Prognostic impact of suspicious extraabdominal lymph nodes on patient survival in advanced ovarian cancer.

OBJECTIVE: To evaluate the clinical impact of suspicious extra-abdominal lymph nodes (EALNs) identified preoperatively on CT and/or PET/CT images in advanced ovarian cancer. METHODS: A retrospective study was conducted with 122 patients diagnosed with stage III or IV ovarian cancer with preoperative CT and/or PET/CT images from 2006 to 2022. Imaging studies were evaluated for the presence, size and location of suspicious EALNs. Suspicious lymph node enlargement was defined by a cut-off ≥5mm short-axis dimension on CT and/or lesions with maximum standardized uptake values of ≥2.5 on PET/CT. This study only included patients who did not have their EALNs surgically removed. RESULTS: A total 109 patients met the inclusion criteria; 36 (33%) had suspicious EALNs and were categorized as "node-positive". The median overall survival (OS) was 45.73 months for the "node-positive" and 46.50 months for the "node-negative" patients (HR 1.17, 95% CI 0.68-2.00, p = 0.579). In multivariate analysis, after adjusting for other variables selected by process of backward elimination using a significance level of p<0.20, suspicious EALNs still showed no clinical significance on OS (aHR 1.20, 95% CI 0.67-2.13, p = 0.537) as well as progression-free survival (aHR 1.43, 95% CI 0.85-2.41, p = 0.174). Old age (aHR 2.23, 95% CI 1.28-3.89, p = 0.005) and platinum resistance (aHR 1.92, 95% CI 1.10-3.36, p = 0.023) affects adversely on OS. CONCLUSION: Suspicious EALNs did not worsen the prognosis of patients with advanced ovarian cancer. However, its impact on survival is not yet clarified. Further investigation is required to assess the clinical significance of suspicious EALNs on preoperative imaging studies.

Risk Factors and Prognosis of Stroke in Gynecologic Cancer Patients.

Increased life expectancy and cancer prevalence rates expose patients to a higher risk of developing other comorbidities such as stroke. This study aimed to evaluate the risk factors for and prognosis of stroke in patients with gynecological cancers. A single-center retrospective cohort study was conducted on patients with cervical, endometrial, and epithelial ovarian cancers. Patients were classified into three groups based on the period of stroke onset: at least one year before cancer diagnosis, within one year before cancer diagnosis to six months after the last treatment date, and six months after the last treatment date. Among the 644 patients, stroke occurred in 54 (8.4%). In univariate analysis, stroke was significantly associated with overall survival. In contrast, in multivariate analysis, stroke was significantly associated with age and hypertension, but not with overall survival. Age, pulmonary thromboembolism/deep vein thrombosis, histological grade, and tumor stage were significantly associated with overall survival. Therefore, it is important to establish an appropriate examination and treatment plan for patients with gynecologic cancers using a multidisciplinary approach that incorporates the patient's age, medical condition, and tumor characteristics rather than excessively considering the adverse effects of stroke on cancer prognosis.

Lipid peroxidation-derived modification and its effect on the activity of glutathione peroxidase 1.

Oxidative stress and the resulting lipid peroxidation are associated with various pathological states, including neurodegenerative diseases and cancer. The end products of lipid peroxidation, such as 4-oxo-2(E)-nonenal (ONE), 4-hydroxy-2(E)-nonenal (HNE), and methylglyoxal (MG), exert several biological effects through modification of various cellular components, including DNA and proteins. Glutathione peroxidase 1 (GPx1) is an intracellular antioxidant enzyme that uses glutathione (GSH) to reduce a variety of peroxides, thereby modulating cellular oxidative stress and redox-mediated responses. GPx1 contains nucleophilic amino acids at its active (one Sec) and GSH-binding (four Arg and one Lys) sites. We found that lipid peroxidation-derived reactive aldehydes (ONE, HNE, and MG) modified the GSH-binding site, resulting in the inhibition of GPx1 activity. Mass spectrometry-based proteomic analysis identified the sites modified by each aldehyde (ONE, 14 sites; HNE, 7 sites; MG, 9 sites). The GSH-binding sites modified were as follows: ONE, Arg57, 103, 184, and 185; HNE, Lys91; MG, Arg103. Upon incubation of GPx1 with each aldehyde, ONE reduced GPx1 activity more significantly than did HNE or MG in a dose- and time-dependent manner. The addition of GSH to GPx1 3 h after incubation with ONE prevented further inhibition by trapping ONE as a ONE-GSH adduct. However, the activity of GPx1 was not restored to the initial level, indicating that ONE modified GPx1 irreversibly. This study suggests that oxidative damage to lipids, resulting in the formation of reactive aldehydes, can amplify cellular oxidative stress via direct inactivation of GPx1, which increases the production of intracellular peroxides.

Cancer Therapy-Related Cardiac Dysfunction in Patients Treated with a Combination of an Immune Checkpoint Inhibitor and Doxorubicin.

Backgrounds: There are scarce data on whether immune checkpoint inhibitors (ICIs) increase the risk of cardiac dysfunction when used with cardiotoxic agents. Thus, we evaluated cardiac dysfunction in patients with sarcoma receiving doxorubicin with or without ICI using echocardiography and left ventricular global longitudinal strain (LVGLS). Methods: A total of 95 patients were included in this study. Echocardiography and LVGLS were evaluated at baseline and follow-up (at 3 and 6 months of chemotherapy) and compared with the doxorubicin (Dox; n = 73) and concomitant ICI with doxorubicin (Dox-ICI; n = 22) groups. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a left ventricular ejection fraction (LVEF) drop of >10% and LVEF of <50% (definite CTRCD), LVEF drop of >10%, LVEF of ≥50%, and LVGLS relative reduction of >15% (probable CTRCD) at six months. Results: There were no significant differences in age, cumulative dose of doxorubicin, and cardiovascular risk factors between the two groups. At baseline, the LVEF was similar in the Dox and Dox-ICI groups (p = 0.493). In the Dox group, LVEF decreased to 59 ± 6% (Δ −7 ± 1.3%, p < 0.001) and LVGLS decreased from −17.3 ± 3.2% to −15.4 ± 3.2% (Δ −10.1 ± −1.9%, p < 0.001) at six months. In the Dox-ICI group, LVEF decreased to 55 ± 9% (Δ −9 ± 2.1%, p < 0.001), along with a significant decrease in LVGLS (from −18.6 ± 1.9% to −15.3 ± 3.6%, Δ −12.4 ± −2.4%, p < 0.001). Over a median follow-up of 192 days, there were no cases with clinical manifestations of fulminant myocarditis. In the Dox group, definite and probable CTRCD were observed in seven (10.1%) and five (7.4%) patients, respectively. In the Dox-ICI group, definite and probable CTRCD were observed in four (19%) and four (19%) patients, respectively. The total number of patients who developed CTRCD was significantly higher in the Dox-ICI group than in the Dox group (38.1% vs. 17.4%, p = 0.042). Serum troponin-T level was significantly higher in the Dox-ICI group than in the Dox group (53.3 vs. 27.5 pg/mL, p = 0.023). Conclusions: ICIs may increase the risk of CTRCD when used with cardiotoxic agents. CTRCD should be monitored in patients treated with ICIs by cardiac biomarkers and echocardiography, including LV-GLS.

Extensive Nevus Comedonicus with Inflammatory Nodules and Cysts Controlled with Adalimumab.

Nevus comedonicus is a very rare skin disorder characterized by the presence of comedo-like dilated pores with keratinous plugs, rarely resulting in painful recurrent inflammatory nodules or cysts. It presents as localized or extensive form. It displays unilaterally or bilaterally segmental distribution. Histopathologically, it is characterized by keratin-filled epidermal invagination with bulbous proliferation of keratinocytes. The condition may be caused by fibroblast growth factor receptor 2 mutation. Although it may be controlled by a variety of therapeutic modalities, it is difficult to achieve complete resolution. We report a case of extensive nevus comedonicus with inflammatory nodules and cysts controlled with adalimumab.

Robust analysis of angiotensin peptides in human plasma: Column switching-parallel LC/ESI-SRM/MS without adsorption or enzymatic decomposition.

Angiotensin (Ang) peptides are the main effectors of the renin-angiotensin system (RAS) regulating diverse physiological conditions and are involved in renal and vascular diseases. Currently, quantitative analyses of Ang peptides in human plasma mainly rely on radioimmunoassay-based methods whose reported levels are quite divergent. Analyses are further complicated by the potential of Ang peptides to bind to solid surfaces, to be enzymatically decomposed during sample preparation, and to undergo post-translational modifications. A column switching-parallel LC/ESI-SRM/MS method has been developed for seven Ang peptides (Ang I, Ang II, Ang III, Ang IV, Ang 1-9, Ang 1-7, and Ang A) in human plasma. Aqueous acetonitrile (5%) containing 50 mM arginine (Arg) as a dissolving solution and a combination of protease inhibitors with formic acid were used to prevent adsorption and enzymatic degradation, respectively. Plasma samples were simply deproteinized with acetonitrile followed by clean-up with an on-line trap column via column-switching. Stable isotope dilution with [13C5,15N1-Val]-Ang peptides as internal standards was employed for quantitative analysis. The current methodology has been successfully applied to determine the plasma levels of Ang peptides in healthy participants, suggesting future applicability to studies of various diseases related to RAS.

Effect of Red Ginseng Oil on Cultured Sebocytes and Outer Root Sheath Cells after Treatment with Lipopolysaccharide.

BACKGROUND: Ginseng has been known in Korea as a health-supportive herbal medicine from time immemorial. Essential oil isolated from fresh ginseng has been shown to display antibacterial and anti-inflammatory activities. OBJECTIVE: The effects of red ginseng oil (RGO) on the lipopolysaccharide (LPS)-treated sebocytes and outer root sheath (ORS) cells were studied. METHODS: The cultured cells were treated with either 0.1% dimethyl sulfoxide, 5 µg/ml LPS, 50 µg/ml RGO, or 5 µg/ml LPS plus 50 µg/ml RGO for 6 and 24 hours. RT-PCR, real-time PCR, enzyme-linked immunosorbent assay, western blot, and immunofluorescence staining were performed for the analysis of inflammatory cytokine. RESULTS: RGO showed the increased gene and protein expression of inflammatory cytokines, including interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor-α in the LPS-treated sebocytes and ORS cells. RGO also showed the increased protein expression of p-c-jun and p-JNK in the LPS-treated sebocytes and ORS cells. Gene expression of TLR2 was increased in LPS-treated sebocytes following treatment with RGO. Additionally, RGO resulted in an increased expression of LL-37 in the LPS-treated sebocytes and ORS cells. Moreover, it remarkably increased the production of sebum in LPS-treated sebocytes. CONCLUSION: RGO might be among the aggravating factors of acne vulgaris. It would be better to stop taking red ginseng in patients with inflammatory acne.

Prognostic Implications of Left Ventricular Global Longitudinal Strain in Patients With Surgically Treated Mitral Valve Disease and Preserved Ejection Fraction.

BACKGROUND: This study investigated whether left ventricular (LV) global longitudinal strain (LV-GLS), as an LV function parameter less affected by mitral valve (MV) repair or prosthesis, is associated with clinical outcomes in patients with surgically treated MV disease. METHODS: Among 750 patients who underwent MV surgery, we assessed LV-GLS by speckle tracking echocardiography in 344 patients (148 men, mean age 58 ± 13 years) who showed preserved LV ejection fraction on echocardiography between 6 months and 2 years after MV surgery and who did not undergo aortic valve surgery. The assessed clinical events included admission for worsening of heart failure and cardiac death. RESULTS: During a period of 42.4 ± 26.0 months, 32 (9.3%) patients were hospitalized for worsening heart failure, and 3 (0.8%) died due to cardiac causes. The absolute value of LV-GLS (|LV-GLS|) was significantly lower in patients with clinical events than in those without (12.1 ± 3.1 vs. 15.0 ± 3.2%, p < 0.001) despite comparable LV ejection fraction between groups. |LV-GLS| showed predictive value for clinical events (cut-off 13.9%, area under the curve 0.744, p < 0.001). Patients with |LV-GLS| ≤14.0% had poorer outcomes than those with |LV-GLS| >14.0% (log-rank p < 0.001). Prognosis was worse in patients with |LV-GLS| ≤14.0% and pulmonary hypertension than among those who with |LV-GLS| ≤14.0% without pulmonary hypertension (log rank p < 0.001). In nested Cox proportional hazard regression models, reduced |LV-GLS| was independently associated with the occurrence of clinical events. CONCLUSIONS: In patients with surgically treated MV and preserved LV ejection fraction, assessment of LV-GLS provides functional information associated with cardiovascular outcomes.

LC-MS analyses of N-acetyl-p-benzoquinone imine-adducts of glutathione, cysteine, N-acetylcysteine, and albumin in a plasma sample: A case study from a patient with a rare acetaminophen-induced acute swelling rash.

Acetaminophen (Paracetamol, APAP) has been widely used for many decades as an analgesic and antipyretic agent but APAP overdose often causes acute adverse reactions, particularly liver damage. The metabolically oxidized form of APAP, N-acetyl-p-benzoquinone imine (NAPQI), is chemically reactive and binds covalently to proteins. Therefore, NAPQI is believed to be the key metabolite that causes hepatotoxicity, especially under conditions of glutathione depletion. Other APAP-induced adverse reactions, such as skin damage, are rare and remain poorly studied. Here, we report a case study of a male patient who presented with an acute swelling skin rash (without hepatotoxicity) caused by therapeutic doses of APAP. Plasma samples were collected at 17 hr after dosing (during the manifestation of symptoms) and at one month (after recovery) and were subjected to LC-MS analysis of NAPQI-adducts. A significant concentration of NAPQI-cysteine adduct (33 pmol/mL) was found together with low concentrations of NAPQI-N-acetylcysteine adduct (2.0 pmol/mL) and NAPQI-glutathione adduct (0.13 pmol/mL). However, the NAPQI-albumin adduct was below the detection limit (below 0.001% modification on albumin) despite a previous report of high concentrations of NAPQI-albumin adduct following acute liver injury. Therefore, the observed APAP-induced skin damage may have had a different cause from APAP-induced liver injury.

Biomimetic trapping cocktail to screen reactive metabolites: use of an amino acid and DNA motif mixture as light/heavy isotope pairs differing in mass shift.

Candidate drugs that can be metabolically transformed into reactive electrophilic products, such as epoxides, quinones, and nitroso compounds, are of special concern because subsequent covalent binding to bio-macromolecules can cause adverse drug reactions, such as allergic reactions, hepatotoxicity, and genotoxicity. Several strategies have been reported for screening reactive metabolites, such as a covalent binding assay with radioisotope-labeled drugs and a trapping method followed by LC-MS/MS analyses. Of these, a trapping method using glutathione is the most common, especially at the early stage of drug development. However, the cysteine of glutathione is not the only nucleophilic site in vivo; lysine, histidine, arginine, and DNA bases are also nucleophilic. Indeed, the glutathione trapping method tends to overlook several types of reactive metabolites, such as aldehydes, acylglucuronides, and nitroso compounds. Here, we introduce an alternate way for screening reactive metabolites as follows: A mixture of the light and heavy isotopes of simplified amino acid motifs and a DNA motif is used as a biomimetic trapping cocktail. This mixture consists of [2H0]/[2H3]-1-methylguanidine (arginine motif, Δ 3 Da), [2H0]/[2H4]-2-mercaptoethanol (cysteine motif, Δ 4 Da), [2H0]/[2H5]-4-methylimidazole (histidine motif, Δ 5 Da), [2H0]/[2H9]-n-butylamine (lysine motif, Δ 9 Da), and [13C0,15N0]/[13C1,15N2]-2'-deoxyguanosine (DNA motif, Δ 3 Da). Mass tag triggered data-dependent acquisition is used to find the characteristic doublet peaks, followed by specific identification of the light isotope peak using MS/MS. Forty-two model drugs were examined using an in vitro microsome experiment to validate the strategy. Graphical abstract Biomimetic trapping cocktail to screen reactive metabolites.

The Relationship between the Blood Level of Persistent Organic Pollutants and Common Gastrointestinal Symptoms.

BACKGROUND: Persistent organic pollutants (POPs) are toxic materials that cannot be broken down naturally and that easily accumulate in the body. Although several studies have attempted to uncover the effects of POPs on the endocrine and nervous systems and on cancer, few focus on the relationship between low-dose POPs and public health. Here, we attempt to determine the relationship between the level of POPs and common gastrointestinal symptoms, including abdominal discomfort, diarrhea, and constipation. METHODS: We recruited 121 subjects who visited Kyungpook National University Medical Center for health screening. Plasma concentrations were evaluated for 40 kinds of POPs including 17 types of polychlorinated biphenyls (PCBs) and 23 types of organochlorine pesticides (OCP). Furthermore, the Korean version of the Rome III criteria was used to identify gastrointestinal symptoms. RESULTS: Based on our results, abdominal discomfort showed an inverse relationship with several PCBs and an inverted U-shaped relationship with several other OCPs including pp-DDD and pp-DDT. The effects of pp-DDD and pp-DDT on abdominal discomfort were similar to those of OCPs on obesity and metabolic syndrome. CONCLUSION: Our results suggest that mild and unspecified gastrointestinal symptoms with no clear causes could be related to POP levels.

Stable isotope labeling by fatty acids in cell culture (SILFAC) coupled with isotope pattern dependent mass spectrometry for global screening of lipid hydroperoxide-mediated protein modifications.

Lipid hydroperoxide-mediated modifications of proteins are receiving increasing attention because of their possible involvement in various degenerative diseases. These biological effects are attributed to the ability of lipid peroxidation-derived aldehydes to react with the nucleophilic sites of proteins. Here we describe a methodology involving metabolic labeling coupled with mass spectrometry-based proteomic analysis that enables global screening of lipid hydroperoxide-mediated protein modifications in a cell system. The lipidome of MCF-7 cells was labeled by incubating the cells with 1.4µM [13C18]-linoleic acid (LA) until the LA to [13C18]-LA ratio became 1:1. This approach was termed SILFAC (stable isotope labeling by fatty acids in cell culture). Analysis of the cellular phospholipids indicated that [13C18]-LA was incorporated quantitatively. The labeled cells were subjected to oxidative stress using a calcium ionophore and l-ascorbic acid, which promote the generation of reactive aldehydes from cellular LA and [13C18]-LA. After protein extraction and digestion with trypsin, isotope pattern dependent MS was used to analyze peptides modified by 1:1 ratios of the 12C and 13C aldehyde isomers. Using the current methodology, we identified the major lipid hydroperoxide-mediated modifications to proteins in MCF-7 cells without the need for chemical labeling or further affinity purification. SIGNIFICANCE: Lipid peroxidation-derived aldehydes (LPDAs) such as 4-oxo-2(E)-nonenal and 4-hydroxy-2(E)-nonenal can readily react with proteins and peptides to produce a variety of covalent modifications and cross-linkages, resulting in protein dysfunction and altered gene regulation. Various analytical approaches have therefore been developed to detect and characterize protein modifications mediated by LPDAs. However, most of the methods are not specific for LPDA modifications or designed for proteins modified by a target aldehyde. Here we describe the coupling of stable isotope labeling by fatty acids in cell culture (SILFAC) with an isotope pattern dependent MS-based proteomic strategy to provide a global screening tool for the identification of lipid hydroperoxide-mediated protein modifications.

Acute Kidney Injury Following Cardiopulmonary Bypass in Children　- Risk Factors and Outcomes.

BACKGROUND: Acute kidney injury (AKI) is the most common and most serious complication following heart surgery. We aimed to determine the prevalence of, and risk factors for, AKI following pediatric cardiac surgery.Methods and Results:We retrospectively analyzed 135 patients aged ≤18 years who underwent cardiac surgery for congenital heart defects; by RACHS-1 category, 58 patients (43%) had an operative risk score ≥3. AKI was defined and classified using the pediatric pRIFLE criteria (Pediatric Risk, Injury, Failure, Loss, and End-stage Kidney Disease); 19 patients (14.1%) developed AKI: 17 had AKI with a severity classified as risk (R) and 2 had AKI classified as injury (I). Body weight, height, body surface area, and preoperative mechanical ventilation were all independently associated with AKI development (P=0.038, 0.040, 0.033 and 0.008, respectively). Preoperative ventilation strongly correlated with AKI severity. Higher pRIFLE classification positively correlated with increased incidence of peritoneal dialysis, increased postoperative mechanical ventilation duration, and longer hospital stay (P=0.009, 0.039 and 0.042, respectively). CONCLUSIONS: In this study, we found a low prevalence of postoperative AKI in pediatric patients undergoing severe cardiac surgery. AKI was associated with worse early postoperative outcomes. Early prediction and appropriate treatment of AKI during the postoperative period are emphasized.

High-yield production of pure tagatose from fructose by a three-step enzymatic cascade reaction.

OBJECTIVE: To produce tagatose from fructose with a high conversion rate and to establish a high-yield purification method of tagatose from the reaction mixture. RESULTS: Fructose at 1 M (180 g l-1) was converted to 0.8 M (144 g l-1) tagatose by a three-step enzymatic cascade reaction, involving hexokinase, plus ATP, fructose-1,6-biphosphate aldolase, phytase, over 16 h with a productivity of 9 g l-1 h-1. No byproducts were detected. Tagatose was recrystallized from ethanol to a purity of 99.9% and a yield of 96.3%. Overall, tagatose at 99.9% purity was obtained from fructose with a yield of 77%. CONCLUSION: This is the first biotechnological production of tagatose from fructose and the first application of solvent recrystallization for the purification of rare sugars.

The Relationship between the Blood Level of Persistent Organic Pollutants and Common Gastrointestinal Symptoms.

BACKGROUND: Persistent organic pollutants (POPs) are toxic materials that cannot be broken down naturally and that easily accumulate in the body. Although several studies have attempted to reveal the effects of POPs on the endocrine and nervous system and on cancer, few studies focus on the relationship between low-dose POPs and public health. We attempted to find a relationship between the level of POPs and common gastrointestinal symptoms, including abdominal discomfort, diarrhea, and constipation. METHODS: We recruited 121 subjects who visited Kyungpook National University Hospital for a health screening. Plasma concentrations were evaluated for 40 kinds of POPs including 17 types of polychlorinated biphenyls and 23 types of organochlorine pesticides. Furthermore, the Korean version of the Rome III criteria was used to identify gastrointestinal symptoms. RESULTS: Our results showed that abdominal discomfort had an inverse relationship with several polychlorinated biphenyls. Moreover, an inverted U-shaped relationship was observed between abdominal discomfort and several other organochlorine pesticides including p,p'-dichlorodiphenyldichloroethane and p,p'-dichlorodiphenyltrichloroethane, and the effects of these pesticides on abdominal discomfort were similar to that of organochlorine pesticides on obesity and metabolic syndrome. CONCLUSION: Our results suggest that mild and unspecified gastrointestinal symptoms with no clear cause could be related to POPs levels.