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Treaty Banning the Bomb Takes UN Closer to its Prime Goal
By Somar Wijayadasa*
NEW YORK (IDN) - On July 7 2017, 122 member states of the United Nations voted to adopt a Treaty for the Prohibition of Nuclear Weapons. It is the first legally binding international agreement to comprehensively prohibit nuclear weapons that may eventually lead towards their total elimination.
All nine nuclear weapons states and the U.S. allies under its nuclear "umbrella" in NATO, Japan, South Korea, and Australia boycotted the negotiations. Netherlands attended the Conference but voted against the treaty, as it is a member of NATO.
The treaty emphasizes the catastrophic humanitarian consequences that would result from any use of nuclear weapons. It forbids participating states to develop, test, use, threaten to use, produce, possess, acquire, transfer, test or deploy nuclear weapons.
It expresses compliance with existing laws relevant to weapons of mass destruction that have been adopted by the UN since 1946, and it emphasizes the "inalienable right" of nations of peaceful uses of nuclear energy.
The treaty to be signed by member states on September 20 during the UN General Assembly, will become international law following its ratification by 50 members states.
This treaty does not create a global law prohibiting nuclear weapons because the countries that possess nuclear weapons may not sign the new treaty.
It would, however, have the same effect as other UN prohibitions on weapons of mass destruction - i.e., all countries will be morally obliged to follow suit. Nonetheless, it marks an important milestone towards a nuclear-free world by banning the weapons under international law.
Nuclear Disarmament: Primary goal of the United Nations
The United Nations was founded in 1945 after the death and destruction of the Second World War. At that time, the United States was the only nation in the world to own and use nuclear weapons that annihilated Hiroshima and Nagasaki. That proved the inhumanely destructive power of nuclear weapons.
At its first General Assembly meeting in 1946, the UN unanimously adopted a resolution to eliminate atomic weapons and other weapons of mass destruction.
During the last seven decades, the UN strived to abolish nuclear weapons to accomplish its noble goal "to save succeeding generations from the scourge of war". Among the significant UN Treaties towards achieving that goal are:
The 1970, the Non-Proliferation Treaty (NPT), ratified by 190 states including five nations that admitted to owning nuclear weapons: China, France, former Soviet Union (Russia), United Kingdom and the United States of America.
According to he NPT, "countries with nuclear weapons will move towards disarmament; countries without nuclear weapons will not acquire them; and all countries can access peaceful nuclear technology."
Despite NPT's explicit provision that "countries without nuclear weapons will not acquire them", India, Israel, Pakistan and North Korea became nuclear states. Together, nuclear weapon countries possess more than 15,000 nuclear weapons. Ninety percent of those weapons are held by USA and Russia.
The 1972 UN ban on biological weapons and the 1993 UN ban on chemical weapons prohibited an entire category of weapons of mass destruction of developing, producing, acquiring, stockpiling, or retaining biological and chemical weapons.
The 1996 Comprehensive Nuclear-Test-Ban Treaty (CTBT) "prohibits any nuclear weapon test explosion or any other nuclear explosion" and has been signed by 183 states, including the United States, Russia, the U.K. France, and China.
In addition to these legally binding international treaties, there are several nuclear-weapons-free zones in the regions of: Latin America (the 1967 Treaty of Tlatelolco), the South Pacific (the 1985 Treaty of Rarotonga), Southeast Asia (the 1995 Treaty of Bangkok) Africa (the 1996 Treaty of Pelindaba) and Central Asia (the 2006 Treaty of Semipalatinsk).
These zones combined comprise 115 states, accounting for 60% of all UN Member States, and all states prohibit nuclear weapons in their respective regions. In 2013, the UN declared September 26 as the International Day for the Total Elimination of Nuclear Weapons.
Nuclear nightmare
Nuclear weapons are the most inhumane and dangerous weapons on earth which can annihilate whole cities, potentially kill millions of people, and destroy the natural environment and lives of future generations through its long-term catastrophic effects.
Volumes have been written about the necessity, morality and consequences of the use of nuclear weapons but the power hungry war-mongers (the nuclear powers) do not care about the disastrous consequences of a nuclear war. They only want all other states to adhere to their diktats.
The fear of a nuclear war is once again on the rise. The ongoing U.S. wars in the Middle East, constant military skirmishes in the Baltic, Mediterranean and China Seas, the incessant threats by NATO and Russia, along with the confrontational U.S. military posture toward Russia, China and North Korea, are creating conditions that could all too easily trigger a catastrophic nuclear war.
Also, the threat of a nuclear exchange by accident, miscalculation or even intent by a deranged person is greater than ever.
Right now, North Korea's nuclear and ballistic missile program poses a serious threat to international peace and security of the entire world. The only way to stop and prevent North Korea or any other belligerent state brandishing the nuclear bomb could be the complete elimination of nuclear weapons.
A nuclear-weapons-free world
In the past, American Presidents have spoken about the need to abolish nuclear weapons.
For example, John F. Kennedy said that these nuclear weapons "must be abolished before they abolish us"; Ronald Reagan said "We must never stop at all until we see the day when nuclear arms have been banished from the face of the Earth"; and in a 2009 Prague speech, Barack Obama vowed "concrete steps towards a world without nuclear weapons".
Since those lofty words, the United States has spent hundreds of billions of dollars to upgrade its nuclear weapons.
In a recent article published in IDN, Alice Slater of the Nuclear Age Peace Foundation wrote "President Obama, before he left office was planning to spend one trillion dollars over the next 30 years for two new bomb factories, new warheads and delivery systems."
The United Nations has decided to hold a High-Level Conference on Nuclear Disarmament in 2018 in order to enhance progress toward the achievement of a nuclear weapons convention – a global treaty to prohibit and eliminate nuclear weapons.
With conflicts and wars raging all over our world, all world leaders and peace loving citizens should focus on developing a new concept of international security under the auspices of the United Nations – to guide the world towards the elimination of nuclear weapons.
It's not just about peace. It's about the survival of all life on earth.
* Somar Wijayadasa, was a Delegate of UNESCO to the UN General Assembly from 1985-1995, and was Representative of UNAIDS at the United Nations from 1995-2000. [IDN-InDepthNews – 31 July 2017]
Photo: Atomic bomb survivors from Japan and others activists march in New York to push for nuclear weapons abolition on April 26, 2015. Credit: OSV Newsweekly | Newscom
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been disarmament their ramesh which trump arabic york will norwegian abolition international world with japanese first version nagasaki 2017 non-proliferation hiroshima this jaura united north free conference general text president weapons have that test states nations nuclear arms 2018 ican security korean from korea treaty global berlin news iran peace


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Cancer Therapy: Clinical
A Phase II Multicenter, Randomized, Double-Blind, Safety Trial Assessing the Pharmacokinetics, Pharmacodynamics, and Efficacy of Oral 2-Methoxyestradiol Capsules in Hormone-Refractory Prostate Cancer
Christopher Sweeney, Glenn Liu, Constantin Yiannoutsos, Jill Kolesar, Dorothea Horvath, Mary Jane Staab, Karen Fife, Victoria Armstrong, Anthony Treston, Carolyn Sidor and George Wilding
Christopher Sweeney
Glenn Liu
Constantin Yiannoutsos
Jill Kolesar
Dorothea Horvath
Mary Jane Staab
Karen Fife
Victoria Armstrong
Anthony Treston
Carolyn Sidor
George Wilding
DOI: 10.1158/1078-0432.CCR-05-0440 Published September 2005
Purpose: To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol can be translated to the clinic.
Experimental Design: Men with hormone-refractory prostate cancer were enrolled into this phase II randomized, double-blind trial of two doses of oral 2-methoxyestradiol capsules (400 and 1,200 mg/d) given in 4-week cycles. Pharmacokinetic sampling was done on day 1 of cycles 1 and 2 and trough samples were obtained weekly.
Results: Thirty-three men were accrued between February and September 2001. The notable toxicity related to therapy was one grade 2 and two grade 3 episodes of liver transaminase elevation, which resolved with continued treatment in two patients. There were two cases of deep venous thromboses. The drug had nonlinear pharmacokinetic, rapid conversion to 2-methoxyestrone and ∼85% conjugation. Trough plasma levels of unconjugated 2-methoxyestradiol and 2-methoxyestrone were ∼4 and 40 ng/mL, respectively. Prostate-specific antigen declines between 21% and 40% were seen in seven patients in the 1,200 mg group and in one patient in the 400 mg group. The higher-dose group showed significantly decreased prostate-specific antigen velocity (P = 0.037) and compared with the 400 mg dose had a longer median time to prostate-specific antigen progression (109 versus 67 days; P = 0.094) and time on study (126 versus 61 days; P = 0.024). There was a 2.5- and 4-fold increase in sex hormone-binding globulin for the 400 and 1,200 mg dose levels, respectively, at days 28 and 56.
Conclusion: 2-Methoxyestradiol is well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with this capsule formulation, still showed some anticancer activity at 1,200 mg/d.
2-Methoxyestradiol
Antiangiogenesis
Genitourinary cancers: prostate
The need for new therapies for prostate cancer is paramount. Prostate cancer is the most common male malignancy in the United States with ∼200,000 new cases of prostate cancer with ∼32,000 deaths per year (1). Standard initial therapy for metastatic disease consists of androgen ablation and patients will become refractory to hormonal therapy after a median time of ∼24 months (2). Only recently has any therapy been shown to prolong overall survival. Specifically, randomized phase III trials of docetaxel-based chemotherapy have shown a modest survival benefit when compared with mitoxantrone plus prednisone (3, 4). Clearly, new therapies are required.
Angiogenesis, the formation of new microvessels from existing vasculature, is fundamental to progressive tumor growth. In the absence of neovascularization, tumor growth is limited to 1 to 2 mm3. Over the last two decades, substantial laboratory and indirect clinical evidence has accumulated to support the central role of angiogenesis in prostate cancer progression. Therefore, the inhibition of angiogenesis may be a viable strategy for the treatment of hormone-refractory prostate cancer. The supporting data include the following. Increased microvessel density in prostate cancer is associated with a shorter time to recurrence and higher stage after a radical prostatectomy as well as a shorter time to recurrence after radiation therapy (5–7). Vascular endothelial growth factor (VEGF) is a potent and specific stimulator of endothelial cell proliferation and angiogenesis (8), and VEGF expression, measured in prostate cancer cytosolic extracts, correlates with microvessel density and is associated with relapse after a radical prostatectomy (9). Furthermore, VEGF is found at higher levels in the plasma of patients with metastatic prostate cancer than in the plasma of patients with localized disease or in the plasma of healthy controls (10). These data are consistent with findings from other cancers in which VEGF has been elevated in urine and plasma and is typically detected at higher levels in cancer patients than in the healthy volunteers (11). Basic fibroblast growth factor (bFGF) is also produced by prostate cancers and is found at increased levels in the serum of patients with prostate cancer when compared with levels in men without prostate cancer. Inhibition of angiogenesis may therefore be a viable strategy for the treatment of prostate cancer.
2-Methoxyestradiol (2ME2) is an estrogen metabolite that is naturally formed in vivo by the sequential hydroxylation and O-methylation of estradiol at the 2-position. 2ME2 binds very poorly to the estrogen receptor (0.05% of estradiol binding; ref. 12) and does not exhibit direct estrogenic activity in many test systems. Several investigations have provided encouraging results for the use of 2ME2 in the treatment of cancer. Preclinical studies have indicated that 2ME2 is both antiproliferative by acting directly on the tumor cell compartment and antiangiogenic. In vitro, 2ME2 inhibits proliferation of many cancer and endothelial cell lines in the submicromolar to low micromolar range and the activity is independent of the estrogen responsiveness of the cell line. For example, the IC50 value for the hormone-independent prostate cancer cell line, DU-145, was 1.8 μmol/L. The inhibition of proliferation is believed to result primarily from the induction of apoptosis possibly through the activation of p53 or death receptor 5 (13) as well as inhibition of hypoxia-inducible factor-1α, a key angiogenic transcription factor (14). Additionally, the rate of tubulin polymerization or depolymerization is inhibited by 2ME2 in certain cell lines (15). In vivo, oral administration of 2ME2 is effective in xenograft and metastatic disease models with no significant toxicity (16, 17). A concomitant reduction in tumor vasculature has also been observed in 2ME2-treated animals (18). The antiangiogenic activity of 2ME2 has been shown in vivo in corneal micropocket (16), Matrigel plug assays (19), and chick chorioallantoic model systems (20).
The doses of 2ME2 assessed in this dose-ranging phase II study were based on the results of the phase I study in patients with locally recurrent or metastatic breast cancer. The phase I study evaluated doses ranging from 200 to 1,000 mg/d (125-625 mg/m2/d). This dose range was selected based on results obtained from nonclinical efficacy studies in mice and safety studies in rats and dogs. In vivo studies in murine models have indicated that substantial antitumor and antiangiogenic activities were observed in the range of 75 to 150 mg/kg/d (225-450 mg/m2/d). To obtain efficacy, safety, pharmacokinetic, and pharmacodynamic data on 2ME2 in men, we conducted a randomized, placebo-controlled phase II study.
This study employed a phase II, multicenter, randomized, double-blind placebo-controlled design that assessed the safety, pharmacokinetic, and pharmacodynamic characteristics and efficacy of 2ME2. The study was conducted at Indiana University and the University of Wisconsin Comprehensive Cancer Center after local institutional review board approval at both locations. Patients were eligible for this protocol if they had documented hormone-refractory disease with increasing prostate-specific antigen (PSA) by Prostate-Specific Antigen Working Group criteria (21) and/or evidence of metastatic disease and had not previously received chemotherapy. Enrollment required progression on medical or surgical androgen ablation, but castrate levels of testosterone were not stipulated. One patient had a total testosterone of 90 ng/dL and all other patients had levels of <30 ng/dL. If PSA was the only evidence of progressive disease, then it had to be >10 ng/mL. If a subject was receiving antiandrogen therapy, progression (at least 25% PSA increase) had to be shown after discontinuing this class of agent for at least 4 weeks for flutamide and 6 weeks for bicalutamide. Liver transaminases had to be less than twice the upper limit of normal, bilirubin <1.5 mg/dL, creatinine <1.8 mg/dL, total WBC count >3,000/mm3, platelets >100,000/mm3, international normalized ratio of prothrombin time ≤1.2, and activated partial thromboplastin time within 2 seconds of the upper limit of normal. A Karnofsky performance status of ≥70 and a stable pain management regimen for at least 2 weeks were required. Patients were also excluded if they had suffered a myocardial infarction within the preceding 3 months, uncontrolled angina in the last 3 months, or uncontrolled congestive heart failure. Major surgery within 21 days of starting 2ME2, administration and coadministration of PC-SPES, or herbal medication containing saw palmetto also precluded enrollment.
Patients were randomized into one of two cohorts, with each cohort consisting of 16 patients. All patients in both cohorts were evaluated for safety as well as the effect of 2ME2 on changes in tumor response and PSA levels. One cohort received 400 mg 2ME2 and the other 1,200 mg 2ME2 administered as a single daily oral dose in a double-blind manner. 2ME2 was delivered as a capsule formulation, with each unit dose containing 200 mg 2ME2 as a micronized crystalline solid. Randomization was done at each site and drug was dispensed from the representative Investigational Drug Services, with patients instructed to take two capsules from one bottle and four from a second bottle. In the 400 mg dose cohort, the second bottle had four placebo capsules. Each cycle of therapy consisted of 28 days of study drug administration. Patients were treated at the same dose level until the appearance of significant treatment-emergent toxicities or disease progression. Evidence of disease progression was defined as the appearance of new lesions >1 cm in size, unidimensional or bidimensional tumor measurements increasing >50%, or increase in PSA according to Prostate-Specific Antigen Working Group definitions (21) or symptomatic progression. Patients were not required to be removed from study due solely to PSA progression if the investigator felt the patient was potentially benefiting (e.g., slower PSA velocity).
Tumor response was evaluated after every cycle by using physical examination and patient interview to monitor for symptomatic progressive disease. Radiographic assessment of tumor response was done after every two cycles for the duration of therapy by using bone scan, chest X-ray, or computed tomography of the abdomen and pelvis (when disease was present at baseline).
Assessment of response
Measurable disease. A complete response was defined as the complete disappearance of all clinically detectable disease measured by physical examination and/or radiographic studies for a period of at least 4 weeks. A partial remission was defined as a >50% decrease in the sum of the products of the two longest perpendicular diameters of all measurable lesions for a period of at least 4 weeks without an increase of >25% in the size of any area known to contain malignant disease and without the appearance of any new areas of malignancy. Progressive disease was defined as an increase of at least 25% in the size of measurable lesions.
Serologic disease. A partial serologic response was at least a 50% decrease in PSA for three consecutive measurements 4 weeks apart (i.e., a sustained response for 2 months). Serologic progressive disease was defined as a 50% increase in PSA from the lowest level recorded and was confirmed 4 weeks later on the study. Stable serologic disease was scored if neither of these variables were met and the patient in consideration did not have measurable disease progression or increase pain or palliative radiation. Time to progression was defined as the period measured from the initiation of therapy until at least a 50% increase in PSA level confirmed at least 4 weeks later, taking as reference the lowest PSA level recorded since the treatment started. The date of the first recorded increase was deemed the date of progression.
Patients were enrolled until 16 patients were treated in each arm. If two or more of these 16 patients showed a tumor response (including PSA response), then an amendment was to be made to allow an additional 16 patients to be enrolled in that arm. If six or more of the 32 patients treated at one dose level had a tumor response, it was considered that this treatment arm would warrant further study. This study had a 95% probability of stopping early for any given arm if the treatment was ineffective (tumor response rate of ≤5%). With a two-stage design, each treatment arm of this study would have at least 80% power to accept the alternative hypotheses and reject the null hypothesis at a 0.05 α level.
Prostate-specific antigen velocity before and after treatment with 2-methoxyestradiol. Regression analyses were done post hoc to estimate the PSA rate of increase (velocity) for each patient as stabilization of disease was noted on study. There were patients who had PSA declines, although there were no PSA declines meeting Prostate-Specific Antigen Working Group definition of "response." A regression line was fitted through the PSA measurements obtained on each subject before and after initiation of therapy. A "change point" regression model was employed to test whether the slope of the regression before and after initiation of therapy (possible change point) changed for each subject. A random-effects model was used where the initial PSA level (intercept) and the rate of change, the slope (i.e., PSA velocity), before and after therapy were allowed to vary by subject. The dose (400 or 1,200 mg qd) was also incorporated into the model as was an interaction term between PSA slope and dose level to test whether dose was related to rate of PSA increase. The mathematical equation of the regression model is:
where yij is the log PSA level of subject i at time point tjj (measured as weeks from enrollment), t0i is the week when treatment with 2ME2 was initiated for this subject, (tij − t0j)− = max[0,(tij − t0j)] counts the number of weeks before treatment initiation, (tij − t0j)− = min[0,(tij − t0j)] counts the number of weeks after treatment initiation, and Xi is the dose level assignment for subject i (1: 1,200 mg, 0: 400 mg).
The following questions were tested through this model: Is the slope before and after treatment different from 0? Slopes that are substantially (i.e., significantly in the statistical sense) higher than 0 indicated PSA increases compared with baseline, whereas negative slopes are associated with PSA decreases. The second question was: Is there a statistically significant treatment effect (measured by the dose-by-week interaction)? A positive interaction effect would imply an increase in PSA velocity in the higher compared with the lower dose, whereas a negative interaction effect would indicate that the PSA velocity is lower in the higher dose compared with the lower dose. Both questions were tested via the t test of whether the regression line slope is equal to 0. The third question was: Are the slopes of PSA increases within each treatment arm different before and after treatment initiation? Appropriate contrast equations were constructed and tested via the F test.
Analysis of duration of therapy with 2-methoxyestradiol. We focused our analyses on the first two cycles of therapy because almost all subjects received at least 8 weeks of treatment. Analyses beyond this point become tenuous as subjects were withdrawn from the study for reasons related to the study outcome in a nonrandom fashion. This has potentially serious and unpredictable effects on the study outcome. For example, if the slope of PSA increase is steeper in the less effective treatment group, subjects may be removed earlier and at lower PSA levels compared with subjects treated with the more effective treatment (which may result in apparently slower PSA increases). Thus, the difference in PSA levels between the two treatments may be attenuated or even reversed in favor of the less effective therapy, inducing serious bias in the analyses.
To assess whether the duration of therapy and time to PSA progression with the low and high doses of 2ME2 were equal between the two groups, we carried out a Kaplan-Meier estimation of the distribution of therapy durations. We compared these between the two groups using the log-rank test.
All analyses were carried out according to the intent-to-treat principle, so all patient results were analyzed according to initial treatment (dose) group randomization status despite treatment adjustments or interruptions for toxicity reasons. Statistical tests were carried out at the 95% significance level.
Blood samples were collected at baseline and on day 1 of all cycles to measure changes in the levels of PSA, sex hormone-binding globulin (SHBG), dihydroepiandrosterone, dihydroepiandrosterone sulfate, dihydrotestosterone, and total and free testosterone levels. The measurements were done in Clinical Laboratory Improvement Amendments–certified laboratories at Indiana University and the University of Wisconsin Comprehensive Cancer Center. Blood and urine samples were also collected to monitor changes in the levels of the angiogenic proteins VEGF (plasma and urine), bFGF (plasma and urine), and vascular cell adhesion molecule (serum only).
VEGF in EDTA plasma was measured by a commercially available 96-well plate quantitative sandwich immunoassay (Quantikine human VEGF, R&D Systems, Minneapolis, MN) with a standard curve ranging from 31.2 to 500 pg/mL. At the time of assaying, all samples and standards were brought to room temperature and prepared on the plate as recommended by the manufacturer. The plate was read at 450 nm using a Molecular Devices (Sunnyvale, CA) SpectraMax 190 plate reader. The standard curve was constructed by plotting VEGF concentration versus absorbance. A linear scale gave the best fit for this assay. The reported limit of sensitivity is 9.0 pg/mL in plasma.
The assay was validated in the laboratories at the University of Wisconsin Comprehensive Cancer Center, showing a mean r2 of 0.999 (range, 0.997-1.00) over 5 months. Within-day variability was assessed with triplicate determinations of each standard curve, with a coefficient of variation (CV) of <10% over the concentration range. Triplicate determinations of VEGF in six subject plasma samples run on a single plate had a mean CV of 7.2% (range, 4.4-11.0%) over the concentration range 36 to 418 pg/mL, and variability did not vary with concentration. Between-day variability was assessed with five-assay standard curve assessments over a 6-month period. The mean CV ranged from 8.2% for the 500 pg/mL standard to 11.5% for the 31.2 pg/mL standard, and the mean CV was <10% over the entire concentration range.
bFGF in EDTA plasma was measured by a commercially available 96-well plate quantitative sandwich immunoassay (Quantikine human VEGF) with a standard curve ranging from 1 to 64 pg/mL. At the time of assay, all samples and standards were brought to room temperature and prepared on the plate as recommended by the manufacturer. The plate was read at 490 nm using a Molecular Devices SpectraMax 190 plate reader. The standard curve was constructed by plotting bFGF concentration versus absorbance. A log scale gave the best fits for this assay. The reported limit of sensitivity is 0.22 pg/mL in plasma. The assay was validated in the laboratories at the University of Wisconsin Comprehensive Cancer Center, showing a mean r2 of 0.996 (range, 0.995-0.999) over 5 months. Within-day variability was assessed with triplicate determinations of each standard curve, with a CV of <10% over the concentration range. Triplicate determinations of bFGF in six subject plasma samples run on a single plate had a mean CV of 4.7% (range, 0.5-8.9%) over the concentration range 2 to 60 pg/mL, and variability did not vary with concentration. Between-day variability was assessed with five-assay standard curve assessments over a 6-month period. The mean CV ranged from 34.9% for the 64 pg/mL standard to 47.4% for the 1 pg/mL standard, and the mean CV was <10% over the entire concentration range.
Toxicity monitoring
Patients were seen weekly for the first 4 weeks and then on day 1 of each 4-week cycle. The occurrence of grade ≥3 nonhematologic or grade 4 hematologic treatment-related toxicity according to the National Cancer Institute Common Toxicity Criteria version 2.0 that did not resolve within 14 days mandated that the patient be taken off study. If the toxicity resolved in 14 days, then a 50% dose reduction was instituted and the patient was allowed to stay on study.
Pharmacokinetic sampling
The pharmacokinetic variables of 2ME2 in plasma were to be determined from the first eight patients of both cohorts on days 1 and 28 of cycle 1. The goal was to define the plasma concentration-time profile of 2ME2 and to assess whether the pharmacokinetic profile of 2ME2 is linear between the two doses. This analysis was also done to establish the dose that provides a potentially effective level of systemic exposure to the drug as indicated by preclinical studies, to determine whether significant drug accumulation occurs during repeated daily dosing, and to determine the intrapatient and interpatient variabilities in the peak and trough plasma concentrations of the drug, both within and between successive weeks of therapy. Blood samples for pharmacokinetic analysis were collected at the following times on day 1 of cycles 1 and 2 (28-day cycles): before dosing, 30, 60, and 90 minutes, and at the 2-, 4-, 8-, 12-, 16-, and 24-hour time point after dosing. Samples were also taken before dosing on days 8, 15, and 22. Pharmacokinetic analyses included plasma area under the curve, elimination half-life (t1/2), tmax, Cmax, Cmin, estimated steady-state plasma concentration (Css), total clearance (Cl), and volume of distribution (Vd). The concentration versus time curves for 2ME2 were adjusted for endogenous levels before calculating these variables. Plasma concentrations of 2ME2 and 2-methoxyestrone were determined using a validated gas chromatographic/mass spectrometric method using trideuterated 2ME2 and 2-methoxyestrone as internal standards.
The pharmacokinetic variables of both dose levels and changes in the pharmacodynamic associations were to be correlated with responses. However, this was not done because there were no serologic responses.
Data safety and monitoring across the two sites
To ensure accuracy of data collected, an external clinical research organization did 100% source data verification on all subjects enrolled and the data were collected centrally. In addition, communication between sites and the sponsor was facilitated by regular scheduled teleconferences with a discussion of adverse events and study progress.
Patient characteristics
A total of 33 patients were accrued to this study and were representative of a hormone-refractory prostate cancer population (Table 1). The patients had a median age of 74 years (range, 57-84 years) and a median Karnofsky performance status of 90 (range, 70-100), with a median on study PSA of 122.40 ng/mL (range, 11-2,500 ng/mL). All but one patient had radiographic evidence of metastatic disease. Bone-only disease was evident in 20 patients; measurable disease with or without bone metastases was seen in 12 patients. The median number of hormonal therapy manipulations was 2 (range, 1-4 agents). Patients remained on study for a median of 16 weeks (range, 4-48 weeks).
Response and time to progression. No patients had a serologic response per Prostate-Specific Antigen Working Group criteria, nor were there any measurable disease responses. However, post hoc evidence of activity as defined by alterations in PSA velocity was observed. A total of eight patients had a decline in PSA of >20% (21-44%), seven were observed in the 1,200 mg group, and one in the 400 mg group. On study, 28 of 33 subjects showed a >1.5-fold increase in PSA. Sixteen patients did not have further data on study after the initial increase in PSA was observed as they were removed from study at this time and a confirmatory PSA was not available. The median time to PSA progression (unconfirmed) for the 400 mg group was 67 days, whereas it was 109 days in the 1,200 mg group (P = 0.094; Fig. 1A).
A, time to PSA progression (Kaplan-Meier plot). B, duration of study therapy (Kaplan-Meier plot).
Prostate-specific antigen velocity. The average monthly PSA increase before therapy for the entire group was 0.06 ng/mL/mo. The pre-therapy PSA velocity in the 400 mg group did not differ from the 1,200 mg group (P = 0.12). The study showed that the 1,200 mg but not the 400 mg dose altered the PSA velocity and induced a "broken-arrow phenomenon" (22) as seen in Fig. 2. The average monthly increase in PSA level after therapy for the 400 mg group was 0.047 ng/mL/mo, which was significantly higher than 0 (P = 0.006), whereas the average monthly increase in PSA level for the 1,200 mg dose in the first 2 months was 0.004 ng/mL/mo, which was not statistically different from 0 (P = 0.801), implying that PSA levels in the high-dose group were stable at least in the first two cycles of therapy. There was a statistically significant dose-related (interaction) effect (P = 0.037). In other words, the 1,200 mg dose significantly slowed PSA velocity over the first two cycles of therapy compared with the 400 mg group. In addition, the PSA velocity after therapy was not significantly different compared with PSA velocity before therapy in the low-dose group (P = 0.277) but was significantly different (lower) in the high-dose group (P < 0.001). It should be noted that the difference in PSA velocity between the two groups was lost when analysis was carried out beyond the second treatment cycle.
PSA velocity before and during the first 8 weeks of therapy in the high-dose (red) and low-dose (blue) groups. Thin lines, individual PSA trajectories for each patient; thick line, average trajectory in each arm. A single pretreatment model (line) was used based on the nonsignificant difference in PSA velocity before treatment initiation.
Median time on therapy
Patients were kept on protocol therapy until clinical evidence of progression or investigator's or patient's decision and patients with a slowly rising PSA were not taken off as soon as it reached 50% above baseline. The investigators and patients were blinded and no toxicities emerged that could differentiate one group from the other. Post hoc analysis indicated that the median time on therapy was 61 days for the low-dose group and 126 days for the 1,200 mg dose group. This was significantly different by log-rank test (P = 0.024; Fig. 1B). The reasons patients were taken off protocol therapy are listed in Table 2. It is of note that in this double-blind design there was no significant difference in the number of patients taken off therapy due to an adverse event. Furthermore, although patients stayed on therapy longer in the higher-dose group, the number of patients taken off study due to disease progression was similar to that in the lower-dose group.
Summary of patient disposition and status at end of treatment
There were no hematologic toxicities of any grade (i.e., no myelosuppression) and there were no grade 4 nonhematologic toxicities on study. Two patients on the 400 mg dose had a grade 3 elevation of transaminase involving aspartate aminotransferase and/or alanine aminotransferase. In one of the cases, the abnormality resolved within 14 days and did not recur with a 50% dose reduction. One patient on the 1,200 mg dose who had a grade 2 elevation was continued on therapy and resolved without holding therapy. There were no apparent adverse events that suggested major estrogenic exposure as seen with diethylstilbesterol. Three patients experienced grade 1 breast discomfort (one in 400 mg and two in 1,200 mg group) and in only one case was it considered related to therapy. Two thrombotic events were observed in 33 (6%) patients, both were grade 3 and occurred in the 400 mg group. One occurred 8 days after being removed from study due to progressive disease and was assessed as unrelated. The other episode was of unknown relationship to therapy and the patient was taken off study at the same time with progressive disease. One episode of amaurosis fugax, grade 2, which occurred after being on therapy for 1 month with "unknown" relationship to the drug, was observed. The event resolved and no clot was seen and patient continued on therapy. The only cardiac event was one episode of atrial fibrillation considered not related to therapy. There were no episodes of myocardial or cerebrovascular insufficiency.
Ultimately, pharmacokinetic analyses were run for seven patients in the 1,200 mg cohort on day 1 of whom five had complete pharmacokinetic analysis on day 28. In the 400 mg cohort, six and five patients had complete analyses on days 1 and 28 of cycle 1, respectively. The plasma concentration attained by unconjugated 2ME2 was in the low nanogram per milliliter range and the average levels increased nonproportionally when the dose was augmented from 400 to 1,200 mg/d (Table 3). Once this was noted, it was decided that completion of the analyses in all 16 patients was not beneficial. The metabolite analysis revealed significant oxidation at the 17-position of 2ME2, resulting in 80% to 95% conversion to 2-methoxyestrone, which is at least 10 times less active than 2ME2 (data not shown). There is also extensive conjugation, with 80% to 90% conversion to the conjugated forms of 2ME2 and 2-methoxyestrone. The conjugated forms have no reported antiproliferative activity. A shift in the tmax from 1.2 hours at 400 mg to 6.7 hours with 1,200 mg dose is consistent with dissolution in the gastrointestinal tract being a rate-limiting process. Steady-state trough levels of unconjugated 2ME2 were observed during the first cycle at approximately days 8 to 15 and remain roughly constant thereafter (data not shown). No correlation was observed between the plasma levels of 2ME2 or its metabolites and the elevation in transaminases seen in the three patients with mild hepatic toxicity. There was an increase in the Cmax, area under the curve, and clearance from days 1 to 28 for both 400 and 1,200 mg groups (all P < 0.05, t test; Table 3).
Noncompartmental pharmacokinetic analysis: unconjugated 2ME2
Steroids. There was no alteration (increase or decrease) of dihydroepiandrosterone, dihydroepiandrosterone sulfate, or dihydrotestosterone levels. However, there was a 2.5-fold increase of SHBG at days 28 and 56 for the 400 mg cohort and a 4-fold increase for the 1,200 mg cohort at days 28 and 56 (Table 4).
Sex hormone binding globulin levels
At baseline, 32 of 33 patients had a testosterone level <50 ng/dL and the other patient's testosterone was 90 ng/dL. One patient refused ongoing androgen suppression, and after one cycle, his free and total testosterone rose from 1.5 and 19 ng/dL to 6 and 185 ng/dL, respectively. With restarting androgen ablation, the free and total testosterone fell to 1.3 and 19 ng/dL and the patient's disease responded. This patient was in the 400 mg group and was removed from study due to rapid progression, which was ultimately due to androgen-mediated growth. This indicates that 2ME2 does not suppress testosterone production and therefore differentiates it from diethylstilbesterol.
There was no alteration in levels of free testosterone. However, evidence of assay interference emerged at one site. Specifically, there was an apparent increase in the average total testosterone of 2.3- and 4.6-fold at days 28 and 56, respectively, for the 400 mg dose. The corresponding apparent increases for the 1,200 mg dose were 4.7- and 4.5-fold. Only three patients at this site had an apparent increase of testosterone above 100 ng/dL. At the second site, there was no alteration of total testosterone levels at either dose or either time point. It was concluded that the most likely cause for this observation was assay interference at one of the sites.
Angiogenesis markers. Plasma and urine VEGF and bFGF and serum vascular cell adhesion molecule were analyzed on day 1 of cycle 1 and then on day 28 of all cycles administered. Neither dose influenced vascular cell adhesion molecule, VEGF, or bFGF levels in either plasma or urine.
Three subjects experienced hepatotoxicity and the relationship between hepatotoxicity and angiogenesis factors was evaluated. Two of two individuals with hepatotoxicity and still on study had plasma bFGF levels corrected for platelets as shown in Fig. 3 on D84. This compares with 3 of 18 individuals without hepatotoxicity being "outliers" at the same time point.
Levels of bFGF in patients with and without hepatotoxicity.
This novel dose-finding, double-blind, randomized, placebo-controlled trial has shown that 2ME2 is a novel well-tolerated agent with only minimal transient hepatic toxicity in a minority of men with hormone-refractory prostate cancer. There were no confirmed serologic or measurable disease responses. The randomized, double-blind, placebo-controlled design provided the opportunity to perform an unbiased post hoc analysis to evaluate whether dose affected PSA velocity and time on therapy. As such, this analysis provides hypothesis-generating data that the 1,200 mg dose had a greater effect on the PSA velocity and time to PSA progression, which was associated with a longer time on therapy. The double-blind design removed investigator bias as the reason for the longer time on therapy and allows the contention that this agent was potentially associated with a clinical benefit. It should be reiterated that patients were kept on study until the physician or patient felt there was no clinical benefit. In some cases, patients came off for rapidly rising PSA (i.e., increase in PSA >50% of baseline) and in others because of symptomatic progression. It is also of note that seven of the eight PSA declines >20% were seen in the 1,200 mg group.
Recently, much attention has been directed at validating PSA changes as a surrogate of drug activity (22). It is recognized that none of these measures have been widely accepted as validated surrogates. Nonetheless, in attempt to quantify whether one or both doses had an effect on the rate of disease progression, we analyzed the PSA velocity before and after therapy. This study showed the 1,200 mg but not the 400 mg dose induced a broken-arrow phenomenon. Specifically, there was a significant decrease in PSA velocity after therapy compared with before therapy (P < 0.001) with the 1,200 mg dose. In contrast, the P indicated no significant change in PSA velocity after therapy versus before therapy with the 400 mg dose (P = 0.277). When analyzed in another manner, it was noted that the average monthly increase in PSA level for the low dose was 0.047 ng/mL/mo, which was significantly higher than 0 (P = 0.006). As such, the 400 mg dose did not reduce the PSA velocity. In contrast, the average monthly increase in PSA level for the high dose in the first 2 months was 0.004 ng/mL/mo. This was not statistically different from 0 (P = 0.801) and indicated that the drug decreased the PSA velocity to almost 0 and delayed disease progression as defined by PSA criterion. In sum, these analyses indicate the high dose significantly slowed the PSA velocity and showed a significant dose-related effect (P = 0.037). It is of note that other investigators have employed a similar design. The most notable example was a study of rosiglitazone in men with a rising PSA level after radical prostatectomy and/or radiation therapy. This study employed a randomized, placebo-controlled design and reported that the drug did not prolong the PSA doubling time or time to disease progression. The authors also noted an unexpected discordance between baseline and post-treatment PSA doubling times in the placebo group in this hormone-naive population. Although our population was hormone refractory, the data from this article reinforce the importance of randomized, blinded, controlled trials when looking at rates of increase of PSA and time to progression (23).
To add significance to our PSA velocity findings, we observed that the decrease in PSA velocity with the 1,200 mg dose was associated with a longer time to PSA progression and the patients in the 1,200 mg group received protocol therapy twice as long. It should also be recalled this was a double-blind, placebo-controlled study and thus removed investigator bias as a confounding variable. It is recognized that these data are hypothesis generating; however, on the whole, they support the contention that 1,200 mg/d 2ME2 capsules are biologically active and have some evidence of clinical activity with minimal to no toxicity. We also acknowledge that the PSA levels in the lower-dose group were numerically but not significantly higher and that this may be a confounding factor.
However, improvements in drug formulation of 2ME2 are required. Specifically, the oral bioavailability was apparently dissolution rate limited and resulted in the nonlinearity of the pharmacokinetics. Moreover, the rapid conversion to 2-methoxyestrone and 85% conjugation resulted in low plasma levels. Reformulation of the drug has improved the bioavailability and has shown increased activity in relevant pharmacokinetic and efficacy models. These new formulations are being evaluated at the University of Wisconsin Comprehensive Cancer Center and Indiana University in two separate phase I trials.
In spite of pharmacokinetic and bioavailability limitations, it is interesting to note that the 1,200 mg dose resulted in more evidence of anticancer activity (i.e., the post hoc evaluation showing an alteration in PSA velocity) and a greater increase in SHBG. The lack of correlation between the pharmacokinetic and pharmacodynamic data may be due to accumulation of the lipophilic agent in tissues as has been seen with nicotine (24, 25). Moreover, the lack of suppression of testosterone in the patient who refused ongoing androgen ablation and the toxicity profile differentiates this agent from diethylstilbesterol. The increase in the SHBG is intriguing. This is a plasma glycoprotein that binds to certain steroids. SHBG, in turn, binds to a specific receptor on cell membranes. The role of SHBG in steroid-induced signal transduction is poorly understood. However, there is evidence that SHBG may mediate the activity of certain agents that induce tumor regressions in patients with prostate cancer. Diethylstilbestrol diphosphate, an estrogen prodrug, is one such agent (26). It is also possible that 2ME2 may exert some of its effects through SHBG in addition to its effects on death receptor 5 (13). There is accumulating evidence that SHBG may have anticancer properties by impairing hormone-induced signal transduction or down-regulation of the level of sex hormones (27–29).
The exploratory analysis of angiogenesis factors (VEGF, vascular cell adhesion molecule, and bFGF) revealed that there was no change with drug administration. This is not surprising as 2ME2 is not expected to directly influence the transcription of either of these genes (14), and changes in bFGF and VEGF are more likely to be markers of disease regression or progression. As clinical activity of 2ME2 in this study was modest, and the majority of patients experienced stable disease, stable levels of angiogenesis factors were expected and observed. However, the intriguing observation that plasma bFGF was possibly associated with hepatotoxicity is worthy of further exploration. These results are consistent with considerable in vitro evidence, suggesting a role for both bFGF and VEGF in liver repair and regeneration. In vitro evaluations have shown that bFGF is generated in response to liver injury due to wounds (30), radiation (31), and chemicals (32) and that administration of bFGF can enhance liver regeneration and repair (33). Based on our review of the literature, these data are the first to show a possible relationship in vivo between drug-induced liver injury and bFGF. This tentative finding supports further study of bFGF as an early marker of drug-induced hepatotoxicity.
In conclusion, 2ME2 is well tolerated with evidence of anticancer activity at the 1,200 mg/d dose. It should be reiterated the evidence of anticancer activity was a dose-response effect on PSA velocity. Reformulation to overcome the low bioavailability holds the promise of producing a more active drug. Moreover, the novel trial design permitted an unbiased evaluation of dose effect and is one that may be required for drugs that stabilize disease rather than induce remissions.
Grant support: EntreMed, Rockville, MD.
Accepted June 8, 2005.
Received February 28, 2005.
Revision received June 3, 2005.
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You are going to email the following A Phase II Multicenter, Randomized, Double-Blind, Safety Trial Assessing the Pharmacokinetics, Pharmacodynamics, and Efficacy of Oral 2-Methoxyestradiol Capsules in Hormone-Refractory Prostate Cancer
Clin Cancer Res September 15 2005 (11) (18) 6625-6633; DOI: 10.1158/1078-0432.CCR-05-0440
Once weekly oral docetaxel in combination with ritonavir
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text:
A week on from gruesome discovery of 83-year-old dog walker's body and police are still looking for answers
Peter Walsh
Peter Wrighton. Photo: Norfolk Police/PA Wire
It is a week on from the gruesome discovery of the body of 83-year-old dog walker Peter Wrighton in woodland near to East Harling.
Peter Wrighton, who has been named as the 83-year-old man who was stabbed to death while walking his two dogs in East Harling, Norfolk. Picture Norfolk Constabualry.
And as the manhunt for the killer of the kind and gentle husband, father and grandfather continues, crime correspondent PETER WALSH takes a look back at a week which has truly shocked Norfolk.
For many people living in and around the quiet rural village of East Harling, life will never be the same.
Certainly for the heartbroken family of Peter Wrighton, from nearby Banham, life sadly can never return to normal following a brutal, violent and frenzied attack while he walked his two dogs, Dylan and Gemma. But the shock and fear which hangs so heavily now above the devastated communities of Banham, East Harling and surrounding areas was nowhere in sight a week ago.
Saturday, August 5 started out as a normal day, including for Mr Wrighton who would be heading to East Harling to walk his dogs in the expansive woodland which draws in pet-owners from across the county and beyond such is its popularity as a dog-walking destination.
Police are still searching for the break through in the East Harling murder. Picture : ANTONY KELLY
Tragically, it was a trip from which Mr Wrighton was to never return from.
The former BT worker, who lived with his wife Ann in the picturesque village of Banham, had made the short drive from his home to the woods in his red Skoda Fabia.
On the way he had stopped off at Kenninghall Post Office, where he was picked up on CCTV buying a few items, before continuing on his journey.
Those final images of Mr Wrighton while he was alive were taken between 10.08am and 10.12am.
Aerial view of murder scene, near East Harling. PIC: Supplied by Norfolk police.
At 10.46am Mr Wrighton's body was discovered by a member of the public with his two dogs found, unharmed, nearby.
Police were called following the find which prompted a rapid response.
People who were working in East Harling later recalled how they thought there had been a crash after several police cars were seen and heard "racing" through the village in the direction of the Fiveways junction.
Police attended the scene and forensic analysis was carried out but at this stage the "sudden death" was being treated as "unexplained" with an animal attack considered as one of the possible causes.
Police press conference for the East Harling murder. Left to right, chief superintendent Mike Fawcett, detective superintendent Andy Smith and corporate communications manager Nicola Atter. Picture : ANTONY KELLY
There was still police activity at the scene on Sunday, August 6 but nothing to suggest the horrific nature of what had happened to Mr Wrighton.
It was not until after an extensive Home Office post-mortem examination, which was carried out on August 6, that police were able to reveal the victim had been subjected to a serious assault.
And so it was that, in the early hours of Monday, August, 7, following the results of the post-mortem examination, that police officially launched a murder probe.
However, the identity of the victim had not been made public at this point with those waking up in and around East Harling on Monday morning only aware that police were investigating the murder of a man.
The news of course caused alarm among those living in the nearby village of East Harling who were concerned not only that someone had been killed but that his killer was on the loose.
That fear however was to be heightened further following a press conference on Monday afternoon at police headquarters in Wymondham during which it emerged that an 83-year-old dog walker, a local man, had been stabbed multiple times in the neck and head.
The gruesome details sent shockwaves reverberating around the community who had never heard anything of its like before.
Over the coming days the area, and surrounding villages, were flooded with police officers and local and national media all looking for answers about what had happened.
There were further press conferences on Tuesday, August 8, when police urged people to check their gardens and bins for a possible weapon and send in CCTV or dash-cam footage, which they hoped might hold vital clues.
Mr Wrighton was not formally identified to the public until Wednesday, August 9 - unusually a day after a description of the victim had been issued by police who said they were not then in a position to identify him.
The past week has raised a number questions, generated many theories but ultimately has yet to provide any answers.
And that will be the biggest concern for everyone.
Animal attack ruled out in East Harling murder case
How you can help catch Peter Wrighton's killer
East Harling murder


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Why millions gathered to say 'no' to Trump
Nour Obeidallah of New York re-creates a popular poster Saturday at the Women's March on Washington. (Michael S. Williamson/The Washington Post)
By E.J. Dionne Jr.
E.J. Dionne Jr.
Columnist covering national politics
This is an update of a column published Friday and includes material from a blog post published Saturday on the Women's March.
Within 48 hours, we learned that Donald John Trump intends to govern as the same fiercely angry man who shook the country in 2016. He confirmed that his administration intends to show no regard for norms — or facts.
His opposition has drawn the obvious conclusion. Its only options are to contain the damage Trump can do, to restrain him in his use of power, and, eventually, to defeat him.
In his inaugural address, Trump offered no outreach to his adversaries with a take-no-prisoners message. They heard it, and were ready to return the favor. Saturday's Women's March on Washington and its counterparts in cities and towns across the country drew millions who signaled plainly that they would not be cowed into silence or demobilized into a sullen indifference.
There was a jubilance in the Washington gathering because so many were grateful to each other for showing up in such large numbers. Those who had spent Jan. 20 in gloom spent Jan. 21 experiencing a sense of relief: In the face of the political troubles to come, they would have allies and friends ready to act.
(Sarah Parnass/The Washington Post)
If power shifted decisively Friday to Donald Trump and a Republican-controlled Congress, passion switched sides as well. As the marches showed, the political energy in the country is now arrayed against Trump and his agenda.
Republicans no longer have Barack Obama and Hillary Clinton to kick around. For years, they were able to direct the country's discontents toward a president they loathed and then a Democratic nominee they disliked even more.
With control of both elected branches, the GOP, including Trump, is the establishment. Over time, this will make the faux populist anti-establishment appeal of Trump's inaugural address ring empty.
It was a speech that offered a dark and gloomy view that cast the world's richest nation as a victim of the rest of the world. He spoke of "carnage" in the country and declared: "We must protect our borders from the ravages of other countries making our products, stealing our companies and destroying our jobs."
Trump invoked a radical nationalism not heard from any president of either party in the post-World War II era. His doctrine owes far more to the ideology of European far-right movements favored by his senior advisor Steve Bannon than to the views of American presidents from Harry Truman, Dwight Eisenhower and John F. Kennedy to Ronald Reagan, both George Bushes and Barack Obama.
"We will seek friendship and goodwill with the nations of the world," Trump said, "but we do so with the understanding that it is the right of all nations to put their own interests first." If some might see this as refreshing honesty about how countries actually behave, it was hard to escape the idea that Trump's "America First" doctrine foreshadowed a willingness to destroy international systems, built in large part by the United States, that have, on the whole, protected us and advanced our values.
And for those who worry about Trump's devotion to democratic values, there was this disconcerting sentence: "We must speak our minds openly, debate our disagreements honestly, but always pursue solidarity."
Solidarity is wonderful. But the word can look like a threat when used in a way that seems to subordinate free speech and open debate. More disquieting, the nature of this solidarity will be defined by a man who now possesses awesome powers and has shown only disrespect for his foes and for an independent media.
By Saturday, Trump and his press secretary, Sean Spicer, had ratified these concerns. Expressing rage at the media for pointing out how relatively small Trump's crowds were — a hint of how shallow his movement's roots might be — both Spicer and Trump lied outright in exaggerating the numbers of those who attended Trump's inauguration in comparison with the throngs that celebrated Obama's.
Challenged Sunday by Chuck Todd of NBC's "Meet the Press" as to why Spicer was asked to go to the podium and offer falsehoods, Kellyanne Conway, Trump's senior counselor, came up with a sound bite that George Orwell might have been embarrassed to include in "1984." It will go down as a defining phrase of the Trump presidency.
"Sean Spicer, our press secretary," she replied, "gave alternative facts."
"Alternative facts?" an astonished Todd exclaimed, and then he spoke the truth: "Alternative facts are not facts. They're falsehoods."
Fear of a presidency willing to declare that up is down and down is up is why so many rallied to say a very loud "no."
Read more from E.J. Dionne's archive, follow him on Twitter or subscribe to his updates on Facebook.
Ruth Marcus: Trump sank to the occasion
Hugh Hewitt: Time to relax about Trump
Eugene Robinson: A leap in the dark
Christine Emba: What's next after the Women's March?
Dana Milbank: My favorite signs at the Women's March on Washington
E.J. Dionne Jr. E.J. Dionne Jr. writes a twice-weekly column for The Washington Post. He is a professor at the McCourt School of Public Policy at Georgetown University, a senior fellow at the Brookings Institution. His latest book, with Miles Rapoport, is "100% Democracy: The Case for Universal Voting." Follow


If you have a sloping block or a decking space that you want to make use of, then look no further than out of ground pools. These offer a unique and luxurious solution to any property with a challenging shape, as they are custom built to your exact specifications.
Having your very own spectacular pool on your property is a dream for many Australians, yet it's one they often think they can't obtain, thanks to a slopping block. Yet a pool doesn't need to be inbuilt to be stunning. A custom design, created by our award-winning team, can be made to suit any block, connecting seamlessly with your home and landscaping.
Not to be confused with above ground pools, out of ground pools in Melbourne are generally built to meet an existing patio, deck or even your home itself. Transforming your outdoor entertaining area, they are becoming increasingly popular for homeowners with sloping blocks – where traditional inground pools aren't an option.
With expert landscaping from our talented team, your new pool can become the focal point of your backyard. You'll be able to look out across the surface of the water from your decking rather than looking down onto it, and with the right work done to your garden your pool will effortlessly complement your home.
With a sloping block comes challenges that aren't apparent with other projects. Your inground pool will need to be adequately supported by the ground – alternatively, additional foundations can be added. We will work with you during our design process to uncover the best options for your home.
What finishes are available for the external walls?
There are a variety of finishes for you to choose from to ensure your pool complements your home. Generally, people prefer timber or stone cladding for maximum durability.
What sort of landscaping will need to be done?
This is dependent on the amount of work required to keep your pool grounded. If it can't be adequately supported by your soil, then foundations and retaining walls may need to be added – in which case you may decide on additional landscaping to keep your yard looking it's best.
Can I choose any shape or size?
All of our pools are custom made to our client's exact specifications, so you can choose any size, shape or depth that you desire.


It's a time when too many are pushed into college without good reasoning, has peak college been reached?
Back when I was in high school, the teachers had one track minds on the subject of college. Apparently, their job as high school teachers was simply to prepare us for college. It was simple. Go to college, work at a fast food restaurant, or land in jail. That's more or less how they explained our life options.
Don't ask me, what do you want to do with your life?
In theory, and with the help of guidance counselors who didn't at all guide, it was their job to also help us figure out "what we wanted to be when we grew up". I never really got any direction on how I was supposed to decide. But that didn't matter as long as I graduated.
So, I did go to a college. One that was highly rated in the field of Electrical Engineering, or EE as it was called. Why EE? Don't know, I liked to tinker with electronics and thus they all assumed it's what I would want to do for 47+ more years.
Sound familiar to you at all? Maybe this is what your kids are experience right now or will soon!
On day one I knew college wasn't for me. I was an EE major who wouldn't see an EE related class for at least a year. Just classed like English, History, and Psychology because I had to fill a schedule. I dropped out within a few weeks for good and was relieved.
The next generation of confused college recruits.
This was over two decades ago and yet the high school philosophy of teaching kids that they need college is pushed even harder now. Worse, it's pushed at an elementary school level now too!
The college promise: Better paying jobs.
We're all told we need to go to college to get a better paying job. These days, better paying often just means longer hours, more stress, and less family time. So we now live in a world where more people go to college than ever before and should have tons of smart, wealthy people now, right? Hardly. Look at the world we live in which is filled with more debt than ever before. Apparently, the idea of budgeting and personal finances was not only yanked from high schools but never added into colleges. If I'm wrong, we never would have bought houses we couldn't afford a decade ago and never would have had that housing bubble.
The college reality for most: Debt.
On top of that, the typical college graduate comes away with debt that will last them for many years to come. Because the market is flooded with graduates there are fewer jobs around that require a college graduate. So we're left with workers who can't find a job in their field.
Watch your step on the way down!
So there is my concept of peak college and I think we've reached it. We've all heard of the term peak oil, right? It's the point when global oil production reaches its maximum rate. After that point, it's all downhill and oil becomes really expensive to get and thus not worth the high costs.
Yea, we can all be college graduates now!
We're almost there with peak oil, but I believe we are there peak college. I believe that we've pulled so many "college educated" people out of the system and don't have the "higher level" jobs to put them in anymore. Roll up to a Starbucks and ask how many employees there are college graduates and watch how many arms go up to see what I mean! There's nothing wrong with working at a Starbucks, but they didn't need a college degree for that.
At the same time, whatever happened to just starting low and working your way up through a company? This used to be how it was done decades ago, but now even the lowest level jobs often require a college degree. For what? College isn't teaching you anything that on the job training can't solve. On top of that, the Internet can teach me just about anything I'll ever need to know for most jobs out there!
I know, certain jobs maybe require some college education but the vast majority do not. On top of that, college isn't for most people. And better still, college isn't a measure of success.
Steve Jobs, maybe you've heard of his little fruit company, Apple?
Many college graduates go on to fail, become homeless, or otherwise, don't succeed in the way they thought. On the flip, many people who dropped out of high school or never graduated college do amazing things. Some examples you say? Sure, how about Michael Dell (Dell Computers), Larry Ellison (Oracle founder, worth billions, owns most of Lanai Island in Hawaii), Dave Thomas (founder of Wendy's), Richard Branson (Virgin, etc), and Steve Jobs (Apple).
Dropping out doesn't mean you'll succeed or fail, nor does graduating. I'm all for getting a high school diploma but not for being forced into higher education. Going to college used to be the exception, not the norm. We used to be a nation (a world even) of inventors, makers, and entrepreneurs. Why isn't that stuff taught in high school?
Become and entrepreneur and work for yourself!
Why on earth would we want to teach kids to get a degree and go work for somebody else? Working for the man used to be for safety and stability as jobs would offer long-term benefits and pensions. Those days are gone and everyone is replaceable.
College can be great, it's just not for everyone. Don't get forced into it.
It's clear that peak college is real and it's here. So maybe it's time to look for alternatives to college. Some quick examples include starting your own business, trade schools, or just getting an entry level job and learning as you go while also working your way up. Experience learned on the job is often more valuable than what a fresh college graduate can offer and that can help as you move up or transfer to different companies.


The killing of a young African-American teen by a neighborhood watch volunteer is putting neighborhood watch groups in the spotlight. The tragedy in Sanford, Florida became front-page news across the country—even replacing the near-constant stream of coverage on the Republican presidential nomination race.
The homeowners association (HOA) of the neighborhood where the shooting took place—and where the father of the young victim, Trayvon Martin, lives—is facing questions. Was its volunteer watchman authorized to carry a gun on patrol? Did he have any training? And did he do enough to avoid the incident, much less its tragic ending? Is the homeowners association responsible for his actions?
Many HOAs carry liability insurance on their directors and officers of the board, but not always on the individual volunteers who carry out business on its behalf. The watchman, George Zimmerman, was the volunteer captain of the neighborhood watch.
According to legal experts, if the association knew Zimmerman regularly carried a weapon while on volunteer patrol, it could provide a basis for a lawsuit (Martin's family has not yet sued the association).
Using professional security firms can help avoid these types of situations. And besides, if there are security and safety problems in the neighborhood, professionals are better equipped than untrained volunteers to handle them.
As increased foreclosures lead to lower income and reduced budgets, some homeowners associations are relying more on volunteers for services they once paid for. They may not realize the importance of running background checks on volunteers. Consulting with an insurance provider about additional coverage is a good idea, too. And finally, ask local law enforcement or an attorney before starting any sort of volunteer neighborhood patrol.
Whether you need to ask for a favor, solicit a donation or delegate a task, the art of persuasion can help you do it better. Unfortunately, most of us don't know the basics of persuasion, so we either fail at asking for something, or we avoid it altogether.
It doesn't have to be that way. Persuasive powers can be yours if you follow these tips. Try them next time you ask for something from a donor or volunteer. You may be surprised at your success.
Use reciprocation to your advantage: It takes effort, but when you give of yourself, it's a lot easier to ask for something in return. So when someone asks for your advice, your time or your expertise, give willingly, and you shall receive.
Adjust your framing: Framing is a popular tactic in business and politics. How an argument, incident or request is framed makes a huge difference in perception. For example, opponents of inheritance taxes call them "death" taxes. Think about whether you are putting something in a negative or positive light.
Tap into the power of timing: They say timing is everything. And they're right! Do your homework to make sure the timing is right before try persuading someone to do something. Don't ask a donor for a gift when they've written a big check in the past six months. Check your volunteer logs to see who has not been putting in hours lately—maybe they're feeling a little guilty about it, and are ready to give some time again.
Congruence is compelling: Congruence means coming together in agreement. Try framing your requests as though congruence was already happening. You know that salespeople often close the deal long before you've made up your mind. They'll start wrapping an item and before you know it, it's yours. Try assuming a donation will happen, or a volunteer will sign on, shake their hands, and seal the deal. Think of it as helping them make a great decision!
Whether you've been in volunteer management for decades, or are starting a new position, you are always in the position of needing to earn the respect of your volunteers.
Present a professional appearance. Everyone judges a book by its cover—fair or not, it's human nature. Put your best possible self forward by dressing well, having good manners and using appropriate language. If you need a refresher, take an etiquette course for business people.
Embrace constructive criticism. Nobody likes to be criticized, but most of us have room for improvement. When a volunteer makes a suggestion or even criticizes your actions, take a moment before you react. Hear what they're saying, and turn it into a positive action.
Don't be self-denigrating. Have some love and respect for yourself! Start by taking good care of your health. Get enough exercise and sleep. Avoid belittling comments about anyone, but especially yourself.
Do your job well. When volunteers see you are competent, your respect level will zoom. No matter what age or how many years of experience you have, you can establish yourself as the best at what you do. It may not happen overnight, but doing a good job is always worthy of respect.
Respect your volunteers. The old saying goes, "you get what you give." And it's true: if you don't respect your volunteers, they will feel it, and will likely react in kind. It's never too late to make a new effort, with every volunteer—new or old—even if your history with a particular person is less than pleasant.
Following these tips can help you establish yourself as a professional, competent and respectable volunteer leader. Your relationships, performance and effectiveness can be improved when you are well-respected by your volunteers.


Orlando, Florida from the 28th of August to the 31st of August.
around the world." Says Michael McGill, Vice President of International Operations.
there and were awarded the Best Doughnut in both Johannesburg and Pretoria.


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