Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer.

LESSONS LEARNED: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC).The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. BACKGROUND: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. RESULTS: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). CONCLUSION: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

Overexpression of the Pluripotent Stem Cell Marker Podocalyxin in Prostate Cancer.

BACKGROUND/AIM: Podocalyxin, a member of the CD34 family of cell surface sialomucins, is overexpressed in human embryonal carcinoma cell lines, as well as in several cancer types, and is associated with poor prognosis. Podocalyxin variants are associated with an increased risk and aggressiveness of prostate cancer. Herein podocalyxin protein expression in prostate cancer was characterized. MATERIALS AND METHODS: Expression of podocalyxin as well as of TRA-1-60 and TRA-1-81 antigens was assessed immunohistochemically in 84 radical prostatectomy specimens and in adjacent normal tissues. RESULTS: Podocalyxin expression and H-scores were considerably higher in prostate tumors compared to normal tissues. High TRA-1-60 and TRA-1-81 staining was detected, however, in a much smaller percentage of prostate tumors, while their expression and H-scores were low in normal tissues. Similar trends for all three proteins were observed in prostatic intraepithelial neoplasia. CONCLUSION: Overexpression of podocalyxin in prostate cancer renders the protein a putative immunohistochemical marker of prostate cancer that may contribute to stratification of patients for optimal treatment.

The extrema of circulating miR-17 are identified as biomarkers for aggressive prostate cancer.

MicroRNAs (miRNAs) constitute short non-coding RNAs that can post-transcriptionally modulate the expression of many oncogenes and tumor suppressor genes engaged in key cellular processes. Deregulated serum miRNA signatures have been detected in various solid cancers including prostate cancer, suggesting that circulating miRNAs could function as non-invasive biomarkers of tumor emergence and progression. To determine whether serum miRNA expression levels are different between patients with aggressive and non-aggressive prostate cancer, we analyzed a panel of miRNAs from the blood of African American (AA) prostate cancer patients using a new recursive partitioning method that allows hypothesis testing of each split. We observed that both extrema of circulating miR-17, i.e. upregulation and downregulation, are associated with aggressive prostate cancer. A similar effect was observed in tumor samples from a separate dataset representing a different population of prostate cancer patients and in AA prostate cancer samples from the TCGA. The dual effect is consistent with the contradictory findings on the role of miR-17 in prostate cancer progression, whereby it controls important oncogenic and tumor-suppressive genes.

Physical and Mental Health Impacts of Household Gardens in an Urban Slum in Lima, Peru.

Rural poverty and lack of access to education has led to urban migration and fed the constant growth of urban slums in Lima, Peru. Inhabitants of these informal settlements lack land rights and access to a public water supply, resulting in poor sanitation, an inability to grow food, and suboptimal health outcomes. A repeated measures longitudinal pilot study utilizing participatory design methods was conducted in Lima between September 2013 and September 2014 to determine the feasibility of implementing household gardens and the subsequent impact of increased green space on well-being. Anthropometric data and a composite of five validated mental health surveys were collected at the baseline, 6-months, and 12-months after garden construction. Significant increases from the baseline in all domains of quality of life, including: physical (p < 0.01), psychological (p = 0.05), social (p = 0.02), environmental (p = 0.02), and overall social capital (p < 0.01) were identified 12 months after garden construction. Life-threatening experiences decreased significantly compared to the baseline (p = 0.02). There were no significant changes in parent or partner empathy (p = 0.21), BMI (p = 0.95), waist circumference (p = 0.18), or blood pressure (p = 0.66) at 6 or 12 months. Improved access to green space in the form of a household garden can significantly improve mental health in an urban slum setting.

A study of circulating microRNAs identifies a new potential biomarker panel to distinguish aggressive prostate cancer.

Prostate cancer is one of the most common cancers in men worldwide. Currently available diagnostic and prognostic tools for this disease, such as prostate specific antigen, suffer from lack of specificity and sensitivity, resulting in over- and misdiagnosis. Hence, there is an urgent need for clinically relevant biomarkers capable of distinguishing between aggressive and nonaggressive forms of prostate cancer to aid in stratification, management and therapeutic decisions. To address this unmet need, we investigated the patterns of expression of a panel of 68 plasma-derived microRNAs (miRNAs) in a cohort of African American (AA) and European American (EA) prostate cancer patients (n = 114). miRNA qPCR results were analyzed using in-depth statistical methods, and a bioinformatics analysis was conducted to identify potential targets of the differentially expressed miRNAs. Our data demonstrate that a new previously unreported circulating miRNA signature consisting of a combination of interacting miRNAs (miR-17/miR-192) and an independent miRNA (miR-181a) are capable of segregating aggressive and nonaggressive prostate cancer in both AA and EA patients. The interacting miRNAs outperformed independent miRNAs in identifying aggressiveness. Our results suggest that these circulating miRNAs may constitute novel biomarkers of prostate cancer aggressiveness in both races and warrant further investigation.

Ventilated cookstoves associated with improvements in respiratory health-related quality of life in rural Bolivia.

BACKGROUND: Household air pollution (HAP) from combustion of biomass fuels worldwide is linked to asthma, respiratory infections and chronic pulmonary diseases. Implementation of ventilated cookstoves significantly reduces exposure to HAP. However, improvements in concurrent respiratory health-related quality of life (HRQoL) have not been previously evaluated with a standardized questionnaire. METHODS: The association between woodsmoke exposure and respiratory HRQoL outcomes was evaluated using an intervention study in a rural community in Bolivia. Indoor carbon monoxide (CO) levels from traditional stoves and from cookstoves with chimneys were analyzed alongside interview results of women heads-of-households using the St. George's Respiratory Questionnaire (SGRQ) in 2009 and 1-year post-intervention. RESULTS: Pronounced improvements in respiratory HRQoL and significant reductions of household CO levels followed installation of ventilated cookstoves. Stove implementation yielded lower indoor CO values and correlated positively with improved SGRQ scores. CONCLUSIONS: This is the first use of a standardized respiratory HRQoL assessment to determine the impact of ventilated cookstove implementation on reducing HAP. This preliminary study utilizes the SGRQ as a valuable tool enabling analysis of these health effects in relation to other respiratory disease states.

Interactions between HIV/AIDS and the environment: toward a syndemic framework.

Although the social, economic, and political dimensions of the HIV/AIDS epidemic have been studied in considerable depth, the relationship between HIV/AIDS and its environmental causes and consequences remains largely unexplored. We reviewed the evidence of interactions between ecosystem health and the HIV/AIDS pandemic. We hypothesized a syndemic between environmental degradation and HIV/AIDS; they exhibit bidirectional, self-reinforcing interactions. We have presented a syndemic framework detailing multiple synergistic relationships. This framework hinges on the vulnerability of populations as the linchpin between the pandemic and environmental health. A coherent research and practice agenda for addressing the syndemic that focuses on the 2 issues as not only concurrent but also intertwined phenomena is urgently needed.

A process-based hierarchical framework for monitoring glaciated alpine headwaters.

Recent studies have demonstrated the geomorphic complexity and wide range of hydrologic regimes found in alpine headwater channels that provide complex habitats for aquatic taxa. These geohydrologic elements are fundamental to better understand patterns in species assemblages and indicator taxa and are necessary to aquatic monitoring protocols that aim to track changes in physical conditions. Complex physical variables shape many biological and ecological traits, including life history strategies, but these mechanisms can only be understood if critical physical variables are adequately represented within the sampling framework. To better align sampling design protocols with current geohydrologic knowledge, we present a conceptual framework that incorporates regional-scale conditions, basin-scale longitudinal profiles, valley-scale glacial macroform structure, valley segment-scale (i.e., colluvial, alluvial, and bedrock), and reach-scale channel types. At the valley segment- and reach-scales, these hierarchical levels are associated with differences in streamflow and sediment regime, water source contribution and water temperature. Examples of linked physical-ecological hypotheses placed in a landscape context and a case study using the proposed framework are presented to demonstrate the usefulness of this approach for monitoring complex temporal and spatial patterns and processes in glaciated basins. This approach is meant to aid in comparisons between mountain regions on a global scale and to improve management of potentially endangered alpine species affected by climate change and other stressors.

Channel and perennial flow initiation in headwater streams: management implications of variability in source-area size.

Despite increasing attention to management of headwater streams as sources of water, sediment, and wood to downstream rivers, the extent of headwater channels and perennial flow remain poorly known and inaccurately depicted on topographic maps and in digital hydrographic data. This study reports field mapping of channel head and perennial flow initiation locations in forested landscapes underlain by sandstone and basalt lithologies in Washington State, USA. Contributing source areas were delineated for each feature using a digital elevation model (DEM) as well as a Global Positioning System device in the field. Systematic source area-slope relationships described in other landscapes were not evident for channel heads in either lithology. In addition, substantial variability in DEM-derived source area sizes relative to field-delineated source areas indicates that in this area, identification of an area-slope relationship, should one even exist, would be difficult. However, channel heads and stream heads, here defined as the start of perennial flow, appear to be co-located within both of the lithologies, which together with lateral expansion and contraction of surface water around channel heads on a seasonal cycle in the basalt lithology, suggest a controlling influence of bedrock springs for that location. While management strategies for determining locations of channel heads and perennial flow initiation in comparable areas could assign standard source area sizes based on limited field data collection within that landscape, field-mapped source areas that support perennial flow are much smaller than recognized by current Washington State regulations.

Salvage radiation for a rising PSA following radical prostatectomy.

The purpose of this study was to evaluate the efficacy and complications of postprostatectomy therapeutic irradiation (RT) in patients with known residual disease. Between 1991 and 2003, 170 patients received therapeutic irradiation for a rising PSA following radical prostatectomy. No patients had clinical or radiological evidence of metastatic disease. The median pre-RT PSA level was 1.2 ng/mL (range, 0.2-43 ng/mL). During irradiation, the PSA level was checked weekly (median PSA determinations: 5, range, 2-7). A patient was considered to have a rise/fall of PSA if the level changed by > or = 0.2 ng/mL. There were 149 patients who received photon irradiation (median dose, 6800 cGy) and 21 patients received a combination of photon and neutron irradiation to a median photon dose equivalent of 7800 cGy. A patient was considered to have biochemical failure if his PSA level postnadir was measured at >0.2 ng/mL. Complications were graded according to the RTOG toxicity scale. The median follow-up time was 49 months (range, 1-137 months). Sixty-four patients (38%) had evidence of biochemical failure. The 7 year overall survival was 84%. At 7 years, the actuarial biochemical relapse free survival (bRFS) was 44%. Of the 59 patients with a preradiation PSA <1 ng/mL, the 5 year bRFS was 81%. This compares with 45% for both the PSA 1-4 and PSA >4 ng/mL group (P = 0.00008). The 3-year bRFS rates for patients whose PSA levels increased, decreased, and remained the same during radiation were 20%, 65%, and 76%, respectively (P = 0.0005). Overall survival at 7 years in the decreased PSA group was 88% compared to 67% for those whose PSA level increased (P = 0.43). Thirty-three percent and 19% of the patients experienced Grade 2 genitourinary (GU) and gastrointestinal (GI) complications, respectively. Six percent and 3% of the patients had Grade 3 GU and GI complications, respectively. On univariate and multivariate analysis, the factors significantly associated with a favorable outcome were a declining PSA during RT and a pre-RT PSA <1 ng/mL (P < 0.001). Radiation therapy is an effective treatment modality for select patients with a biochemical recurrence following radical prostatectomy. Patients with a low preradiation PSA level (<1.0 ng/mL) had a significantly better outcome, which supports the early use of therapeutic radiation. The observation that patients with a rising PSA level during treatment do poorly supports the routine practice of monitoring these levels during radiotherapy.

Intermittent androgen deprivation for patients with recurrent/metastatic prostate cancer.

This study was designed to assess the duration of response to intermittent androgen deprivation therapy (IAD) in patients with recurrent and/or metastatic prostate cancer. Between January 1993 and March 2000, 74 patients with recurrent and/or metastatic prostate cancer had IAD with either luteinizing hormone-releasing hormone agonist (LHRH) or an LHRH with an oral antiandrogen. Forty-one patients were treated for an increasing prostate-specific antigen (PSA) level after primary local treatment. Of the remaining 33 patients, 17 patients were treated for metastases (9 for bone metastases, 8 for lymph nodes metastases, and 16 for local recurrence). Patients who had undergone IAD completed between 1 and 6 cycles. A cycle was defined as the period during which the patient was actively taking the hormone medication. Seventy-four patients completed the first cycle, 49 completed the second cycle, and 23 completed the third cycle. The pattern of PSA changes with each cycle, the length of each cycle, and the time interval between successive cycles were studied. The time to progression (defined as an increasing PSA level on two consecutive measurements or radiologic evidence of progression of disease while the patient was on androgen deprivation) was also studied. The median PSA before the IAD was 11.4 ng/mL (range 0.12-378). The median PSA nadir at the end of each cycle increased progressively (0.1 ng/mL after the first cycle to 3.3 ng/mL after the fifth cycle). The time interval between the cycles progressively decreased from 9.5 months between the first and second cycles to 6 months between the third and fourth cycles. The 4-year actuarial androgen-independent free survival was 71%. For the subgroups of patients treated for biochemical failure, locoregional recurrence, and bone metastases, the 4-year actuarial progression-free survival rates were 80%, 67%, and 45% respectively (P = 0.018). The median time of 18 months to progression in patients with bone metastases is similar to that reported with continuous hormonal therapy. In patients with biochemical failure, the median time to progression (more than 5 years) suggests that the IAD approach may be a viable option for this group of patients.

Fast neutron irradiation for prostate cancer.

The purpose of this study was to summarize the progress made using fast neutron irradiation in the treatment of prostate cancer at Wayne State University between 1991 and the year 2001. The results of three Phase II studies and one Phase III st udy involving nearly 700 patients is summarized in this paper. The Phase II studies weredose finding studies looking at doses of 15, 9, 10, and 11 nGy, respectively. The randomized protocol was a study of sequence looking at the results of treating patients with neutron first versus neutron radiation last. The results demonstrated that the best combination of tumor control probabilities and normal tissue complications was found in a mix of approximately 50% neutrons and 50% photons. Thus, the standard doses become 10 nGy and 40 Gy of photons. The randomized trial demonstrated that the sequence has significant importance and the disease-free survival was 93% for patients treated with neutrons first versus 73% for patients treated with neutrons last. There was no difference in the rate of acute or chronic complications. Finally, an analysis was performed demonstrating which patients may best benefit from the use of neutron irradiation. It was shown that patients with one, two, or three adverse risk factors had a significant improvement in disease-free survival when part of the treatment included neutron radiation versus standard photon radiation alone. Neutron radiation can be delivered safely with effort to see that it is superior to that which can be achieved by conformal photon irradiation by itself. Future work will be done to expand the role of neutron radiation in other clinical disease sites.

Therapeutic postprostatectomy irradiation.

The purpose of this study was to determine the outcome of patients receiving external beam radiation for an elevated postprostatectomy prostate-specific antigen (PSA) level. Between December 1991 and September 1998, 108 patients received definitive radiation therapy for elevated postprostatectomy PSA levels. The median dose of irradiation was 68 Gy (range, 48-74 Gy). During treatment, the PSA levels were checked an average of 5 times (range, 3-7 times). Prostate-specific antigen values were judged to decline or increase during treatment if they changed by more than 0.2 ng/mL. After treatment, biochemical failure was defined as a measurable or rising PSA > 0.2 ng/mL. Median follow-up was 51 months (range, 3-112 months). Fifty-eight patients (54%) had evidence of biochemical failure. The 3- and 5-year actuarial biochemical relapse-free (bNED) survivals for all patients were 55% and 39%, respectively. Upon univariate analysis, intratreatment PSA and preradiation PSA were significant predictors of bNED survival. Patients with a PSA level that decreased during treatment had a 5-year bNED survival of 43% compared to 10% in patients with an increasing PSA level (P = 0.0002). Using the preradiation therapy PSA value as a continuous variable, higher preradiation therapy PSA levels were associated with an increased risk of failure (P = 0.004). Cut points of pretreatment PSA were derived at 0.9 ng/mL and 4.2 ng/mL using the Michael Leblanc recursive partitioning algorithm. The 5-year bNED rate for patients with a preradiation therapy PSA < 0.9 ng/mL was 45% versus 42% for patients with preradiation therapy PSA between 0.9 and 4.2 ng/mL and 21% for patients > or = 4.2 ng/mL (P = 0.0003). Patients with a Gleason score of < or = 7 had a 5-year bNED rate of 38% compared to 37% for patients with a Gleason score > 7 (P = 0.27). Other factors examined individually that did not reach statistical significance included time from surgery to radiation therapy, race, seminal vesicle involvement, pathological stage, surgical margin, and perineural invasion. Upon multivariate analysis, only preradiation therapy PSA (P < 0.001) and the PSA trend during radiation therapy (P < 0.001) were significant factors. The results of therapeutic radiation for patients with elevated postprostatectomy PSA levels are sufficiently poor; other strategies should be explored as alternatives, including early adjuvant postprostatectomy irradiation or the use of combined hormonal and radiation therapy in the salvage situation.