Better Classification Of Patients Research Articles

MRI-guided dynamic risk assessment in cervical cancer based on tumor hypoxia at diagnosis and volume response at brachytherapy

Background and purposeImprovements in treatment outcome for patients with locally advanced cervical cancer (LACC) require a better classification of patients according to their risk of recurrence. We investigated whether an imaging-based approach, combining pretreatment hypoxia and tumor response during therapy, could improve risk classification. Material and methodsNinety-three LACC patients with T2-weigthed (T2W)-, dynamic contrast enhanced (DCE)- and diffusion weighted (DW)-magnetic resonance (MR) images acquired before treatment, and T2W- and, for 64 patients, DW-MR images, acquired at brachytherapy, were collected. Pretreatment hypoxic fraction (HFpre) was determined from DCE- and DW-MR images using the consumption and supply-based hypoxia (CSH)-imaging method. Volume regression at brachytherapy was assessed from T2W-MR images and combined with HFpre. In 17 patients with adequate DW-MR images at brachytherapy, the apparent diffusion coefficient (ADC), reflecting tumor cell density, was calculated. Change in ADC during therapy was combined with volume regression yielding functional regression as explorative response measure. Endpoint was disease free survival (DFS). ResultsHFpre was the strongest predictor of DFS, but a significant correlation with outcome was found also for volume regression. The combination of HFpre and volume regression showed a stronger association with DFS than HFpre alone. Patients with disease recurrence were selected to either the intermediate- or high-risk group with a 100 % accuracy. Functional regression showed a stronger correlation to HFpre than volume regression. ConclusionThe combination of pretreatment hypoxia and volume regression at brachytherapy improved patient risk classification. Integration of ADC with volume regression showed promise as a new tumor response parameter.

Abstract 3705: Development and analytical validation of a novel assay for HER2 assessment on circulating tumor cells using Parsortix® isolation and BioView imaging technologies

Abstract Background. HER2 testing in tissue biopsies is extensively performed in breast cancer (BC) patients. However, tissue biopsy is invasive and repeated examination is impractical. Additionally, lack of concordance between primary tumor and metastatic sites are often observed. Liquid biopsy, on the other hand, enables less invasive and recurrent sample collection for ongoing monitoring. In this study, we developed an end-to-end Research Use Only assay for concomitant evaluation of HER2 gene amplification and protein overexpression in circulating tumor cells (CTCs). Methods. Blood was drawn from healthy volunteers into Streck Cell-Free DNA tubes, spiked with SKBR3 (HER2+) and Hs 578T (HER2-) breast cancer cells and processed on ANGLE's Parsortix® PC1 System, a microfluidic device that captures CTCs from metastatic breast cancer patients’ blood based on their size and deformability, without relying on specific markers. Captured cells were harvested and spun onto positively charged slides and stained with the Portrait HER2 immunofluorescence (IF) panel, consisting of a nuclear dye, epithelial and mesenchymal markers, leukocytes’ markers, and an antibody targeting HER2. Slides were then de-stained and subjected to HER2 FISH using a commercially available kit. All slides were imaged twice using BioView Allegro Plus, a platform equipped with artificial intelligence for automated imaging, CTC candidate identification and reporting. First, an automated scan after IF was performed to identify CTCs based on marker expression and morphology profiles. Second, an automated relocation of the CTCs based on IF results and reimaging using higher magnification to ensure precise analysis of the FISH signals in single cells. The workflow is being implemented in a cohort of BC patients. Results. Following IF, HER2 protein expression in SKBR3 cells was significantly higher (p<0.0001) than that of HER2-negative cells, with 100% analytical specificity and sensitivity. Following FISH, 100% of the cells were de-stained and presented sharp HER2/CEP17 foci, with 96% of the SKBR3 cells and only 4% of the Hs 578T cells displaying HER2 amplification. Additionally, in a small cohort of metastatic BC patients’, 100% of the identified CTCs are retained and evaluable from IF to FISH. Conclusions. An assay integrating HER2 identification by IF and FISH to characterize CTCs in metastatic BC patients was successfully developed. The assay enables the identification of both HER2 protein and gene copy information from each target cell with minimal cell loss, with the potential for minimally invasive patient monitoring during treatment and better classification of patients who may qualify and benefit from HER2-targeted therapies. An added value of the assay is the practicality of utilizing preserved blood samples, allowing streamline batch shipping of clinical samples. Citation Format: Mariacristina Ciccioli, Alex Young, Laila Vlietinck, Chassidy Johnson, Anne-Sophie Pailhes-Jimenez. Development and analytical validation of a novel assay for HER2 assessment on circulating tumor cells using Parsortix® isolation and BioView imaging technologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3705.

Cutoff Values of MASK-air Patient-Reported Outcome Measures

In clinical and epidemiological studies, cutoffs of patient-reported outcome measures can be used to classify patients into groups of statistical and clinical relevance. However, visual analog scale (VAS) cutoffs in MASK-air have not been tested. To calculate cutoffs for VAS global, nasal, ocular, and asthma symptoms. In a cross-sectional study design of all MASK-air participants, we compared (1) approaches based on the percentiles (tertiles or quartiles) of VAS distributions and (2) data-driven approaches based on clusters of data from 2 comparators (VAS work and VAS sleep). We then performed sensitivity analyses for individual countries and for VAS levels corresponding to full allergy control. Finally, we tested the different approaches using MASK-air real-world cross-sectional and longitudinal data to assess the most relevant cutoffs. We assessed 395,223 days from 23,201 MASK-air users with self-reported allergic rhinitis. The percentile-oriented approach resulted in lower cutoff values than the data-driven approach. We obtained consistent results in the data-driven approach. Following the latter, the proposed cutoff differentiating "controlled" and "partly-controlled" patients was similar to the cutoff value that had been arbitrarily used (20/100). However, a lower cutoff was obtained to differentiate between "partly-controlled" and "uncontrolled" patients (35 vs the arbitrarily-used value of 50/100). Using a data-driven approach, we were able to define cutoff values for MASK-air VASs on allergy and asthma symptoms. This may allow for a better classification of patients with rhinitis and asthma according to different levels of control, supporting improved disease management.

The evolving nature of asthma and contemporary management of this respiratory disorder

wheezing and increased airway responsiveness to a variety of environmental stimuli. The definition of asthma involves various phenotypes and endotypes.The immunopathogenesis of asthma involves many immune cell sand involves the airway epithelium as well as both innate and adaptive components of the immune system. Understanding the Immunology of asthma is essential in its treatment.Asthma is a rising significant global public health burden. The annual prevalence of severe asthma episodes is estimated from 1% to 21% for adults and over 20% for children aged 6–7 years. The prevalence of asthma varies widely around the world, ranging from 0.2% to 21.0% in adults and from 2.8% to 37.6% in 6- to 7-year-old children. The development of novel asthma phenotyping & endo typing plus better classification of patients using machine learning and big data have markedly improved asthma treatment outcomes in both children and Adults.Several research groups have developed cluster analyses of phenotypes and endo-types in severe asthma. These clusters support the importance of disease heterogeneity in asthma and suggest differences in pathophysiologic mechanisms that define these clusters.Biomarkers of asthma include Serum Immunoglobulin, Fractional excretion of nitric oxide and blood eosinophils amongst others. There are five food and drug administration approved biologicals for the treatment of severe asthma.

The evolving burden of asthma and contemporary advances in management: Implications for clinical practice in Southern Africa

Asthma is a rising significant global public health burden especially in the developing countries. The annual prevalence of severe asthma episodes is estimated from 1% to 21% for adults and over 20% for children aged 6–7 years. The prevalence of asthma varies widely around the world, ranging from 0.2% to 21.0% in adults and from 2.8% to 37.6% in 6- to 7-year-old children. The International Study of Asthma and Allergies in Children (ISAAC) reports a significant increase in the global prevalence of asthmatic episodes among children. t was estimated that more than 339 million people had Asthma globally in 2016. It is a common disease among children. The common disease asthma is probably not a single disease, but rather a complex of multiple, separate syndromes that overlap. Most asthma-related deaths occur in low- and lower-middle income countries. According to the World Health Organization (WHO) estimates, there were 417,918 deaths due to asthma at the global level and 24.8 million DALYS attributable to Asthma in in 2016. The WHO has estimated that the economic costs associated with asthma have exceeded those of TB and HIV/AIDS combined, and the Global Initiative for Asthma Program forecasted the number of asthma patients to grow globally to greater than 400 million by the year 2025. Since its first description by Hippocrates, asthma remains a treatable yet incurable disease. It is now clear that asthma is a complex syndrome with variable severity, natural history and response to treatment In Namibia a prevalence of Asthma of 11.2 % has been reported in adult populations. The increase in asthmatic episodes, morbidity and mortality among populations in Africa, Latin America and parts of Asia is a rising public health concern. The development of novel asthma phenotyping & endo typing plus better classification of patients using machine learning and big data have markedly improved asthma treatment outcomes in both children and Adults. Several research groups have developed cluster analyses of phenotypes in severe asthma. These clusters support the importance of disease heterogeneity in asthma and suggest differences in pathophysiologic mechanisms that define these clusters. Precision medicine is "an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.

The first composite score predicting Digital Ulcers in systemic sclerosis patients using Clinical data, Imaging and Patient history\u2014CIP-DUS

BackgroundDigital ulcers (DU) present a challenging complication in systemic sclerosis (SSc). The aim of this study was to combine clinical characteristics and imaging methods to a composite score for the prediction of DU in SSc patients.MethodsSeventy-nine SSc patients received clinical examination, their patient history was taken and nailfold capillaroscopy (NC), colour Doppler ultrasonography (CDUS) and fluorescence optical imaging (FOI) of the hands were performed at baseline. Newly developed DU over a period of approximately 12 months were registered. We used criteria with area under the curve (AUC) of at least 0.6 in regard to the development of these new DU to create the score (CIP-DUS, clinical features, imaging, patient history—digital ulcer score).ResultsTwenty-nine percent of all SSc patients developed new DU during follow-up (48.1% diffuse, 18.4% limited SSc). Based on the cross-validated (cv) AUC, a weight (cvAUC > 0.6 and ≤ 0.65: 1; cvAUC > 0.65 and ≤ 0.7: 2; cvAUC > 0.7: 3) was assigned to each selected parameter. The performance of the final CIP-DUS was assessed with and without the CDUS/FOI component. For the scleroderma patterns in NC, three points were appointed to late, two to active and one point to early capillaroscopy pattern according to Cutolo et al. The CIP-DUS including the CDUS and FOI parameters resulted in a good diagnostic performance (AUC after cross-validation: 0.83, 95%CI 0.74 to 0.92) and was well calibrated (chi-square = 12.3, p = 0.58). The cut-off associated with the maximum of sensitivity and specificity was estimated at ≥ 10 points resulting in a sensitivity of 100% and specificity of 74% for new DU during follow-up. Excluding CDUS and FOI parameters leads to a non-statistically significant lower performance (AUC after cross-validation: 0.81, 95%CI 0.72 to 0.91). However, including CDUS and FOI resulted in a better classification of patients in respect to the outcome new DU in follow-up due to significantly better reclassification performance (NRI = 62.1, p = 0.001) and discrimination improvement (IDI = 9.7, p = 0.01).ConclusionA new score was introduced with the aim to predict digital ulcers. If applied correctly and with the new imaging techniques proposed, all patients at risk of digital ulcers throughout 12 months could be identified.

Optimisation of children z-score calculation based on new statistical techniques.

BackgroundExpressing anthropometric parameters (height, weight, BMI) as z-score is a key principle in the clinical assessment of children and adolescents. The Centre for Disease Control and Prevention (CDC) growth charts and the CDC-LMS method for z-score calculation are widely used to assess growth and nutritional status, though they can be imprecise in some percentiles.ObjectiveTo improve the accuracy of z-score calculation by revising the statistical method using the original data used to develop current z-score calculators.DesignA Gaussian Process Regressions (GPR) was designed and internally validated. Z-scores for weight-for-age (WFA), height-for-age (HFA) and BMI-for-age (BMIFA) were compared with WHO and CDC-LMS methods in 1) standard z-score cut-off points, 2) simulated population of 3000 children and 3) real observations 212 children aged 2 to 18 yo.ResultsGPR yielded more accurate calculation of z-scores for standard cut-off points (p<<0.001) with respect to CDC-LMS and WHO approaches. WFA, HFA and BMIFA z-score calculations based on the 3 different methods using simulated and real patients, showed a large variation irrespective of gender and age. Z-scores around 0 +/- 1 showed larger variation than the values above and below +/- 2.ConclusionThe revised z-score calculation method was more accurate than CDC-LMS and WHO methods for standard cut-off points. On simulated and real data, GPR based calculation provides more accurate z-score determinations, and thus, a better classification of patients below and above cut-off points. Statisticians and clinicians should consider the potential benefits of updating their calculation method for an accurate z-score determination.

Abstract A30: Depicting clinically relevant molecular alterations in oropharynx squamous cell carcinoma samples treated with an organ preservation protocol

Abstract Introduction: Head and neck cancers are among the most common human malignancies in the world, with high rates of morbidity and mortality. These tumors are mostly caused by heavy tobacco smoking; however, high-risk human papillomavirus (HR-HPV) infection has been increasingly associated with tumors in the oropharynx. Oropharynx squamous cell carcinomas (OPSCC) associated with HR-HPV infection represent a distinct clinical and epidemiologic entity, with differences in clinical presentation and treatment outcome reflecting distinct genetic and biologic profiles. Initial treatment decisions are critical to improve patient survival; therefore, considering that multimodality therapy is often toxic, treatment choice should balance tolerability, function preservation, and global response to therapy. Molecular markers may be beneficial in a better classification of patients, thus aiding in a more consistent tailoring of patient treatment and follow-up. Objective: The aim of this study was to identify specific clinical and molecular profiles that classify subgroups of OPSCC patients according to their outcome. Materials and Methods: Thirty OPSCC samples from patients treated with a chemoradiation-based organ-preservation protocol were included in this study. P16 protein expression was used as a surrogate marker for HR-HPV. The methylation status of 5 genes was evaluated by quantitative methylation-specific PCR (qMSP), and next-generation sequencing of a 15-gene panel was performed using the Ion Torrent PGM platform. Results: The majority of patients (93.3%) were male, tobacco users (85.2%), presented with advanced disease (90%), and 36.7% were HR-HPV positive. Specific gene-promoter hypermethylation was observed in 32.1-50% of the OPSCC evaluated and, as expected, CCNA1 methylation was associated with HPV(+ve) cases (p=0.035). Eighteen patients (58.1%) had at least 1 gene mutated: 87.5% of HPV(-ve) and 57.1% of HPV(+ve) cases. Interestingly, 60% of smokers HPV(+ve) cases were wild-type for TP53 variants (p=0.003). The absence of deleterious variants in several genes (EZH2, FAT1, FBWX7, HRAS, IRF6, PIK3CA, and PTEN) was significantly associated with a complete response of the primary tumor site to the organ-preservation treatment protocol (p&amp;lt;0.004). Conclusions: Even though all samples analyzed were of the oropharynx, several differences regarding molecular and clinical characteristics were identified. An association between molecular markers and the profile of therapy response can be useful in decision-making of the initial treatment and improve patient survival. More cases are being evaluated in order to assess whether the differences identified are able to significantly classify these patients into molecular subgroups associated with different outcomes and help in more thorough patient management. Citation Format: Ana Carolina de Carvalho, Matias Eliseo Melendez, Cristovam Scapulatempo Neto, Gabriela Carvalho Fernandes, Lidia Maria Rebolho Batista Arantes, Bruna Pereira Sorroche, Gisele Caravina de Almeida, Rui Manuel Reis, Sandra Perdomo, André Lopes Carvalho. Depicting clinically relevant molecular alterations in oropharynx squamous cell carcinoma samples treated with an organ preservation protocol [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A30.

Comprehensive profiling and quantitation of oncogenic mutations in non small-cell lung carcinoma using single molecule amplification and re-sequencing technology.

Activating and resistance mutations in the tyrosine kinase domain of several oncogenes are frequently associated with non-small cell lung carcinoma (NSCLC). In this study we assessed the frequency, type and abundance of EGFR, KRAS, BRAF, TP53 and ALK mutations in tumour specimens from 184 patients with early and late stage disease using single molecule amplification and re-sequencing technology (SMART). Based on modelling of EGFR mutations, the detection sensitivity of the SMART assay was at least 0.1%. Benchmarking EGFR mutation detection against the gold standard ARMS-PCR assay, SMART assay had a sensitivity and specificity of 98.7% and 99.0%. Amongst the 184 samples, EGFR mutations were the most prevalent (59.9%), followed by KRAS (16.9%), TP53 (12.7%), EML4-ALK fusions (6.3%) and BRAF (4.2%) mutations. The abundance and types of mutations in tumour specimens were extremely heterogeneous, involving either monoclonal (51.6%) or polyclonal (12.6%) mutation events. At the clinical level, although the spectrum of tumour mutation(s) was unique to each patient, the overall patterns in early or advanced stage disease were relatively similar. Based on these findings, we propose that personalized profiling and quantitation of clinically significant oncogenic mutations will allow better classification of patients according to tumour characteristics and provide clinicians with important ancillary information for treatment decision-making.

Sleep disorders diagnosis by genetic assessment

Diagnosis of Sleep Disorders (SD) is frequently a difficult task. Environmental and genetic factors influence the clinical SD phenotype masking its correct identification. The definition of such factors will help the physicians to easily classify SD. Accordingly a better treatment for such disorders should be obtained. The objective of the present work is to identify, on a cohort of SD patients, the possible genetic factors involved. Four hundred and twenty-one SD patients were assessed at the Out Patient Sleep Clinic of Hospital Santo António/CH Porto – by means of clinical history, physical and neurological evaluation, night sleep polygraphic EEG-Video recording (EEG, EOG, EMG – chin and L Limbs; Respiratory effort; O 2 saturation; EKG; snoring). For Narcolepsy without (N) or with Cataplexy (NC) and for Hypersomnia (H) qualification/quantification a MSLT was performed on the day after night registration. Blood venous sample was taken after informed consent. Ethical approval was obtained for research studies. For the purpose of distinction between diverse Sleep Disorders HLA–DRB1 ∗ was genotyped using a PCR-Sequence Specific Primer (SSP) methodology. A control population (223 individuals) was matched to age, gender, ethnicity and geographical origin. Statistical analysis was performed and the phenotypic frequencies were evaluated by chi- square of 2 × 2 contingency tables. Odds Ratios and their respective 95% confidence interval were calculated. Values of p < 0.05 were considered as statistically significant. From the 421 SD patients studied 302 were classified as obstructive sleep apnea syndrome (OSAS); 64 as H; 37 NC and 16 N. Significant values ( p < 0.05) of HLA–DRB1 ∗ alelles were found to OSAS: HLA-DRB1 ∗ 09 (1% OSAS vs. 6% PC); NC: HLA-DRB1 ∗ 13 (14% NC vs. 30% PC) and 15 (76% NC vs. 21% PC); N: HLA-DRB1 ∗ 15 (44% N vs. 21% PC); H: HLA–DRB1 ∗ 03 (33% H vs. 15% PC). Our studies emphasize that the HLA–DRB1 ∗ genetic characterization of SD patients may identify different profiles. The results point out to the identification of susceptibility alleles, HLA–DRB1 ∗ 15 for N and NC and HLA–DRB1 ∗ 03 for Hypersomnia. The frequencies of HLA–DRB1 ∗ 09 in OSAS and of HLA–DRB1 ∗ 13 in NC indicate that these alleles may act as protective factors. These findings point to the value of immunogenetic approach to a better understanding of the pathophysiology of SD and to a better classification of patients with sleep disorders. ∗ Studies on SAOS were granted by a CESPU Project .

P-168 Familial myelodysplastic syndrome/acute leukemia in adult setting – Experience from a single Brazilian center

Introduction: Myelodysplastic syndromes (MDS) are a group of heterogenous clonal stem cell disorders characterized by inefficient haematopoiesis with one or more cytopenias and increased risk of transformation to acute leukemia. Purpose: The current diagnosis includes peripheral blood morphology, bone marrow biopsy and cytogenetic exam. Clonal cytogenetic abnormalities are described in 40-60% of cases. In 1997, the established System of International Prognostic Score was based on the number of cytopenias on the peripheral blood, precentage bone marrow blasts and karyotype abnomalities. In this system are described a limited number of cytogenetic abnormalities and the importance of their forecast is underestimated. This score classify patients into four risk groups, allow overall survival and estimate the risk of progression to acute leukemia. Materials and Methods: In September 2012 the Revised International Prognostic Scoring System (R-IPSS) was developed in the framework of a project of the International Working Group for Prognosis in MDS (IWG-PM) peak. For scoring according to IPSS-R, it was taken into account: severity of cytopenias (Hb level, the number of platelets, the absolute number of neutrophils), the percentage of bone marrow blasts and cytogenetic exam. It was found that this system prognostic allows a better classification of patients with MDS into risk groups. We analyzed 25 patients diagnosed with MDS, according to theWHO classification 2001, with low risk and intermediate-1 during the period 2008-2012. These patients have been hospitalized in three centers of Hematology Departments from Romania. Results: The lot of patients was evaluated according to R-IPSS (2012) and it was found that the new system allows a better prognosis estimation and more accurate patient risk group classification. Conclusions: Although according to IPSS (1997), all patients included in this studywere low risk (0-1) but applying the new scoring system has allowed a better classification of patients, six of them were with intermediate and high risk (3,5-6).

Are there financial savings associated with supplementing current diagnostic practice for preeclampsia with a novel test? Learnings from a modeling analysis from a German payer perspective

Objective: To quantify the financial impact of adding a novel serum test to the current diagnostic toolkit for preeclampsia (PE) detection in Germany. Methods: A decision-analytic model was created to quantify the economic impact of adding a recently developed novel diagnostic test for PE (Roche Diagnostics, Rotkreuz, Switzerland) to current diagnostic practice in Germany. The model simulated a cohort of 1000 pregnant patients receiving obstetric care and quantified the budget impact of adding the novel test to current German PE detection and management practices. Results: The model estimates that the costs associated with managing a typical pregnancy in Germany are €941 when the novel test is used versus €1579 with standard practice. This represents savings of €637 per pregnant woman, even when the test is used as a supplementary diagnostic tool. The savings are attributed to the novel test’s ability to better classify patients relative to current practice, specifically, its ability to reduce false negatives by 67% and false positives by 71%. Conclusion: The novel PE test has the potential to provide substantial cost savings to German healthcare payers, even when used as an addition to standard practice. Better classification of patients at risk for developing PE and declassification of those that are not compared to current practice leads to economic savings for the healthcare system. Furthermore, by reducing the rates of false-positive and false-negative classification relative to current standard of care, the test helps better target healthcare spending and lowers overall costs associated with PE care.

Detection of Previously Unidentified Metastatic Disease as a Leading Cause of Screening Failure in a Phase III Trial of Zibotentan Versus Placebo in Patients with Nonmetastatic, Castration Resistant Prostate Cancer

Understanding the extent of disease in asymptomatic patients with castration resistant prostate cancer is important when making treatment decisions and designing clinical trials. The ENTHUSE M0 (ENdoTHelin A USE) trial (NCT00626548) was a large phase III study comparing the endothelin A receptor antagonist zibotentan with placebo in patients with nonmetastatic, castration resistant prostate cancer. The study was stopped prematurely after early efficacy review indicated that it was unlikely to meet its co-primary objectives of improved overall and progression-free survival vs placebo. Screening failed in an unexpectedly high number of patients. We investigated this screening failure rate to promote better classification of patients thought to have nonmetastatic castration resistant prostate cancer and inform the design of future clinical trials in this setting. The number of patients enrolled in and subsequently excluded from study was analyzed by geographic region and by the specialty of the investigating clinician (oncology or urology) who enrolled the study patients. Of 2,577 patients enrolled in a total of 350 hospital based centers in 39 countries screening failed in 1,155 (45%). The most common reason for screening failure was the detection of metastatic disease in 32% of all screened patients and in 71% of those in whom screening failed. The leading reasons for failed screening did not differ between investigator specialties overall or by geographic region. The high frequency of asymptomatic metastasis in men thought to have nonmetastatic, castration resistant prostate cancer highlights the importance of periodic staging assessments for the condition. Optimal treatment modalities may differ for metastatic and nonmetastatic disease.

Incremental Value of High-Sensitivity Cardiac Troponin T for Risk Prediction in Patients with Suspected Acute Myocardial Infarction

High-sensitivity cardiac troponin assays have better analytical precision and sensitivity than earlier-generation assays when measuring cardiac troponin at low concentrations. We evaluated whether use of a high-sensitivity assay could further improve risk stratification compared with a standard cardiac troponin assay. We enrolled consecutive patients presenting with acute chest pain, 30% of whom were diagnosed with acute coronary syndrome. Blood samples were drawn at the time of presentation. We measured cardiac troponin T with a standard fourth-generation assay (cTnT) and a high-sensitivity assay (hs-cTnT) (both Roche Diagnostics) and followed the patients for 24 months. Of the 1159 patients, 76 died and 42 developed an acute myocardial infarction (AMI). Prognostic accuracy of hs-cTnT for death was significantly higher [area under ROC curve (AUC) 0.79, 95% CI 0.74-0.84] than that of cTnT (AUC 0.69, 95% CI 0.62-0.76; P < 0.001). After adjustment for Thrombolysis in Myocardial Infarction (TIMI) risk score (that included the cTnT assay result), hs-cTnT above the 99th percentile (0.014 μg/L) was associated with a hazard ratio for death of 2.60 (95% CI 1.42-4.74). Addition of hs-cTnT to the risk score improved the reclassification of patients (net reclassification improvement 0.91; 95% CI 0.67-1.14; P < 0.001). Subgroup analyses showed that this effect resulted from the better classification of patients without AMI at time of testing. hs-cTnT outperformed cTnT in the prediction of AMI during follow-up (P=0.02), but was not independently predictive for this endpoint. Concentrations of hs-cTnT >0.014 μg/L improve the prediction of death but not subsequent AMI in unselected patients presenting with acute chest pain.

What Makes a Good Predictor?

EACH YEAR, RESEARCHERS IDENTIFY THOUSANDS OF potential new “tools” for predicting patients’ medical futures. There is heightened interest for discovering, validating, and incorporating into clinical practice predictors that improve treatment choices and outcomes thereof. Thousands of articles report on potential predictors. A search of PubMed clinical queries under prognosis (specific strategy) yields 165 746 articles for cancer, 72 354 for cardiovascular disease, and even 3749 for rheumatoid arthritis. These run the gamut, including genetic tests, biomarkers, and an increasing variety of imaging modes, lengthening the list of candidate predictors. However, very few of these proposed predictors eventually change practice. Why? What makes a good predictor? A good predictor is one that has a favorable risk-benefit ratio, reasonable cost, acceptability, and convenience. As for any intervention in health care, proper evidence ideally requires randomized trials demonstrating that using the predictor improves decision making and subsequent clinical outcomes without inordinate adverse events. It also requires formal cost-effectiveness analyses, integrating benefits, risks, and cost. However, hardly any of the predictors in the literature or even those routinely adopted in clinical practice have had their effectiveness proven in randomized trials. Only a few examples of such trials exist; eg, trials evaluating the benefits of screening for abdominal aneurysms or measuring brain-type natriuretic peptide in patients with dyspnea. Conversely, a comprehensive randomized trial agenda trying to evaluate every proposed predictor in each proposed disease application and population would require millions of trials, which is unrealistic. Which candidate predictors should be evaluated by randomized trials and how should they be chosen for best results? A commonsense checklist might be to, first, preferably test predictors for diseases with major morbidity. Second, some effective treatment should be available. Third, the treatment should not be equally effective (or equally risky) for all persons. Fourth, consideration of the predictor should allow more accurate classification of individuals into categories in which treatment is or is not indicated. Fifth, the incremental prediction should be accomplished beyond what can be achieved with information already available. Sixth, there should be consensus about and standardization of established, routine predictors. Seventh, the predictor should be unambiguously defined and measured. Most published research on predictors is irrelevant or tangential to this checklist. Almost all articles report statistically significant results, but this means little. Many investigators deal with whether a predictor in isolation has any ability to predict something. This, however, does not consider that many clinical facts and routine laboratory predictors may already inform prognosis. Thus, it is often not clear whether the new test adds incremental prognostic information beyond known factors. Much of the literature is chaotic, and data dredging and selective reporting abound. Strong studies with clear design, purpose, and knowledge are clearly needed. In this issue of JAMA, Polonsky et al present such a welldesigned study addressing coronary artery calcium score (CACS) as a predictor of coronary heart disease (CHD). Is this predictor good enough? In regard to the aforementioned checklist, first, CHD indeed carries major morbidity. Second, effective lipid-lowering treatments are available for preventive purposes. Third, the absolute effectiveness of the treatments (absolute risk reduction) varies at different categories of baseline risk. Patients at greater than 20% risk of CHD over 10 years should be treated, those with less than 10% should not, and those with 10% to 20% are in the gray zone of intermediate risk. Fourth, Polonsky et al suggest that CACS does allow for a better classification of patients into categories in which, seemingly, treatment is or not indicated. Fifth, this is accomplished in addition to the information available from established routine predictors,

Prognostic value of cell-cycle regulators and cellular biomarkers in laryngeal squamous cell carcinoma

Objective Combining information derived from cellular biomarkers as telomerase and genes encoding cyclin dependent kinase inhibitors (p16 INK4a and p15 INK4b) is needed to facilitate the stratification of individual patients within the conventional clinicopathologic parameters. Design and methods One hundred forty laryngeal squamous cell carcinoma (LSCC) tissue specimens were investigated for telomerase activity and the deletions of p16 INK4a and p15 INK4b genes. Results Of the 140 tissues assayed, 71% demonstrated high telomerase activity, 68.6% and 80% showed deletions in p16 INK4a and p15 INK4b genes, respectively. Significant difference was observed between telomerase activity, p16 INK4a and p15 INK4b deletions among each other and with advanced stage, poorly differentiated grades, high proliferation and DNA aneuploidy. The markers and the aforementioned clinicopathological factors were correlated with progression in univariate analysis; and associated with survival in multivariate analysis. Conclusion Progression of LSCC is accompanied by a parallel increase in telomerase activity and deletions in cell-cycle regulators (p16 INK4a, p15 INK4b) which may assist in prognostication and better classification of patients for treatment.

Phenotypic and Genetic Characterization of Circulating Tumor Cells by Combining Immunomagnetic Selection and FICTION Techniques

The presence of circulating tumor cells (CTCs) in breast cancer patients has been proven to have clinical relevance. Cytogenetic characterization of these cells could have crucial relevance for targeted cancer therapies. We developed a method that combines an immunomagnetic selection of CTCs from peripheral blood with the fluorescence immunophenotyping and interphase cytogenetics as a tool for investigation of neoplasm (FICTION) technique. Briefly, peripheral blood (10 ml) from healthy donors was spiked with a predetermined number of human breast cancer cells. Nucleated cells were separated by double density gradient centrifugation of blood samples. Tumor cells (TCs) were immunomagnetically isolated with an anti-cytokeratin antibody and placed onto slides for FICTION analysis. For immunophenotyping and genetic characterization of TCs, a mixture of primary monoclonal anti-pancytokeratin antibodies was used, followed by fluorescent secondary antibodies, and finally hybridized with a TOP2A/HER-2/CEP17 multicolor probe. Our results show that TCs can be efficiently isolated from peripheral blood and characterized by FICTION. Because genetic amplification of TOP2A and ErbB2 (HER-2) in breast cancer correlates with response to anthracyclines and herceptin therapies, respectively, this novel methodology could be useful for a better classification of patients according to the genetic alterations of CTCs and for the application of targeted therapies.

Diagnóstico, clasificación y patogenia de la diabetes mellitus

Diabetes mellitus (DM) is a metabolic disorder characterized by the presence of chronic hyperglycemia accompanied by greater or lesser impairment in the metabolism of carbohydrates, lipids and proteins. The origin and etiology of DM can vary greatly but always include defects in either insulin secretion or response or in both at some point in the course of disease. When characteristic symptoms of DM are clearly present and blood glucose levels are high enough, the diagnosis is usually unequivocal. However, it is important to remember that the diagnosis is made in asymptomatic patients in most cases, based on the results of routine tests. The prevalence of DM, its specific complications and the presence of other diseases that often accompany DM make this disease one of today's main social and public health problems. The great increase in information available on the etiology and pathophysiology of DM and its chronic complications has led necessarily to the revision of diagnostic criteria and reclassification of the processes involved. Revised diagnostic criteria and classifications were agreed upon in 1997 and 1998 by the American Diabetes Association and the World Health Organization, respectively, and new recommendations were published. Thanks to cross-representation on the committees, the conclusions and final recommendations are, in general, very similar, although a few minor differences are present. Clarification of diagnostic criteria and better classification of patients suffering from DM should allow us to make better choices among the various treatment options available and to improve prognosis.

The prognostic significance of the biomarkers p21WAF1/CIP1, p53, andbcl-2 in laryngeal squamous cell carcinoma

The clinical course of laryngeal squamous cell carcinoma (LSCC) varies considerably among patients. New biologic markers are needed to facilitate the stratification of individual patients within the conventional clinicopathologic stages of LSCC. Eighty-three LSCCs from an equal number of patients who received at least 10 years of follow-up were investigated for p53, p21WAF1/CIP1, and bcl-2 protein expression by immunohistochemical techniques. The results were correlated with various clinicopathologic parameters, DNA content, and patient outcome by univariate and multivariate statistical analyses. Stage IV disease, large tumor size (>3 cm), positive lymph node status, extranodal extension, and p53 overexpression (in > 75% of cells) correlated significantly with prognosis in univariate analysis. There was no correlation between patient outcome and age, gender, race, histologic differentiation, or expression of bcl-2 or p21WAF1/CIP1. In multivariate analysis, lymph node status and p53 overexpression were the only factors significantly associated with survival. High p53 expression and positive lymph node status were independent predictors of the outcomes of patients with LSCC. These factors may assist in prognostication and better classification of patients for treatment.

Nonverbal selective reminding test: Efficacy in the assessment of adults with temporal lobe epilepsy

Although the relationship of verbal memory tests to left temporal lobe epilepsy (LTLE) has reportedly been well established, research on the relationship of nonverbal memory to right TLE (RTLE) has yielded mixed findings, thus bringing into question the clinical utility of nonverbal memory assessment. In the present study, we used a selective reminding procedure for nonverbal spatial material to control for procedural factors, such as verbal mediation, which may in part be the basis for these mixed findings. A sample of 39 LTLE patients and 33 RTLE patients were given both a test of verbal selective reminding (VSR) and a test of nonverbal selective reminding (NVSR) as part of a presurgical evaluation. Diagnosis of RTLE and LTLE was rendered after an extensive presurgical evaluation including magnetic resonance imaging, video-electroencephalography, the intracarotid sodium amytal procedure, and intracranial electrodes when necessary. Results obtained from the NVSR allowed better classification of patients than did VSR, yielding 40% above chance classification. More important, given impaired performance, the probability that a patient had RTLE was 0.70. VSR performance did not allow for classification significantly above chance levels. Although combining the resultsfrom the VSR and NVSR resulted in the best classification, the gain was minimal (72% vs. 70% for NVSR alone), particularly because 26 patients could not be classified. Our results support previous findings of a relationship between nonverbal memory performance and RTLE epilepsy but bring into question the unequivocal acceptance of an exclusive relationship of verbal memory to LTLE.