text:
What was the brief/ approach for the design of AND?
The Brief was to create an entire new identity for the property, a former nightclub space. There were some key constraints: a moderate budget and a need to address acoustic into the surrounding environment.
AND's design was to challenge consumers' expectations of a nightclub, blurring the lines between venue and large format, interactive art installation. The space was to engage patrons at all time with its tactility, inviting them to touch and play with the built environment. As such, almost every detail in the property is bespoke. When a limited budget is in play, ingenuity and creative use of materials is the order of the day.
Big Rig Diner
How does the design of the venues you've worked on represent the particular brand and appeal to a particular audience?
Complete authorship and a high level of consistency [are important] – from design, product offering, name, identity and marketing.
Each project needs to be relevant to the time and place that we are in, especially economically. For example, when I did De Nom in Sydney (in 18th Century French Salon style), it was pre-GFC, it was ok in people's eyes to be ostentatious with a fit-out so over-the-top and opulent. At the moment, such design could be considered in poor taste.
De Nom
Ruby Rabbit
What makes a successful bar/club/restaurant interior?
An entertainment property must do just that… Entertain. People get enough of real life at home or in their day-to-day lives. A good bar, restaurant or club, must have a sense of wonder and a spirit of adventure to deliver people more than real life.
How does your background/experience give you an edge when working on new venues such as AND?
I never approach an entertainment space as a designer first and consumer second; it's always visa versa. If I work on a concept and then go " I would love to see that" then we go for it, designing backwards from there. My job is to imagine first and then worry about how the hell we make it happen.
Big Rig Diner
Paul Schell


text:
Therefore, brothers and sisters, you must be patient as you wait for the coming of the Lord.
Courageous patience
7 Therefore, brothers and sisters, you must be patient as you wait for the coming of the Lord. Consider the farmer who waits patiently for the coming of rain in the fall and spring, looking forward to the precious fruit of the earth. 8 You also must wait patiently, strengthening your resolve, because the coming of the Lord is near. 9 Don't complain about each other, brothers and sisters, so that you won't be judged. Look! The judge is standing at the door!
10 Brothers and sisters, take the prophets who spoke in the name of the Lord as an example of patient resolve and steadfastness.
BibleZone in Spanish has all you need to capture Spanish-speaking children's imagination and make Bible stories stick! Create a classroom where children encounter God's Word and reflect on how the Bible matters in their life. BibleZone tells the complete Bible story - not just a Bible verse - and helps Hispanic children use their natural enthusiasm with fun, cooperative games, group activities, and storytelling that gets them involved in both the telling and the listening. BibleZone where the Bible comes to life!
Each BibleZone kit includes a teacher's guide with accompanying CD. With each kit comes three transparencies, which you can project onto the wall or duplicate and hand out to the class.
BibleZone covers three age levels: preschool (ages 3-5), early elementary (grades 1-3), and older elementary (grades 4-6). Note: For reasons beyond our control, the zillies previously offered with this program are no longer available. However, the zillies for each lesson are easily accessible and available in stores that sell party supplies (such as Party City, etc.) and in department stores (like WalMart, Target, K - Mart, etc.). They are also available through companies like Oriental Trading Company and others.
For many of the presented activities, if prepared in advance, materials can be substituted for others that are available or you can make them yourself, depending on your budget.
Despite this, we continue to believe that Zona Biblica is one of the best programs for children that can be offered in our churches and that we will continue to bless the lives of many children by helping them personally know our Lord Jesus Christ through this church program.
Need help selecting the appropriate Curriculum Resource?Be sure to check out our Curriculum Finder to help you find the right resources for your group.

subset: commoncrawl


text:
Welcome to the Genes Reunited community boards!
- The Genes Reunited community is made up of millions of people with similar interests. Discover your family history and make life long friends along the way.
- You will find a close knit but welcoming group of keen genealogists all prepared to offer advice and help to new members.
- And it's not all serious business. The boards are often a place to relax and be entertained by all kinds of subjects.
- The Genes community will go out of their way to help you, so don't be shy about asking for help.
Quick Search
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Electoral Rolls
Looking for living relatives?
Search our UK Electoral Rolls (2002-2013) and find your living relatives today.
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Import Gedcom
Profile | Posted by | Options | Post Date |
Eric | Report | 19 Nov 2012 11:32 |
The importation of a gedcom file does not state EMPHATICALLY that any current trees will be lost. |
RolloTheRed | Report | 19 Nov 2012 13:22 |
GRU use Microsoft IIS 7.0. The server, networking, backups and so on are under the control of Bright Solid whose main business is corporate networking services ( not family history). It is usual for IIS servers and SQL database to be backed up regularly so it is likely that backups do exist of the family tree database going back some time. |
Researching: |
Porkie_Pie | Report | 19 Nov 2012 15:20 |
Eric, Sorry to hear you have lost 5 years of research But it is normal for people to backup their own research and not rely on any one source to keep your info safe, You will find that these things happen on other sites and not just GR, |
SparklingAnninGlos | Report | 19 Nov 2012 17:26 |
Have you checked with Phil Moir that all is definitely lost? |
Researching: |
Eric | Report | 20 Nov 2012 16:25 |
Hi |
KenSE | Report | 20 Nov 2012 16:52 |
Look at the first post on the Announcements board page. Click on his name and you will get a Genes email message proforma which you can fill in and send to him. |
Researching: |
Eric | Report | 20 Nov 2012 18:23 |
Thanks again |


text:
Survey of Energy Resources 2007
Crude Oil and Natural Gas Liquids Country Note
Proved recoverable reserves (crude oil and NGLs, million tonnes) |
170 |
Production (crude oil and NGLs, million tonnes, 2005) |
18.4 |
R/P ratio (years) |
9.3 |
Year of first commercial production |
1972 |
Denmark's proved recoverable reserves are the fourth largest in Europe (excluding the Russian Federation). The Danish Energy Authority (DEA) does not employ the terms 'proved' and 'additional' reserves, but uses the categories 'ongoing', 'approved', 'planned' and 'possible' recovery. The figure for proved reserves (203 million m3 or 1 277 million barrels) reported by the DEA to the Danish WEC Member Committee has been calculated as the sum of 'ongoing' and 'approved' reserves, while the figure for additional reserves has been calculated as the sum of 7 million m3 'planned' reserves and 47 million m3 'possible' reserves. The reserve numbers are the expected values in each category.
All the oil fields discovered so far are located in the North Sea. Out of 23 fields or areas with reserves in the ongoing/approved category, four (Dan, Gorm, Halfdan and South Arne) account for 83% of the total volume.
Assuming an average future recovery factor of 24%, the proved amount in place corresponding to the ongoing/approved reserves of 203 million m3 is 846 million m3 (approximately 5.3 billion barrels); beyond these quantities is an estimated additional amount in place of 146 million m3 (918 million barrels), of which 54 million m3 (340 million barrels) is deemed to be recoverable.
The principal fields in production in 2005 were Halfdan, Dan, South Arne, Gorm and Skjold, which together accounted for 80% of national oil output. About three-quarters of Danish crude is exported, chiefly to other countries in Western Europe.


text:
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OpinionMore 'dark money' will influence politics in Michigan if Snyder doesn't veto
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2:41 pm
Wed May 11, 2011
Local joker dressed as Batman arrested in Petoskey
A man dressed up as Batman was arrested in downtown Petoskey today after hanging off the wall of a building, according to the Petoskey News-Review.
The man was spotted while hanging off the wall of a building.
He was arrested and charged with trespassing and possession of dangerous weapons.
From the News-Review:
A 31-year-old Harbor Springs man who, police say, was on the roof of a business in downtown Petoskey, dressed as Batman was arrested early Wednesday morning for trespassing and possession of dangerous weapons, according to a Petoskey Department of Public Safety news release.
Petoskey police received a report of a man on the roof of a business, located in the 400 block of East Mitchell Street, about 12:40 a.m. May 11, today, according to the release. Additional information supplied by central dispatch included the fact that the man was dressed as Batman.
Responding officers, including Michigan State Police troopers, saw "a male subject, dressed in a Batman costume, hanging off the western wall of the building," according to the release. The officers got onto the roof and pulled the man back onto it.
Officers detained the man and located a baton-type striking weapon, a can of chemical irritant spray and a pair of lead lined gloves. The suspect was arrested for trespassing and possession of dangerous weapons.
The man was lodged at the Emmet County Jail and his name is being withheld pending his arraignment, said public safety director John Calabrese.
Calabrese said it is unclear what the man's motivations were. "I think he enjoys doing this," he said.
It's unclear whether the man was trying to recreate this moment from the Adam West Batman television series.


text:
- Products:
- 1-1 of 1
Jiggler Lord BerlueRichard Mens Paisley Collar Shirt
Jiggler Lord Berlue Richard Paisley Collar and Cuffs Mens Shirt
Lord Berlue was an 18th century dandy with an immaculate dress code and extravagant lifestyle. His passion for fine tailoring and flamboyant detailing was the inspiration behind his original designs and is what influences the present day eccentric shirts.
Available in a choice of two colourways, the Richard shirt features all the classic characteristics of the traditional formal shirt with a slight paisley collar and cuff trim. In a tailored silhouette, it includes all your favourite iconic detailing such as long sleeves, a button down collar, a contrast button placket and buttoned cuffs.
This shirt delivers an on trend boost to your collection of formal attire. Wear it with a leather belt, slim fit trousers and brogues for a look that makes an instant impression.
Useful info:
- Mens shirt by Jiggler Lord Berlue
- Richard
- Tailored fit
- Long sleeve
- Paisley collar and cuffs
- Button down collar
- Contrast front button fastening
- Buttoned cuffs
- Available in mid grey or sky
- Weekly Price
- From £0.97 per week
- Price
- £74.00
- Low stock, selling fast
- Availability
- Low stock selling fast
- Products:
- 1-1 of 1


text:
StartUpHire is the place to find UX / Interaction Designer jobs. Review the list of UX / Interaction Designer career opportunities to the left. These UX / Interaction Designer jobs represent some of the most rewarding careers available.
You can refine your job search for UX / Interaction Designer career opportunities by adding a job title, company name, or keyword to the search box above … or click the "Advanced Search" link for more options.
Don't see the employment opportunity you're looking for? Check back soon for more UX / Interaction Designer jobs, or sign up for an email alert (link below) to receive periodic updates on new UX / Interaction Designer jobs.
Job Description: The Product Development team?s UX Interaction Designer plays a key role in creating effective and comprehensive solutions for user interfaces with thoughtful interaction/information architecture and user-centric design: ad creation, programmatic buying, ad
11/9/2013 Boston, MA Save This JobJob Description: The Product Development team?s UX Interaction Designer plays a key role in creating effective and comprehensive solutions for user interfaces with thoughtful interaction/information architecture and user-centric design: ad creation, programmatic buying, ad
11/4/2013 Boston, MA Save This JobJob Description: How innovative are you" Are you a creative UX Designer that has keen attention to detail and creative gumption that sets you apart from everyone else in the industry" PaySimple is seeking a highly motivated, technically-savvy team player to work with our team.
12/2/2013 Denver, CO Save This JobLocation Chandler, AZ Job Description The Interaction Designer is responsible for helping to guide the visual development and user experience for the world leading sales & marketing software for small business. The Interaction Designer should have a thorough understanding of
11/18/2013 Chandler, AZ Save This JobDescription: SpotHero is looking for a solid Interaction Designer to help take our product to the next level. Our ideal candidate has had multiple successful experiences crafting engaging and simple user experiences for both mobile and web. Our products have many UX
10/22/2013 Chicago, IL Save This JobJob Site CountryUS, Canada DescriptionPingIdentity is looking for a Senior Interaction Designer (IXD) to be the lead on our PingOne and CloudDesktop product. Senior User Interaction Designer will work closely with our product marketing and engineering team to design new user
11/28/2013 Denver, CO Save This JobWho you are: Do you cringe at poorly designed software and websites? Have you ever bored friends with prolonged tangents on ?ill-conceived/implemented user interactions? or ?the marriage of form and function?? And do you pride yourself on composing eye-catching visuals? Well, you
11/9/2013 Austin, TX Save This JobWANTED: An amazing Senior UI/UX Visual Designer We?re looking for an amazing Senior UI/UX Visual Designer for a full time position in our sunny San Luis Obispo office (the happiest city in America, according to Oprah). Minimum Qualifications and Requirements You have created
11/2/2013 San Luis Obispo, CA Save This JobXoom Corporation (Nasdaq: XOOM), one of the fastest growing digital money transfer companies in the world, is revolutionizing the international money transfer market by providing people with an easy, convenient and cost-effective means of sending money worldwide. We are looking
11/21/2013 San Francisco, CA Save This JobWANTED: An amazing Senior UI/UX Visual Designer We?re looking for an amazing Senior UI/UX Visual Designer for a full time position in our sunny San Luis Obispo office (the happiest city in America, according to Oprah). Minimum Qualifications and Requirements You have created
10/13/2013 San Luis Obispo, CA Save This JobBoku is the leader in online payments, enabling consumers to buy goods and services with their mobile phone. We're looking for a talented Information Architect to join our team to lead research and design efforts. You will work with product and engineering to develop strategies
11/3/2013 San Francisco, CA Save This JobCompany BitTorrent is the world?s largest peer-based technology company. We?ve created a globally recognized ecosystem of technology protocols, consumer software, and electronics devices that help people find, share and move digital media. Our technologies are used by hundreds
12/3/2013 San Francisco, CA Save This JobPosition Summary: Adaptive Computing is seeking a User Experience Designer/Manager who will be responsible for creating great experiences for two key product lines relating to High Performance Computing (HPC) and Enterprise Private Cloud solutions. You will work collaboratively
11/2/2013 Provo, UT Save This JobJob Type Contract Job Description HRsmart, Inc. is looking for a talented UI/UX Designer to help continuously innovate and revamp products to keep us at the top of the market. We are looking for an outstanding User Interface / Experience Designer to join our Product Management
11/2/2013 Richardson, TX Save This JobAs our Senior Mobile Visual Designer, you will be a key player in ensuring that the Xoom experience is efficient, engaging and intuitive on all mobile screens. You will be part of a team that brings the Xoom experience to life on mobile screens. Responsibilities: Create user
10/22/2013 San Francisco, CA Save This JobAt Hearsay Social our users? experiences are our inspiration, our challenge, and ultimately the mark of our success. Whether we are white boarding, researching, sketching, explaining, chatting, or long-term visioning, our long-term goal is to design world-class software that
11/3/2013 San Francisco, CA Save This JobCornerstone OnDemand (Nasdaq: CSOD) is seeking a UI Designer with a strong technical background to design products that users find essential to their daily life?regardless of whether they use a desktop computer, laptop or other device. You will work closely with Engineers and
11/5/2013 Santa Monica, CA Save This JobDescription UX / Web Designer We are looking for a passionate, self-driven, and experienced senior UI / Web designer that will be responsible for designing for a variety of platforms including smartphones, tablets, and web browsers. UI designer would need to have a strong
10/12/2013 Exton, PA Save This JobArt.com is one of the top 100 internet retailers in the world. We are working on building our next generation website platform and need your help with doing so. Do you have a passion for engaging and visually stunning website features where you can showcase your work to the
10/14/2013 Emeryville, CA Save This JobCatch.com, creator of mobile and web applications, is seeking a talented Visual / Interaction Designer to join our team. We are seeking someone who: - Is a maker and a do-er at heart who can execute quickly. Catch has a culture of iteration, not perfection. - Has experience with
11/10/2013 San Francisco, CA Save This Job


text:
Up the Creek Xpeditions is not responsible for any cancellations or modifications of tours due to weather condition, road hazards, vehicle breakdowns, or other unforeseen conditions that may hinder the ability for the tour to take place as scheduled. We reserve the right to cancel or modify any trip due to circumstances beyond our control. In such cases, we cannot be responsible for paying any expenses you may have incurred other than to refund monies due to you for tour price.
In the event that you must cancel your reservation, you will be charged as follows: If Up The Creek Xpeditions cancels the tour for any reason (weather, etc.), then you will receive a FULL REFUND.


text:
The National Marine Fisheries Service office in Boston is closed through Nov. 23. There will be no landings report until it reopens.
- Community
Gloucester Calendar
Saturday, Dec. 7 Annisquam Sewing Circle Christmas fair, 8:30 a.m. to noon, Annisquam Village Hall. Leonard Street. Lunch at 12:30 p.m. Fresh holiday greens, decorations, handicrafts, costume jewelry, home-baked goods, gourmets, culinaries and family
Continued ... -
Gloucester Goings On
Events listed here are open to the public and sponsored by nonprofit groups unless otherwise noted. Press releases may be sent to Goings on, Gloucester Daily Times, 36 Whittemore St., Gloucester, MA 01930, sent via email to email@example.com or
Continued ... -
Marine Weather
Coastal waters east of Ipswich Bay and the Stellwagen Bank National Marine Sanctuary: Today, northwest winds 10 to 15 knots with gusts up to 20 knots. Seas 2 to 4 feet. Patchy fog. Rain. Visibility 1 to 3 nautical miles. Tonight, northwest winds 15 t
Continued ... - Pet of the Week
- Postpartum help on the North Shore
- Friends & Neighbors
- Today in History
- Friday, December 6, 2013
- Thank You Notes
- Rockport Goings On
- Rockport Calendar
- Manchester Calendar
- Cape Ann Religion Calendar
- Births
Gloucester Calendar


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Bayern Munich's goalkeeper Manuel Neuer attends a training session in Marrakech Stadium December 20, 2013. Bayern Munich could hardly have expected that their opponents in the final of the Club World Cup would be a team of average league players languishing in ninth place in the Moroccan championship. The quirks of the competition, however, mean that is exactly who the European and Bundesliga champions will face when they take on Raja Casablanca in Marrakech on Saturday. REUTERS/Louafi Larbi (MOROCCO - Tags: SPORT SOCCER)
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Section Title
Brand Standards
Communicators' Forum: Events
With Tom Szczepanski, Senior Executive Director, Marketing & Annual Giving, Office of University Development
October 24 • 8–10 a.m. • Blau Auditorium, Ross School of Business
Register now at: http://www.doodle.com/82rexcsfuuamwx89
Specialty Forum Sub-group Signup
Session details
In November, the "Victors for Michigan" campaign begins. Get ready for the big kickoff at the October Communicators' Forum, as Tom Szczepanski and his OUD colleagues share a behind-the-scenes look at the creation of marketing elements for "Victors for Michigan."
The presentation will cover the marketing and communications plan, as well as feature new details and insights that will help ensure the University delivers a unified campaign message to its various constituents.
We'll also be unveiling some format changes for Communicators' Forum this year, including the introduction of "subject-specific" meetings on a wide range of topics, including video, digital, writing, and more. Details to come.
Morning refreshments will be served from 8–8:30 a.m. We hope to see you there!
Presentations from past events
Did you miss an event? We've got you covered. You can now download a PDF of any of this year's presentations. We've also included contact names for fellow communicators, which we hope you'll take advantage of to connect with and tap into the vast and deep expertise that exists on our campus.
- May. 2013 - United We Brand (PDF, 13.5 MB)
- Feb. 2013 – History and Heritage (PDF, 151 MB)
- Nov. 2012 – Managing the News (PDF, 19 MB)
- Oct. 2012 – Making Research Relevant (PDF, 23 MB)
- Sept. 2012 – Looking Back Looking Ahead (PDF, 17 MB)


text: aboutshopideaslocalbloghelp my accountcart Fruit of the Vine in Lace BamHuey from New Hue Handspuns Home » Shop » Knit & Crochet » Yarn » New Hue Handspuns » Lace BamHuey » Fruit of the Vine $66.00 http://www.theloopyewe.com/asset/catalog-entry-photo/8d8b74b4-9d67-7740-0717-a50749a969c5~v2-600x600.jpg Fruit of the Vine in Lace BamHuey from New Hue Handspuns http://www.theloopyewe.com/shop/p/57A39B11-Lace-BamHuey-Fruit-of-the-Vine?ref=amazon-universal-wishlist In Stock for $66.00 Quantity Add to Cart Add to Wishlist Material 40% Bamboo 60% Merino Wool Weight Laceweight Physical Weight 3.0 oz / 85 g Yardage 400 yd / 365.8 m Care Hand wash cold and lay flat to dry. Tweet Pin it Share Handpainted and then handspun by Cheryl Newhouse from Oregon, this is truly a luxury laceweight. Perfect for special shawls, scarves, cowls and more. Discover the pleasure of knitting with handspun. We currently have 3 skeins in stock and available — we first started selling this in May 2012. More To See Lace BamHuey Customer Photos Inspiration from others. Suggestions Patterns and similar items. Products


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Amy feels threatened when Sheldon (Jim Parsons, right) hires a young female assistant (Margo Harshman, left), on The Big Bang Theory, Thursdays at 8/7c. Photo: Monty Brinton/CBS ©2012 CBS Broadcasting, Inc. All Rights Reserved.


text:
Acute lymphoblastic leukemia (ALL) is a fast-growing type of leukemia in which too many immature white blood cells are found in the blood and bone marrow. Learn about acute lymphoblastic leukemia and find information on how we support and care for people with ALL before, during, and after treatment.
The Hematologic Oncology Center provides specialized care for all types of cancers of the blood, including leukemia, lymphoma, multiple myeloma and Waldenström's macroglobulinemia.
The center also includes the hematopoietic stem cell transplantation program, which is one of the largest and most experienced in the world.
To make sure your care is as seamless as possible, a dedicated team of clinicians, who are highly specialized experts in your type of blood cancer, will care for you throughout the treatment process, from diagnosis though long-term follow-up.
Your care team will include oncologists, surgeons, hematologists, physician assistants, nurses, and clinical social workers who are committed to delivering safe, high-quality patient care.
We develop personalized, comprehensive treatment plans for all our patients, offering the latest therapies and supportive resources and taking your individual needs into account.
In addition to conventional treatment approaches, you may have the opportunity to participate in clinical trials that offer access to new, innovative treatments for your type of cancer.
A variety of services and programs also support your care, including nutrition services, emotional support and counseling, pain management, donor services for stem cell transplantation, and support for cancer survivors.
Learn more about treatment and care in the Hematologic Oncology Center
Contact us
New patients: See Center page for phone numbers by treatment program
All other inquiries: 617-632-6140
Fax: 617-632-3730
Adult acute lymphoblastic leukemia (ALL; also called acute lymphocytic leukemia) is a cancer of the blood and bone marrow. This type of cancer usually gets worse quickly if it is not treated.
Normally, the bone marrow makes blood stem cells (immature cells) that develop into mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.
The myeloid stem cell develops into one of three types of mature blood cells:
The lymphoid stem cell develops into a lymphoblast cell and then into one of three types of lymphocytes (white blood cells):
In ALL, too many stem cells develop into lymphoblasts or lymphocytes. These cells may also be called leukemic cells. These leukemic cells are not able to fight infection very well. Also, as the number of leukemic cells increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding. The cancer can also spread to the central nervous system (brain and spinal cord).
This summary is about adult acute lymphoblastic leukemia. See the following PDQ summaries for information on other types of leukemia:
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. People who think they may be at risk should discuss this with their doctor. Possible risk factors for ALL include the following:
The early signs of ALL may be similar to the flu or other common diseases. A doctor should be consulted if any of the following problems occur:
These and other symptoms may be caused by adult acute lymphoblastic leukemia or by other conditions.
The following tests and procedures may be used:
The prognosis (chance of recovery) and treatment options depend on the following:
The extent or spread of cancer is usually described as stages. It is important to know whether the leukemia has spread outside the blood and bone marrow in order to plan treatment. The following tests and procedures may be used to determine if the leukemia has spread:
When cancer cells spread outside the blood, a solid tumor may form. This process is called metastasis. The three ways that cancer cells spread in the body are:
The new (metastatic) tumor is the same type of cancer as the primary cancer. For example, if leukemia cells spread to the brain, the cancer cells in the brain are actually leukemia cells. The disease is metastatic leukemia, not brain cancer.
The disease is classified as untreated, in remission, or recurrent.
Untreated adult ALL
The ALL is newly diagnosed and has not been treated except to relieve symptoms such as fever, bleeding, or pain.
Adult ALL in remission
The ALL has been treated.
Recurrent adult acute lymphoblastic leukemia (ALL) is cancer that has recurred (come back) after going into remission. The ALL may come back in the blood, bone marrow, or other parts of the body.
Different types of treatment are available for patients with adult acute lymphoblastic leukemia (ALL). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
The treatment of adult ALL is done in phases:
Treatment called central nervous system (CNS) sanctuary therapy is usually given during each phase of therapy. Because chemotherapy that is given by mouth or injected into a vein may not reach leukemia cells in the CNS (brain and spinal cord), the cells are able to find "sanctuary" (hide) in the CNS. Intrathecal chemotherapy and radiation therapy are able to reach leukemia cells in the CNS and are given to kill the leukemia cells and prevent the cancer from recurring (coming back). CNS sanctuary therapy is also called CNS prophylaxis.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column (intrathecal chemotherapy), an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Combination chemotherapy is treatment using more than one anticancer drug. The way the chemotherapy is given depends on the type and stage of the cancer being treated.
Intrathecal chemotherapy may be used to treat adult ALL that has spread, or may spread, to the brain and spinal cord. When used to prevent cancer from spreading to the brain and spinal cord, it is called central nervous system (CNS) sanctuary therapy or CNS prophylaxis. Intrathecal chemotherapy is given in addition to chemotherapy by mouth or vein.
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. External radiation therapy may be used to treat adult ALL that has spread, or may spread, to the brain and spinal cord. When used this way, it is called central nervous system (CNS) sanctuary therapy or CNS prophylaxis.
Stem cell transplant is a method of giving chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells.
Targeted therapy drugs called tyrosine kinase inhibitors are used to treat some types of adult ALL. These drugs block the enzyme, tyrosine kinase, that causes stem cells to develop into more white blood cells (blasts) than the body needs. Two of the drugs used are imatinib mesylate (Gleevec) and dasatinib.
This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.
Biologic therapy is a treatment that uses the patient's immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body's natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's clinical trials database.
Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.
A link to a list of current clinical trials is included for each treatment section. For some types or stages of cancer, there may not be any trials listed. Check with your doctor for clinical trials that are not listed here but may be right for you.
Standard treatment of adult acute lymphoblastic leukemia (ALL) during the remission induction phase includes the following:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with untreated adult acute lymphoblastic leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.
Standard treatment of adult ALL during the post-remission phase includes the following:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with adult acute lymphoblastic leukemia in remission. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.
Standard treatment of recurrent adult ALL may include the following:
Some of the treatments being studied in clinical trials for recurrent adult ALL include the following:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent adult acute lymphoblastic leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.
For more information from the National Cancer Institute about adult acute lymphoblastic leukemia, see the following:
For general cancer information and other resources from the National Cancer Institute, see the following:
This information is provided by the National Cancer Institute.
This information was last updated on September 10, 2009.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult acute lymphoblastic leukemia. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.
Note: Estimated new cases and deaths from acute lymphoblastic leukemia (ALL; also called acute lymphocytic leukemia) in the United States in 2009: [1]
Sixty percent to 80% of adults with ALL can be expected to attain complete remission status following appropriate induction therapy. Approximately 35% to 40% of adults with ALL can be expected to survive 2 years with aggressive induction combination chemotherapy and effective supportive care during induction therapy (appropriate early treatment of infection, hyperuricemia, and bleeding). A few studies, including a Cancer and Leukemia Group B study (CLB-8811), that use intensive multiagent approaches suggest that a 50% 3-year survival is achievable in selected patients, but these results must be verified by other investigators.[2][3][4][5]
As in childhood ALL, adult patients with ALL are at risk of developing central nervous system (CNS) involvement during the course of their disease. This is particularly true for patients with L3 histology.[6] Both treatment and prognosis are influenced by this complication. The examination of bone marrow aspirates and/or biopsy specimens should be done by an experienced oncologist, hematologist, hematopathologist, or general pathologist who is capable of interpreting conventional and specially stained specimens. Diagnostic confusion with acute myelocytic leukemia (AML), hairy-cell leukemia, and malignant lymphoma is not uncommon. Proper diagnosis is crucial because of the difference in prognosis and treatment of ALL and AML. Immunophenotypic analysis is essential because leukemias that do not express myeloperoxidase include M0 and M7 AML as well as ALL.
Appropriate initial treatment, usually consisting of a regimen that includes the combination of vincristine, prednisone, and anthracycline, with or without asparaginase, results in a complete remission rate of up to 80%. Median remission duration for the complete responders is approximately 15 months. Entry into a clinical trial is highly desirable to assure adequate patient treatment and also maximal information retrieval from the treatment of this highly responsive, but usually fatal, disease. Patients who experience a relapse after remission can be expected to succumb within 1 year, even if a second complete remission is achieved. If there are appropriate available donors and if the patient is younger than 55 years of age, bone marrow transplantation may be a consideration in the management of this disease.[7] Transplant centers performing five or fewer transplants annually usually have poorer results than larger centers.[8] If allogeneic transplant is considered, transfusions with blood products from a potential donor should be avoided if possible.[5][9][10][11][12][13][14]
Patients with L3 morphology have improved outcomes, as evidenced in a Cancer and Leukemia Group B study (CLB-9251), when treated according to specific treatment algorithms.[15][16] Age, which is a significant factor in childhood ALL and in AML, may also be an important prognostic factor in adult ALL. In one study, overall the prognosis was better in patients younger than 25 years; another study found a better prognosis in those younger than 35 years. These findings may, in part, be related to the increased incidence of the Philadelphia chromosome (Ph1) in older ALL patients, a subgroup associated with poor prognosis.[2][3] Elevated B2-microglobulin is associated with a poor prognosis in adults as evidenced by lower response rate, increased incidence of CNS involvement, and significantly worse survival.[17] Patients with Ph1-positive ALL are rarely cured with chemotherapy. Many patients who have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph1 , have no evidence of the abnormal chromosome by cytogenetics. Because many patients have a different fusion protein from the one found in chronic myelogenous leukemia (p190 vs. p210), the bcr-abl fusion gene may be detectable only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase chain reaction (RT-PCR). These tests should be performed whenever possible in patients with ALL, especially those with B-cell lineage disease. Two other chromosomal abnormalities with poor prognoses are t(4;11), which is characterized by rearrangements of the MLL gene and may be rearranged despite normal cytogenetics, and t(9;22). In addition to t(9;22) and t(4;11), patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years compared to patients with a normal karyotype.[18] L3 ALL is associated with a variety of translocations that involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus: t(2;8), t(8;12), and t(8;22).
Long-term follow-up of 30 patients with ALL in remission for at least 10 years has demonstrated 10 cases of secondary malignancies. Of 31 long-term female survivors of ALL or acute myeloid leukemia under 40 years of age, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.[19]
American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
Gaynor J, Chapman D, Little C, et al.: A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. J Clin Oncol 6 (6): 1014-30, 1988.
Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988.
Zhang MJ, Hoelzer D, Horowitz MM, et al.: Long-term follow-up of adults with acute lymphoblastic leukemia in first remission treated with chemotherapy or bone marrow transplantation. The Acute Lymphoblastic Leukemia Working Committee. Ann Intern Med 123 (6): 428-31, 1995.
Larson RA, Dodge RK, Burns CP, et al.: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 85 (8): 2025-37, 1995.
Kantarjian HM, Walters RS, Smith TL, et al.: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72 (5): 1784-9, 1988.
Bortin MM, Horowitz MM, Gale RP, et al.: Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s. JAMA 268 (5): 607-12, 1992.
Horowitz MM, Przepiorka D, Champlin RE, et al.: Should HLA-identical sibling bone marrow transplants for leukemia be restricted to large centers? Blood 79 (10): 2771-4, 1992.
Linker CA, Levitt LJ, O'Donnell M, et al.: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78 (11): 2814-22, 1991.
Barrett AJ, Horowitz MM, Gale RP, et al.: Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 74 (2): 862-71, 1989.
Dinsmore R, Kirkpatrick D, Flomenberg N, et al.: Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia. Blood 62 (2): 381-8, 1983.
Jacobs AD, Gale RP: Recent advances in the biology and treatment of acute lymphoblastic leukemia in adults. N Engl J Med 311 (19): 1219-31, 1984.
Doney K, Buckner CD, Kopecky KJ, et al.: Marrow transplantation for patients with acute lymphoblastic leukemia in first marrow remission. Bone Marrow Transplant 2 (4): 355-63, 1987.
Vernant JP, Marit G, Maraninchi D, et al.: Allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia in first complete remission. J Clin Oncol 6 (2): 227-31, 1988.
Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001.
Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996.
Kantarjian HM, Smith T, Estey E, et al.: Prognostic significance of elevated serum beta 2-microglobulin levels in adult acute lymphocytic leukemia. Am J Med 93 (6): 599-604, 1992.
Wetzler M, Dodge RK, Mrózek K, et al.: Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 93 (11): 3983-93, 1999.
Micallef IN, Rohatiner AZ, Carter M, et al.: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haematol 113 (2): 443-5, 2001.
Leukemic cell characteristics including morphological features, cytochemistry, immunologic cell surface and biochemical markers, and cytogenetic characteristics are important. In adults, FAB L1 morphology (more mature appearing lymphoblasts) is present in fewer than 50% of patients and L2 histology (more immature and pleomorphic) predominates.[1] Chromosomal abnormalities including aneuploidy and translocations have been described and may correlate with prognosis.[2] In particular, patients with Philadelphia chromosome (Ph1)-positive t(9;22) acute lymphoblastic leukemia (ALL) have a poor prognosis and represent more than 30% of adult cases. The bcr-abl fusion gene resulting from the breakpoint in the Ph1 may, on occasion, be detectable only by pulse-field gel electrophoresis or reverse-transcriptase polymerase chain reaction. Bcr-abl-rearranged leukemias that do not demonstrate the classical Ph1 carry a poor prognosis that is similar to those that are Ph1-positive.
Using heteroantisera and monoclonal antibodies, ALL cells can be divided into early B-cell lineage (80% approximate frequency), T cells (10%–15% approximate frequency), B cells (with surface immunoglobulins), (<5% approximate frequency), and CALLA+ (common ALL antigen), 50% approximate frequency.[1][3][4][5]
About 95% of all types of ALL except B cell, which usually has an L3 morphology by the FAB classification, have elevated terminal deoxynucleotidyl transferase (TdT) expression. This elevation is extremely useful in diagnosis; if concentrations of the enzyme are not elevated, the diagnosis of ALL is suspect. However, 20% of cases of acute myeloid leukemia (AML) may express TdT; therefore, its usefulness as a lineage marker is limited. Because B-cell leukemias are treated according to different algorithms, it is important to specifically identify these cases prospectively by their L3 morphology, absence of TdT, and expression of surface immunoglobulin. These patients will typically have one of three chromosomal translocations: t(8;14), t(2;8), or t(8;22).
Brearley RL, Johnson SA, Lister TA: Acute lymphoblastic leukaemia in adults: clinicopathological correlations with the French-American-British (FAB) co-operative group classification. Eur J Cancer 15 (6): 909-14, 1979.
Chromosomal abnormalities and their clinical significance in acute lymphoblastic leukemia. Third International Workshop on Chromosomes in Leukemia. Cancer Res 43 (2): 868-73, 1983.
Sobol RE, Royston I, LeBien TW, et al.: Adult acute lymphoblastic leukemia phenotypes defined by monoclonal antibodies. Blood 65 (3): 730-5, 1985.
Foon KA, Billing RJ, Terasaki PI, et al.: Immunologic classification of acute lymphoblastic leukemia. Implications for normal lymphoid differentiation. Blood 56 (6): 1120-6, 1980.
There is no clear-cut staging system for this disease.
For a newly diagnosed patient with no prior treatment, untreated adult acute lymphoblastic leukemia (ALL) is defined as an abnormal white blood cell count and differential, abnormal hematocrit/hemoglobin and platelet counts, abnormal bone marrow with more than 5% blasts, and signs and symptoms of the disease.
In remission
A patient who has received remission-induction treatment of ALL is in remission if the bone marrow is normocellular with 5% or less blasts, there are no signs or symptoms of the disease, no signs or symptoms of central nervous system leukemia or other extramedullary infiltration, and all of the following laboratory values are within normal limits: white blood cell count and differential, hematocrit/hemoglobin level, and platelet count.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Successful treatment of acute lymphoblastic leukemia (ALL) consists of the control of bone marrow and systemic disease as well as the treatment (or prevention) of sanctuary-site disease, particularly the central nervous system (CNS).[1][2] The cornerstone of this strategy includes systemically administered combination chemotherapy with CNS preventive therapy. CNS prophylaxis is achieved with chemotherapy (intrathecal and/or high-dose systemic) and, in some cases, cranial radiation therapy.
Treatment is divided into three phases: remission induction, CNS prophylaxis, and remission continuation or maintenance. The average length of treatment of ALL varies between 1.5 and 3 years in the effort to eradicate the leukemic cell population. Younger adults with ALL may be eligible for selected clinical trials for childhood ALL.
It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is morphologically indistinguishable from the Philadelphia chromosome (Ph1).[3] The Ph1 occurs in only 1% to 2% of patients with acute myelocytic leukemia, but it occurs in about 20% of adults and a small percentage of children with ALL.[4] In the majority of children and in more than one half of adults with Ph1-positive ALL, the molecular abnormality is different from that in Ph1-positive chronic myelogenous leukemia (CML).
Ph1-positive ALL has a worse prognosis than most other types of ALL, though many children and some adults with Ph1-positive ALL may have complete remissions following intensive ALL treatment clinical trials. Imatinib mesylate, an orally available inhibitor of the BCR-ABL tyrosine kinase, has been shown to have clinical activity as a single agent in this disease.[5][6][Level of evidence: 3iiiDiv] In one study, 10 patients with Ph1-positive ALL and 10 patients with CML lymphoid blast crisis were treated with doses of imatinib ranging from 300 mg to 1000 mg per day.[5] Of these 20 patients, 4 had complete hematologic remission and 10 had marrow responses. Responses were short lived, with the majority of these patients relapsing at a median of 58 days after the start of therapy. In another study, 48 patients with Ph1-positive ALL were treated with 400 mg to 800 mg of imatinib per day.[6] The overall response rate was 60%, with 9 out of 48 patients (19%) achieving a complete remission. The responses again were short, with a median duration of 2.2 months. While there are no randomized clinical trials comparing chemotherapy with or without imatinib for this disease, because of the responses observed in monotherapy trials, imatinib is generally incorporated into the treatment of patients with Ph1-positive ALL. If a suitable donor is available, allogeneic bone marrow transplantation should be considered because remissions are generally short with conventional ALL chemotherapy clinical trials. Many patients who have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph1, have no evidence of the abnormal chromosome by cytogenetics. Because many patients have a different fusion protein from the one found in CML (p190 vs. p210), the bcr-abl fusion gene may be detectable only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase chain reaction (RT-PCR). These tests should be performed whenever possible in patients with ALL, especially those with B-cell lineage disease. Two other chromosomal abnormalities with poor prognosis are t(4;11), which is characterized by rearrangements of the MLL gene and may be rearranged despite normal cytogenetics, and t(9;22). In addition to t(9;22) and t(4;11), patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years compared to patients with a normal karyotype. In multivariate analysis, karyotype was the most important predictor of disease-free survival.[7][Level of evidence: 3iiDii] L3 ALL is associated with a variety of translocations which involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus (t(2;8), t(8;12), and t(8;22)). Unlike bcr-abl-positive ALL and t(4;11) ALL, there is some evidence such as was found in a Cancer and Leukemia Group B study (CLB-9251) that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens.[8][9][10]
Clarkson BD, Gee T, Arlin ZA, et al.: Current status of treatment of acute leukemia in adults: an overview of the Memorial experience and review of literature. Crit Rev Oncol Hematol 4 (3): 221-48, 1986.
Hoelzer D, Gale RP: Acute lymphoblastic leukemia in adults: recent progress, future directions. Semin Hematol 24 (1): 27-39, 1987.
Peterson LC, Bloomfield CD, Brunning RD: Blast crisis as an initial or terminal manifestation of chronic myeloid leukemia: a study of 28 patients. Am J Med 60(2): 209-220, 1976.
Secker-Walker LM, Cooke HM, Browett PJ, et al.: Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. Blood 72 (2): 784-91, 1988.
Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344 (14): 1038-42, 2001.
Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71, 2002.
Fenaux P, Lai JL, Miaux O, et al.: Burkitt cell acute leukaemia (L3 ALL) in adults: a report of 18 cases. Br J Haematol 71 (3): 371-6, 1989.
Reiter A, Schrappe M, Ludwig WD, et al.: Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group. Blood 80 (10): 2471-8, 1992.
Standard treatment options for remission induction therapy:
Most current induction regimens for patients with adult acute lymphoblastic leukemia (ALL) include prednisone, vincristine, and an anthracycline. Some regimens, including a Cancer and Leukemia Group B study (CLB-8811), also add other drugs, such as asparaginase or cyclophosphamide. Current multiagent induction regimens result in complete response rates that range from 60% to 90%.[1][2][3]
Imatinib mesylate is often incorporated into the therapeutic plan for patients with Ph1-positive ALL. Several studies have suggested that the addition of imatinib results in complete response rates, event-free survival rates, and overall survival rates that are higher than those in historical controls. In each of these studies, common toxicities were nausea and liver enzyme abnormalities necessitating interruption and/or dose reduction of imatinib. (For more information on nausea, refer to the PDQ summary on Nausea and Vomiting.) Subsequent allogeneic transplant does not appear to be adversely affected by the addition of imatinib to the treatment regimen. At the present time, no conclusions can be drawn from these studies regarding which imatinib dose or schedule should be used.[4][5][6]
Two additional subtypes of adult ALL require special consideration. B-cell ALL [which expresses surface immunoglobulin and cytogenetic abnormalities such as t(8;14), t(2;8), and t(8;22)] is not usually cured with typical ALL regimens. Aggressive brief duration high-intensity regimens (such as CLB-9251) similar to those used in aggressive non-Hodgkin lymphoma have shown high response rates and cure rates (75% complete remission; 40% failure-free survival).[7][8] T-cell ALL, including lymphoblastic lymphoma, similarly has shown high cure rates when treated with cyclophosphamide-containing regimens.[3] Whenever possible, such patients should be entered in clinical trials designed to improve the outcomes in these subsets. (Refer to the B cell (Burkitt) lymphoma and T cell (lymphoblastic) lymphoma sections in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during remission induction treatment. Facilities must be available for hematological support as well as for the treatment of infectious complications.
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate.[9][10] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than 20,000/mm3.[11] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[12] Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[13][14] Careful instruction in personal hygiene, dental care, and recognition of early signs of infection are appropriate in all patients. Elaborate isolation facilities, including filtered air, sterile food, and gut flora sterilization are not routinely indicated but may benefit transplant patients.[15][16] Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that are not responding to antibiotics.[17] Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 weeks), though further studies are necessary.[18] To detect the presence or acquisition of resistant organisms, serial surveillance cultures may be helpful in such patients. As suggested in a Cancer and Leukemia Group B study (CLB-9111), the use of myeloid growth factors during remission induction therapy appears to decrease the time to hematopoietic reconstitution.[19][20]
Treatment options for remission induction therapy under clinical evaluation:
Standard treatment options for central nervous system (CNS) prophylaxis:
The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with untreated adult acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004.
Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006.
Wassmann B, Pfeifer H, Goekbuget N, et al.: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 108 (5): 1469-77, 2006.
Slichter SJ: Controversies in platelet transfusion therapy. Annu Rev Med 31: 509-40, 1980.
Murphy MF, Metcalfe P, Thomas H, et al.: Use of leucocyte-poor blood components and HLA-matched-platelet donors to prevent HLA alloimmunization. Br J Haematol 62 (3): 529-34, 1986.
Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. N Engl J Med 337 (26): 1870-5, 1997.
Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997.
Hughes WT, Armstrong D, Bodey GP, et al.: From the Infectious Diseases Society of America. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 161 (3): 381-96, 1990.
Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 6 (2): 167-84, 1988.
Armstrong D: Symposium on infectious complications of neoplastic disease (Part II). Protected environments are discomforting and expensive and do not offer meaningful protection. Am J Med 76 (4): 685-9, 1984.
Sherertz RJ, Belani A, Kramer BS, et al.: Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. Am J Med 83 (4): 709-18, 1987.
Schiffer CA: Granulocyte transfusions: an overlooked therapeutic modality. Transfus Med Rev 4 (1): 2-7, 1990.
Wade JC, Schimpff SC, Hargadon MT, et al.: A comparison of trimethoprim-sulfamethoxazole plus nystatin with gentamicin plus nystatin in the prevention of infections in acute leukemia. N Engl J Med 304 (18): 1057-62, 1981.
Scherrer R, Geissler K, Kyrle PA, et al.: Granulocyte colony-stimulating factor (G-CSF) as an adjunct to induction chemotherapy of adult acute lymphoblastic leukemia (ALL). Ann Hematol 66 (6): 283-9, 1993.
Larson RA, Dodge RK, Linker CA, et al.: A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 92 (5): 1556-64, 1998.
Current approaches to postremission therapy for adult acute lymphoblastic leukemia (ALL) include short-term, relatively intensive chemotherapy followed by longer-term therapy at lower doses (maintenance), high-dose marrow-ablative chemotherapy or chemoradiation therapy with allogeneic stem cell rescue (alloBMT), and high-dose therapy with autologous stem cell rescue (autoBMT). Several trials, including a Cancer and Leukemia Group B study (CLB-8811), of aggressive postremission chemotherapy for adult ALL now confirm a long-term disease-free survival rate of approximately 40%.[1][2][3][4][5] In the latter two series, especially good prognoses were found for patients with T-cell lineage ALL, with disease-free survival rates of 50% to 70% for patients receiving postremission therapy. These series represent a significant improvement in disease-free survival rates over previous, less intensive chemotherapeutic approaches. In contrast, poor cure rates were demonstrated in patients with Philadelphia chromosome (Ph1)-positive ALL, B-cell lineage ALL with an L3 phenotype (surface immunoglobulin positive), and B-cell lineage ALL characterized by t(4;11). Administration of the newer dose-intensive schedules can be difficult and should be performed by physicians experienced in these regimens at centers equipped to deal with potential complications. Studies in which continuation or maintenance chemotherapy were eliminated had outcomes inferior to those with extended treatment durations.[6][7] Imatinib has been incorporated into maintenance regimens in patients with Ph1-postive ALL.[8][9][10]
AlloBMT results in the lowest incidence of leukemic relapse, even when compared with a bone marrow transplant from an identical twin (syngeneic BMT). This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD). The improvement in disease-free survival in patients undergoing alloBMT as primary postremission therapy is offset, in part, by the increased morbidity and mortality from GVHD, veno-occlusive disease of the liver, and interstitial pneumonitis.[11]
The results of a series of retrospective and prospective studies published between 1987 and 1994 suggest that alloBMT or autoBMT as postremission therapy offer no survival advantage over intensive chemotherapy, except perhaps for patients with high risk or Ph1 positive ALL.[12][13][14][15] The use of alloBMT as primary postremission therapy is limited by both the need for an HLA-matched sibling donor and the increased mortality from alloBMT in patients in their fifth or sixth decades. The mortality from alloBMT using an HLA-matched sibling donor in these studies ranged from 20% to 40%.
Following on the results of these earlier studies, the International ALL Trial (ECOG-2993) was launched as an attempt to examine the role of transplant as postremission therapy for ALL more definitively and accrued patients from 1993 to 2006.[16] Patients with Ph1 negative ALL between the ages of 15 to 59 received identical multiagent induction therapy resembling previously published regimens.[1][2][3] Patients in remission were then eligible for HLA typing; patients with a fully matched sibling donor underwent alloBMT as consolidation. Those patients lacking a donor were randomly assigned to receive either an autoBMT or maintenance chemotherapy. The primary outcome measured was overall survival (OS), with event-free survival, relapse rate, and nonrelapse mortality as secondary endpoints. A total of 1,929 patients were registered and stratified according to age, white blood cell count, and time-to-remission. High-risk patients were defined as those having a high white blood cell count at presentation or those older than age 35. Ninety percent of patients in this study achieved remission after induction therapy. Of these patients, 443 were found to have an HLA-identical sibling, 310 of whom underwent alloBMT. For the 456 patients in remission who were eligible for transplant but lacked a donor, 227 received chemotherapy alone, while 229 underwent an autoBMT. By donor-to-no-donor analysis, standard risk ALL patients with an HLA-identical sibling had a 5-year OS of 53% compared with 45% for patients lacking a donor (P = .01). In subgroup analysis, the advantage for patients with donors remained significant for patients with standard risk ALL (OS = 62% vs. 52%; P = .02). For patients with high-risk disease (age older than 35 or high white blood cell count), the difference in OS was 41% versus 35% (donor vs. no donor), but was not significant (P = .2). Relapse rates were significantly lower (P < .00005) for both standard and high-risk patients with HLA-matched donors. In contrast to alloBMT, autoBMT was less effective than maintenance chemotherapy as postremission treatment (5-year OS = 46% for chemotherapy vs. 37% for autoBMT; P = .03). The results of this trial seem to confirm the existence of a graft versus leukemia effect for adult Ph1 negative ALL and support the use of sibling donor alloBMT as the consolidation therapy providing the greatest chance for long term survival for standard risk adult ALL in first remission.[16][Level of evidence: 2A] The results also suggest that in the absence of a sibling donor, maintenance chemotherapy is preferable to autoBMT as postremission therapy.[16][Level of evidence: 2A]
The use of alloBMT as primary postremission therapy is limited both by the need for an HLA-matched sibling donor and by the increased mortality from alloBMT in patients in their fifth or sixth decade. The mortality from alloBMT using an HLA-matched sibling donor ranges from 20% to 40%, depending on the study. The use of matched unrelated donors for alloBMT is currently under evaluation but, because of its current high treatment-related morbidity and mortality, is reserved for patients in second remission or beyond. The dose of total body radiation therapy administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival.[17][Level of evidence: 3iiB]
Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin lymphoma have shown improved outcome of prolonged disease-free status for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive).[18] Retrospectively reviewing three sequential cooperative group trials from Germany, Hoelzer and colleagues found a marked improvement in survival, from zero survivors in a 1981 study that used standard pediatric therapy and lasted 2.5 years, to a 50% survival rate in two subsequent trials that used rapidly alternating lymphoma-like chemotherapy and were completed within 6 months. Aggressive CNS prophylaxis remains a prominent component of treatment. This report, which requires confirmation in other cooperative group settings, is encouraging for patients with L3 ALL. Patients with surface immunoglobulin but L1 or L2 morphology did not benefit from this regimen. Similarly, patients with L3 morphology and immunophenotype but unusual cytogenetic features were not cured with this approach. A white blood cell count of less than 50,000 per microliter predicted improved leukemia-free survival in univariate analysis. Because the optimal postremission therapy for patients with ALL is still unclear, participation in clinical trials should be considered. (Refer to the B-cell (Burkitt) lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease. Some authors have suggested that there is a subgroup of patients at low-risk for CNS relapse for whom CNS prophylaxis may not be necessary. However, this concept has not been tested prospectively.[19]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with adult acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Cuttner J, Mick R, Budman DR, et al.: Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study. Leukemia 5 (5): 425-31, 1991.
Dekker AW, van't Veer MB, Sizoo W, et al.: Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group. J Clin Oncol 15 (2): 476-82, 1997.
Finiewicz KJ, Larson RA: Dose-intensive therapy for adult acute lymphoblastic leukemia. Semin Oncol 26 (1): 6-20, 1999.
Horowitz MM, Messerer D, Hoelzer D, et al.: Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission. Ann Intern Med 115 (1): 13-8, 1991.
Sebban C, Lepage E, Vernant JP, et al.: Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol 12 (12): 2580-7, 1994.
Forman SJ, O'Donnell MR, Nademanee AP, et al.: Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 70 (2): 587-8, 1987.
Fière D, Lepage E, Sebban C, et al.: Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin Oncol 11 (10): 1990-2001, 1993.
Goldstone AH, Richards SM, Lazarus HM, et al.: In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 111 (4): 1827-33, 2008.
Corvò R, Paoli G, Barra S, et al.: Total body irradiation correlates with chronic graft versus host disease and affects prognosis of patients with acute lymphoblastic leukemia receiving an HLA identical allogeneic bone marrow transplant. Int J Radiat Oncol Biol Phys 43 (3): 497-503, 1999.
Patients with acute lymphoblastic leukemia (ALL) who experience a relapse following chemotherapy and maintenance therapy are unlikely to be cured by further chemotherapy alone. These patients should be considered for reinduction chemotherapy followed by allogeneic bone marrow transplantation. Patients for whom an HLA-matched donor is not available are excellent candidates for enrollment in clinical trials that are studying autologous transplantation, immunomodulation, and novel chemotherapeutic or biological agents.[1][2][3][4][5][6][7] Low-dose palliative radiation therapy may be considered in patients with symptomatic recurrence either within or outside the central nervous system.[8]
Patients with Ph1-positive ALL will often be taking imatinib at the time of relapse and thus will have imatinib-resistant disease. Dasatinib, a novel tyrosine kinase inhibitor with efficacy against several different imatinib-resistant BCR/ABL mutants, has been approved for use in Ph1-positive ALL patients who are resistant to or intolerant of imatinib. The approval was based on a series of trials involving patients with chronic myelogenous leuekmia, one of which included small numbers of patients with lymphoid blast crisis or Ph1-positive ALL. In one study, 10 such patients were treated with dasatinib in a dose escalation study.[9] Seven of these patients had a complete hematologic response (<5% marrow blasts with normal peripheral blood counts), three of whom had a complete cytogenetic response. The common toxicities were reversible myelosuppression (89%) and pleural effusions (21%). Virtually all of these patients relapsed within 6 months of the start of treatment with dasatinib.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent adult acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Herzig RH, Bortin MM, Barrett AJ, et al.: Bone-marrow transplantation in high-risk acute lymphoblastic leukaemia in first and second remission. Lancet 1 (8536): 786-9, 1987.
Thomas ED, Sanders JE, Flournoy N, et al.: Marrow transplantation for patients with acute lymphoblastic leukemia: a long-term follow-up. Blood 62 (5): 1139-41, 1983.
Sallan SE, Niemeyer CM, Billett AL, et al.: Autologous bone marrow transplantation for acute lymphoblastic leukemia. J Clin Oncol 7 (11): 1594-601, 1989.
Paciucci PA, Keaveney C, Cuttner J, et al.: Mitoxantrone, vincristine, and prednisone in adults with relapsed or primarily refractory acute lymphocytic leukemia and terminal deoxynucleotidyl transferase positive blastic phase chronic myelocytic leukemia. Cancer Res 47 (19): 5234-7, 1987.
Biggs JC, Horowitz MM, Gale RP, et al.: Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 80 (4): 1090-3, 1992.
Gray JR, Wallner KE: Reversal of cranial nerve dysfunction with radiation therapy in adults with lymphoma and leukemia. Int J Radiat Oncol Biol Phys 19 (2): 439-44, 1990.
Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354 (24): 2531-41, 2006.
About PDQ
Additional PDQ Summaries
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
Our licensed social workers are here to help adult patients and their loved ones face the many new concerns and anxieties following a cancer diagnosis, offering emotional support and assistance with obtaining needed resources.
Our support groups are geared to specific cancers and methods of treatment. They give patients the opportunity to meet and share information and moral support. Our experienced, compassionate staff facilitates and guides discussion.
Concierge Services is your one-stop place to learn about Dana-Farber programs, services and resources, as well as information on getting around Boston, finding lodging or restaurants, and activities in the area.
The Creative Arts program provides patients, family members and caregivers with a variety of options to support well-being during cancer treatment. From dance and drama to music and writing, the program offers a range of creative outlets to suit every interest.
Dana-Farber and Brigham and Women's Hospital, including parking facilities, are fully accessible to people with disabilities. There are wheelchairs at the main entrance, and security staff can provide personal assistance. We also have many educational materials available in large print and audiotape formats.
The Ethics Consultation Service is available for patients and families who may be facing difficult decisions and choices regarding care. Our goal is to bring together patients, families and health care providers to talk about ethical concerns and help everyone involved arrive at a resolution that is right for all.
This comprehensive resource offers guidance, information and resources to support the entire family, including how to talk to children about cancer, advice for the well partner, and creating a support network.
Find practical tips and suggestions for individuals caring for a family member or friend with cancer, including creating a caregiving plan, finding community resources, and looking after your own well-being.
Dana-Farber offers several services to help you and your family manage the financial side of cancer treatment. From creating bill payment schedules and estate planning advice to debt management and resource assistance for patients in need, our team is here for you.
One-to-One connects adult patients, family members and caregivers with individuals who have gone through cancer themselves, providing an experienced and reassuring perspective for those facing a cancer diagnosis, treatment and recovery.
The Eleanor and Maxwell Blum Patient and Family Resource Center and its satellite resource rooms are staffed by health care professionals and provide computer stations, books, brochures, videos, and CDs to help you find information and support on a variety of issues about cancer treatment and care.
The Dana-Farber pharmacy fills prescriptions for all pediatric and adult patients. Our pharmacists are an extension of the patient care team and work closely with your physicians to provide seamless, convenient, safe care.
More than 1,200 Dana-Farber patients and their families have enjoyed free trips to baseball games, theater shows, museums, and other attractions this year through the Recreational Resources program.
The Sexual Health Program provides education, consultation and personalized rehabilitation for patients and their partners who have experienced changes in sexual health during and after cancer treatment.
Through all stages of cancer treatment and survivorship, our Spiritual Care staff is available 24 hours a day to provide emotional and spiritual support for adults and pediatric patients and family members.
Young adults with cancer face very different challenges than patients who were diagnosed earlier in childhood or later in adulthood. The Young Adult Program can help you to find the resources and expertise available at Dana-Farber to help support your cancer experience.
Integrative therapies, also known as complementary therapies, range from acupuncture and massage to nutritional guidance and music therapy. Patients treated at the Zakim Center credit its services with easing nausea, improving circulation, and reducing pain, stress, and anxiety associated with cancer treatment.
Blood is made up of three basic types of cells:
Your body is constantly producing blood cells. Blood cells are made in the bone marrow, the spongy tissue inside your bones. They come from a type of cell called a stem cell. The stem cell divides in response to signals made by your body. It will either become a red blood cell, a white blood cell, or a platelet. These signals are called growth factors. Blood cells live for a specified time in your body. White blood cells live for a few hours to a few months. Red blood cells live for 120 days. Platelets live for five to nine days.
Chemotherapy affects rapidly growing cells more than slower growing cells. Some normal cells have a fast rate of growth. These include your blood cells. A side effect of chemotherapy may destroy young blood cells as they are growing. It can take anywhere from seven to 21 days for your blood cells to reach their lowest numbers.
Your nurse or doctor will tell you when your blood cells counts are expected to be low. This is called your nadir. You will have your blood tested periodically to see how many of each type of blood cell you have. This is called having your counts checked.
Rec blood cells are measured by values called hemoglobin (Hgb) and hematocrit (Hct). The normal value for hemoglobin is 14.0 to 18.0; hematocrit is 37 to 52. If your red blood cell count is low, you may feel more tired or short of breath than usual. This is called anemia. Your doctor may order a red blood cell transfusion for you. Sometimes your red blood cells may be low because of the disease itself. Your doctor may prescribe a growth factor called erythropoietin (EPO) to help increase your red blood cell counts.
One type of white blood cells are neutrophils. When neutrophils are low, this is called neutropenia. You may not see the usual signs of infection so review the signs of infection at the bottom of this page.
A normal white blood cell count is 4,000 to 10,000. Sometimes your doctor may order a growth factor called GM-CSF or G-CSF to help your white blood cells recover more rapidly. The neutrophils fight most common infections. For that reason, this portion of the white cell count is also monitored. This is called the Absolute Neutrophil Count (ANC).
A normal platelet count is 130,000 to 400,000. A platelet count below 50,000 may make you more at risk for bleeding. This is called thrombocytopenia. If your platelet count drops, your doctor may order a platelet transfusion for you.
Talk with your nurse or physician about avoiding crowds and public places such as shopping malls, airplanes, buses, trains, etc. You may need to wear a mask if your white blood count is very low.
Good hygiene is important. Shower or bathe daily and pat yourself dry. Wash hands often and well. Always wash them before eating and after using the bathroom.
Be sure to notify your nurse or doctor immediately if you have any abnormal bleeding. This includes nose bleeds, blood in urine or stool, dark tarry stools, bleeding gums or easy bruising.
Be sure to let your nurse or doctor know if you develop any of the following signs of an infection:


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After the last patch zephyr gets 30 health when his cyclones reach their end of lifetime at 50 seconds. So you don't have to heal yourself manually.
But if you reach your maximum of cyclones (8 for example) and get another cyclone through killing a unit or casting your ultimate you still get only 15 health for this expiring cyclones.
Is this intended or did S2 forget to fix this? Because you cant find any descriptions of this in the tool tips.
Last edited by Sucker`; 03-14-2011 at 12:05 PM.
At first he was like
but thenOriginally Posted by DrScout
Originally Posted by DrScout
Because there is a max active of 2,4,6,8 cyclones, when you spawn more than the max it effectively kills the oldest one, the ondeath tags only heal for 15 where the onexpired tags heal 30. Not sure if it's intended that way or an oversight.
S2 Games: Dedicated employees serving dedicated gamers. Continuous development. Never-ending improvement.
Click the picture
I was going to ask this. I'm not sure if it's intended but definitely noted that doing it manually is helpful.
Never, under any circumstances, take a sleeping pill and a laxative on the same night
Team Supporter/Pusher
The pseudo-heal on killing when you have maxactive cyclones is stupid IMO, so I'm not changing anything in regards to that.
If it was up to me it'd be removed.
Anyway balance, closed.
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Tech Support and Customer Support: https://www.heroesofnewerth.com/support/
Look for my highlighted text (important information) and grey text (interesting but not required information).


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I love Tolkien. Just recently finished listening to the audiobooks about a week ago. I'm fortunate to have a job where I can listen to my mp3 player. I finished 20000 Leagues Under the Seas on friday, I forgot how wonderful that book was.
I'm now interested in listening to a huge list of classics, I found a great amazon list here, and she made a part 2 which I will investigate once I make my way through the first one. I'm thinking we need to compile a list here in the book club of all the most important classics of western lit. This literature is the backbone of our culture and has helped me understand the world we live in, I think such a list would be a great addition to the book club.
I am currently reading "Guns, Germs and Steel" by Jared Diamond. If you have the time there is a three part video about it here.
Ohh, I just finished the Poisonwood Bible and it was fantastic. You'll love it. I am also reading A Voyage Long and Strange which is about the discovery of America and alot of it pertains to the Christian influence and treatment of the American Indians. It's written in a way that is insightful, yet often vary amusing.
I am currently reading "Anvil of the Stars" by Greg Bear. I enjoyed "Forge of God" a lot more. must admit I am struggling to get into Anvil and I'm already more than half way into it. Will see where it takes me. Next in line is "Parenting Beyond Belief" by Dale McGowan (thanx for the recommendation on here) and then I'll return to Isaac Asimov again ( been trying to re-read a lot of his books, Just finished robots1 through 4)
Looking forward to finding more good suggestions on here
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the.ronin wrote:When I was younger (high school), we used to go out at night with glow sticks tied to our wetsuit drawstrings. We'd hit up places like Leo Careo and Zeroes (noticed you were in So Cal too). Good times ... except once ...
We got a little drunk and decided to hit up a Topanga midnight session. My buddy chickened out so got stuck with video camera duty. Didn't take long for my eyes to adjust since it was a full moon and the lights from PCH and the restaurants was shining. But no sooner do I hear this woosh woosh woosh ... look up and make an outline of a longboarder charging at me full tilt. Too late to duck dive so I turtle and feel him run over me. When I resurface I just hear mad cursing ... what the f*ck this f*ck that etc etc. I get out to the lineup, sit, and notice 2 dudes coming at me from my 10 and 2 oclock. To my rear, a VERY pissed off dude is paddling to me - still cursing. These guys looked like they just got out of prison. The guy to my back finally gets to me and goes on - "You gotta make yourself f*cking known man!! What the f*ck!!" ... I figure I'm in for a serious ass beating anyway so I just start going OFF on these guys. Profanities are flying meanwhile I'm slowly trying to paddle away from the center while sitting on my board. Out of the corner of my eye I spot a wave coming and, believe you me, I'm paddling out of there like a bat out of hell. I catch the wave as far as I can, jump off my board and run straight to shore past my buddy who still has the camera in hand - "Get the f*ck back to the car NOW dude!!!" We get in the car, I'm still soaking in my wetsuit, board half assed out the window, and peel out of there like motherf*ckers.
The video is priceless ... "There goes crazy Rob for a midnight session at Topanga" ... I disappear into the night ... few minutes later some cursing, then more cursing, then a bunch of people cursing ... "Ok Rob is about to get his ass kicked" few seconds of silence ... "Ok Rob might be dead" ... I emerge out of the darkness running like hell yelling "Get the f*ck back in the car NOW dude!!" ... shaky camera and a lot of laughter from my buddy as he's running after me.
So, yeah, night surfing can be pretty cool.
pkbum wrote:wow how the hell do you surf during the midnight? can you see anything?
LucasG wrote:lol! Where is the video?! We got to see it! :p
Encountering wildlife while surfing RELATED: Surf Chat Author: gd6 Replies: 23 |
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4 Meetup Groups match "JavaScript Frameworks" near Mentor, OH
Node.js is hot and heavy. Come meet with other Node.js enthusiasts and see how server-side JavaScript is not only new but a very powerful way to develop. We will also aim to cover topics regarding jQuery, JavaScript performance and other popular front-end development. We hope to share and develop with all who are welcome to join us here in Northeast Ohio.
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Meet other developers using Meteor. Share your knowledge, apps, and get feedback from others. Meteor is an open-source platform for building top-quality web apps in a fraction of the time, whether you're an expert developer or just getting started.
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Come and meet people that share your passion for Joomla! We are a group of users, designers, developers, and administrators that deal with Joomla! on a regular basis, and we encourage any Joomla! user (from novice to expert) to join and share their insights. We intend to cover other topics (such as MySQL, PHP, jQuery, Testing, Performance Tuning, etc.) as well, but mainly from the perspective of the Joomla! framework. So, come and join, and we'll see you soon. Joomla! User Group North East Ohio …
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Making Monsters: Evil Tiki Pictures
Ed, Marsha and Jordu head to beautiful Hawaii where a local company has asked them to create, build and install an evil tiki statue for their entranceway.
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Lenovo Enhanced Performance USB Keyboard - US English
Part number: 73P2620
The Lenovo Enhanced Performance Keyboard combines legendary keyboard quality, a two port USB hub for desktop expansion capability, a variety of specia... Learn More >
What is Electronic Download?
*Only products labeled as ELECTRONIC DOWNLOAD will be delivered via download. All other products will ship with order. When purchasing Electronic Download software you will receive an authorization key as well as a link to direct-download your software via the email address you designate in the checkout process. You will receive no hard discs, DVDs, or other tangible download method with your delivery. Should you experience any issues such as non-delivery or loss of your Electronic Download email, you may access your Digital Locker to request that the email be resent. Note that once any order which includes an Electronic Download item has been placed, that portion of your order will be non-refundable. |