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Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Cyclooxygenase-2 (COX-2) overexpression is associated with increased tumor invasiveness and proliferation in CRC, and COX-2 inhibition has demonstrated chemopreventive activity. This study investigated the addition of celecoxib, a selective COX-2 inhibitor, to the irinotecan, 5-fluorouracil, and leucovorin (IFL) regimen for patients with previously untreated metastatic CRC.Forty-seven patients enrolled in this single-arm phase II study received celecoxib at 400 mg orally twice daily in combination with weekly irinotecan (125 mg/m(2)), 5-fluorouracil (500 mg/m(2)), and leucovorin (20 mg/m(2)) for 4 weeks every 6 weeks. The primary endpoint was response rate (RR) as measured by Response Evaluation Criteria in Solid Tumors. The protocol was amended midway to additionally exclude patients with Eastern Cooperative Oncology Group performance status 2 and require all patients with specific cardiovascular risk factors to take daily aspirin (81 mg).The objective RR was 31.9% (95% confidence interval [CI], 19%-47%). Median progression-free survival was 8.7 months (95% CI, 5.8-10.6), and the median overall survival was 19.7 months (95% CI, 15.4-22.8). All cardiac events were observed before protocol modification. The median overall survival before and after protocol modification was 11.4 versus 24.2 months, respectively (P0.0001); tumor RR and progression-free survival were not statistically different before or after protocol modification. The trial was halted after an interim analysis demonstrated that the primary endpoint would not be met.Celecoxib plus IFL chemotherapy for patients with metastatic CRC is tolerable, but does not appear to increase the efficacy of IFL.

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML. Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine., Analysis of draining lymph nodes of individuals vaccinated BNT162b2 mRNA vaccine against SARS-CoV-2 identifies viral spike-specific follicular helper CD4+ T cells that persist for months and contribute to long-term immunity.

Previous studies suggest compounds such as sulforaphane (SFN) derived from cruciferous vegetables may prevent prostate cancer development and progression. This study evaluated the effect of broccoli sprout extract (BSE) supplementation on blood histone deacetylase (HDAC) activity, prostate RNA gene expression, and tissue biomarkers (histone H3 lysine 18 acetylation (H3K18ac), HDAC3, HDAC6, Ki67, and p21). A total of 98 men scheduled for prostate biopsy were allocated into either BSE (200 µmol daily) or a placebo in our double-blind, randomized controlled trial. We used nonparametric tests to evaluate the differences of blood HDAC activity and prostate tissue immunohistochemistry biomarkers between treatment groups. Further, we performed RNA-Seq analysis on the prostate biopsies and identified 40 differentially expressed genes correlated with BSE treatment, including downregulation of two genes previously implicated in prostate cancer development, AMACR and ARLNC1. Although urine and plasma SFN isothiocyanates and individual SFN metabolites were statistically higher in the treatment group, our results did not show a significant difference in HDAC activity or prostate tissue biomarkers. This study indicates BSE supplementation correlates with changes in gene expression but not with several other prostate cancer biomarkers. More research is required to fully understand the chemopreventive effects of BSE supplementation on prostate cancer.

Colorectal cancer and adenoma adjacent to cancer exhibit distinct microRNA (miRNA) alterations in an apparent mucosa-to-adenocarcinoma sequence. The pattern of microRNAs in screen-detected polyps in relation to histologic features and cancer risk has not been investigated. miRNA expression analysis was performed on normal mucosa (NM), hyperplastic polyps (HP), tubular adenomas (TA), tubulovillous adenomas or high-grade dysplasia (TVHG), and serrated polyps [sessile serrated adenoma/polyps (SSA/P) and traditional serrated adenomas (TSA)] in biopsy specimens from 109 patients undergoing screening/surveillance colonoscopy. Generalized linear models were used to identify differentially expressed miRNAs by histologic type and logistic regression to identify miRNA predictors of histopathology. False discovery rate (FDR) was used to control for multiple comparisons. We identified 99 miRNAs differing in at least one of five histopathologic groups (FDR ≤0.05). In a comparison of HPNM versus TVHG, the top most upregulated and downregulated miRNAs in HPNM included miR-145, -143, -107, -194, and -26a (upregulated), and miR-663, -1268, -320b, -1275, and -320b (downregulated; FDR P < 0.05). miR-145 and -619 showed high accuracy to discriminate low- from high-risk polyps without serrated histology (TVHG vs. HPNM + TA; CI, 95.6%), whereas miR-124, -143, and -30a showed high accuracy of separating high-risk polyps (TVHG + TSA) from low-risk polyps (HPNM + TA + SSA/P; CI, 96.0%). For TSAs, miR-125b and -199a were uniquely downregulated relative to HPNMs, and miR-335, -222, and -214 discriminated between non-serrated and serrated histology. Our data support the presence of colorectal cancer–associated miRNA alterations in screen-detected adenomas that may be useful for risk stratification for surveillance interval planning. Cancer Prev Res; 9(12); 942–9. ©2016 AACR.

Background MicroRNAs are dysregulated in colorectal cancer and subsets correlated with advanced tumor stage and metastasis. Data are lacking on microRNA dysregulation from early to late-stage disease. Objective The purpose of this study was to identify a microRNA signature associated with the primary tumor and metastatic site in stage IV disease and to examine whether the signature is evident in earlier stages. Design A microRNA profile was generated and then explored in normal colon tissue (n = 5), early stage (stage I and II; n = 10), and late-stage (stage III and IV; n = 14) colorectal primary tumors via polymerase chain reaction to delineate molecular events that may promote colorectal carcinogenesis. Setting Genome-wide microRNA expression profiling was performed. Patients A total of 14 patient-matched stage IV primary colorectal cancer tumors and corresponding liver metastases were included. Main outcome measures MicroRNA array technology was used to identify microRNA expression-predictive metastatic potential in the primary tumor. Results A distinct 9-member signature group of microRNAs was concurrent in stage IV primary colorectal cancer and their corresponding liver metastases, when compared with surrounding unaffected colon and liver tissue (microRNA-18b, microRNA-93, microRNA-182, microRNA-183, microRNA21, microRNA-486-5p, microRNA-500a, microRNA-552, and microRNA-941). Of the microRNA panel, only microRNA486-5p was differentially expressed in early stage colorectal cancer samples compared with normal tissue (p = 0.001) and additionally differentially expressed between late-stage colorectal cancer samples and normal tissue (p Limitations Our microRNA profile was generated in a small subset of patients and will require validation in more samples. Conclusions We identified a distinct microRNA signature in primary colon and matched metastatic disease. On additional investigation, 1 microRNA was differentially expressed in both early and late-stage cancer patient samples, and it may herald an early event in colorectal carcinogenesis. This study warrants additional investigation with a larger patient cohort to better understand the effect of microRNAs in carcinogenesis. See Video Abstract at http://links.lww.com/DCR/A723.

To identify new therapeutic targets in acute myeloid leukemia (AML), we performed small-molecule and small-interfering RNA (siRNA) screens of primary AML patient samples. In 23% of samples, we found sensitivity to inhibition of colony-stimulating factor 1 (CSF1) receptor (CSF1R), a receptor tyrosine kinase responsible for survival, proliferation, and differentiation of myeloid-lineage cells. Sensitivity to CSF1R inhibitor GW-2580 was found preferentially in de novo and favorable-risk patients, and resistance to GW-2580 was associated with reduced overall survival. Using flow cytometry, we discovered that CSF1R is not expressed on the majority of leukemic blasts but instead on a subpopulation of supportive cells. Comparison of CSF1R-expressing cells in AML vs healthy donors by mass cytometry revealed expression of unique cell-surface markers. The quantity of CSF1R-expressing cells correlated with GW-2580 sensitivity. Exposure of primary AML patient samples to a panel of recombinant cytokines revealed that CSF1R inhibitor sensitivity correlated with a growth response to CSF1R ligand, CSF1, and other cytokines, including hepatocyte growth factor (HGF). The addition of CSF1 increased the secretion of HGF and other cytokines in conditioned media from AML patient samples, whereas adding GW-2580 reduced their secretion. In untreated cells, HGF levels correlated significantly with GW-2580 sensitivity. Finally, recombinant HGF and HS-5–conditioned media rescued cell viability after GW-2580 treatment in AML patient samples. Our results suggest that CSF1R-expressing cells support the bulk leukemia population through the secretion of HGF and other cytokines. This study identifies CSF1R as a novel therapeutic target of AML and provides a mechanism of paracrine cytokine/growth factor signaling in this disease.

Interleukin-1 receptor-associated kinase 1 (IRAK1), an essential mediator of innate immunity and inflammatory responses, is constitutively active in multiple cancers. We evaluated the role of IRAK1 in acute myeloid leukemia (AML) and assessed the inhibitory activity of multikinase inhibitor pacritinib on IRAK1 in AML. We demonstrated that IRAK1 is overexpressed in AML and provides a survival signal to AML cells. Genetic knockdown of IRAK1 in primary AML samples and xenograft model showed a significant reduction in leukemia burden. Kinase profiling indicated pacritinib has potent inhibitory activity against IRAK1. Computational modeling combined with site-directed mutagenesis demonstrated high-affinity binding of pacritinib to the IRAK1 kinase domain. Pacritinib exposure reduced IRAK1 phosphorylation in AML cells. A higher percentage of primary AML samples showed robust sensitivity to pacritinib, which inhibits FLT3, JAK2, and IRAK1, relative to FLT3 inhibitor quizartinib or JAK1/2 inhibitor ruxolitinib, demonstrating the importance of IRAK1 inhibition. Pacritinib inhibited the growth of AML cells harboring a variety of genetic abnormalities not limited to FLT3 and JAK2. Pacritinib treatment reduced AML progenitors in vitro and the leukemia burden in AML xenograft model. Overall, IRAK1 contributes to the survival of leukemic cells, and the suppression of IRAK1 may be beneficial among heterogeneous AML subtypes.

Research has found that patient-subjects in early phase cancer trials exhibit unrealistic optimism regarding the risks and possible benefits of trial participation. Unrealistic optimism is associated with therapeutic misconception and failures to appreciate research-related information. This is the first study to assess whether those who decline to participate in these trials also exhibit unrealistic optimism. It is also the first study to assess whether there are significant differences in appreciation of research-related risks/benefits and therapeutic misconception between these two groups. We approached 261 patients at two academic medical centers who were offered enrollment in a Phase I, II, or I/II cancer trial (between 2012 and 2016). Two hundred thirty-three patients agreed to enroll in an early phase cancer trial, 171 of whom agreed to be interviewed for the study. Twenty-eight patients declined the offer to enroll, 15 of whom agreed to be interviewed for the study. Subjects participated in a structured face-to-face interview with a research associate trained to administer the study questionnaires. Acceptors demonstrated a significantly higher level of unrealistic optimism than decliners ( p.05). Decliners had significantly less therapeutic misconception than acceptors (3.37 [ SD = 0.85] vs. 3.79 [ SD = 0.77], p = .042). There was a significant difference on one of the appreciation questions between acceptors and decliners ( p = .009). Comparative assessment of acceptors and decliners to early phase cancer trials casts light on whether unrealistic optimism is consequential for the decision to participate in these trials. The different levels of unrealistic optimism exhibited by these groups suggest that it may be a factor that affects the decision to participate.

Purpose: We conducted a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, >5 cm) extremity soft tissue sarcoma undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (DCE-MRI) to assess response to treatment. Experimental Design: Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. Results: Eighteen subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3–4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ΔKtrans after 2 weeks of sorafenib correlated with histologic response (R2 = 0.67, P = 0.012) at surgery. Conclusion: The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally invasive tool for rapid assessment of drug effect in soft tissue sarcoma. Clin Cancer Res; 19(24); 6902–11. ©2013 AACR.

Background Previous research on ascertainment of cancer family history and cancer screening has been conducted in urban settings. Purpose To examine whether documented family history of breast or colorectal cancer is associated with breast or colorectal cancer screening. Methods Medical record reviews were conducted on 3433 patients aged 55 and older from four primary care practices in two rural Oregon communities. Data collected included patient demographic and risk information, including any documentation of family history of breast or colorectal cancer, and receipt of screening for these cancers. Results A positive breast cancer family history was associated with an increased likelihood of being up-to-date for mammography screening (OR 2.09, 95% CI 1.45–3.00 relative to a recorded negative history). A positive family history for colorectal cancer was associated with an increased likelihood of being up-to-date with colorectal cancer screening according to U.S. Preventive Services Task Force low risk guidelines for males (OR 2.89, 95% CI 1.15–7.29) and females (OR 2.47, 95% CI 1.32–4.64) relative to a recorded negative family history. The absence of any recorded family cancer history was associated with a decreased likelihood of being up-to-date for mammography screening (OR 0.70, 95% CI 0.56–0.88 relative to recorded negative history) or for colorectal cancer screening (OR 0.75, 95% CI 0.60–0.96 in females, OR 0.68, 95% CI 0.53–0.88 in males relative to recorded negative history). Conclusion Further research is needed to determine if establishing routines to document family history of cancer would improve appropriate use of cancer screening.

Purpose: Becoming certified as a patient-centered medical home now requires practices to measure how effectively they provide continuity of care. To understand how continuity can be improved, we studied the association between provider practice characteristics and interpersonal continuity using the Usual Provider Continuity Index (UPC). Methods: We conducted a mixed-methods study of the relationship between provider practice characteristics and UPC in 4 university-based family medicine clinics. For the quantitative part of the study, we analyzed data extracted from monthly provider performance reports for 63 primary care providers (PCPs) between July 2009 and June 2010. We tested the association of 5 practice parameters on UPC: (1) clinic frequency; (2) panel size; (3) patient load (ratio of panel size to clinic frequency); (4) attendance ratio; and (5) duration in practice (number of years working in the current practice). Clinic, care team, provider sex, and provider type (physicians versus nonphysician providers) were analyzed as covariates. Simple and multiple linear regressions were used for statistical modeling. Findings from the quantitative part of the study were validated using qualitative data from provider focus groups that were analyzed using sequential thematic coding. Results: There were strong linear associations between UPC and both clinic frequency ( 0.94; 95% CI, 0.62‐1.27) and patient load ( 0.37; 95% CI, 0.48 to 0.26). A multiple linear regression including clinic frequency, patient load, duration in practice, and provider type explained more than 60% of the variation in UPC (adjusted R 2 0.629). UPC for nurse practitioners and physician assistants was more strongly dependent on clinic frequency and was at least as high as it was for physicians. Focus groups identified 6 themes as other potential sources of variability in UPC. Conclusions: Variability in UPC between providers is strongly correlated with variables that can be modified by practice managers. Our study suggests that patients assigned to nurse practitioners and physician assistants have continuity similar to those assigned to physicians. (J Am Board Fam Med 2013; 26:356‐365.)

Here we describe a multiplexed immunohistochemical platform, with computational image processing workflows including image cytometry, enabling simultaneous evaluation of 12 biomarkers in one formalin-fixed paraffin-embedded tissue section. To validate this platform, we used tissue microarrays containing 38 archival head and neck squamous cell carcinomas, and revealed differential immune profiles based on lymphoid and myeloid cell densities, correlating with human papilloma virus status and prognosis. Based on these results, we investigated 24 pancreatic ductal adenocarcinomas from patients who received neoadjuvant GVAX vaccination, and revealed that response to therapy correlated with degree of mono-myelocytic cell density, and percentages of CD8+ T cells expressing T cell exhaustion markers. These data highlight the utility of in situ immune monitoring for patient stratification, and provide digital image processing pipelines (https://github.com/multiplexIHC/cppipe) to the community for examining immune complexity in precious tissue sections, where phenotype and tissue architecture are preserved to thus improve biomarker discovery and assessment.

Animal and human studies suggest fish oil and green tea may have protective effect on prostate cancer. Fatty acid synthase (FAS) has been hypothesized to be linked to chemoprotective effects of both compounds. This study evaluated the independent and joint effects of fish oil (FO) and green tea supplement (epigallocatechin-3-gallate, EGCG) on FAS and Ki-67 levels in prostate tissue. Through a double-blinded, randomized controlled trial with 2 × 2 factorial design, 89 men scheduled for repeat prostate biopsy following an initial negative prostate biopsy were randomized into either FO alone (1.9 g DHA + EPA/day), EGCG alone (600 mg/day), a combination of FO and EGCG, or placebo. We used linear mixed-effects models to test the differences of prostate tissue FAS and Ki-67 by immunohistochemistry between pre- and post-intervention within each group, as well as between treatment groups. Results did not show significant difference among treatment groups in pre-to-post-intervention changes of FAS (P = 0.69) or Ki-67 (P = 0.26). Comparing placebo group with any of the treatment groups, we did not find significant difference in FAS or Ki-67 changes (all P > 0.05). Results indicate FO or EGCG supplementation for a short duration may not be sufficient to produce biologically meaningful changes in FAS or Ki-67 levels in prostate tissue.

PurposeRecent research has found unrealistic optimism (UO) among patient-subjects in early-phase oncology trials. Our aim was to investigate the cognitive and motivational factors that evoke this bias in this context. We expected perceptions of control to be a strong correlate of unrealistic optimism.MethodsA study of patient-subjects enrolled in early-phase oncology trials was conducted at two sites in the USA. Respondents completed questionnaires designed to assess unrealistic optimism and several risk attribute variables that have been found to evoke the bias in other contexts.ResultsOne hundred and seventy-one patient-subjects agreed to be interviewed for our study. Significant levels of perceived controllability were found with respect to all nine research-related questions. Perceptions of control were found to predict unrealistic optimism. Two other risk attribute variables, awareness of indicators (p=0.024) and mental image (p=0.022), were correlated with unrealistic optimism. However, in multivariate regression analysis, awareness and mental image dropped out of the model and perceived controllability was the only factor independently associated with unrealistic optimism (pConclusionPatient-subjects reported that they can, at least partially, control the benefits they receive from participating in an early-phase oncology trial. This sense of control may underlie unrealistic optimism about benefiting personally from trial participation. Effective interventions to counteract unrealistic optimism may need to address the psychological factors that give rise to distorted risk/benefit processing.

Small-bowel adenocarcinoma is rare and fatal. Because of data paucity, there is a tendency to extrapolate treatment from colon cancer, particularly in the adjuvant stetting.The purpose of this study was to evaluate the current surgical and adjuvant treatments of small-bowel adenocarcinoma and compare with colon cancer.This was a retrospective cohort study.The linked Surveillance, Epidemiology, and End Results and Medicare database was used at a tertiary referral hospital.Patients with small-bowel adenocarcinoma and colon cancer identified from 1992 to 2010, using International Classification of Diseases for Oncology, 3 Revision, site, behavior, and histology codes were included.Overall survival and cancer-specific survival were estimated using the Kaplan-Meier method and competing risk analysis.A total of 2123 patients with small-bowel adenocarcinoma and 248,862 patients with colon cancer were identified. Five-year overall survival rates for patients with small-bowel adenocarcinoma and colon cancer were 34.9% and 51.5% (p0.0001). A total of 1550 patients with small-bowel adenocarcinoma (73.0%) underwent surgery, compared with 177,017 patients with colon cancer (71.1%). The proportion of patients who received chemotherapy was similar, at 21.3% for small bowel and 20.0% for colon. In contrast to colon cancer, chemotherapy did not improve overall or cancer-specific survival for patients with small-bowel adenocarcinoma, regardless of stage. Predictors of poor survival for small-bowel adenocarcinoma on multivariate analysis included advanced age, black race, advanced stage, poor tumor differentiation, high comorbidity index, and distal location. Chemotherapy did not confer additional survival benefit compared with surgery alone (HR, 1.04 (95% CI, 0.90-1.22)).This was a retrospective review. The reliance on Medicare data limited granularity and may have affected the generalizability of the results.The prognosis for small-bowel adenocarcinoma is worse than that for colon cancer, and only surgery improves survival. In contrast to colon cancer, a survival benefit from current chemotherapy regimens for small-bowel adenocarcinoma is not seen, suggesting that it may be overused and needs more rigorous study.

Outbreaks of smallpox (i.e., caused by variola virus) resulted in up to 30% mortality, but those who survived smallpox infection were regarded as immune for life. Early studies described the levels of neutralizing antibodies induced after infection, but smallpox was eradicated before contemporary methods for quantifying T-cell memory were developed. To better understand the levels and duration of immunity after smallpox infection, we performed a case-control study comparing antiviral CD4 + and CD8 + T-cell responses and neutralizing antibody levels of 24 smallpox survivors with the antiviral immunity observed in 60 smallpox-vaccinated (i.e., vaccinia virus-immune) control subjects. We found that the duration of immunity following smallpox infection was remarkably similar to that observed after smallpox vaccination, with antiviral T-cell responses that declined slowly over time and antiviral antibody responses that remained stable for decades after recovery from infection. These results indicate that severe, potentially life-threatening disease is not required for the development of sustainable long-term immunity. This study shows that the levels of immunity induced following smallpox vaccination are comparable in magnitude to that achieved through natural variola virus infection, and this may explain the notable success of vaccination in eradicating smallpox, one of the world's most lethal diseases.

Invasive aspergillosis (IA) occurs in

Aging is usually accompanied by diminished immune protection upon infection or vaccination. Although aging results in well-characterized changes in the T cell compartment of long-lived, outbred, and pathogen-exposed organisms, their relevance for primary Ag responses remain unclear. Therefore, it remains unclear whether and to what extent the loss of naive T cells, their partial replacement by oligoclonal memory populations, and the consequent constriction of TCR repertoire limit the Ag responses in aging primates. We show in this study that aging rhesus monkeys (Macaca mulatta) exhibit poor CD8 T cell and B cell responses in the blood and poor CD8 responses in the lungs upon vaccination with the modified vaccinia strain Ankara. The function of APCs appeared to be maintained in aging monkeys, suggesting that the poor response was likely intrinsic to lymphocytes. We found that the loss of naive CD4 and CD8 T cells, and the appearance of persisting T cell clonal expansions predicted poor CD8 responses in individual monkeys. There was strong correlation between early CD8 responses in the transitory CD28+ CD62L− CD8+ T cell compartment and the peak Ab titers upon boost in individual animals, as well as a correlation of both parameters of immune response to the frequency of naive CD8+ T cells in old but not in adult monkeys. Therefore, our results argue that T cell repertoire constriction and naive cell loss have prognostic value for global immune function in aging primates.

BACKGROUND: Th use of beta-blockers or statins has been associated with decreased mortality after noncardiac surgery. There are no prior perioperative studies of concurrent use of other cardioprotective drugs. OBJECTIVE: To ascertain whether combinations of aspirin, beta-blockers, statins, and/or angiotensin-converting enzyme (ACE) inhibitors were associated with decreased mortality 6 months after vascular surgery. PATIENTS AND DESIGN: We performed a retrospective cohort study on the 3020 patients who underwent vascular surgery between January 1998 and March 2005 at 5 regional Veterans Affairs (VA) medical centers. The Cochran-Mantel-Haenszel test was used to assess associations with 6-month all-cause mortality for the combination drug exposures compared to no exposure while adjusting for propensity score. RESULTS: Exposure to all 4 of the study drugs compared to none had a propensity-adjusted relative risk (aRR) of 0.52 (95% confidence interval [CI], 0.26-1.01; P = 0.052), number needed to treat (NNT) 19; 3 drugs vs. none, aRR 0.60 (95% CI, 0.38-0.95; P = 0.030), NNT 38; 2 drugs vs. none, aRR 0.68 (95% CI, 0.46-0.99; P = 0.043), NNT 170; and 1 drug vs. none, aRR 0.88 (95% CI, 0.63-1.22; P = 0.445). ACE inhibitor exposure was common in all combinations. CONCLUSIONS: Combination use of 2 to 3 study drugs, some of which included ACE inhibitors, was associated with decreased mortality after vascular surgery. Combination use of all 4 study drugs was not statistically significant due to the small number of events in this group. Further prospective studies of combination perioperative aspirin, beta-blockers, statins, and ACE inhibitors are warranted. Journal of Hospital Medicine 2010;5:218–225. © 2010 Society of Hospital Medicine.

We have recently shown in non-human primates that caloric restriction (CR) initiated during adulthood can delay T-cell aging and preserve naïve CD8 and CD4 T cells into advanced age. An important question is whether CR can be initiated at any time in life, and whether age at the time of onset would modulate the beneficial effects of CR. In the current study, we evaluated the impact of CR started before puberty or during advanced age on T-cell senescence and compared it to the effects of CR started in early adulthood. Our data demonstrate that the beneficial effects of adult-onset CR on T-cell aging were lost by both early and late CR onset. In fact, some of our results suggest that inappropriate initiation of CR may be harmful to the maintenance of T-cell function. This suggests that there may be an optimal window during adulthood where CR can delay immune senescence and improve correlates of immunity in primates.

Purpose: To determine the safety and efficacy of weekly high-dose oral calcitriol and docetaxel, given to patients with non-resectable, incurable pancreatic cancer. Patients and Methods: Twenty-five patients were enrolled onto this phase II study. Patients were treated with oral calcitriol 0.5 μg/kg on day 1, followed by docetaxel 36 mg/m2 IV on day 2, administered weekly for three consecutive weeks, followed by 1 week without treatment. Patients followed a low-calcium diet and increased their hydration. The primary end-point of the trial was time-to-progression. Results: Three of 25 patients attained a partial response (12%, 95% CI 3 to 31) and seven (28%) achieved stable disease. Median time-to-progression was 15 weeks, and median overall survival was 24 weeks. Toxicities observed (hyperglycemia, fatigue) were mostly attributable to the docetaxel or its pre-treatment. Conclusions: This regimen of high-dose calcitriol with docetaxel may have activity in incurable pancreatic cancer, with a modest increase in TTP when compared to historical findings using single-agent docetaxel. However, results do not appear superior to those seen with gemcitabine, with or without erlotinib.

For patients with potentially resectable pancreatic cancer, diagnostic laparoscopy may identify liver and peritoneal metastases that are difficult to detect with other staging modalities. The aim of this study was to utilize a population-based pancreatic cancer database to assess the cost effectiveness of preoperative laparoscopy. Data from a state cancer registry were linked with primary medical record data for years 1996–2003. De-identified patient records were reviewed to determine the role and findings of laparoscopic exploration. Average hospital and physician charges for laparotomy, biliary bypass, pancreaticoduodenectomy, and laparoscopy were determined by review of billing data from our institution and Medicare data for fiscal years 2005–2006. Cost-effectiveness was determined by comparing three methods of utilization of laparoscopy: (1) routine (all patients), (2) case-specific, and (3) no utilization. Of 298 potentially resectable patients, 86 underwent laparoscopy. The prevalence of unresectable disease was 14.1% diagnosed at either laparotomy or laparoscopy. The mean charge per patient for routine, case-specific, and no utilization of laparoscopy was $91,805, $90,888, and $93,134, respectively. Cost analysis indicates that the case-specific or routine use of laparoscopy in pancreatic cancer does not add significantly to the overall expense of treatment and supports the use of laparoscopy in patients with known or suspected pancreatic adenocarcinoma.

Racial differences in the incidence of prostate cancer are manifest worldwide, possibly due to the different dietary habits. To elucidate the relationship between the recent trend of phytoestrogenic isoflavone intake and the increased incidence of prostate cancer in Japan, we conducted an age-stratified dietary survey of soybean foods in 102 Japanese healthy men (age range: 10-59 years) and measured the serum isoflavones and equol levels in them and 100 Korean healthy men. The intergroup comparison among the age-stratified groups showed significant differences in the daily intake of genistein and daidzein between the teenager group and the other groups of age >or=30 years (P

Primary androgen suppression therapy for clinically localized prostate cancer is increasingly common in the United States despite a lack of supportive evidence for its use. We determined which demographic and clinical factors predict overall and cancer specific survival with this treatment strategy in patients enrolled in the Prostate Cancer Outcomes Study.In 1994 to 1995 the Prostate Cancer Outcomes Study recruited 3,533 men diagnosed with prostate cancer. Clinical and treatment information was abstracted from medical records and demographic characteristics were obtained from patient surveys 6, 12, 24 and 60 months after diagnosis. Overall and cancer specific mortality was analyzed through December 2002 using the Kaplan-Meier method and Cox regression.A total of 276 patients had organ confined (cT1-2) prostatic adenocarcinoma and received primary androgen suppression therapy within 1 year of diagnosis. Median followup for censored patients was 7.6 years (range 1.1 to 8.1). Five-year overall and cancer specific survival was 66% (95% CI 59-72) and 91% (95% CI 86-94), respectively. Independent predictors of shorter overall survival were patient age 75 years or older, prostate specific antigen 20 ng/ml or greater, Gleason score 7 or greater and abnormal digital rectal examination. Gleason score 7 or greater, prostate specific antigen 20 ng/ml or greater and a low comorbidity index were independent predictors of shorter cancer specific survival.The use of primary androgen suppression therapy in the Prostate Cancer Outcomes Study data set resulted in 91% 5-year cancer specific survival. Advanced age, and factors that reflect tumor burden and biology were predictive of overall survival, while cancer specific survival was predicted by tumor factors and the burden of comorbid conditions. A nomogram for predicting overall survival at 5 years was constructed.

Prior research has identified unrealistic optimism as a bias that might impair informed consent among patient-subjects in early-phase oncology trials. However, optimism is not a unitary construct; it also can be defined as a general disposition, or what is called dispositional optimism. The authors assessed whether dispositional optimism would be related to high expectations for personal therapeutic benefit reported by patient-subjects in these trials but not to the therapeutic misconception. The authors also assessed how dispositional optimism related to unrealistic optimism.Patient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception.Dispositional optimism was found to be significantly associated with higher expectations for personal therapeutic benefit (Spearman rank correlation coefficient [r], 0.333; P.0001), but was not associated with the therapeutic misconception (Spearman r, -0.075; P = .329). Dispositional optimism was found to be weakly associated with unrealistic optimism (Spearman r, 0.215; P = .005). On multivariate analysis, both dispositional optimism (P = .02) and unrealistic optimism (P.0001) were found to be independently associated with high expectations for personal therapeutic benefit. Unrealistic optimism (P = .0001), but not dispositional optimism, was found to be independently associated with the therapeutic misconception.High expectations for therapeutic benefit among patient-subjects in early-phase oncology trials should not be assumed to result from misunderstanding of specific information regarding the trials. The data from the current study indicate that these expectations are associated with either a dispositionally positive outlook on life or biased expectations concerning specific aspects of trial participation. Not all manifestations of optimism are the same, and different types of optimism likely have different consequences for informed consent in early-phase oncology research.

Although most patients with chronic myeloid leukemia (CML) treated with imatinib mesylate achieve a complete cytogenetic response (CCR), some patients will relapse. To determine the potential of real-time quantitative BCR-ABL reverse transcriptase–polymerase chain reaction (RT-PCR) to predict the duration of continued CCR, we monitored 85 patients treated with imatinib mesylate who achieved a CCR. With a median follow-up of 13 months after CCR (29 months after imatinib mesylate; median 6 RQ-PCR assays), 23 patients (27%) had disease progression (predominantly loss of CCR). Compared with the median baseline level of BCR-ABL mRNA, 42% of patients achieved at least a 2-log molecular response at the time of first reaching CCR. Failure to achieve a 2-log response at the time of CCR was an independent predictive marker of subsequent progression-free survival (hazard ratio = 5.8; 95% CI, 1.7-20; P = .005). After CCR, BCR-ABL mRNA levels progressively declined for at least the next 15 months, and 42 patients (49%) ultimately achieved at least a 3-log reduction in BCR-ABL mRNA. Patients failing to achieve this 3-log response, at any time during therapy, had significantly shorter progression-free survival (hazard ratio = 8.1; 95% CI, 3.1-22; P < .001). The achievement of either a 2-log molecular response at the time of CCR or a 3-log response anytime thereafter is a significant and independent prognostic marker of subsequent progression-free survival.

Background: Calcitriol, the natural ligand for the vitamin D receptor, has significant potential in prostate cancer treatment. Measurement of its antineoplastic activity in prostate cancer clinical trials may be complicated by effects of calcitriol on prostate-specific antigen (PSA) production. We examined the effects of calcitriol at similar concentration on cell proliferation, androgen receptor (AR) expression, and PSA production in vitro and on PSA concentrations in prostate cancer patients. Experimental Design: LNCaP prostate cancer cell proliferation was examined by cell counts 6 days after exposure to a range of concentrations of calcitriol. AR and PSA protein was quantified in LNCaP cells over 96 hours after exposure to 1 nmol/L calcitriol. Serum PSA and free PSA was serially measured by immunoassay over a period of 8 days in patients with hormone-naïve prostate cancer after a single dose of 0.5 μg/kg calcitriol. Results: Calcitriol treatment resulted in dose-dependent growth inhibition of LNCaP with ∼50% growth inhibition at the clinically achievable concentration of 1 nmol/L. Time-dependent up-regulation of AR expression and of PSA production in LNCaP cells was shown at the same concentration. No significant change in serum PSA or free PSA over 8 days was seen in eight subjects treated with a single dose of 0.5 μg/kg calcitriol. The analysis was powered to detect a 1.23-fold change between the baseline and day 8 serum PSA. Conclusions: At clinically achievable concentrations, calcitriol inhibits growth and induces AR and PSA expression in LNCaP cells. We did not detect similar changes in serum PSA or free PSA in patients exposed to similar concentrations of calcitriol. Thus, a PSA flare, predicted by preclinical systems, is unlikely to occur in patients and therefore unlikely to complicate interpretation of clinical trial outcomes.

Prostate cancer screening allows early cancer detection but not all patients benefit from subsequent therapy. Thus, identifying patients who are likely to harbor aggressive cancer could significantly decrease the number of prostate biopsies performed.Data were collected on 1,563 consecutive referred men with serum PSA 10 ng/ml or less who underwent an initial prostate biopsy. Predictors of aggressive cancer (Gleason sum 7 or greater) were identified using CART analysis. Model building was done in a randomly selected training set (70% of the data) and validation was completed using the remaining data.Cancer was detected in 406 men (26.1%). Gleason 7 or greater cancer was found in 130 men (8.3%). CART created a decision tree that identified certain groups at risk for aggressive cancer, namely 1) PSAD greater than 0.165 ng/ml/cc, and 2) PSAD greater than 0.058 to 0.165 ng/ml/cc or less, age greater than 57.5 years and prostate volume greater than 22.7 cc. The incidence of aggressive prostate cancer was 1.1% when PSAD was 0.058 ng/ml/cc or less in the validation set. The sensitivity and specificity of CART for identifying men with aggressive cancer were 100% and 31.8% for model building data, and 91.5% and 33.5% for the validation data set, respectively.CART identified groups at risk for aggressive prostate cancer. Application of this CART could decrease unnecessary biopsies by 33.5% when only a diagnosis of high grade prostate cancer would lead to subsequent therapy.

It is theorized that repeated gastric distention leads to dilatation of the cardia and the development of GERD. We hypothesize that cardia circumference correlates with the presence and the severity of GERD, and we developed software to measure cardia circumference from static endoscopic images. Our aims were to validate the software and to quantify cardia circumference along the spectrum of GERD.Software-based measurements were compared with actual measurements in animal and mechanical models. A retrospective review of an endoscopic database and patient charts produced 273 subjects, grouped as follows: controls, GERD,or = 3-cm Barrett's esophagus, or3-cm Barrett's esophagus. A blinded abstractor measured cardia circumference by using images from the database.Software and actual measurements correlated closely and were reproducible among observers. Median cardia circumference for each group was the following: control, 31.8 mm; GERD, 37.8 mm;or = 3-cm Barrett's esophagus, 38.4 mm; and3-cm Barrett's esophagus, 45.0 mm (p0.001). By using 34.3 mm as a cutoff, cardia circumference was 85.3% sensitive and 89.6% specific for the diagnosis of GERD.There was a direct relationship between cardia circumference and the presence of GERD. This finding augments our understanding of the anatomic contributions of the esophagogastric junction in the pathogenesis of GERD. Cardia measurement may prove to be a useful diagnostic tool.

BACKGROUND The current study was performed to identify risk factors and risk groups for carcinoma detection in men undergoing repeat prostate biopsies. METHODS The medical records of all men who had a negative initial prostate biopsy and underwent at least one repeat biopsy between 1992 and 2003 were reviewed to extract age, race, family history of prostate carcinoma, body mass index, referral indication, all prostate-specific antigen (PSA) values, digital rectal examination, PSA density (PSAD), the presence of a hypoechoic lesion, and the presence of high-grade prostatic intraepithelial neoplasia (HGPIN) on initial biopsy. Risk factors for a subsequent diagnosis of prostate carcinoma were identified using the log-rank test and a stepwise, stratified Cox regression model. Based on the risk factors identified by Cox regression analysis, recursive partitioning was further used for risk stratification. RESULTS A total of 373 patients underwent 975 biopsy procedures. During a median follow-up of 37.0 months, prostate carcinoma was detected in 107 of 373 patients (28.9%). Independent predictors of a positive biopsy (P < 0.05) were PSA doubling time (PSADT), PSAD, referral indication, the presence of HGPIN, patient age, and family history of prostate carcinoma. Recursive partitioning identified 4 distinct risk groups that were characterized by their PSADT and PSAD and the presence of HGPIN and had estimated 2-year and 5-year carcinoma detection rates of 3 ± 1% and 21 ± 4%, 28 ± 5% and 40 ± 7%, 22 ± 6% and 58 ± 8%, and 66 ± 9% and 100%, respectively. CONCLUSIONS The authors identified a series of independent risk factors for prostate carcinoma detection after an initial negative prostate biopsy and characterized clinically meaningful and distinct patient risk groups. Despite a negative initial biopsy, patients with high-risk features remain at risk for the detection of prostate carcinoma. Cancer 2005. Published 2005 by the American Cancer Society.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.