Cytosolic zinc mediates the cytotoxicity of thiol-reactive electrophiles in rat vascular smooth muscle cells.

The aberrant increase or dysregulation of cytosolic Zn2+ concentration ([Zn2+]cyt) has been associated with cellular dysfunction and cytotoxicity. In this study, we postulated that Zn2+ mediates the cytotoxicity of thiol-reactive electrophiles. This notion was grounded on earlier research, which revealed that thiol-reactive electrophiles may disrupt Zn2+-binding motifs, consequently causing Zn2+ to be released from Zn2+-binding proteins, and leading to a surge in [Zn2+]cyt. The thiol-reactive electrophiles N-ethylmaleimide (NEM) and diamide were observed to induce an increase in [Zn2+]cyt, possibly through the impairment of Zn2+-binding motifs, and subsequent stimulation of reactive oxygen species (ROS) formation, resulting in cytotoxicity in primary cultured rat vascular smooth muscle cells. These processes were negated by the thiol donor N-acetyl-L-cysteine and the Zn2+ chelator TPEN. Similar outcomes were detected with co-treatment involving Zn2+ and Zn2+ ionophores such as pyrithione or disulfiram. Moreover, TPEN was found to inhibit cytotoxicity triggered by short-term exposure to various thiol-reactive electrophiles including hydrogen peroxide, acrylamide, acrylonitrile, diethyl maleate, iodoacetic acid, and iodoacetamide. In conclusion, our findings suggest that cytosolic Zn2+ acts as a universal mediator in the cytotoxic effects produced by thiol-reactive electrophiles.

Improved regression model for anaerobic ammonium oxidation by repeated and prolonged batch assay under stressful salinity and pH conditions.

The aim of this study was to propose repeated and prolonged batch (RPB) assay as a promising specific anammox activity (SAA) methodology assessing the anammox activity under stressed salinity and pH conditions. Response surface analysis (RSA) was used as a regression tool to evaluate statistical significance. The feasibility of RPB was investigated at 0 to 15 g-NaCl/L of salinity and pH 6 to 8 with reflecting the results of preliminary SAA. As a result, conventional SAA was statistically insignificant. In addition, the RSA results obtained from repeated batch did not meet the statistical significance despite ten times iterative reaction. Interestingly, the RPB assay (i.e., applied both repeated and prolonged reaction) was effective to obtain the reliable results. Candidadus Brocadia and Candidadus Jettenia were functional anammox microbiome during RPB. Outcomes of this study suggest that RPB assay can be applied to accurately determine the anammox activity under various stressful conditions.

Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library.

Cancer is characterized by altered cellular metabolism, and metabolic enzymes are considered as a promising target for anticancer therapy. Pyrimidine metabolism dysregulation is associated with various types of cancer, particularly lung cancer, which is one of the leading causes of cancer-related mortality worldwide. Recent studies have shown that small-cell lung cancer cells are particularly reliant on the pyrimidine biosynthesis pathway and are sensitive to its disruption. DHODH, the rate-limiting enzyme of the de novo pyrimidine production pathway, is essential in the production of RNA and DNA and is overexpressed in malignancies such as AML, skin cancer, breast cancer, and lung cancer, thereby highlighting DHODH as a viable target for developing drugs to combat lung cancer. Herein, rational drug design and computational techniques were used to discover novel DHODH inhibitors. A small combinatorial library was generated, and the top hits were synthesized and tested for anticancer activity against three lung cancer cell lines. Among the tested compounds, compound 5c possessed a stronger cytotoxicity (TC50 of 11 µM) compared to the standard FDA-approved drug (Regorafenib, TC50 of 13 µM) on the A549 cell line. Furthermore, compound 5c demonstrated potent inhibitory activity against hDHODH at a nanomolar level of 421 nM. DFT, molecular docking, molecular dynamic simulations, and free energy calculations were also carried out to understand the inhibitory mechanisms of the synthesized scaffolds. These in silico studies identified key mechanisms and structural features that will be crucial for future studies.

Mediating Effects of Social Support and Resilience on the Association between COVID-19-Related Stress and Mental Health in Korean Young Adults.

Young adults were vulnerable to mental health issues during the COVID-19 pandemic. However, the underlying pathway by which COVID-19-related stress influences mental health outcomes among young adults remains unclear. This study aimed to examine the mediating effects of social support and resilience between COVID-19-related stress and mental health outcomes. A sample of 1000 Korean young adults was obtained via online survey. Participants completed self-report questionnaires assessing COVID-19-related stress, social support, resilience, depression, and anxiety. Overall, 48.1% and 23.4% of participants were classified as having depression and anxiety states, respectively. Path analysis using AMOS version 26.0 (IBM Corp., Armonk, NY, USA) showed that the direct effects of stress from social distancing difficulties on depression and anxiety were much greater than those of stress from fear of infection and anger toward others. In addition, there were significant indirect effects of social support and resilience in the relationship between stress related to difficulties due to social distancing and mental health outcomes. The mediating roles of social support and resilience suggest that interventions to increase these factors can be effective strategies to reduce the risks of depression and anxiety among young adults suffering from stress related to social distancing difficulties.

Combined machine learning and biomolecular analysis for stability assessment of anaerobic ammonium oxidation under salt stress.

In this study, the stability of the total nitrogen removal efficiency (TNRE) was modeled using an artificial neural network (ANN)-based binary classification model for the anaerobic ammonium oxidation (AMX) process under saline conditions. The TNRE was stabilized to 80.2 ± 11.4% at the final phase under the salinity of 1.0 ± 0.02%. The results of terminal restriction fragment length polymorphism (T-RFLP) analysis showed the predominance of Candidatus Jettenia genus. Real-time quantitative PCR analysis revealed the average abundance of Ca. Jettenia and Kuenenia spp. increased in 3.2 ± 5.4 × 108 and 2.0 ± 2.2 × 105 copies/mL, respectively. The prediction accuracy using operational parameters with data augmentation was 88.2%. However, integration with T-RFLP and real-time qPCR signals improved the prediction accuracy by 97.1%. This study revealed the feasible application of machine learning and biomolecular signals to the stability prediction of the AMX process under increased salinity.

Improved insights into the adaptation and selection of Nitrosomonas spp. for partial nitritation under saline conditions based on specific oxygen uptake rates and next generation sequencing.

Partial nitritation (PN) is a bioprocess that is essential for developing cost-effective biological nitrogen removal processes. Understanding the abundant bacterial communities responsible for nitrification under salt stress conditions is important to achieve a stable PN system for treating saline wastewater. Therefore, in this study, we identified the core nitrifying communities and investigated their correlations with the process parameters in a nitrifying bioreactor that was used for treating saline high-strength ammonia wastewater. A PN system worked efficiently under saline conditions with varying operational factors, such as temperature, dissolved oxygen (DO), and alkalinity. Interestingly, the specific oxygen uptake rate (SOUR) became similar under salt-free and saline media after the salt adaption. Next generation sequencing results suggested that the inactivation of Nitrobacter winogradskyi was a key factor for the PN reaction under salt stress conditions. We also found that Nitrosomonas europaea, a freshwater type ammonia-oxidizing bacteria (AOB), was predominantly found under both salt-free and saline conditions, whereas other halotolerant or halophilic AOB species, including Nitrosomonas nitrosa and Nitrosomonas mobilis, became selectively abundant under saline conditions. This implies that adaptation (training of N. europaea) and selection (presence of N. nitrosa and N. mobilis) were simultaneously attributed to selective ammonia conversion for the PN reaction. The redundancy analysis showed that the salinity and ammonia loading rates were statistically significant process parameters that determined the nitrifying bacterial community, suggesting that these parameters drive the adaptation and selection of the core AOB species during the PN reaction. Furthermore, the correlation analysis revealed that the abundance of N. nitrosa and N. mobilis was critically correlated with the specific oxygen uptake rates in saline media containing ammonia.

Gender Differences in Sexual Behaviors and Their Relevance to Mental Health among High School Students with Sexual Experience in South Korea.

We explored gender differences in sexual behavior, and their relevance to mental health among high school students in South Korea. This study was based on data from the 14th Korea Youth Risk Behavior Web-Based Survey (2018). The subjects were 2460 high school students who reported sexual experiences. Student's t-test, ANOVA, and Rao-Scott chi-squared test were performed to identify the significance of the differences. Boys had earlier sexual debuts (Rao-Scott χ2 = 53.55, p < 0.001), a lower frequency of using contraceptives (Rao-Scott χ2 = 26.57, p < 0.001), and lower rates of sex education in school (Rao-Scott χ2 = 11.20, p = 0.004). With respect to mental health factors, there was a difference in suicidality according to sexual risk behaviors, with a stronger association found in boys. In girls, there was an association between pregnancy experiences and suicidal ideation (Rao-Scott χ2 = 9.90, p = 0.003), plans (Rao-Scott χ2 = 17.25, p < 0.001), and attempts (Rao-Scott χ2 = 23.11, p < 0.001). Our findings suggest differences by gender and age group in the association between sexual behavior and mental health. It is necessary to devise a sex education strategy for adolescents considering gender and early versus late adolescent development period.

Gender Differences in Lifestyle and Mental Health among Senior High School Students in South Korea.

Gender differences in health outcomes have long been a concern worldwide. We investigated the gender differences in the lifestyle and mental health status of senior students in general high schools who were preparing for college entrance exams. This secondary analysis was based on data from the 14th Korea Youth Risk Behavior Web-Based Survey (2018). The data of 8476 students in the third year (12th grade) of general high school, among a total of 60,040 middle and high school students nationwide, were analyzed. Mean and standard error (SE) and weighted percentage data were obtained, and the Rao-Scott χ2 test was performed. Boys reported more risky behaviors related to drinking and smoking, while girls had more negative perceptions of their bodies and overall health. In addition, girls showed unhealthier lifestyle-related behaviors (breakfast, physical activity, weight control) and greater vulnerability to poor mental health, including lower sleep satisfaction, stress, depression, and suicidal thoughts. Our results suggest that education and health institutions should consider the needs of each gender separately. A gender-specific approach to maintaining healthy lifestyles and good health status among senior high school students is highly recommended.

Leisure Factors Predicting the Happiness of Self-Employed Workers in South Korea.

South Korea's employment status is characterized by a high rate of self-employment and many small-scale self-employed businesses with no employees. This study explored leisure factors relating to self-employed individuals' subjective happiness based on data from the 2019 National Leisure Activity Survey. The extracted data (N = 2343) were analyzed using descriptive statistics, t-test, ANOVA, Pearson's correlation coefficient, Kendall's τb coefficient, Eta correlation coefficient, phi coefficient, and Cramer's V. And a three-step hierarchical regression analysis was performed to identify multidimensional variables that predict happiness more effectively. In Model 3, which additionally inserted positive and intrinsic factors into Model 2, the explanatory power was significantly increased. The predictors of subjective happiness among self-employed people identified in the final regression model were high economic status (ß = 0.05), perceived health status (ß = 0.32), financial constraints (ß = -0.09), leisure recognition (ß = 0.20), and work-life balance (leisure-oriented ß = 0.09; work-oriented ß = -0.13). This study's findings will contribute to the establishment of basic data, to prepare empirical measures to improve self-employed individuals' quality of life.

Physical Comorbidity According to Diagnoses and Sex among Psychiatric Inpatients in South Korea.

People with mental disorders are susceptible to physical comorbidities. Mind-body interventions are important for improving health outcomes. We examined the prevalence of physical comorbidities and their differences by diagnoses and sex among psychiatric inpatients. The dataset, from National Health Insurance claims data, included 48,902 adult inpatients admitted to psychiatric wards for at least 2 days in 2016 treated for schizophrenia, schizotypal and delusional disorders, or mood disorders. We identified 26 physical comorbidities using the Elixhauser comorbidity measure. Among schizophrenia-related disorders, other neurological disorders were most common, then liver disease and chronic pulmonary disease. Among mood disorders, liver disease was most common, then uncomplicated hypertension and chronic pulmonary disease. Most comorbid physical diseases (except other neurological disorders) were more prevalent in mood disorders than schizophrenia-related disorders. Male and female patients with schizophrenia-related disorders showed similar comorbidity prevalence patterns by sex. Among patients with mood disorders, liver disease was most prevalent in males and third-most in females. In both diagnostic groups, liver disease and uncomplicated diabetes mellitus were more prevalent in males, and hypothyroidism in females. Mental health professionals should refer to a specialist to manage physical diseases via early assessments and optimal interventions for physical comorbidities in psychiatric patients.

Effects of social support on mental health outcomes in disasters: A cross-sectional study.

This study examined the mediating effects of social support on the association between disaster distress and mental health outcomes. We analyzed the data of 1006 participants with either direct or indirect exposure to one or more disasters. Disaster distress, social support, depression, and anxiety were significantly correlated. Multiple regression and mediation analyses with bootstrapping showed that social support was a partial mediator between disaster distress and depression, and between disaster distress and trait anxiety. It was a complete mediator between disaster distress and state anxiety. The results suggest that enhancing social support may reduce the negative effects of disaster distress on depression and anxiety. Therefore, comprehensive interventions incorporating disaster distress management and enhanced social support are essential in national disaster management policies and psychiatric and mental health nursing services for individuals who have experienced disasters.

Association of depression, pain, resilience, social support with post-traumatic stress in sexual abuse: A quantile regression approach.

Post-traumatic stress levels and factors influencing the sexual abuse period may differ between victims. This cross-sectional study conducted a secondary analysis of primary online survey data extracted from a previous study. We examined the extent of trauma (types, timing) and depression, pain, resilience, and social support associated with post-traumatic stress affecting the post-traumatic stress percentile. Among 3000 adults aged 19-65 years, 1223 adults experienced childhood sexual abuse, adulthood sexual abuse, or childhood and adulthood sexual abuse. We conducted descriptive statistics, multiple linear regression, and simultaneous quantile regression. Quantile regression analysis showed the 80th percentile groups in childhood sexual abuse, education, depression, and social support were significantly associated with post-traumatic stress. Depression was significantly and positively associated with post-traumatic stress. Resilience was significantly and negatively associated with post-traumatic stress in adulthood sexual abuse victims. Depression and pain were significantly and positively associated with post-traumatic stress in childhood and adulthood sexual abuse victims. Post-traumatic stress severity and influencing factors differed according to victims' age when the sexual abuse occurred, implying interventions should be tailored to each victim's post-traumatic stress level.

Nurse Staffing and Health Outcomes of Psychiatric Inpatients: A Secondary Analysis of National Health Insurance Claims Data.

PURPOSE: The present study investigated the association between nurse staffing and health outcomes among psychiatric inpatients in Korea by assessing National Health Insurance claims data. METHODS: The dataset included 70,136 patients aged 19 years who were inpatients in psychiatric wards for at least two days in 2016 and treated for mental and behavioral disorders due to use of alcohol; schizophrenia, schizotypal and delusional disorders; and mood disorders across 453 hospitals. Nurse staffing levels were measured in three ways: registered nurse-to-inpatient ratio, registered nurse-to-adjusted inpatient ratio, and nursing staff-to-adjusted inpatient ratio. Patient outcomes included length of stay, readmission within 30 days, psychiatric emergency treatment, use of injected psycholeptics for chemical restraint, and hypnotics use. Relationships between nurse staffing levels and patient outcomes were analyzed considering both patient and system characteristics using multilevel modeling. RESULTS: Multilevel analyses revealed that more inpatients per registered nurse, adjusted inpatients per registered nurse, and adjusted inpatients per nursing staff were associated with longer lengths of stay as well as a higher risk of readmission. More adjusted inpatients per registered nurse and adjusted inpatients per nursing staff were also associated with increased hypnotics use but a lower risk of psychiatric emergency treatment. Nurse staffing levels were not significantly associated with the use of injected psycholeptics for chemical restraint. CONCLUSION: Lower nurse staffing levels are associated with negative health outcomes of psychiatric inpatients. Policies for improving nurse staffing toward an optimal level should be enacted to facilitate better outcomes for psychiatric inpatients in Korea.

Prevalence of Traumatic Experiences in South Korean Adults.

Although a variety of traumatic experiences can impact health over the lifetime, little is known about the prevalence of such experiences in South Korea. The purpose of this study was to examine the frequencies of traumatic experiences and their differences by gender and age. South Korean adults (N = 3000) aged 19-65 years completed a self-report survey assessing childhood and adulthood trauma and sociodemographic characteristics. Overall, 79.5% of the participants reported at least one traumatic experience in adulthood. Unemployment or job loss and academic or work difficulties were commonly reported. The most distressing adulthood trauma was the unexpected death of a loved one, followed by diseases in loved ones. Childhood trauma was higher in males than in females. In males, childhood trauma was higher at a younger age, but in females, it was higher at an older age. Adulthood trauma was higher in females than in males and at older ages for both males and females. The current findings demonstrate the differences in traumatic experiences by gender and age in the South Korean general population. These results could help improve assessment of and targeted intervention for psychological trauma through trauma-informed strategies in public health practice.

Functional Health in Korean Middle-Aged Women with Poor Sleep Quality.

PURPOSE: To develop and test a structural model of functional health in middle-aged women based on the theory of unpleasant symptoms. METHODS: The direct and indirect effects of menopause status, childhood trauma, post-traumatic stress, social support, and sleep quality on functional health of 264 Korean women were examined. FINDINGS: Menopause status and poor sleep quality had a negative direct effect and social support had a positive direct effect on functional health. Menopause status had a negative indirect effect on functional health through poor sleep quality. CONCLUSIONS: Biopsychosocial nursing intervention programs need to be developed to improve functional health in middle-aged women. IMPLICATIONS FOR NURSING PRACTICE: It is important to mediate quality of sleep to improve functional health in middle-aged women. 목적 불쾌증상 이론을 바탕으로 중년 여성의 건강기능을 평가하기 위함이다. 방법 264명의 한국 여성을 대상으로 건강기능에 영향을 미치는 폐경, 아동기 외상, 외상 후 스트레스, 사회적 지지의 직ㆍ간접적 영향을 확인하였다. 결과 폐경과 낮은 수면의 질은 건강기능에 부적 영향을 미쳤으며, 사회적 지지는 건강기능에 정적 영향을 미쳤다. 폐경은 건강기능에 간접적 영향을 미쳤다. 결론 중년여성의 건강기능을 증진하기 위해 신체ㆍ심리ㆍ사회적 요인을 고려한 통합적 중재가 필요하다. 간호실무 적용점: 중년여성의 건강기능을 유지하기 위해 수면의 질을 중재하는 것이 중요하다.

Reporting and methodologic evaluation of meta-analyses published in the anesthesia literature according to AMSTAR and PRISMA checklists: a preliminary study.

BACKGROUND: There have been few recent reports on the methodological quality of meta-analysis, despite the enormous number of studies using meta-analytic techniques in the field of anesthesia. The purpose of this study was to evaluate the quality of meta-analyses and systematic reviews according to the Assessment of Multiple Systematic Reviews (AMSTAR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the anesthesia literature. METHODS: A search was conducted to identify all meta-analyses ever been published in the British Journal of Anaesthesia (BJA), Anaesthesia, and Korean Journal of Anesthesiology (KJA) between Jan. 01, 2004 and Nov. 31, 2016. We aimed to apply the AMSTAR and PRISMA checklists to all published meta-analyses. RESULTS: We identified 121 meta-analyses in the anesthesia literature from January 2004 through the end of November 2016 (BJA; 75, Anaesthesia; 43, KJA; 3). The number of studies published and percentage of 'Yes' responses for meta-analysis articles published after the year 2010 was significantly increased compared to that of studies published before the year 2009 (P = 0.014 for Anaesthesia). In the anesthesia literature as a whole, participation of statisticians as authors statistically improved average scores of PRISMA items (P = 0.004) especially in the BJA (P = 0.003). CONCLUSIONS: Even though there is little variability in the reporting and methodology of meta-analysis in the anesthesia literature, significant quality improvement in the reporting was observed in the Anaesthesia by applying the PRISMA checklist. Participation of a statistician as an author improved the reporting quality of the meta-analysis.

Does preoperative anxiety felt by patients requested to participate in clinical trials related to general anesthesia before elective surgery depend on temperament?

BACKGROUND: Preoperative anxiety may differ according to patient temperament. It will be increased when patients are requested to participate in a study involving anesthesia. The purpose of this study was to show that the anxiety felt when patients are requested to participate may differ according to temperament in both patients who agree and disagree to participate. METHODS: Three hundred and twenty-one patients over age 18 with American Society of Anesthesiologists 1 and 2 completed a survey questionnaire. The degree of anxiety was measured according to patient temperament. It was compared on the basis of the State-Trait Anxiety Inventory (STAI) and visual analogue scale (VAS). RESULTS: In the agreed group, the degree of anxiety measured by "usual, present STAI" and VAS in the monitors (those who want to know as much as possible about anesthesia and surgery) was significantly higher than that in the blunters (those who want to know as little as possible) (P = 0.041 for the "usual STAI", 0.017 for "present STAI", and 0.001 for VAS, respectively). Among patients with a lower educational level, the numbers of blunters and monitors were 57 (79%) and 32 (59%), respectively, indicating that the ratio of blunters was significantly higher (P = 0.026). CONCLUSIONS: Both traits of patients in each group were influenced by psychological burdens. The anxiety of the monitors who agreed to participate was significantly higher than that of blunters. In addition to temperament, education level affects participation. Obtaining consent for participation by understanding temperament and considering factors that may reduce the participation rate will be required.

The sedative effects of the intranasal administration of dexmedetomidine in children undergoing surgeries compared to other sedation methods: A systematic review and meta-analysis.

STUDY OBJECTIVE: Administration of intranasal dexmedetomidine for sedation is comfortable and effective in children who are afraid of needles, and it offers efficient sedation similar to that of intravenous administration. We performed a systematic review and meta-analysis to evaluate the clinical effects of the pre-procedural administration of intranasal dexmedetomidine. DESIGN: We identified randomized controlled trials (RCTs) that compared intranasal dexmedetomidine administration to other administration methods of various sedatives or placebo from MEDLINE, EMBASE, Cochrane, KoreaMed and hand searches of trial registries. SETTING: Pediatrics who underwent interventional procedures and surgeries. PATIENTS: Children under the age of 18. INTERVENTIONS: Studies were included if they were compatible with the criteria that dexmedetomidine was administered intranasally. MEASUREMENTS: We pooled data on the sedation status as the primary outcome and considered the behavioral score, blood pressure, heart rate and side effects to be secondary outcomes. Risk ratio (RR) and the standardized mean difference (SMD) with 95% confidence intervals (CIs) were calculated for dichotomous and continuous outcomes, respectively. MAIN RESULTS: This meta-analysis included 11 RCTs. The SMD for the sedative effects of intranasal dexmedetomidine was -2.45 (random, 95% CI; -3.33, -1.58) for continuous outcomes and RR of unsatisfactory patient outcome was 0.42 (M-H, random 95% CI; 0.26, 0.68 I2=45%) for dichotomous outcomes compared to that of intranasal saline. The SMD for the sedative effects of intranasal dexmedetomidine was -0.41 (random, 95% CI; -1.09, 0.27 I2=69%) for continuous outcomes and RR was 0.43 (M-H, random 95% CI; 0.32, 0.58 I2=0%) for dichotomous outcomes compared to that of per os benzodiazepines. CONCLUSIONS: This review suggests that intranasal dexmedetomidine is associated with better sedative effects than oral benzodiazepines without producing respiratory depression, but it had a significantly delayed onset of effects.

Prognostic factors in second-line treatment of urothelial cancers with gemcitabine and paclitaxel (German Association of Urological Oncology trial AB20/99).

BACKGROUND: In the treatment of urothelial cancer, identification of patients who are likely to benefit from further therapy after cisplatin failure is crucial for reasonable treatment decisions. OBJECTIVE: Validate the prognostic factor model (PFM) for survival developed by Bellmunt et al. in a different patient cohort with a different chemotherapy regimen. DESIGN, SETTING, AND PARTICIPANTS: Baseline parameters of 102 patients treated within a randomized phase 3 trial of second-line gemcitabine and paclitaxel (GP) comparing short-term to prolonged chemotherapy (German Association of Urological Oncology trial AB20/99) were analyzed. Patients were stratified according to the PFM based on a score including performance status, presence of hepatic metastases, and hemoglobin levels. MEASUREMENTS: The baseline parameters of the GP cohort were compared with those of patients treated in the phase 3 trial of vinflunine versus best supportive care. Univariate and multivariate analyses of baseline parameters with respect to overall survival (OS) and treatment response were performed. OS of patients stratified according to the PFM was compared by log-rank test. RESULTS AND LIMITATIONS: The vinflunine and the GP cohorts differed, as patients after perioperative (neoadjuvant or adjuvant) treatment were included in the latter cohort. According to the PFM, prognostic subgroups with significant difference in OS (11.8 mo [95% confidence interval (CI), 6.3-17.3], 8.1 mo [95% CI, 4.8-11.4], 3.2 mo [95% CI, 0.0-7.9]; p=0.007) were identified. The PFM identified risk groups in patients with failed treatment of metastatic disease (14.1 mo [95% CI, 8.9-19.3], 7.3 mo [95% CI, 0.0-17.8], 3.8 mo [95% CI, 0.0-9.0]; p=0.006) but not in patients treated (neo)adjuvantly. Lymph node-only disease was a strong predictor of treatment response that overruled every other single predictive parameter (0.284, p=0.0266). CONCLUSIONS: The PFM was successfully validated in the GP and should be used to tailor second-line treatment strategy. Patients with lymph node-only disease may benefit from second-line treatment even if anemia or impaired performance status is present. TRIAL REGISTRATION: German Cancer Society 01-09 (www.krebsgesellschaft.de).