Motivations and influences on the use of complementary medicine in patients with localized prostate cancer treated with curative intent: results of a pilot study.

OBJECTIVES: To analyse descriptively the use of complementary medicine (CM) by patients with localized prostate cancer treated with curative intent, assessing the major influences on their choice to use CM, and the major critics and advocates of CM. PATIENTS AND METHODS: From January 1997 to June 2000, 351 men with stage T1c-T3 adenocarcinoma of the prostate were treated with either radical prostatectomy (RP) or brachytherapy. On the final date all patients were mailed a questionnaire relating to their use of CM and the results analysed cross-sectionally. RESULTS: In all, 238 (67.8%) patients returned the questionnaires, of whom 37% acknowledged using some type of CM, with a similar overall use of CM among those treated with RP or brachytherapy. Of these, 43% began using CM before and 32% after starting conventional treatment, and most indicated they would never discontinue these therapies. The most common reason for using CM was the patient's impression that it made them feel better, and secondarily that they felt it helped to cure their cancer. Physicians were the most common source of information about CM, with twice as many patients identifying physicians as being advocates rather than critics of CM. Many patients felt their urologist or radiation oncologist was neutral or chose not to discuss CM. However, when these physicians discussed CM, more patients felt that they encouraged rather than discouraged the use of CM. CONCLUSIONS: These data on the motivations for patient choices relating to CM are novel; the sources of information, both positive and negative, that patients find useful in their decision to use these therapies were explored. Interestingly, physicians were generally supportive of the use of such approaches.

Loss of heterozygosity at 13q14 and 13q21 in high grade, high stage prostate cancer.

BACKGROUND: Loss of heterozygosity (LOH) at chromosome 13q has been frequently detected in prostate cancer, and three regions (i.e., 13q14, 13q21, and 13q33) may harbor tumor suppressor genes important in this neoplasm. In this study, we examined the frequency of 13q LOH in advanced prostate cancers, in order to determine the clinicopathologic relevance of 13q LOH. METHODS: LOH was determined by analyzing microsatellite markers in 41 cases of microdissected predominantly high grade prostate cancer tissues and their matched nonneoplastic cells. The results were compared with those generated previously for lower grade, asymptomatic cancers. RESULTS: The frequencies of LOH at 13q14, 13q21, and 13q33 were 62% (21/34), 57% (20/35), and 34% (11/32), respectively. In comparison to previous results, LOH at 13q14 and 13q21 but not 13q33 was more frequent in prostate cancers that produced local clinical symptoms (bladder outlet obstruction) than those that did not (P < 0.05). LOH at 13q14 was also significantly more frequent in high grade and high stage cancers than those that were lower grade and lower stage (P < 0.05). CONCLUSIONS: Although the target genes on 13q have not been identified in carcinomas of the prostate, LOH at 13q14 in particular is associated with clinically significant prostate cancers. Further fine mapping of these loci may lead to identification of tumor suppressor genes that are deleted in aggressive carcinomas of the prostate.

Aberrant localization of the neuronal class III beta-tubulin in astrocytomas.

BACKGROUND: The class III beta-tubulin isotype (betaIII) is widely regarded as a neuronal marker in development and neoplasia. In previous work, we have shown that the expression of betaIII in neuronal/neuroblastic tumors is differentiation dependent. In contrast, the aberrant localization of this isotype in certain nonneuronal neoplasms, such as epithelial neuroendocrine lung tumors, is associated with anaplastic potential. OBJECTIVE: To test the generality of this observation, we investigated the immunoreactivity profile of betaIII in astrocytomas. DESIGN: Sixty archival, surgically excised astrocytomas (8 pilocytic astrocytomas, WHO grade 1; 18 diffuse fibrillary astrocytomas, WHO grade 2; 4 anaplastic astrocytomas, WHO grade 3; and 30 glioblastomas, WHO grade 4), were studied by immunohistochemistry using anti-betaIII monoclonal (TuJ1) and polyclonal antibodies. A monoclonal antibody to Ki-67 nuclear antigen (NC-MM1) was used as a marker for cell proliferation. Antibodies to glial fibrillary acidic protein (GFAP) and BM89 synaptic vesicle antigen/synaptophysin were used as glial and neuronal markers, respectively. RESULTS: The betaIII immunoreactivity was significantly greater in high-grade astrocytomas (anaplastic astrocytomas and glioblastomas; median labeling index [MLI], 35%; interquartile range [IQR], 20%-47%) as compared with diffuse fibrillary astrocytomas (MLI, 4%; IQR, 0.2%-21%) (P <.0001) and was rarely detectable in pilocytic astrocytomas (MLI, 0%; IQR, 0%-0.5%) (P <.0001 vs high-grade astrocytomas; P <.01 vs diffuse fibrillary astrocytomas). A highly significant, grade-dependent relationship was observed between betaIII and Ki-67 labeling and malignancy, but this association was stronger for Ki-67 than for betaIII (betaIII, P <.006; Ki-67, P <.0001). There was co-localization of betaIII and GFAP in neoplastic astrocytes, but no BM89 synaptic vesicle antigen/synaptophysin staining was detected. CONCLUSIONS: In the context of astrocytic gliomas, betaIII immunoreactivity is associated with an ascending gradient of malignancy and thus may be a useful ancillary diagnostic marker. However, the significance of betaIII-positive phenotypes in diffuse fibrillary astrocytomas with respect to prognostic and predictive value requires further evaluation. Under certain neoplastic conditions, betaIII expression is not neuron specific, calling for a cautious interpretation of betaIII-positive phenotypes in brain tumors.

Quality specifications for glucose meters: assessment by simulation modeling of errors in insulin dose.

BACKGROUND: Proposed quality specifications for glucose meters allow results to be in error by 5-10% or more of the "true" concentration. Because meters are used as aids in the adjustment of insulin doses, we aimed to characterize the quantitative effect of meter error on the ability to identify the insulin dose appropriate for the true glucose concentration. METHODS: Using Monte Carlo simulation, we generated random "true" glucose values within defined intervals. These values were converted to "measured" glucose values using mathematical models of glucose meters having defined imprecision (CV) and bias. For each combination of bias and imprecision, 10,000-20,000 true and measured glucose concentrations were matched with the corresponding insulin doses specified by selected insulin-dosing regimens. Discrepancies in prescribed doses were counted and their frequencies plotted in relation to bias and imprecision. RESULTS: For meters with a total analytical error of 5%, dosage errors occurred in approximately 8-23% of insulin doses. At 10% total error, 16-45% of doses were in error. Large errors of insulin dose (two-step or greater) occurred >5% of the time when the CV and/or bias exceeded 10-15%. Total dosage error rates were affected only slightly by choices of sliding scale among insulin dosage rules or by the range of blood glucose. To provide the intended insulin dosage 95% of the time required that both the bias and the CV of the glucose meter be <1% or <2%, depending on mean glucose concentrations and the rules for insulin dosing. CONCLUSIONS: Glucose meters that meet current quality specifications allow a large fraction of administered insulin doses to differ from the intended doses. The effects of such dosage errors on blood glucose and on patient outcomes require study.

Genetic algorithm for scheduling of laboratory personnel.

BACKGROUND: Staffing core laboratories with appropriate skilled workers requires a process to schedule these individuals so that all workstations are appropriately filled and all the skills of each worker are exercised periodically to maintain competence. METHODS: We applied a genetic algorithm to scheduling laboratory personnel. Our program, developed in Visual Basic 4.0, maximizes the value of a fitness function that measures how well a given scheduling of individuals and their skills matches a set of work tasks for a given work shift. The user provides in an Excel spreadsheet the work tasks, individuals available to work on any given date, and skills each individual possesses. The user also specifies the work shift to be scheduled, the range of dates to be scheduled, the number of days that an individual stays on a given workstation before rotating, and various parameters for the genetic algorithm if they differ from the default values. RESULTS: For >22 months, the program matched individuals to those tasks for which they were qualified and maintained personnel skills by rotating job duties. The schedules generated by the program allowed supervisory personnel to anticipate dates far in advance of when worker availability would be limited, so staffing could be adjusted. In addition, the program helped to identify skills for which too few individuals had been trained. This program has been well accepted by the staff in the clinical laboratories of a 670-bed university medical center, saving 37 h of labor per month, or approximately $11,000 per year, in time that supervisory personnel have spent developing work schedules. CONCLUSIONS: The genetic algorithm approach appears to be useful for scheduling in highly technical work environments that employ multiskilled workers.

A prospective pilot evaluation of urinary and immunohistochemical markers as predictors of clinical stage of urothelial carcinoma of the bladder.

OBJECTIVE: To determine, in patients newly diagnosed with bladder cancer, whether p53, epidermal growth factor receptor (EGFR), microvessel density (MVD), urinary bladder tumour antigen (BTA TRAKtrade mark, Bion Diagnostic Sciences, Redmond, WA) and cytology were predictive of clinical stage, evaluated as a function of the clinical stage obtained at transurethral resection of the bladder tumour with and without the addition of clinical grade, a known strong predictor of clinical stage. PATIENTS AND METHODS: Between December 1997 and September 1998, 22 men and seven women with a cystoscopic diagnosis of urothelial bladder carcinoma were prospectively enrolled in the study. Urine was collected for cytological and BTA TRAK evaluation before transurethral resection. Tumour grade and clinical stage were obtained from the transurethral resection specimen. MVD was evaluated by computerized calculations of 'optimal MVD' (OMVD) and 'area-weighted MVD' (AWMVD) while p53 and EGFR information was obtained by manual immunohistochemical techniques; 21 patients had sufficient tissue for all immunohistochemical assessments and comprised the study group. Univariate and multivariate comparisons were carried out to determine the contribution of each variable to the prediction of clinical stage. RESULTS: Although there was a trend, cytological analysis and p53 and MVD immunoreactivity did not significantly correlate with clinical stage, while tumour grade, BTA TRAK and EGFR immunoreactivity did. In a univariate analysis, tumour grade and BTA TRAK were related to clinical stage. In a multivariate analysis, grade was the single best predictor of clinical stage. This analysis also showed that the addition of BTA TRAK and MVD information to grade incrementally improved the predictive ability of grade. CONCLUSIONS: This pilot study suggests that BTA TRAK and MVD contribute incremental information to tumour grade in predicting the clinical stage of urothelial carcinomas of the bladder; grade remains the most important predictor. These results suggest that further work with BTA TRAK and MVD in more patients and on biopsy material obtained during clinic cystoscopy is warranted for the future development of less invasive methods of identifying patients with invasive bladder cancer.

Polymorphism at codon 72 of p53 is not associated with cervical cancer risk.

P53 allelic polymorphism at codon 72 has been studied as a possible predisposing factor for cervical carcinogenesis with inconsistent results. Storey and colleagues recently published the interesting finding of a 7-fold increased risk for cervical cancer in women homozygous for the arginine allele at codon 72. This stimulated a number of independent investigations, the majority of which found no association of cervical cancer and arginine homozygosity. With the use of a modified Storey method for determining codon 72 allelotypes, DNA was examined from 431 microdissected, formalin-fixed, archival cervical conization specimens ranging from low-grade squamous lesions to invasive cancer. An alternative independent method using restriction fragment length polymorphism analysis was performed on all arginine homozygotes and all indeterminate cases for confirmation and final allelotype assignment. With the use of Storey's method alone, logistic regression suggested an association (odds ratio, 1.42) between arginine homozygosity and invasive disease. However, with the use of the combined method for accurate allelotyping, this trend disappeared (odds ratio, 1.00), the discordance was clearly resolvable as being due to methodologic variables. With the use of two separate methods for codon 72 allelotyping and accounting for a number of the issues raised in previously published reports, there is no increased risk for invasive cervical cancer associated with arginine homozygosity at codon 72 of p53.

The effect of siberian ginseng (Eleutherococcus senticosus) on substrate utilization and performance.

It has been suggested that Eleutherococcus senticosus (ES), also known as Siberian ginseng or ciwuija, increases fat utilization in humans. The purpose of this study was to examine the physiological responses to supplementation with ES in endurance cyclists. Using a randomized, double-blind crossover design, 9 highly-trained men (28 +/- 2 years, VáO2max 57.3 +/- 2.0 ml á kg-1 á min-1) cycled for 120 min at '60% VáO2max followed by a simulated 10-km time trial. Diet was controlled, and ES (1,200 mg á day-1) or a placebo (P) were administered for 7 days prior to each of the two trials. Oxygen consumption, respiratory exchange ratio, and heart rate were recorded every 30 min, and rating of perceived exertion, plasma [lactate], and plasma [glucose] were recorded every 20 min during the 120 min of steady state cycling. There were no significant differences (p >.05) between the ES and P groups at any steady-state time interval or during the cycling time trial (ES = 18.10 +/- 0.42, P = 17.83 +/- 0.47 min). In contrast with previous reports, the results of this study suggest that ES supplementation does not alter steady-state substrate utilization or 10-km cycling performance time.

Alternative medicine use in patients with localized prostate carcinoma treated with curative intent.

BACKGROUND: Alternative medicine therapies are estimated to be used by 7-64% of cancer patients but up to 72% do not inform their physician. To the authors' knowledge little useful information is available regarding the prevalence of alternative medicine use by patients with prostate carcinoma. Thus, the authors attempted to evaluate the prevalence of alternative medicine use by prostate carcinoma patients treated with curative intent by either radical prostatectomy, brachytherapy alone, or a combination of brachytherapy and external radiation therapy. METHODS: Between January 1997 and May 1998, 234 men with clinically localized prostate carcinoma underwent radical prostatectomy (54 patients) or brachytherapy (180 patients) with (74 patients) or without (106 patients) external beam radiation therapy. In July 1998 a questionnaire was mailed to all patients comprised of multiple questions regarding alternative medicine use to which 190 patients (81%) responded. The overall prevalence and types of alternative medicine therapies used were assessed and the relation between age at procedure, pretreatment prostate specific antigen level, clinical stage, pretreatment Gleason score, and type of treatment with the use of alternative medicine therapies was evaluated using univariate and multivariate analysis. RESULTS: The prevalence of alternative medicine use by prostate carcinoma patients responding to the survey was 43% (81 of 190 patients). No significant differences in alternative medicine use were observed between the patients who received brachytherapy alone (38%), those who underwent radical prostatectomy (40%), and those treated with combined brachytherapy and external beam radiation therapy (51%). Vitamins, prayer or other religious practices, and herbal medicines were the most commonly used therapies in these patients. Higher pretreatment Gleason scores were associated with a greater use of alternative medicine therapies on both multivariate and univariate analyses. Finally, using multivariate analysis, younger prostate carcinoma patients were more likely to use alternative medicine therapies than older patients. CONCLUSIONS: Alternative medicine use is very prevalent among patients treated for localized prostate carcinoma. Because some of these treatments may have a potential biologic impact on tumor behavior and, consequently, on definitive or surrogate therapeutic endpoints, patients should be questioned carefully regarding alternative medicine use during routine tumor follow-up.

Three distinct regions of allelic loss at 13q14, 13q21-22, and 13q33 in prostate cancer.

Chromosome 13 is one of the most frequently altered chromosomes in cancer, including carcinoma of the prostate. Two known tumor suppressor genes, RB1 and BRCA2, map to chromosome 13; however, recent reports suggest that unknown genes on 13q are more likely to be involved in the development of prostate cancer. In order more fully to define the genetic changes on chromosome 13 in prostate neoplasms, we analyzed 27 polymorphic microsatellite markers spanning the q arm for loss of heterozygosity in 40 primary tumors and in metastases from 11 other patients who died of prostate cancer. Of the 40 primary tumors, 23 (58%) showed LOH for at least one marker. Three distinct regions at q14, q21-22, and q33, defined by markers D13S267-->D13S153, D13S166-->D13S1225, and D13S259-->D13S274, showed the most frequent LOH, suggesting their involvement in the development of prostate cancer. For the 12 patients whose tumors showed LOH at these markers, the average age at diagnosis was 58 years, which was younger than that (63 years, P < 0.05) for the 28 patients whose tumors lacked LOH. Ten of the 11 (91%) metastases showed LOH with one or more markers. Two of the three most frequently deleted regions (i.e., q14 and q21-22) in the primary tumors and markers linked to the RB1, BRCA2, and EDNRB genes showed high frequencies (56-71%) of LOH in metastases. These results demonstrate that allelic loss on chromosome 13 at q14, q21-22, and q33 occurs in a subset of primary prostate tumors and is a frequent event in metastatic lesions of prostate cancer.

Cellular distribution of retinoic acid receptor-alpha protein in serous adenocarcinomas of ovarian, tubal, and peritoneal origin: comparison with estrogen receptor status.

Retinoids are effective growth modulators of human ovarian carcinoma cell lines. Their effects are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are transcriptional factors and members of the steroid/thyroid receptor superfamily. To our knowledge, until now, the cellular distribution of RAR proteins in human ovarian tumor specimens is unknown. This study provides new data on the differential cellular localization of RAR alpha protein in 16 serous adenocarcinomas originating from the ovaries, fallopian tubes, and the peritoneum. Using an affinity-purified antiserum specific for RAR alpha and a monoclonal antibody recognizing the full-length estrogen receptor molecule (clone 6F11), we performed immunohistochemistry on frozen tissue sections and examined the relationship between RAR alpha and estrogen receptor protein expression by comparing the percentage of immunostained tumor cells for either receptor. Our findings indicate a strong linear relationship between the percentages of RAR alpha- and estrogen receptor-labeled tumor cells as determined by linear regression analysis (P < 0.005, r = 0.825). A modest inverse relationship was found between the percentage of RAR alpha-positive tumor cells and histological grade, attesting to a differentiation-dependent trend (P < 0.04). No significant relationship was found between RAR alpha-labeled cells and clinical stage (P = 0.139), site of tumor origin (ovaries versus fallopian tubes versus peritoneum) (P = 0.170), and primary versus metastatic lesion (P = 0.561). Thus, serous adenocarcinomas are capable of expressing RAR alpha and estrogen receptor despite high histological grade and advanced stage of neoplastic disease. Compared with the heterogeneous localization of RAR alpha in cancer cells, there was widespread RAR alpha immunoreactivity in tumor-infiltrating lymphocytes, vascular endothelial cells, and stromal fibroblasts, underscoring the value of immunohistochemistry in the accurate determination of RAR/(RXR) content in tumor specimens.

Early prostate-specific antigen failure following radical perineal versus retropubic prostatectomy: the importance of seminal vesicle excision.

OBJECTIVES: Because of renewed interest in the radical perineal prostatectomy, we chose to evaluate factors influencing differences in biochemical failure as measured by prostate-specific antigen (PSA) between radical perineal and the radical retropubic prostatectomies. METHODS: We undertook a retrospective review of 87 men with clinically localized prostate cancer who underwent radical retropubic (64%) or radical perineal (36%) prostatectomy, noting age, race, preoperative PSA, Gleason score, clinical stage, capsular penetration, surgical approach, and completeness of seminal vesicle (SV) excision. The two groups were comparable with respect to tumor factors such as preoperative PSA, Gleason score, clinical stage, and capsular penetration. Time to postoperative PSA failure (0.2 ng/mL or greater) was evaluated with univariate and multivariate analysis of multiple contributing factors. RESULTS: Twenty-eight percent of patients had a PSA level rising to 0.2 ng/mL or greater in the follow-up period. Patients who underwent perineal prostatectomy had a higher PSA failure rate (45%) than those treated by the retropubic approach (18%) and patients with incomplete SV excision had a higher failure rate (69%) than patients with bilateral SV excision (20%). When time to PSA failure was examined by multivariate analysis, completeness of SV excision, clinical stage, and Gleason score had a statistically significant impact on this outcome. In perineal prostatectomy patients, bilateral SV excision had a significantly longer time to PSA failure than in patients with incomplete excision. There was no significant difference in time to PSA failure between patients who underwent radical retropubic prostatectomy and the patients who underwent perineal prostatectomy with bilateral SV excision. CONCLUSIONS: Incomplete excision of SVs during a radical perineal prostatectomy contributes to an earlier postoperative biochemical recurrence as measured by a rising PSA, and may explain the higher disease recurrence rate for radical perineal prostatectomies as opposed to radical retropubic prostatectomies in this study.

Cathepsin D and chromogranin A as predictors of long term disease specific survival after radical prostatectomy for localized carcinoma of the prostate.

BACKGROUND: The accumulation of chromogranin A (Chr A) and cathepsin D (Cath D) gene products may be important in prostate carcinoma progression. This study assessed whether the levels of immunoreactivity for Chr A and Cath D are better predictors of disease specific survival than conventional pathologic parameters of the primary tumor such as Gleason score, capsular penetration, seminal vesicle invasion, and percent tumor in the specimen for patients with clinically localized prostate carcinoma managed by radical prostatectomy. METHODS: Seventy-one patients with modified Jewett clinical stages A1 to B2 adenocarcinoma of the prostate underwent a radical prostatectomy after a negative metastatic workup. No neoadjuvant or adjuvant treatments were given and all disease recurrences and causes of death were recorded. Analysis of prostatectomy specimens was undertaken to determine the conventional pathologic parameters of the primary tumor and Chr A and Cath D immunohistochemical staining. Univariate and multivariate analyses were performed to determine the independent contributions of Chr A and Cath D in predicting survival. RESULTS: On univariate analysis Chr A was the only variable that reached statistical significance for disease specific survival (P = 0.035). Cath D nearly reached significance with a P value of 0.079 for disease specific survival. On multivariate analysis, the only independent factor predicting disease specific survival was the Chr A staining score (P < 0.05). In patients with unequivocal foci of Chr A immunoreactivity, the 14-year disease specific survival was 50% compared with 68% for patients lacking such foci. CONCLUSIONS: The level of Chr A immunohistochemical staining is a strong predictor of disease specific survival and is superior to standard pathologic prognostic factors. Such findings lay the groundwork for future prospective study of the utility of such markers on biopsy specimens to predict patient outcome.

p53, bcl-2 and retinoblastoma proteins as long-term prognostic markers in localized carcinoma of the prostate.

PURPOSE: The accumulation of p53 and bcl-2 gene products as well as the loss of the retinoblastoma (Rb) gene product have been associated with prostate cancer progression. We assessed whether the levels of immunoreactivity for p53, Rb and bcl-2 are better long-term predictors of disease specific survival than conventional pathological parameters of the primary tumor, such as Gleason score, capsular penetration, seminal vesicle invasion and percent tumor in the specimen, in patients with clinically localized prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: A total of 71 patients with clinical stages A1 to B2 adenocarcinoma of the prostate underwent radical prostatectomy after a negative metastatic evaluation. No neoadjuvant or adjuvant treatments were given and causes of death were recorded. Prostatectomy specimens were analyzed to determine the conventional pathological parameters, and p53, Rb and bcl-2 immunohistochemical staining. Univariate and multivariate analyses were done to determine the independent contributions of p53, Rb and bcl-2 in predicting survival. RESULTS: On multivariate analysis the independent factors predicting disease specific survival were p53 staining score (p < 0.001) and Rb staining score (p < 0.001). In patients with p53 immunoreactive tumors the 15-year disease specific survival was 38% compared to 87% for those with less immunoreactivity. Analysis of Rb immunoreactivity for 15-year disease specific survival yielded 92 and 66% high and low staining levels, respectively. Best subset analysis revealed that the combination of p53 score and Rb score yielded the best predictive value for disease specific survival. CONCLUSIONS: p53 and Rb immunohistochemical staining scores were independent predictors of disease specific survival and were superior to conventional pathological prognostic factors of the primary tumor. These findings lay the groundwork for the prospective study of these markers in patients treated with radical prostatectomy.

Predictive value of intraoperative biopsies and liver function tests for preservation injury in orthotopic liver transplantation.

Eighty liver allografts were studied to determine the predictive value of intraoperative biopsies and postoperative liver function tests for the development of preservation injury (PI). Peak transaminase (aspartate transaminase [AST] and alanine transaminase [ALT]) and prothrombin time (PT) values achieved by each patient during postoperative days (POD) 1 through 7 were determined. PI in day 0 preperfusion biopsies (0Pre) (obtained immediately before implantation) and postperfusion biopsies (0Post) (obtained immediately after revascularization) was categorized by histological criteria as present or absent. PI in biopsies taken during POD 2 through 14 was histologically graded as either moderate-to-severe, mild, or absent. Of the 80 allografts, 8 were omitted because of primary nonfunction or postoperative complications. 0Pre and 0Post biopsies were available on 25 of 72 (35%) and 69 of 72 (96%) allografts, respectively. Only 2 (8%) of the 0Pre biopsies showed histological PI compared with 48 (70%) of the 0Post biopsies. Fifty-nine patients were biopsied between POD 2 through 14. Of these, 15, 28, and 16 patients developed moderate-to-severe, mild, or no evidence of PI, respectively. The presence of PI in the 0Post biopsy strongly correlated with the development of PI during POD 2 through 14 (P < .0005). Peak AST and ALT values in patients with moderate-to-severe PI on POD 2 through 14 were significantly elevated compared with those patients with either mild (P = .01 and .03) or no PI (P = .02 and .006). Because of extensive overlap in AST and ALT values between the three groups, however, transaminase values were not useful in predicting the presence or absence of PI in the individual case. The development of PI during POD 2 through 14 correlated with advanced donor age (P = .06) but was unassociated with 0Pre biopsy findings, cold ischemia time, or peak PT values. We conclude that the 0Post biopsy is a valuable tool for the prediction of subsequent PI in the early postoperative period. In contrast, 0Pre biopsy findings and peak AST and ALT values are not useful in the assessment of PI.

Mathematical tools for demonstrating the clinical usefulness of biochemical markers.

Various approaches have been proposed for evaluating the diagnostic value of biochemical markers. Careful design of experimental protocol is key in carrying out any evaluation of clinical diagnostic value. A prospective cohort study is the best clinical trial design and should include an appropriate reference (gold) standard applied in every patient, the results of which are assessed blindly. The spectrum of patients evaluated should reflect the population in which the test will be used, be appropriately broad to avoid bias, and include both symptomatic and asymptomatic patients. The handling of indeterminate results and the eligibility criteria for inclusion in the study should be carefully defined. Although sensitivity, specificity, and predictive value have long been used as indices of test accuracy, newer methods such as receiver operating characteristic curve (ROC) analysis, logistic regression analysis and likelihood ratios are more robust indicators that overcome many limitations of the traditional indices. The area under the ROC curve (AUC) is the best global indicator of test accuracy, but comparisons of AUC for different tests must take correlation between the tests into account if they have been performed in the same patients. Logistic regression analysis allows the diagnostic information from several tests to be evaluated multivariately, provides a probability estimate for a given outcome, and requires few assumptions regarding the underlying distributions of test data. Logistic regression also provides a straightforward method for calculating likelihood ratios. Likelihood ratios are useful for interpreting test results in the individual patient because they provide a convenient means to directly determine predictive value without having to calculate sensitivity and specificity for a given decision limit. Application of these methods is demonstrated using specific examples.

A qualitative and quantitative analysis of the entorhinal cortex in schizophrenia.

The entorhinal cortex (ERC) has been implicated in schizophrenia by a number of studies. There is anatomical observation of neuronal heterotopias in the rostral ERC, which is consistent with a hypothesis of neurodevelopmental abnormalities in this disease. In view of the significant cytoarchitectonic variation of the ERC throughout its rostro-caudal extent, we performed a detailed subareal analysis of the rostral two-thirds of the entorhinal cortex (ERCr) in 14 postmortem schizophrenic brains and 14 matched controls (mean ages of 48 and 47 respectively). This systematic evaluation included both a qualitative microscopic analysis of morphogenetic anomalies that would be consistent with neurodevelopmental pathology and quantitative measurements of total neuronal number, average neuronal density, laminar volume and laminar depth from the cortical surface in cytoarchitectonically matched subareas of schizophrenic and control brains. Parcellation of the entire ERC on the basis of cytoarchitectonic criteria identified five distinct regions, similar to those described in the macaque, except that in the human brain three of the regions were further divisible into two or three subareas, yielding nine distinct cellular compartments. Five rostral areas, prorhinal (Pr), lateral (28L), intermediate rostral and caudal (281r and 281c), and sulcal (28S), comprise the ERCr. Gross and microscopic examination of these subdivisions throughout the ERCr failed to reveal laminar disorganization in any of the schizophrenic brains. The brains also did not differ significantly with respect to total neuronal number, total volume and neuronal density per laminar and subareal subdivision, or laminar thickness per entorhinal subarea. However, neuronal number and density were reduced by 12-18% in Pr and 28L, suggesting that mild quantitative abnormalities may exist in the ERCr and might possibly be revealed in a larger sample of schizophrenic brains. We have failed to confirm previous reports of laminar disorganization in the ERCr in brains of patients with schizophrenia; to the extent that this region is implicated in schizophrenia, the structural changes are likely to consist of more subtle cellular disturbances.

Robotics and the changing face of the clinical laboratory.

Rapid changes in healthcare coupled with parallel advances in technology have stimulated the evolution of new approaches for laboratory automation. In particular, the emergence of commercially available laboratory robotic systems offers promise for streamlining the clinical laboratory. Increasing cost-containment pressures make the application of this technology extremely attractive, and several organizations have begun to systematically integrate robotic devices into their laboratory automation schemes. Integration of these technologies, however, presents many challenges for software developers, instrument manufacturers, and laboratory workers. Differing needs across laboratories require flexibility and intelligence in robots, instruments, and control systems. Standardization of mechanical and electronic interfaces will be key to making these systems easy to integrate. Systems engineering, aided by simulation modeling and artificial intelligence schemes, will be important to assist in the design of optimal configurations. Software for the overall control of integrated automation will be needed that can be tailored by the laboratorian to fit the requirements of the individual laboratory. Thus, laboratory workers will need to be actively involved in implementing this new wave of laboratory automation, becoming well-versed in computers, electronics, and systems engineering.