Predictor Of Therapeutic Effect Research Articles

Machine learning models for early prediction of potassium lowering effectiveness and adverse events in patients with hyperkalemia

The aim of this study was to develop a model for early prediction of adverse events and treatment effectiveness in patients with hyperkalemia. We collected clinical data from patients with hyperkalemia in the First Hospital of Zhejiang University School of Medicine between 2015 and 2021. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to analyze the predictors on the full dataset. We randomly divided the data into a training group and a validation group, and used LASSO to filter variables in the training set. Six machine learning methods were used to develop the models. The best model was selected based on the area under the curve (AUC). Shapley additive exPlanations (SHAP) values were used to explain the best model. A total of 1074 patients with hyperkalemia were finally enrolled. Diastolic blood pressure (DBP), breathing, oxygen saturation (SPO2), Glasgow coma score (GCS), liver disease, oliguria, blood sodium, international standardized ratio (ISR), and initial blood potassium were the predictors of the occurrence of adverse events; peripheral edema, estimated glomerular filtration rate (eGFR), blood sodium, actual base residual, and initial blood potassium were the predictors of therapeutic effect. Extreme gradient boosting (XGBoost) model achieved the best performance (adverse events: AUC = 0.87; therapeutic effect: AUC = 0.75). A model based on clinical characteristics was developed and validated with good performance.

Androgen receptor expression is useful to predict the therapeutic effect in HER2-positive breast carcinoma.

Although HER2-positive (HER2+) invasive breast carcinomas (BC) have a different clinical therapeutic responsiveness according to estrogen and progesterone receptor expression, the relationship with androgen receptors (AR), which are the same family of steroid hormones, is poorly understood. We investigated the relationship between AR expression in HER2 BCs and therapeutic responsiveness and prognosis in this study. We evaluated patients with HER2 (H) + invasive BC undergoing surgery after neoadjuvant chemotherapy (± HER2-targeted therapies) from 2007-2017, classified as hormone receptor-positive (Allred score: 2-8) (luminal B: LH) and receptor-negative groups (Allred: score 0) (non-luminal: NLH). AR expression was assessed by immunostaining pre-neoadjuvant chemotherapy biopsy specimens, positive with Allred score ≥ 4. The pathological complete response, disease-free survival, and overall survival rates were compared between AR-positive and AR-negative groups. We classified 82 patients with HER2 + invasive BC into LH (n = 45, 54.9%) and NLH groups (n = 37, 45.1%), and AR + was observed in 43 patients (52.4%) (LH: 23, 51.1%; NLH: 20, 54.1%; p = 0.79). Quasi-pathological complete response was observed in 40 patients (48.8%) (LH: 18, 40%; NLH: 22, 59.5%; p = 0.08) overall, and in 31 AR + patients (72.1%) (LH: 15, 34.9%; NLH: 16, 37.2%), significantly higher than in the AR - group for both subgroups (p < 0.001). Regarding prognosis, disease-free survival was relatively better in the AR + group in all HER2 + BCs (p = 0.085), and overall survival was significantly better in the AR + group for NLH (p = 0.029). High AR expression may be a useful predictor of therapeutic effects and prognosis in both subgroups of HER2 + BCs.

Decreased cortical thickness of left premotor cortex as a treatment predictor in major depressive disorder.

This study aimed to examine the cerebral cortex characteristics (thickness, surface area, and curvature) in patients with major depressive disorder (MDD), and explore whether these cortex characteristics are predictors for the antidepressant therapeutic effect. 105 patients with MDD and 49 healthy controls (HCs) were recruited. Both groups were given magnetic resonance image (MRI) scans at baseline period, and then the cerebral cortex characteristics (thickness, surface area, and curvature) were calculated using the DPABISurf software. The Hamilton Depression Scale-24 (HAMD-24) reductive rate was used to measure antidepressant therapeutic effect and Snaith Hamilton Rating Scale (SHAPS) reduction was performed to assess the change of anhedonia after treatment of 8 weeks. Correlation analysis was performed to identify the relationship between cortex characteristics and antidepressant therapeutic effect in patients with MDD. There were no significant differences in the cortical curvature and surface area between MDD and HC groups, while significant decreases were found in the cortical thickness of inferior frontal cortex (IFC), premotor cortex (PMC), orbital and medial prefrontal cortex (OMPFC) in the left hemisphere of MDD group, comparing with HC group (P < 0.05 for all, corrected by threshold-free cluster enhancement). In MDD group, the cortical thickness of left PMC had significant positive correlations with 8-week HAMD-24 reduction (r = 0.228, P = 0.020) and HAMD-24 reductive rate (r = 0.193, P = 0.048); and a negative correlation with the 8-week SHAPS reduction (r = -0.240, P = 0.018). Decreased cortical thickness in left PMC may be a predictor of therapeutic effect in MDD. Determining the cortical thickness of this region before treatment can provide certain reference value for clinical antidepressant treatment.

Drug-Related Hypertension Associated with the Efficacy of Apatinib on Hepatocellular Carcinoma.

PurposeWe retrospectively evaluated the efficacy and safety of apatinib as a first-line treatment for advanced hepatocellular carcinoma (HCC) and explored whether drug-related hypertension (HTN) could predict its efficacy.Patients and MethodsThis retrospective analysis included patients with advanced HCC who received oral treatment with apatinib. We evaluated the effectiveness by overall survival (OS), progression-free survival (PFS), time to progression (TTP), and disease control rate (DCR), and assessed the safety of the drug based on the occurrence of adverse events. In order to explore whether apatinib-related HTN can be used as a predictor of therapeutic effect, patients were divided into an HTN group and a non-HTN group and adjusted for propensity score-matched (PSM) to reduce mixed deviation. Subgroup analyses of negative prognostic factors for advanced HCC were also performed, including alpha-fetoprotein (AFP), Child–Pugh Score, macrovascular invasion, and extrahepatic metastasis.ResultsA total of 208 patients were analyzed, of which 40.9% (n =85) developed drug-related HTN. For all patients, the OS was 13.4 months (95% CI, 12.2–14.6), the PFS was 5.7 months (95% CI, 5.1–6.3), and the TTP was 6.9 months (95% CI, 6.0–7.8). The OS of the HTN group and the non-HTN group was 17.4 months (m) and 12.5m (p=0.001), and the PFS was 7.4m and 4.7m (p=0.000), respectively. After PSM, the OS (p=0.001) and PFS (p=0.003) of the HTN group were still significantly better than the non-HTN group. Subgroup analysis suggested that overall survival was significantly longer in patients with HTN when serum AFP ≤400 μg/L or extrahepatic metastases. Moreover, OS in the HTN group increased significantly with or without macrovascular invasion. In addition, through the analysis of two groups of patients with PFS>6m and PFS≤6m, we know that the patients with drug-related HTN may develop resistance later, so they have longer survival time.ConclusionApatinib demonstrates compelling anti-cancer activity and acceptable safety in advanced HCC. Apatinib-related HTN can potentially predict prolonged survival in patients with advanced HCC.

Pre-treatment serum testosterone level can be a useful factor to predict the improvement in bladder outlet obstruction by tadalafil for male patients with lower urinary tract symptoms induced by benign prostatic obstruction

Introduction To investigate possible pre-treatment factors related to the therapeutic effect of tadalafil on bladder outlet obstruction (BOO). Materials and methods Eighty untreated outpatients with lower urinary tract symptoms (LUTS) due to BOO received 5 mg tadalafil daily for 12 months. Subjective symptoms and objective findings were evaluated before and 12 months after treatment. At 12 months, the patients were divided into two groups according to an improvement grade in BOO index (BOOI). Patient characteristics including age, serum total testosterone level (TT), PSA, and prostate volume, and subjective and objective parameters on LUTS were set as candidates of pre-treatment factors, and the parameters that influenced the improvement of BOO were statistically analysed. Results A total of 69 patients with mean age of 69.8 years and mean prostate volume of 48.8 mL were included. Subjective symptoms and BOOI were significantly ameliorated after 12 months. In terms of an improvement of BOOI, 30 patients (43.5%) showed insignificant improvement in BOO, whereas 39 patients (56.5%) exhibited excellent improvement. Comparison of pre-treatment factors between the groups showed that TT was the only independent predictor related to the improvement in BOO. The improvement of BOO was significantly better in patients with higher TT. Conclusions Pre-treatment TT was considered to be a useful predictor of therapeutic effects of tadalafil for BOO.

In vivo imaging of activated macrophages by 18F-FEDAC, a TSPO targeting PET ligand, in the use of biologic disease-modifying anti-rheumatic drugs (bDMARDs)

Rheumatoid arthritis (RA) is a chronic disease with systemic inflammation resulting in destruction of multiple articular cartilages and bones. Activated macrophage plays a pivotal role during the disease course and has been one of main targets to inhibit inflammatory reaction of RA by using biological disease-modifying anti-rheumatic drugs (bDMARDs). 18F-FEDAC is one of PET imaging agents targeting TSPO, which is overexpressed in activated macrophages. The aim of this study was to evaluate the roles of 18F-FEDAC PET as an in vivo imaging of activated macrophages on etanercept (ETN), a TNF-antagonist as one of bDMARDs in collagen induced arthritis mice. In RAW 264.7 cells, the expressions of TSPO as well as iNOS and infiltrated nucleus of NF-κB were induced by activation with lipopolysaccharide and interferon-gamma. TSPO expression was slightly attenuated by ETN treatment, not by methotrexate (MTX) as a cytotoxic agent. However, cell uptake of 18F-FEDAC did not show significant changes according to both of the treatments. Similarly in CIA mice, 18F-FEDAC uptake in inflamed paws on PET imaging did not show significant changes during both of the treatments, contrary to the uptake decrease of 18F-FDG, a glucose analog to reflect metabolic or active inflammatory activity. Interestingly, when we divided joints according to the degree of 18F-FEDAC uptake before ETN treatment, the joints of high 18F-FEDAC uptake showed better response to ETN than the joints with low 18F-FEDAC uptakes. In case of 18F-FDG, there was no such kinds of patterns. We can speculate that 18F-FEDAC PET imaging may identify activated macrophage-induced arthritis because that 18F-FEDAC can reflect activated macrophages, which is the therapeutic target of ETN by TNF antagonistic effect. Thus, in vivo imaging using 18F-FEDAC may be used as a predictor of therapeutic effects among those kinds of bDMARDs having anti-inflammatory actions to inhibit activated macrophage.

Clinical significance of morphologic response and tumor shrinkage as predictive factors of Capeox+bevacizumab in 1st line treatment of metastatic colorectal cancer.

805 Background: Capeox + bevacizumab (BV) is one of the standard treatment for metastatic colorectal cancer (mCRC) and well known to sometimes cause morphologic response (MR). However, it is not well known the predictive value of MR in palliative chemotherapy of Capeox + BV as 1st line. The aim of this study was to investigate the clinical significance of MR and tumor shrinkage as predictive factors of Capeox+BV in 1st line treatment of mCRC. Methods: A total of 159 patients with CLM were selected from 316 mCRC patients treated with Capeox+BV as 1st line chemotherapy from February 2006 to August 2016. Among these patients, 92 patients were enrolled in the this study, who satisfied following criteria; (1) tumor responce was assesed by enhanced computed tomography (CT) images every 2-3 months, and (2) dose intensity of BV at first 4 courses were above 80%. Tumor response of RECIST1.1 and MR were evaluated by 2 radiologists. They classified them as optimal, incomplete or no morphologic response according to the morphologic criteria. Results: An optimal morphologic response (OR) was observed in 34% of all patients. The median progression-free survival (mPFS) was 9.3 months in this cohort, 13.5 months in patients with OR and 11.6 months in those with incomplete/no morphologic response. And the median overall survival (mOS) was 19.5 months, 30.3 months and 23.8 months, respectively. There were no statistical significance between OR and the other, irrespective of mPFS and mOS. On the other hand, mPFS was 14.6 months in responder as CR or PR of RECIST and 8.6 months in non responder as SD or PD (p &lt; 0.0001). Furthermore, mOS, 31.9 months and 18.5 months, respectively (p &lt; 0.0001). Besides in 17 patients fulfilled both responder of RECIST and OR, the mOS reached 45.4 months, which was remarkably longer compared to the other groups ( &lt; 0.0001). Conclusions: Among mCRC patients with CLM treated with Capeox+BV as the 1st line, the response of RECIST well reflected the therapeutic effect. On the other hand, MR solely was not a predictor of therapeutic effect in this study. However, both responder of RECIST and OR may be on-treatment predictors to identify excellent prognostic group.

Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy.

An association between inflammatory/immunonutritional status and patient prognosis has been reported in various types of cancer. The aim of this study was to evaluate the utility of inflammatory/immunonutritional factors as therapeutic predictors for patients with locally advanced pancreatic cancer treated with chemoradiotherapy (CRT). Ninety-six patients with histologically proven locally advanced pancreatic adenocarcinoma who underwent CRT were enrolled in this study. We evaluated significance of inflammation-based factors as predictors of therapeutic effect and prognosis. The median progression free survival (PFS) and overall survival (OS) of all patients was 10 and 18 months, respectively. A Glasgow prognostic score (GPS) of 2 and plasma fibrinogen levels ≥ 400 mg/dL were independent predictors of poor PFS and OS. A prognostic nutritional index (PNI) ≥ 45 was a predictor of a significantly better reduction rate of the primary tumor. The prognosis between patients with GPS 0/1 and fibrinogen <400 mg/dL, GPS 2 or fibrinogen ≥400 mg/dL, and GPS 2 and fibrinogen ≥400 mg/dL were significantly different. Patients with GPS 2 and/or plasma fibrinogen ≥ 400 mg/dL had significantly higher incidence of metastasis within 6 months after CRT. GPS, fibrinogen, PNI are useful therapeutic and prognostic predictors in patients with locally advanced pancreatic cancer treated with CRT.

Psychodynamically oriented inpatient psychotherapy of depressive disorders - First findings from a naturalistic, multicenter study

While the general effectiveness of psychodynamic psychotherapy in both outpatient and inpatient treatment has been proven, few studies document the effectiveness of clinical inpatient treatment of depression through psychodynamic psychotherapy. This paper presents first results of a naturalistic multicenter intervention study. Included were female inpatients suffering from depressive symptoms who had been admitted to 15 psychodynamically oriented psychosomatic hospital units (N = 487). The mean duration of treatment was 61.8 days. Data were acquired at admission (T1) and discharge (T2). Our findings support previous evidence and show that psychodynamically oriented inpatient psychotherapy of depressive disorders is efficient. High pre-post effect sizes were documented in all psychometric instruments used (BDI, HAM-D, SCL-90-R, BSS, GAF). Initial subgroup comparisons reveal that the benefits for patients with comorbid personality disorder are significantly lower than for depressed patients without comorbid personality disorder. Psychodynamic inpatient psychotherapy, as practiced under naturalistic conditions, is an effective treatment of depression. Predictors of therapeutic effects within different therapeutic settings, however, remain unclear. The sustainability of the therapeutic effects found and their impact on psychodynamic relevant constructs have still to be proven.

Glycated Albumin: A More Sensitive Predictor of Cardiovascular Disease than Glycated Hemoglobin?

Type 2 diabetes is an established risk factor for car-diovascular disease (CVD). Compared to non-diabetic subjects, patients with type 2 diabetes have a 2 to 4-fold increased risk of development of CVD [1]. Intensive glycemic control aiming at HbA1c below 7% has been shown to reduce the risk of development of microvas-cular disease in patients with type 2 diabetes; however, its effect on CVD was rather modest [2].Moreover, recent trials aiming to achieve near-normal glycemic control (i.e., HbA1c below 6%) to improve CVD outcomes in patients with type 2 diabetes failed to show a reduction of the primary endpoints (death from CVD, non-fatal myocardial infarct and non-fa-tal stroke) by intensive glycemic control compared to standard care [3-5]. The findings revealed a modest ef-fect of glycemic control on CVD outcome, and un-derpinned the importance of avoiding hypoglycemia in the treatment of type 2 diabetes, but also suggested the limitation of HbA1c as a predictor of therapeutic effect on CVD outcome.Glycated albumin (GA) is a ketoamine which is formed by binding of albumin and glucose by nonenzymatic glycation reaction. Since the turnover of albumin is relatively short, GA reflects the average glucose value in the previous 1 to 2 weeks, whereas HbA1c reflects the average glucose value in the previous 1 to 2 months [6]. Moreover, it has been reported that albumin is more rapidly glycated compared to hemoglobin [7]. Therefore, glycated albumin may reflect glycemic con-trol more sensitively than does HbA1c.A recently-developed enzyme method for measure-ment of GA has allowed GA to be more rapidly and easily determined [8]. Recent studies have shown that GA is more strongly correlated with postprandial gly-cemic excursion compared with HbA1c [9-12]. Since postprandial glycemic excursion has been shown to be a risk factor for CVD [13-14], GA may predict CVD outcome more sensitively than does HbA1c.This was shown to be the case. It has been reported that GA was more strongly associated with coronary atherosclerosis [15-16]. It has been also reported that GA and GA to HbA1c ratio but not HbA1c predict-

Skin rash as useful marker of erlotinib efficacy in NSCLC and its impact on clinical practice

Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor used in treatment of advanced NSCLC. Patients harboring EGFR or KRAS mutations represent minority of all patients in caucasian population and there is no available predictor for a predominant group of patients harboring the wild-type EGFR and wild-type KRAS genes. Skin rash is the most frequent manifestation of cutaneous toxicity of erlotinib. Rash is associated with a good therapeutic response. We aimed at the evaluation of rash as a predictor of therapeutic effect of erlotinib in patients harboring the wild-type EGFR and KRAS wild-type genes and to assess its possible usage in a clinical practice.Totally 184 patients with advanced stage NSCLC (IIIB, IV) harboring the wild-type EGFR and wild-type KRAS genes were analysed. Comparison of ORR, PFS and OS according to the occurrence of rash was performed. In order to assess the impact of rash in clinical practice it was conducted landmark analysis of the group of patients whose rash was observed during first month of treatment (n=124). Patients in whom progression was observed during the first month of treatment were excluded from the landmark analysis. The comparison of ORR was performed using Fisher's exact test, visualization of survival was performed using Kaplan-Meier survival curves and the differences in survival were tested using the log-rank test. Median PFS in patients who were observed with rash during the treatment was 3.0 vs. 1.2 months in patients with no rash (p<0.001), median of OS in patients who were observed with rash during the treatment was 13.9 vs. 5.8 months in patients with no rash (p<0.001). ORR in patients who were observed with rash during the treatment was 17.4% vs. 3.3% in patients with no rash (p=0.001). Median of PFS after 1 month of treatment in patients who were observed with rash during the first month was 2.9 vs. 1.1 months in patients with no rash (p=0.027). Median of OS after 1 month of treatment in patients who were observed with rash during the first month was 13.8 vs. 9.9 months in patients with no rash (p=0.082). Rash is strongly associated with better survival and ORR in patients harboring wild-type EGFR and wild-type KRAS genes. Occurrence of rash during the first month of treatment is a useful predictor of better effect of erlotinib after one month of treatment. Patients who were not observed with rash during the first month of treatment are in high risk of progression. Optimization of the treatment of these patients can contribute restaging after two months of treatment, assessment of plasma levels of erlotinib and eventually attempt to dose escalation.

Drug and Device Effects on Peak Oxygen Consumption, 6-Minute Walk Distance, and Natriuretic Peptides as Predictors of Therapeutic Effects on Mortality in Patients With Heart Failure and Reduced Ejection Fraction

Although peak oxygen consumption (peak VO(2)), 6-minute walk distance (6MW), and natriuretic peptides (BNP and NT-proBNP) are predictors of mortality in heart failure (HF) patients, it is not known whether therapy-induced changes in these measures can predict therapeutic effect on mortality. The objective of this analysis is to quantitatively assess the relationship between therapeutic effects on commonly proposed short-term markers in HF trials and therapeutic effects on long-term outcome in patients with HF and left ventricular dysfunction. We identified drug or device therapies for which there exists at least 1 randomized, controlled trial (RCT) assessing mortality over at least 6 months in at least 500 patients. For each of these therapies, we identified RCTs assessing the short-term changes in VO(2), 6MW, BNP, and NT-proBNP (few of the mortality RCTs assessed the short-term changes in markers). For each intervention, we calculated the odds ratio for mortality (using random effect meta-analysis when necessary), as well as the trial level average drug- or device-induced change in the markers. We assessed the correlation between the odds ratio for death with the placebo-corrected change in the functional parameter or biomarker across the interventions. We identified mortality RCTs of 27 distinct therapies (n=73 267 patients) with a median follow-up of 19 months, that directed the search for RCTs of the effect of those interventions on the functional markers and biomarkers. There were 54 peak VO(2) trials (n=4646 patients), 34 6MW trials (n=6995 patients), 15 BNP trials (n=7233), and 6 NT-proBNP trials (n=1946) included in this analysis. There was no significant correlation between the average therapy-induced placebo-corrected change in peak VO(2) and the odds ratio for mortality (r=0.158, P=0.26). Increased drug or device-induced average change in 6MW was correlated with increased odds ratio for mortality (r=0.373, P=0.036). There was no significant correlation between the average therapy-induced, placebo-corrected change in the natriuretic peptides and the odds ratio for mortality (BNP: r=-0.065, P=0.82, NT-proBNP: r=-0.667, P=0.15). There was no apparent relation between change in the functional parameter or biomarker and categorical effect on mortality. This analysis, limited to trial level data from different therapeutic eras, suggests that drug- or device-induced effects on peak VO(2), 6MW, and natriuretic peptides found in short-term trials do not predict the corresponding average long-term therapeutic effects on mortality for patients with HF and left ventricular dysfunction.

P53 mutation, but not in vitro predictor genes of therapeutic efficacy of cisplatin, is clinically relevant in comparing partial and complete responder cases of maxillary squamous cell carcinoma

To predict the efficacy of cisplatin and radiation therapy for maxillary squamous cell carcinoma, we examined the mRNA expression of 14 cisplatin-resistant genes and p53 mutation in specimens biopsied from patients prior to initiation of therapy. Five of 10 patients had mutations in the p53 gene, of whom four had residual tumors pathologically following chemoradiotherapy (p=0.0476). Of 14 genes examined, the mRNA expression of ATP7B was significantly lower in cases that were resistant to chemoradiotherapy. Six genes including multidrug resistance protein 1 (MDR-1), multidrug resistance associated protein 1 (MRP-1), Cu++ transporting, beta polypeptide (ATP7B), xeroderma pigmentosum, complementation group A (XPA), excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC-1) and B-cell CLL/lymphoma 2 (BCL2) were down-regulated in cases of recurrent cancers. These results show that the evaluation of p53 mutation provides the most useful predictor of therapeutic effects. In responder cases, the drug-resistant genes that were determined in cell lines by culture do not necessarily translate into clinical relevance.

Therapeutics Effects on 6-minute Walk Distance as a Predictor of Therapeutic Effects on Mortality in Heart Failure Randomized Trials

Introduction: Six-minute walk (6-MW) distance predicts mortality for patients with heart failure (HF) and reduced ejection fraction (EF). It is not known whether intervention-induced changes in this measure can predict the effect of such therapies on mortality. Methods: PubMed was systematically reviewed for randomized, placebo-controlled trials (RCTs) of interventions for patients with HF and reduced EF. The dataset was limited to therapies that had mortality data from RCTs of >500 patients with >6 months of follow up.

Quantitative Evaluation of Drug or Device Effects on Ventricular Remodeling as Predictors of Therapeutic Effects on Mortality in Patients With Heart Failure and Reduced Ejection Fraction: A Meta-Analytic Approach

The purpose of this study was to quantitatively assess the relationship between therapy-induced changes in left ventricular (LV) remodeling and longer-term outcomes in patients with left ventricular dysfunction (LVD). Whether therapy-induced changes in left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), and end-systolic volume (ESV) are predictors of mortality in patients with LVD is not established. Searches for randomized controlled trials (RCTs) were conducted to identify drug or device therapies for which an effect on mortality in patients with LVD was studied in at least 1 RCT of > or = 500 patients (mortality trials). Then, all RCTs involving those therapies were identified in patients with LVD that described changes in LVEF and/or volumes over time (remodeling trials). We examined whether the magnitude of remodeling effects is associated with the odds ratios for death across all therapies or associated with whether the odds ratio for mortality was favorable, neutral, or adverse (i.e., statistically significantly decreased, nonsignificant, or statistically significantly increased odds for mortality, respectively). Included were 30 mortality trials of 25 drug/device therapies (n = 69,766 patients; median follow-up 17 months) and 88 remodeling trials of the same therapies (n = 19,921 patients; median follow-up 6 months). The odds ratio for death in the mortality trials was correlated with drug/device effects on LVEF (r = -0.51, p < 0.001), EDV (r = 0.44, p = 0.002), and ESV (r = 0.48, p = 0.002). In (ordinal) logistic regressions, the odds for neutral or favorable effects in the mortality RCTs increased with mean increases in LVEF and with mean decreases in EDV and ESV in the remodeling trials. In patients with LVD, short-term trial-level therapeutic effects of a drug or device on LV remodeling are associated with longer-term trial-level effects on mortality.

Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFNα2b

The Janus-activated kinase/signal transducers and activators of transcription (STAT) pathway of IFN signaling is important to immunoregulation and tumor progression. STAT1 plays a prominent role in the effector immune response, whereas STAT3 is implicated in tumor progression and down-regulation of the response to type I IFNs. The goal of this study was to understand the effects of high-dose IFNalpha2b (HDI) in relation to the balance of pSTAT1 and pSTAT3. We evaluated STAT1 and STAT3 jointly as mediators of IFNalpha effects in the setting of a prospective neoadjuvant trial of HDI, in which tissue samples were obtained before and after 20 doses of HDI therapy. Double immunohistochemistry for pSTAT1 and pSTAT3 was done on paired fixed (9 patients) or frozen (12 patients) biopsies. HDI was found to up-regulate pSTAT1, whereas it down-regulates pSTAT3 and total STAT3 levels in both tumor cells and lymphocytes. Higher pSTAT1/pSTAT3 ratios in tumor cells pretreatment were associated with longer overall survival (P = 0.032). The pSTAT1/pSTAT3 ratios were augmented by HDI both in melanoma cells (P = 0.005) and in lymphocytes (P = 0.022). Of the immunologic mediators and markers tested, TAP2 was augmented by HDI (but not TAP1 and MHC class I/II). IFNalpha2b significantly modulates the balance of STAT1/STAT3 in tumor cells and host lymphocytes, leading to up-regulation of TAP2 and augmented host antitumor response. The pSTAT1/pSTAT3 ratio in tumor cells at baseline may serve as a useful predictor of clinical outcome in cutaneous melanoma; the modulation of this ratio may serve as a predictor of therapeutic effect.

Proliferating cell nuclear antigen as a predictor of therapeutic effect of continuous 5-fluorouracil administration in gastric cancer.

The change of proliferating cell nuclear antigen (PCNA) expression was examined in three gastric cancer cell lines, MKN28, MKN45 and MKN74, during continuous or bolus exposure to 5-fluorouracil (5-FU). The cytotoxic effect of 5-FU was almost the same in all the cells. PCNA expression was higher at 24 and 72 h after continuous 5-FU treatment than before treatment. Continuous 5-FU treatment of cells revealed higher expression of PCNA protein and mRNA than did bolus treatment. Flow cytometry revealed that 5-FU increased cell population at the late G1 or S phase 24 and 72 h after treatment. PCNA values at the late G1 and S phase were significantly higher than those at other phases 24 h after treatment. These results suggest that PCNA expression increased due to cell cycle accumulation at late G1 and S phases. Thus PCNA values just after chemotherapy of gastric cancer may be useful in predicting the therapeutic effects of continuous 5-FU administration.