Prolongation of off-cycle interval by finasteride is not associated with survival improvement in intermittent androgen deprivation therapy in LNCaP tumor model.

BACKGROUND: We have previously reported that finasteride administration in intermittent androgen deprivation therapy (IADT) can improve survival of nude mice bearing LNCaP xenograft tumors when the duration of off-cycle in IADT was fixed. A recent retrospective study showed that addition of finasteride doubled the duration of the off-cycle, without changing progression to castration resistance. In view of the above difference, we attempted to investigate the relationship of 5alpha-reductase inhibition with the off-cycle interval and overall survival in a murine model. METHODS: Subcutaneous LNCaP tumors were established in nude mice (Balb/C-Nu). After the tumors reached a size of 0.5 cm in diameter, the mice were castrated and followed up for 2 weeks after which they were randomized to continuous androgen deprivation (CAD), CAD plus finasteride, IADT, and IADT plus finasteride. The off-cycle was discontinued when the tumor volume was doubled. Subsequent cycles were carried out similarly. RESULTS: Use of finasteride during the off-cycle of IADT doubled the first off-cycle duration. However, prolongation of the off-cycle by finasteride did not translate into an increase in overall survival. CONCLUSIONS: The survival advantage of IADT + finasteride over IADT that we previously reported was lost when the off-cycle prolongation by finasteride was allowed. Maximum possible lengthening of the off-cycle by 5alpha-reductase inhibition is not associated with survival improvement in this animal model.

Hypoxia inducible factor-alpha activation in lymphoma and relationship to the thioredoxin family.

Hypoxia inducible factors (HIFs) activate oncogenic pathways, while thioredoxins (Trx), including Trx1 and Trx reductases-1 and -2 (TrxR1 and TrxR2), promote HIF-alpha stabilization. In immunoblotting studies in lymphoma cell lines we found that Raji and SUDHL4 cells exhibited normoxic HIF-2alpha protein stabilization. Five cell lines showed increased TrxR1 expression, while only Namalwa, HF1 and SUDHL4 had Trx1 and TrxR2 activation. Tissue microarrays in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) identified different HIF expression among histological subgroups (e.g. 44% DLBCL vs. 11% of FL cases with moderate-to-high expression of HIF-1alpha and HIF-2alpha, P = 0.0017). These data demonstrate that HIF and the thioredoxin family are abnormally activated in lymphoma.

Multicenter Phase II Study of Sequential Brentuximab Vedotin and Doxorubicin, Vinblastine, and Dacarbazine Chemotherapy for Older Patients With Untreated Classical Hodgkin Lymphoma.

PURPOSE: To improve the curability of older patients with newly diagnosed Hodgkin lymphoma. PATIENTS AND METHODS: We conducted a multicenter phase II study that administered brentuximab vedotin (Bv) sequentially before and after standard doxorubicin, vinblastine, and dacarbazine (AVD) for untreated patients with Hodgkin lymphoma age 60 years or older. After two lead-in doses of single-agent Bv (1.8 mg/kg once every 3 weeks), patients received six cycles of AVD chemotherapy followed by four consolidative doses of Bv in responding patients. RESULTS: Patient characteristics included median age of 69 years (range, 60 to 88 years), 63% male, median Eastern Cooperative Oncology Group performance status 1, 81% stage III to IV disease, 60% International Prognostic Score 3 to 7, median Cumulative Illness Rating Scale-Geriatric comorbidity score of 7 (52% grade 3 to 4); and 12% had loss of instrumental activities of daily living at diagnosis. Thirty-seven (77%) of 48 patients completed six cycles of AVD, and 35 patients (73%) received at least one Bv consolidation. Overall response and complete remission rates after initial Bv lead-in dose were 18 (82%) of 22 and 8 (36%) of 22, respectively, and 40 (95%) of 42 and 34 (90%) of 42, respectively, after six cycles of AVD among 42 response-evaluable patients. Twenty (42%) of 48 patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%); 33% had grade 2 peripheral neuropathy, which was reversible in a majority of patients. By intent-to-treat, the 2-year event-free survival, progression-free survival, and overall survival rates were 80%, 84%, and 93%, respectively. Furthermore, 2-year progression-free survival rates for patients with a Cumulative Illness Rating Scale-Geriatric comorbidity score of ≥ 10 versus < 10 were 45% versus 100%, respectively (P < .001), and with baseline loss versus no loss of instrumental activities of daily living were 25% versus 94% (P < .001), respectively, the latter persisting on multivariable analyses. CONCLUSION: Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes. Furthermore, geriatric-based measures were strongly associated with patient survival.

The methodology used to measure differential gene expression affects the outcome.

Confirmation of gene expression by a second methodology is critical in order to detect false-positive findings associated with microarrays. However, the impact of methodology upon the measurement of gene expression has not been rigorously evaluated. In the current study, we compared differential gene expression between PC3 and PC3-M human prostate cancer cell lines using three separate methods: microarray, quantitative RT/PCR (qRT/PCR), and Northern blotting. The PC3 to PC3-M ratio of gene expression was determined for each of 24 different genes evaluated, by each of the three methods. Comparison of gene expression ratios between Northern and microarray, Northern and qRT/PCR, and microarray and qRT/PCR, gave correlation coefficients (r) of 0.72, 0.39, and 0.63, respectively. In each instance, one to two outlier genes were apparent. Their exclusion from analysis gave r values of 0.79, 0.72, and 0.83, respectively. These findings demonstrate that the assessment of differential gene expression is dependent upon the methodology used in each situation where outcome between different methodologies was compared, the presence of a relatively limited number of outlier genes precludes high overall correlation between the methods. Validation of gene expression by different methods should be performed whenever possible.

Acanthosis nigricans: a common finding in overweight youth.

We evaluated the prevalence of acanthosis nigricans among urban youth. Youth (7-17 years) at nine pediatric practices completed surveys on demographics and family history of diabetes and had weight and height measured. Acanthosis nigricans was scored and digital photography of the neck performed. A total of 618 youth were included in the analysis: mean age 11.5 years; 51% female; 61% African American, 27% Hispanic, 12% Caucasian, and 32% with body mass index >or=95th percentile. Acanthosis was found in 19%, 23%, and 4% of the African American, Hispanic, and Caucasian youth, respectively, and in 62% of youth with a body mass index >or=98 th percentile. Using multiple logistic regression, we found increasing body mass index z-score, presence of maternal gestational diabetes, female gender, and not being Caucasian each were independently associated with acanthosis nigricans. Acanthosis was common among overweight youth and was associated with risk factors for glucose homeostasis abnormalities. Acanthosis nigricans can be a trigger to counsel families on its causes and consequences; and thus motivate them to make healthy lifestyle changes that can decrease the risk of developing cardiovascular disease or diabetes.

Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor.

Selective Estrogen Receptor Modulators (SERMs) are a new class of drugsthat bind to estrogen receptor (ER) and elicit agonistic or antagonistic responses, depending on the target tissue. We have developed an in vitro system in which some SERMs (4-hydroxytamoxifen and resveratrol) demonstrate estrogenic response through wild-type (wt) ER, whereas others (raloxifene and GW7604) remain antiestrogenic. This system mimics the tamoxifen-resistant phenotype in clinic, when resistant tumors contain wtER. We used Atlas cDNA arrays to study gene expression profiles after ER activation by different SERMs in MDA-MB-231 human breast cancer cells stably transfected with wtER. Cells were treated with estradiol, four different SERMs, and the pure antiestrogen ICI 182,780. The obtained expression data were analyzed using GeneSpring software. Real-time reverse transcription-PCR was used to verify the array data. Our results showed that treatment with various compounds altered the expression of a diverse group of genes, revealing sets of overlapping genes that may represent a complex network of genes of interrelated signal transduction pathways. Sets of "agonistic" and "antagonistic" genes were identified on the basis of the known response to different SERMs. Further analysis of selected sets of genes revealed functionally related group of genes in each set, encoding proteins that were related to cell proliferation, survival, and apoptosis. Flow cytometry data indicated an antiapoptotic activity in cells treated with agonists versus apoptotic activity in cells treated with antagonists. A model for estradiol-like (survival) and antiestrogen-like (apoptosis) activities of SERMs on the basis of their gene expression profiles is suggested.

LY293111 improves efficacy of gemcitabine therapy on pancreatic cancer in a fluorescent orthotopic model in athymic mice.

Pancreatic cancer has an abysmal prognosis because of late diagnosis and lack of effective therapeutics. New drugs are desperately needed. The present study determined the effect of the LTB4 receptor antagonist, LY293111, on tumor growth and metastases in a fluorescent orthotopic model of pancreatic cancer. Pancreatic cancer cells (S2-013) with stable expression of enhanced green fluorescent protein were implanted into the duodenal pancreatic lobe of athymic mice. Animals were allocated to four groups (eight mice per group): control (no treatment); LY293111; gemcitabine; and LY293111 + gemcitabine. Monitoring of the surgical procedure and follow-up examinations at 2, 3, and 4 weeks after implantation to monitor tumor growth and metastases were performed using a fluorescence microscope and the reversible skin-flap technique. A staging and scoring system was developed to evaluate tumor progression, based on the TNM classification. Control animals developed end-stage disease with invasive cancer, metastases, and cachexia. Tumor growth and incidence of metastases were significantly reduced in all treated mice. However, combined treatment with LY293111 and gemcitabine was most effective. LY293111 is a novel therapeutic agent for pancreatic cancer, which improves the efficacy of gemcitabine. It is well tolerated and can be administered orally and, therefore, provides a new hope for patients suffering from pancreatic adenocarcinoma.

Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status.

PURPOSE: To evaluate (1) whether there were racial differences in the androgen receptor gene CAG repeat length and in clinical or laboratory attributes of prostate cancer at the time of diagnosis; (2) whether there were differences in race, Gleason score, prostate-specific antigen (PSA) level, and stage at diagnosis by androgen receptor gene CAG repeat length; and (3) whether sociodemographic, clinical, and laboratory based factors might be associated with advanced-stage prostate cancer. To our knowledge, our study is the first to report on CAG repeat lengths in a cohort of prostate cancer patients, which includes large numbers of African-American men. METHODS: CAG repeat lengths on the androgen receptor gene were evaluated for 151 African-American and 168 white veterans with prostate cancer. The chi(2) test, t test, and logistic regression analyses were used to evaluate the associations between CAG repeat lengths and race, stage, histologic grade, and PSA levels at diagnosis. RESULTS: The mean age of the cohort at the time of diagnosis was 68.7 years. At presentation, 42.0% had stage D prostate cancer, 26.5% had Gleason scores of 8 to 10, and 53.0% had PSA levels >/= 10 ng/dL. Mean androgen receptor gene CAG repeat length for white veterans was 21.9 (SD, 3.5) versus 19.8 (SD, 3.2) for African-American veterans (P =.001). Men with shorter CAG repeats were more likely to have stage D prostate cancer (P =.09) but were not more likely to have a higher PSA concentration or Gleason score. CONCLUSION: In this cohort of men with prostate cancer, short CAG repeat length on the androgen receptor gene was associated with African-American race and possibly with higher stage but not with other clinical or pathologic findings.

Clinical Trial Laboratory Data Nested With in Subject: Components of Variance, Sample Size and Cost.

Nesting of experimental factors is well established in statistical design literature related to agricultural, environmental and engineering studies. It is perhaps not sufficiently discussed in biological and laboratory experiments stemming from the use of human bio-specimens, where sample size considerations are often provided a priori on subject level, but there is little advice regarding the needed number of units at lower levels. Motivated by an example from spectroscopic microscopy and lung cancer, we revisit the experimental nesting frame work and discuss how variability, cost of sampling and sample size at lower levels may be coherently utilized. We show how the number of subjects may have to be adjusted to account for inadequate sampling decisions made at lower levels.

Clinical outcomes with the MammoSite radiation therapy system: results of a prospective trial.

OBJECTIVE: The purpose of this study was to report the treatment-induced adverse events and cosmetic and treatment outcomes of accelerated partial breast irradiation (APBI) delivered with the MammoSite radiation therapy system (RTS) in breast cancer patients undergoing breast-conserving therapy (BCT). METHODS: This is a prospective clinical trial that was approved by the institutional review board. The study included female breast cancer patients undergoing breast-conserving therapy in the form of surgery and APBI delivered with the MammoSite RTS. Patients and tumor characteristics, treatment-induced acute adverse events based on the Common Toxicity Criteria for Adverse Events (CTCAE) version 2.0, chronic AEs according to Radiation Therapy Oncology Group (RTOG) scale, treatment outcomes (including local control, disease-free survival, and overall survival), and cosmetic outcomes are reported. RESULTS: The study included 36 eligible patients treated consecutively in our institution between November 2003 and August 2009. The age range was 45-83 years. A total of 29 patients had invasive disease (median size 1.1 cm), while 7 patients had in situ disease only (median size 0.8 cm). The skin distance in most of the patients (91.7 %) was ≥1 cm; only three patients (8.3 %) had skin distance <1 cm. The median balloon diameter was 5 cm (range 4-6 cm). At a median follow-up of 42 months (range 4-65 months), local control, disease-free survival, and overall survival were 100 %. None of the patients experienced any grade 3 or 4 toxicities; 16.7 and 5.6 % of the patients had late grade 2 fibrosis and telangiectasia, respectively. At last follow-up, cosmetic outcome was rated as good or excellent in 94 % of the patients. CONCLUSION: APBI delivered with the MammoSite RTS is a feasible, tolerable, and effective treatment modality. Multicenter, randomized, controlled clinical trials with a larger number of patients are required for verification.

Characteristics of Certifying Urologists Performing Cystectomies in the United States.

INTRODUCTION: The surgical volume and training of the surgeon performing radical cystectomy can have a significant impact on bladder cancer outcomes. We hypothesize significant variability in the training and volume of surgeons performing radical cystectomy in the United States. METHODS: The 6-month case log data of urologists certifying between 2003 and 2013 were obtained from the American Board of Urology. Cases specifying an ICD-9 code for bladder cancer and a CPT code for radical cystectomy were analyzed for surgeon specific variables. RESULTS: A total of 5,335 radical cystectomies in the case log system were performed by 2,102 urologists, with 289 (5.4%) performed laparoscopically or robotically. Median urologist age was 42 years (range 36 to 50). Median number of cystectomies performed was 2 (IQR 1-3) with the top 10% of urologists performing 5 or more cystectomies. Half of cystectomies were performed by a urologist who performed only 1 during the certification period. On multivariable analysis stated specialty of oncology and nonprivate practice type were associated with top 10% cystectomy volume. For minimally invasive cystectomy 54% of surgeons logged only a single minimally invasive cystectomy. Factors predictive of performing minimally invasive cystectomy on multivariable analysis were male gender, more recent certifying year and original certification year, endourology and urolithiasis specialization, and Northeast practice region. CONCLUSIONS: Despite the high level of complexity associated with the surgical management of bladder cancer with radical cystectomy, the majority of cystectomies seem to be performed by low volume surgeons who have most often applied for their first certification with the American Board of Urology.

The burden of mucosal barrier injury laboratory-confirmed bloodstream infection among hematology, oncology, and stem cell transplant patients.

OBJECTIVE: To evaluate the impact and burden of the new National Healthcare Safety Network surveillance definition, mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI), in hematology, oncology, and stem cell transplant populations. DESIGN: Retrospective cohort study. SETTING: Two hematology, oncology, and stem cell transplant units at a large academic medical center. METHODS: Central line-associated bloodstream infections (CLABSIs) identified during a 14-month period were reviewed and classified as MBI-LCBI or non-MBI-LCBI (MBI-LCBI criteria not met). During this period, interventions to improve central line maintenance were implemented. Characteristics of patients with MBI-LCBI and non-MBI-LCBI were compared. Total CLABSI, MBI-LCBI, and non-MBI-LCBI rates were compared between baseline and postintervention phases of the study period. RESULTS: Among 66 total CLABSI cases, 47 (71%) met MBI-LCBI criteria. Patients with MBI-LCBI and non-MBI-LCBI were similar in regard to most clinical and demographic characteristics. Between the baseline and postintervention study periods, the overall CLABSI rate decreased from 3.37 to 3.21 infections per 1,000 line-days (incidence rate ratio, 0.95; 4.7% reduction, P=.84), the MBI-LCBI rate increased from 2.08 to 2.61 infections per 1,000 line-days (incidence rate ratio, 1.25; 25.3% increase, P=.44), and the non-MBI-LCBI rate decreased from 1.29 to 0.60 infections per 1,000 line-days (incidence rate ratio, 0.47; 53.3% reduction, P=.12). CONCLUSIONS: Most CLABSIs identified among hematology, oncology, and stem cell transplant patients met MBI-LCBI criteria, and CLABSI prevention efforts did not reduce these infections. Further review of the MBI-LCBI definition and impact is necessary to direct future definition changes and reporting mandates.

Adverse Events During Hematopoietic Stem Cell Infusion: Analysis of the Infusion Product.

BACKGROUND: Stem cell transplantation is a treatment option for patients with cancer. However, a risk of adverse events might be associated with the infusion itself. An understanding of the types and grades of adverse events occurring during infusion and the patient and infusion characteristics that might be associated with these events could allow for interventions to minimize these complications. The risk factors associated with transplant-related adverse events are not well understood. MATERIALS AND METHODS: We retrospectively analyzed the adverse events occurring within 1 hour after infusion in 460 patients with cancer undergoing stem cell transplantation at the Northwestern University Robert H. Lurie Comprehensive Cancer Center from January 1, 2008 and May 1, 2011. Of the 460 patients, 382 received autologous transplants and 78 allogeneic transplants. The incidence, types, and National Cancer Institute Common Terminology Criteria grade of toxicity for adverse events were noted (primary objective). Univariate analyses were performed to study which patient and infusion characteristics might be associated with the occurrence of adverse events (secondary objectives). RESULTS: Of the 460 patients, 261 (56.7%) experienced adverse events (66.7% during allogeneic infusion and 54.7% during autologous infusion). Most events were cardiopulmonary. Univariate analysis of the infusion and patient characteristics revealed that a second transplant (P = .005) was associated with more adverse events for autologous transplant patients. For allogeneic transplant patients, a higher infusion red blood cell volume (P = .01) was associated with more adverse events. CONCLUSION: Adverse events are common during stem cell infusion and are generally cardiopulmonary.

Assessing statistical competencies in clinical and translational science education: one size does not fit all.

INTRODUCTION: Statistics is an essential training component for a career in clinical and translational science (CTS). Given the increasing complexity of statistics, learners may have difficulty selecting appropriate courses. Our question was: what depth of statistical knowledge do different CTS learners require? METHODS: For three types of CTS learners (principal investigator, co-investigator, informed reader of the literature), each with different backgrounds in research (no previous research experience, reader of the research literature, previous research experience), 18 experts in biostatistics, epidemiology, and research design proposed levels for 21 statistical competencies. RESULTS: Statistical competencies were categorized as fundamental, intermediate, or specialized. CTS learners who intend to become independent principal investigators require more specialized training, while those intending to become informed consumers of the medical literature require more fundamental education. For most competencies, less training was proposed for those with more research background. DISCUSSION: When selecting statistical coursework, the learner's research background and career goal should guide the decision. Some statistical competencies are considered to be more important than others. Baseline knowledge assessments may help learners identify appropriate coursework. CONCLUSION: Rather than one size fits all, tailoring education to baseline knowledge, learner background, and future goals increases learning potential while minimizing classroom time.

Analysis of the safety and efficacy of intra-arterial thrombolytic therapy in ischemic stroke.

BACKGROUND AND PURPOSE: Intra-arterial thrombolytic therapy (IAT) may be a treatment option for patients with ischemic stroke. We analyzed the safety and efficacy of IAT on the basis of published data. METHODS: We searched computerized databases for studies using IAT in >/=10 patients with ischemic stroke. Some studies had control patients for comparison. Data were collected on age, stroke territory, time to treatment, medication, site of arterial occlusion and recanalization on angiogram, outcomes, and symptomatic intracranial hemorrhage (SICH). RESULTS: The analysis included 27 studies with 852 patients who received IAT and 100 control subjects. There were more favorable outcomes in the IAT than in the control group (41.5% versus 23%, P=0.002), with a lower mortality rate for IAT (IAT, 27.2%; control group, 40%, P=0.004). The IAT group had an odds ratio of 2.4 (95% CI, 1.45 to 3.85) for favorable outcome. SICH was more frequent in the IAT group compared with the control group (9.5% versus 3%, P=0.046). The subgroup of patients receiving a combination of intravenous thrombolytic therapy and IAT had more favorable outcomes than the IAT alone subgroup, but this trend did not reach statistical significance (53.6% versus 41.5%, P=0.1). Among the patients treated with IAT, those who had supratentorial strokes were more likely to have favorable outcomes than those with infratentorial strokes (42.2% versus 25.6%; P=0.001; odds ratio, 2.0; 95% CI, 1.33 to 3.0). CONCLUSIONS: IAT for ischemic stroke appears efficacious but carries an increased risk of SICH. Further prospective studies are needed to prove the safety and efficacy of IAT in stroke.

Antiplatelet effect of aspirin in patients with cerebrovascular disease.

BACKGROUND AND PURPOSE: Aspirin is used commonly to prevent ischemic strokes and other vascular events. Although aspirin is considered safe and effective, it has limited efficacy with a relative risk reduction of 20% to 25% for ischemic stroke. We sought to determine if aspirin as currently used is having its desired antiplatelet effects. METHODS: We ascertained patients with cerebrovascular disease who were taking only aspirin as an antiplatelet agent. Platelet function was evaluated using a platelet function analyzer (PFA-100). PFA test results were correlated with aspirin dose, formulation, and basic demographic factors. RESULTS: We ascertained 129 patients, of whom 32% were taking an enteric-coated aspirin preparation and 32% were taking low-dose (< or =162 mg/d) aspirin. For the entire cohort, 37% of patients had normal PFA-100 results, indicating normal platelet function. For the patients taking low-dose aspirin, 56% had normal PFAs compared with 28% of those taking > or =325 mg/d of aspirin, while 65% of patients taking enteric-coated aspirin had normal PFAs compared with 25% taking an uncoated preparation (P<0.01 for both comparisons). Similar results were obtained if PFA results were analyzed using mean closure times (low-dose aspirin, 183 sec; high-dose aspirin, 233 sec; enteric-coated, 173 sec; uncoated, 235 sec; P<0.01 for comparisons). Older patients and women were less likely to have a therapeutic response to aspirin, independent of aspirin dose or formulation. CONCLUSIONS: A significant proportion of patients taking low-dose aspirin or enteric-coated aspirin have normal platelet function as measured by the PFA-100 test. If these results correlate with clinical events, they have broad implications in determining how aspirin is used and monitored.

Variation in estradiol, estradiol precursors, and estrogen-related products in nipple aspirate fluid from normal premenopausal women.

The purpose of the study was to measure the concentrations of estradiol, its primary precursors, and factors with which it interacts in the breast, and determine their sources of variation. Nipple aspirate fluid (NAF) was collected from premenopausal women during the mid-luteal phase of the menstrual cycle. The fluid was diluted and unconjugated steroids were extracted. Estradiol was further purified by a solvent partition into aqueous NaOH. Androgens were measured in the non-phenolic fraction. Water-soluble, conjugated steroids and proteins were measured in the aqueous residue. All analytes were measured by immunoassays. Permutation methods were used to determine the correlations over multiple periods of time. The average concentration of estradiol in NAF was 435 pmol/L after purification but was many times higher when assayed without purification. Estrone and dehydroepiandrosterone (DHEA) sulfates were present in 3.7 and 75 micromol/L concentrations, respectively, while unconjugated androstenedione and DHEA were present in nanomole per liter concentrations. Lack of the steroid sulfates in NAF in 19% of subjects had no effect on NAF estradiol levels but was associated with a 77% lower concentration of unconjugated DHEA. Progesterone was present in concentrations that were 3- to 4-fold higher than normal serum concentrations (mean: 291 nmol/L). Cathepsin D, epidermal growth factor, and interleukin 6 had average values of 3.4 microg/mL, 424 ng/mL, and 1.7 ng/mL, respectively. Correlations between breasts were between 0.57 and 0.84 for the several analytes; correlations over time ranged from 0.64 and 0.93 with estrone sulfate highest in both categories. The lower correlation between breasts than within breasts indicates that local factors play an important role in determining the levels of many of these analytes in the breast. The high stability of the concentrations of several analytes over time indicates that fluctuations in environmental factors have little immediate effect on levels in the breast, and portends their utility as surrogate breast cancer risk markers.

Phase I pharmacokinetic and pharmacodynamic analysis of unconjugated soy isoflavones administered to individuals with cancer.

Preclinical studies suggest that the isoflavone genistein may have prostate cancer chemopreventive activity. Genistein has been shown to alter cellular levels of protein-tyrosine phosphorylation and is present at high levels in soy. This study was designed to measure the pharmacokinetic parameters of two different preparations of unconjugated soy isoflavones, PTI G-2535 and PTI G-4660 (which contain 43% and 90% genistein, respectively), in human subjects with cancer, to evaluate toxicity and obtain pilot data on in vivo effects on protein-tyrosine phosphorylation. Cohorts of four patients were given single doses of each preparation; each dose was separated by 1 week. Sequential cohorts received genistein at 2, 4, or 8 mg/kg orally. Pharmacokinetic sampling was performed after each dose, and tyrosine phosphorylation was measured in proteins extracted from peripheral blood mononuclear cells. One of 13 patients treated developed a treatment-related rash. No other toxicities were observed. Maximal plasma concentrations (C(max)) ranged between 4.3 and 16.3 micro M for total genistein and 0.066 and 0.17 micro M for free genistein. For PTI G-2535 and PTI G-4660, half-life was 15.03 and 22.41 h, respectively, and volume of distribution was 189.9 and 653.8 liters, respectively, and there was a trend toward higher area under the concentration curve for PTI G-2535 (P = 0.07 at the 8 mg/kg dose). Treatment-related increases in tyrosine phosphorylation were observed in peripheral blood mononuclear cells. Oral administration of soy isoflavones gives plasma concentrations of genistein that have been associated with antimetastatic activity in vitro.

Effect of LY293111 in combination with gemcitabine in colonic cancer.

New adjuvant therapies are needed for the treatment of stage III colon cancer. The essential fatty acids, linoleic and arachidonic acid enhance tumorigenesis through the cyclooxygenase and lipoxygenase pathways. Leukotriene B4 (LTB4) is a product of 5-lipoxygenase (5-LOX) which has tumor-promoting effects. The LTB4 receptor antagonist, LY293111 inhibited tumor growth and induced apoptosis in vitro. The effectiveness of LY293111, alone and in combination with gemcitabine was investigated in a heterotopic xenograft model in athymic mice using HT29 and LoVo human colonic cancer cells. The combined therapy markedly inhibited tumor growth and could warrant consideration as a new therapeutic option.

Risk assessment for inpatient survival in the long-term acute care setting after prolonged critical illness.

OBJECTIVE: The past decade has witnessed growth in the long-term acute care (LTAC) hospital industry. There are no reliable risk assessment models that can adjust outcomes across such facilities with different criteria for admitting patients. Variation in reported outcomes makes it difficult to determine whether a patient, or group of patients, may benefit from such care. This study sought to determine the extent to which survival in the LTAC setting is associated with age, race, residual organ system failures (OSFs), or APACHE (acute physiology and chronic health evaluation) III scores at the time of admission to LTAC. DESIGN: Retrospective medical record review. SETTING: Four freestanding facilities of a LTAC hospital. PATIENTS: A sample of 300 hospital admissions weighted to represent the study hospital population. MEASUREMENTS: Inpatient survival modeled as a function of age, APACHE III score calculated within 72 h prior to LTAC admission, and residual OSFs present on admission to LTAC. RESULTS: Logistic regression analysis shows age and OSF were most predictive of inpatient survival (receiver operating characteristic curve area = 0.81). APACHE III score was not predictive of survival in the multivariate model. CONCLUSIONS: Survival in LTAC is primarily associated with age and OSFs, which should be used to adjust for patient populations among LTAC settings when comparing outcomes. Our model identifies a group of patients with the poorest likelihood of survival in the LTAC setting, and may be used to facilitate dialogue with patients and family in cases where continued aggressive care is least effective.