Individual Patient Risk Assessment Research Articles

Bcl-2 and apoptosis in chronic lymphocytic leukemia.

The Bcl-2 family of pro- and antiapoptotic proteins are key regulators of the apoptosis cascade and the mitochondrial-mediated pathway of caspase activation. Of this family, Bcl-2 was the first identified and remains the best characterized. Aberrant expression of Bcl-2 is common in chronic lymphocytic leukemia (CLL) and is associated with poor response to chemotherapy and decreased overall survival. Bcl-2 is an attractive target for novel therapeutic agents. Antisense oligonucleotides directed against Bcl-2 are effective in vitro and are being evaluated in clinical trials in CLL. Small molecule Bcl-2 inhibitors are in preclinical development and should be ready for clinical evaluation in the next few years. Strategies that induce apoptosis and bypass Bcl-2 may also be therapeutically useful in CLL. Thus, over the next decade, one can envision incorporating measurements of apoptotic proteins such as Bcl-2 into the risk assessment and treatment algorithms for individual patients. In addition, we anticipate that in the next decade, rationally designed therapies targeting specific molecular defects in the malignant CLL lymphocytes will be introduced into the clinic.

Advances in the treatment of Hodgkin's lymphoma.

Given the successful treatment for most patients with Hodgkin's lymphoma, efforts have been directed primarily toward improving outcomes for the minority of patients with poor prognosis or relapsed disease or reducing the late effects of therapy for long-term survivors. Recently, a simple and clinically useful prognostic scoring system was developed for patients with advanced disease. This system allows better risk assessment for individual patients and more uniformity among patients participating in clinical trials. In addition, trials using newer chemotherapeutic regimens such as Stanford V or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) are maturing with promising results. Other studies are helping to define the role of high-dose therapy for patients with Hodgkin's lymphoma, although biologic treatments such as cellular or antibody-based therapies are still in early phases of development. Lastly, positron emission tomographic scanning is emerging as a useful tool in staging and following Hodgkin's lymphoma.

Genetic features of B-cell chronic lymphocytic leukemia.

The genetic features of B-cell chronic lymphocytic leukemia (CLL) are currently being reassessed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). Conventional cytogenetic studies by chromosome banding are difficult in CLL mainly because of the low in vitro mitotic activity of the tumor cells, which leads to poor quantity and quality of metaphase spreads. Molecular genetic analyses are limited because candidate genes are known for only a few chromosomal aberrations that are observed in CLL. FISH was found to be a powerful tool for the genetic analysis of CLL as it overcomes both the low mitotic activity of the CLL cells and the lack of suitable candidate genes for analysis. Using FISH, the detection of chromosomal aberrations can be performed at the single cell level in both dividing and non-dividing cells, thus circumventing the need of metaphase preparations from tumor cells. Probes for the detection of trisomies, deletions and translocation breakpoints can be applied to the regions of interest with the growing number of clones available from genome-wide libraries. Using the interphase cytogenetic FISH approach with a disease specific set of probes, chromosome aberrations can be found in more than 80% of CLL cases. The most frequently observed abnormalities are losses of chromosomal material, with deletions in band 13q14 being the most common, followed by deletions in 11q22-q23, deletions in 17p13 and deletions in 6q21. The most common gains of chromosomal material are trisomies 12q, 8q and 3q. Translocation breakpoints, in particular involving the immunoglobulin heavy chain locus at 14q32, which are frequently observed in other types of non-Hodgkin's lymphoma, are rare events in CLL. Genes affected by common chromosome aberrations in CLL appear to be p53 in cases with 17p deletion and ataxia telangiectasia mutated (ATM), which is mutated in a subset of cases with 11q22-q23 aberrations. However, for the other frequently affected genomic regions, the search for candidate genes is ongoing. In parallel, the accurate evaluation of the incidence of chromosome aberrations in CLL by FISH allows the correlation of genetic abnormalities with clinical disease manifestations and outcome. In particular, 17p abnormalities and deletions in 11q22-q23 have already been shown to be among the most important independent prognostic factors identifying subgroups of patients with rapid disease progression and short survival. In addition, deletion 17p has been associated with resistance to treatment with purine analogs. Therefore, genetic abnormalities may allow a risk assessment for individual patients at the time of diagnosis, thus giving the opportunity for a risk-adapted management.

PROSTATE CANCER: ASSESSMENT OF RISK USING DIGITAL RECTAL EXAMINATION, TUMOR GRADE, PROSTATE-SPECIFIC ANTIGEN, AND SYSTEMATIC BIOPSY

Refinement in the local staging and risk assessment for prostate cancer patients utilizing clinical parameters is ongoing. DRE, tumor grade, and PSA provide some useful information for risk assessment in individual patients. More recent studies using percent free PSA levels and systematic biopsy results have added additional staging information and may play a more significant role in the future in risk assessment. This information should supplement additional imaging tests in the management of these patients.

Malignant progression in Barrett's esophagus: pathology and molecular biology.

Due to its increasing incidence, esophageal adenocarcinoma and its precursor lesions have received increasing attention in recent years. The histopathologic steps in the process of malignant progression in Barrett's esophagus are well described and include the following: (a) metaplasia of the normal esophageal squamous epithelium to a specialized intestinal glandular epithelium, (b) development of dysplasia (classified histologically as low and high grade), and (c) development of adenocarcinoma characterized by invasive and metastatic potential. Intestinal metaplasia can be identified by the presence of goblet cells, the detection of which can be aided by finding mucin stained by Alcian blue at low pH. Despite this well-characterized sequence, the timing of the development of dysplasia and the subsequent transition to carcinoma and the risk of development of carcinoma in low- and high-grade dysplasia are not precisely known. In addition, there are problems in the identification of dysplasia, including sampling error and interobserver discrepancies among pathologists. A better understanding of the mechanisms of these events would allow early identification and elimination of high-risk lesions before adenocarcinoma with its attendant poor prognosis were able to develop. In order to better understand this process and to potentially identify early markers of malignant transformation, a variety of molecular studies have been carried out in recent years on adenocarcinoma and its precursor lesions in Barrett's esophagus. On the phenotypic level, increased expression and changes in pattern of expression of proliferation marker (Mib-1) Ki-67 antigen, overexpression of p53 protein, overexpression of growth factors such as epidermal growth factor (EGF), c-erbB2, and transforming growth factor (TGF)-a, decreased and abnormal expression of the cell adhesion molecule E-cadherin, and, in carcinomas, increased expression of serine proteases have all been described. A new area of interest is the family of rab proteins, which play an important role in maintaining cell polarity in the gastrointestinal tract. Increased expression of one of these proteins, rab11, has been described in low-grade, but not high-grade dysplasia. In cytogenetic studies, an increased S-phase fraction, followed by an increased tetraploid (4N) fraction and then aneuploidy, has been described. So far, the specific genes which have been most thoroughly investigated have been p53, APC, p16, and the sites of probable tumor suppressor genes, including 3p (FHIT), 13q, and 18q. With only a few exceptions (i.e., rab11 expression, and possibly mutations of FHIT), the numerous molecular abnormalities which have been described occur late in malignant progression, which means that the best marker which presently exists to identify high-risk lesions in Barrett's esophagus is the histologic identification of dysplasia in endoscopic biopsies, especially high-grade dysplasia. We are presently beginning studies using laser microdissection and competitive genomic hybridization (CGH), which could help to identify new chromosomal areas that might contain genes that are crucial in the early phases of malignant progression in Barrett's esophagus. In the future, identification of such early molecular events which predispose to carcinoma development will allow more precise and earlier risk assessment for individual patients, therefore, enabling more effective therapy.

Use of the Percentage of Free Prostate-Specific Antigen to Enhance Differentiation of Prostate Cancer From Benign Prostatic Disease: A Prospective Multicenter Clinical Trial

Context.—The percentage of free prostate-specific antigen (PSA) in serum has been shown to enhance the specificity of PSA testing for prostate cancer detection, but earlier studies provided only preliminary cutoffs for clinical use.Objective.—To develop risk assessment guidelines and a cutoff value for defining abnormal percentage of free PSA in a population of men to whom the test would be applied.Design.—Prospective blinded study using the Tandem PSA and free PSA assays (Hybritech Inc, San Diego, Calif).Setting.—Seven nationwide university medical centers.Participants.—A total of 773 men (379 with prostate cancer, 394 with benign prostatic disease) 50 to 75 years of age with a palpably benign prostate gland, PSA level of 4.0 to 10.0 ng/mL, and histologically confirmed diagnosis.Main Outcome Measures.—A percentage of free PSA cutoff that maintained 95% sensitivity for prostate cancer detection, and probability of cancer for individual patients.Results.—The percentage of free PSA may be used in 2 ways: as a single cutoff (ie, perform a biopsy for all patients at or below a cutoff of 25% free PSA) or as an individual patient risk assessment (ie, base biopsy decisions on each patient's risk of cancer). The 25% free PSA cutoff detected 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with greater than 25% free PSA were more prevalent in older patients, and generally were less threatening in terms of tumor grade and volume. For individual patients, a lower percentage of free PSA was associated with a higher risk of cancer (range, 8%-56%). In the multivariate model used, the percentage of free PSA was an independent predictor of prostate cancer (odds ratio [OR], 3.2; 95% confidence interval [CI], 2.5-4.1; P<.001) and contributed significantly more than age (OR, 1.2; 95% CI, 0.92-1.55) or total PSA level (OR, 1.0; 95% CI, 0.92-1.11) in this cohort of subjects with total PSA values between 4.0 and 10.0 ng/mL.Conclusions.—Use of the percentage of free PSA can reduce unnecessary biopsies in patients undergoing evaluation for prostate cancer, with a minimal loss in sensitivity in detecting cancer. A cutoff of 25% or less free PSA is recommended for patients with PSA values between 4.0 and 10.0 ng/mL and a palpably benign gland, regardless of patient age or prostate size. To our knowledge, this study is the largest series to date evaluating the percentage of free PSA in a population representative of patients in whom the test would be used in clinical practice.

Theoretical modelling of arteriovenous malformation rupture risk: a feasibility and validation study

Purpose: To explore the feasibility of using a theoretical computational model to simulate the risk of spontaneous arteriovenous malformation (AVM) haemorrhage. Methods: Data from 12 patients were collected from a prospective databank which documented the angioarchitecture and morphological characteristics of the AVM and the feeding mean arterial pressure (FMAP) measured during initial superselective angiography prior to any treatment. Using the data, a computational model of the cerebral circulation and the AVM was constructed for each patient (patient-specific model). Two model risk (Risk model) calculations (haemodynamic- and structural-weighted estimates) were performed by using the patient-specific models. In our previously developed method of haemodynamic-weighted estimate, Risk model was calculated with the simulated intranidal pressures related to its maximal and minimal values. In the method of structural-weighted estimate developed and described in this paper, the vessel mechanical properties and probability calculation were considered in more detail than in the haemodynamic-weighted estimate. Risk model was then compared to experimentally determined risk which was calculated using a statistical method for determining the relative risk of having initially presented with AVM haemorrhage, termed Risk exp. Results: The Risk model calculated by both haemodynamic- and structural-weighted estimates correlated with experimental risks with χ 2=6.0 and 0.64, respectively. The risks of the structural-weighted estimate were more correlated to experimental risks. Conclusions: Using two different approaches to the calculation of AVM haemorrhage risk, we found a general agreement with independent statistical estimates of haemorrhagic risk based on patient data. Computational approaches are feasible; future work can focus on specific pathomechanistic questions. Detailed patient-specific computational models can also be developed as an adjunct to individual patient risk assessment for risk-stratification purposes.

Molecular cytogenetic analysis of B-cell chronic lymphocytic leukemia.

The genetic alterations underlying the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) are difficult to assess. Cytogenetic studies are hindered by the low in vitro mitotic activity of the tumor cells and the limited resolution of chromosome banding. Molecular genetic analyses are hampered by nonclonal cells contained in the specimens and by the limited knowledge of candidate genes involved. As a complement to cytogenetic and molecular genetic techniques, fluorescence in situ hybridization (FISH) has proven powerful in the molecular cytogenetic analysis of B-CLL. FISH allows the detection of aberrations such as trisomies, deletions, and translocation breakpoints on the single cell level in dividing as well as non-dividing cells without the prerequisite of detailed physical maps or knowledge of involved genes. As detected by the interphase cytogenetic FISH approach, the most common chromosome abnormalities of B-CLL are deletions in band 13q14, followed by deletions in 11q22-q23, trisomy 12, deletions in 17p13, and deletions in 6q21. Abnormalities in 17p13 seem to involve the TP53 tumor suppressor gene, but as yet no candidate genes have been identified for the other frequent aberrations. Toward the identification of such genes by positional cloning, FISH can be applied for detailed aberration mapping at the molecular level. Furthermore, the accurate detection of chromosome aberrations in B-CLL by FISH provides a valid basis for the evaluation of their prognostic significance. Inactivation of TP53 in 17p13 and deletions in 11q22-q23 have already been shown to be among the most important independent prognostic factors. Genetic abnormalities may eventually provide biological parameters, allowing a risk assessment for individual patients at the time of diagnosis of this clinically heterogeneous disease.

Cerebral microemboli in patients with antiphospholipid syndrome.

CNS involvement is one of the hallmarks underlying poor prognosis in SLE and for therapeutic strategies it is difficult to assess which patients are at risk. As detectability of cerebral microembolic signals (MES) using long-term transcranial Doppler ultrasonography (TCD) proved to be predictive of past and future thromboembolic events in patients with carotid artery stenosis, we investigated whether MES might be similarly useful in patients with antiphospholipid syndrome (APS). Our study population consisted of 46 SLE patients and five with primary APS (pAPS). Twelve of the 46 patients with SLE, 10 of them with secondary APS (sAPS), and four of five patients with pAPS had a history of cerebrovascular ischaemia (CVI). MES in the middle cerebral artery were detected in 14 of 16 patients with and in one of 35 without CVI (P < 0.001). Antiphospholipid antibodies (aPL) were positive in 12 of 15 patients with and 18 of 36 without MES, and the rate of MES correlated to the titre of aPL. MES from APS patients resembled in their energy distribution those from patients with symptomatic carotid disease and were significantly different from those associated with artificial heart valves. In conclusion, cerebral MES are detectable in APS patients and correlate with a history of CVI. Whether this innovative method may provide individual risk assessment in APS patients has to be addressed in prospective studies.

Mediastinitis After Coronary Artery Bypass Graft Surgery

This study from Duke University Medical Center addresses both the risk factors for the development of mediastinitis, as well as the long-term impact of mediastinal infection on survival in 6459 consecutive patients undergoing coronary artery bypass graft (CABG) surgery at that institution from 1987 to 1994. Data on 20 preoperative and intraoperative variables were collected prospectively and analyzed using univariate and multivariate analyses, with evaluation of long-term survival in the infected and uninfected groups. Eight-three patients (1.3%) developed mediastinitis, defined as deep sternal wound infection requiring extensive debridement and drainage. The mean postoperative hospital stay was prolonged in the mediastinitis group (25 versus 10 days, no statistical analysis provided). Variables associated with an increased incidence of mediastinitis by univariate analysis included obesity (P =.009), New York Heart Association congestive heart failure (NYHA CHF) class (P =.002), diabetes mellitus (P =.009), priorsternotomy (P =.009), duration of cardiopulmonary bypass (P =.02), presence of comorbid conditions (P =.03) and poor hemostasis at sternotomy closure (P =.09). Multivariate logistic regression analysis revealed four independent predictors of mediastinitis development: NYHA CHF class (P =.002), obesity (P =.0002), prior sternotomy (P =.008), and duration of cardiopulmonary bypass (P =.05). Variables without significant influence included age, number of internal mammary artery grafts utilized, duration of preoperative stay, and chronic obstructive pulmonary disease. The median duration of follow-up in the mediastinitis group was 1.5 years, with a follow-up of 3.4 years in the patients without mediastinitis. Interval and cumulative mortality rates were higher in the mediastinitis group up to 2 years following CABG surgery, a difference which persisted when controlled for variables associated with late postoperative mortality, including age, ejection fraction, cere-brovascular disease, and mitral insufficiency. Patients developing mediastinitis suffered a nearly fourfold increase in mortality in the 1–2 postoperative years (8.1% versus 2.3%). The authors provide a review of the literature addressing risk factors for mediastinitis development. In addition, they propose a model of preoperative risk assessment in individual patients, using NYHA CHF class III or IV, obesity, and prior heart surgery as variables. According to their data, patients possessing one factor have a threefold increased incidence of postoperative mediastinitis, and those possessing all three have a nearly 20-fold increased risk of this postoperative complication.

G-actin as a risk factor and modulatable endpoint for cancer chemoprevention trials

Because tumorigenesis is an ongoing process, biomarkers can be used to identify individuals at risk for bladder cancer, and treatment of those at risk to prevent or slow further progression could be an effective means of cancer control given accurate individual risk assessment. Tumorigenesis proceeds through a series of defined phenotypic changes, including those in genetically altered cells destined to become cancer as well as in surrounding normal cells responding to the altered cytokine environment. A panel of biomarkers for the changes can provide a useful system for individual risk assessment in cancer patients and in individuals exposed to carcinogens. The use of such markers can increase the specificity of chemoprevention trials by targeting therapy to patients likely to respond, and thereby markedly reduce the costs of the trials. Previous studies in our laboratories showed the cytoskeletal proteins G- and F-actin reflect differentiation-related changes in cells undergoing tumorigenesis and in adjacent "field" cells, and a pattern of low F-actin and high G-actin is indicative of increased risk. Actin changes may be a common feature in genetic and epigenetic carcinogenic mechanisms. In a group of over 1600 workers exposed to benzidine, G-actin correlated with exposure, establishing it as an early marker of effect. In another study, a profile of biomarkers was monitored in patients who underwent transurethral resection of bladder tumor (TURBT) and received Bacillus Calmette Guerin (BCG) and/or DMSO. The primary objective was to determine how the defined biomarkers expressed in the tumor and the field correlate with clinical response and recurrence. DMSO, known to modulate G-actin in vitro, was used as an agent. Results strongly support the hypothesis that cytosolic G-actin levels measured by quantitative fluorescence image analysis (QFIA) can be an important intermediate endpoint marker for chemoprevention and that the p300 (M344) and DNA ploidy markers identify a high-risk group that requires more aggressive therapy and recurrence monitoring. Further research with other markers has shown that DD23 and nuclear actin, both of which identify late, specific changes, may increase the battery of useful markers. Taken together these studies show how biomarkers are employed to study individuals at risk, aid in the selection of chemopreventive compounds and assist in the understanding of the pathogenesis of malignancy.

Risk stratification and outcome assessment of the adult cardiac surgical patient.

Comparisons between institutions are already occurring, and comparisons between individual providers may also become a reality. In spite of the negative views of such comparisons, they are likely to be mandated because of pressure from health care regulators, insurers, and patients. Despite awareness of the importance of demographic variables and concurrent medical problems in influencing outcome, valid comparisons are presently difficult to conduct in the open heart surgical population. Current methods of risk stratification each have limitations. A method for risk assessment based on multivariate analysis from a large group of patients that can be prospectively validated at multiple institutions would be valuable, not only for mortality rate comparisons, but also for patient counseling, research, and hospital management uses. Caution must be applied when using risk assessment in individual patients. Physicians need to be involved in the development of such severity stratifying systems, since inclusion of inappropriate or medically irrelevant data can influence the outcome of multivariate analyses. Ongoing research and evolution of scoring systems also need to occur since therapy changes over time. It is likely that models will need to be developed for application preoperatively, at ICU admission, and for the complex, long-term patient at 7 days or beyond, in order to fully inform medical decision-making.

Quantitative characteristics of the Feyrter (APUD) cells of the neonatal rabbit lung in normoxia and chronic hypoxia.

Our studies show that the apparent number of Feyrter cells in the lung declines during the neonatal period in normoxic rabbits, and that in hypoxic animals a uniformly and significantly lower number of cells occurs as compared with the normoxic rabbits. There is some indication of degranulation of cells in the hypoxic groups. It is suggested that environmental and/or physiological factors associated with the start of extrauterine life, or lung development, may affect the apparent number and probable level of activity of these cells. These changes seem to be enhanced by hypoxia. Mast cells are scarce, and Feyrter cells are relatively more numerous along the airways. These cell types could possibly represent storage sites for 5-hydroxytryptamine, as suggested also by other investigators. Intraepithelial nerve fibres in bronchi and bronchioles were found but they were not limited to innervations of Feyrter cells or related cell bodies.