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Purpose Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction. Patients and Methods The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Children's Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated. Results SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor–associated protein (GABARAP) gene expression predict decreased survival among all patients. GABAA δ receptor subunit gene expression was predictive of a poor outcome among Evans stage IV-S patients. An index of five coexpressed GABAA receptor subunits was identified (GABAA profile [GAP score]). Patients with a higher GAP score (> −1) had a survival advantage. Multivariate analysis showed that GABARAP and GABAA α2 receptor subunit gene expression levels and GAP score remained predictors of clinical outcome after accounting for current prognostic indicators. Conclusion Dysregulation of the GABAergic system may constitute a fundamental event in the development of NB, and assessment of GABAergic system gene expression could provide improved patient stratification and potential new therapies.

Purpose Adverse events in chemotherapy clinical trials are assessed and reported by clinicians, yet clinician accuracy in assessing symptoms has been questioned. We compared patient reporting of eight symptoms using a validated instrument, the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (QLQ-C30 or QLQ) with physicians' reporting of the same symptoms in the study's adverse events log. Patients and Methods Thirty-seven men with metastatic, androgen-independent prostate cancer enrolled onto a phase II trial of weekly calcitriol and docetaxel completed the QLQ every 4 weeks for up to 28 weeks. A patient-reported symptom was defined as an increase in a QLQ symptom score by at least 10 points (0 to 100 scale), sustained for at least 4 weeks. A physician-reported symptom was considered present if it was ever documented in the adverse event log. Results Forty-nine (new or worsened) symptoms were detected by both physician and QLQ, 48 symptoms were detected by the physician alone, and 55 symptoms were detected by the QLQ alone. They agreed on the absence of a symptom in 102 instances of 254 possible opportunities. Their uncorrected agreement was 59.4%, but Cohen's κ, a coefficient of agreement that corrects for chance, was 0.15, indicating only slight agreement. Using the QLQ as the standard, overall physician sensitivity and specificity was 47% and 68%, respectively, although it varied considerably among symptoms. Conclusion Even in a tightly controlled clinical trial, physician reporting was neither sensitive nor specific in detecting common chemotherapy adverse effects. Tools for collecting patient-reported adverse event data in chemotherapy clinical trials should be developed.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the impairment of cognitive functions and by beta amyloid (Abeta) plaques in the cerebral cortex and the hippocampus. Our objective was to determine genes that are critical for cellular changes in AD progression, with particular emphasis on changes early in disease progression. We investigated an established amyloid precursor protein (APP) transgenic mouse model (the Tg2576 mouse model) for gene expression profiles at three stages of disease progression: long before (2 months of age), immediately before (5 months) and after (18 months) the appearance of Abeta plaques. Using cDNA microarray techniques, we measured mRNA levels in 11 283 cDNA clones from the cerebral cortex of Tg2576 mice and age-matched wild-type (WT) mice at each of the three time points. This gene expression analysis revealed that the genes related to mitochondrial energy metabolism and apoptosis were up-regulated in 2-month-old Tg2576 mice and that the same genes were up-regulated at 5 and 18 months of age. These microarray results were confirmed using northern blot analysis. Results from in situ hybridization of mitochondrial genes-ATPase-6, heat-shock protein 86 and programmed cell death gene 8-suggest that the granule cells of the hippocampal dentate gyrus and the pyramidal neurons in the hippocampus and the cerebral cortex are up-regulated in Tg2576 mice compared with WT mice. Results from double-labeling in situ hybridization suggest that in Tg2576 mice only selective, over-expressed neurons with the mitochondrial gene ATPase-6 undergo oxidative damage. These results, therefore, suggest that mitochondrial energy metabolism is impaired by the expression of mutant APP and/or Abeta, and that the up-regulation of mitochondrial genes is a compensatory response. These findings have important implications for understanding the mechanism of Abeta toxicity in AD and for developing therapeutic strategies for AD.

OBJECTIVE To identify predictors of delayed therapy with curative intent, an increasingly common option in contemporary patients with prostate cancer who initially choose watchful waiting. PATIENTS AND METHODS The characteristics of all patients at one institution and diagnosed with T1–4NXM0 prostate cancer between 1993 and 2000 were prospectively recorded. Factors recorded included: age, tumour stage, histological type, Gleason score, serum prostate specific antigen (PSA) level, prostate volume, PSA density (PSAD), percentage of positive biopsy cores, and the initial treatment selection. Outcomes, including all cancer-directed interventions, all serum PSA values, and initial outcomes of all interventions with curative intent, were determined by review of all medical records and cancer registry data. RESULTS Of 187 patients on watchful waiting, 175 had stage T1 or T2 cancer and were analysed primarily. Thirty-eight (22%) of these patients received delayed intervention with curative intent (15 radical prostatectomy, 17 external beam radiotherapy, six brachytherapy). Age (P

Objective: To identify risk factors for delayed cancer-directed intervention in modern era prostate cancer patients who initially elect expectant management. Materials and Methods: An observational, cohort study of expectantly managed patients, diagnosed with clinical T1–4NxM₀ prostate cancer between 1993 and 2000 was carried out. Data including TNM stage, age, serum prostate-specific antigen (PSA), prostate gland volume by transrectal ultrasound, Gleason score, percent biopsies positive for cancer, imaging results, initial treatment selection, and outcome data were collected on all patients. Results: 192 of 561 patients (34.3%) elected expectant management, and follow-up data were available for 187 (97.4%) patients. With a median follow-up of 3.6 years, 90 (48.1%) patients had a cancer-directed intervention. Gleason score (p = 0.0097) and percent of positive biopsy cores (p = 0.03) were independent predictors of time to intervention. As expected, PSA doubling time became the most significant predictor of intervention (p = 0.0057) when added to the model. These independent covariates are able to characterize low-, intermediate- and high-risk groups for cancer-directed intervention. Conclusions: Cancer-directed intervention is common in patients who choose expectant management in the PSA era. Gleason score and percent of positive biopsy cores predict cancer-directed interventions, thus, these patients may be least suitable for expectant management.

Summary Background Molecular mechanisms of neuroprotection that lead to ischaemic tolerance are incompletely understood. Identification of genes involved in the process would provide insight into cell survival and therapeutic approaches for stroke. We developed a mouse model of neuroprotection in stroke and did gene expression profiling to identify potential neuroprotective genes and their associated pathways. Methods Eight mice per condition were subjected to occlusion of the middle cerebral artery for 15 min (preconditioning), 60 min (injurious ischaemia), or preconditioning followed 72 h later by injurious ischaemia. RNA was extracted from the cortical regions of the ischaemic and non-ischaemic hemispheres. Three pools per condition were generated, and RNA was hybridised to oligonucleotide microarrays for comparison of ischaemic and non-ischaemic hemispheres. Real-time PCR and western blots were used to validate results. Follow-up experiments were done to address the biological relevance of findings. Findings Microarray analysis revealed changes in gene expression with little overlap among the conditions of injurious ischaemia, ischaemic preconditioning, or both. Injurious ischaemia induced upregulation of gene expression; 49 (86%) of 57 genes regulated showed increased expression in the ischaemic hemisphere. By contrast, preconditioning followed by injurious ischaemia resulted in pronounced downregulation; 47 (77%) of 61 regulated genes showed lower expression. Preconditioning resulted in transcriptional changes involved in suppression of metabolic pathways and immune responses, reduction of ion-channel activity, and decreased blood coagulation. Interpretation Preconditioning reprogrammes the response to ischaemic injury. Similar changes reported by others support an evolutionarily conserved endogenous response to decreased blood flow and oxygen limitation such as seen during hibernation.

10105 Background: Gynecologic symptoms and sexual dysfunction from endocrine therapy are troublesome side effects for a significant number of patients. This study explored amelioration of vaginal dryness and dyspareunia with fluocinonide cream, a strong topical corticosteroid. Methods: A single-arm, open-label phase II trial of topical fluocinonide 0.05% cream to improve vaginal symptoms in women on endocrine therapy in the adjuvant setting for early stage breast cancer was performed. Patients with vaginal symptoms applied topical vaginal fluocinonide 0.05% cream twice a day for two weeks then once daily for two weeks. Patients were assessed for symptoms by weekly completion of the Mayo/North Central Cancer Treatment Group Patient Pretreatment Questionnaire. The primary outcome was a change from baseline in patient-reported effects of vaginal dryness and dyspareunia on a scale from 0 (no symptoms) to 4 (very severe symptoms) from time of enrollment and at 4 weeks. Secondary outcomes were decrease in vaginal itching and total vaginal index score. Comparisons were made with Wilcoxon sign rank test with 2.5% significance level. Results: Thirty-four women were accrued. At 4 weeks compared with baseline, vaginal dryness improved from a median score of 2 (moderate symptoms) to 0 (no symptoms) ( P < .001) and dyspareunia from 3 (severe symptoms) compared with 1 (mild symptoms) ( P = .002). Percentage of patients who had > 2 point improvement in vaginal dryness and dyspareunia was 69.0% and 75% respectively. Secondary analysis showed decrease in vaginal itching score from 1 to 0 ( P = .001) and vaginal index score of 6 to 1 ( P = .002). Twenty-one patients experienced low-grade toxicities which were mostly limited to skin irritation. Conclusions: Fluocinonide 0.05% cream improves vaginal dryness and dyspareunia experienced by women receiving endocrine therapy and has the potential to improve quality of life of cancer survivors and compliance of endocrine therapy. Clinical trial information: NCT00297011.

Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. We treated 20 patients who had recurrent prostate cancer with 200 μmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50 % PSA declines, the primary endpoint. Only one subject experienced a ≥50 % PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (

MicroRNA (miR)-320a, miR-145, and miR-192 have been shown to play a role in colorectal carcinogenesis and metastasis. We examined if there is a difference in expression during the histologic progression from normal mucosa (NM) to high-grade dysplastic adenomas (HG).Genome-wide miRNA expression profiling was performed on 113 colon adenomas. Information included histologic type, tumor grade, location, sex, age, family, and smoking history. A 2-way ANOVA was performed to evaluate the effect of the following factors adjusted for scan dates: location, sex, age, family history, smoking, and histology.The expression of miR-320a increased; miR-145 and miR-192 expression decreased (P .0001), with higher histologic grade, and were independent of age, sex, family history, and smoking status.The miRs studied had statistically significant changes in expression with progression of histologic grade. These changes may signify progression of normal mucosa to HG and potentially serve as early markers for disease progression and differentiating high- from low-risk adenomas.

Cancer treatment-related fatigue is the most prevalent and distressing symptom of cancer therapy. Interventions to minimize fatigue are needed. The purpose of this study was to examine the relationship between exercise and fatigue over the first three cycles of chemotherapy in women receiving either cyclophosphamide, methotrexate, and fluorouracil (CMF) or doxorubicin and cyclophosphamide (AC) for breast cancer.Seventy-two newly diagnosed women with breast cancer were instructed in a home-based moderate-intensity exercise intervention. Measures of functional ability, energy expenditure, and fatigue were obtained at baseline and posttest. Subjects maintained daily records of four types of fatigue, and exercise duration, intensity, and type.Exercise significantly reduced all four levels of fatigue (P0.01). As the duration of exercise increased, the intensity of fatigue declined (P0.01). There was a significant carry-over effect of exercise on fatigue, but the effect lasted only 1 d. The level of fatigue at study entry was not associated with number of days of exercise or amount of exercise a woman engaged in.The impact of exercise on fatigue was significant and suggests the effectiveness of a low- to moderate-intensity regular exercise program in maintaining functional ability and reducing fatigue in women with breast cancer receiving chemotherapy.

This research investigated the role of reporter gender in reporting about sensitive genderspecific cancers. On ABC, CBS, and NBC national newscasts from 1972 through 1995, male reporters presented 75 percent of all gender-specific cancer stories, delivered more stories over time, and delivered 96 percent of male-cancer stories and 72 percent of female-cancer stories. Female reporters delivered fewer female-cancer stories over time and never broke the sensitivity barrier regarding male-specific cancers. Male reporters delivered cancer as a science story, focused on treatment and therapy, and mentioned more medical research, journals, and organizations. Female reporters were more likely to report on health policy or famous women with cancer.

Patients treated with high doses of interleukin-2 (IL-2) develop profound anorexia, malaise, loss of energy, mucositis, nausea, and vomiting, which may contribute to poor nutrition. We hypothesized that total parenteral nutrition (TPN) administration would ameliorate these changes and could improve fluid and electrolyte balance. A retrospective analysis of protein and energy intake was performed in 21 sequential patients who received a normal diet (controls) and 16 subsequent patients who received TPN during IL-2 treatment. The effect of TPN on laboratory abnormalities induced by IL-2 was also evaluated. Within 24 h of starting IL-2, mean energy intake declined to 2.5-2.8 kcal/kg in controls in contrast to the energy intake of 25-29 kcal/kg in patients receiving TPN. Protein nutrition was affected in a similar fashion, with a markedly lower protein intake in controls (0.08-0.12 g/kg) than in the TPN group (1.02-1.10 g/kg). TPN improved serum calcium and potassium concentrations, particularly during spontaneous diuresis after completion of IL-2 treatment. Unexpectedly, TPN decreased the frequency and severity of cholestatic jaundice caused by IL-2. Patients receiving TPN had an increased propensity for hyperglycemia and hypophosphatemia. High-dose intravenous bolus IL-2 therapy resulted in a markedly negative nutritional balance in control patients. A brief period of TPN during IL-2 treatment was well tolerated and corrected calorie and protein malnutrition. TPN administration also improved control of serum electrolytes. TPN did not adversely affect tumor progression or patient survival.

Background As of May 1, 1995, the National Marrow Donor Program had a donor registry consisting of over 1.35 million HLA-typed volunteers recruited from most major cities and states in the United States. This registry represents the largest single HLA-typed pool of normal individuals in the world. Methods We analyzed the HLA-A, -B, -DR locus phenotypes of the National Marrow Donor Program donors in order to estimate gene and haplotype frequencies for major racial groups of the United States: Caucasian American, Asian American, African American, Latin American, and Native American. The large size of the database allowed us to calculate the frequencies of relatively rare antigens and haplotypes with more accuracy than previous studies. Results We observed 89,522 distinguishable HLA-A, -B phenotypes in 1,351,260 HLA-A, -B-typed donors and 302,867 distinguishable HLA-A, -B, -DR phenotypes in 406,503 HLA-A, -B, -DR-typed donors. Gene and haplotype frequencies differed remarkably among the five racial groups, with African Americans and Asian Americans having a large number of haplotypes that were specific to their racial groups, whereas Caucasian Americans, Latin Americans, and Native Americans shared a number of common haplotypes. Conclusions These data represent an important resource for investigators in the fields of transplantation and population genetics. The gene and haplotype frequencies can be used to aid clinicians in advising patients about the probability of finding a match within a specific ethnic group, or to determine donor recruitment goals and strategies. The information is also a valuable resource for individuals who are interested in population genetics, selection and evolution of polymorphic human genes, and HLA-disease association.

The objective of this study was to use a randomized controlled trial design to test the impact of an educational intervention delivered by specially trained community health workers among Chinese, Korean, and Vietnamese participants ages 50 to 75 years on knowledge, attitudes, beliefs, and intentions regarding colorectal cancer screening.Baseline data were collected on participants' demographic characteristics, knowledge, attitudes, beliefs about cancer, its risk factors, and intention to keep up to date on cancer screening in the future. Fifteen intervention sessions were held between April and June of 2011. Follow-up surveys were administered in the postintervention period to both intervention and control participants. Those randomized to the control group received educational pamphlets in their native language.The intervention had the greatest influence on the Chinese subgroup, which had improved scores relative to the control group for perceived behavior control and intentions (preintervention vs postintervention change: control group, -0.16; intervention group, 0.11; P = .004), behavioral beliefs on cancer screening (preintervention vs postintervention change: control group, -0.06; intervention group, 0.24; P = .0001), and attitudes toward behavior (preintervention vs postintervention change: control group, -0.24; intervention group, 0.35; P ≤ .0001). The intervention had no effect on behavioral beliefs about cancer, control beliefs, or perceived behavioral control (reliance on family). Although the intention to stay up to date for cancer screening increased in 2 study groups (Chinese and Vietnamese), these increases were not significant.An educational program delivered by culturally specific community health educators using culturally appropriate language influences some knowledge, attitude, and behavioral beliefs but not others.

Objective To test whether treatment with assisted movement with enhanced sensation (AMES) using vibration to the antagonist muscle would reduce impairments and restore upper limb function in people with incomplete tetraplegia. Design Prospective, pre-post study. Setting Laboratory and rehabilitation hospital. Participants We recruited 15 arms from 10 individuals (8 men; mean age, 40.5y; mean years postspinal cord injury [SCI], 3) with chronic, incomplete tetraplegia. Intervention Two or three 20-minute sessions per week over 9 to 13 weeks (25 sessions total) on the AMES device, which combines repeated movement with targeted vibration to the antagonist muscle. Main Outcome Measures Strength and active motion tests on the AMES device; International Standards for the Neurological Classification of SCI (ISNCSCI) motor and sensory examinations; Modified Ashworth Scale (MAS); grasp and release test (GRT); Van Lieshout Test (VLT); and Capabilities of Upper Extremity questionnaire (CUE). Results The AMES strength test scores improved significantly in metacarpophalangeal flexion ( P =.024) and extension ( P =.007) and wrist flexion ( P =.001) and extension ( P P =.001) and wrist ( P =.001). The MAS and ISNCSCI scores remained unchanged, whereas the GRT scores increased ( P =.025). Post hoc analysis showed a trend from pre- to posttreatment ( P =.068) and a significant change from pretreatment to 3-month follow-up ( P =.046). There was no significant change in the VLT ( P =.951) or the CUE ( P =.164). Five of the 10 participants reported a return of sensation to the digits after the first, second, or third treatment session. Conclusions People with chronic, incomplete tetraplegia may experience improvements in impairments and function after treatment on a device combining assisted movement and proprioceptive stimulation. Further investigation is warranted.

Background: Nonsustained ventricular tachycardia (NSVT) predicts mortality in several disorders but its significance in patients with sustained ventricular tachyarrhythmias is unknown. We analyzed the clinical features and outcome associated with NSVT (>; 3 beats at >; 100 beats/min) recorded on a 48-hour Holter in the absence of antiarrhythmic drugs. Methods: Patients enrolled in the ESVEM trial (n = 486) were grouped according to the duration of the longest recorded episode of NSVT, and in the second analysis, according to frequency of recorded episodes. Assessments were on an intention-to-treat basis. Results: Patients without NSVT were more likely to have ischemic heart disease and had significantly lower frequencies of single and paired premature ventricular complexes (PVCs). There were no significant differences with respect to age, sex, presenting arrhythmia, years since last myocardial infarction, functional class, or present ejection fraction. The cumulative probabilities of arrhythmia recurrence and all-cause mortality at 4 years in patients without NSVT (60%± 7% and 32%± 6%, respectively) were not significantly different than those of patients with NSVT (63%± 3% and 41%± 3%, respectively). Cox regression models indicated that ejection fraction and functional class were significant predictors of outcome, but variables based on the presence, duration, and frequency of recorded episodes of NSVT were not. Conclusions: NSVT is common in patients with spontaneous and inducible sustained ventricular tachyarrhythmias and at least 10 PVCs/hour (ESVEM enrollment criteria), but is not a significant predictor of arrhythmia recurrence, sudden death, or all-cause mortality in patients with these characteristics.

Summary Background and objectives Recognition of CKD by primary care practitioners is essential in rural communities where nephrology access is limited. This study determined the prevalence of undocumented CKD in patients cared for in rural primary care practices and evaluated characteristics associated with undocumented CKD as well as CKD management. Design, setting, participants, & measurements A retrospective cohort study, conducted within the Oregon Rural Practice Based Research Network, consisted of 865 CKD patients with serum creatinine$1.5 mg/dl in males and $1.3 mg/dl in females and an estimated GFR,60 ml/min per 1.73 m 2 . Documentation of a CKD diagnosis and laboratory values were abstracted by chart review. ResultsOfCKDpatients,51.9%hadnodocumentationofCKD.UndocumentedCKDoccurredmorefrequentlyin female patients (adjusted odds ratio=2.93, 95% confidence interval=2.04, 4.21). The association of serum creatinine reporting versus automating reporting of estimated GFR on CKD documentation was dependent on patient sex, years of practitioner experience, and practitioner clinical training. Hypertensive patients with documented CKD were more likely to have a BP medication change than patients with undocumented CKD (odds ratio=2.07, 95% confidence interval=1.15, 3.73). Only 2 of 449 patients with undocumented CKD were comanaged with a nephrologist compared with 20% of patients with documented CKD (odds ratio=53.20, 95% confidence interval=14.90, 189.90). Conclusions Undocumented CKD in a rural primary care setting is frequent, particularly in female patients. Depending on practitioner characteristics, automatic reporting of estimated GFR might improve documentation of CKD in this population.

Following transplantation of hematopoietic lineage cells, genetic markers unique to the transplanted cells have been detected in non-hematopoietic recipient cells of human liver, vascular endothelium, intestinal epithelium and brain. The underlying mechanisms by which this occurs are unclear. Evidence from mice suggests it is due in part to fusion between cells of hematopoietic and non-hematopoietic origins; however, direct evidence for this in humans is scant. Here, by quantitative and statistical analysis of X- and Y-chromosome numbers in epithelial and non-epithelial intestinal cells from gender-mismatched hematopoietic cell transplant patients, we provide evidence that transplanted cells of the hematopoietic lineage incorporate into human intestinal epithelium through cell fusion. This is the first definitive identification of cell fusion between hematopoietic cells and any epithelial cell type in humans, and provides the basis for further understanding the physiological and potential pathological consequences of cell fusion in humans.

Despite improved understanding of molecular lesions in relapsed/refractory acute leukemia, outcomes remain dismal. Aberrantly activated tyrosine kinase signaling pathways play a critical role in the pathogenesis of acute leukemia. Identification of drugs that target the drivers of disease has the potential to improve treatment. We have developed an FDA regulated (IDE# G110198) in vitro kinase inhibitor assay that can identify potential therapeutic targets in primary acute leukemia samples and provide individualized treatment options in a clinically relevant time frame. We designed a Phase 2 clinical trial (NCT01620216) to validate the role of this pre-clinical kinase inhibitor screen for selecting effective individualized therapies. After obtaining informed consent, peripheral blood or bone marrow is isolated using a ficoll-density gradient and plated with dose-escalating concentration gradients of five kinase inhibitors (nilotinib, dasatinib, sorafenib, sunitinib, and ponatinib). Cell line controls are used for each drug. Samples are deemed sensitive based on IC50 and comparison to the median of all samples tested in our laboratory (over 1000 primary samples to date). Patients who satisfy eligibility are treated with FDA approved dosing using the selected inhibitor. Inclusion is limited to patients age ≥ 21 with relapsed/refractory acute leukemia (AML and ALL) and patients age ≥ 65 with a history of myelodysplasia who have developed AML, have failed hypomethylating agents, and are not candidates for standard induction. Only patients with samples that demonstrate in vitro sensitivity to 1 of the trial drugs are eligible. Additional eligibility includes: ECOG ≤ 2, adequate organ function, and no active GVHD. Cycles are 28-days. Marrow biopsy for response assessment and correlative studies is obtained on days 15, 28, and day 1 of subsequent cycles. The primary objective is to determine the clinical activity, defined as > 25% decrease in bone marrow blast counts. Secondary objectives include overall response (defined by the International Working Group), overall survival, and progression free survival. Correlative studies include high-throughput sequencing, expression profiling, correlation of target inhibition with clinical response, and PK analysis. The treatment approach is deemed worthy of ongoing study if clinical activity is observed in at least 4 of 24 patients. 43 patients have been screened with 12 demonstrating in vitro sensitivity. Nine have been enrolled on treatment. Median age is 64 (31-71) years with 5 males and 4 females. Two patients had ALL. The remainder had AML. Drugs utilized to date include dasatinib (n=3) and sorafenib (n=6). Of the three patients who exhibited in vitro sensitivity but were not enrolled, sensitivity to sorafenib, sunitinib, and dasatinib was seen. Clinical activity was seen in 4 subjects with AML -all treated with sorafenib- with median change in marrow blast in this group of 69% (44-95%). Median time on treatment for responding patients was 39 days (18-110 days). One subject with refractory AML who had failed allogeneic transplant had a 95% decrease in marrow blasts with prolonged disease control (Figure 1). Two patients were taken off study due to drug-related AEs (pancreatitis and diarrhea). No unanticipated AEs were seen. Our in vitro kinase inhibitor assay identified potential therapies for the treatment of ALL and AML. Although the numbers are too small to draw any specific conclusions regarding response, the 4 responders were FLT3-ITD+ AML, a known target of sorafenib, and appear to have proliferative disease with higher baseline blast counts. The relatively small panel of available treatment drugs with overlapping target profiles may have contributed to the preferential treatment of patients with FLT3-ITD+ AML and to the significant screen fail rate. Our results using a larger panel of targeted agents have shown a high level of sensitivity to at least one drug. Accordingly, we are expanding the platform of clinically available targeted agents. The study continues to enroll patients with the goals of defining additional molecular abnormalities and optimizing assay characteristics, while prospectively testing the therapeutic potential of additional drugs. Correlative studies are ongoing. We have initiated another study using this assay to help select targeted therapies to be added to AML induction (NCT02779283). Figure Figure. Table Table. Disclosures Spurgeon: Gilead Sciences: Research Funding; Bristol Myers Squibb: Research Funding; Acerta Pharma: Research Funding; Genentech: Research Funding; Janssen: Research Funding. Maziarz:Incyte: Membership on an entity's Board of Directors or advisory committees; Athersys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tyner:Janssen Research & Development: Research Funding; Inctye: Research Funding; Genentech: Research Funding; Constellation Pharmaceuticals: Research Funding; AstraZeneca: Research Funding; Leap Oncology: Consultancy; Agios Pharmaceuticals: Research Funding; Array Biopharma: Research Funding; Aptose Biosciences: Research Funding; Seattle Genetics: Research Funding; Takeda Pharmaceuticals: Research Funding. Druker:Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy.

Introduction: Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies represents an ongoing challenge. Large-scale sequencing efforts have identified that many hematologic malignancies, such as acute myeloid leukemia (AML), are driven by a spectrum of mutations and may require combinations of targeted agents to be treated effectively. In addition, the emergence of genetically heterogeneous subclones leading to relapse, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways further necessitate combinatorial therapies. To identify combinations of targeted drugs for AML and other hematologic malignancies, we performed ex vivo profiling of pairs of small-molecule inhibitors for sensitivity against primary patient samples. Methods: Freshly isolated primary mononuclear cells from patients (n=122) with various hematologic malignancies (AML n=58, CLL n=42, ALL n=12, and MPN or MDS/MPN n=10) were cultured in the presence of a panel of 48 drug combinations in equimolar dose series encompassing different classes of compounds, including kinase inhibitors, bromodomain inhibitors, BH3 mimetics, and histone deacetylase inhibitors. For comparison, cells were also tested against graded concentrations of each inhibitor alone, and sensitivity was assessed by MTS-based viability assay. IC50 and AUC values were derived using a probit regression model. Efficacy of each combination relative to its single agents was calculated as a Combination Ratio (CR) value, defined as the combination IC50 or AUC divided by the lowest single agent IC50 or AUC value. A CR value < 1 indicates the combination is more effective relative to the single agent. Associated clinical characteristics were obtained where possible. For the 2 largest diagnostic groups, AML and CLL, expanded panels of clinical, prognostic, mutational, cytogenetic, and surface antigen data were compiled for comparisons according to CR values for each combination. Results: Unsupervised hierarchical clustering of CR values revealed several distinct clusters (Figure 1). Myeloid leukemia patient samples were enriched within a cluster of sensitivity to combinations pairing the Bcl-2 inhibitor venetoclax with select tyrosine kinase inhibitors (dasatinib, doramapimod, sorafenib, or idelalisib). A subset of samples within this cluster showed sensitivity to combinations involving the MEK inhibitor trametinib and a second kinase inhibitor (idelalisib, palbociclib, or quizartinib). In contrast, a discrete subcluster of predominantly lymphoid leukemia patients showed sensitivity to combinations of the histone deacetylase inhibitor panobinostat in tandem with either the JAK inhibitor ruxolitinib or the multi-kinase inhibitor sorafenib. Importantly, apart from venetoclax which as a single agent demonstrated potent and selective efficacy in CLL patient samples, the single agent efficacies do not align selectively to a combination efficacy-derived cluster (Figure 1). Comparison of CR values within each of the 4 diagnostic groups revealed partial overlap in statistically significant effective combinations, while also highlighting unique sensitivities by group, such as idelalisib-quizartinib for AML and ibrutinib-quizartinib for CLL. Further relevant clinical and genetic features were compared within each of the 2 largest groups, AML and CLL. Among AML samples, patients harboring mutations in NPM1 or DNMT3A demonstrated significant sensitivity to combinations of JQ1 and sorafenib (median CR: 0.357) or JQ1 and palbociclib (median CR: 0.119), respectively. AML patients featuring surface expression of CD11b (Integrin aM) or CD58 (LFA-3) were sensitive to combinations of venetoclax and JQ1 or venetoclax and doramapimod, respectively. Among CLL samples, patients harboring deletion of 13q showed significant sensitivity to combinations of palbociclib with either venetoclax or trametinib (median CR: 0.267 and 0.116, respectively). Conclusions: The data reveal multiple specific patterns of ex vivo drug combination efficacy beyond that of either single agent, which are associated with select, actionable diagnostic and genetic subsets, warranting their evaluation in the clinic. These findings highlight the heuristic value of an integrated approach for identifying novel treatment strategies for improved disease control and patient outcomes. Figure 1 Figure 1. Disclosures Druker: Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy. Tyner:Constellation Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Research Funding; Inctye: Research Funding; Genentech: Research Funding; Aptose Biosciences: Research Funding; Seattle Genetics: Research Funding; Array Biopharma: Research Funding; AstraZeneca: Research Funding; Leap Oncology: Consultancy; Janssen Research & Development: Research Funding.

The present study was performed as a retrospective analysis of the role of pretransplant splenectomy to determine the incidence of late bacterial infections, acute and chronic graftversus-host disease (GVHD), relapse, and survival among 358 patients receiving HLA-identical marrow grafts for chronic myelogenous leukemia. Sixty-eight (19%) of the 358 patients had undergone splenectomy before transplantation. There was a trend towards more grade Il-IV acute GVHD among splenectomized patients, but this was not significant in the multivariate analysis. The incidence of chronic GVHD was similar for splenectomized and nonsplenectomized patients. Late infectious complications did not significantly differ between splenectomized and control patients (rates per patient year were 0.16 and 0.14, respectively). The overall risk of leukemic relapse was significantly increased for splenectomized patients (56% Y 32% HE VALUE OF splenectomy or splenic irradiation preceding allogeneic marrow transplantation for chronic myelogenous leukemia (CML) has been controversial. Some studies suggest that splenectomy might be of benefit in terms of tumor eradication"3 or hematologic recovery.'~' Other reports indicate that splenectomy has no impact on relapse and survival.'"' A recent randomized trial of patients with CML transplanted in first chronic phase showed that splenic irradiation did not modulate relapse or survival." This trial and other reports suggest that the incidence and seventy of acute graft-versus-host disease (GVHD) might be increased in patients with pretransplant splenectomy or splenic irradiafindings8 Several investigators report that splenectomy had no influence on the incidence of infectious complications occurring in the early posttransplant peri~d.~.~ In contrast, patients who develop functional asplenia associated with extensive chronic GVHD do have an increased risk for late bacterial infections.14 The present study was performed as a retrospective analysis of the role of pretransplant splenectomy among 358 con

To determine the risk of, and risk factors for, developing cataracts after bone marrow transplantation.Four hundred and ninety-two adults who underwent bone marrow transplantation in Seattle were followed for 2 to 18 (median, 6) years. Before transplantation, patients received a preparative regimen of chemotherapy plus total body irradiation (TBI) (n = 407) or chemotherapy alone, without TBI (n = 85). TBI was administered in a single dose of 10 Gy (n = 74) or in fractionated doses totaling 12-15.75 Gy (n = 333). The risk of cataracts was determined for groups of patients with respect to the type of preparative regimen received and other pretransplant and posttransplant variables.One hundred and fifty-nine patients (32%) developed cataracts between 0.5 to 11 (median, 2.3) years after transplantation. The probability of cataracts at 11 years after transplantation was 85%, 50%, 34%, and 19% for patients receiving 10 Gy of single-dose TBI,12 Gy fractionated TBI, 12 Gy fractionated TBI, and no TBI, respectively (p0.0001). Among those developing cataracts, the severity was greater in patients after single-dose TBI (59% probability of surgical extraction) than after12 Gy fractionated TBI, 12 Gy fractionated TBI, or no TBI (33%, 22% and 23%, respectively). Patients given corticosteroids after transplant had a higher probability of cataracts (45%) than those without steroids (38%) (p0.0001). In a proportional hazards regression model, the variables that were correlated with an increased probability of cataracts were single-dose TBI (relative risk (RR) = 2.46) and steroid therapy (RR = 2.34), while a decreased probability of cataracts was correlated with a nonTBI preparative regimen (RR = 0.41). The yearly hazard of developing cataracts in recipients of single-dose TBI was highest during the third year after transplantation, while in recipients of fractionated TBI, the hazard was distributed among years one through seven. The probability of cataracts in all groups reached a plateau at 7 years after transplantation, after which the development of cataracts was extremely unlikely.TBI is the major risk factor for developing cataracts after BMT. Single-dose TBI results in the highest risk of cataracts. However, the risk of cataracts in recipients of fractionated-TBI is significantly higher than in patients who receive no TBI. In addition to TBI, steroid therapy is an independent risk factor for cataracts after BMT.

It is generally believed that breast cancer is a multistage process and that multiple and varying genetic events occur on the pathway to disease. We hypothesize that disease heterogeneity has an impact on our ability to identify risk factors. If a genetic alteration occurred in 50% of cases and a risk factor was associated only with that specific alteration, a risk estimate of 1.6 would be detected rather than the true risk estimate of 2.5 if analyses had been limited to those cases with the genetic alteration. Based on the literature we know that many genetic alterations occur in less than 50% of breast tumors. Thus, if environmental factors are related to some, but not all genetic alterations, we are decreasing our ability to identify potentially important risk factors. We therefore hypothesize that identification of dietary factors associated with breast cancer has been hampered by our inability to identify and capture the unique disease pathways which exist and contribute to the heterogeneity of common cancers such as breast cancer.

We examined the association between exposure to PM-10 air pollution and daily mortality in Utah County, Utah, for 1985–1992. We confirmed the previous finding that exposure to fine particulate air pollution (particulate diameter of

Agent Orange (AO) exposure (AOe) is a potential risk factor for the development of prostate cancer (PCa). However, it is unknown whether AOe specifically increases the risk of lethal PCa. The objective of this study was to determine the association between AOe and the risk of detecting high-grade PCa (HGPCa) (Gleason score ≥7) on biopsy in a US Veteran cohort.Risk factors included clinicodemographic and laboratory data from veterans who were referred for an initial prostate biopsy. Outcomes were defined as the presence versus the absence of PCa, HGPCa, or low-grade PCa (LGPCa) (Gleason score ≤6) in biopsy specimens. Risk among AOe veterans relative to unexposed veterans was estimated using multivariate logistic regression. Separate models were used to determine whether AOe was associated with an increased risk of PCa, HGPCa, or LGPCa.Of 2720 veterans who underwent biopsy, PCa was diagnosed in 896 veterans (32.9%), and 459 veterans (16.9%) had HGPCa. AOe was associated with a 52% increase in the overall risk of detecting PCa (adjusted odds ratio, 1.52; 95% confidence interval, 1.07-2.13). AOe did not confer an increase in the risk of LGPCa (adjusted odds ratio, 1.24; 95% confidence interval, 0.81-1.91), although a 75% increase in the risk of HGPCa was observed (adjusted odds ratio, 1.75; 95% confidence interval, 1.12-2.74). AOe was associated with a 2.1-fold increase (95% confidence interval, 1.22-3.62; P.01) in the risk of detecting PCa with a Gleason score ≥8.The current results indicated that an increased risk of PCa associated with AOe is driven by an increased risk of HGPCa in men who undergo an initial prostate biopsy. These findings may aid in improved PCa screening for Vietnam-era veterans.

To support antimicrobial stewardship, some healthcare systems have begun creating outpatient antibiograms. We developed inpatient and primary care outpatient antibiograms for a regional health maintenance organization (HMO) and academic healthcare system (AHS). Antimicrobial susceptibilities from 16,428 Enterococcus, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa cultures from 2010 were summarized and compared. Methicillin susceptibility among S. aureus was similar in inpatients and primary care outpatients (HMO: 61.2% versus 61.9%, P = 0.951; AHS: 62.9% versus 63.3%, P > 0.999). E. coli susceptibility to trimethoprim/sulfamethoxazole was also similar (HMO: 81.8% versus 83.6%, P = 0.328; AHS: 77.2% versus 80.9%, P = 0.192), but ciprofloxacin susceptibility differed (HMO: 88.9% versus 94.6%, P < 0.001; AHS: 81.2% versus 90.6%, P < 0.001). In the HMO, ciprofloxacin-susceptible P. aeruginosa were more frequent in primary care outpatients than in inpatients (91.4% versus 79.0%, P = 0.007). Comparison of cumulative susceptibilities across settings yielded no consistent patterns; therefore, outpatient primary care antibiograms may more accurately inform prudent empiric antibiotic prescribing.

In this paper, the authors present an objective system to evaluate interviewer performance for use in epidemiologic studies. With this quality control system, all study interviews are audio-taped, and a random sample of interviews are coded according to interviewer behaviors, such as whether the interviewer asked the questions exactly as written and used the probes appropriately. With the use of data obtained from a large case-control study of colon cancer, the authors observed that 94.2% of all questions were asked in the same manner by all interviewers and that 89.5% of all probing behaviors were appropriate. They show that questions that required additional interviewer behaviors were more likely to result in variation in response that can be attributed to the interviewer. These findings have implications for study design and interpretation of study results. From simulations, the authors have estimated the impact of uncorrected interviewer variability on study power and ability to detect disease associations. Uncorrected interviewer variability could decrease study power from 84% to 56%. From simulations, the authors observed that odds ratios could be biased downward from 1.8 to 1.3. These findings illustrate the importance of using a continuous quality control program in epidemiologic research.

DNA methylation of promoter regions is a common event in prostate cancer, one of the most common cancers in men worldwide. Because prior reports demonstrating that DNA methylation is important in prostate cancer studied a limited number of genes, we systematically quantified the DNA methylation status of 1,505 CpG dinucleotides for 807 genes in 78 paraffin-embedded prostate cancer samples and three normal prostate samples. The ERG gene, commonly repressed in prostate cells in the absence of an oncogenic fusion to the TMPRSS2 gene, was one of the most commonly methylated genes, occurring in 74% of prostate cancer specimens. In an independent group of patient samples, we confirmed that ERG DNA methylation was common, occurring in 57% of specimens, and cancer-specific. The ERG promoter is marked by repressive chromatin marks mediated by polycomb proteins in both normal prostate cells and prostate cancer cells, which may explain ERG's predisposition to DNA methylation and the fact that tumors with ERG DNA methylation were more methylated, in general. These results demonstrate that bead arrays offer a high-throughput method to discover novel genes with promoter DNA methylation such as ERG, whose measurement may improve our ability to more accurately detect prostate cancer.

PURPOSE Hepatic venoocclusive disease (VOD) is a common complication of cytoreductive therapy for marrow transplantation. Only 25% of patients who develop VOD have severe disease. We tested the hypothesis that early clinical signs of VOD would predict which patients would recover and which would die. PATIENTS AND METHODS We evaluated 355 consecutive patients who had transplants between August 6, 1987 and July 21, 1988 for occurrence of VOD and whether it was reversible within 100 days of transplant. Total serum bilirubin and weight gain from day -7 through day +16 posttransplant were compared among patients with no, severe, or nonsevere VOD. Logistic regression models were developed to estimate probabilities of severe VOD at each of six time intervals. The accuracy of these models was tested by applying them to 392 consecutive patients who underwent transplantation between July 22, 1988 and July 20, 1989. RESULTS As early as day -1, bilirubin and weight gain were significantly different between patients whose VOD proved to be severe and patients with reversible VOD or no disease. Regression models were used to generate coefficients (beta 0, beta 1, beta 2) for the equation P = 1/(1 + e-z), where P is the probability of severe VOD and z = beta 0 + beta 1 (In total serum bilirubin [mg/dL]) + beta 2 (percent weight gain). Application of this equation to the next 392 patients allowed us to calculate sensitivity, specificity, and positive predictive value for a range of probabilities. CONCLUSION The course of VOD after cytoreductive therapy can be predicted by knowing the serum bilirubin and weight gained within 1 to 2 weeks of transplantation. Probability estimates derived from patient data are highly specific and moderately sensitive. Such probability estimates may be useful when considering potentially risky interventions to treat VOD, such as recombinant human tissue plasminogen activator.

In the context of competing risks the Kaplan-Meier estimator is often unsuitable for summarizing failure time data. We discuss some alternative descriptive methods including marginal probability and conditional probability estimators. Two-sample test statistics are also presented.

The number and types of mononuclear cells obtained by bronchoalveolar lavage from 105 marrow transplant patients with and without cytomegalovirus pneumonia were studied to determine whether: (1) CMV pneumonia was associated with local recruitment of lymphocytes and lymphocytes of particular subtypes to the lung, and (2) whether local recruitment was affected by the known risk factors for the development of CMV pneumonia, namely acute graft-versus-host disease and total body irradiation. Results showed a significant increase in the number of lymphocytes (P = 0.014) and in the number of lymphocytes marking for CD8 (P = 0.0045) and CD16 (P = 0.052) in BAL from all patients compared with BAL from normal subjects. However, no significant differences were observed in BAL cellular characteristics between patients with and without pneumonia nor between patients with CMV or other etiologies of pneumonia. There were also no significant differences in BAL characteristics when patients were analyzed for the presence of acute GVHD, the use of TBI, or the type of transplant. These results do not provide evidence for local recruitment of lymphocytes to the lung unique of patients with CMV pneumonia nor to patients with GVHD and CMV pneumonia, in contrast to what is observed in murine CMV pneumonia.

BACKGROUND: The use of adjuvant chemoradiation for pancreatic adenocarcinoma (PAC) is accepted in North America, but there is a paucity of data to support this practice. The relation between adjuvant therapy and survival was assessed in a population-based cohort of patients with PAC. METHODS: A review was conducted of all cases of resected PAC from 1996 to 2003 using data from the state cancer registry augmented with data from primary medical record review. Use of adjuvant therapy was ascertained from registry data. Survival was assessed using the Kaplan-Meier method, and a Cox proportional hazards model was developed for multivariate analysis. RESULTS: A total of 298 patients from 27 hospitals met criteria for inclusion. There were 228 patients (76.5%) who were resected with curative intent, with a median overall survival of 12 months. The 6-month, 1-year, and 5-year survival rates were 80.2%, 58.4%, and 6.7%, respectively. Of the 228 patients resected, 122 (53.5%) received adjuvant treatment and had a median survival of 13.0 months versus 11.0 months for those with no adjuvant treatment (P = .16). After adjustment for surrogates of performance status, significant predictors of overall survival included no weight loss, T1/T2 pathologic stage, a microscopically complete resection (R0), and receipt of adjuvant therapy. CONCLUSIONS: An R0 resection and adjuvant therapy were found to be independently associated with an increase in overall survival in patients with resected PAC. These data underscore the importance of adjuvant therapy in resected PAC and the need for ongoing clinical trials to refine the efficacy and timing of adjuvant therapy in this disease. Cancer 2010. © 2010 American Cancer Society.

Byung S Park1,2,3, Motomi Mori1,2,31Division of Biostatistics, Department of Public Health and Preventive Medicine, 2Biostatistics Shared Resource, Knight Cancer Institute, 3Biostatistics and Design Program, Oregon Clinical and Translational Science Institute, Oregon Health and Science University, Portland, OR, USAAbstract: Genome-wide mRNA expression profiling using microarrays is widely available today, yet analysis and interpretation of the resulting high dimensional data continue to be a challenge for biomedical scientists. In a typical microarray experiment, the number of biological samples is quite modest compared with the number of genes on a microarray, and a probability of falsely declaring differential expression is unacceptably high without any adjustment for multiple comparisons. However, a stringent multiple comparison procedure can lead to an unacceptably high false negative rate, potentially missing a large fraction of truly differentially expressed genes. In this paper we propose a new “balancing factor score” (BFS) method for identifying a set of differentially expressed genes. The BFS method combines a traditional P value criterion with any other informative factors (referred to as balancing factors) that may help to identify differentially expressed genes. We evaluate the performance of the BFS method when the observed fold change is used as a balancing factor in a simulation study and show that the BFS method can substantially reduce the false negative rate while maintaining a reasonable false discovery rate.Keywords: balancing factor score method, microarrays, multiple comparisons, false discovery rate, false negative rate

Host factors that influence binding of Candida albicans to murine spleen, lymph node, and kidney were studied. Organs were harvested from BALB/cByJ and AKR/J mice immunocompromised by irradiation, cyclophosphamide, and cortisone acetate alone or in combination. Tissues from treated mice and untreated littermates were compared for their ability to bind C. albicans in ex vivo assays. Immunosuppressive regimens decreased yeast binding to splenic marginal zones, but when mice recovered for 5 days after treatment, adherence to spleen was similar to adherence in untreated littermates. Adherence to lymph node and kidney in treated mice was not different from binding to these tissues in untreated mice. Total serum immunoglobulin titers correlated with binding of yeast cells to mouse spleen. Blocking studies ruled out a mannosyl-fucosyl receptor-mediated binding. These results suggest that ex vivo adherence of C. albicans represents a host immune defense mechanism by which the immunocompetent host binds blood-borne yeast cells to host immune cells in reticuloendothelial organs to prevent dissemination to other organs.

The role of fatty acids (FA) in prostate carcinogenesis is unclear. Interest in the inter-relationship among different types of FA has resulted in new analytic approaches to FA and their role in cancer development. We evaluated the association between erythrocyte FA and prostate cancer in 127 prostate cancer patients and 183 screen negative controls. We present three approaches to the analyses of the FA and prostate cancer association; (1) individual or common groups of FA, (2) biologically meaningful FA ratios and (3) principal components analysis. Monounsaturated FA and the alpha-linolenic:eicosapentaenoic ratio were associated with reduced risk of prostate cancer. However, Factor 1, which was strongly correlated with some long chain saturated FA, was associated with an increased risk of prostate cancer. We provide an example of modeling FA and their inter-relationships on the risk of prostate cancer. Comparing three approaches suggests the importance of considering the impact of the entire fatty acid profile in disease prevention.

Residual disease or rapidity of response to induction therapy is among the most powerful predictors of outcome in pediatric acute lymphoblastic leukemia (ALL).Utilizing a multiparameter flow cytometric chemosensitivity assay (FCCA), we studied the relationship between in vitro drug sensitivity of diagnostic leukemic blasts from 30 children with ALL and rapidity of response to induction therapy. We also analyzed the in vitro drug sensitivity of de novo leukemic blasts among various clinical subsets.Compared to rapid early responders (RERs), slow early responders (SERs) had a significantly greater in vitro drug resistance to dexamethasone (DEX; P = 0.04) and prednisone (P = 0.05). The studies with all other drugs showed a non-significant trend with the SER having a higher in vitro drug resistance compared to the RER. Risk group stratified analyses indicated that in vitro resistance to asparaginase (ASP), DEX, and vincristine (VCR) were each significantly related to having very high risk ALL. Additionally, a significantly higher in vitro drug resistance to ASP and VCR was associated with unfavorable lymphoblast genetics and ultimate relapse.Our data indicate that this FCCA is a potentially simple and rapid method to detect inherent resistance to initial ALL therapy very early in induction, thus allowing for treatment modification shortly thereafter.

Of 1506 marrow transplant patients from 1980 through 1986 reviewed for risk factors for invasive candidal infection defined by positive blood cultures, biopsy, or histologic evidence of tissue invasion, 171 (11.4%) had invasive infection, with a significantly higher incidence in the more recent years of review; 40% (69 patients) had evidence of tissue-invasive disease without fungemia. Of 102 patients with fungemia, 45% had candidemia alone with a mortality of 39%. Mortality in patients with tissue involvement was 90% with or without fungemia. Factors that increased infection were age, acute graft-versus-host disease, and donor mismatch. Factors that decreased infection included conditioning with 12 Gy of fractionated irradiation and cyclophosphamide, transplantation for aplastic anemia, and more rapid engraftment. Among fungemic patients, the number of days of fungemia was a risk factor for tissue invasion while more rapid engraftment was protective.

A phase I dose escalation trial of recombinant human macrophage colony- stimulating factor (rhM-CSF) in combination with conventional antifungal therapy was conducted in 24 marrow transplant recipients with invasive fungal infection. Daily doses ranged from 100 to 2,000 micrograms/m2/d. Toxicity, such as constitutional symptoms, directly ascribed to rhM-CSF was not observed; however, transient, dose-related thrombocytopenia was observed. Patients who received 2,000 micrograms/m2/d of rhM-CSF had a mean reduction in platelet count of 61,000/mm3 during the rhM-CSF infusion period, which was significant when compared with patients who received lower doses of rhM-CSF (P = .008). Fourteen of the 16 patients who received rhM-CSF after undergoing allogeneic bone marrow transplantation had no change in the severity of graft-versus-host disease (GVHD) while receiving rhM-CSF. One had an increase in the severity of GVHD and one had a decrease. There were no effects on neutrophil, monocyte, or lymphocyte counts. Six patients had resolution of their infections, 12 were not evaluable for response, and six did not respond. Ten patients survived 100 days after initiation of rhM-CSF and 14 died. Further trials with rhM-CSF to assess antifungal activity are indicated.

Forty-seven patients with hematologic neoplasia received recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) by daily 2-hour infusion following allogeneic bone marrow transplantation from HLA-identical sibling donors in a phase I-II dose-escalation trial. Dose levels ranged from 30 to 500 micrograms/m2/d. At doses at or below 250 micrograms/m2/d, toxicity felt to be caused by rhGM-CSF was negligible. However, three of five patients treated with 500 micrograms/m2/d had unacceptable side effects caused by rhGM-CSF. Two different graft-versus-host disease (GVHD) prophylactic regimens were administered. Twenty-seven evaluable patients were administered regimens that did not contain methotrexate (MTX) (Group I) and reached an absolute neutrophil count of 1,000/microL by a median of day 14. In contrast, 18 patients who received GVHD prophylactic regimens containing MTX (Group II) reached an absolute neutrophil count of 1,000/microL on a median of day 20. Patients in Group I had fewer febrile days and, of those discharged, had shorter initial hospitalizations than patients in Group II. The overall incidence of severe acute GVHD (grade 2 or greater) in the rhGM-CSF-treated patients was 28% and was similar to that in historical “good risk” patients who did not receive rhGM-CSF. These preliminary data suggest rhGM-CSF is unlikely to exacerbate GVHD in HLA-identical sibling donor transplants and indicate the need for randomized trials of rhGM-CSF in allogeneic marrow transplant patients.

Terminal hair density was graded at seven sites in 19 male patients enrolled in a dysplastic nevus syndrome (DNS) registry and in 22 matched control subjects. An inverse relation between density of nevi and terminal hair for all sites combined was observed for both patients and control subjects ( p =0.0001, regression analysis). In addition, the registry patients had significantly less terminal cutaneous hair overall ( p =0.007, Wilcoxon rank sum test) compared with the controls.

Physician-reported performance status (PS) is an important prognostic factor and frequently influences treatment decisions. To the authors' knowledge, the extent, prognostic importance, and predictors of disagreements in PS assessment between physicians and patients have not been adequately examined.Using North Central Cancer Treatment Group (NCCTG) clinical trial data from 1987 through 1990, the authors compared PS (Eastern Cooperative Oncology Group [ECOG] and Karnofsky [KPS]) and nutrition scores reported by physicians and patients individually. Differences were analyzed using a Student t test for paired data and degree of disagreement by kappa statistic. The effect of disagreement on overall survival was determined by the Kaplan-Meier method and Cox regression analysis. Predictors of disagreement were identified by logistic regression.In all, 1636 patients with advanced lung and colorectal cancer had a median survival of 9.8 months (95% confidence interval [95% CI], 9.4-10.4 months). Percent disagreement between patients and physicians regarding KPS, ECOG PS, and nutrition score were 67.1%, 56.6%, and 58.0%, respectively. Physicians were more likely to rate patients better than individual patients were to rate themselves: ECOG (mean 0.91 vs 1.30; P.0001), KPS (mean 83.3 vs 81.7; P.0001), and nutrition score (mean 1.6 vs 2.1; P.0001). Disagreement between patients and their physicians was associated with increased risk of death: KPS (hazards ratio [HR] of 1.16; 95% CI, 1.04-1.30 [P = .008]) and nutrition scores (HR of 1.44; 95% CI, 1.29-1.61 [P.0001]) after adjustment for covariates. Patient sociodemographic factors that predict disagreement were identified.Physicians and patients frequently disagree regarding PS and nutritional status. Disagreement is associated with an increased risk of death in patients with advanced malignancies. These findings illustrate the limitations of physician-only assessed PS.

Background Recent years have brought important developments in preoperative imaging and use of laparoscopic staging of patients with pancreatic adenocarcinoma (PAC). There are few data about the optimal combination of preoperative studies to accurately identify resectable patients. Study Design We conducted a statewide review of all patients with surgically managed PAC from 1996 to 2003 using data from the Oregon State Cancer Registry, augmented with clinical information from primary medical record review. We documented the use of all staging modalities, including CT, endoscopic ultrasonography, and laparoscopy. Primary outcomes included resection with curative intent. The association between staging modalities, clinical features, and resection was measured using a multivariate logistic regression model. Results There were 298 patients from 24 hospitals who met the eligibility criteria. Patients were staged using a combination of CT (98%), laparoscopy (29%), and endoscopic ultrasonography (32%). The overall proportion of patients who went to surgical exploration and were resected was 87%. Of patients undergoing diagnostic laparoscopy, metastatic disease that precluded resection was discovered in 24 (27.6%). For patients who underwent diagnostic laparoscopy and were not resected, vascular invasion was the most common determinant of unresectability (56.6%). In multivariate analysis, preoperative weight loss and surgeon decision to use laparoscopy predicted unresectability at laparotomy. Conclusions This population-based study demonstrates that surgeons appear to use laparoscopy in a subset of patients at high risk for metastatic disease. The combination of current staging techniques is associated with a high proportion of resectability for patients taken to surgical exploration. With current imaging modalities, selective application of laparoscopy with a dual-phase CT scan as the cornerstone of staging is a sound clinical approach to evaluate pancreatic cancer patients for potential resectability.

Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen-independent prostate cancer (AIPC) who are initiating docetaxel-based chemotherapy.Baseline plasma samples were stored (-80 degrees C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo-controlled trial comparing weekly docetaxel plus high-dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate-specific antigen (PSA) decline.C-reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20-1.65 [P.0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P.0001) of shorter overall survival. When categorized as normal (or=8 mg/L) or abnormal (8 mg/L), elevated CRP was found to be a significant predictor of shorter overall survival (HR of 2.96; 95% CI, 1.52-5.77 [P = .001]), as was hemoglobin (P = .007). Elevated CRP was also associated with a lower probability of PSA decline (odds ratio of 0.74 for each ln(CRP) increase; 95% CI, 0.60-0.92 [P = .007]). CONCLUSIONS.: Elevated plasma CRP concentrations appear to be a strong predictor of poor survival and lower probability of PSA response to treatment in patients with AIPC who are receiving docetaxel-based therapy.

to 11/30/2014 was obtained. Undocumented status was indicated on the initial intake form. Diagnoses, reason for consult, length of stay, PCCS interventions and discharge disposition were analyzed. Results. 428 patients were referred to the PCCS. 40.2% were 18-65 years old, and 59.8% were >65 years old. 49.8% were female. Approximately 11% of these patients died within 2 days of completion of their PCCS consultation. 14% of patients were identified as UAU. More than 1/3 of these patients returned home with no palliative care services due to undocumented status and returned frequently to ED for symptom exacerbations. The most common reason for consult for these patients was discharge planning/placement, and for four of these patients, the ultimate disposition was remaining in the city hospital until their death due to their lack of insurance and their undocumented status. Conclusion. To date, very little data on the experience of undocumented and uninsured patients exists outside of anecdote and case report. Characterizing the end-of-life care in the uninsured and undocumented patients provides much needed data to help hospital systems provide palliation and discharge to appropriate care systems for this vulnerable population. Implications for Research, Policy or Practice. Characterization of care for this vulnerable population allows for identification of policy and system changes that may allow palliative care to reach this vulnerable patient population.

We studied whether treatment of dogs with recombinant human granulocyte colony-stimulating factor (rhG-CSF), after 920 cGy total body irradiation (TBI) and transplantation of 3.3 +/- 1.0 x 10(8) bone marrow cells per kilogram from a DLA-identical littermate, accelerated hematopoietic recovery and influenced the incidence of subsequent marrow graft failure or graft-versus-host disease (GVHD). Ten animals were treated with 100 micrograms rhG-CSF/kg/d from days 1 through 10 after TBI. Results were compared with those of historical control of 14 dogs not administered rhG-CSF. Neither group of dogs received GVHD prophylaxis. The median time to recovery of 1,000 neutrophils/mm3 was 8 days for dogs administered rhG-CSF compared with 14 days in controls (logrank test: P less than .03). The median time to reach 100 monocytes/mm3 was 17 days in G-CSF-treated dogs compared with 49 days in controls (P less than .002). The median time to attain 500 lymphocytes/mm3 was 15 days versus 31 days, respectively (P less than .01). The median time to reach 20,000 platelets/mm3 was 26 versus 20 days (P = .68). Graft failure occurred in 1 of 10 G-CSF-treated dogs versus 2 of 14 controls (two-tailed Fisher's exact test: P = 1.00). GVHD was seen in 4 of 9 rhG-CSF-treated dogs compared with 1 of 12 controls (P = .12). Two G-CSF-treated dogs died of GVHD versus none of the controls (P = .17). No unusual toxicities were seen in dogs receiving rhG-CSF. In summary, rhG-CSF significantly accelerated recovery of neutrophils, monocytes, and lymphocytes after DLA-identical littermate marrow transplantation without altering platelet recovery. Graft failure was not seen more often than in controls, but there was a trend toward an increased incidence of GVHD.

The loss of naïve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this naïve T cell loss, less is known about the contribution of other mechanisms to the depletion of naïve T cells in aging primates. We examined the role of homeostatic cycling and proliferative expansion in different T cell subsets of aging rhesus macaques (RM). BrdU incorporation and the expression of the G1-M marker Ki-67 were elevated in peripheral naïve CD4 and even more markedly in the naïve CD8 T cells of old, but not young adult, RM. Proliferating naïve cells did not accumulate in old animals. Rather, the relative size of the naïve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated naïve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the naïve pool loss. The turnover increased exponentially when the naïve CD8 T cell pool decreased below 4% of total blood CD8 cells. These results link the shrinking naïve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the naïve pool and constrict the T cell repertoire. Thus, homeostatic T cell proliferation exhibits temporal antagonistic pleiotropy, being beneficial to T cell maintenance in adulthood but detrimental to the long-term T cell maintenance in aging individuals.

Prostate-specific antigen (PSA) kinetics have failed to predict for the presence of prostate cancer in screening populations in which many patients harbor subclinical disease. We hypothesized that the prebiopsy PSA doubling time (PSADT) and PSA velocity (PSAV) could predict for cancer detection in a referral population with a suspicion of prostate cancer.Data were collected from 1699 consecutive veterans with a PSA level of 10 ng/mL or less who underwent prostate biopsy. Logistic regression analysis was performed on the following: age, race, family history, digital rectal examination findings, PSA, PSA density, PSADT, PSAV, prostate volume, and ultrasound lesions. Model building was accomplished with 70% of the data, and validation was done using the remaining 30%. These data were also analyzed using classification and regression tree analysis.Using logistic regression analysis (P0.05) on the model building set, prostate cancer was associated with age (older than 70 years), PSA level (greater than 2.9 ng/mL), PSA density (more than 0.12 ng/mL/cm3), digital rectal examination findings, and the presence of a lesion on ultrasonography. A PSADT of 2 to 5 years was marginally associated with prostate cancer detection (odds ratio 1.6, 95% confidence interval 1.1 to 2.3), and a PSADT of less than 2 years or longer than 5 years and PSAV were not predictive. On classification and regression tree analysis, PSADT was not selected as a predictive factor. Furthermore, neither PSADT nor PSAV was predictive of Gleason score 7 or worse cancer.In contrast to its prognostic value after the diagnosis of prostate cancer has been established, PSA kinetics offer little to clinical decision making as predictors of cancer or high-grade cancer in men with a PSA level of 10 ng/mL or less.