Predictors Of Good Response Research Articles

Evaluating signal-to-noise ratios, loudness, and related measures as indicators of airborne sound insulation

Subjective ratings of the audibility, annoyance, and loudness of music and speech sounds transmitted through 20 different simulated walls were used to identify better single number ratings of airborne sound insulation. The first part of this research considered standard measures such as the sound transmission class the weighted sound reduction index (R(w)) and variations of these measures [H. K. Park and J. S. Bradley, J. Acoust. Soc. Am. 126, 208-219 (2009)]. This paper considers a number of other measures including signal-to-noise ratios related to the intelligibility of speech and measures related to the loudness of sounds. An exploration of the importance of the included frequencies showed that the optimum ranges of included frequencies were different for speech and music sounds. Measures related to speech intelligibility were useful indicators of responses to speech sounds but were not as successful for music sounds. A-weighted level differences, signal-to-noise ratios and an A-weighted sound transmission loss measure were good predictors of responses when the included frequencies were optimized for each type of sound. The addition of new spectrum adaptation terms to R(w) values were found to be the most practical approach for achieving more accurate predictions of subjective ratings of transmitted speech and music sounds.

8506 Cisplatin dose intensity correlates with outcome in patients with locally advanced head and neck squamous cell carcinoma receiving concurrent cisplatin based chemoradiation: a multi-institutional experience

World Health Organization estimated that there were 600,000 new cases of head and neck cancers and 300,000 deaths each year worldwide. Scientific modalities to predict the treatment outcomes are not available yet. We conducted this study to (1) compare CT perfusion parameters before and after chemoradiation among patients with head and neck squamous cell carcinoma and (2) to evaluate the prognostic value of each perfusion parameter in predicting the response to chemoradiation.We conducted a prospective study among all patients with head and neck squamous cell carcinoma registered for chemoradiotherapy (CRT) at Regional Cancer Research Center, Shimla, Himachal Pradesh, India during the period June 2012 through June 2013. CTp data were acquired on a 64-slice CT scanner (Light speed VCT Xte; GE Healthcare) with 14 cm z-axis coverage using Volume Helical Shuttle (VHS) feature at baseline, on completion of 40 Gy and 66 Gy of chemoradiation. We dichotomised the treatment outcome as complete response and non-response (partial responders/stable disease/progressive disease) using RECIST 1.1 criteria. We compared all perfusion parameters at baseline, 40 Gy and 66 Gy of CRT between responders and non-responders. We dichotomised the perfusion parameters as high (>median value) and low (≤median value) to analyze association between perfusion parameters and treatment outcome. We calculated the sensitivity, specificity, predictive values, and likelihood ratios for each dichotomized perfusion parameter using Wilson Score method.We followed 24 patients (23 of them men) from start of the treatment till completion of it. All had Stage III or Stage IV of the disease. Blood flow (BF) and blood volume (BV) decreased and Mean Transit Time (MTT) increased significantly (p < 0.05) at 66 Gy among responders to CRT as compared to non-responders. Patients with high BF (>106 ml/100 g/min) at baseline were five times more likely (p = 0.004) to respond to treatment as compared to those with low BF. BF was found to be 83.3% predictive of complete response. Other perfusion parameters were not significantly predictive of outcome (p > 0.05) Combination of high BF (>106 ml/100 g/min) and low (≤47 ml/100 g/min) permeability surface (PS) was 100% predictive of response to CRT irrespective of the stage of tumor.High BF at baseline is the single best predictor of response to chemoradiaton. A combination of high BF and low PS was found to be 100% predictive of complete response irrespective of the stage of the tumor.

Molecular analysis of tamoxifen-resistant pathways in breast cancer cell-lines and breast cancer tissues

e22094 Background: Oestrogen receptor positive (ER+) breast cancer (BC) is heterogeneous with regard to their clinical behaviour and response. The ER and Progesterone receptors (PgR) are currently the best predictors of response to the anti-oestrogen agent tamoxifen, yet up to 30–40% of ER+ breast cancers will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance is required. There has been an explosion of greater understanding since the arrival of new cutting-edge genomic profiling technology. Methods: RNA from the BC cell lines and frozen tissue was extracted and qualified using Qiagen Mini Kit and BioAgilent respectivelly. Probe preparation and scanning of the chips were carried out according to Affymetrix protocol. The normalisation and analysis of data (Limma) was performed using Bioconductor software. RT- PCR probes were purchased from Applied Biosystem and performed on ABI7500 instrument. The IHC-P was done using Ventana. TMA prepared with TMABooster, Alphelys (Plaisir, France). Results: Gene expression changes were studied in the TR breast cell lines MCF7 (tenovus), T47D and ZR by using the Affymetrix Hu133 plus 2.0 platform. Common genes of significant expression from the 3 TR cell lines were validated by real-time PCR (RT-PCR) and immuno-histochemistry (IHC-P) staining. 7 (MAGEA2, AKR1C3, VGLL1, THRAP5, GREB1, PDZK1, MYBL1, HnRNPA2B1, PGR) out of the 9 chosen genes were successfully validated. Proliferation studies on MageA2 overexpressing clones were performed. Stable overexpression of MageA2 in T47D and MCF-7 confers a proliferation advantage in tamoxifen-containing media as shown in proliferation and cell cycle analysis. MageA2 has been shown to alter the p53 pathway. The expression of KAP1, which interacts with p53 and inactivates it, was enhanced by MageA2 overexpression. In addition, overexpression of MageA2 is seen to increases histone deacetylase (HDAC3), and p53 expression as seen by immunoblotting. Validation of MageA2 on TMA of 100 patients is underway. Conclusions: MageA2 is a possible selective molecular target for the reversal of tamoxifen resistance. No significant financial relationships to disclose.

Identification of responders to cardiac resynchronization therapy by contractile reserve during stress echocardiography

The identification of responders to cardiac resynchronization therapy (CRT) remains a challenge. We assessed the role of dyssynchrony (DYS) and contractile reserve (CR) in identifying CRT responders. Sixty-nine patients (55% with ischaemic aetiology) referred for CRT (ejection fraction < or =35%, New York Heart Association > or =III, and QRS duration > or =120 ms) underwent baseline evaluation of DYS and dobutamine stress-echo [up to 40 microg/kg/min: CR was defined as a wall motion score index (WMSI) variation > or =0.20]. CRT responders were identified by clinical and/or echocardiographic [end-systolic volume (ESV) decrease > or =15%] follow-up criteria. During a median follow-up of 11 months, 46 patients (66%) were classified as clinical responders. Reverse remodelling was found in 34 of the 59 patients (58%) with echocardiographic follow-up. CR was present in 78% of clinical responders (P = 0.001) and in 69% with reverse remodelling (P = 0.005). DYS was equally present in the two groups. Reverse remodelling was correlated with rest-stress changes in ESV (r = 0.439, P = 0.003) and in WMSI (r = 0.450, P = 0.001), but not with DYS. CR (OR = 6.2, 95% CI = 1.4-27.6, P = 0.015) was the best predictor of response to CRT. Patients with CR show a favourable clinical and reverse LV remodelling response to CRT. This finding shifts the focus from electrical (dyssynchrony) to the myocardial substrate of functional response.

The Combined Dexamethasone/CRH Test (DEX/CRH Test) and Prediction of Acute Treatment Response in Major Depression

BackgroundIn this study the predictive value of the combined dexamethasone/CRH test (DEX/CRH test) for acute antidepressant response was investigated.Methodology/Principal FindingsIn 114 depressed inpatients suffering from unipolar or bipolar depression (sample 1) the DEX/CRH test was performed at admission and shortly before discharge. During their stay in the hospital patients received different antidepressant treatment regimens. At admission, the rate of nonsuppression (basal cortisol levels >75.3 nmol/l) was 24.6% and was not related to the later therapeutic response. Moreover, 45 out of 114 (39.5%) patients showed an enhancement of HPA axis function at discharge in spite of clinical improvement. In a second sample, 40 depressed patients were treated either with reboxetine or mirtazapine for 5 weeks. The DEX/CRH test was performed before, after 1 week, and after 5 weeks of pharmacotherapy. Attenuation of HPA axis activity after 1 week was associated with a more pronounced alleviation of depressive symptoms after 5-week mirtazapine treatment, whereas downregulation of HPA system activity after 5 weeks was related to clinical response to reboxetine. However, early improvement of HPA axis dysregulation was not necessarily followed by a beneficial treatment outcome.Conclusions/SignificanceTaken together, performance of a single DEX/CRH test does not predict the therapeutic response. The best predictor for response seems to be an early attenuation of HPA axis activity within 1 or 2 weeks. However, early improvement of HPA system dysfunction is not a sufficient condition for a favourable response. Since a substantial part of depressive patients display a persistence of HPA axis hyperactivity at discharge, downregulation of HPA system function is not a necessary condition for acute clinical improvement either. Our data underline the importance of HPA axis dysregulation for treatment outcome in major depression, although restoration of HPA system dysfunction seems to be neither a necessary nor a sufficient determinant for acute treatment response.

Development and Therapeutic Potential of an Anti-CD79b Antibody-Drug Conjugate, Anti-CD79b-Vc-MMAE, for the Treatment of Non-Hodgkin's Lymphoma

Antibody-drug conjugates (ADCs), antibodies linked to potent cytotoxic drugs via specialized chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. We have previously shown that ADCs targeted to CD79b are highly effective in xenograft models of non-Hodgkin's lymphoma. Here we report the development of an ADC consisting of a humanized anti-CD79b antibody (hu-anti-CD79b) conjugated to monomethylauristatin E (MMAE) through engineered cysteines (THIOMABS) by a maleimidocaproyl-valinecitrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker (hu-anti-CD79b-thioMAb-MC-vc-PAB-MMAE) that is designed to be cleaved by cathepsins. To determine the potential of this ADC, hu-anti-CD79b-thioMAb-MC-vc-PAB-MMAE (referred to as anti-CD79b-vcMMAE henceforth), as a therapeutic for NHL we interrogated its potency across a large panel of NHL cell lines. Strikingly, anti-CD79b-vcMMAE has very potent activity across a large panel of NHL cell lines in vitro with 68% (23 out of 34) cell lines having greater than 50% reduction in cell viability. Quantitative FACS across the cell line panel revealed that of the 11 insensitive cell lines, 9 had negligible surface CD79b, suggesting a threshold effect in that below a specific level of antigen on the cell surface resulted in cells being insensitive to anti-CD79b-vcMMAE. Within the sensitive cell lines, there was not a direct correlation per se with anti-CD79b-vcMMAE IC50 values and cell surface expression levels and this prompted us to investigate other potential molecular parameters. Gene expression profiling and gene set enrichment analysis revealed that genes predominantly involved in antigen processing and presentation and genes induced by IFN-gamma were significantly enriched in the less sensitive cell lines to CD79b-vcMMAE. Classifying our NHL cell lines as GCB or ABC subtypes by gene expression revealed that both ABC and GCB were responsive. In addition, the activity of anti-CD79b-vcMMAE was very potent in p53 mutant as well as p53 wild-type cell lines. Since the pre-clinical evidence suggests that anti-CD79b-vcMMAE will be a very promising drug candidate for NHL and we have established that cell surface expression is perhaps the best predictor of response, we wished to determine the prevalence of expression of CD79b on the cell surface of primary human lymphoma and CLL samples to estimate a patient population that may gain benefit. Strikingly, CD79b was detected in all cases of CLL, MZL, HCL, DLBCL, FL, and MCL. Furthermore, CD79b expression was detected in all cases that had relapsed from prior chemotherapy regimens, highlighting the clinical relevance of this target and potential therapeutic utility of anti-CD79b-vcMMAE. To assess the potential of anti-CD79b-vcMMAE in vivo we compared its efficacy to R-CHOP in three xenograft models of NHL. In all three models, a single dose of anti-CD79b-vcMMAE resulted in complete sustained tumor remission and was more effective than R-CHOP. These data suggest that anti-CD79b-vcMMAE could be broadly efficacious as a treatment for NHL.

EXPRESSION OF S100A2 CALCIUM-BINDING PROTEIN PREDICTS RESPONSE TO PANCREATECTOMY FOR PANCREATIC CANCER

Background: Current methods of preoperative staging and predicting outcome following pancreatectomy for pancreatic cancer are inadequate. We evaluated the utility of multiple biomarkers from distinct biological pathways as predictive markers of response to pancreatectomy and patient survival. Methods: We assessed the relationship of candidate biomarkers known, or suspected, to be aberrantly expressed in pancreatic cancer, with disease specific survival and response to therapy in a cohort of 601 patients. Results: Of the 17 candidate biomarkers examined, only elevated expression of S100A2 was an independent predictor of survival in both the training (n = 162), and validation sets (n = 439, HR 2.19, 95% CI: 1.48 - 3.25; p < 0.0001) when assessed in a multivariate model with clinical variables. Patients with high S100A2 expressing tumours had no survival benefit with pancreatectomy compared to those with locally advanced disease, whereas those without high S100A2 expression had a survival advantage of 10.6 months (19.4 Vs 8.8 months) and a HR of 3.23 (95% CI: 2.39 - 4.33; P < 0.0001). Of significance, patients with S100A2 negative tumours had a significant survival benefit from pancreatectomy even in the presence of involved surgical margins (median 15.7 months; p = 0.0007) or lymph node metastases (median 17.4 months; p = 0.0002). Conclusion: S100A2 expression is the best predictor of response to pancreatectomy for pancreatic cancer reported to date, and high S100A2 expression may represent the development of a metastatic phenotype. Prospective measurement of S100A2 expression in diagnostic biopsies has potential clinical utility as a predictive marker of response to pancreatectomy and other therapies that target loco-regional disease.

Abstract 4349: Usefulness of Echocardiographic Measures of Dyssynchrony in Patients with Borderline QRS Duration for Selection for Resynchronization Therapy

Although echo dyssynchrony has not replaced routine selection criteria for cardiac resynchronization therapy (CRT) in patients with wide QRS, our objective was to test the hypothesis that dyssynchrony may assist in selection of patients for CRT with borderline QRS duration. We studied 119 heart failure patients referred for CRT; all were Class III-IV with ejection fraction (EF) ≤35%: 79 had Wide-QRS ≥130ms (169 ±28ms), and 40 had Borderline-QRS 100 –130ms (116 ±7ms). Dyssynchrony was assessed using tissue Doppler (TDI) longitudinal velocities from apical views (≥65ms opposing wall delay) and speckle tracking radial strain (≥130 ms septal to post. wall delay). Pulsed Doppler assessed interventricular mechanical delay (IVMD) (≥40ms), and filling time/RR interval (FT/RR ≤40%). Patients were followed for 8±5 months. Response to CRT was defined as ≥15% increase in EF. Overall, 77% of the Wide-QRS group were EF responders in contrast to 65% of the Borderline-QRS group. TDI was 87% sensitive and 67% specific for predicting response in the Wide-QRS group, but only 46% specific in the Borderline-QRS group. Radial dyssynchrony was the best predictor of response in the Borderline-QRS group with 80% sensitivity and 92% specificity. Although IVMD and FT/RR had low sensitivities, they were 100% specific. EF response to CRT is less frequent in patients with Borderline-QRS than in those with Wide-QRS. Radial dyssynchrony appears to be the best predictor of EF response in Borderline-QRS patients; IVMD and FT/RR were highly specific. A combined echo assessment of dyssynchrony has potential to assist in selection of patients for CRT with borderline QRS.

PIES (Predictors of Improvement after Electrical Stimulation) in Gastroparesis

Purpose: Objective criteria to predict response to Gastric Electrical Stimulation (GES) in medically-refractory gastroparesis (GP) have not been identified. Temporary GES (tGES) (GIE. 2005;61:455–6) improves GP symptoms and may be used to assess response to permanent GES (pGES). We examined long term outcomes in a large group of GP patients to define clinical and tGES-derived mucosal electrogastrogram criteria that may predict outcome to pGES. Methods: 394 consecutive GP patients (320 F, 74 M, mean age 43 years) were consented for GES over 15 years, with diagnoses: 240 idiopathic (ID), 103 diabetes mellitus (D) and 51 post-surgical (PS). To predict response to pGES 150 patients underwent tGES prior to pGES (ID 88, D 40, PS 22). All patients were assessed by symptom scores [nausea (N), vomiting (V), and total symptom (TSS)] and IDIOMS (a HRQOL measure) at baseline (b), after tGES (t) and at the latest (L) follow-up after GES, as well as a ratio (Rt) of frequency to amplitude in tGES mucosal EGG. Linear regression determined independent variables predicting the latest vomiting score. Results: Median follow-up was 57 months (range 10 months to 12 years). In analysis by etiology, virtually all patients (I, P < 0.001, DM, P≤ 0.001 and PS, P≤ 0.001) had very good responses. Among all GP patients linear regression analysis identified 3 predictors of improvement in vomiting scores: pt age, baseline vomiting score and Rt. In subset analysis, these predictors were most significant for ID. Among all categories of GP, linear regression analysis identified a low Rt derived by the use of mEGG as the single best predictor of response to tGES and pGES. Conclusion: Permanent GES for severe GP results in significant and sustained improvement of overall symptoms and quality of life. The independent predictors of response (age, Vb score, and Rt) were most significant in ID patients. Rt derived from endoscopic tGES mucosal EGG is an accurate predictive criterion of symptom improvement with GES, especially improvement in vomiting. Future studies with larger sample sizes may identify and standardize these and other factors that may predict outcomes after GES.Table: Subset AnalysisFigureSymptom Outcome: IDIOMs, Nausea (N), vomiting (V) and total symptom score (TSS) at baseline (b) after temporary GES (tGES) and at the latest (last) date of evaluation (last). All parameters showed significant improvement (see text for P values)

Prediction of Serotonergic Treatment Efficacy Using Age of Onset and Type A/B Typologies of Alcoholism

Previously, we reported that ondansetron was efficacious at treating early-onset (< or =25-years old) but not late-onset (> or =26-years old) alcoholics in a double-blind, randomized, placebo-controlled clinical trial (n = 321 enrolled patients, 271 of them randomized). Randomized participants underwent 11 weeks of treatment with ondansetron (1, 4, or 16 microg/kg twice daily; n = 67, 77, and 71, respectively) or identical placebo (n = 56), plus weekly standardized group cognitive behavioral therapy. For this study, we reanalyzed the original sample to determine whether the Type A/B typological classification predicts ondansetron treatment response. In this comparative analysis, k-means clustering was applied to 19 baseline measures of drinking behavior, psychopathology, and social functioning, similar to those used by Babor in the original typological derivation. A 2-factor solution described robustly 2 groups phenomenologically consistent with Type A/B classification. Subjects were subdivided into early- and late-onset alcoholics. Seventy-two percent of Type B subjects had early-onset alcoholism (EOA); 67% of Type A subjects had late-onset alcoholism (LOA). The A/B typology better discriminated 2 clusters based upon baseline severity of alcoholism. There was a significant effect (p < 0.05) for Type B alcoholics to respond to ondansetron (4 microg/kg); however, Type A alcoholics receiving ondansetron showed no beneficial effect. Early-onset vs. late-onset classification predicted ondansetron response substantially better than Type A/B classification, which did not add to the prediction of treatment outcome. Further analyses showed that ondansetron was effective in the 33% of Type A alcoholics with EOA but ineffective in the 28% of Type B alcoholics with LOA. Type A/B classification best discriminates alcoholic subtypes based upon baseline severity. Early- vs. late-onset classification is, however, a better predictor of response to ondansetron treatment because it might be more closely related to fundamental neurobiological processes associated with the underlying pathophysiology of alcoholism.

Leucocytapheresis for inflammatory bowel disease in the era of biologic therapy

(Table is included in full-text article.)The development of biologicals such as infliximab to intercept TNF-alpha validates the current perception that certain cytokines are major factors in the immunopathogenesis of inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease. Furthermore, major sources of inflammatory cytokines include activated peripheral granulocytes and monocytes (GM), which in patients with IBD are elevated with increased survival time and are found in vast numbers within the inflamed intestinal mucosa. Hence, elevated GM should be appropriate targets of therapy in IBD. Accordingly, in recent years technologies such as the Adacolumn have been developed for selective depletion of elevated GM by extracorporeal adsorption (GMA). Published data show that GMA in patients with steroid-dependent or steroid-refractory IBD is associated with striking efficacy and tapering or discontinuation of steroids, whereas in steroid-naïve patients GMA spared patients from steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse significantly suppressed relapse, thus sparing the patients from the morbidity associated with active IBD. First ulcerative colitis episode, steroid naivety and short disease duration seem to be good predictors of response to GMA and on the basis of our experience, GMA seems to have an excellent safety profile.

Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen

BackgroundEstrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30–40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings.ResultsWe developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29–3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response.ConclusionWe have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

Mucosal EGG, Performed Endoscopically, Predicts Response to Temporary and Permanent GES in Gastroparetic Patients

Introduction: Temporary Gastric Electrical Stimulation (tGES) alleviates the symptoms of gastroparesis (GP) and most patients who have tGES undergo permanent (pGES) device implantation. We previously reported on the use of tGES via PEG or endoscopy (GIE, 2005 61: 455-6) as well as endoscopic tGES in a large number of pts (GIE, 2006:63; 5, AB103.). We now report on the use of mucosal EGG as a predictor of response to temporary and permanent GES. Patients: Of 394 consecutive patients (74 m, 274 f, mean age 43 years) from our regional database, we examined 150 patients who underwent tGES followed by pGES, and who also had mucosal EGG performed at the time of tGES: with diagnosis: idiopathic (I, 88), diabetic (D, 40), post surgical (PS, 22). Methods: Temporary GES was performed as previously reported (above) and if successful, was followed by permanent GES. During follow-up (10 months to 5 ½ years), of patients responding to tGES, symptom outcome was correlated with pGES. Patients were assessed by symptom scores [nausea (N), vomiting (V), and total symptom (TSS)] and IDIOMS (a HRQOL measure) at baseline (b), after tGES (t) and at the latest (L) available follow-up. The ratio of frequency to amplitude ratio in tGES mucosal electrogastrograms (Rt) was assessed in all patients undergoing tGES. Using linear regression, with latest vomiting score as the dependent variable, we determined the independent variables that predicted this outcome. Results: In subset analysis by etiology, virtually all patients I (p < 0.0001) DM (p ≤ 0.0001), and PS (p ≤ 0.001) had very good responses in all assessed scores and IDIOMS to both tGES and pGES. Among all categories of GP, linear regression analysis identified a low Rt derived by the use of mEGG as the single best predictor of response to tGES and pGES. Other predictors of improvement in vomiting score after pGES: patient age, [Age ALL: t (p) -2.49 (0.01); I: t (p)-1.86 (0.06); D: t (p) -1.2 (0.23); PS: t (p) 0.28 (0.78)] and baseline vomiting score [Vb ALL: t (p) 3.5 (< 0.001); I: t (p) 3.23 (0.001); D: t (p) 1.79 (0.08); PS: t (p) 1.04 (0.31)]. In subset analysis, the above predictors were most significant for ID. Conclusions: Endoscopic mucosal EGG derived Rt, may be predictive of response to GES, especially improvement in vomiting, for certain GP patients. The lack of significance in D and PS groups may be due to a smaller sample size. Further trials of this diagnostic test can refine its exact role in the selection of GP patients for stimulation therapies. Tabled 1 INDEPENDENT ALL IDIOPATHIC DIABETIC POST-SURGICAL t-stat. (p)value t- (p) t- (p) t- (p) Rt 2.87 (< 0.005) 2.76 (0.007) -0.44 (0.66) 1.08 (0.3) Open table in a new tab

Thiopurine methyltransferase activity combined with 6-thioguanine metabolite levels predicts clinical response to thiopurines in patients with inflammatory bowel disease

Background/aims 6-Mercaptopurine and its prodrug azathioprine are effective for the treatment of inflammatory bowel disease. Thiopurine methyltransferase is important for the metabolism of thiopurines. However, there is controversy as to the clinical utility of measuring thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels. Our aim was to determine if thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide level monitoring would predict response to therapy with thiopurines in patients with inflammatory bowel disease. Methods Baseline thiopurine methyltransferase enzyme activity prior to initiation of therapy with either 6-mercaptopurine or azathioprine was determined in 39 patients with inflammatory bowel disease. The association between clinical response and thiopurine methyltransferase activity and 6-thioguanine nucleotide levels singly or in combination were analysed. Results Seventeen of 39 patients (44%) responded to 6-mercaptopurine or azathioprine therapy. Thiopurine methyltransferase enzyme activity below the mean of 30.5 U was significantly associated with clinical response. The thiopurine methyltransferase low phenotype was associated with response in 65% vs. 29% in individuals with thiopurine methyltransferase enzyme activity above 30.5 U ( p = 0.05). There was no correlation between thiopurine methyltransferase activity and 6-thioguanine nucleotide levels. The maximal 6-thioguanine nucleotide levels did not predict clinical response. When combining thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels, the combination of thiopurine methyltransferase low/6-thioguanine nucleotide high was associated with response in 7/7 (100%) vs. only 2/8 (25%) with the combination of thiopurine methyltransferase high/6-thioguanine nucleotide low ( p = 0.01). Conclusions Thiopurine methyltransferase activity inversely correlated with clinical response to thiopurine treatment in inflammatory bowel disease. Thiopurine methyltransferase enzyme activity below 30.5 U combined with a post-treatment 6-thioguanine nucleotide level >230 pmol/8 × 10 8 erythrocytes was the best predictor of response.

Practical and conceptual limitations of tissue Doppler imaging to predict reverse remodelling in cardiac resynchronisation therapy

Recent, conflicting results about the use of tissue Doppler imaging derived (TDI-) asynchrony indices to predict reverse remodelling after cardiac resynchronisation therapy (CRT) have raised questions about their physiological meaning and methodological limitations. In 41 patients, baseline TDI-derived septal to lateral delays of peak velocities (TDI-SL), standard deviation of peak velocities over 12 segments (Ts-SD), and peak 2D longitudinal strain (strain-SL) were compared with volumetric response (reduction in end-systolic volume of > or =15%) after at least 6 months of CRT. Timing of peak TDI velocities was compared to timing of 2DS velocities and strain-SL. Influence of sample position, transverse motion, and interobserver inconsistency of the chosen peak velocities was assessed. Diagnostic accuracy of TDI-based delays was compared to accuracy of visual and 2D strain-based assessment. After 7.0+/-3.2 months of CRT, 24 patients were classified as responders. TDI-SL and Ts-SD were similar between responders and nonresponders at baseline, did not predict response, and were unaffected by CRT. Visual asynchrony scoring and strain-SL were better predictors of response than TDI-SL and Ts-SD. TDI measurements were highly susceptible to sample location and transverse motion components and poorly correlated with the timing of longitudinal contraction. There was a considerably poor agreement between observers with regard to scoring of TDI-SL and Ts-SD. TDI-based measurements of asynchrony do not appear robust predictors of volume response to CRT.

Role of plant functional traits in determining vegetation composition of abandoned grazing land in north‐eastern Victoria, Australia

AbstractQuestion: In the Northern Hemisphere, species with dispersal limitations are typically absent from secondary forests. In Australia, little is known about dispersal mechanisms and other traits that drive species composition within post‐agricultural, secondary forest. We asked whether mode of seed dispersal, nutrient uptake strategy, fire response, and life form in extant vegetation differ according to land‐use history. We also asked whether functional traits of Australian species that confer tolerance to grazing and re‐colonisation potential differ from those in the Northern Hemisphere.Location: Delatite Peninsula, NE Victoria, Australia.Methods: The vegetation of primary and secondary forests was surveyed using a paired‐plot design. Eight traits were measured for all species recorded. ANOSIM tests and Non‐metric Multi‐dimensional Scaling were used to test differences in the abundance of plant attributes between land‐use types.Results: Land‐use history had a significant effect on vegetation composition. Specific leaf area (SLA) proved to be the best predictor of response to land‐use change. Primary forest species were typically myrmecochorous phanerophytes with low SLA. In the secondary forest, species were typically therophytes with epizoochorous dispersal and high SLA.Conclusions: The attributes of species in secondary forests provide tolerance to grazing suggesting that disturbance caused by past grazing activity determined the composition of these forests. Myrmecochores were rare in secondary forests, suggesting that species had failed to re‐colonise due to dispersal limitations. Functional traits that resulted in species loss through disturbance and prevented re‐colonisation were different to those in the Northern Hemisphere and were attributable to the sclerophyllous nature of the primary forest.

Treatment of Depressive Symptoms in Adult Survivors of Childhood Trauma

ABSTRACT This study examined differences in depression symptoms between four Personality Disorder (PD) groups in 123 adult survivors of abuse who completed a 6-week inpatient program for Post-traumatic Stress Disorder (PTSD). Data were collected at admission, discharge, 3-months, and 1-year post-treatment. Participants completed self-report measures at each time point. Based on Millon Clinical Multiaxial Inventory-II scores, participants were divided into four PD groups: avoidant, borderline, dependent, and histrionic. MANOVAs and ANOVAs were calculated to examine depression symptoms over time. Depression and hopelessness symptoms decreased post-treatment, and treatment gains were maintained at 1-year. Multiple regressions were calculated to determine which PD trait was the best predictor of response to treatment for depression. High dependent PD traits were the only significant predictor of lowered depression symptoms.

MAP4/OP18 mRNA expression predicts progression in patients treated with vinorelbine plus carbolpatin in advanced lung cancer patients in a Multicenter trial

14088 Background: Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. MAP4 and stahmin have been previously reported as potential markers of resistance to treatment based on microtubule-destabilizing agents. Methods: In this multicenter study, we have used quantitative PCR to analyse expression of MAP4, stathmin, beta-tubulin III, BRCA1 and ERCC1 in mRNA isolated from peripheral blood samples of 51 non-small-cell lung cancer patients treated with vinorelbine/carboplatin. Results: In a preliminary set, 29 patients with stage IIIB and IV were analyzed. Lower levels of MAP4/OP18 mRNA expression are statistically related with response to vinorelbine-based treatment (p=0,029). This significant relationship is maintained in a second analysis after third cycle of treatment (p=0,032). Higher levels of MAP4/op18 were associated with a lower TTP (p=0,05). Conclusions: Our preliminary results suggest that the ratio MAP4/OP18 may be a good predictor of response for patients with non-small-cell lung cancer treated with vinorelbine-based chemotherapy. No significant financial relationships to disclose.

Combining resistance and pharmacology for optimum patient care

Therapeutic drug monitoring is now incorporated into the treatment guidelines of many countries. In this review, we describe the use and limitations of therapeutic drug monitoring, and how added benefit might accrue from integrating therapeutic drug monitoring with resistance testing in the form of inhibitory quotients. Although the unselected use of therapeutic drug monitoring in current (ritonavir-boosted) protease inhibitor or nonnucleoside reverse transcriptase inhibitor-containing regimens has yet to be established, therapeutic drug monitoring is likely to be useful in selected groups of patients, such as children, pregnant women, patients with malabsorption, or in specific clinical scenarios, such as liver impairment, drug interactions, suspected toxicity, assessing adherence or treatment failure. One problem with therapeutic drug monitoring is that efficacy targets relate mainly to drug-sensitive virus. Inhibitory quotients may be a better predictor of response in treatment-experienced patients. In this review, we discuss the different derivations of inhibitory quotients. Inhibitory quotients have been shown to be predictive of virological response in heavily pretreated patients receiving lopinavir, amprenavir, saquinavir, atazanavir and tipranavir. Lack of standardization and consensus on which inhibitory quotient to use are major factors which limit their introduction into clinical practice.

Does cyclosporine achieve a real advantage for treatment of idiopathic nephrotic syndrome in children? A long-term efficacy and safety study

Cyclosporine (CsA) was found to be efficient in decreasing proteinuria in both steroid-dependent and steroid-resistant nephrotic patients. We aimed to explore the potential long-term benefits and hazards of CsA and their predictors among a large group of nephrotic patients. In this retrospective analysis, we included 197 pediatric patients with idiopathic nephrotic syndrome (INS) of whom 103 were steroid dependent and 94 steroid resistant. CsA induced complete remission in 132 (67%) and partial response in 13 (6.6%). Cyclosporine was received for a period of 22.16 +/- 12.21 months. Univariate analysis showed that the response to CsA was significantly better in steroid-dependent children, in minimal change disease (MCD), diffuse mesangial proliferative glomerulonephritis (DMP) and focal segmental glomerulosclerosis (FSGS) than in other pathological lesions and in those who had lower quantities of pretreatment proteinuria. Only the prior response to steroids and concomitant use of ketoconazole with CsA were valid predictors for better response to CsA with multivariate analysis. Discontinuation of the drug in 40 patients resulted in relapse in 26 patients while the remaining 14 patients maintained remission. Renal dysfunction developed in 18 patients of whom 12 recovered completely on drug discontinuation. Thirty-seven patients developed hypertension. Multivariate analysis showed that all side-effects were significantly more prevalent in CsA-resistant patients. CsA is effective and well tolerated in the long-term treatment of INS in children, however two thirds of cases showed relapse after CsA discontinuation.