A simple foot pedal device in a horizontal bore imaging facility replicates weightbearing outcomes for Hallux Valgus patients.

BACKGROUND: Weightbearing images are important to the diagnosis of foot pathologies as are the three dimensional views available from CT and MRI. Standard three-dimensional imaging hardware, however, does not have a simple tool to obtain weightbearing images. The current research aimed to design, build and test a simple device to apply load in a horizontal bore imaging facility. METHODS: With the immediate need in hallux valgus studies, hallux valgus subjects were imaged using the new loading device, which could be easily transported and had no additional electronics. RESULTS: Testing showed that the usual angular measures of the foot (intermetatarsal and hallux valgus) replicated the results from the standard of care standing plain film results. With application of load, HV angle changed from 29.9° non-weightbearing to 32.2° weightbearing, while IM angle changed from nonweightbearing 15.8° to weightbearing 16.5°. CONCLUSION: The pedal-like device can provide weightbearing images in a horizontal bore MRI facility.

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer.

BACKGROUND: We previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival. PATIENTS AND METHODS: Patients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value ≥ 10 ng/ml and CEA measurements within ± 30 days of the CTC collection were included. RESULTS: We included 217 patients with mCRC who had a CEA value of ≥ 10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of ≥ 25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (≥ 3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3-5- and 6-12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6-12 weeks. CONCLUSIONS: This study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC.

Intraosseous hemangioma of the clivus: a case report and review of the literature.

Intraosseous hemangiomas are benign vascular tumors that are encountered most commonly in vertebrae and rarely in the skull. When presenting in the skull, they are commonly found in the calvarium in frontal and parietal bones and seldom in the skull base. We encountered a patient with an incidental finding on magnetic resonance imaging (MRI) of an enhancing lesion in the clivus. Here we report an unusual location of a clival intraosseous hemangioma. A 62 year old man worked up for carpal tunnel syndrome had imaging of his cervical spine that revealed an enhancing clival lesion, which extended into the left occipital condyle. Endoscopic endonasal biopsy was performed on the abnormality revealing a capillary hemangioma. Patient tolerated the biopsy well and no further surgical intervention is indicated at this time. Patient will be followed at six month intervals. Primary intraosseus hemangiomas of the skull are extremely rare and usually occur in the calvarium. This is one of the few reported case of an intraosseus hemangioma in the clivus. We present this case in part because it is unusual, but more importantly, with the wider use of MRI, it is likely that these lesions will be discovered more frequently, and conceivably confused for more dangerous lesions.

Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents.

BACKGROUND: Early predictive markers for response are needed for advanced colorectal cancer (ACC) patients. We assessed the value of circulating tumour cells (CTC) in ACC patients treated with chemotherapy plus targeted agents (CAIRO2 phase III trial) and compared the results with computed tomography (CT) imaging. MATERIALS AND METHODS: CTC were determined at baseline and at different time points during treatment. Patients were stratified into low (less than three CTC per 7.5 ml of blood) or high CTC (three or more CTC per 7.5 ml of blood). RESULTS: A total of 467 patients were assessable for CTC analysis. Among them, 129 patients (29%) with high baseline CTC had a significantly decreased progression-free survival [PFS; hazard ratio (HR) 1.5] and overall survival (OS; HR 2.2) compared with 322 patients with low baseline CTC. This difference remained statistically significant during treatment. The sensitivity and specificity of high CTC at baseline for the prediction of progressive disease on CT imaging were 16.7% and 70.1%, respectively, and of high CTC at 1-2 weeks after the start of treatment 20.0% and 95.1%, respectively. The combined analysis of CTC and CT imaging provided a more accurate outcome assessment than either modality alone. CONCLUSIONS: The CTC count before and during treatment independently predicts PFS and OS in ACC patients treated with chemotherapy plus targeted agents and provides additional information to CT imaging.

Circulating tumor cells and bone metastases as detected by FDG-PET/CT in patients with metastatic breast cancer.

BACKGROUND: We evaluated the relationship between the detection and prognostic significance of circulating tumor cells (CTCs) and sites of metastases detected by 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: From May 2004 to January 2008, 195 patients with relapsed/progressive MBC underwent whole-body FDG-PET/CT and provided blood samples for assessment of CTC count. RESULTS: Higher CTC numbers were detected in patients with bone metastases relative to those with no bone lesions (mean 65.7 versus 3.3, P = 0.0122) and in patients with multiple bone metastases relative to those with one or two bone lesions (mean 77.7 versus 2.6, P < 0.001). CTCs predicted overall survival (OS) in 108 patients with multiple sites of metastases including bone (P = 0.0008) but not in 58 without bone metastases (P = 0.4111) and in 29 with bone involvement only (P = 0.3552). All 15 patients but one with human epidermal growth factor receptor 2 (HER-2) positive tumors who were treated with trastuzumab-based regimens had <5 CTCs at progression. In multivariate analysis, CTCs, but not bone metastases, remained a significant predictor of OS. CONCLUSION: Presence of extensive bone metastases as detected by FDG-PET/CT is associated with increased CTC numbers in MBC.

Adolescent alcohol exposure produces sex differences in negative affect-like behavior and group I mGluR BNST plasticity.

Adolescent alcohol exposure increases the risk of developing alcohol use disorders (AUDs), yet the mechanisms responsible for this vulnerability remain largely unknown. One potential target for alcohol-induced changes is the circuitry that modulates negative affect and stress, two sexually dependent drivers of alcohol relapse. The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic region that critically regulates negative affective- and stress-induced relapse. Group I metabotropic glutamate receptors (mGluR) are a target of interest due to their regulation of stress, anxiety behaviors, and BNST plasticity. The current studies investigate sex-dependent sensitivity to the effects of adolescent intermittent ethanol vapor exposure (AIE) on negative affect during acute and protracted alcohol withdrawal and following stress in adulthood. This work also assessed whether BNST group I mGluR-mediated long-term depression (LTD) was disrupted at these timepoints. During acute withdrawal, AIE altered LTD induced by the group I mGluR antagonist DHPG in females, but not males. During adulthood, stress unmasked persistent changes in DHPG-induced LTD and behavior that were not present under basal conditions. Females with an AIE history demonstrated enhanced negative affective-like behavior in the novelty-induced hypophagia test following restraint stress-a phenotype that could be blocked with systemic mGluR5 allosteric antagonism via MTEP. Conversely, males with an AIE history demonstrated elevated freezing in a contextual fear conditioning paradigm. These studies demonstrate long-lasting, sex-dependent phenotypes produced by AIE and suggest pharmaceutical interventions for alcohol use and comorbid disorders may be more effective if designed with sex differences in mind.

Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer.

BACKGROUND: We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs. PATIENTS AND METHODS: CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of > or = 3 or <3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS). RESULTS: Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), >/=65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS. CONCLUSION: Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.

Arctic lakes and streams as gas conduits to the atmosphere: implications for tundra carbon budgets.

Arctic tundra has large amounts of stored carbon and is thought to be a sink for atmospheric carbon dioxide (CO(2)) (0.1 to 0.3 petagram of carbon per year) (1 petagram = 10(15) grams). But this estimate of carbon balance is only for terrestrial ecosystems. Measurements of the partial pressure of CO(2) in 29 aquatic ecosystems across arctic Alaska showed that in most cases (27 of 29) CO(2) was released to the atmosphere. This CO(2) probably originates in terrestrial environments; erosion of particulate carbon plus ground-water transport of dissolved carbon from tundra contribute to the CO(2) flux from surface waters to the atmosphere. If this mechanism is typical of that of other tundra areas, then current estimates of the arctic terrestrial sink for atmospheric CO(2) may be 20 percent too high.

Structural mechanisms of QacR induction and multidrug recognition.

The Staphylococcus aureus multidrug binding protein QacR represses transcription of the qacA multidrug transporter gene and is induced by structurally diverse cationic lipophilic drugs. Here, we report the crystal structures of six QacR-drug complexes. Compared to the DNA bound structure, drug binding elicits a coil-to-helix transition that causes induction and creates an expansive multidrug-binding pocket, containing four glutamates and multiple aromatic and polar residues. These structures indicate the presence of separate but linked drug-binding sites within a single protein. This multisite drug-binding mechanism is consonant with studies on multidrug resistance transporters.

Transformation of a tundra river from heterotrophy to autotrophy by addition of phosphorus.

Continuous enrichment of an arctic river with only 10 parts per billion phosphate-phosphorus caused an immediate growth of attached algae for more than 10 kilometers downstream, showing that phosphorus alone limited photosynthesis. As a result of the increased photosynthesis, there was an increase in bacterial activity in films on rocks on the bottom of the stream. The major source of energy became the photosynthetic carbon fixed in the stream rather than the organic material entering from the surrounding tundra, and the overall metabolism of the stream shifted from heterotrophy to autotrophy. An increase in the size and developmental stage of some of the dominant aquatic insects illustrates the food limitation in this nutrient-poor habitat.

Dose-response relationship of luteinizing hormone to luteinizing hormone--releasing hormone in man.

In previous clinical studies with highly purified porcine luteinizing hormone-releasing hormone (LH-RH), administration of the somewhat arbitrarily chosen doses of 700-1500 mug resulted in increased serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The present study determined the minimum effective dose as well as the relationship of the response of serum LH and FSH to the dose of LH-RH administered. Three normal men received i.v. injections of 1.1-810 mug of LH-RH. A dose of 10 mug of LH-RH caused a statistically significant elevation in serum LH. 30 mug of LH-RH significantly increased serum FSH levels. A highly significant linear trend was observed in the log dose-response curve. The results indicate that both LH and FSH release occurs in man with doses of LH-RH much lower than previously used and that a linear log dose-response relationship can be obtained.

Weight-bearing recommendations after first metatarsophalangeal joint arthrodesis fixation: a biomechanical comparison.

BACKGROUND: This study sought to determine whether several metatarsophalangeal (MTP) fusion techniques require complete immobilization or if some level of weight-bearing could be recommended after surgery. A comparison of synthetic composite to actual bone was included in order to examine the validity of the testing conditions. METHODS: Four MTP fusion modalities were tested in synthetic composite bone models: unlocked plating, locked plating, crossed lag screws, and an unlocked plate with a single lag screw. Stiffness was calculated and then used to find the two most rigid constructs; the load to failure was recorded. Stiffness and load to failure testing for the two more rigid constructs in paired cadaveric bones were followed. RESULTS: The unlocked plate plus screw and crossed screw constructs were stiffest (p < 0.008). Loads to failure of the unlocked plate plus screw and crossed screws in synthetic bone were 131 and 101 N, respectively and in cadaveric bone were 154 and 94 N, respectively, which are less than the estimated 25% body weight required at the MTP joint. The plate plus screws were statistically more stiff than crossed screws (p = 0.008), but there was no statistical difference between synthetic and cadaveric bone in load to failure (p = 0.296). CONCLUSIONS: The plate plus screw offered the greatest stiffness; the failure test showed that no construct could withstand weight-bearing as tolerated; and, synthetic composite models of the MTP joint did not provide the consistent results in stiffness and failure.

5-Fluorouracil interferes with paclitaxel cytotoxicity against human solid tumor cells.

Paclitaxel, a naturally occurring antimitotic agent, has shown efficacy in the treatment of certain solid tumors, particularly metastatic breast carcinoma and drug-refractory ovarian cancers. Recent studies have demonstrated that paclitaxel, in addition to its effects on microtubules and cell cycle arrest, possesses significant cell-killing activity in solid tumor cells by the induction of apoptosis. However, the mechanism by which paclitaxel leads to cell death and its relationship with paclitaxel-induced mitotic arrest is presently unclear. In this study, we attempted to determine whether pre-arresting tumor cells at other phases of the cell cycle could affect paclitaxel-induced apoptosis. We found that 5-fluorouracil (5-FU), another antineoplastic agent that usually arrests tumor cells at the G1-S phase of the cell cycle, could significantly repress the cell-killing activity of paclitaxel in solid tumor cells, even when it was added simultaneously with paclitaxel. Further studies indicated that 5-FU actually inhibits the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death, suggesting that 5-FU might interfere with paclitaxel cytotoxicity at an early stage, probably by preventing tumor cells from entering G2-M phase. Because recent clinical trials have used a combination of paclitaxel and 5-FU in the treatment of metastatic breast cancers, our results also suggest that the combination of these two drugs might not be as valuable in clinical chemotherapy.

Effect of forage type with or without corn supplementation on animal performance, beef fatty acid composition, and palatability.

Thirty-two steers were used to examine forage type (legumes [ and ] vs. grasses [ and ]) with or without individual corn grain supplementation (0 vs. 0.75% of live weight [LW]/d) on beef fatty acid composition and palatability. In each year, steers ( = 16/yr) were randomly assigned to forage type ( = 8/forage type per yr) and to supplementation treatments within forage type ( = 4/supplementation treatment/forage type per yr). Forage types (grasses vs. legumes) were replicated in 2 paddocks of perennial and annual forage type pastures. A mixed model was developed with forage type, corn grain supplementation, and the 2-way interaction as fixed effects and 2 different error terms, one for testing forage and another for testing grain supplement and grain supplement × forage interaction. Corn grain supplementation increased ( = 0.01) ADG by 0.29 kg/d and final LW by 13 kg. Hot carcass weight, dressing percentage (DP), and KPH were greater ( < 0.05) for steers supplemented with corn grain. Carcasses from steers grazing legumes had greater ( = 0.04) DP compared with carcasses from steers grazing grasses. Alpha-linolenic acid concentration was higher ( < 0.05) in LM of steers grazing legumes than in LM of steers grazing grasses, both without supplementation. Supplementation decreased ( < 0.05) linolenic acid levels for both forage types; however, the magnitude of this reduction was greater for legumes than for grasses. The ratio of -6 to -3 PUFA was greater ( = 0.03) in the LM of corn grain-supplemented steers than in the LM of nonsupplemented steers. Supplementation of corn grain decreased ( < 0.05) the percentage of odd-chain fatty acids and increased ( < 0.05) the percentage of MUFA in the LM. Warner-Bratzler shear force values were not altered ( > 0.05) by forage type, supplementation, or the 2-way interaction. Beef finished on legumes had greater concentrations of -3 PUFA, whereas beef supplemented with corn grain had a greater ratio of -6 to -3 fatty acids. On a gravimetric basis (mg/100 g LM), -3 PUFA and CLA contents were not altered with supplementation, indicating that corn grain can be supplemented at this level in a forage-finishing beef system without negative consequences on perceived beneficial fatty acids.

Modification of renin reactivity by lipids extracted from normal, hypertensive, and uremic plasma.

Plasma renin reactivity (PRR), the in vitro rate of angiotensin generation after addition of renin, is greater in plasma of hypertensive patients and uremic patients than in plasma of normotensive control subjects. To determine if this difference is due to different substrate reactivities, substrate was denatured and replaced with homologous substrate. After a 180 min incubation, PRR in normal plasma (73 ng/ml +/- 5 SE) was less (P less than 0.01) than that in hypertensive (112 ng/ml +/- 15 SE) or uremic (123 ng/ml +/- 39 SE) plasma. To determine if uremic plasma lacks a renin inhibitor, buffer or plasma was added to renin-renin substrate. Less angiotensin was generated (P less than 0.05) with normal (72 ng/ml +/- 4 SE) and uremic (88 ng/ml +/- 4 SE) plasma during 30 min than with buffer (107 ng/ml +/- 4 SE). After 180 minutes, less angiotensin was generated with normal (P less than 0.05) but not uremic plasma (P greater then 0.6), than with buffer. In vitro angiotensin generation was inhibited by lipids extracted from normal plasma. Lipids were separated into acetone soluble (neutral lipids) and acetone insoluble (phospholipid) fractions. Acetone soluble lipids, extracted from normal plasma, competitively inhibit renin: renin was not inhibited by acetone insoluble lipids. Acetone soluble lipids extracted from uremic plasma inhibited PRR to a lesser extent than lipids from either normal plasma or hypertensive plasma (P less than 0.01). Increased PRR in uremic plasma may be related to the deficiency of a circulating acetone soluble renin inhibiting factor.

Relation of large birthweight to maternal diabetes mellitus.

The records of 517 pregnancies which terminated in the delivery of infants weighing 9 lb or more were reviewed. The obstetric patient most likely to deliver a large birthweight infant was characterized. Toxemia, prolonged labor, and puerperal morbidity occurred with increased frequency. Many of the deliveries were complicated by fetopelvic disproportion with resultant increase in mid-forceps deliveries, cesarean sections, and perinatal morbidity. Five of the 517 patients delivering large birthweight infants were known to have diabetes mellitus prior to the pregnancy included in this study. An additional 369 patients were evaluated with intravenous glucose tolerance tests. Thirty-eight (10.3%) of the 369 tested proved to have diabetic glucose tolerance curves. The likelihood of finding maternal diabetes mellitus increased with the infant's birthweight. Multiple regression analysis of other clinical variables failed to predict which patients would prove to have diabetes. Identification of diabetic puerperas requires that glucose tolerance tests be performed in all who delivered large birthweight infants.

Maternal risk factors in infants with very low birth weight.

To determine whether maternal risk factors associated with the delivery of very low birth weight infants under 1501 g are different from those associated with low birth weight infants of 1501 to 2500 g, prenatal data on 12,247 deliveries were evaluated. The sample contained 302 very low birth weight infants. Maternal race, age, height, weight, gravidity, parity, past pregnancy performance, and pregnancy complications were analyzed. Factors related to very low birth weight but not to low birth weight infants were previous abortions, previous fetal deaths, and hypertensive vascular disease. Race, maternal height, and prepregnancy weight were not related to very low birth weight but were associated with an increase in low birth weight. There was no significant difference in the rate of very low birth weight or low birth weight by maternal age from 14 to 40 years. These results contradict the concept of a uniform set of predisposing factors for birth of all infants weighing 2500 g or less.

Free/total PSA ratio improves differentiation of benign and malignant disease of the prostate: critical analysis of two different test populations.

OBJECTIVES: To evaluate the ability of free PSA (fPSA), total PSA (tPSA), and the free/total PSA (f/t PSA) ratio to differentiate between benign prostate disease (benign prostatic hyperplasia [BPH] and no evidence of malignancy [NEM]) and prostate cancer (CaP) using two different testing populations, and to compare predictive probabilities for the two test populations. METHODS: One test population consisted of sera from 531 men with clinically well-defined and biopsy-confirmed BPH (n = 255) or CaP (n = 276), with tPSA values ranging from 2 to 20 ng/mL. All of these serum samples were retrospective and obtained from patients evaluated in academic settings before any treatment. A second test population consisted of a prospective analysis of sera obtained from 4870 men, collected by urologists throughout the United States and processed at a single pathology laboratory. All these patients had a systematic biopsy evaluated and diagnosed at the same pathology laboratory, with the diagnosis categorized as either NEM (n = 2961) or CaP (n = 1909). No additional information on concurrent disease or pre- or current treatment status was known for this test population. For both populations, two tPSA reflex range groups, 2 to 10 and 2 to 20 ng/mL, were evaluated. RESULTS: Both test populations benefited from the application of either fPSA alone or the f/t PSA ratio to differentiate benign from malignant disease (t test P value less than 0.001). The receiver operating characteristic (ROC) curve for the f/t PSA ratio had an area under the curve (AUC) of 72% for n = 531 versus 63% for n = 4870, irrespective of the tPSA reflex range. Average fPSA values demonstrated a linear correlation to a range of tPSA concentrations for both test populations. Predictive probabilities (adjusted for established cancer prevalence rates in the academic population [n = 531]) calculated using f/t PSA ratios also demonstrated their value in contrasting the performance characteristics in the two test populations. CONCLUSIONS: The fPSA and f/t PSA ratio improved the differentiation of benign disease and CaP in two different patient samples. The f/t PSA ratio demonstrated an increased sensitivity and specificity when applied to differentiate clinically well-defined BPH and CaP (n = 531). The differences in the results between the two test samples are probably attributable to the variability of the patient's disease and treatment status in the larger, less refined, community-based population. The use of predictive probabilities provides the opportunity to provide patient-specific cancer probabilities instead of using population-based specific single cutoffs.

Ability to predict biochemical progression using Gleason score and a computer-generated quantitative nuclear grade derived from cancer cell nuclei.

OBJECTIVES: To determine the ability to predict prostate cancer progression using shape, size, and chromatin texture nuclear grading features preselected by logistic regression analyses based on expert-selected prostate cancer cell nuclei captured using a computer-assisted image analysis system. METHODS: One hundred fifteen patients with clinically localized prostate cancer were identified at the Johns Hopkins medical institutions. The mean follow-up period was 10.4 +/- 1.7 years in 70 patients without disease progression, whereas the mean time to progression for the entire group was 3.8 +/- 2.5 years. Using 5-microns Feulgen-stained tissue sections, approximately 150 cancer cell nuclei were selected and captured for each case using a CAS-200 Image Analysis System. Thirty-eight different nuclear morphometric descriptors (NMDs) were calculated for each cell nucleus. The variance of the NMDs for each tumor was examined by univariate and multivariate logistic regression analyses and by Cox survival analyses to assess their ability to predict prostate cancer progression. RESULTS: Postoperative Gleason scoring was significantly correlated with disease progression (P < 0.00001; sensitivity, 73%; specificity, 84%; receiver operating characteristic curve area under the curve (ROC-AUC), 83%). Using backward stepwise logistic regression at a stringency of P < 0.05, the variances of 11 of the NMDs were found to be multivariately significant for progression prediction (P < 0.00001; sensitivity, 78%; specificity, 83%; ROC-AUC, 86%). A single value, termed the quantitative nuclear grade (QNG), was created from the variances of these, 11 multivariately significant NMDs using the logistic regression function. The QNG and the postoperative Gleason score were combined to create a model for the prediction of progression having a sensitivity of 89%, specificity of 84%, and ROC-AUC of 92%. These two parameters (QNG and Gleason score) clearly separated the patient sample into three statistically distinct risk groups and predicted the time to progression on the basis of Kaplan-Meier survival probability analysis. CONCLUSIONS: The QNG, combined with the postoperative Gleason score, may assist in the more accurate stratification of patients undergoing radical prostatectomy into low-, moderate-, and high-risk groups for cancer recurrence and may permit the early initiation of adjuvant therapy.