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After being slapped with a discrimination lawsuit this past spring by a transgender employee, Forever 21 is being sued again for discrimination. This time, the plaintiff, Mickael Louis, is citing discrimination on the basis of sex and gender.
According to Louis's complaint, which was filed in the Eastern District of New York court this past week, he worked as an assistant store manager from January 2014 through April 2015 at Forever 21's Kings Plaza location in Brooklyn, during which time a number of store managers, including Patrick Walmsley and Andy Liu, subjected him to "same-sex sexual harassment, [and] racist nicknames [such as "Nutella"] and ridicule." Louis claims that he suffered extensive harassment from his bosses, including come-ons such as "I love muscular black guys like you" and "I bet you have a big dick," which ultimately resulted in him quitting.
Louis further alleges that the managers took part in "racial profiling" of both employees and customers, telling him to keep the number of black employees who work as cashiers to a minimum and to generally watch out for black shoppers, because they're "ghetto" and "because they steal."
Per Louis's complaint, Forever 21, Walmsley and Liu are liable for violations of federal and New York state laws against discrimination and harassment, namely as a result of the "creation and fostering of a racially and sexually hostile and offensive work environment." He alleges that their "unlawful actions were intentional, done with malice and/or showed a deliberate, willful, wanton and reckless indifference to [his] rights, thereby causing him to "suffer monetary and/or economic harm, as well as emotional harm and distress."
In addition to a jury trial, Louis is seeking monetary damages to compensate for his "emotional harm and distress" and for the "harm to his professional and personal reputations and loss of career fulfillment."
As for the lawsuit that 22-year old transgender Alexia Daskalakis filed against Forever 21 in April 2015, which specifically cites the same store manager, Patrick Walmsley, for discrimination and harassment, that case is still pending in the Eastern District of New York. In her suit, Daskalakis alleges that the fast fashion giant's male supervisors insulted her and subjected her to bias because of her transgender identity.
Fellow Los Angeles-based fast fashion giant, Nasty Gal, is similarly facing a number of discrimination lawsuits at the moment. Nasty Gal is currently facing three separate lawsuits in connection with its alleged practice of discriminating against employees of the basis of sex and pregnancy. In short: Nasty Gal allegedly discriminated against and wrongfully terminated at least three employees because of their gender and the fact that they were pregnant. (These cases are still pending).
The Los Angeles-based fast fashion retailer and its "girl boss" owner, Sophia Amoruso, is also facing a lawsuit for discriminating against another female employee based on a mental or physical disability, in violation of both federal and California state law. Yes, not only has the retailer been accused of failing to "provide [state mandated] pregnancy leave and reinstatement [of employment after such leave]" for a number of employees, Nasty Gal is in legal trouble for allegedly discriminating against a seriously ill employee, as well.


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Emergency Dental Care in Alexandria, VA
For When the Unexpected Happens
Our dentistry is designed to keep your smile strong and healthy, preventing unforeseen pain or tooth breakage and minimizing your need for emergency treatment.
But no matter how careful you are with your smile, emergencies happen. And when a dental emergency occurs, you can count on the office you know and trust to help you feel better.
Just call our regular phone number 703-299-8444 and we will let you know how to contact us directly.
If you knock a tooth out, please don't discard it. Put it in a cup of milk or coconut water, or under your tongue until you get to us.

subset: commoncrawl


text: Award-winning Accreditation programme in the prison service Her Majesty's Young Offenders Institute (HMYOI) Feltham in London recently became the first prison in the world to be awarded Autism Accreditation, after working with us to adapt its national accreditation programme to the prison environment. Our charity's work helping HMYOI Feltham in London to improve its work with autistic prisoners was recognised by the Royal College of Speech and Language Therapists. We were jointly awarded the Sternberg Clinical Innovation Award with our project partners Barnet, Enfield and Haringey Mental Health NHS Trust, and HMYOI Feltham. The project involved developing and implementing standards across the prison to improve the identification and support of autistic people at Feltham. Although the exact number of autistic people in UK prisons isn't known, they currently represent 4.5% of the population at Feltham. We are now hoping to roll the programme out more widely, by working with other prisons and young offender institutions to improve autism practice, and ultimately lower re-offending rates. Read full coverage of this story on the NAS website and in OT magazine.


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Grupo Corpo gives dance a Brazilian spin
Ask the average person what he or she thinks about contemporary dance, and many will say it is brooding, serious, maybe even overwrought. Since its founding in 1975 in Belo Horizonte, Brazil, however, the legendary ensemble Grupo Corpo has taken a different approach.
"I don't like the idea that it has to be dark, drastic, heavy, down," choreographer Rodrigo Pederneiras said, "Therefore, my creative process flows in a different direction.
"I'm guided by a Brazilian way to see the life," he says, "which is colorful, rhythmic and always looking forward."
Society for the Performing Arts brings the company to the Wortham Theater Center for two lively performances Thursday and Friday.
The program both nights features "Ímã," Pederneiras' renowned 2009 dance set to an original score by & 2 (the Brazilian trio of Alexandre Kassin, Moreno Veloso and Domenico Lancelotti). This unusual dance integrates the language of Lindy Hop with the more abstract theme of the law of magnetism, attempting to embrace how particles repel or attract one another.
The other featured work, "Sem Mim (Without Me)," evokes the rhythms of the sea. It's set to music by Carlos Núñes and José Miguel Wisnik based on the "Sea of Vigo Song Cycle" by 13th-century Galician-Portugese composer Martín Codax.
More Information
Grupo Corpo
When: 8 p.m. Thursday-Friday
Where: Wortham Theater Center, 501 Texas
Tickets: $35-$70; 713-227-4772 or www.spahouston.org
Another significant characteristic of Grupo Corpo: The entire company aspires to move as one. Pederneiras often refers to "our body" when talking about the dancers and artistic staff. While individual artists shine during performances, the ensemble has always preferred to imagine itself as a singular entity.
Early dances in the company's repertory, such as "Maria Maria" and "O ultimo trem" (choreographed by Oscar Arais and produced by his Argentinian team), showed a tendency toward narrative.
"I personally believe that dance isn't a type of art that should be seen as a story line," Pederneiras said. "In our works, we don't develop histories. Rather, we try to evoke feelings and emotions. Our main goal is to touch deeply, to enchant, to move and to captivate the audience."
That philosophy has held fast since Pederneiras became resident choreographer in the early 1980s, a move he says caused a drastic stylistic change. Further experimentation unfolded.
"Until the beginning of the '0s, we always created choreographies with erudite music. [They] were neoclassical creations," he said.
The company seems to be in its artistic prime, after many years of successful innovation and extensive touring.
"Our third phase, and the most important in my point of view, was marked by the search for our Brazilian identity. Corroborating this idea, all soundtracks since 1992 were especially composed for our creations by Brazilian musicians," he explained.
Does he have any advice for aspiring choreographers and fledgling dance companies?
"I believe that the most important thing is to believe in the people you're working with. The continuity of a work is developed on its creation, and it will determine its direction. It is very important to stay connected when working as a team and trust your colleagues 100 percent," he said.


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Takeaways From BuzzFeed's 'Honest' Call Centre Employees Video
Employees in the new video are far from engaged, how can you ensure that this does not happen in your contact centre?
BuzzFeed has published a new video in which contact centre employees are being 'honest' about their feelings towards customers on the phone. While they're all bright-smiled and look like the perfect customer service representatives, there isn't a sparkle in their eyes and what they're saying is the exact opposite of the cheerful tone they express it in.
Gems include: "I know how long you've been holding and I don't care", "I'm going to tell you the issue is resolved, so I can go on break", "I wasn't sorry you were on hold for five minutes, I was hoping you'd hang up" and "This job has made me dead inside".
What the full video below:
How can you ensure that your employees do care about what happened that made the customer contact you in the first place, rather than them silently wishing they were 'dead inside'?
Check out these helpful articles and interviews with customer experience leaders to optimise your call centre strategy and ensure your employees feel engaged and empowered to deliver an exceptional customer experience:
- The Business Value of Integrating the Contact Centre Within Your Omni-Channel Strategy
- The Biggest Contact Centre Pain Point? Inconsistent Information
- How Retailer Argos Changed Their Contact Strategy to Make Customer Service Digital
- 9 Innovative Ways to Increase Employee Engagement
- YO! Sushi's Customer Service Motto? Happy Team, Happy Guests


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Currently there is no way to adjust the pooling (number of instances) for a map service shared to portal or ArcGIS Online via the Share As Web Layer pane in ArcGIS Pro. Currently the workflow is:
- Share As Web Layer
- Configure all of the parameters
- Analyze
- Publish
- Login to ArcGIS Server Manager
- Find the Service you just shared
- Click Pooling
- Edit the Service and Adjust the Min and Max number of instances.
In ArcMap the Workflow is:
- From an Mxd Share as Service
- Select Service
- Configure all of the parameters in the Service Editor
- Pooling is an option in the Services Editor and the Min and Max number of Instances can be adjusted here.
- Analyze
- Publish
I have laid out the two workflows to show that a simpler workflow in ArcGIS Pro could improve the user experience of the publishers that know that a service they are publishing will receive more traffic. We have several services that we know are going to receive a large amount of traffic and it is nice to be able to adjust the number of instances during the time of publishing.
Thank you for everything and have a delightful day.
Joe Guzi


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What We Do
We sell Solar Power on long term fixed price contracts
at prices which in many cases are at or below prevailing alternatives.
We have successfully brought down the cost of power from INR 17.91 /kWh in 2009
We have lowered our cost of energy through value engineering, operational performance monitoring and efficient financial strategy. This allows us to deliver cost-effective energy for our customers. Our in-house EPC expertise lowers system costs and our advanced in-house operations and maintenance capability allows us to increase power yields and monitor project performance near real-time. Coupled with our efficient financial strategy, we believe that we are able to offer low-cost solar power solutions at high efficiency yields.
We manage the entire development and operation process, providing customers with long term fixed price PPAs, as a result of solar not being subject to variable commodity prices Our in-house focus on high engineering standards and asset quality ensures high levels of availability and service to our customers.
We have lowered our cost of energy through value engineering, operational performance monitoring and efficient financial strategy.
Our integrated project development, EPC, financing and O&M services has allowed us to generate efficiencies of scale that further drive down system costs.
As opposed to relying on third-party providers, our integrated profile affords us greater control over project development, construction and operation, which provides us with greater insight and certainty on our construction costs and timeline.
We hire from local communities and generally lease land with few alternative uses, providing local communities with a stream of discretionary cash flow without displacing alternative businesses. As a result we are able to build long-term community relationships, which allows us to improve our time of completion, further reducing project development risk.
"Not only did the plant provide electricity to all the nearby underserved villages, it also provided employment to most of us in the village" - Jagir Singh, Lessor - Project land, Punjab.


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I was recently gifted Flea Market Style by Emily Chalmers and this book is a treasure trove of beautiful homes decorated with mostly flea market, garage sale, and dumpster finds. No matter your preference of vintage style, whether it be retro, bohemian or mid-century; page after page this book will inspire you, I promise.
Emily Chalmers also happens to be the proprietor of the London shop Caravan, located in Old Spitalfields Market, one of my favorite markets in the world!
I just love how the tabletop items in those last few photos are displayed!
Wednesday, November 28, 2007
Flea Market Style : Emily Chalmers
1 comment:
- rebekah said...
I'm going to buy it! It looks like such a great book.
- December 7, 2007 at 9:16 AM
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The purchase order, together with these terms and conditions (collectively the "Purchase Order"), constitutes the entire and exclusive agreement between Abacus Solutions, LLC ("Abacus") and the vendor (the "Vendor") identified in the Purchase Order.
Vendor's written or oral acceptance, acknowledgement of this Purchase Order, or commencement of performance constitutes Vendor's acceptance of these terms and conditions. Any terms different from or in addition to the terms of the Purchase Order, whether communicated orally or contained in a written correspondence shall not form a part of the Purchase Order, even if Vendor purports to condition its acceptance of the Purchase Order on Abacus's agreement to such different or additional terms. The Purchase Order does not constitute a firm offer within the meaning of O.C.G.A. § 11-2-205, and may be revoked at any time prior to acceptance. Notwithstanding the foregoing, if a master agreement covering procurement of the Work described in the Purchase Order exists between Vendor and Abacus, the terms of such master agreement shall prevail over any inconsistent terms in this Purchase Order.
The following terms shall have the meanings assigned to them.
Abacus may reject any or all of the Work which does not conform to the applicable requirements within 10 business days of Vendor's delivery of the Work. At Abacus's option, Abacus may (i) return the nonconforming Work to Vendor for a refund or credit; (ii) require Vendor to replace the non-conforming Work; or (iii) repair the non-conforming Work so that it meets the requirements. As an alternative to (i) through (iii), Abacus may accept the non-conforming Work conditioned on Vendor providing a refund or credit in an amount Abacus reasonably determines to represent the diminished value of the non-conforming Work. Abacus's payment to Vendor for Work prior to Abacus's timely rejection of such Work as nonconforming will not be deemed as acceptance by Abacus.
Abacus shall have the right at any time to make changes in drawings, designs, specifications, materials, packaging, time and place of delivery, and method of transportation. If any such changes cause an increase or decrease in the cost, or the time required for the performance, an equitable adjustment shall be made and the Purchase Order shall be modified in writing accordingly. Vendor agrees to accept any such changes subject to this paragraph.
Vendor will secure and maintain insurance providing coverage for liabilities to third parties for bodily injury (personal injury) and damage to property in amounts sufficient to protect Abacus in the event of such injury or damage, and will be in compliance with any and all laws, regulations or orders addressing the liabilities of an employer to its employees for injuries and disease suffered in connection with employment. Vendor further will maintain such additional types and limits of insurance as is customary for a company of similar size and similar operations to Vendor in the jurisdiction or jurisdictions in which Vendor's operations take place.
Without limiting the foregoing, Vendor agrees to abide by the requirements of 41 CFR 60-1.4(a), 60-300.5(a) and 60-741.5(a). These regulations prohibit discrimination against qualified individuals based on their status as protected veterans or individuals with disabilities, and prohibit discrimination against all individuals based on their race, color, religion, sex, sexual orientation, gender identity or national origin and require affirmative action to employ and advance in employment individuals without regard to race, color, religion, sex, sexual orientation, gender identity, national origin, disability or veteran status. Vendor's failure to comply with this provision shall constitute a material breach of this Purchase Order.
The Purchase Order will be construed in accordance with, and all disputes will be governed by, the laws of the State of Georgia, without regard to its conflict of laws rules. The parties specifically waive application of the UN Convention on Contracts for the International Sale of Goods. Vendor irrevocably consents to the personal jurisdiction of the state and federal courts in and for Cobb County, Georgia, and irrevocably waives any claim it may have that any proceedings brought in such courts have been brought in an inconvenient forum.
Looking to quote prices on hardware you need to purchase? Need to have a custom networking solution built for you? Trying to sell decommissioned hardware? We can do all these for you and more. Fill out the form below or contact us by phone: 770-738-1101


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About Us
The Seahorse Trust was set up in 1999 as an umbrella organisation to preserve and conserve the national world, especially the marine environment using Seahorses as our flagship species. We work in partnership with many organisations and people from all over the world, it is this unique partnership that allows us to benefit from the natural world so well.
Seahorses are a unique fish species that occupy the coastal areas of most of the world and it is these very areas that are most under threat, being vulnerable to human and natural interference they suffer badly and by working together we can make a difference to their future and the future of these fragile eco-systems.
Although we are a small charity, we are very effective and by using the seahorse as our flagship species, we make a difference in so many ways, in education, conservation and lobbying for protected areas and to have marine and terrestrial species protected.


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The spring of our youth,
In the middle of winter,
Decision to invade the seas,
5am in shorts by our towels,
A quick run and dip,
Nearly frozen lake,
We sprint over the pier,
Some 100 metres and –
Splashing sounds resonating,
Now dampened beneath the sea,
And I dive as they ascend,
For a legendary tale to be told,
A mermaid's kiss? Or Thor's hammer?
Except, all there was, was darkness,
And the million stings of jellyfishes.
Run, Dip, and Sting
The spring of our youth,


text:
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If you have any questions about the site, please feel free to contact us. We are always looking for ways to better serve our members - YOU are important to us!
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BRG does not endorse any commercial products or services that may be advertised or available on other websites, nor do we assume any legal liability for the accuracy, completeness, or usefulness of any information. Links from our site constitute external sites and are beyond our control and management. We encourage you to read the security and privacy policies for those sites.


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Acute Promyelocytic Leukemia (APL): Comparison Between Children and Adults
Anna Maria Testi1, Mariella D'Angiò1, Franco Locatelli2, Andrea Pession3 and Francesco Lo Coco4,5
Department of Cellular Biotechnologies and Hematology, Sapienza
University of Rome, Italy
2 Department of Pediatric Hemato-Oncology, IRCCS Ospedale Bambino Gesù, Roma University of Pavia, Italy
3 Department of Pediatric Hemato-Oncology, University of Bologna, Italy
4 Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy
5 Laboratory of Neuro-Oncoematology, Santa Lucia Foundation, Rome, Italy
Received: February 10, 2014
Accepted: April 10, 2014
Meditterr J Hematol Infect Dis 2014, 6(1): e2014032, DOI 10.4084/MJHID.2014.032
This article is available on PDF format at:
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The outcome of adults and children with Acute Promyelocytic Leukemia (APL) has dramatically changed since the introduction of all trans retinoic acid (ATRA) therapy. Based on the results of several multicenter trials, the current recommendations for the treatment of patients with APL include ATRA and anthracycline-based chemotherapy for the remission induction and consolidation, and ATRA combined with low-dose chemotherapy for maintenance. This has improved the prognosis of APL by increasing the complete remission (CR) rate, actually > 90%, decreasing the induction deaths and by reducing the relapse rate, leading to cure rates nowadays exceeding 80% considering both adults and children.[1-9] More recently the combination of ATRA and arsenic trioxide (ATO) as induction and consolidation therapy has been shown to be at least not inferior and possibly superior to ATRA plus chemotherapy in adult patients with APL conventionally defined as non-high risk (Sanz score).[10]
Childhood APL has customarily been treated on adult protocols. Data from several trials have shown that the overall outcome in pediatric APL appears similar to that reported for the adult population; however, some clinical and therapeutic aspects differ in the two cohorts which require some important considerations and treatment adjustments.
Epidemiology of Pediatric APL
Compared to that of Adults
In childhood, APL is very rare disease; its incidence seems to be different according to various geographic areas. In the United States, as in Central and Northern Europe, the percentage of APL patients is 5-7% of all pediatric acute myeloid leukemia (AML) cases; a higher frequency (about 20%) is reported in children of Latino/Hispanic descent.[6-8;11-16] In the AML Berlin-Frankfurt-Münster (BFM) studies, 8-10 APL children were registered per year, compared to 16-18 pediatric patients treated, each year, within the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA)-Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) AIDA trials.[6,14,17] Both in the Latino/Hispanic and in Western countries, however, the number of adult APL is much higher compared to that of children, like it is observed in the other forms of AML (110-120 new adult APL cases/a year, in Italy).[5,18] Consequently, pediatric patients have represented only a minimum percentage in trials enrolling both children and adults. Between November 1996 and June 2004, the Programa Espanol de Tratamientos en Hematologia (PETHEMA) LPA96 and LPA99 studies included 639 consecutive patients with newly diagnosed APL from Spain, Netherlands, Belgium, Argentina and the Czech Republic; 67 of them (10.5%) were aged less than 18 years.[2,3] In the Italian GIMEMA AIDA-0493 and -2000 protocols, a total of 1095 adults with APL (age 18-61) were included; in this time frame, a total of 247 (22.6%) children received the same treatments.[5,6,17,18]
Data from single institutions, as well as population-based study, suggested that the Latino-American population has a higher proportion of APL among AML diagnoses, which account for as much as 37.5%. In centers of Brazil, it has been reported that APL represents 28.2% of all AML cases, a fraction that is very similar to that reported by Melo et al (28%) in another Brazilian center. These figures have been confirmed by information from Mexico (20%), Venezuela (27.8%) and Peru (22%). The increased incidence has also been reported in pediatric age.[19,22]
In China, the lack of population-based registries makes it difficult to determine the real incidence of APL, which is estimated on the basis of its relative frequency among other AML subtypes in large clinical trials. According to data so far published, it appears that the Chinese population has a higher prevalence of APL when compared to most non-Chinese studies.[23,24] The most striking ethnic difference is evident in children. In a single-center large series of 629 Chinese patients with de novo AML, 138 (22%) were diagnosed as having APL, cytogenetically confirmed; the incidence of APL was higher in the pediatric age (34%) compared to both adults (19%) and elderly (3%). In Peking Union Medical College, 51 (31.6%) of the 141 cases of pediatric AML, registered between 1996 and 2004, were diagnosed as having APL; in the Children's hospital of Zhejiang University School of Medicine, between 1997 and 2005, 49 (26.5%) of the 185 newly diagnosed pediatric AML, were APL. The percentage of APL could be higher in children than in adults, in this country, but a population-based cancer registry would be necessary to confirm this data.[23-25] Also in low-income countries such as Iraq, the real incidence of pediatric (< 15 years) APL is still unknown; it is estimated on the basis of its relative frequency among other pediatric AML subtypes diagnosed at a single institution. At the Pediatric Oncology Unit, College of Medicine, in Baghdad, which represents a referral center for childhood cancer in Iraq, the overall high incidence of childhood APL is recorded: approximately 30% of pediatric AML are morphologically diagnosed as APL.[26] The same high incidence is not registered among adult and elderly patients (age > 15 years), but in this country many adult patients with leukemia are not referred to a specific oncology center. Thus, the presumed higher prevalence of APL may reflect underestimation of AML cases. Indeed, it is difficult to identify the reasons behind the apparent high prevalence of Iraqi childhood APL; in fact, epidemiological and environmental studies are not carried out, and pediatric and adult cancer registries are still not available.
Ethnic variability may also account for the different incidence of APL in the various countries; environmental factors may play a role; however, the incidence in the different age groups is still not explained. In addition, the diagnostic poor facilities, have to be considered as possible bias for the reported higher incidence of childhood APL in the developing countries.
Are there Clinical and Biological Differences in Pediatric APL Compared to Adults?
Some pediatric trials have shown clinical and biological
differences between adults and pediatric APL. Pediatric APL is
diagnosed at a median age of 9-12 years; diagnosis at age < 1
is very rare in all countries. In our GIMEMA-AIEOP AIDA-0493 study, one
of the 124 children was under 2 years, and only one of the successive
123 children treated with GIMEMA AIDA-2000 protocol was aged <
Among the 66 children included in the PETHEMA LPA96 and
LPA99 studies, only 6 of them were less than 3 years old (9%).[7] The
BFM-AML Study Group reported 81 children and adolescents treated with
three consecutive protocols (AML-BFM-93, -98 and -2004 studies); only
one of them was under 1 year of age and 4% (2 cases) of the 53 children
of the first North American Intergroup trial (INT0129) were aged ≤ 2
APL seems to be more frequent in children with an age ≥ 10
years: 61% in the PETHEMA studies, 50% in the Italian GIMEMA-AIEOP AIDA
and 65% in the BFM protocols.[6,7,14]
A higher frequency of APL in older
children has been also described in two small series of Chinese
patients (10/19 and 18/37 children aged over 10 years, in the two
studies, respectively).[23,24]
However it should be noted that, in the
pediatric APL series reported to date in the literature, the median age
ranged widely, from 7.2 years in the German Austrian Swiss study to 15
years in the European APL study.[28,29]
In most countries, the incidence
of the disease increases during the second decade of life reaching a
plateau during early adulthood when the incidence remains constant,
until it decreases after 60 years of age.
The female sex seems to be predominant among children but not in adults; the predominance of girls (71%) was reported in the French pediatric study published by de Botton et al., by the Children Cancer Group (CCG) and Pediatric Oncology Group (POG) (60%) and by the PETHEMA group (59%) but not in our GIMEMA-AIEOP large group that reported a female/male ratio of almost 1.[6,8,13] An equally even distribution of the two sexes in children and adults had been previously noted by Guglielmi et al, in a series of 196 Italian APL patients.[30]
High body mass index (BMI) is more frequent in APL than in other AML subtypes, both in adults and children. Estey reported, in 1999, that an increasing BMI was strongly associated with a diagnosis of APL among patients affected by AML; in a cohort of 1245 patients with AML, which included 120 APL, the mean BMI was 27.6 and 25 in APL and no-APL patients, respectively.[31] At our Hematology Department, in the "Sapienza" University of Rome, 90 patients (62.5%), of a group of 144 consecutive patients, both adults and children, who received the GIMEMA AIDA protocols, were overweight, and of them 66% were over 40 years.
Increased BMI is present in children with APL, but seems to increase with age in all APL patients.[32]
Compared to the disease in adults, childhood APL is more frequently associated with hyperleukocytosis and a higher number of circulating blasts; in spite of this, the outcome results are comparable. It should be noted that the three largest pediatric studies reported a relatively high proportion of children with hyperleukocytosis at presentation, ranging from 35% to 48%. In both GIMEMA-AIEOP AIDA and European APL 93-2000 trials approximately 35% of pediatric patients were classified as high risk patients according to WBC count.[6,17] A significantly higher median value of WBC counts at diagnosis had been previously reported in children by Guglielmi et al (3.6x109/L vs 2,6x109/L, respectively in children and adults).[30] One large recent European APL study, reporting the analysis of 84 children treated with 2 consecutive trials, confirmed this observation and described the difference between children ≤12 vs ≥ 13 years of age (WBC 10.8 vs 2.6x109/l respectively). Using the commonly adopted cut-off value of 10x109/L, the incidence of hyperleukocytosis is clearly higher in children than in adolescents and in adults, in whom it is usually around 20% to 25%.[33] The 749 adults, who entered the same European APL protocols, had a similar median WBC levels (2.3x109/l) as adolescents; thus the biggest difference in WBC count at onset is observed between young children and patients aged more than 13.[28,33] Also in smaller series of children with APL, a WBC count at presentation over 10x109/l seems to be more common; in the first French childhood series, 13/31 (42%) children had WBC greater than 10.0x109/l, and 7 of them presented WBC over 25.0x109/l at diagnosis.[8] In the BFM pediatric APL series, 30/81 children (30%) presented WBC ≥ 10x109/l, with 3 of them showing leucocytes count ≥ 100x109/l.[14] In the Japanese series of 58 children with APL, 35 (60%) had hyperleukocytosis at disease presentation.[34]
Other characteristics, such as the microgranular M3 variant (M3v according to French-American-British –FAB- classification) and the promyelocytic leukemia/retinoic acid receptor-alpha (PML/RARα) isoforms bcr2 and bcr3 have been reported with increased incidence in children (25% and 37.5%, respectively) as compared to adults (12% and 25%, respectively), although isoform bcr1 remains the most common in all age groups.[8,28] A higher prevalence of M3v morphology (32% vs 16.5%) and the bcr3 type of PML/RARα transcript (56.5% vs 35.5%) have been reported for pediatric APL in some series.[30] However the association of M3v and bcr2 and bcr3 isoform with pediatric age is not clearly defined and not always reported in very recent trials. Bally et al. found higher incidence of M3v in patients with APL aged < 18 ( 23% ≤12 y, 24% 13 to 18 y; 13 % 19 to 60 y; p=0.03) but no difference regarding PML/RARα isoforms (bcr1: 50% ≤12 y, 62% 13 to 18 y; 61 % 19 to 60 y; bcr2: 14% ≤12 y, 9% 13 to 18 y; 9 % 19 to 60 y; bcr3: 36 ≤ 12 y, 29% 13 to 18 y; 30% 19 to 60 y; p= 0.79).[33] Similarly, M3v and the PML/RARα isoforms bcr2 and bcr3 were found not to be increased in the AIEOP-GIMEMA and PETHEMA studies when compared to adults. In fact, the incidence of 18% and 43% of M3v and of the bcr3 isoform in the PETHEMA pediatric series do not differ from the 19% and 44% reported for the whole series of APL patients included in the PETHEMA LPA96 and LPA99 studies.[2,3,5-7]
A low incidence of additional cytogenetic rearrangements has been reported in pediatric APL by Raimondi et al and in children included in the European APL93 trial (11% of children vs 27% of adults carrying chromosomal abnormalities in addition to PML/RARα).[35] On the contrary, these findings were not confirmed by Ortega at al in the PETHEMA LPA96 and LPA99 trials in which the proportion of children with additional chromosomal abnormalities did not differ from that reported in the PETHEMA study of adult patients.[2,3,7]
FMS-like tyrosine kinase (FLT3) mutations have been examined as a prognostic indicator in adult and pediatric APL. Mouse models have demonstrated that FLT3 mutations cooperate with RARα translocations by conferring a proliferative advantage to cells in maturation arrest. The differentiation arrest caused by t(15;17) likely cooperates with the proliferative advantage conferred by FLT3 mutations in APL development and/or progression. Studies of APL patients (mostly adults) have shown that 20-30% of patients harbor in their leukemic cell the FLT3/internal tandem duplication (ITD) and another 10-20% carry the FLT3/tyrosine kinase domain (TKD) mutation. As to the prognostic significance of FLT3 mutations in APL, there is no consensus at present and divergent conclusions have been reported in the published studies. The European cooperative APL Group found that there was a trend toward shorter overall survival in patients with FLT3/ITD (but not in those with FLT3/TKD) due to very poor post-relapse survival.[36] On the contrary, no correlation between FLT3 mutations and survival have been found by Stock, et al. in 78 adult patients treated on Cancer and Leukemia Group B (CALGB) C9710.[37] Nevertheless in the UK Medical Research Council (MRC) AML10 and AML12 trials that included 203 adult and children with APL, patients with FLT3 mutations [both FLT3/ITD and missense mutations in the activation loop domain of the tyrosine kinase domain (FLT3/ALM)] had a higher rate of induction death but no difference in relapse risk or overall survival.[38] The prevalence and the prognostic significance of FLT3 mutations have not been well defined in childhood APL. One earlier study examined FLT3 mutations in a pediatric APL population; among 29 children, FLT3 mutations were present in 10 (34.5%) of them and were strongly associated with higher leukocyte count.[39] The largest study on FLT3 mutations restricted to pediatric patients with APL examined 104 patients aged < 21 years; 81 treated within cooperative group trials CCG-2891 (n=13), CCG-2911 (n=18) and CALGB C9710 (n=50) and 23 treated according to institutional standard therapy.[40] This study demonstrated a high prevalence of both FLT3/ITD and FLT3/TKD mutations in childhood APL (40%). Furthermore, a strong correlation between FLT3 mutations and WBC count at diagnosis (median diagnostic WBC count for children with FLT3 mutations 32.95x109/l compared to 3.6x109/l in those with wild-type FLT3 -p=0.004) and a significantly higher proportion of M3v in FLT3 mutated compared to FLT3 wild type patients (47% versus 15%, p=0.035) were found. In the same study, analysis of induction death by FLT3 mutational status in the high WBC count group showed an early death rate (EDR) of 47% and 0% in FLT3 mutant and FLT3 wild type patients, respectively (p=0.052). The association of FLT3 mutant genotype with induction death in patients with higher WBC count may indicate direct contribution of the FLT3 activation to coagulation dysregulation. If the link between FLT3 mutated status, coagulopathy and induction death observed in this study is further substantiated, interruption of the FLT3 signal transduction pathway by FLT3 inhibitors may represent an attractive therapeutic strategy to ameliorate the rapidly progressive coagulopathy and counteract early death risk.
Other reported characteristics of childhood APL, compared to adults, include more frequent organomegaly and a higher incidence of the expression of the T-antigen CD2 and of the stem cell marker CD34, which are generally also correlated with bcr3 isoform and M3v.[30]
The true incidence of central nervous system involvement (CNS) at diagnosis is unknown both in children and adults. One small pediatric study described initial CNS leukemia in 3/40 (7,5%) patients while a large more recent pediatric trial reported an incidence of less than 2-5%.[6-8;14,41] Patients with APL commonly present with coagulopathy. Approximately 80% of them have a prolonged INR, elevated fibrinogen degradation products, low fibrinogen, and thrombocytopenia, all potential causes of the severe hemorrhages. Therefore, it is recommended in modern guidelines that lumbar puncture at diagnosis is not performed in light of the high risk of bleeding.
Current Treatment Approach in Childhood APL
Specific therapeutic
strategies for pediatric APL have been derived from adult trials that
included children. Most of these approaches include the simultaneous
combination of ATRA and anthracycline-containing chemotherapy. In the
firstly published study of a German-Austrian-Swiss group, 95% of the 22
children treated with ATRA followed by chemotherapy achieved CR and the
5-year Overall Survival (OS) and Event-Free-Survival (EFS) were 87% and
76% respectively.[29] The European
APL93 study included 31 children
receiving ATRA followed by or combined to daunorubicin and cytarabine;
the CR rate was 97%, and the 5-year OS and EFS were 90% and 71%,
respectively.[8] The Italian
GIMEMA-AIEOP AIDA-0493 trial (ATRA and
idarubicin as induction followed by 3 polychemotherapy consolidation
courses), the largest pediatric APL series during the ATRA era,
reported a CR rate of 96% and a 10-year OS and EFS of 89% and 76%
respectively. Similar results were obtained in children treated with
PETHEMA LPA96 study that included the same idarubicin and ATRA
combination followed by three anthracycline-based consolidation courses
(CR 92%; OS 71%).[7] The main
characteristics and therapeutic results of
these studies are summarized in Table
1. All of these studies confirm
the virtual absence of leukemia resistance using state-of-the-art
treatment. Sample size, eligibility criteria, and some differences in
patients characteristics with potential impact on responses to therapy
can explain the apparently different results, which are not
statistically significant.
|Table 1. FIRST pediatric protocols (atra+chemo) for pediatric APL.
Since the
introduction of ATRA, the EDR, mainly because of bleeding, is
dramatically reduced in the pediatric APL studies (3-7%); similar
results have been reported in most of adult cooperative group trials
However significant higher EDR have been recently observed
in unselected population-based studies by Park et al[42] and Lehamann et
al[43] (17.3% and 29%,
respectively, with a higher incidence for older
patients), in which all adult patients with newly diagnosed APL are
reported. The apparently lower EDR in adults and especially in children
enrolled in the clinical trials may partially reflect earlier referral
to specialized centers, without delay in ATRA administration. In
children, the fewer age-related comorbidities could explain the lower
EDR. However, to better establish the size of the problem, all authors
of clinical trials studies should be requested to report all
information for patients who were excluded from the study because of
eligibility criteria.
The APL trials conducted in the 1990-2000 decade provided an important source for the investigation of prognostic factors to be used for treatment stratification. In particular the so called Sanz's score for the relapse risk (low: initial WBC < 10x109/l and platelet count > 40x109/l; intermediate: WBC < 10x109/l and platelet count ≤ 40x109/l; high-risk WBC ≥10x109/l) was developed to dissect relapse risk categories for patients receiving AIDA-like regimens adopted by the GIMEMA and PETHEMA groups.[1,9] This in turn allowed the design of distinct strategies which were aimed at sparing unnecessary toxicity for patients with low-risk (WBC < 10x109/l), whereas more intensive post induction chemotherapy including cytarabine were adopted for high risk (WBC > 10x109/l) patients. The results of both GIMEMA and PETHEMA trials using a risk adapted approach for adult APL, showed a significant improvement in patient outcome.[18,44] Other large trials conducted by the French European APL group, the British MRC, the Japanese Adult Leukemia Study Group (JALSG) and the German AML Cooperative Group (AMLCG) confirmed the advantage of risk adapted strategies using mainly WBC count as a prognostic factor. Overall, studies reported in recent years with ATRA-based and risk adapted chemotherapy, resulted in CR rates of up to 95% and OS rates > 85% for adult APL.[45] In the pediatric setting, initial WBC count is the most important prognostic factor influencing the outcome and children with WBC count higher than 10x109/l (who usually have a younger age as compared to children with low WBC counts) have a higher risk of relapse. In the pediatric series of GIMEMA-AIEOP AIDA 0493 trial, a leukocyte count at diagnosis ≥ 10x109/l had a negative impact on EFS (59% vs 83% at ten years); the 5-year cumulative incidence of relapse (CIR), among the 61 children treated with PETHEMA trials, was higher for those with presenting WBC ≥ 10x109/l, compared to those with lower WBC count (31% vs 3.5%).[6,7] The PETHEMA LPA 99 and GIMEMA AIDA-2000, risk-adapted trials, were adopted also in the pediatric population and confirmed the improvement in results as reported in adults. For children in the previous PETHEMA LAP96 study, the 5-year disease-free survival (DFS) was 75%, whereas, in the LPA99 study, it was 89%.[7] The 6-year OS and DFS rates for the 123 children treated with AIDA 2000 risk-adapted regimen resulted superior compared to those achieved in children who received the AIDA 0493 protocol (96% vs 89.7% and 82.5% vs 73.1%, respectively). For the low-risk children, the less intensive anthracycline-based plus ATRA consolidation was equally effective as the previous cytarabine-containing regimen (6-year OS and DFS 94.2% and 95.6% vs 76.7% and 82.7%, respectively). The role of ATRA combined with cytarabine and anthracyclines during consolidation resulted in a significant improvement in OS and DFS in the high-risk group (96.8% and 82.3% vs 81.6 and 65.2, respectively for AIDA-2000 vs-0493).[17]
As mentioned above, the incidence of CNS involvement in APL, both at diagnosis and relapse, remains to be established, as does the need for prophylactic intrathecal chemotherapy in children and adolescents as an integral part of first-line therapy. Approximately 10% of relapses have a CNS component.[1] The risk of CNS involvement seems to be extremely low in patients without hyperleukocytosis at diagnosis and, in any case, it is more frequent for those with initial WBC > 10x109/l. Other risk factors for CNS recurrence remain a controversial matter. Some authors have previously suggested that FLT3-ITD mutation, which correlate with hyperleucocytosis and an increased expression of adhesion molecules, such as CD56, can promote leukemic infiltration in the CNS. In the PETHEMA LAP96 and LAP99 studies, CNS relapse was associated with CNS hemorrhage before or during induction treatment, which emerged as a novel and independent prognostic factor.[46] This has not been reported before and could have potential therapeutic implications. Therefore, CNS prophylaxis could be considered at least for high-risk patients. In addition, high-dose cytarabine, that ready penetrates the blood-brain barrier could represent a valuable tool to prevent CNS involvement in APL.
Has Cytarabine, at High Doses, a Role in the Consolidation Treatment of Children with APL?
The PETHEMA-LPA2005 study suggested that the addition of high-dose cytarabine (1 g/m2/day x 4 days) to consolidation therapy could reduce the incidence of relapse in patients defined at high risk. Other European adult trials have confirmed this finding. [44,45,47] Two questions remain unanswered: 1) can cytarabine replace anthracycline in the consolidation treatment of APL? 2) is there any benefit of adding cytarabine to the consolidation schedules? Both questions are a matter of investigation in children, mainly in those at high-risk. The 5-year DFS of PETHEMA LPA96 (anthracycline monotherapy in consolidation) and GIMEMA-AIEOP AIDA 0394 (polychemotherapy combination with high-dose cytarabine in consolidation) showed no clear difference in the outcome of pediatric APL (5-year EFS 76% vs 77%).[6,7] Luo et al. suggested that the children included in the PETHEMA trials (without cytarabine) had a significant higher EFS (3.5-year EFS 79.6% vs 37.5%; p 0.012), lower frequency of sepsis during treatment (7.7% vs 78.8%; p 0.0015) and lower hospitalization cost than those treated with protocols containing high-dose cytarabine (USA $ 4,700 vs 20,000; p < 0.0001).[48] On the contrary the BFM protocol, in line with other reports, combined cytarabine at intermediate-high dose to anthracyclines for consolidation therapy of pediatric APL and reported 5-year EFS and OS rates of 73% and 89%, respectively.[14] These results support the efficacy of high-dose cytarabine in combination therapy for pediatric APL. In the Japanese childhood acute myeloid leukemia cooperative study (AML99-M3), cytarabine was combined with ATRA and anthracycline both in induction and consolidation; the 7-year EFS and OS of the 58 enrolled children were 91% and 93%, respectively, and the CIR plateaued at 3.6% after 2 years. In this last trial, the addition of ATRA in the consolidation phase also contributed to improve the results (Table 2).[34] Furthermore, the European Leukemia Network recommended including at least one consolidation cycle of high-dose cytarabine for young high-risk patients.[1]
|Table 2. Pediatric protocols for pediatric APL (atra+chemo+hd-ca).
Are there Particular Treatment Issues for Children with APL?
optimal pediatric dose of ATRA has not yet been established; the
idiopathic intracranial hypertension, commonly called pseudotumor
cerebri (PTC), can complicate the treatment of APL with ATRA. The
diagnosis of PTC is based on increased intracranial pressure with
normal cerebrospinal fluid composition and negative cerebral imaging
studies (computed tomography or magnetic resonance imaging scan). This
side effect is more common in children and adolescents, but the
incidence decreases with the use of a lower dose of ATRA, without
apparently compromising the outcome results. In the European APL 93
trial with the dose of 45 mg/m2
severe headache episodes were more
frequent in the pediatric population than in adults (16% vs 1-2%).[8,28]
Several studies have also reported increased neurotoxicity of ATRA in
children, particularly in younger age (<10 years). In an attempt
reduce ATRA related toxicity the daily dose administered in children
treated according to GIMEMA-AIEOP AIDA and PETHEMA protocols, was
reduced to 25 mg/m2.[6,7] This dose proved to be equally
effective with a
lower incidence of side effects in a previous adult APL dose reduction
trial. Available data also suggest that a half dose of ATRA can be as
effective as the standard dose of 45 mg/m2
per day.[49] The apparently
lower incidence of PTC and headache, together with the excellent
therapeutic results obtained with ATRA at 25 mg/m2
suggest that such
dose could be the recommended standard for children.[50]
Another issue of particular importance in children with APL is the difficulty in swallowing the 10-mg gel caps of ATRA, since the medication is not available in liquid form. Some studies suggest that the contents of an ATRA capsule can be mixed with milk and administered in a nasogastric tube, for comatose patients, reaching a high serum level.[50,51] Similarly, in very young children it is possible to soften capsules in warm milk and so chew them alone or mixed in a spoonful of soft food. An intravenous liposomal formulation of ATRA has been tested in newly diagnosed patients with APL unable to swallow or absorb medications and has been shown to be effective in inducing CR. Unlike oral ATRA, liposomal ATRA was able to produce molecular CR without addition of chemotherapy. In patients with newly diagnosed APL, using polymerase chain reaction (PCR) assay with a sensitivity level of 10-4, Estey et al reported that liposomal ATRA monotherapy induced molecular CR in a significant fraction of patients within 3 months. In more than 30% of patients, PCR negativity persisted for years thereby indicating that liposomal ATRA as a single agent may be curative in APL. However, this ATRA formulation is no longer available.[52]
A relevant problem, linked to the use of chemotherapy in the pediatric population, is a risk of cardiomyopathy, a real threat for children with APL treated with regimens that include high doses of anthracyclines. As suggested by Van Dalen et al, the risk of developing clinical heart failure is dose-dependent, increasing from 0% for 150 mg/m2 of cumulative anthracycline dose, up to 14.3% for doses of 600 mg/m2.[53] Relatively high-dose anthracyclines (450–750 mg/m2) used in modern chemotherapy plus ATRA regimens have proven successful to achieve high cure rates in adults and children with APL, although the high cumulative anthracycline dose was potentially associated with high risk of late cardiotoxicity.[4,6,7,44] Although no severe acute cardiotoxicity was observed in our first GIMEMA-AIEOP study, longer follow-up is needed to define the late cardiotoxicity of anthracycline regimens. Late subclinical cardiotoxicity was observed in 52% of the adult survivors of APL treated on the GIMEMA AIDA-0493 and-2000 protocols.[54] To reduce the risk of developing clinically significant cardiotoxicity and heart failure, which is approximately 5% at 15 years after anthracycline therapy for childhood cancer, the AML BFM study group limited the cumulative anthracycline dose to 350 mg/m2 in most APL patients obtaining results comparable to those reported for studies with higher doses.[14] In the PETHEMA 2005 study, a lower anthracycline dose provided equivalent efficacy with less myelosuppression in patients at low and intermediate risk.[44] Based on these findings, the International Consortium for Childhood Acute Promyelocytic leukemia (ICC APL) was established and a new study (ICC APL 01) was launched and is still actually ongoing with the goal to investigate the safety and efficacy of a regimen with a reduced cumulative anthracycline dose of 355-405 mg/m2 in combination with ATRA and a high dose of cytarabine in one consolidation course for low risk and two courses for high risk patients. Due to the obvious concerns of irreversible heart failure in children who receive high cumulative doses of daunorubicin, also the CALGB C9710 study utilized a cumulative dose of daunorubicin of 500 mg/m2 for those >15 years of age and 400 mg/m2 in children 3–14 years of age.
Role of Arsenic Trioxide (ATO) in Pediatric APL
Treatment strategies
for childhood APL aim to decrease the incidence of relapse and
chemotherapeutic toxicity. The introduction of ATRA has been crucial
for both antileukemic efficacy in APL and for reducing EDR.
Furthermore, in more recent studies, Arsenic Trioxide (ATO), first
introduced for the treatment of relapsed patients has resulted highly
effective in achieving high cure rates in association with reduced
toxicity in adults with APL.[55-59]
Arsenic compounds had been used as therapeutic agents for more than 2000 years in Western and Eastern medicine, particularly in China. Despite the advent of new cytotoxic drugs the empirical use of arsenic as an antileukemic agent continued in China throughout the past century leading ATO to be introduced into the treatment of APL in the 1970s. The specific mechanism of ATO in APL treatment is still under investigation. A dual mechanism of action has been described; as demonstrated by Chen et al[55] and Shao et al,[56] at low concentration ATO exerts a partial differentiating effect by inducing the stimulation of both PML-RARα and PML leading to the degradation through the proteasome pathway. On the contrary at high concentrations, ATO induces apoptosis through caspase activation, reactive oxygen species (ROS) production and induction of mitochondria mediated intrinsic apoptotic pathway. Several studies have shown the benefits of ATO in the treatment of relapsed APL, with a remission rate of 80-90% and long term DFS of 60-80%, and also as induction and consolidation therapy for adults with newly diagnosed APL, demonstrating that ATO is the most active single agent in this disease.[55-59]
However, experience with ATO for treating pediatric APL is limited compared to that achieved with adults APL studies. Two small but significant series[27,60] reported the use of ATO a single agent for both remission induction and post-remission therapy in children with newly diagnosed APL. In both studies, the morphological CR rate was approximately 90% (91% and 89.5% respectively in George et al[60] and Zhou et al[27]), and no resistant cases were recorded. The use of ATO as a single agent in post-remission therapy led to an estimated 5-year OS and EFS of 91% and 81% and 84% and 73%, respectively in George's[60] and Zhou's[27] series, respectively. These results were comparable with those achieved with ATRA plus chemotherapy. ATO-related toxicity was minimal and transient during induction, and neutropenia was the most common side-effect during the 3-year post-remission ATO therapy.[27,60]
A striking convergence regarding the antileukemic effects of ATRA and ATO is the degradation of PML/RARα through distinct pathways, with ATRA targeting the RARα and ATO targeting the PML moieties of the fusion protein. The combined use of ATRA and ATO synergistically induces differentiation, apoptosis and accelerates tumor regression in vivo. Shen et al[61] suggested that ATRA-ATO combination for treating adult APL significantly shortened the time to achieve CR, reduce the disease burden and improved DFS compared with approaches based on the use of either ATRA or ATO alone.[61] These benefits of combining ATRA and ATO have been confirmed by several groups in adults and, more recently, in pediatric APL.[27,62] The retrospective analysis at Pediatric Department, Pecking University, Medical School, showed that the application of ATRA and ATO as induction and consolidation therapy for newly diagnosed children with APL resulted in excellent outcomes and improved the long-term prognosis. Children treated with ATRA-ATO combination had significant better CR and EFS rates, compared to those who received ATRA-based regimes (CR 95.3% and 80%; EFS 92.5% and 70.4%, respectively). Arsenic was well tolerated in children and was devoid of major acute side-effects.[63] Table 3 summarizes the results in pediatric APL with ATO as first-line therapy.
|Table 3. Chinese experiences in pediatric APL: ATO as first-line therapy.
The long-term safety
of ATO in children is unclear. Reported late
effects include hyperpigmentation, neutropenia, muscular atrophy and
peripheral neuropathy. One study reported a significant association
between the children's neurocognitive function and their chronic
environmental ATO exposure.[50]
What is the Role of Stem Cell Transplant in Pediatric APL?
large multicenter studies have shown that regimes combining upfront
ATRA and chemotherapy and/or ATO lead to a high curability rate in APL,
suggesting that hematopoietic stem cell transplantation (HSCT) is not
recommended as consolidation therapy for patients in first complete
remission (CR1). However, despite optimal therapeutic results, relapses
still occur in 15% to 25% of the cases.
While, for patients relapsing after ATRA plus chemotherapy, ATO as salvage for re-induction is an established recommendation, the post-consolidation approach to relapsed or refractory APL is less clearly defined. Although most relapsed patients (> 80%) can achieve a second CR (CR2) with ATRA, ATO, chemotherapy (CT), or a combination of these agents, only occasional cases have demonstrated second remission for as long as 8-10 years following treatment with chemotherapy and/or ATRA.
For this reason most relapsed APL patients would receive autologous (auto), allogeneic (allo) or haploidentical cell transplantation (HSCT). Auto-HSCT is one of the therapeutic options for patients who achieve a CR2 and are in molecular remission (MR). Allo-HSCT may be useful to consolidate patients in CR2 and to treat patients with persistent minimal residual disease due to a potent graft versus leukemia effect, the greatest asset of an allo-HSCT in this setting.[64]
In the largest study by Sanz et al,[65] the investigators retrospectively analyzed outcomes in 625 patients with APL who had been treated as part of the European Cooperative Group for Blood and Marrow Transplantation (EBMT) and who underwent either an auto- or allo-HSCT. In this registry survey, similar outcomes were shown for both auto and allo-HSCT, although the allo-HSCT showed a higher incidence of non-relapse mortality (transplant related mortality TRM), whereas the auto-HSCT group had a higher risk of relapse. This study including patients in CR1 or CR2 suggested that, even in the ATRA era, HSCT had to be considered as consolidation therapy, especially for patients in CR2.[65]
The majority of reports on the use of HSTC for treatment of relapsed or refractory APL deal primarily with adult patients making the benefit of these therapies for children still unclear. The Dana Farber Cancer Institute reported a favorable outcome among children undergoing allo-HSCT for relapsed and refractory APL with a probability of survival at 5 years of 73%. This group also reported a TRM of 33% and a low relapse rate (15%).[66] The largest study by Dvorak et al.[67] reported 32 pediatric patients underwent auto or allo-HSCT for treatment of primary-refractory (3 patients) or relapsed (29 patients) APL. The incidence of TRM and relapse for auto-transplant in children were 0% and 27%, and the 5 year EFS and OS of 73% and 82%, respectively; for the allo-HSCT the incidence of TRM and relapse were 19% and 10%; the 5 year EFS and OS were 71% and 76%, respectively. This study demonstrates that auto or allo-HSCT are both effective therapies for the treatment of children with relapsed or refractory APL without significant difference in EFS and OS but, as previously described in adults, with a low TRM for auto-HSCT and a low incidence of relapse for allo-HSCT.[67] Notwithstanding the successful results, the limits of the above mentioned studies are the retrospective nature, the relatively small number of patients included, mainly as concerns pediatric age, and the different therapeutic strategies, according to the single institute policy.
The optimal stem cell transplantation strategy for advanced APL still remains controversial, as several factors influence the choice. The type of salvage regimens, donor selection, conditioning regimens and graft versus host disease (GVHD) prophylaxis should be included in the context of prospective clinical trials. However, the superior protection from relapse afforded by allo-HSCT and the favorable survival described in the few pediatric experiences reported, suggest performing allo-HSCT for children with relapsed or refractory APL for whom a suitable HLA-donor is available. On the other hand, children, without a suitable donor, achieving molecular remissions after salvage therapy can be considered candidates for high dose chemotherapy and auto-HSCT as a valid post-consolidation strategy.
Future Directions
For patients with newly diagnosed, non-high risk
APL, the front-line use of ATRA-ATO combination is extremely
encouraging and will probably become the standard regimen also in the
pediatric age. Future controlled prospective trials should address the
role of ATO in induction and consolidation chemotherapy and establish
whether ATO could reduce cytotoxic chemotherapy intensity in children
with APL. Oral arsenic is also very effective, and its combination with
oral ATRA warrants further investigation also in the pediatric
setting.[68,69] Next ATO-based
pediatric APL trials should include
longitudinal assessment of neurological and neurocognitive outcomes,
evaluation of the growth assessment in treated children and
pharmacokinetic studies will be necessary to investigate how the faster
metabolism in children can promote drug excretion and influence the
right dose to administer, in particular in younger patients.
New drugs, such as FLT3 inhibitors, anti-CD33 monoclonal antibodies and tamibarotene (a synthetic retinoid more potent and less toxic than ATRA) may offer additional options for patients with high-risk or relapsed/refractory APL.
Future efforts should focus on decreasing the delay in referral and diagnosis; unfortunately intracranial bleeding is still the major cause of early death and a small percentage of patients, adults and children, in all countries, are still diagnosed after the occurrence of life-threatening bleeding. More importantly, as reported by Park et al,[42] there is a clear need to provide the knowledge necessary to recognize APL as a medical emergency, which requires specific and simultaneous actions, including a prompt initiation of ATRA, aggressive supportive care to counteract the coagulopathy, and patient referral to experienced medical centers when the disease is first suspected. Finally, more studies are warranted to clarify the reasons for the different epidemiology of pediatric APL in several countries.
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- Mantadakis E, Samonis G, Kalmanti M. A comprehensive review of acute promyelocytic leukemia in children. Acta Haematol 2008; 119: 73-82. http://dx.doi.org/10.1159/000117712. PMid: 18285695
- Creutzig U, Zimmermann M, Dworzak M, et al. Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses. Report from AML-BFM Study Group. Br J Haematol. 2010; 149(3): 399-409. http://dx.doi.org/10.1111/j.1365-2141.2010.08107. PMid: 20230404
- Gregory J, Feusner J. Acute promyelocytic leukemia in children. Best Pract Res Clin Haematol. 2003; 16(3): 483-494.PMid:12935964
- Douer D, Preston-Martin S, Chang E, et al. High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia. Blood. 1996; 87: 308-313. PMid: 8547657
- Testi AM, Foa R, Tomei G, et al. GIMEMA-AIEOP AIDA protocols for
the treatment of newly diagnosed acute promyelocytic leukemia (APL) in
children: analysis of 247 patients enrolled in two sequential Italian
multicenter trials. Blood (ASH Annual Meeting abstracts) 2010: 116:
Abstract 871
- Lo Coco F, Avvisati G, Vignetti M, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 2010; 116: 3171-3179. http://dx.doi.org/10.1182/blood-2010-03-276196 PMid:20644121
- Hermander P, Milanes MT, Svarch E, et al. High relative proportion of acute promyelocytic leukemia in children: experience of multicenter study in Cuba. Leuk Res 2000; 24: 739-740. PMid:10991702
- Rego EM, Kim HT, Ruiz-Arguelles GJ, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood 2013; 121: 1935-1943. http://dx.doi.org/110.1182/blood-2012-08-449918. PMid:23319575
- Jacomo RH, Melo RA, Souto FR, et al. Clinical features and outcome of 143 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines. Haematologica 2007; 92 (10): 1431-1432. PMid:18024380
- Ribeiro RC, Rego E. Management of APL in developing countries: epidemiology, challenges and opportunities for international collaboration. Haematology (Am Soc Hematol Educ Program) 2006 (1): 162-168. PMid:17124056.
- Zhang L and Zhu X. Epidemiology, diagnosis and treatment of acute promyelocytic leukemia in children: the experience in China. Mediterr J Haematol Infect Dis. 2012,4(1): e2012012. http://dx.doi.org/10.4084/MJHID.2012.012. PMid:22550558
- Wang H, Hao L, Wang X, et al. Retrospective study of arsenic trioxide for childhood acute promyelocytic leukemia in China: a single-center experience. Int J Hematol. 2010; 91(5): 820-825. http://dx.doi.org/10.1007/s12185-010-0575-z. PMid:20461563
- So CC, Wan TS, Chow JL, et al. A single-center cytogenetic study of 629 Chinese patients with de novo acute myeloid leukemia-evidence of major ethnic differences and a high prevalence of acute promyelocytic leukemia in Chinese patients. Cancer Genetics 2011; 204: 430-438. http://dx.doi.org/10.1016/j.cancergen.2011.06.003. PMid:21962893
- Testi AM, Al-Hada SA, Al-Jadiry MF, et al. Impact of International collaboration on prognosis of childhood acute promyelocytic leukemia in Iraq. Haematologica 2006; 91: 509-512. PMid:16533724
- Zhou J, Zhang Y, Li J, et al. Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood. 2010; 115(9): 1697-1702. http://dx.doi.org/10.1182/blood-2009-07-230805. PMid:20029047
- Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all-trans retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of the maintenance therapy in newly diagnosed acute promyelocytic leukemia: the European APL group. Blood 1999; 94: 1192-1200. PMid:10438706
- Mann G, Reinhardt D, Ritter J, at al. Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children. Ann Hematol. 2001 Jul;80(7):417-22. PMid:11529468
- Guglielmi C, Martelli MP, Diverio D, et al. Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome. A cooperative Italian study on 196 cases. Br J Haematol. 1998; 102(4): 1035-1041. PMid:9734655
- Estey E, Thall P, Kantarjian H, et al. Association between increased body mass index and a diagnosis of acute promyelocytic leukemia in patients with acute myeloid leukemia. Leukemia 1997; 11 (10): 1661-1664. PMid: 9324286
- Breccia M, Mazzarella L, Bagnardi V, et al. Increased BMI correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols. Blood 2012; 119: 49-54. http://dx.doi.org/10.1182/blood-2011-07-369595. PMid:22049518
- Bally C, Fadlallah J, Leverger G, et al. Outcome of acute promyelocytic leukemia (APL) in children and adolescents: an Analysis in two consecutive trials of the European APL Group. J Clin Oncol. 2012; 30(14): 1641-1646. http://dx.doi.org/10.1200/JCO.2011.38.4560. PMid:22473162
- Imaizumi M, Tawa A, Hanada R, et al. Prospective study of a therapeutic regimen with all-trans retinoic acid and anthracyclines in combination of cytarabine in children with acute promyelocitic leukaemia: the Japanese childhood acute myeloid leukaemia cooperative study. Br J Haematol. 2011; 152(1): 89-98. http://dx.doi.org/10.1111/j.1365-2141.2010.08332.x. PMid:20735397
- Raimondi SC, Privitera E, Williams DL, et al. New recurring chromosomal translocations in childhood acute lymphoblastic leukemia. Blood. 1991 May 1;77(9):2016-2022. PMid:2018838
- Callens C, Chevret S, Cayuela J, et al. Prognostic implications of FLT3 and Ras gene mutation in patients with acute promyelocytic leukemia (APL): a retrospective study from European APL Group. Leukemia 2005; 19: 1153-1160. PMid:15889156
- Stock W, Najib K, Moser BK, et al. High incidence of FLT3 mutations in adults with acute promyelocytic leukemia (APL): correlation with diagnostic features and treatment outcome (CALGB 9710). J Clin Oncol 2008; 26: abstr 7002.
- Gale R, Hills R, Pizzey A, et al. Relationship between FLT3 mutation status, biologic characteristics and response to target therapy in acute promyelocytic leukemia. Blood 2005; 106: 3768-3776. PMid:16105978
- Arrigoni P, Beretta C, Silvestri D, et al. FLT3 internal tandem duplication in childhood acute myeloid leukemia: association with hyperleucocytosis in acute promyelocytic leukemia. Br J Haematol 2003; 120 (1): 89-92. PMid:12492581
- Kutny MA, Moser BK, Laumann K, et al. FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2012; 59(4): 662-667.http://dx.doi.org/10.1002/pbc.24122. PMid: 22378655
- Biondi A, Rovelli A, Cantù-Rainoldi A, et al. Acute promyelocytic leukemia in children: experience of the Italian Paediatric Hematology and Oncology Group (AIEOP). Leukemia 1994; 8: 1264-1268. PMid:8057659
- Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2011; 118: 1248-1254. PMid: 21653939
- Lehmann S, Ravn A, Carlsson L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011 Jul;25(7):1128-34. doi: 10.1038/leu.2011.78. Epub 2011 Apr 19.
- Sanz MA, Montesinos P, Rayon C, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high risk patients: further improvements in treatment outcome. Blood. 2010; 115 (25): 5137-5146. http://dx.doi.org/10.1182/blood-2010-01-266007. PMid:20393132
- Lo Coco F, Cicconi L. History of Acute promyelocytic leukemia: A Tale of Endless revolution. Mediterr J Hematol Infect Dis. 2011; 3(1): e2011067. http://dx.doi.org/10.4084/MJHID.2011.067 PMid:22220264
- Montesinos P, Diaz-Mediavilla J, Deben G, et al. Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis. Haematologica 2009; 94: 1242-1249. doi: 10.3324/haematol.2009.007872 PMid: 19608685
- Lengfelder E, Haferlach C, Saussele S, et al. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia. 2009; 23(12): 2248-2258. http://dx.doi.org/10.1038/leu.2009.183. PMid:19741727
- Luo XQ, Ke ZY, Huang LB, et al. Improved outcome for Chinese children with acute promyelocytic leukemia: a comparison of two protocols. Pediatr Blood Cancer. 2009;53(3):325-328. http://dx.doi.org/10.1002/pbc.22042. PMid:19422024
- Castaigne S, Lefebvre P, Chomienre C, et al. Effectiveness and pharmacokinetics of low-dose all-trans retinoic acid (25 mg/m2) in acute promyelocytic leukemia. Blood 1993; 82: 3560-3563. PMid:8260694
- Abla O, Ribeiro RC. How I treat children and adolescents with acute promyelocytic leukaemia. Br J Haematol. 2013; Sep 30. http://dx.doi.org/10.1111/bjh.12584. PMid:24117210
- Shaw PJ, Atkins MC, Nath CE, Earl JW. ATRA administration in the critically ill patient. Leukemia 1995; 9: 1288. PMid: 7630206
- Estey EH, Giles FJ, Kantarjian H, et al. Molecular remissions induced by liposomal-encapsulated all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Blood. 1999;94(7):2230-2235. PMid:10498593
- van Dalen EC, Raphael MF, Caron HN & Kremer LC. Treatment including anthracyclines versus treatment not-including anthracyclines for childhood cancer. Cochrane database Syst Rev, ICD006647. http://dx.doi.org/10.1002/14651858.CD006647.pub3. PMid:21249679
- Pellicori P, Calicchia A, Lo Coco F, et al. Subclinical anthracycline cardiotoxicity in patients with acute promyelocytic leukemia in long-term remission after the AIDA protocol. Congest Heart Fail. 2012 Jul-Aug;18(4):217-221. http://dx.doi.org/10.1111/j.1751-7133.2011.00278.x. PMid:22809260
- Chen GQ, Shi XG, Tang W, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 1997; 89: 3345-3353. PMid:9129041
- Shao W, Fanelli M, Ferrara FF, et al. Arsenic trioxide as an inducer of apoptosis and loss of PML/RARa protein in acute promyelocytic leukemia cells. J Nat Cancer Inst. 1998; 90: 124-133. PMid:9450572
- Tallman MS. What is the role of arsenic in newly diagnosed APL? Best Pract Res Clin Haematol. 2008; 21: 659-666. http://dx.doi.org/10.1016/j.beha.2008.09.002. PMid:19041605
- Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide in the
treatment of acute promyelocytic leukemia (APL). Clinical efficacy and
pharmacokinetics in relapsed patients. Blood 1997; 89: 3354-3360.
- Soignet SL, Frankel SR, Douer D, et al. United States multicenter
study of arsenic trioxide in relapsed acute promyelocytic leukemia. J
Clin Oncol 2001; 19: 3852-3860. PMid:11559723
- George B, Mathews V, Poonkuzhali B, et al. Treatment of children
with newly diagnosed acute promyelocytic leukemia with arsenic
trioxide: a single center experience. Leukemia. 2004
Oct;18(10):1587-1590. PMid:15356649
- Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3
combination yields a high quality remission and survival in newly
diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 2004;
101: 5328-5335. PMid:15044693
- Zhang l, Zhu X, Zou Y, et al. Effect of arsenic trioxide on the
treatment of children with newly diagnosed acute promyelocytic leukemia
in China. Int J Hematol 2011; 93: 199-215.
http://dx.doi.org/10.1007/s12185-011-0768-0. PMid:21287409
- Cheng Y, Zhang L, Wu J. et al. Long-term prognosis of childhood acute promyelocytic leukaemia with arsenic trioxide administration in induction and consolidation chemotherapy phases: a single-centre experience. Eur J Haematol. 2013; 91(6):483-489. http://dx.doi.org/10.1111/ejh.12194. PMid:24033687
- Lo-Coco F, Romano A, Mengarelli A, et al. Allogeneic stem cell
transplantation for advanced acute promyelocytic leukemia: results in
patients treated in second molecular remission or with molecularly
persistent disease. Leukemia. 2003 Oct;17(10):1930-3. PMid:14513040
- Sanz MA, Labopin M, Gorin NC, et al. Hematopoietic stem cell
transplantation for adults with acute promyelocytic leukemia in the
ATRA era: a survey of the European Cooperative Group for Blood and
Marrow Transplantation. Bone Marrow Transplant. 2007 Apr;39(8):461-9.
- Bourquin JP, Thornley I, Neuberg D, et al. Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood. Bone Marrow Transplant. 2004 Nov;34(9):795-8. PMid:15354207
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http://dx.doi.org/10.1016/j.bbmt.2008.04.015 PMid:18541203
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maintenance regimens for first complete remission of acute
promyelocytic leukemia: a 10-year follow-up study. Blood 2011; 118:
6535-6543. http://dx.doi.org/10.1182/blood-2011-05-354530 PMid:21998212
- Au WY, Li Ck, Lee V, et al. Oral arsenic trioxide for relapsed acute promyelocytic leukemia in pediatric patients. Pediatr Blood Cancer 2012; 58: 630-632. http://dx.doi.org/10.1002/pbc.23306 PMid:21898784


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Fixed Assets, Depreciation: what does it all mean? This post covers the Depreciation Basics
"Fixed Assets are are an asset that the business owns that is expected to be used by the business for more than a year."
"Depreciation is a method of allocating the cost of an asset over its useful life"
So for example: Sally runs a florist business and has just purchased a new van for deliveries. The Van cost $30,000. Now most vehicles last for at least 10 years. So rather than claiming the full cost in the first year and getting the benefits for another 9 years, the vehicle is depreciated over time allocating a portion of the cost to expenses each year while reducing the value of the car.
All assets have a different rate of depreciation and the IRD has a depreciation rate finder to give you an idea of what rate of depreciation you could use.
There are two ways that you can calculate depreciation. They are Diminishing Value and Straight Line Basis. We will look into these methods in our next post.
So what assets need to be depreciated?
All assets purchased by the business that cost over $500 (excluding GST) will need to be added to the fixed asset register and depreciated each year that the business has the asset in its possession. Land and buildings are not able to be depreciated, however chattels can be listed and depreciated separately.
Still Feeling unsure about your responsibilities??
If you are feeling unsure about your responsibilities around Depreciation of Fixed Assets in your business it might be time to look at getting some professional advice. We can help make sure you have all your assets sorted and are claiming the correct amount of depreciation each year. Get in touch to see how we can help.
Further Reading:
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Athletic Club Bar and Grill
Athletic Club Bar and Grill
A unique bar set on the ground level of the hotel's atrium, The Athletic Club will satisfy all tastes with a great, varied menu. Looking for the best entertainment in Tennessee? With live and pre-recorded sports on two 10ft screens, 12 additional screens, trivial games and individual table-top speakers that put you in control, The Athletic Club is a fantastic bar and is open from 11am until 11pm every day.
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- Category: Uncategorised
- Written by Damian
- Hits: 7292
Welcome to the web site of the
European College of Human Ecology
- Initiative -
- News -
The III. international summer program in Emmendingen
"Urban Concepts in Sustainable Transition"
has finished successful on 2018 August, 13th with the
presentation of the results at the Volkshochschule nördlicher Breisgau in Emmendingen. An Exhibition shows the results during September 2018
All results are printed in the Charrette Book to download here.
From 2018 July 7th to 10th the XXIII conference of the Society for Human Ecology will be held in Lisbon . The European College of Human Ecology, official co-sponsor of the conference, will held a special symposium about "New Directions in Higher Human Ecology Education". Please visit the SHE-Conference-Website.
On 2017 June 6th the European College of Human Ecology gGmbH was founded notarial in Emmendingen with its head office in the Markgrafenstrasse 53 in 79312 Emmendingen, Germany. Klaus Markus Hofmann and Dr. Wolfgang H. Serbser were appointed as Managing Directors for the new company.
The international summer program in Emmendingen with the topic of "Urban Concepts in Sustainable Transition" will be conducted in summer 2018 from July, 29th to August, 12th. The registration period ends on 2018, April, 30th.
Check out our facebook page
- Quite Recently -
An exhibition in the city hall of Emmendingen showed the results of the past summer universities and the integrated planing of the colllege in March 2017
The second international Summer University closed on August, 14th 2016. The closing event presents the successful results in an exhibition in the old meetinghall of Wehrle Werk AG Industries.
During the international conference of the Society for Human Ecology in April 2016 in Santa Ana members ofthe DGH-Committee and the College of Atlantic agree to lunch a second summer university in 2016 in Emmendingen and to continue their joint activities.
- Past -
The Wehrle-Werk AG Emmendingen shows the synergy of college and factory
and presents a own study Machbarkeitstudie Wehrle 2025
May, 24th 2012 the
1. International College Forum Frankfurt took place
during the Global Business Week 2012 in
in the IHK Frankfurt am Main.
November 11th to 13th 2011 the
Annual Meeting of the Council for European Urbanism Germany
took place in the town hall of Emmending, to discuss
the Result of the Charrettee Emmendingen


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John Burke recalls eating out abroad
Most travellers are neither gourmets nor connoisseurs of wine – and that goes for me too. When in France, my choice is a brasserie where the wine is as ordinary as it is called or else a self-service restaurant, such as Le Berigny in Dieppe which doubles as the station buffet.
In the German-speaking lands, there are no less than 7,000 local breweries, often with a choice of brands for washing down such fare as a Bauernfrühstuck or rösti or Wiener Schnitzel. Yet in two countries it has to be fish: Norway and Portugal. My first taste of octopus (polpo) was in Lisbon, but I have also eaten swordfish on Grenada and barramundi (a bit like buttered cod) with chips in Darwin.
Ostend too was seafood only, and that was during my brief career as a gastronomic professional in Belgium where leisuredly eating one's fill is a national custom. While based there for Reuter, the expatriates' weekly Brussels Times paid me to visit restaurants where I was probably more expert on writing about the decor than the cuisine.
That work ranged from eating hearty Dutch dishes at the top of the Euromast in Rotterdam to dining on wild boar or pheasant in front of log fires in the Ardennes. The local liqueur on those occasions was green, either Pisang Ambon, distilled from Indonesian bananas, or one derived from pine-trees. I have also sampled the four strengths of Trappist beer, indentified by caps of different colours.
There have been other culinary novelties in various countries, such as reindeer meat at Rovaniemi on the Arctic Circle and skyr (a mild yoghurt) at the Naust boat restaurant in Reykjavik. Sometimes the ambience was more memorable than the delicacies, although these have ranged from oysters at the Duchesse Anne in St Malo to snails at the Ritz-Carlton in Montreal where I also drank Caribou (a blend of red wine, whiskey and maple sugar) at Les Filles du Roy.
Named after the 800 girls who Louis XIV shipped to colonial Canada, it is one of several ancient or famous eating-places that are a must for any traveller. They range from Munich's rebuilt Hofbräuhaus, which dates back to 1589, to U Kalicha in Prague whose name and pictures are out of the Good Soldier Schweik although it is too grand to be the tavern where the Czech bumpkin quaffed beer from Pilsen.
They also include the Hauptmann von Köpenick, a public-house named after the cobbler who, donning a captain's uniform, collected a squad of troops to rob Berlin's easternmost townhall in 1906. And even the communists in Leipzig maintained Auerbachs Keller, the ancient basement restaurant immortalised in Goethe's Faust.
I have dined in even classier surroundings. British Columbia's tourism minister stood me lunch at the Union Club (founded 1879) in Victoria, and I was a guest of his Jamaican counterpart at the Liguanea in Kingston. As the model for the colonial club in Ian Fleming's Dr No, it featured in the film.
Also in the Caribbean I discovered rum punch as well as sorrel, a non-alcoholic drink even more delicious than сок от слива (plum-juice) in Bulgaria, while my one pisco sour – as potent as ούζο in Greece – was when lunching with a diplomat from the British Embassy in Lima. I remember a table-top grill in La Paz, while in Montevideo the steak came straight out of an open oven.
As for Brazil, one normally pays per kilogram, but it was all-you-can-eat plus the usual complimentary coffee at Velho Madalosso, the famous Italian restaurant in the Santa Felicidade district of Curitiba. The wine was a white Andino from Argentina, and my guide's young son tinkled Two Lovely Black Eyes on the piano.
At the Thalia social club in the same city, there was a lavish German buffet plus Bavarian folk-music, and another unique experience was in Asuncion where I had maize empanadas in the canteen of Paraguay's historic and dominant Colorado Party.
When I crossed America coast-to-coast as a freelance photographer for BBC-TV, my schedule was usually too tight to eat much. While photographing the Great Salt Lake, my guide fetched hamburgers; in St Paul-Minneapolis, another efficient guide bought me a hot dog at airport departures – plus Cokes each time!
I did, however, have a KC steak at the Golden Ox in Kansas City, a yard of ale in a tall pipe of a glass in Cincinatti's Sheraton-Gibson, and a business lunch at Detroit's country club. And there was a working breakfast at Illinois Athletic Club. I asked Chicago's convention manager whether he was track or field, to which the reply was: "Negative. I come here because the ham 'n eggs are so good".
The worst experience was having to get through spicy Mexican food in Red Rocks Park because my guide from Denver was obviously on an expense-account. Precious daylight was wasted when I could have been photographing more of the Rockies.
It would have been fine south of the border, because I always try the local cuisine such as red Egri Bikaver with goulash, while serenaded by gipsies, in Budapest. Yet I was warned off rice-wine in Macau, because it is even more like fire-water than Sebastian Stroh's 80% rum in Austria.
Hyatt's manager in Manila once invited me to lunch, but was amazed when this westerner asked for a Filipino menu. It was rice with everything plus soy sauce, and the glass of green mango juice had frosted sugar on the rim. Travellers in Israel are restricted anyway to a kosher diet (except in Christian hostels), while the menu at the baptismal site of Yardenit by the Jordan is even based on Jewish recipes from the Roman era.
The one place abroad where I avoided bars and cafes downtown was Benidorm. I mean, who wants pub grub or fish 'n chips with brown ale in the romantic land of paella, gazpacho, sangria...


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Social Login, Social Sharing, Social Commenting and more!Add to List
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This plugin enables Social Login and Social Sharing. Along with that it also captures users' profile data, with their permission of course, and automatically creates a profile in your WP database. The plugin can also feed the data into your existing email software such as MailChimp or any other marketing, sales or analytics software.
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Make your users your brand ambassadors and drive high quality referrals to your website – 82% of users consider buying or trying products and services based on their friends' recommendations. With social share, you give users the tools to share your content, product details and other information with their own networks.
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Our solution allows websites to collect more than 200 user data points- such as demographics, name, education, verified email address and many more – in order to better understand users. This enables businesses to personalize users' web experiences and then build long-term relationships with them.
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Single Sign-On creates a single authentication system for multiple web properties allowing users to navigate websites with a single account.
This plugin runs on LoginRadius SaaS (Software-as-a-Service).
Features of this Plugin
- A clean, user friendly WP admin U/I with tab structure with various options for social login, sharing and commenting
- Users can register by logging in with their social ID, such as Gmail, Twitter, Facebook etc and will not require usernames/passwords
- 30+ ID providers available, choose as many ID providers as you like
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- It automatically creates an account for each user
- Fully compatible with s2member
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- Supports WordPress Multisite feature
- Auto approve user's comments from social ID providers
- Fetched data, including email addresses, name, date of birth, etc.
- Twitter does not provider email addresses, so in case a user logs in with Twitter, you have the option for a pop-up window to appear asking users to fill his/her email address and that can be verified
- Personalize ID providers i.e integrate FB, Google, Twitter apps in to your LoginRadius so that it will show your website name/logo in the ID providers login pop-up
- Options to show a social login interface (widget) on a login, register, and/or comment page
- Option to integration data with mailchimp, salesforce, google analytics, hubspot, etc.
- Enable email verification from the end user
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A Senior Citizen's Response to Raising the Social Security Age
Posted March 22, 2013
That's exactly the problem with Insiders... they make their millions in the protected bubble of Wall Street or Washington. And they expect "average" citizens like us to pay for their lifestyles and their mistakes. If you're like me, you've had enough.
They'll Steal Your Savings, Too
Written by Adam EnglishPosted March 20, 2013
The United States is not as far away from the latest Eurozone outrage as we'd like to think...
More Precious than Silver and Gold?
Posted March 18, 2013
Only one precious metal looks like a buy right now...
From Drones to Dictatorship?
Written by Brittany StepniakPosted March 15, 2013
The loss of rights, liberty, and our democratic republic... goodbye, Fifth Amendment!
Silver Enters Twilight Zone
Posted March 13, 2013
When reality comes back around -- and it always does -- silver prices will rise dramatically to reflect the true fundamental picture.
Am I Being Paranoid?
Posted March 12, 2013
American neighborhoods are increasingly being policed by cops armed with the weapons and tactics of war...
The Revolting Change to the Revolving Door
Written by Adam EnglishPosted March 7, 2013
Cronyism is now being fed with tons of cash as Obama promotes an insider.
Exposing "The System"
Posted March 5, 2013
The banks committing the most atrocious financial crimes outperformed the market last year by at least 2.5 times. That's your current financial system.
The Incredible Shrinking Pension
Posted February 28, 2013
A good politician is quite as unthinkable as an honest burglar...
The Basic Struggle
Posted February 21, 2013
The Establishment is a general term for those people in finance, business and the professions who hold the principal measure of power and influence in this country irrespective of what administration occupies the White House.


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March 20, 2008
March 4, 2008
Guerlain's $62,000.00 Lipstick: KissKiss Gold and Diamonds
KissKiss Gold and Diamonds by Guerlain is a custom lipstick case adorned in diamonds, 199 in fact, to total 2.2 carats and made of 18K gold. KissKiss is a replica of sorts of their KissKiss original top release in 2005, created by Olivier Echaudemaison and designer Herve Van Der Straeten for Guerlain. The gold encasing can be engraved (don't fret, its refillable), and the lipstick is available in 15 customizable shades. So if you happen to have $62K laying around and are addicted to the finer things in life-to include luxe cosmetics-place your order while you can.


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While using lots of cosmetic makeup products we collect, From natural skin care to perfume, there's a lot of products rehearsing our precious and devastatingly limited counter-space.
The good news is, there are plenty of lovely, genius and cheap methods to organizing and holding skin care products. So when the clutter is simply too much on bearing and the urge to DIY is way too strong to combat,
These 15 Of The Pinterest's BEST Beauty Storage Hacks helps you to save the day!
1. Cheap shoe storage with Tension Rods
2. organize your eye shadow with an ice tray
3. Hanging your hair dryer with command hooks
4. Organize your perfume bottles using spice rack
5. Organize your makeup with this hanging bucket, it's easy to make
With a few cutlery caddies plus a clothesline, you could have an adorable hanging organizer for that beauty supplies you like most. It's great for your shampoos and conditioners, makeup brushes and also your hot hair tools.
6. Organize your bath product with shoe organizer
A hanging shoe organizer is ideal for storing larger hair products behind the entrance — one more hack for producing space and then there was none.
7. hang your beauty product with curtain rod
Keeping your bathrooms organized and clean just became so much more enjoyable
8. Using cake stand for your nail polish collections
9. Organize beauty products essentials with lantern jars
10. Organizing your hairsprays with a wine rack
11. Manage your hair tools with this magazine holder
12. Using IKEA socker pot holder for your makeup Brush
13. Using IKEA Raskog cart for your makeup collection
14. DIY Cheap Makeup storage using cardboard
15. Drawer Dividers
Make the beautification process very simple by limiting your top drawers to products you utilize several times weekly,or even daily. Cabinet Dividers more simplify the day cosmetic search. And do not leave out the region around the commode: A bin together with the toilet tank or a shelf mounted above it provides more storage.


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We went live with our revamped website on Monday December 7, 2015. And if you're reading this, you're looking at it! The launch completes nearly a year of planning and input from employees, vendors, and customers.
The launch is phase one of two distinct phases. The first phase addresses the need for a fresh design and better alignment with mobile devices, social media, and stakeholders expectations of "friction-free" access to information. The second phase, set for release after the holidays, increases functionality for authorized users to make website edits, approve layouts & proofs, and digitally sign documents. This allows contracted jobs to move forward through pre-press and production at a faster rate with fewer errors.
We invite you to check it out and give us some feedback. Thanks!