%), supraclavicular LNs (18.4%), and peritoneum (13.5%) were found to be the common metastasis sites. Among 37 patients with a single metastasis, 17 (45.9%) had LN metastases and 20 (54.1%) had organ metastases. The 1- and 2-year OS rates were 73.9% and 55.0%, respectively, whereas the PFS rates were 67.2% and 42.9%, respectively. SCC Ag after recurrence and high metastatic burden were significant factors affecting the OS (p=0.004 and p0.001, respectively). Distant organ recurrence, short disease-free interval (≤2 years), and high metastatic burden were unfavorable factors for PFS (p=0.003, p=0.011, and p=0.002, respectively).A favorable oncologic outcome can be expected by performing salvage treatments in selected patients with a long disease-free interval, low metastatic burden, and/or lymphatic-only metastasis.

Epimedium koreanum Nakai (EKN) is a popular plant in Korean and Chinese medicine for treating a variety of ailments. The aqueous extract of EKN has a significant inhibitory impact on influenza A virus (IAV) infection by directly blocking viral attachment and having a virucidal effect, according to this study. Using fluorescent microscopy and fluorescence-activated cell sorting (FACS) with a green fluorescent protein (GFP)-tagged Influenza A/PR/8/34 virus, we examined the effect of EKN on viral infection. By viral infection, EKN strongly suppresses GFP expression, and at a dosage of 100 µg/mL, EKN decreased GFP expression by up to 90% of the untreated infected control. Immunofluorescence and Western blot analyses against influenza viral proteins revealed that EKN decreased influenza viral protein expression in a dose-dependent manner. EKN inhibited the H1N1 influenza virus's hemagglutinin (HA) and neuraminidase (NA), preventing viral attachment to cells. Furthermore, EKN had a virucidal impact and inhibited the cytopathic effects of H1N1, H3N2 and influenza B virus infection. Finally, our findings show that EKN has the potential to be developed as a natural viral inhibitor against influenza virus infection.

Adverse effects of smoking on kidney function have been demonstrated in both general populations and in populations with chronic kidney disease (CKD). Therefore, quitting smoking can have a significant impact on the mortality and disease progression of CKD. This study examined and compared factors associated with quitting status of smoking, in patients with and without CKD, among Korean adult male smokers, using the Korea National Health and Nutrition Examination Survey from 2008 to 2019, excluding 2013.Wald test with multiple logistic regression was performed to investigate factors associated with quitting smoking in both CKD and non-CKD groups, along with the interaction effects between groups.Of the 15747 eligible individuals, 909 had CKD, of whom 703 (weighted percentage: 74.4%) were quitters. In the non-CKD group, 8393 (weighted percentage: 50.4%) succeeded in quitting. Regular exercise was the only factor associated with quitting in both groups. The adjusted odd ratios with confidence intervals were 1.29 (95% CI: 1.17-1.42) and 2.84 (95% CI: 1.52-5.31) in the non-CKD and CKD groups, respectively (interaction p=0.0153). Unlike in the CKD group, marriage and higher systolic blood pressure were also associated with quitting, and lifetime smoking amount and secondhand smoke exposure at home were negatively associated with smoking cessation in the non-CKD group.Exercise was the only factor associated with quitting smoking in the CKD group.

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 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. To suppress latent HIV-1 in a stable fashion, we depleted 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 were 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 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. Thus, epigenetic silencing by itself appears to be insufficient to permanently silence HIV-1 proviral transcription.Author SummaryThe “block and lock” strategy for a functional HIV-1 cure is based on the premise that permanent inactivation of the HIV-1 can be achieved by epigenetic silencing of the proviral DNA. For cellular genes, long-term silencing is achieved during cell differentiation by the induction of specific epigenetic modifications involving histone and DNA methylation. During HIV-1 silencing, histone methylation and DNA methylation are observed, but both sets of modifications can be reversed upon activation of T-cells through the T-cell receptor or potent latency reversing agents. In an attempt to enhance silencing of HIV-1 transcription, we used an inhibitor of H3K27 demethylases to increase H3K27 methylation. This in turn led to enhanced DNA methylation of HIV-1. Unfortunately, although the treatment effectively silenced HIV-1 and prevented viral reactivation, the silencing effects were short-lived and quickly reversed after removal of the drug.

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., Author summary The “block and lock” strategy for a functional HIV-1 cure is based on the premise that permanent inactivation of the HIV-1 can be achieved by epigenetic silencing of the proviral DNA. For cellular genes, long-term silencing is achieved during cell differentiation by the induction of specific epigenetic modifications involving histone and DNA methylation. During HIV-1 silencing, histone methylation and DNA methylation are observed, but both sets of modifications can be reversed upon activation of T-cells through the T-cell receptor or potent latency reversing agents. In an attempt to enhance silencing of HIV-1 transcription, we used an inhibitor of H3K27 demethylases to increase H3K27 methylation. This in turn led to enhanced DNA methylation of HIV-1. Unfortunately, although the treatment effectively silenced HIV-1 and prevented viral reactivation, the silencing effects were short-lived and quickly reversed after removal of the drug.