Prediction Of Therapeutic Outcome Research Articles

Patient-specific modelling of whole heart anatomy, dynamics and haemodynamics from four-dimensional cardiac CT images

There is a growing need for patient-specific and holistic modelling of the heart to support comprehensive disease assessment and intervention planning as well as prediction of therapeutic outcomes. We propose a patient-specific model of the whole human heart, which integrates morphology, dynamics and haemodynamic parameters at the organ level. The modelled cardiac structures are robustly estimated from four-dimensional cardiac computed tomography (CT), including all four chambers and valves as well as the ascending aorta and pulmonary artery. The patient-specific geometry serves as an input to a three-dimensional Navier-Stokes solver that derives realistic haemodynamics, constrained by the local anatomy, along the entire heart cycle. We evaluated our framework with various heart pathologies and the results correlate with relevant literature reports.

Circulating Plasma MiR-141 Is a Novel Biomarker for Metastatic Colon Cancer and Predicts Poor Prognosis

BackgroundColorectal cancer (CRC) remains one of the major cancer types and cancer related death worldwide. Sensitive, non-invasive biomarkers that can facilitate disease detection, staging and prediction of therapeutic outcome are highly desirable to improve survival rate and help to determine optimized treatment for CRC. The small non-coding RNAs, microRNAs (miRNAs), have recently been identified as critical regulators for various diseases including cancer and may represent a novel class of cancer biomarkers. The purpose of this study was to identify and validate circulating microRNAs in human plasma for use as such biomarkers in colon cancer.Methodology/Principal FindingsBy using quantitative reverse transcription-polymerase chain reaction, we found that circulating miR-141 was significantly associated with stage IV colon cancer in a cohort of 102 plasma samples. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of candidate plasma microRNA markers. We observed that combination of miR-141 and carcinoembryonic antigen (CEA), a widely used marker for CRC, further improved the accuracy of detection. These findings were validated in an independent cohort of 156 plasma samples collected at Tianjin, China. Furthermore, our analysis showed that high levels of plasma miR-141 predicted poor survival in both cohorts and that miR-141 was an independent prognostic factor for advanced colon cancer.Conclusions/SignificanceWe propose that plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis and that high levels of miR-141 in plasma were associated with poor prognosis.

Effect of laparoscopic esophagomyotomy on chest pain associated with achalasia and prediction of therapeutic outcomes

The effect of myotomy for achalasia on chest pain has not been clarified. The current study aimed to investigate the therapeutic effect of laparoscopic myotomy on chest pain associated with achalasia and to identify prognostic factors for outcomes. Between March 2005 and September 2008, 95 patients were available for detailed interviews and for assessment of clearance by timed barium esophagogram (TBE) before and after surgery. Of the 95 patients, 47 (24 men; mean age, 42.9 ± 13.5 years) who experienced chest pain before surgery were studied. The subjects were asked in detail about dysphagia and chest pain before surgery and 6 months after surgery. The frequency and severity of the symptoms were graded on a scale of 0 to 4. In addition, the values obtained by multiplying the grade for frequency by the grades for severity of the two symptoms were defined as the dysphagia score and the chest pain score, respectively. The patients with chest pain scores of 0 after surgery were defined as group A and those with scores smaller than their preoperative scores as group B. The remaining patients with other scores were defined as group C. The background factors and clinical conditions of the three groups were compared. The mean chest pain score decreased from 5.0 ± 3.2 to 1.0 ± 1.6 (p < 0.001). The score after surgery was 0 for 27 patients and showed a decrease for 15 patients. Although the three groups did not differ in their characteristics, differences were noted in postoperative TBE factors (i.e., groups A and B had significantly shorter barium columns than group C at 1 and 5 min after surgery (p = 0.001). Laparoscopic myotomy had a therapeutic effect on chest pain associated with achalasia, and improvement in postoperative esophageal clearance may influence the therapeutic effect.

Genomics and pharmacogenomics of dementia.

Dementia is a major problem of health in developed countries, and a prototypical paradigm of chronic disability, high cost, and social-family burden. Approximately, 10-20% of direct costs in this kind of neuropathology are related to pharmacological treatment, with a moderate responder rate below 30% and questionable cost-effectiveness. Over 200 different genes have been associated with the pathogenesis of dementia. Studies on structural and functional genomics, transcriptomics, proteomics and metabolomics have revealed the paramount importance of these novel technologies for the understanding of pathogenic cascades and the prediction of therapeutic outcomes in dementia. About 10-30% of Western populations are defective in genes of the CYP superfamily. The most frequent CYP2D6 variants in the Iberian peninsula are the *1/*1 (57.84%), *1/*4 (22.78%), *1×N/*1 (6.10%), *4/*4 (2.56%), and *1/*3 (2.01%) genotypes, accounting for more than 80% of the population. The frequency of extensive (EMs), intermediate (IMs), poor (PMs), and ultra-rapid metabolizers (UMs) is about 59.51%, 29,78%, 4.46%, and 6.23%, respectively, in the general population, and 57.76, 31.05%, 5.27%, and 5.90%, respectively, in AD cases. The construction of a genetic map integrating the most prevalent CYP2D6+CYP2C19+CYP2C9 polymorphic variants in a trigenic cluster yields 82 different haplotype-like profiles, with *1*1-*1*1-*1*1 (25.70%), *1*1-*1*2-*1*2 (10.66%), *1*1-*1*1-*1*1 (10.45%), *1*4-*1*1-*1*1 (8.09%), *1*4-*1*2-*1*1 (4.91%), *1*4-*1*1-*1*2 (4.65%), and *1*1-*1*3-*1*3 (4.33%), as the most frequent genotypes. Only 26.51% of AD patients show a pure 3EM phenotype, 15.29% are 2EM1IM, 2.04% are pure 3IM, 0% are pure 3PM, and 0% are 1UM2PM. EMs and IMs are the best responders, and PMs and UMs are the worst responders to a combination therapy with cholinesterase inhibitors, neuroprotectants, and vasoactive substances. The pharmacogenetic response in AD appears to be dependent upon the networking activity of genes involved in drug metabolism and genes involved in AD pathogenesis (e.g., APOE). AD patients harboring the APOE-4/4 genotypes are the worst responders to conventional antidementia drugs. To achieve a mature discipline of pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (i) to educate physicians and the public on the use of genetic/genomic screening in daily clinical practice; (ii) to standardize genetic testing for major categories of drugs; (iii) to validate pharmacogenomic information according to drug category and pathology; (iv) to regulate ethical, social, and economic issues; and (v) to incorporate pharmacogenomic procedures both to drugs in development and drugs on the market in order to optimize therapeutics.

DNA methylation based biomarkers in non-invasive cancer screening.

DNA methylation plays a critical role in the regulation of gene expression, differentiation and in the development of cancer and other diseases. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as the most frequent mechanism for gene inactivation in cancers. Feasibility of using DNA methylation based biomarkers for early detection of cancer has been shown. Potential of using DNA methylation for prediction of therapeutic outcome and patient survival has also been shown. DNA originated from cancer cells has been routinely detected in clinical specimens (ex. Plasma/serum, sputum, urine etc.) from cancer patients. Presence of methylated DNA sequences in clinical specimens and potential of using them as biomarkers have been recognized. Novel methylation based biomarkers that can be used in clinical specimens, obtained non-invasively from cancer patients, offer significant practical advantages. More resources need to be committed to this area of biomarker research. Thus, we review recent findings on DNA methylation based cancer biomarkers with particular focus on these applicable to the clinical specimens obtained non-invasively from cancer patients.

Non Predictive Value of An Initial Tc-99m-MIBI Scintigraphy On the Prediction of Therapeutic Outcome in Non Hodgkin and Hodgkin Lymphoma: Preliminary Results of a Prospective Study in 81 Patients.

Abstract 4762 IntroductionTc-99m-MIBI, a radioactive tracer used in routine to explore myocardial perfusion, parathyroids or in oncology for high-grade glioma, has been described as a promising agent for the functional characterization of p-glyco-protein expression and the prediction of the therapeutic outcome in patients (pts) with Hodgkin (HL) and non-Hodgkin's lymphoma (NHL)( Liang LA, 2001; Kao CH 2002). As resistance to chemotherapy is the major cause of treatment failure in NHL, the goal of treatment is to avoid an incomplete response after first line chemotherapy. This prospective study was designed to investigate the relationship between uptake by Tc-99m-MIBI scintigraphy and response to treatment in aggressive and follicular NHL, and HL. Patients and MethodsStudy protocol was a monocentric prospective study conducted between 10/2005 and 11/2008. Inclusion criteria included untreated pts with a histological diagnosis of HL or high grade NHL or follicular (FL) and managed in a hematological regional care network: HEMATOLIM, aged 18 years and more, with an initial and final assessment by a CT scan and/or TEP scan and with an informed consent. Were excluded pregnant or lactating women, pts without social security coverage or with initial corticosteroids. During the initial assessment, a Tc-99m-MIBI was performed with an injection of 20 mCi of tracer before any therapeutics. Images were obtained 10 minutes after intra-venous injection of Tc-MIBI. The rate of complete response (CR) and incomplete response (IR) at the end of first line therapy was evaluated with and compared with MIBI uptake. ResultsThe study included 81pts, sex ratio 1.61, median age 55 years (18-84)with an histological diagnosis of HL 41.9% (n=34), FL 9.9% (n=8), and aggressive NHL 48.2% (n=39) including DLBCL 38.3% (n=31), T cell NHL 4.9% (n=4), NK cell NHL 2.5% (n=2) and MCL 2.5% (n=2). Stade Ann Arbor I 6.2% (n=5), II 43.2% (n=35), III 12.3% (n=10) and IV 38.3% (n=31). Performans status were 0 for 51.85% (n=42), 1 for 35.8% (n=29), 2 for 11.11% (n=9) and 3 for 1.24% (n=1). LDH rate were increased 28.4% (n=23), normal 69.1% (n=56) and missing 2.5% (n=2). PSS for HL was favorable 41.18% (n=14), intermediate 47.06 (n=16) and unfavorable 11.76% (n=4). FLIPI score for FL was favorable 25% (n=2), intermediate for 62.5% (n=5) and non favorable for 12.5% (n=1). IPIa score was 0 for 29.03% (n=9), 1 for 32.26% (n=10), 2 for 19.35% (n=6) and 3 for 19.35% (n=6). All patients received chemotherapy in first line. For unfavorable pts a consolidation therapy has been added by radiotherapy 27.16% (n=22), or autologous stem cell transplantation for 8.54% (n=7). For 81 pts, MIBI results had positive uptake (MIBI+) 77.8% (n=63) and no uptake (MIBI-) 22.2% (n=18). For 75/81 pts eligible for final evaluation (6 deaths due to toxicity (n=3) or to NHL (n=3)), MIBI results showed 76% (n=57) MIBI+ and 24% (n=18) MIBI-. At the end of first line therapy, 82% of MIBI+ (n= 48/57) at diagnosis were in CR and 83% of MIBI – (15/18) were also in CR. There was no significant difference between the rate of MIBI+ and MIBI- for pts in CR by histological type. The distribution of disease localization were : thoracic (T) 59.3% (n=48), thoraco-abdominal (TA) 24.7% (n=20), abdominal (A) 13.6% (n=11), cranial 1.2% (n=1) and knee 1.2% (n=1). According to the results of MIBI, 83% of pts with a T localization were MIBI+ (n=40) versus 17% MIBI- (n=8), 70% of pts with a TA localization were MIBI+ (n=14) versus 30% MIBI- (n=6) and 63% of patients with a A localization were MIBI+ (n=7) versus 37% MIBI- (n=4). OS at 3 years is 90% and 3 years PFS is 79% with no significantly difference according to the response to MIBI. Sensitivity of MIBI is 80.77%, specificity 27.59%, positive predictive value is 66.67% and negative predictive value 44.44%. ConclusionThis prospective study on 81 untreated pts with HL, and several varieties of aggressive NHL do not confirm the encouraging results previously reported by an asian study obtained on 25 pts considering Tc-99m as a useful predictive tool for chemoresistance.In our study, lack of MIBI uptake does not predict a decrease in the rate of complete response to treatment. Several explanations can be advanced: heterogeneous histology and prognostic score, small population. Disclosures:No relevant conflicts of interest to declare.

Psychotherapist self-disclosure and transparency in the Internet age.

Summary and Recommendations Self-disclosure is a broad term that includes psychotherapists’verbal and nonverbal, intentional and unintentional, avoidable andunavoidable disclosures about themselves and their lives. Themeaning of self-disclosure can commonly be understood onlywithin the context of psychotherapy, which includes client, setting,type of psychotherapy, and psychotherapist factors. Self-disclosures that are clinically appropriate in one context may notbe in another. Some treatment plans may call for extensive self-disclosure while others may call for minimal self-disclosure. In-tentional self-disclosures must be constructed to enhance the treat-mentplanandmustfirstandforemostbeconsiderateoftheclient’swelfare.Clinicians must ensure that the self-disclosures are not done tofulfill their needs but rather those of the clients. Clinically drivenself-disclosure that is done for the welfare of the client can be verybeneficial for treatment and can enhance therapeutic alliance,the best predictor of therapeutic outcome. Any form of extensiveself-disclosure, whether intentional or unintentional, shouldbe documented and its clinical meaning should be discussed in theclinical records.Our modern “bare it all” culture and the fact that many mentalhealth clients view themselves as informed consumers rather than“patients” have created an expectation of caregivers’ transparency.Digital technologies have significantly increased psychotherapisttransparency and have drastically changed the playing field. Cli-nicians must be aware that all their online postings, blogs, or chatsmay be viewed by their clients and will stay online, in some form,forever. They should search themselves online periodically bysimply putting their names, in different combinations (i.e., Dr.Smith, Smith, PhD, or Jane Smith), into a Google search. Anothereasy way to keep track of one’s online presence is by signing upfor “Google Alerts” (at http://www.google.com/alerts?hl en) inorder to get instant alerts when one’s name is mentioned in a newposting. When clients intrude into clinicians’ personal lives, clini-cians should consider the clinical, ethical, and legal implicationsand, if necessary, consult with their professional association, ex-perts in the field, and a knowledgeable attorney, if necessary.Removing inaccurate, negative or slanderous material from theInternet can be very challenging and may require professional orlegal assistance.The effect of the Internet on self-disclosure and clinical practicehas yet to be fully understood and thoroughly studied. The threeinvited expert commentaries to follow address these and relatedchallenges, issues, and dilemmas that psychologists face regardingself-disclosure, in general, and specifically in the Internet age.

Predictors of therapeutic outcome and process

This article presents an intensive study of the outcome and process of the psychotherapeutic treatments conducted at the Blanquerna Psychotherapy Service in Barcelona. It analyzes in detail the relation between outcome (improvement) and process (therapeutic alliance). Specifically, it discusses (a) the therapeutic process in terms of the relation between therapeutic alliance and psychotherapy outcome and (b) the effects of the temporary weakening of the therapeutic alliance and temporary symptomatic relapse on therapeutic outcome and process. Two hundred thirty-nine clients were included in the study, and the assessment instruments were the CORE Outcome Measure and the short version of the Working Alliance Inventory. In addition to good outcome of psychotherapy and maintenance of therapeutic change after treatment, the results also demonstrated the significance of different aspects of the therapeutic alliance as predictors of the therapeutic outcome and process.

Ecto‐calreticulin in immunogenic chemotherapy

The conventional treatment of cancer relies upon radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Nonetheless, there are circumstances in which conventional anti-cancer therapy can induce a modality of cellular demise that elicits innate and cognate immune responses, which in turn mediate part of the anti-tumor effect. Although different chemotherapeutic agents may kill tumor cells through an apparently homogeneous apoptotic pathway, they differ in their capacity to stimulate immunogenic cell death. We discovered that the pre-apoptotic translocation of intracellular calreticulin (endo-CRT) to the plasma membrane surface (ecto-CRT) is critical for the recognition and engulfment of dying tumor cells by dendritic cells. Thus, anthracyclines and gamma-irradiation that induce ecto-CRT cause immunogenic cell death, while other pro-apoptotic agents (such as mitomycin C and etoposide) induce neither ecto-CRT nor immunogenic cell death. Depletion of CRT abolishes the immunogenicity of cell death elicited by anthracyclines, while exogenous supply of CRT or enforcement of CRT exposure by pharmacological agents that favor CRT translocation can enhance the immunogenicity of cell death. For optimal anti-tumor vaccination and immunogenic chemotherapy, the same cells have to expose ecto-CRT and to succumb to apoptosis; if these events affect different cells, no anti-tumor immune response is elicited. These results may have far reaching implications for tumor immunology because (i) ecto-CRT exposure by tumor cells allows for the prediction of therapeutic outcome and because (ii) the re-establishment of ecto-CRT may ameliorate the efficacy of chemotherapy.

Androgen receptor (AR) level in the prostatectomy specimen predicts time to disease progression post androgen suppression therapy

5065 Background: The androgen receptor (AR) plays an important role in the initiation and growth of prostate cancer and its subsequent response to hormone therapy. Previous analyses, including our own, have determined that elevated AR protein in the prostatectomy specimen is associated with progression of disease. We hypothesized that AR levels may also be predictive of response to androgen deprivation therapy (ADT) by evaluating time to castrate rise in PSA in patients treated with ADT at the time of a biochemical recurrence. By utilizing quantitative immunofluorescence (IF) and spectral imaging we evaluated AR content as an independent predictor of therapeutic outcome. Methods: 63 of 881 patients treated by radical prostatectomy had received ADT for a biochemical rise in PSA and or clinical progression of their disease. 32 of 63 patients had progressed post-ADT with a castrate rise in PSA. Tissue microarrays with triplicate patient cores were stained with a multiplex immunofluorescent assay (IF) which contained the nuclear marker DAPI, along with the following antibodies: Androgen Receptor (AR), Racemase (AMACR), CK18, HMWK and p63. IF images were acquired with spectral un-mixing employed to develop antibody-cell-specific gray scale images. Utilizing image analysis algorithms, quantitative features including intensity and area for selected antigens was generated. Results: Eleven IF antigen features were evaluated after feature selection and filtering using the concordance index with respect to outcome. A total of 5 features were statistically significant for predicting time to progression post therapy of which 2 features (AR intensity within AMACR (+) and (-) epithelial cells; p=0.0003 and p=0.0021, respectively) demonstrated that elevated levels of AR were associated with a shortened time to castrate rise in PSA post ADT. Clinical features alone were not found to be statistically significant with respect to predicting outcome. Conclusions: AR levels in the prostatectomy sample appears to be a useful indicator for determining therapeutic ADT response and potentially guiding future treatment decision and patient monitoring. No significant financial relationships to disclose.

Biomarkers for Diagnosis and Prediction of Therapeutic Outcome

Biomarkers for Diagnosis and Prediction of Therapeutic Outcome

Pharmacodynamics of PEG-IFN α differentiate HIV/HCV coinfected sustained virological responders from nonresponders

Pegylated interferon (PEG-IFN) has become standard therapy for hepatitis C virus (HCV) infection. We evaluated whether PEG-IFN pharmacodynamics and pharmacokinetics account for differences in treatment outcome and whether these parameters might be predictors of therapeutic outcome. Twenty-four IFN-naïve, HCV/human immunodeficiency virus-coinfected patients received PEG-IFN alpha-2b (1.5 microg/kg) once weekly plus daily ribavirin (1000 or 1200 mg) for up to 48 weeks. HCV RNA and PEG-IFN alpha concentrations were obtained from samples collected frequently after the first 3 PEG-IFN doses. We modeled HCV kinetics incorporating pharmacokinetic and pharmacodynamic parameters. Although PEG-IFN concentrations and pharmacokinetic parameters were similar in sustained virological responders (SVRs) and nonresponders (NRs), the PEG-IFN alpha-2b concentration that decreases HCV production by 50% (EC50) was lower in SVRs compared with NRs (0.04 vs. 0.45 microg/L [P = .014]). Additionally, the median therapeutic quotient (i.e., the ratio between average PEG-IFN concentration and EC50 [C/EC50]), and the PEG-IFN concentration at day 7 divided by EC50 (C(7)/EC50) were significantly increased in SVRs compared with NRs after the first (10.1 vs. 1.0 [P = .012], 2.8 vs. 0.3 [P = .007], respectively) and second (14.0 vs. 1.1 [P = .016], 5.4 vs. 0.4 [P = .02], respectively) PEG-IFN doses. All 3 parameters may be used to identify NRs. In conclusion, PEG-IFN concentrations and pharmacokinetic parameters do not differ between SVRs and NRs. In contrast, pharmacodynamic measurements-namely EC50, the therapeutic quotient, and C(7)/EC50--are different in coinfected SVRs and NRs. These parameters might be useful predictors of treatment outcome during the first month of therapy.

1H NMR spectroscopy for the prediction of therapeutic outcome in patients with fulminant hepatic failure

A high-resolution (1)H NMR study of serum and urine of fulminant hepatic failure patients (n = 22) [surviving (n = 12) and non-surviving (n = 10)] is reported. Glutamine in serum and urine glutamine:creatinine ratio were higher in non-surviving patients compared with surviving patients [serum glutamine, 3.08 (1.68-7.11) vs 0.56 (0.34-0.99) mM, median and range; p = 0.0001 and urine glutamine:creatinine ratio, 1.72 (0.24-7.76) vs 0.39 (0.1-0.84), p = 0.1], and urine urea:creatinine ratio was higher in surviving patients compared with non-surviving patients [10.83 (0.2-22.6) vs 2.09 (0.96-4.0), p = 0.002]. On the other hand, no significant differences were found in the conventionally employed clinical parameters such as serum alanylaminotransferase, aspartylaminotransferase and bilirubin except prothrombin time (p = 0.02). The difference in serum glutamine and urine urea was significant in the two categories of patients and distinctly different values of serum glutamine for both the categories of patients correctly predicted the outcome. These results promise immense potential for NMR spectroscopy in rapidly deciding on the need for advanced therapeutic intervention such as artificial liver support or emergency liver transplantation in FHF.

Arrayed Primer Extension Resequencing of Mutations in the TP53 Tumor Suppressor Gene: Comparison with Denaturing HPLC and Direct Sequencing

Mutations of TP53 (17p13.1; OMIM 191170; PubMed accession number X54156) are common in cancers and are typically missense within exons 4–9, impairing the capacity of p53 to transactivate genes involved in cell cycle arrest, apoptosis, and DNA repair (1). Functionally, mutations may differ according to their nature and position, as well as to the presence of a common polymorphism at codon 72 (arginine or a proline) in the mutant allele (2). Knowing TP53 mutation status has potential applications for cancer prognosis (3)(4) and early diagnosis (5), identification of mutagen “fingerprints” (1)(6), and prediction of therapeutic outcomes (7)(8). To achieve this purpose, sensitive, fast, and cost-effective methods are needed to assess the whole coding sequence plus exon/intron boundaries. Current approaches are based on mutation prescreening with single strand conformational polymorphism analysis, temporal temperature gradient electrophoresis, or denaturing HPLC (DHPLC) combined with direct sequencing of relevant PCR fragments [reviewed in Ref. (9)]. These methods are labor-intensive, difficult to standardize, and in some cases, of limited sensitivity. In recent years, 2 microarray methods for resequencing TP53 have been described: the Affymetrix p53 GeneChip array, described elsewhere (10)(11), and the Arrayed Primer Extension (APEX), based on incorporation of 4 dye terminators into oligonucleotide primers that each identify a base in the target sequence (12). In 2002, we described an APEX array for resequencing TP53 exons 2–9, which contain 95% of known mutations in TP53 (13). Here we compare the sensitivity and detection limits of APEX with a standard method, DHPLC/direct sequencing, and discuss the potential of APEX for application to cancer diagnostic or prognostic purposes. Specimens in the comparison set included 6 cell lines with mutations in different TP53 exons (see Table 1 of the Data Supplement that accompanies the online version of this Technical …

Assessing the functional nature of binge eating in the eating disorders

This study explored the functional nature of binge eating through the development of a new self-report instrument called the Binge Eating Adjective Checklist. Participants were 405 adult females who presented to a specialized eating disorders clinic. A subset of participants with bulimia nervosa also completed additional psychometrics and treatment. Those participants who reported greater reductions in negative affective and somatic states during a binge episode were also more distressed on measures of perfectionism, self-esteem, ineffectiveness, and interceptive awareness. They were also less likely to achieve abstinence from bingeing and vomiting over the course of treatment. Thus, the instrument appears to offer a methodology for studying the phenomenology of binge eating and the prediction of therapeutic outcome in bulimia nervosa.

Optimization of adenoviral vectors to direct highly amplified prostate-specific expression for imaging and gene therapy

Gene expression-based imaging coupled to gene therapy will permit the prediction of therapeutic outcome. A significant challenge for successful gene therapy is to achieve a high-level of specific gene expression; however, tissue-specific promoters are weak. We postulate that if the weak activity of tissue-specific promoters can be amplified to the levels of strong viral promoters, which have been successful in preclinical scenarios, while retaining specificity, the therapeutic index of gene therapy can be greatly augmented. With this in mind, we developed a two-step transcriptional activation (TSTA) system. In this two-tiered system, a modified prostate-specific antigen promoter was employed to drive a potent synthetic transcriptional activator, GAL4-VP2. This, in turn, activated the expression of a GAL4-dependent reporter or therapeutic gene. Here we demonstrate that recombinant adenoviral vectors (Ads) in which we have incorporated prostate-targeted TSTA expression cassettes retain cell specificity and androgen responsiveness in cell culture and in animal models, as measured by noninvasive optical bioluminescence imaging. We investigated the mechanism of TSTA in different adenoviral configurations. In one configuration, both the activator and the reporter components are inserted into a single Ad (AdTSTA-FL). The activity of AdTSTA-FL exceeds that of a cytomegalovirus promoter-driven vector (AdCMV-FL), while maintaining tissue specificity. When the activator and reporter components are placed in two separate Ads, androgen induction is more robust than for the single AdTSTA-FL. Based on these findings, we hope to refine the TSTA Ads further to improve the efficacy and safety of prostate cancer gene therapy.

Double-Phase Tc-99m MIBI Scintigraphy as a Therapeutic Predictor in Patients with Non-Hodgkin’s Lymphoma

Tc-99m MIBI is a promising agent for the functional characterization of P-glycoprotein expression and the prediction of therapeutic outcome in human tumors. The purpose of this study was to determine whether tumor clearance of Tc-99m MIBI may have a predictive value in the clinical outcome in patients with non-Hodgkin's lymphoma. Seventeen patients with histologically proved non-Hodgkin's lymphoma underwent Tc-99m MIBI scintigraphy before starting chemotherapy. Early and late images were obtained after the injection of 740 MBq (20 mCi) Tc-99m MIBI. Tumor-to-normal soft tissue ratios were measured on early and late images, and the percentage retention (%R) was calculated. These findings were correlated with other prognostic factors. Of all 40 tumor lesions, 22 (55%) showed Tc-99m MIBI tumor uptake, whereas the other 18 (45%) lesions had no uptake. According to the location, the diagnostic accuracy of Tc-99m MIBI scans was 66.7% (12 of 18) for lesions of the head and neck, 66.7% (8 of 12) for those of the chest, and 20% (2 of 10) for those of subdiaphragmatic regions (P = 0.037). The mean %R of complete responders was 91.8 +/- 14.8% and for partial responders or nonresponders it was 65.4 +/- 17.7% (P = 0.014). The %R of Tc-99m MIBI showed a significant negative correlation with the serum lactate dehydrogenase level (r = -0.757), the score of the international prognostic index (r = -0.643), and the Ann Arbor stage (r = -0.733). The slow tumor clearance of Tc-99m MIBI can predict a good response to chemotherapy in patients with non-Hodgkin's lymphoma and differentiate responding and nonresponding tumors early in the course of chemotherapy.

Scintigraphic prediction of therapeutic outcomes of splenectomy in patients with thrombocytopenia.

In patients with thrombocytopenia, platelet scintigraphy has been used to locate the site of platelet sequestration and destruction and to determine whether splenectomy will be of benefit. However, its efficacy in predicting the outcome of splenectomy is controversial. We assessed the feasibility of platelet scintigraphy in this regard. Platelet scintigraphy was performed in five patients (2 women, 3 men, mean age 48 years) before splenectomy. Four patients were diagnosed with idiopathic thrombocytopenic purpura and one with hypersplenism due to portal hypertension caused by intrahepatic chemotherapy against metastatic liver tumors of rectal cancer. Platelets labeled with 37 MBq of In-111 oxine or 1110 MBq of Tc-99m HMPAO were intravenously injected. Anterior images were obtained with a gamma camera 3-5 and 23-29 hours post-injection in five patients. Additional images were obtained 48 hours post-injection in three patients. For the analysis, a spleen/liver ratio (S/L ratio) was calculated using mean counts in regions of interest defined on the spleen and the liver. Serum platelet counts were measured before and after the operation; in three patients, splenectomy effectively resolved the thrombocytopenia (Group A), while it was ineffective in two patients (Group B). The S/L ratios were apparently higher in Group A than in Group B; in Group A, the ratios were 6.05, 6.97 and 3.16 at 3-5 hours, 12.67, 7.48 and 3.46 at 23-29 hours and 17.66 and 8.12 at 48 hours, whereas, in Group B, they were 0.67 and 0.66 at 3-5 hours, 0.52 and 0.54 at 24 hours, and 0.42 at 48 hours. The results of this study indicate that platelet scintigraphy is of value in predicting the therapeutic efficacy of splenectomy in patients with thrombocytopenia.

Antibody-based diagnostic for 'refractory' periodontitis.

About 10-15% of US adults are 'refractory' to therapy for chronic periodontitis. Recently, studies suggest that these patients have elevated lysine decarboxylase activity in the sulcular microbiota. The aim of this study was to determine whether an elevated IgG antibody response to lysine decarboxylase, alone or with antibody to other bacterial antigens and baseline clinical measurements, would predict 'refractory' patients with high accuracy. Chronic periodontitis patients were treated using scaling and root planing (SRP) followed by maintenance SRP and 3-monthly re-examinations. If there was a loss of mean full mouth attachment or more than three sites appeared with > 2.5 mm new loss within a year, the subjects were re-treated (modified Widman flap surgery and systemically administered tetracycline). If attachment loss as above recurred, the subjects were 'refractory'. Baseline clinical measurements and specific antibody responses were used in a logistic regression model to predict 'refractory' subjects. Antibody to a peptide portion of lysine decarboxylase (HKL-Ab) and baseline bleeding on probing (BOP) prevalence measurements predicted attachment loss 3 months after initial therapy [pIAL = loss (0) or gain (1)]. IgG antibody contents to a purified antigen from Actinomyces spp. (A-Ab) and streptococcal d-alanyl glycerol lipoteichoic acid (S-Ab) were related in 'refractory' patients (R2 = 0.37, p < 0.01). From the regression equation, the relationship between the antibodies was defined as linear (pLA/S-Ab = 0) or non-linear pLA/S-Ab = 1). Using pLA/S-Ab, pIAL and age, a logistic regression equation was derived from 48 of the patients. Of 59 subjects, 37 had 2-4 mm attachment loss and were assigned as 'refractory' or successfully treated with 86% accuracy. HKL-Ab facilitated an accurate prediction of therapeutic outcome in subjects with moderate periodontitis.

Magnetic resonance prediction of outcome after thrombolytic treatment

Treatment of clinical stroke with recombinant tissue plasminogen activator (rt-PA) carries the risk of hemorrhagic complications. Hence, predictors of therapeutic outcome with respect to (a) reperfusion and (b) tissue recovery would be very useful to identify potentially salvageable brain tissue. Magnetic resonance (MR) parameters, especially the apparent diffusion coefficient of water (ADC), perfusion-weighted imaging (PWI) and T2 relaxometry are thought to provide this information. We evaluated the prognostic implications of ADC, PWI and T2 relaxometry immediately before initiation of thrombolytic treatment in a model of clot embolism in rats. Animals (n = 14) were treated with intraarterial rt-PA (10 mg/kg) at 90 min after embolism. MR imaging was repeatedly performed at 4.7 T before and up to 5.5 h after embolism. ADC was calculated from diffusion-weighted images (b-values: 30, 765, 1500 s/mm2), arterial spin tagging was used for PWI, and quantitative T2 relaxometry was performed with a Carr-Purcell-Meiboom-Gill (CPMG) sequence. A reperfusion index was calculated to assess the quality of thrombolytic recanalization. The decline of ADC at the end of the experiment to below 80% of control was defined as unfavorable outcome. The probability of tissue injury at the end of the experiments increased with the severity of ADC changes before the initiation of treatment (probability of unfavorable outcome: 21%, 44%, 65% for ADC values of 80–90%, 70–80% and <70% of control, respectively). Pretreatment PWI or T2 relaxometry also correlated with outcome but—alone or in combination with pretreatment ADC maps—did not improve injury prediction over that obtained by ADC alone. Outcome was influenced positively by successful reperfusion the quality of which, however, could not be predicted by pre-treatment MR characteristics. The data demonstrate that ADC mapping performed before the initiation of thrombolytic treatment provides reliable risk assessment of impeding brain injury but due to uncertainties of postischemic reperfusion does not allow precise outcome prediction in individual experiments.