Functional genomic landscape of acute myeloid leukaemia.

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.

An open protocol for modeling T Cell Clonotype repertoires using TCRß CDR3 sequences.

T cell receptor repertoires can be profiled using next generation sequencing (NGS) to measure and monitor adaptive dynamical changes in response to disease and other perturbations. Genomic DNA-based bulk sequencing is cost-effective but necessitates multiplex target amplification using multiple primer pairs with highly variable amplification efficiencies. Here, we utilize an equimolar primer mixture and propose a single statistical normalization step that efficiently corrects for amplification bias post sequencing. Using samples analyzed by both our open protocol and a commercial solution, we show high concordance between bulk clonality metrics. This approach is an inexpensive and open-source alternative to commercial solutions.

GMEPS: a fast and efficient likelihood approach for genome-wide mediation analysis under extreme phenotype sequencing.

Due to many advantages such as higher statistical power of detecting the association of genetic variants in human disorders and cost saving, extreme phenotype sequencing (EPS) is a rapidly emerging study design in epidemiological and clinical studies investigating how genetic variations associate with complex phenotypes. However, the investigation of the mediation effect of genetic variants on phenotypes is strictly restrictive under the EPS design because existing methods cannot well accommodate the non-random extreme tails sampling process incurred by the EPS design. In this paper, we propose a likelihood approach for testing the mediation effect of genetic variants through continuous and binary mediators on a continuous phenotype under the EPS design (GMEPS). Besides implementing in EPS design, it can also be utilized as a general mediation analysis procedure. Extensive simulations and two real data applications of a genome-wide association study of benign ethnic neutropenia under EPS design and a candidate-gene study of neurocognitive performance in patients with sickle cell disease under random sampling design demonstrate the superiority of GMEPS under the EPS design over widely used mediation analysis procedures, while demonstrating compatible capabilities under the general random sampling framework.

Feasibility of indocyanine green-guided localization of pulmonary nodules in children with solid tumors.

BACKGROUND: Clearing all pulmonary metastases is essential for curing pediatric solid tumors. However, intraoperative localization of such pulmonary nodules can be challenging. Therefore, an intraoperative tool that localizes pulmonary metastases is needed to improve diagnostic and therapeutic resections. Indocyanine green (ICG) real-time fluorescence imaging is used for this purpose in adult solid tumors, but its utility in pediatric solid tumors has not been determined. METHODS: A single-center, open-label, nonrandomized, prospective clinical trial (NCT04084067) was conducted to assess the ability of ICG to localize pulmonary metastases of pediatric solid tumors. Patients with pulmonary lesions who required resection, either for therapeutic or diagnostic intent, were included. Patients received a 15-minute intravenous infusion of ICG (1.5 mg/kg), and pulmonary metastasectomy was performed the following day. A near-infrared spectroscopy iridium system was optimized to detect ICG, and all procedures were photo-documented and recorded. RESULTS: ICG-guided pulmonary metastasectomies were performed in 12 patients (median age: 10.5 years). A total of 79 nodules were visualized, 13 of which were not detected by preoperative imaging. Histologic examination confirmed the following histologies: hepatoblastoma (n = 3), osteosarcoma (n = 2), and one each of rhabdomyosarcoma, Ewing sarcoma, inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, and papillary thyroid carcinoma. ICG guidance failed to localize pulmonary metastases in five (42%) patients who had inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, or papillary thyroid carcinoma. CONCLUSIONS: ICG-guided identification of pulmonary nodules is not feasible for all pediatric solid tumors. However, it may localize most metastatic hepatic tumors and high-grade sarcomas in children.

Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with approximately four new cases per 100,000 persons per year. Standard treatment for AML consists of induction chemotherapy with remission achieved in 50 to 75% of cases. Unfortunately, most patients will relapse and die from their disease, as 5-y survival is roughly 29%. Therefore, other treatment options are urgently needed. In recent years, immune-based therapies have led to unprecedented rates of survival among patients with some advanced cancers. Suppression of T cell function in the tumor microenvironment is commonly observed and may play a role in AML. We found that there is a significant association between T cell infiltration in the bone marrow microenvironment of newly diagnosed patients with AML and increased overall survival. Functional studies aimed at establishing the degree of T cell suppression in patients with AML revealed impaired T cell function in many patients. In most cases, T cell proliferation could be restored by blocking the immune checkpoint molecules PD-1, CTLA-4, or TIM3. Our data demonstrate that AML establishes an immune suppressive environment in the bone marrow, in part through T cell checkpoint function.

covidscreen: a web app and R Package for assessing asymptomatic COVID-19 testing strategies.

BACKGROUND: COVID-19 has caused over 305 million infections and nearly 5.5 million deaths globally. With complete eradication unlikely, organizations will need to evaluate their risk and the benefits of mitigation strategies, including the effects of regular asymptomatic testing. We developed a web application and R package that provides estimates and visualizations to aid the assessment of organizational infection risk and testing benefits to facilitate decision-making, which combines internal and community information with malleable assumptions. RESULTS: Our web application, covidscreen, presents estimated values of risk metrics in an intuitive graphical format. It shows the current expected number of active, primarily community-acquired infections among employees in an organization. It calculates and explains the absolute and relative risk reduction of an intervention, relative to the baseline scenario, and shows the value of testing vaccinated and unvaccinated employees. In addition, the web interface allows users to profile risk over a chosen range of input values. The performance and output are illustrated using simulations and a real-world example from the employee testing program of a pediatric oncology specialty hospital. CONCLUSIONS: As the COVID-19 pandemic continues to evolve, covidscreen can assist organizations in making informed decisions about whether to incorporate covid test based screening as part of their on-campus risk-mitigation strategy. The web application, R package, and source code are freely available online (see "Availability of data and materials").

CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells.

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.

Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial.

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.

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies.

Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.

Phase 1-2 study of vorinostat (SAHA), cladribine and rituximab (SCR) in relapsed B-cell non-Hodgkin lymphoma and previously untreated mantle cell lymphoma.

Altered DNA methylation and histone acetylation in lymphoma provided the rationale for using vorinostat (SAHA), cladribine and rituximab (SCR) in non-Hodgkin lymphomas (NHL) in this phase 1-2 study (NCT00764517). Treatment included cladribine 5 mg/m2 intravenously (IV) (days 1-5), rituximab 375 mg/m2 IV (weekly 4× for cycle 1 and 1×/month) and vorinostat orally once daily (days 1-14) every 28 days for up to six cycles. Phase 1 included relapsed patients (n = 10) in a standard 3 + 3 dose escalation design (vorinostat: 200, 300 and 400 mg). No dose-limiting toxicities were seen. The phase 2 dose for vorinostat was 400 mg po (days 1-14). The majority of phase 2 patients had mantle cell lymphoma (MCL) (n = 57; 39 previously untreated, 10 relapsed). The primary objective was objective response rate [complete response (CR) + partial response] which was 39% (7/18) in relapsed patients and 97% (38/39) with 80% (31/39) attaining a CR in previously untreated MCL. At a median follow-up of 42 months, median progression-free survival (PFS) and overall survival (OS) for relapsed NHL were 19·5 [95% confidence interval (CI): 2·0-33·0] and 25·0 (95% CI: 12·0-45·0) months respectively. Median PFS for previously untreated MCL was 84·0 months; OS could not be estimated. Toxicities were primarily haematological.

MiR-486-5p Downregulation Marks an Early Event in Colorectal Carcinogenesis.

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 < 0.01). 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.

Perceptions of control and unrealistic optimism in early-phase cancer trials.

PURPOSE: Recent 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. METHODS: A 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. RESULTS: One 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 (p<0.0001). CONCLUSION: Patient-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.

Randomized, double-blind, placebo-controlled study of methylphenidate for the treatment of depression in SSRI-treated cancer patients receiving palliative care.

OBJECTIVE: To determine the effectiveness of methylphenidate for depression treatment in patients with advanced cancer. DESIGN: An 18-day randomized, double-blind, placebo-controlled clinical trial of methylphenidate for treatment of depression in selective serotonin reuptake inhibitor-treated patients with advanced cancer in hospice or receiving palliative care. The primary outcome was depression remission, defined as a ≥50% reduction in score on the Montgomery-Asberg Depression Rating Scale. RESULTS: Among 47 enrolled participants, 34 were randomized. At study day 18, 85% of the methylphenidate and 60% of the placebo group were in depression remission (P = .22). Mean time to depression remission was 10.3 days [standard error (SE) 1.8] in the methylphenidate and 8.1 (SE 1.3) in the placebo group (P = .48). The mean baseline score for the Hospital Anxiety and Depression Scale (HADS) was 10.4 in each group and decreased by 3.6 (SE 1.1) in the methylphenidate and 2.3 (SE 1.2) in the placebo group (P = .51) by day 18. Once in remission, 1 methylphenidate and 5 placebo participants relapsed to depression (P = .18). There was no difference in mortality between the groups during the trial. Trial results were limited by small sample size attributed to difficulties in recruiting terminally ill patients. CONCLUSIONS: This trial failed to demonstrate that methylphenidate treatment in selective serotonin reuptake inhibitor-treated patients had a significant effect on depression remission in patients with advanced cancer. This study underscores the difficulties in conducting trials for symptom management in patients with shortened life expectancy.

Durability of Vaccine-Induced Immunity Against Tetanus and Diphtheria Toxins: A Cross-sectional Analysis.

BACKGROUND: Many adult immunization schedules recommend that tetanus and diphtheria vaccination be performed every 10 years. In light of current epidemiological trends of disease incidence and rates of vaccine-associated adverse events, the 10-year revaccination schedule has come into question. METHODS: We performed cross-sectional analysis of serum antibody titers in 546 adult subjects stratified by age or sex. All serological results were converted to international units after calibration with international serum standards. RESULTS: Approximately 97% of the population was seropositive to tetanus and diphtheria as defined by a protective serum antibody titer of ≥0.01 IU/mL. Mean antibody titers were 3.6 and 0.35 IU/mL against tetanus and diphtheria, respectively. Antibody responses to tetanus declined with an estimated half-life of 14 years (95% confidence interval, 11-17 years), whereas antibody responses to diphtheria were more long-lived and declined with an estimated half-life of 27 years (18-51 years). Mathematical models combining antibody magnitude and duration predict that 95% of the population will remain protected against tetanus and diphtheria for ≥30 years without requiring further booster vaccination. CONCLUSIONS: These studies demonstrate that durable levels of protective antitoxin immunity exist in the majority of vaccinated individuals. Together, this suggests that it may no longer be necessary to administer booster vaccinations every 10 years and that the current adult vaccination schedule for tetanus and diphtheria should be revisited.

Dispositional optimism and therapeutic expectations in early-phase oncology trials.

BACKGROUND: 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. METHODS: Patient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception. RESULTS: 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. CONCLUSIONS: 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.

Effects of ω-3 Fatty Acids and Catechins on Fatty Acid Synthase in the Prostate: A Randomized Controlled Trial.

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.

Treatment and Survival of Small-bowel Adenocarcinoma in the United States: A Comparison With Colon Cancer.

BACKGROUND: 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. OBJECTIVE: The purpose of this study was to evaluate the current surgical and adjuvant treatments of small-bowel adenocarcinoma and compare with colon cancer. DESIGN: This was a retrospective cohort study. SETTINGS: The linked Surveillance, Epidemiology, and End Results and Medicare database was used at a tertiary referral hospital. PATIENTS: 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. MAIN OUTCOME MEASURES: Overall survival and cancer-specific survival were estimated using the Kaplan-Meier method and competing risk analysis. RESULTS: 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% (p < 0.0001). 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)). LIMITATIONS: This was a retrospective review. The reliance on Medicare data limited granularity and may have affected the generalizability of the results. CONCLUSIONS: 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.

A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer.

INTRODUCTION: 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. PURPOSE: 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. METHODS: 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 (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p = 0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. CONCLUSIONS: Treatment with 200 µmoles/day of sulforaphane-rich extracts did not lead to ≥50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent.

Improving colorectal cancer screening in Asian Americans: Results of a randomized intervention study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: An educational program delivered by culturally specific community health educators using culturally appropriate language influences some knowledge, attitude, and behavioral beliefs but not others.

Assisted movement with proprioceptive stimulation reduces impairment and restores function in incomplete spinal cord injury.

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, 40.5 y; 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<.000). The AMES active motion scores improved in the hand (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.