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How to get shiny Pokemon in Pokemon X and Y (All Methods/Updated Version)
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Author boss gameing ( ago)
mega blastoust
Author The Creeper Bros. ( ago)
CUZ im straight up gangsta
Author The Creeper Bros. ( ago)
All of my Pokemon have pokerus
Author Emma Foley ( ago)
But in the poke radar method you can't step on the out side paches of grass
Author serena180 ( ago)
My way i can get any pokemon shiny any time i want
Author serena180 ( ago)
The best way
Author serena180 ( ago)
Besy way power saves pro
Author joshuay uile ( ago)
Shiny mega Gengar is awesome
Author Max Carlquist ( ago)
When I played the storyline I was locking for an eevee in a rout and I
found a shiny eevee
Author Jace Zhu ( ago)
if you beat the Pokemon league. go to the lab in sycamores lab and talk to
every lady
Author MishaMellow ( ago)
Hey could you please tell me how you record your pokemon videos?? I've been
trying to look up tutorials but everyone pretty much says oh set up a
camera and point it at your 3ds! thumbs up and I don't want to do that
cause I'd get shitty audio quality knowing my luck.
Author FluttershyJAC ( ago)
what the things that you use to find
Author kailey smith ( ago)
Idk why I'm watching this if I'm breeding eevee
Author Aleygames aka tug3 ( ago)
Hmm... I think i'm gonna try for a shiny Eevee!
* Three weeks later...*
................. I give up..... ;-;
* Nephew comes up * Nephew: I GOT A SHINY FENNEKIN!
Me: ....... * Inhale*.... I GIVE UP LIFE.
Author corn-dog "Corndog" lebron ( ago)
Does the masuda method (day care breeding) work with a foreign ditto?
Author Frisk Dreemurr ( ago)
how do ya get a pokeradar
Author Joe hey han ( ago)
how can i hatch different pokemoon
Author Yuno Stobbe ( ago)
do you need a talonflame of another region to get a shiny out of an egg
cuzz I have a talonflame but not from another region
Author lupita jimenez ( ago)
I caught a shiny pumpikco or that pumpkin pokemon without watching that xD
Author Battery ( ago)
shiny pansear PANSEAR
Author jonnyrocke nintendo fan ( ago)
I found a shiny bedlum
Author Yuno Gasai ( ago)
my only shiny was a magikarp.
Author issac Parada ( ago)
i just got it on my 11 try
Author zach Barahona ( ago)
I let a shiny roselia escape by accident
Author Linh Cat ( ago)
shiny mega gardevoir😄😄😄
Author Quinn Parker ( ago)
I tried the friend safari method and I got a shiny Surviper on my first
Author SJR Gaming ( ago)
Shiny mewtwo shiny diancie and shiny xerneas
Author Anthony Santosuosso ( ago)
what emulator are you using that is so stable?
Author Itachi Uchiha ( ago)
Shiny Greninja, Shiny Yveltal, and Shiny Xerneas
Author ella-rose Treacy ( ago)
I put in wurmple in wonder trade and got a shiny absol lvl 100
Author Sydosys GD ( ago)
that level 50 Basculin you encountered was not a shiny Basculin have two
forms a red form and a blue form these forms are both normal.
Author NightcoreElements ( ago)
Shiny Mega Blaziken lv. 100 with Pokerus 4ever.
Author Zach Shafer ( ago)
how do you get a poke radar?
Author Ice_Tiger ( ago)
Goddamn it guys ;( the only shiny I got was a yanmega through WT xD I've
never gotten a real shiny by myself.
Author woody ort ( ago)
i got my shiny froakie on the 6th egg :O
Author Ryolu Celestial ( ago)
LOL gloom with pokerus
Author Shalee Gherbaz ( ago)
First shiny was a level 100 banette through a wonder trade... Only realised
months later that it was shiny, I was just happy that I got a level 100!
Then today after a 3 chain (without me realising what chains are) I got a
shiny Pikachu. I seem to not be able to find them if I'm trying
Author Orion11790 Gaming ( ago)
I found a shiny goldeen on my 6th chain
Author Joaquin Roxas ( ago)
I have shiny arceus
Author Stephanie Hannah ( ago)
Shiney mega charizard x
Author andrea saturno ( ago)
my first shiny was a shiny swanna and I trade it for hopa.
Author cristy d ( ago)
anybody got a mew willing to trade for my celebi..jirachi...hoopa or
keldeo? plss
Author Andy fuchu ( ago)
i got a shiny chespin from my 2nd egg
Author Annoyed Person ( ago)
Something with a lot of pee pee.
Author Alecto Anarchy ( ago)
I caught a shiny Dugtrio in the badlands on Route 13. Third Dugtrio I found
on that route, too. My first shiny Pokemon, and it was a pathetic one. ಠ_ಠ
Author GhostGaming lee ( ago)
shiny gardivore has an awesome black dress and blue skin
Author XTheMatrixX ( ago)
My First shinys are shiny shellos and gatriodon in pokemon diamond,
In white, shint timburr and lilligant
Author Aj Honsinger ( ago)
i saw a shiny but i ran a way because i had no pokeballs
Author Withos Empire ( ago)
Sorry for all the comments, but favorite shiny mega is mega gallade.
Author Withos Empire ( ago)
I did the breeding methond. I had three boxes full of oshawott. Sent them
all away to lucky trainers.
Author Withos Empire ( ago)
For the breeding I go back and forth on the edge kf fhe trail so you ru.
Into a sign and into the lampost in campifer township
Author Stinging Nettle ( ago)
I remember my very first playthrough of Emerald(First pokemon game) I found
a random Shiny Marill and a few hours later found a Shiny Wingull, and
right after that a shiny Gloom :P It was pretty dope
Author CreepaKingdom ( ago)
In the mesoodu method with my servine which I got in a trade so i want s
shiny snivy
Author CreepaKingdom ( ago)
In my dream I got a shiny eevee
Author Sonoramic Aes ( ago)
the only shiny I have is a wurmple lvl 100 with an eviolite
Author shanobian ( ago)
basculin would rather kill itself than be with you
Author NightRising Wolf ( ago)
Everyone count how many times he says "uh" I got to 34 and stopped to
comment this
Author Joshua Moore ( ago)
shiny mega Charizard X
Author king prawnz ( ago)
my very first shiny was a heliopitile i think thays how you spell it
Author mastrtonberry2 ( ago)
Why are you hunting shinies without False Swipe?
Author The Hatchet Attack ( ago)
Shiny Ageislash
Author Jabed Miah ( ago)
Mega charzard x
Author Jazmin Merino ( ago)
I'm cool so my number is 3454-1956-4319 please😁1
Author Mirrai Channel ( ago)
buddy.. you talk too much... show more, less talk
Author Umbreon Shiny ( ago)
Anyone wants to share Charizardite x for my charizardite y?
Author Isaac Royall (royallhornetgaming) ( ago)
shiny mega rayquaza
Author Ricky Hytower ( ago)
Author David Juarez ( ago)
I Got Box full of Pokerus
Author Michael S ( ago)
If u playing x plz can I have xearneas plz I need it I'll give anything
execpet zygard or my y legend btw I'm I youtuber not popular I just have 2
get further to get stronger
Author Michael S ( ago)
I want fast shines
Author Holly Selman (1349 years ago)
I have a shiny bellossom and I would love if anyone wants to trade for a
shiny ponyta so 😊
Author Jacob Jorgensen ( ago)
shiny mega charizard y
Author Scott Rutherford ( ago)
Anyone wanting to trade me a shiny and I will give u pokerus? .
Author Yoshimarcus Channel ( ago)
If someone has a shiny Gengar please tell me in the comments
Author dominique herbert ( ago)
friend code 5344-0100-4236 add me :)
Author Jack Young ( ago)
that was not a shiny basculin
Author Renata Pittman ( ago)
I found a shiny Druddigon its green and gold and the original ks blue and
Author OmqItsMich :3 ( ago)
I've found 3 shinys in X and Y I found two or them in one day a shiny
watchdog and a shiny swirlix I forgot what the other one is tho
Author Julian Gunther ( ago)
a thing called suction cup pokemon. lol
Author Scarlet Iroichi ( ago)
i think rattat was my first shiny
Author Scarlet Iroichi ( ago)
that happened to me.. i feinted my first shiny
Author FantomSprite ( ago)
Sorry I'm kind of a noob what is a chain big noob me
Author MyNameIsNone OfYourBusiness ( ago)
The only shiny I've ever seen was a cunchoo in a horde. After I cleared the
other 4 I accidentally crit killed the shiny 😔
Author Dylan Tang ( ago)
You can just buy the power saver for 3ds and change any Pokemon shiny
Author Patrick Arnaiz ( ago)
Fave shiny evo is Gengar!!!
Author Sylver 763 ( ago)
Thnx 4 uploading this video. i really helped. :)
Author tjm0720 ( ago)
friend code: 2809-9661-7216
anyone feel free to add me. looking for safari friends
Author Bob Rock ( ago)
guys did you see greninja's level at the start is was level 90 and when he
encountered the shiny bascluin it was level 83
Author Marshall C ( ago)
just shiny delibird
Author DarkRider YT ( ago)
Once I found a shiny ditto, and it died by recoil :V
Author Kourtney Mount ( ago)
dude plz make a video how to evolve litleo into pyroar with a fire stone
Author Rehono Tharp ( ago)
My first shiny pokemon was a Raticate that I happened across in Pokemon
Heartgold. And then my game decided to delete all my data along with my
Raticate and I have yet to find another shiny...
Author Jack Jensen ( ago)
My first shiny Pokemon was a Snover that I ran into on accident, I had to
use my only master ball on it :/
Author Cloudtail59 ( ago)
One time I was wonder trading and I got a shiny salamence
Author Nerf academy 101 ( ago)
Author Spiikey HD ( ago)
yuo suk
Author Dragonmaster123 Draginod ( ago)
trying to get shiny buldum if you have wanna trade?
Author Fernando Naula ( ago)
shiny hypno /tepic/arceus for shiny lucario or gengar
Author Amelia Wren ( ago)
I have shiny articuno, shiny lucario and shiny giratina all from wonder
Author jason flamm ( ago)
what item is that
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Vast Right-Wing Conspiracy deepens: Obama DOJ grants immunity to Homebrew Hillary's ex email tech who took the Fifth
**Written by Doug Powers
While many focus on the GOP race, let's check back in with what's going on behind-the-scenes with the only candidate who is under federal investigation.
A former State Department computer tech who originally took the 5th to any questions about his role in setting up Homebrew Hillary's under-the-radar email system has been given a green light by the DOJ to sing like a canary:
The Justice Department has granted immunity to the former State Department staffer who worked on Hillary Rodham Clinton's private email server, a sign the FBI investigation into possible criminal wrongdoing is progressing.
A senior U.S. law enforcement official said the FBI had secured the cooperation of Bryan Pagliano who worked on Clinton's 2008 presidential campaign before setting up the server in her New York home in 2009.
As the FBI looks to wrap up its investigation in the coming months, agents will likely want to interview Clinton and her senior aides about the decision to use a private server, how it was set up, and whether any of the participants knew they were sending classified information in emails, current and former officials said.
Wow, is the Obama Justice Department now part of the Vast Right Wing Conspiracy? I doubt that anybody involved in this at a higher level has a fear of prosecution from the Obama DOJ, but it sure looks like Pagliano sensed early on that Team Hillary was trying to promote him to the position of "fall guy."
The Hillary campaign released their customary response to this kind of news:
**Written by Doug Powers
Twitter @ThePowersThatBe
Call off the controversy: Harry Reid and Chuck Schumer vouch for Loretta Lynch's ethics after Clinton meeting
June 30, 2016 09:19 PM by Doug Powers
Husband of presidential candidate under federal investigation met privately with US Attorney General, but no big deal
June 29, 2016 08:47 PM by Doug Powers
Hillary shares secret to earning trust (apparently it has something to do with lying constantly)
June 27, 2016 10:27 PM by Doug Powers
Hillary joins NYC gay pride parade blaming 'Republican hate' for ISIS-influenced registered Dem's attack on Orlando club
June 27, 2016 06:31 AM by Doug Powers
Looks like Hillary's server wasn't the only thing that could be scrubbed with a cloth
June 24, 2016 01:52 PM by Doug Powers
Categories: 2016 Campaign, Corruption, Feature Story, Hillary Clinton

subset: commoncrawl


text:
CES: Intel's Mooly Eden talks up the practical side of ultrabooks
Virtues of notebook variant go beyond benchmarks
CHIPMAKER Intel gave its attention at the CES conference to promoting the real-world benefits of ultrabooks.
The company highlighted a design and marketing effort to shift its focus from benchmarks and statistics to examples of real-world capabilities and applications that will be improved by what it hopes will become a growing ultrabook market.
Ultrabooks, which combine high-performance chips with ultra-thin hardware designs, have been an area of particular interest for Intel in recent months. Once limited to high-end notebooks, the market niche is expanding to include lower cost designs and hybrid systems that include touchscreen tablet components.
As part of that expansion, Intel sees a need to better connect with the needs of consumers and digital content creators.
Mooly Eden, general manager of Intel's PC client group, told reporters that the company is looking to get a better picture of how users both consume and generate content and how Intel can develop products to better accommodate those tasks.
"People would like to create in order to express themselves," Eden explained.
"People do not want to wait for the computer, they want the computer to wait for them."
Eden also pointed to several of the key features of the Ivy Bridge platform. The platform will add support for DirectX 11 and contactless near field communications (NFC) that will allow users to bind their notebooks with a credit card, creating an automated yet secure method for online purchases.
Additionally, the rollout of Windows 8 promises to add a number of touch features for Ultrabooks. Eden predicted there will be several convertible tablets that combine touchscreen and multi-touch gesture support with hardware keyboards.
"People do not want to give away the real keyboard, but they want to experience the best of both worlds," Eden said.
"People will use touchscreen in their notebook and in a few weeks you will be surprised that you could do anything without it."
The continued development of the ultrabook concept has also brought a number of architectural and design challenges. With vendors increasingly looking to lighten and slim down their designs, Intel has had to take new approaches to such things as battery and processor socket designs.
The company has had to work on not only improving designs but also making the new components affordable to build and deploy.
"The big challenge is if you want to take a 32 or 40mm notebook and transition it to 18mm, there are many components that need to be redesigned and manufactured in a high enough volume to drive the cost down." µ
Further reading
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OK Google, how do we create a stable society from this constitutional crisis?
Intel to stick chips inside BMW's self-driving cars by 2021
Robo-cars on the rise
Hackers breach dating website Muslim Match and expose 150,000 users
790,000 personal messages also leaked in SQL-injection hack
Windows 10 Build 14379 arrives as Microsoft preps for impending Anniversary Update
Build delivers fixes for Action Centre and Live Tile interface


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Aaron Sanchez of the Toronto Blue Jays
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From Business: Golob Physical Therapy is a privately owned practice specializing in manual physical therapy. Clients are provided compassionate and individualized care that facili…
13. Mary Golob Pt
8044 Market StWilmington, NC 28411
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'Company' coming to DVD
The first season of "Three's Company" will be released on DVD Nov. 11, with a portion of proceeds being donated to United Cerebral Palsy in memory of star John Ritter.
The first season of "Three's Company" will be released on DVD Nov. 11, with a portion of proceeds being donated to United Cerebral Palsy in memory of star John Ritter.
Longtime Fox News television commentator Tony Snow on Tuesday was tapped to launch the net's second nationally syndicated radio show. Announcement by Fox News veep Jack Abernethy marks the news org's…
Jaws dropped at Fox and sighs of relief likely went up everywhere else on Tuesday in reaction to surprisingly soft opening-night numbers for the Murdoch net's Monday bows of "Next Joe Millionaire"…
Fox hit six out of the park last week -- including grand slams Wednesday and Thursday -- to record one of the most dominant victories for any net this year.
The Disney Channel edged out Nickelodeon/Nick at Nite to finish first among all basic-cable networks last week, but the big story was the powerhouse numbers racked up by two original movies: USA…
Televisa telenovela "Amor Real" (Real Love) nabbed a 43.1 rating for its two-hour finale Sunday night, ranking it among the top eight novelas in Mexican history.
Canuck network CTV has acquired local rights to MTV reality series "Newlyweds: Nick and Jessica" and has extended its deal with Comedy Central's satirical newser "The Daily Show With Jon Stewart."
Fox bowed its new Monday lineup to surprisingly low ratings Monday, as neither "The Next Joe Millionaire" nor drama "Skin" drew much of an aud, according to preliminary nationals from Nielsen.
Spain's merged digital TV platform Digital Plus added 50,000 new subscribers in September, its controlling shareholder Sogecable announced Monday.
Veteran scribe Glenn Gordon Caron has set up his first-ever project at NBC, teaming with exec producers Kelsey Grammer and Steve Stark for an hourlong drama about a woman with psychic abilities.
ABC is going "Nowhere" with feature scribe Jeff Lieber ("Tuck Everlasting") and producer Aaron Spelling.


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Looking for a good hotel for my family of four, probably in Downtown Indianapolis. What would you recommend?
Recent ActivityView all United States activity »
- 1 Do you have suggestions on my first roadtrip South-West USA?
- 2 Need Advice For Trip with 16year old son-
- 3 The city never sleeps, but we needed to
- 4 The Great Debate, What is Worth Precious Money and Time in NYC
- 5 Christmas Napa Valley
- 6 Island of Oahu: looking for cheap accommodation
- 7 Southwest charging USD15/ for early bird check in
- 8 Sacramento to South Lake Tahoe to Riverside, CA
- 9 Your favourite places in New York City
- 10 Phone SIM
- 11 3 days in NYC with my Grandma!
- 12 Las vegas +21
- 13 1st Visit to USA with kids in Jul-Aug, SFO,LA,SD & LAS - 21 days. Need Help
- 14 Road trip from Boston to Florida
- 15 60th birthday trip to Vermont, NH, Maine in October
- 16 Zion NP & Las Vegas with Kids for 3 days in July - Please Help
- 17 Trip Idea for Thanksgiving Break
- 18 Limited time on Maui: Advice please
- 19 Savanah Sojourn
- 20 Gotta Go To Stanford U Medical Center
- 21 ONE WAY car rental from NYC to BOS
- 22 San Francisco - Best place to see street art
- 23 Travel suggestions from Mystic, CT to Bar Harbor, Maine
- 24 Black Hills, Mount Rushmore, Badlands Trip Report
- 25 Driving from San Francisco Airport to San Rafael
Indianapolis -- Please recommend a good Downtown hotel for family
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It's been a few years ago, but we stayed at the Embassy Suites and liked it. It would have the separate area for the others in your family. It used to have ducks in the atrium (central area that were kinda neat.
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Crown Plaza Hotel at Union Station. Built inside part of the old historic Union Station. You can sleep in authentic old restored Pullman cars located on 2 tracks inside the hotel (the cars have modern rooms, not the old Pullman berths). Lots of fun for kids (and us adults who like trains). Easy walking to anywhere downtown.
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Home > News > Science group to meet at USD
June 16th, 2006
Scientists from the West Coast and Pacific Rim will discuss findings related to ice ages, theories of time, nanotechnology, environmental issues, and brain structure and memory.
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Ultrathin, flat lens resolves chirality and color: Multifunctional lens could replace bulky, expensive machines June 25th, 2016
Nanotechnology and math deliver two-in-one punch for cancer therapy resistance June 24th, 2016
Researchers discover new chemical sensing technique: Technique allows sharper detail -- and more information -- with near infrared light June 24th, 2016
Soft decoupling of organic molecules on metal June 23rd, 2016
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20 November 2012 5:55 AM, PST | Digital Spy | See recent Digital Spy - Movie News news »
Coronation Street legend Julie Goodyear has opened up about her friendship with the late Bill Tarmey. The 70-year-old actress, who played Bet Lynch in the ITV soap, said her relationship with the Jack Duckworth legend was "very deep". "We never lost touch. Never. He was very much the family man. His wife Ali was his absolute soulmate," she told the Radio Times.
> Coronation Street Bill Tarmey dies: Reactions from soapland
> Bill Tarmey 1941-2012: Obituary for Coronation Street's Jack Duckworth
> Corrie's Bill Tarmey, 1941-2012: Jack Duckworth's finest moments "And don't forget that he also had this beautiful singing voice - when he had his This Is Your Life, he sang 'The Wind Beneath My Wings' to Ali and there wasn't a dry eye in the house. "He (more) »
- By Paul Millar
Similar News Items"Coronation Street" (1960)
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William Tarmey (I)
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Mo is a 17h, 13 yr old never raced TB. He's had one owner for the past 7 years and is now offered for sale as the owner is military and wants to find him…$6,800
Solid lower level eventer. Has been shown at rated and schooling shows. Extensive schooling up to training level. Can cross over to dressage or the…$9,000
Looking to reassign my 7 year old, 15.2 hand BLM mustang gelding. Captured from Green Mountain Wyoming. He has had groundwork and is rideable, but I would…No Price Listed
Niño is an imported PRE stallion currently schooling I1 with scores at PSG with correct dressage gaits that are FEI quality. He's sired by Militar stallion…$90,000
SEQUOIA'S CUE is an 8 year old Bay Thoroughbred Gelding standing 16 Hands and registered with The Jockey Club. Raced off and on since he was 2 and His…$3,100
Escalera-CEN is a beautiful black mare that produces outstanding foals. Standing 16.3 and close 1300 lbs, she's a big mare with good bone and feet. Bred…$12,000
Looking for your next prospect? Wiglaf ASH is a wonderfully athletic colt with the best temperament. His pedigree and temperament make him a great AA prospect…$6,500
(This is not a sales ad) Stallion Service available by AI via Select Breeding Services. Now accepting inquiries for the 2015 breeding season. Minstrel…No Price Listed


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Age-discrimination lawsuits have shot up in recent years, climbing 29% last year alone. But a recent pro-business ruling by the U.S. Supreme Court will make it harder for employees to prove age bias in the workplace (see Pair of Supreme Court rulings redefine race, age bias).
Employee advocacy groups are crying foul. Speaking at an EEOC hearing last month, they complained that the ruling has "decimated" the effect of age-discrimination laws. The EEOC is listening. It promised to consider new regulations that would clarify how age-bias laws should be enforced.
And Sen. Patrick Leahy (D-Vt.), chairman of the Senate Judiciary committee, said Congress will look at bolstering age-discrimination laws in light of the court's ruling (as it did this year with pay-discrimination laws after the Ledbetter court decision).
Related Articles...
- How to Fire an Employee the Legal Way: 6 Termination Guidelines
- Prepare to determine, when the allegations fly: Sexual harassment--or just some clueless guy?
- Hotel's bid for 'cool' valets teaches lesson on job standards
- EEOC sues San Antonio apartment company for race bias
- You can insist on bilingual ability if the job requires it


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The family friend driving the vehicle in the Feb. 12, 2015 crash that cause the death of Chiefland standout football star and all around nice guy Deshawn Roland has been arrested on charges of DUI manslaughter, two counts of DUI with serious bodily injury, DUI property damage, driving while his license was revoked for being a habitual traffic violator and not wearing a seat belt.
Rural areas, such as Levy County, are presented with certain challenges for economic development, David Pieklik, executive director for the Nature Coast Business Development Council, told members and guests at the monthly meeting of the Greater Chiefland Area Chamber of Commerce last Friday.
"Our challenges are not unique," he said.
One in 10 jobs are created in places like Chiefland and Williston, but that figure used to be one in four. Ninety percent of these businesses have 20 or less employees, he said.
Episcopal Children's Services will hold a "Meet and Greet" Tuesday, June 28 to introduce the community to the agency which has served children and families in Florida for 50 years but is new to the area.
Starting July 1, the Jacksonville-based nonprofit takes over administration of Head Start and related programs from Childhood Development Services. ECS plans to fill 150 full- and part-time teaching, staff support and management positions in the three-county area.
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Chiefland police on Monday arrested a registered sexual predator after a woman reported he forced his way into her home while she was out and sexually battered her 15-year-old son.
When qualifying for public office closed on Friday, June 24 at noon, most Levy County constitutional offers, one state senator and three candidates for school board heaved a sigh of relief as they drew no opposition.
Williston, Friday, July 1
The holiday weekend kicks off with the annual Pre-4th Extravaganza. Floats and marching units will mark the nation's birthday with a parade at 5 p.m. down Noble Avenue. After the parade, the action moves to Williston's Horseman's Park for an evening of free entertainment and fellowship.
By Mike Wright
Freeway upgrades first. Parkway extension second.
That's the consensus of a group of elected and appointed officials representing six Florida counties grappling with what to do about Interstate 75 congestion between Gainesville and Tampa.
The I-75 Relief Task Force decided on a tentative plan that calls for upgrades to the freeway before entertaining thoughts of extending the Suncoast Parkway north to the Gainesville-Ocala area.
The Chiefland City Commission got some welcome news on Monday, an email from a person involved in the Suwannee Valley Community Hospital assures that the developers CBC Real Estate and Neuterra Health are proceeding with plans to build the facility.
Frank Shupp, in an email sent Monday to City Manager Mary Ellzey, wrote: "The Hospital status in as follows: The Certificate of need is 'alive'."
CareerSource Citrus Levy Marion will help FedEx hit the ground running when it opens its new distribution hub by hosting two hiring events next month.
The hiring events are Wednesday, July 6 from 9 a.m. to noon and Thursday, July 7 from 5-8 p.m. at the College of Central Florida Klein Conference Center, 3001 SW College Road, in Ocala.
Talks of a band shell for Fanning Springs park Fort Fanning have met with positive responses from city council members.
At the June 21 council meeting, Fanning Springs Chamber of Commerce President Michael Michaelis and Chamber Member Scott DeBerry presented a short video to the council that featured details and images of similar projects along with interviews with chamber members and others on why they felt the project would benefit the city.
The structure could be used for movie nights, concerts, plays and more.
Copyright © 2016
The Chiefland Citizen is your source for local news, sports, events, and information in Levy County and Chiefland Florida, and the surrounding area.


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is still very sexy even at her age. She got divorced long ago and George is the
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couldn�t understand why till one night she came to his bedroom is short robe to
talk about it. As you may see their conversation ended with really wild and messy
Amanda�s sons grew up it was very painful for her to watch them having fun at
parties and clubs and dating young girls. She did her best to stay # 1 for them.
Sons often joked that she�s she only woman in the world they will ever love. Once
they had pretty frank conversation about sex and Amanda said desperately she�s
not able to explain everything they ask her about but she�s able to show! That
was nasty but her sons took her right. It was their first incest experience so
they recorded it on video.
grew up without mother. She died when Helen was a just small kid. Her father Artur
took care of her, protected and cherished her. Sure, for Helen loved him not like
a father but like a man. But she couldn�t confessed herself in it till the day
he kissed her lips while she was sleeping. She woke up and finally realized how
happy she is. She never enjoyed sex with guys from her college as much as she
enjoyed it with Artur. She got her cunt eaten out as never before and then stuffed
with her father�s strong cock.
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GOP Majority and Social Security Privatization
Only Available in Archive Formats.
President Bush made the privatization of Social Security one of his main campaign pledges when elected in 2000. But as NPR's Mara Liasson reports, the Republican majority in both the House and Senate does not guarantee Bush a legislative victory.
Please keep your community civil. All comments must follow the NPR.org Community rules and terms of use, and will be moderated prior to posting. NPR reserves the right to use the comments we receive, in whole or in part, and to use the commenter's name and location, in any medium. See also the Terms of Use, Privacy Policy and Community FAQ.


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The dashboard tail light is on whent it is at night time or when it is dark or becomes dark. Daytime does not happen like this at all. I checked all the tail light bulbs and replaced some that I had doubt on it. The problem does not go away.
Dashboard Tail Light on on 1999 Toyota Camry
1 answer
If you use the wrong bulb number it will cause the light to come on. It measures resistance in the circuit. If the resistance is incorrect (wrong bulb or bad bulb) it will turn the light on.


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The collision in northern Texas left one injured and three missing Tuesday morning.
The Oakland, Calif. City Council passed an ordinance to ban the storage and handling of coal and coke at bulk terminals in the city, representing the latest blow to Terminal Logistics Solutions' plan for a dry bulk terminal to handle coal and other goods.
The Ocean Carrier Equipment Management Association said that a key benefit of the terminal weighing approach is that shippers will not be required to perform any additional actions in order to provide the verified gross mass of containers.
Registration takes less than 1 minute.
The Calgary-based Class I railroad cited lower-than-anticipated bulk volumes, the devastating wildfires in northern Alberta and a strengthening Canadian dollar as the primary reasons for the downward revision in earnings expectations.
Guillermo A. Sanchez-Badia of Miami was sentenced late last week to 12 years in prison for his role in a scheme to defraud two commercial lenders and the U.S. Export-Import Bank out of more than $11 million.
Ocean carriers should "embrace the obvious solution" terminal operators can offer to ensure compliance with the International Maritime Organization's new verified gross mass regulations, says Federal Maritime Commission Chairman Mario Cordero.


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Labrador saves owner's life for a SECOND time by jumping on her back and dislodging a piece of toast in the back of her throat
- Sharon Brookes, from Ludlow, Shropshire, thought she was a 'goner' when a piece of toast became stuck in her throat
- But her Labrador Judy jumped up to save her and dislodged the food
- It's the second time Judy has saved her 61-year-old owner
- Four years ago, Judy also brought Miss Brookes a Mars bar when she fell into a diabetic coma
- Miss Brookes thinks her faithful dog deserves an award for her bravery
They say a dog is a man's best friend.
But Sharon Brookes's Labrador isn't just a companion - she's also her life saver.
Seven-year-old Judy, a Labrador-springer spaniel-cross, has rescued her 61-year-old owner from death - twice.
The first life-saving act was four years ago when Judy helped bring Miss Brookes a Mars bars after she fell into a diabetic coma.
To the rescue: Judy the Labrador saved her owner Sharon Brookes's life after managing to dislodge a piece of toast which became stuck in her throat
Saved: Miss Brookes says she thought she was a 'goner' before Judy jumped up and 'punched' Miss Brookes on the back, managing to dislodge the toast
Now clever Judy has managed to dislodge a piece of toast from Miss Brookes's throat after she started choking in her home in Little Hereford, Ludlow, Shropshire.
Miss Brookes, who has had Judy since she was a puppy, said: 'There was nobody else in the house and I just thought that was it - I thought I was a goner. I wouldn't be here without her.'
Pensioner Miss Brookes was snacking on toast in her kitchen when a piece got stuck in her throat.
When she started to choke, her faithful dog knew something was wrong and jumped to the rescue.
Judy 'punched' Miss Brookes on the back and managed to dislodge the food.
Miss Brookes said: 'I was eating some toast and all of a sudden started choking on a corner and couldn't shift it.
I'll toast to that! Miss Brookes, from Ludlow, Shropshire, thinks Judy deserves an award for her two life-saving acts
Grateful: It's the second time Judy has come to her owner's rescue, after managing to spot when Miss Brookes fell into a diabetic coma four years earlier
Miss Brookes, a retired cleaner, has had Judy, a labrador-springer spaniel-cross, since she was a puppy. She says she is her best friend
'Fortunately Judy started fussing around me and realised I was in trouble. All of a sudden she jumped up and hit me on the back and I spat it out.'
It's not the first time Judy has come to her owner's rescue.
Four years ago, the retired cleaner began to feel dizzy and believes she fell into a diabetic coma.
Miss Brookes said: 'I was dozing on the sofa and started to drift into unconscious state as my blood sugar was too low.
'Judy realised something wrong and managed to get my friend to bring me a Mars bar and feed me.'
Miss Brookes thinks the pet deserves an award for her two acts of bravery.
She said: 'I call her 'Her Majesty' as she acts like a queen in the house. She's full of devilment but I don't know what I'd do without her.
'They say a dog is a man's best friend. Well, she is certainly mine.'
Judy managed to alert Miss Brookes's friend to her diabetic coma and the friend took Miss Brookes a Mars bar
Lifesaver: Miss Brookes says she wouldn't be here without Judy and her heroic actions
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Costello has the need for speed
Shaun Costello will compete in the Victorian State Circuit Racing Championships today at Phillip Island.LUKE MCMANUS April 12, 2014 3:04am
Shaun Costello has stepped up into Formula Ford this season and will compete at Phillips Island today.
Shaun Costello will rev the engine of a different machine today as part of the Victorian State Circuit Racing Championships.
A successful graduate of the go-kart medium, Costello will try his hand at the Formula Fords and mark a significant step in a promising racing career.
Formula Fords, a common pathway for prospective drivers, has been in Costello's sights ever since his maiden go-kart state title.
Following a similar path to Echuca's Jayden Wallis, Costello compiled a nice collection of race wins and, at the ripe age of 16, believed the time was right to take the next step.
''It's going to be awesome, I'm really excited to race,'' he said.
''I've had a couple of practice runs and it felt absolutely amazing, so I can't wait to finally race.''
Costello used two test days at Winton Raceway as preparation for today's opening round of the Victorian championship but said little could prepare him for the challenges awaiting at the Phillip Island circuit.
Aside from his competitors, Costello will need to contend with the jump in speed when he plants his foot at the top of the Phillip Island straight.
Costello reached 180km/h at Winton but hopes to top 240km/h during tomorrow's race.
The already swift speeds topped in his go-kart will seem like child's play.
''I can't wait to get back in the seat,'' Costello said.
''I'm keen to go as fast as I can.''
As Costello embarks on his Formula Ford career, he will have to wait a little while longer until he can shake the go-karter tag.
Costello will race at September's National Rotax Championships in Ipswich before ''we can fully focus on Formula Fords''.
Costello is sure to travel the distance after an Echuca business, A and R Water Solutions, jumped on board, giving the family-owned team a rare but significant boost, according to Shaun's father and team manager, Simon.
Thankyou for your comment.Your comment will appear once it has been approved by MMG staff.
Cancer nurse's future secured
The Shepparton Biggest Ever Blokes Lunch committee will continue to fund the prostate cancer specialist nurse position at Goulburn Valley Health for the next four-and-a-half years.
Slow start but important win for Lions
Mulwala has overcome a sluggish first half to record an important victory beating Echuca United by 45 points on Saturday.
Promoted: Fighting for the CFA
The brave and selfless women and men of our CFA brigades need our support like never before and I will stand with them all the way.
More than just points on the line
Moama netball coach Clare Shalders knows her side is up against it when it takes on Echuca United at home for the Three Jacks Trophy in round 12 Murray Netball League action tomorrow.
The Australian Sheep and Wool Show
SPONSORED: TAKE a trip to Bendigo this July and enjoy a country-style holiday, plus a jam-packed program of events at the Australian Sheep and Wool Show 2016.
The Australian Sheep and Wool Show
SPONSORED: TAKE a trip to Bendigo this July and enjoy a country-style holiday, plus a jam-packed program of events at the Australian Sheep and Wool Show 2016.
Swans flex muscles
Avenel win easy
Hall offence
Berrigan Shire councillor Daryll Morris says he has been sickened by some of the vitriol and personal attacks to surface since the council's proposal to redevelop Finley's Memorial Hall and School of Arts site was revealed in October last year.
The Australian Sheep and Wool Show
SPONSORED: TAKE a trip to Bendigo this July and enjoy a country-style holiday, plus a jam-packed program of events at the Australian Sheep and Wool Show 2016.
Have a pie for a mate
If you are in the mood for a warm treat next Friday and want to get involved in the recent push to aid struggling dairy farmers, then Ambience Bakery Cafe will have you covered.
Talented Kayla's Canadian tour
Deniliquin's Kayla Smith will travel to Canada on Wednesday to compete in two major athletics meets.
Lawyers arrive to discuss Murray Goulburn claim
About 30 Murray Goulburn suppliers turned out to a Shepparton meeting last week with lawyers proposing legal action against the big processors.
Youngsters give it their all
Benalla Rovers soccer players represent at Country Leagues Football Association Championships.
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text:
Inc.com, the daily resource for entrepreneurs.
URL: http://www.inc.com/
Updated: 7 min 37 sec ago
Jay Pharoah: The Biggest Business Lesson from the Success of Kim Kardashian
Jay Pharoah, stand-up comic and Saturday Night Live star, explains why you need to be willing to take big risks if you want to be successful in business.
Why Steve Jobs Was Proud to Steal Ideas
The science of "not Invented here" syndrome and why borrowing others' ideas is smarter, but harder on the brain.
5 Communication Mistakes You Should Stop Making Right Now
Just say no to these outdated, ineffective practices
7 Top Summer Bikes for Urban Commuters
Ride like a pro. Or at least ride.
This fitness app will make you rethink your business
Can you cultivate a billionaire mindset while launching your startup? Here's a fitness app that can help. LIFTSession
Why the Most Successful Companies Don't Put Customers First
They let their people do it
Chris Sacca on Donald Trump: He's 'Pathological' and a Lousy Businessman
In an interview with Inc. editor James Ledbetter at the GrowCo Conference in Las Vegas, investor Chris Sacca explains why he believes "theres a 100 percent chance Mark Cuban will be president."
Why The Smartest Founders Always Succeed
Hint: they don't succumb to vanity activities.
5 Easy, Powerful Steps to Successful Positive Thinking
In a must-watch TED Talk, positive psychologist Shawn Achor gives five definitive ways you can become more positive - and attract more opportunities.
How Reddit Lets Its Users Guide the Product
Alexis Ohanian, co-founder of Reddit, explains why some of the website's most important features had nothing to do with the people working there.
Why Defining Your Company Values Is Important
Connect your employees and customers to your values.
Congress is About to Screw up the Economy in an Unprecedented Way
The IRS has been granted more time to snoop for fraud. But delays in $100 billion in refunds could impact 30 million taxpayers--especially those who really need their refunds quickly.
5 Reasons Customer Retention Should Be a Priority for Your Business
Instead of focusing so intently on getting new customers, try devising strategies to keep your existing ones instead.
What You Need to Know About Socially Responsible Investing
Here's how to use your nest egg's powers for good.
Why Everyone's Eyes Should Be On Cybersecurity
Cybersecurity will undergo a few upgrades in the coming year or two, in an attempt to stump hackers.
Why Creativity Doesn't Have To Be Chaotic, And Structure Doesn't Have To Be Boring
The two should work hand-in-hand. Here's how.
Warren Buffett's Unusual Approach to Scheduling Meetings
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Machree Gibson Wins Heman Sweatt Legacy Award
Just three generations have passed since UT was integrated, and the courageous ones who did the integrating are still active among us.
Friday was a night to celebrate that group, the Precursors, and all those who have come after with the Heman Marion Sweatt Legacy Award ceremony.
Hosted by UT and its Division of Diversity and Community Engagement in partnership with the Texas Exes Black Alumni Network, it was a black-tie evening of warmth and fellowship. The ceremony opened with a powerful duet of Barbara Smith Conrad's favorite spiritual, "When I Rise, Give Me Jesus."
Heman Sweatt, the first African-American who challenged UT's admissions policies in order to enter the University, was remembered gratefully. "Superman knows he can take the bullets," UT vice-president for diversity Greg Vincent said. "Heman Sweatt did not know he could take the bullets—but he endured."
Powers added, " What a great debt we owe to Heman Sweatt, to Barbara Smith Conrad, and the Precursors. We still have challenges, and we have a ways to go, but to the people who stood early on the road and took those bullets—we owe you a great debt of gratitude."
This year's Legacy Award was given to Texas Exes president Machree Garrett Gibson, a former Texas Assistant Secretary of State and longtime Capitol player once dubbed the "Conscience of the Senate." Gibson worked as the Senate legislative director for Gov. Ann Richards and is now a partner in the firm of Graydon Gibson & Brown L.L.P.
Through the years, Gibson, BBA '82, JD '91, Life Member, has also served her alma mater through countless committees and leadership positions. Powers called her "a friend, the boss, the czar, a queen."
Gibson spoke from the heart about the support that brought her to and through UT and beyond, individually thanking her husband of 30 years, two children, extended family, friends from all stages, and colleagues from all over. "Now I didn't come this far on my own. I was born into a loving family with strong ties to the University," she said. "You see, I've been standing on the shoulders of giants all my life."
Gibson's father, Felix, wasn't allowed by law to attend UT, so he went to the University of Utah instead. Still, Gibson said, "he loved The University of Texas, even though it didn't love him back in 1954." A few months ago, when he was being wheeled out of his hospital room at the end of his life, with his worried family all around, he told them goodbye as he always did: "Hook 'em."
Gibson closed the ceremony by accepting the award in her late father's name.
Photo by Shelton Lewis. Courtesy the Division of Diversity and Community Engagement.
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Mitzi Irene Nuhn Dreher:
Ditto to all of the above comments!!!!...
Fred Theobald:
Adding Gregg Abbott is a disgrace. Shame on whoever made this decision!...
Kathleen A. Bergeron:
A study would be good, as long as it truly looks at all the impacts, like requir...
Tim Taliaferro:
Jennifer, a bit more detail on item 1. Technically, students do all pay the same...
Jeanne La Rose:
I saw the movie last night and was truly inspired by Freddy's courage and attitu...


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Fax: (716) 845-3894
Original Article
Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response†
Version of Record online: 29 NOV 2010
DOI: 10.1002/cncr.25748
Copyright © 2010 American Cancer Society
Volume 117, Issue 10, pages 2127–2135, 15 May 2011
Additional Information
How to Cite
Chanan-Khan, A., Miller, K. C., Lawrence, D., Padmanabhan, S., Miller, A., Hernandez-Illatazurri, F., Czuczman, M. S., Wallace, P. K., Zeldis, J. B. and Lee, K. (2011), Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. Cancer, 117: 2127–2135. doi: 10.1002/cncr.25748
- †
This study was presented in part at the 2006 American Society of Hematology Meeting, December 9-12, 2006, Orlando, Florida.
Publication History
- Issue online: 26 APR 2011
- Version of Record online: 29 NOV 2010
- Manuscript Accepted: 30 AUG 2010
- Manuscript Revised: 16 JUL 2010
- Manuscript Received: 1 APR 2010
- Abstract
- Article
- References
- Cited By
- chronic lymphocytic leukemia;
- lenalidomide;
- tumor flare reaction;
- prophylaxis;
- nonsteroidal anti-inflammatory drugs.
- Top of page
- Abstract
- Acknowledgements
In patients with chronic lymphocytic leukemia (CLL), treatment with lenalidomide induces a unique, previously uncharacterized, immune response called tumor flare reaction (TFR). The clinical significance of this reaction remains unknown.
Forty-five patients with CLL who were treated with lenalidomide in a phase 2 clinical trial were evaluated for the clinical features, intensity, and duration of TFR. Correlation was made with tumor response and the immune cellular microenvironment. Steroids for the prophylaxis of TFR was not given to patients in Group A (n = 29) whereas patients in Group B (n = 16) received low-dose prednisone as well as a slow dose escalation of lenalidomide for the prevention of TFR.
Thirty (67%) patients experienced a TFR, with a grade 2 or 3 reaction (according to National Cancer Institute Common Toxicity Criteria [version 3.0]) observed in 33% of patients (47% in Group A and 9% in Group B; P = .05). The median time to onset of the TFR was 6 days, and was longer in the patients receiving prophylaxis (4 days vs 9 days, respectively; P = .01). A complete response was observed in 7 of 30 (23%) patients with TFR and 1 of 15 (7%) patients without TFR. The median progression-free survival was 19.9 months and 19.4 months, respectively, for patients with versus those without TFR (P = .92).
TFR is a unique immune-mediated phenomenon noted with lenalidomide treatment only in patients with CLL that correlates with clinical response. It can be effectively managed with anti-inflammatory agents. Cancer 2011. © 2010 American Cancer Society.
Lenalidomide is an immunomodulatory drug that has antitumor activity in multiple myeloma and myelodysplastic syndromes.1, 2 Although a full understanding of lenalidomide's mechanism of action still needs to be defined, preclinical evaluations have reported on its ability to modulate the immunological microenvironment via activation of the T and natural killer (NK) cells3 as well as by down-regulation of several critical prosurvival cytokines in the tumor microenvironment, including interleukin-6, tumor necrosis factor-α, and vascular endothelial growth factor.4 In addition, it may affect antigen-presenting cell function and antibody-dependent cell-mediated cytotoxicity. Because of its effect on the tumor microenvironment as well established antitumor activity in other B-cell cancers, we investigated its clinical efficacy in patients with chronic lymphocytic leukemia (CLL). In a phase 2 clinical trial, we observed significant clinical responses to treatment with lenalidomide alone (updated results: an overall response rate of 58% with an 18% complete response [CR] rate) in patients with recurrent or refractory CLL.5 Although the majority of side effects noted during the conduct of the clinical study6 were consistent with those reported previously for lenalidomide, tumor flare reaction (TFR) was a unique observation6, 7 that to our knowledge was not reported in studies of lenalidomide in the treatment of other disease entities.1, 2, 8 It is interesting to note that in patients with CLL, this reaction was observed during treatment with both thalidomide and lenalidomide.7, 9, 10
Clinically, TFR presents as an acute inflammatory reaction that primarily involves tumor-bearing sites. Although our initial study reported on this phenomenon as a possible side effect, to our knowledge to date there has been no account that completely characterized the clinical features and the natural course of TFR. Because TFR is associated with morbidity and, more importantly, mimics disease progression, its correct diagnosis and management are critical for its effective use in patients with CLL. More importantly, the clinical significance of this immunological phenomenon and its correlation with the antitumor effects of lenalidomide remain unknown. In this article, we reported to our knowledge for the first time the clinical features of lenalidomide-associated TFR, described its effective management strategies, and demonstrated that the occurrence of TFR is an important immunological phenomenon that correlates with clinical response in patients with CLL who are treated with lenalidomide.
- Top of page
- Abstract
- Acknowledgements
Clinical Trial Design
Forty-five patients with recurrent or refractory CLL were enrolled in a phase 2 clinical trial.6 The first 29 patients enrolled received single-agent lenalidomide at a dose of 25 mg orally for 21 days of a 28-day schedule (Group A). These individuals also received allopurinol (at a dose of 300 mg daily, 2 to 3 days before treatment and continued for up to 14 days) for the prevention of tumor lysis syndrome (TLS). In this study, TLS was observed in only 2 patients. We thereafter investigated a lower starting dose of lenalidomide with subsequent intrapatient dose escalation. Subsequently, 16 patients who were enrolled initiated treatment with lenalidomide at a dose of 10 mg/day and escalated by 5 mg every 1 to 2 weeks to a maximum of 25 mg (Group B). Furthermore, the first 29 patients enrolled did not receive TFR prophylaxis (Group A). However, because of frequent TFR, the subsequent 16 patients enrolled received low-dose oral prednisone (20 mg daily for 5 days followed by 10 mg for 5 days) as TFR prophylaxis from treatment on Days 1 to 10 of Cycle 1 (Group B). TFR prophylaxis was not given in subsequent cycles. The severity of the TFR was graded according to the National Cancer Institute Common Toxicity Criteria (version 3.0) (ie, grade 1, mild pain not interfering with function; grade 2, moderate pain [pain or analgesics interfering with function, but not interfering with activities of daily living (ADL)]; grade 3, severe pain [pain or analgesics interfering with function and ADL]; and grade 4, disabling pain). Treatment with lenalidomide can result in the development of a rash, independent of TFR. Therefore, patients in whom the only presenting feature was a rash without any other sign of TFR were excluded from the TFR group but were included in the non-TFR patient group.
Immune Effector Cell Profile
Peripheral blood was obtained at baseline for analysis of the immune cell profile. Samples were analyzed immediately at the time of harvesting for NK and T-cell repertoire using flow cytometry with the following antibody panels (all provided by BD Biosciences, San Jose, Calif): CD16/CD56/CD45 panel (NK cells), CD3/CD4/CD45 panel (CD4+ T lymphocytes), and CD3/CD8/CD45 panel (CD8+ T lymphocytes). All antibodies were titered and used at saturating concentrations.
Statistical Analysis
Comparisons between the 2 groups were performed with the following statistical analysis:the Wilcoxon-Mann-Whitney U test was used for complete continuous data, the log-rank test was used for censored time-to-event data, and the chi-square test was used for discrete variables. If the time-to-event curves crossed, the modified Kolmogorov-Smirnov test for censored data was applied.11 The Kaplan-Meier method was used to estimate time-to-event distributions. If the assumptions of the chi-square test were violated, the Fisher exact test was applied. For correlative studies, the Wilcoxon rank sum test was used for bi-level comparison, a nonparametric analysis assessing whether 2 independent samples of marker values come from the same distribution. The tri-level comparisons were made using the Kruskal-Wallis test, testing for equality of medians across ≥3 groups. Any P value <.05 was considered to be statistically significant. All calculations were performed with SAS statistical software (version 9.1; SAS Institute Inc, Cary, NC).
Clinical Feature of TFR
The TFR often included a sudden onset (within hours of the first dose) of painful and tender enlargement of disease-involved lymph nodes, the spleen, and/or liver, which was often accompanied by low-grade fever, localized erythema, and/or generalized rash. The rash was often diffuse, erythematous, nonpruritic, and maculopapular in character. One patient also experienced bone pain concurrently with TFR that resolved with resolution of the TFR. Six of 45 patients also had an increase in their circulating leukemic cells (CD19+/CD5+) in the peripheral blood that eventually resolved with continued treatment (Table 1). The clinical characteristics of a typical TFR are illustrated in Figure 1.
|All Patients N = 45 (%)
|All Patients With Flare N = 30 (%)
|Group Aa N = 29 (%)
|Group Bb N = 16 (%)
|Lymph node swelling
|28 (62)
|28 (93)
|18 (62)
|10 (63)
|5 (11)
|5 (17)
|3 (10)
|2 (13)
|10 (22)
|10 (33)
|6 (21)
|4 (25)
|Bone pain
|1 (2)
|1 (3)
|1 (3)
|0 (0)
|Increase in ALC
|6 (13)
|6 (20)
|3 (10)
|3 (19)
- Top of page
- Abstract
- Acknowledgements
A total of 45 patients were enrolled on this clinical study. The patients had a median age of 64 years and had received a median of 3 prior treatments. Among the patients enrolled, 80% were male, 64% had advanced Rai stage, and 51% overexpressed zeta-associated protein (ZAP)-70 protein (Table 2).
|All Patients N = 45
|Group Aa N = 29
|Group Bb N = 16
|Median age (range), y
|64 (42-75)
|63 (47-74)
|65 (42-75)
|Sex, no. (%)
|36 (80)
|22 (76)
|14 (88)
|9 (20)
|7 (24)
|2 (12)
|Rai stage, no. (%)
|16 (36)
|10 (34)
|6 (38)
|29 (64)
|19 (66)
|10 (62)
|Median no. of prior treatments (range)
|3 (1-9)
|3 (1-9)
|1.5 (1-6)
|Median LDH, IU/L (range)
|565 (106-1450)
|561 (106-1429)
|601 (134-1450)
|Median baseline ALC, ×109/L (range)
|43.6 (0.7-339)
|45.9 (0.7-339)
|35.1 (3.5-327)
|ZAP-70, no. (%)
|23 (51)
|15 (52)
|8 (50)
|13 (29)
|8 (28)
|5 (31)
|9 (20)
|6 (21)
|3 (19)
|Allopurinol prophylaxis, no. (%)
|35 (78)
|22 (76)
|13 (81)
|1 (2)
|1 (3)
|Not given/unknown
|9 (20)
|6 (21)
|3 (19)
|TFR, no. (%)
|30 (67)
|19 (66)
|11 (69)
|Grade 1
|20 (67)
|10 (53)
|10 (91)
|Grade 2
|7 (23)
|7 (37)
|0 (0)
|Grade 3
|3 (10)
|2 (11)
|1 (9)
|Median time to onset (range), d
|6 (0-56)
|4 (0-38)
|9 (2-56)
|Median duration (95% CI), d
|14 (10-26)
|13 (10-25)
|28 (14-97)
|Clinical response
|CR, no. (%)
|8 (18)
|5 (17)
|3 (19)
|Treatment discontinuationd
Occurrence of TFR
Thirty patients (67%) experienced a TFR, 20 of which (67%) were grade 1, 7 (23%) were grade 2, and 3 (10%) were grade 3 (Table 2). The onset of the TFR was recorded as early when it occurred within 24 hours of the first dose of lenalidomide and, in >90% of cases, was noted only during the first treatment cycle. The median time interval from the initiation of lenalidomide treatment to the occurrence of a TFR was 6 days (range, 0 days-56 days). The median time to resolution of the TFR was 14 days (95% confidence interval [95% CI], 10 days-26 days). In Group A (n = 29 patients), 18 (62%) patients experienced TFR at the 25-mg dose and 1 patient developed TFR at the 15-mg dose. The median lenalidomide dose at the time of TFR in Group A was 25 mg (range, 15 mg-25 mg). The majority of TFRs occurring in Group A were of grade 1 in severity (53%), followed by 37% with grade 2 and 11% with grade 3.
Of the patients in Group B (starting dose of 10 mg), only 12 patients reached the 25-mg dose through dose escalation. Six patients required 42 days and 3 patients required >100 days (105 days, 133 days, and 182 days, respectively) to reach the 25-mg dose. Four patients did not reach 25 mg. The time to escalate to 25 mg of lenalidomide was computed (using censored data for patients who did not reach the 25-mg dose). The median time to reach the 25-mg dose of lenalidomide for these 16 patients was 46 days from the initiation of treatment (95% CI, 42 days-63 days). Among patients starting at the 10-mg dose (n = 16), 9 experienced TFR at the 10-mg dose and 2 patients experienced a TFR at a dose of 20 mg of lenalidomide. The median lenalidomide dose at the time of TFR in Group B was 10 mg (range, 10 mg-20 mg). In Group B, nearly all TFRs (91%) were grade 1, with none reported as grade 2 and only 1 patient (9%) experiencing a grade 3 TFR.
Risk Factors for TFR
We further analyzed the baseline clinical features of patients to ascertain risk factors predictive of TFR. We observed a statistically significant difference in the median age of the patients who either developed or did not develop a TFR (61 years vs 71 years, respectively; P = .004 using the 2-sided Wilcoxon test). Furthermore, patients who developed a TFR tended to have a higher stage of disease (73% with Rai stage III-IV disease vs 47% incidence), although this did not reach statistical significance (P = .08). To determine whether the increased incidence of TFR in patients with a higher disease stage was because of bulky disease, we correlated the presence of bulky disease (defined as any single lymph mode mass measuring 5 cm in any single dimension) with the clinical disease stage of the patients. The incidence of bulky disease in patients with Rai stage I, II/III, and IV disease was 100%, 50%, and 62%, respectively. There was no significant difference noted with regard to the incidence of TFR among patients with bulky versus nonbulky disease (65% [n = 17] vs 63% [n = 5]; P = 1.00). Furthermore, there was no significant association noted between TFR and gender, number of prior therapies, baseline absolute lymphocyte count, or ZAP-70 status in either group (P >.1).
Effect on Immune Cellular Microenvironment
Lenalidomide modulates the components of the immune cellular microenvironment and this might be an important mechanism underlying development of the TFR. Therefore, we investigated in a subset of patients (n = 18) whether baseline levels of immune effector cells including NK and T-lymphocyte subsets in peripheral blood correlated with the occurrence and intensity of TFR.
NK Cells
Pretreatment NK cell levels were analyzed as described earlier. We investigated whether pretreatment NK cell levels predict the intensity of a TFR. The median pretreatment NK cell level in patients with grade 1 versus those with grade 2 and 3 TFRs was 264 cells/mm3 (range, 36-1355) and 579 cells/mm3 (range, 164-2439), respectively (Fig. 2A). Using the Wilcoxon rank sum test, we found a statistically significant relation between pretreatment NK cell level and the intensity of the TFR (P = .05). We observed that individuals who developed more intense TFRs (grades 2 and 3) had a higher baseline NK cell level compared with those with less intense or no TFRs (grades 0 and 1). Furthermore, individuals with either normal or elevated baseline NK cell levels appeared to have a better quality of response to lenalidomide; among the 5 patients who achieved a CR, all but 1 patient had a normal or elevated baseline NK cell level. The median pretreatment NK cell level among patients with a clinical response (CR and partial response) compared with those with no response [all others]) was 448 cells/mm3 (range, 100-2439) and 303 cells/mm3 (range, 36-609), respectively. Clinical outcome (response vs no response) was compared using a logistic regression model and did not conclusively establish an association between pretreatment NK cell level and clinical outcome (P = .24). The 2 patients with stable disease also had elevated baseline NK cell levels, indicating that other as yet unidentified factors may also be important in the antileukemic effect of lenalidomide in patients with CLL.
T Cells
Pretreatment T suppressor (CD4+) and T cytotoxic (CD8+) cells were analyzed as described earlier (Figs. 2B-2D). A logistic regression model was used to determine an effect from T cells with respect to TFR grade (grade 1 vs grade 2 and grade 3). The logarithmic transform of the T cell count was used. The median number of CD4+ cells for the grade 1 TFR group (n = 12) was 729 cells/mm3 (range, 11-2073) versus 598 cells/mm3 (range, 182-5689) for the grade 2 (n = 6) and grade 3 TFR groups, respectively (P = .34). The median number of pretreatment CD8+ cells in patients with grade 1 versus those with grade 2 and grade 3 TFRs was 575 cells/mm3 (range, 141-2080) and 873 (range, 494-4021), respectively (P = .15). Using the Kruskal-Wallis test, we observed no significant relation between of baseline CD4+ counts and the intensity of the TFR (P = .9). It is interesting to note that the baseline level of CD8+ cytotoxic cells was found to be correlated with the intensity of the TFR (P = .05). In addition, the CD4/CD8 ratio at baseline was found to be a strong indicator of the intensity of the TFR (P = .01).
Management of TFR
In our clinical trial, management of the TFR included the use of a nonsteroidal anti-inflammatory drug (NSAID) (ibuprofen at a dose of 400-600 mg every 4-6 hours) with or without oral morphine sulfate (5-10 mg every 4-6 hours as needed) for additional pain control. Overall, 11 (37%) of the 30 patients exhibiting a TFR required treatment with ibuprofen; 7 (23%) were in Group A and 4 (13.3%) were in Group B. Only 3 (10%) patients (2 in Group A and 1 in Group B) received supplemental morphine sulfate for pain control. No patients required discontinuation of treatment or a dose reduction of lenalidomide for a TFR. The high incidence of TFR in Group A prompted us to investigate the prevention of this reaction with the use of low-dose corticosteroid therapy. None of the patients in Group A was given steroids either for the prevention or treatment of a TFR.
Correlation Between TFR and Response to Therapy
Lenalidomide induced a rapid and sustained decline in the peripheral blood tumor burden.6 Clinical response was compared among patients with or without a TFR. Despite a low sample size in our analysis, the probability of achieving a CR with lenalidomide alone was found to be correlated with the intensity of the TFR (Fig. 3). At the time of last follow-up, 8 patients had achieved a CR (5 in Group A and 3 in Group B). Among the 15 patients without a TFR, only 1 CR (7%) was observed versus 7 (23%) patients in the TFR group. Among patients with a grade 1 TFR, there were 4 CRs in 20 patients (20%); among patients with a grade 2 TFR, there were 2 CRs in 7 patients (29%); and among those with a grade 3 TFR, there was 1 CR in 3 patients (33%). The median progression-free survival (PFS) for patients with or without a TFR was 19.9 months and 19.4 months, respectively (P = .92).
Impact of Steroid Prophylaxis and Slow Dose Escalation
The impact of slow dose escalation of lenalidomide and low-dose corticosteroid prophylaxis was evaluated by comparing Groups A and B. Nineteen (66%) patients in Group A and 11 (69%) patients in Group B developed a TFR (P = .83, chi-square test). Among these individuals, grade 2 and 3 TFRs were observed in 9 patients (47%) and 1 patient (9%) n Groups A and B, respectively (P = .05). The median time to the onset of the TFR was 4 days in Group A and 9 days in Group B (P = .01). The median time to resolution of a TFR was 13 days in Group A and 26 days in Group B (P = .16). We further evaluated the impact of steroids on PFS in patients treated with lenalidomide. The median PFS for patients who did not receive corticosteroids prophylaxis (Group A) compared with those who did (Group B) was 23 months versus 17.8 months, respectively (P = .74 by the log-rank test and P = .88 using the modified Kolmogorov-Smirnov test). Our analysis failed to demonstrate a statistically significant difference in PFS.
- Top of page
- Abstract
- Acknowledgements
Lenalidomide is clinically active as a single agent in patients with CLL. Two clinical studies in patients with recurrent or refractory CLL reported response rates of 58% and 32%, respectively, with lenalidomide monotherapy.5, 12 In the current study, TFR, an adverse event that to our knowledge has not been reported with lenalidomide treatment in patients with other disease entities, occurred in 67% of individuals with CLL who were treated with lenalidomide. These rates are lower than observed in the previous study by Andritsos et al, who reported serious TFRs in 3 of 4 patients (75%), although the differences in lenalidomide dose, TFR prophylaxis administration, study population, and total patient numbers could account for these differences.13
In the current study, the use of an NSAID, ibuprofen, was effective in managing the pain associated with TFR and rarely oral morphine sulfate was administered for severe pain. We observed that prophylaxis with prednisone decreased the severity but not the incidence of TFR. In our experience, TFR was well tolerated, with none of the patients requiring discontinuation or a dose reduction of therapy.
Lenalidomide-associated TFR was characterized by a proinflammatory clinical picture suggestive of an immune-mediated tumor recognition phenomenon. We note that the immunomodulatory activity of lenalidomide in vivo may be integrally related to the development of the TFR.14 The presence of an adequate amount of NK cells in peripheral blood circulation appeared to be correlated with the intensity of the TFR and also improved the response to therapy. Pre-existing immune factors (such as NK cells) that are associated with clinical response to lenalidomide suggest that lenalidomide requires immune components for its antitumor activity. We observed a higher intensity of TFR in patients who initiated therapy with lenalidomide at a higher dose and without prophylaxis and the intensity of the TFR appeared to be correlated with a higher probability of achieving a CR. The exact clinical impact of TFR remains uncertain; although our analysis was limited by small sample size, it did not demonstrate any benefit in the PFS despite a higher CR rate in the TFR group. A potential clinical significance of TFR maybe a high probability of achieving a CR, which in turn may be associated with an improved PFS. In the clinical trial reported by Ferrajoli et al, no association between TFR and response was noted.12 The disparity in this observation may reflect different patient populations and variable dosing schedules as well as starting dose. Ongoing clinical trials with a large sample size should be able answer this question.
The identification and careful characterization of a TFR is important in the treatment of CLL patients with lenalidomide to avoid unnecessary morbidity or the premature discontinuation of effective therapy. We recommend close monitoring of patients with CLL for signs of TFR (ie, enlargement of lymph nodes, rash, and changes in the ALC) during the first 10 days of lenalidomide therapy. It is particularly important to monitor lymph nodes close to the liver and kidneys. If a TFR occurs, we recommend treatment with an NSAID such as ibuprofen (at a dose of 400- 600 mg every 6 hours), with steroid use considered only in cases of more intense TFRs. Although in the current study we did not need to withhold or reduce the dose of lenalidomide out of concerns for TFR, in severe cases of TFR this may be warranted along with steroid treatment. Alternatively, a slow dose escalation strategy such as that used in Group B in the current study may reduce the intensity of TFR and should be considered. The dose of lenalidomide can be increased again once the TFR subsides. In severe cases, therapy with low-dose corticosteroids can be used to decrease the severity of the TFR although, as previously discussed, this can potentially undermine antitumor responses. In our experience, it is not necessary to discontinue lenalidomide therapy for a TFR.
In conclusion, the occurrence of a TFR appears to result from the immune-stimulating activity of lenalidomide in patients with CLL. Preclinical evaluations suggest that 1 possibly important effect of lenalidomide may be the activation of T cell-mediated anti-CLL effects. Although these in vitro observations add new information regarding the potential immunologic effect of lenalidomide and thus may explain clinical immunologic phenomenon such as TFR, clinical validations are pending.15 Our clinical observation that the intensity of the TFR is correlated with the probability of achieving a CR is interesting and requires further validation and may suggest that this is an important phenomenon linked to lenalidomide's response in patients with CLL. Because of its high incidence, its considerable morbidity, and its clinical presentation resembling progressive disease, the early recognition and accurate diagnosis of TFR is imperative for the effective use of lenalidomide in patients with CLL. Further studies are warranted to elucidate the underlying pathophysiological mechanisms responsible for the development of the lenalidomide-associated TFR in patients with CLL.
- Top of page
- Abstract
- Acknowledgements
We acknowledge Celgene Corporation for their support in funding this clinical trial and the Leukemia & Lymphoma Society for their grant support (to A.C.K.). We would also like to acknowledge the contributions of S. Bilgrami, Gregory Wilding, Laurie Musial, and Sikander Ailawadhi in the preparation of this article.
- Top of page
- Abstract
- Acknowledgements
This project is partly supported by the Jerra Barit Myeloma Research Fund (to A.C.K.) and the Leukemia & Lymphoma Society (to A.C.K.). Celgene Corporation has provided funding for this clinical trial. Dr. Chanan-Khan has received support from Millennium Pharmaceuticals and Celgene Corporation. Ms. Miller is a member of the Speakers' Bureau for Millennium Pharmaceuticals and the Advisory Board for Celgene Corporation. Dr. Zeldis is the Chief Medical Officer for Celgene Corporation, owns stock in the company, and is salaried. Dr. Ailawadhi is a member of the Speakers' Bureau for both Celgene Corporation and Millennium Pharmaceuticals.
- Top of page
- Abstract
- Acknowledgements
- 1Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002; 100: 3063-3067., , , et al.
- 2Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005; 352: 549-557., , , et al.
- 3Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006; 108: 618-621., , , et al.
- 4
- 5Clinical activity of lenalidomide in relapsed or refractory chronic lymphocytic leukemia (CLL) patients: updated results of a phase II clinical trial. Leuk Lymphoma. 2007; 48(suppl 1): S166., , , et al.
- 6Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006; 24: 5343-5349., , , et al.
- 7Characterization of IMiDs (immunomodulating agents) induced "flare reaction" in patients with chronic lymphocytic leukemia (CLL) and correlation with changes in serum cytokine levels [abstract]. Blood. 2005; 106: 5049., , , et al.
- 8Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group [abstract]. J Clin Oncol. 2007; 25: LBA8025., , , et al.
- 9Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL). Blood. 2005; 106: 3348-3352., , , et al.
- 10N9986: a phase II trial of thalidomide in patients with relapsed chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50:588-592., , , , ,
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Windows 7 Graphic Apps software downloads
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Image Dream brings out the hidden beauty of your pictures.
Price: $49.99 / Demo
Turn average photos into stunning images.
Price: $39.99 / Shareware
Photo-Lux is an easy-to-use but powerful and fast image viewer and more.
Price: $70.00 / Shareware
Image management with integrated editing tools, keyword lists and descriptions
Price: $79.99 / Shareware
View, organize, and enhance your photos more quickly and easily than ever before
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Advanced graphic batch converterr with lot of image processing features.
Price: $19.99 / Demo
"Xorax Contact Sheet" is a simple tool that generates contact sheet (index file)
Price: $44.99 / Shareware
Image management and digital darkroom package with extensive interactive manual.
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Multi-frame GIF Creator.
Price: $39.00 / Shareware
Best Game, Video and Desktop Recording software - much less Lag/CPU/HDD usage
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Utility to create HTML album for your photos.
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A program that reduces visible noise in digital photographic images
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An all-in-one software for software developers, graphic designers and home user
Price: $279.00 / Trialware
Capture One is a raw converter and workflow software
Price: $95.00 / Trialware
The powerful browser based tool for viewing and manipulating digital images
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AnyRail makes model railroad design so easy, it's fun!
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Free batch image converter and picture editor: JPG,PNG,GIF, BMP,TIF/TIFF
Price: FREE / Freeware
Irripro software is able for easily designing irrigation system in powerful way.
Price: FREE / Freeware
PDF Multitool extracts data from PDF as CSV, XML, XLS, Text
Price: $109.99 / Shareware
The easiest way to create perfect design projects!
Price: $9.95 / Shareware
Screen capture program that lets you save, copy or print the captured image.
Price: $129.99 / Shareware
TurboCAD Deluxe: Powerful 2D/3D drafting, modeling, and photorealistic rendering
Price: $55.00 / Shareware
Multipage tif, pdf, eps, ai, dcx viewer, editor and converter.
Price: FREE / Freeware
Prints a greeting card on 8.5x11 half-fold card stock.
Price: FREE / Freeware
Irripro software is able for easily designing irrigation system in powerful way.
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