text:
First. I would like to invite everyone to a special Zazen & Talk by my Dharma Bro. BRAD WARNER, to be live streamed from Treeleaf this Sunday June 5th (and available any time after). Brad will introduce his new book, DON'T BE A JERK, ...Read More »
A physical practice
Hey all. It's been a long while, hasn't it? Life has taken many twists and turns for me....
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First. I would like to invite everyone to a special Zazen & Talk by my Dharma Bro....
Another Memorial Day, Another Donut
With palms together, I often say Zen saved my life, but that is only partly true and now Memorial Da...
THE MYSTERIOUS MATSUOKA (Part 3 of a Series)
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I came to zazen through a series of fortunate accidents, the right encounters at the right times. Near the end of high school, my best friend's dad was cleaning out his attic and found an old, dusty copy of Philip Kapleau's Three Pillars of Zazen that he had read in college.Read More »
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text:
Warzone Europe
Warzone Europe is a Warzone! The WA Delegate may eject nations as it pleases, but bans are temporary. The region cannot be password-protected and has no Founder.
WA Delegate: The WZEU Governor of Apulita (elected )
Longest-serving Delegate: The WZEU Governor of Apulita (725 days)
Embassies: Warzone Africa, Warzone Airspace, Warzone Australia, Warzone Sandbox, Equilism, the Rejected Realms, Mordor, The East Pacific, Osiris, Spiritus, Hippy Haven, the West Pacific, Kingdom of Alexandria, and One big Island.
Tags: Offsite Forums, Neutral, Game Player, Monarchist, Surreal, Independent, Featured, Medium, Warzone, Regional Government, Democratic, Silly, and 6 others.Social, Casual, Snarky, Founderless, Serious, and Magical.
Regional Power: Moderate
Warzone Europe contains 40 nations, the 333rd most in the world.
Today's World Census Report
The Most Subsidized Industry in Warzone Europe
Nations ranked highly spend the most on developing and supporting industry, a practice known as 'corporate welfare.'
As a region, Warzone Europe is ranked 3,600th in the world for Most Subsidized Industry.
|WA Category
|The Republic of Warzone Master Man
|Moralistic Democracy
|"We shall overcome all"
|The Hat-less Chairman of North Campbell Nation
|Father Knows Best State
|"No People's Republic, No new Warzone Asia!"
|The Socialist State of Garrior
|Democratic Socialists
|"Chill, okay, friend"
|The Senior IM and MoD of WZEU of Ancian
|Father Knows Best State
|" Warzone Independance"
|The WZEU Gendarmerie Officer of Dimension Facilities
|Psychotic Dictatorship
|"Into the future, two steps at a time!"
|The Theocracy of Backpackus
|Left-wing Utopia
|"The Odyssey of Running a Nation"
|The Graiý Hes of Daerith
|Iron Fist Consumerists
|"Godt beþiren hlælp ts Kinýg!"
|The Republic of DoTheJakartaShake
|Inoffensive Centrist Democracy
|"Undod Mewn Amrywaieth"
|The Nomadic Peoples of M0
|Democratic Socialists
|"Make each day your masterpiece."
|The Feared Nation of United states of euroasia
|Corporate Police State
|"Memento mori"
Last poll: "Election Interest!"
Regional Happenings
- : The Protectorate of Imperial Puppet 3 arrived from Warzone Sandbox.
- : The Borderlands of Imperial Puppet 2 arrived from The North Pacific.
- : The Empire of Imperial Puppet 1 arrived from The North Pacific.
- : The Original Councillor of ProfessorHenn arrived from Cynosure.
- : The Grand Duchy of Castle Blackhaven departed this region for Warzone Africa.
- : The Grand Duchy of Castle Blackhaven arrived from Warzone Australia.
- : Saint dumas ii departed this region for The Legion of Light.
- : The Queendom of Romanovian Federal Russia departed this region for The North Pacific.
- : The Queendom of Romanovian Federal Russia arrived from The North Pacific.
- : Saint dumas ii arrived from KAISERREICH.
Warzone Europe Regional Message Board
Hey Hey
The Dingo Ate your baby
What do you guys think about my flag?
No triple posting.
Hi larry
Hi larry
I'm very confused by all of this...
Its from spongebob
5 days until Apu's 2-year mark in the big chair! Let's see how this goes...
inb4 coup. :P

subset: commoncrawl


text:
Creatin' "Ain't Misbehavin'"
Song of the rabbit and the duck
Jeff Smith 9 a.m., July 30
Serving beer on cask allows for the inclusion of numerous flavor-enhancing ingredients. Many go with hops, coffee beans, cacao nibs, herbs, and spices. For this session IPA collaborated with Ensanada's Cervezeria Wendlandt at Monkey Paw Pub & Brewery -- they're infusing corn chips, lemon, lime, and tamarind sugar.
805 16th Street, San Diego, 92101
Get directions
Please log in to submit event corrections


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Moshe Manoah Is Definitely An Fantastic Achiever
Actual estate enhancement calls for lot of commitment to the portion in the builders. They need to have extreme patience too require a huge passion to do well. These promotions demand land acquisition in the existing homeowners. Acquisition of land is rarely an uncomplicated task. There may be litigation in… Read more »


text:
The Best Way to Learn
It's easy to learn a new skill by following walkthroughs, guides, and tutorials. But one of the most effective ways to learn something new is by trial and error or experiential learning. Manu Kapur, a researcher at the Learning Sciences Lab at the Singapore National Institute of Education calls this "productive failure".
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I stayed here for 4 nights and i wish i had more time.
The staff were really helpful and always willing to do more. The room was clean with everything working properly. The pool was clean too and always enough seats - when the pool staff get to knnow you after 1 or 2 days they tend to reserve your bed for you.
We had half board but only found out that we could eat at the casino on the 3rd night - the food in the casino was to die for! I had to keep asking if they were sure that it was covered because it was that good. We spent 2 and half hours eating and drinking! We ate in the hotel the first two nights and i was really pleased with that also.
We went to a Moroccan themed night that the hotel had planned which consisted of us eating traditional moroccan food with a Moroccan show. This was fantastic! The food was really good and i am Moroccan so i can judge Moroccan food really well, the portions were massive too. They had live bands, belly dancers and gymnasts etc.
The hotel was about 10 minutes in a cab from old marrakesh and possibly 2-3 minutes from new marrakesh so it was a good balance. The hotel is stuck on to a casino if you go to the back of the hotel. From there you can also access shisha cafes and other bars.
I only managed to wake up for breakfast once ( its a holiday!), but the one day that i did go down i had a good full breakfast. Eating breakfast in the garden is like nothing ive experienced before, listening to the birds and the trees, it was actually very quiet on my table i think every one was just enjoying the food an the surroundings. I had soup and some croissants with almond something in them - it was really good! The fruit was fresh too.
The main thing i remember about this hotel is about how attentive the staff were. I was feeling very poorly one day and the staff asked if i was alright, i told them about how i felt and the next morning i had the receptionist knocking on my door checking to see how i am and if they could go to the pharmacy for me! You cant buy service like that.
- Official Description (provided by the hotel):
- Not far from the bustling Medina full of history, in the heart of the peaceful Hivernage and in a 8-hectare green park, the Es Saadi Palace is at 10-minute walk from Jemaa el -Fna. Facing the snow-capped Atlas Mountains, the Palace has the largest outdoor swimming-pool of Hivernage (2 400m²) and a 3 000 m² Spa including a Dior Institute. It covers 82 suites, 10 unique villas and 8 ksars (160m² rammed clay house). The Es Saadi Palace includes 2 restaurants including a gourmet Moroccan restaurant and 3 bars. Guests have privileged access to the casino with the famous restaurant L'Epicurien and its late-dining concept, and at the Theatro nightclub, the Es Saadi Marrakesh Resort facilities. It offers free Wi-Fi and private parking on site. Marrakech-Menara Airport is at 10 minutes. ... more less
- Reservation Options:
- TripAdvisor is proud to partner with Hotels.com, Booking.com, Expedia, Hotwire, HotelTravel.com, Cheap Tickets, Agoda, Priceline, Odigeo and Travelocity so you can book your Es Saadi Marrakech Resort - Palace reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
- Also Known As:
- Es Saadi Palace Marrakech


text:
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Native Plants
Q. Who is Mr. Smarty Plants?
A: There are those who suspect Wildflower Center volunteers are the culpable and capable culprits. Yet, others think staff members play some, albeit small, role. You can torture us with your plant questions, but we will never reveal the Green Guru's secret identity.
Did you know you can access the Native Plant Information Network with your web-enabled smartphone?
Ask Mr. Smarty Plants is a free service provided by the staff and volunteers at the Lady Bird Johnson Wildflower Center.
rate this answer
Friday - November 12, 2010
From: New Iberia, LA
Region: Southeast
Topic: Compost and Mulch, Seeds and Seeding, Herbs/Forbs
Title: Black-eyed Susans in potting soil on ground
Answered by: Brigid & Larry Larson
QUESTION:I would like to know if black eyed susans can be planted in just potting soil instead of mixing it in with dirt from the ground? I don't want to leave it in the pots. I want to plant it, but the ground is very hard, so I want to know if I can plant it above the ground in potting soil.
Yes, I see that your soil is one that the USDA calls "Level, poorly drained clayey soils' - so I bet it's hard to dig up. Good News - Rudbeckia hirta (Black-eyed susan) is a native to your area and will grow happily in moist to dry, well-drained soils. Yes, the plants can be grown in potting soil, but better alternatives are to grow them from seed, amend your soil, or build a raised bed.
The seeds will germinate nicely if you merely scratch up your regular soil and then just scatter the seeds on the ground making sure they make good contact with the earth. Black-eyed Susan is so adaptable that you really don't have to do much to help it along. Many of the Black-eyed Susans found in nurseries are hybrid, bred for their showy blossoms. The Lady Bird Johnson Wildflower Center recommends that you purchase seeds from a native seed source like Native American Seed. However, from the phrasing of your question, it sounds like you already have your plants in pots.
I would recommend that you amend your soil with some compost, before planting. That would loosen up the dirt and add nutrients to the soil. Black-eyed Susans are a very hardy perennial. Just be sure to plant them at the same soil level that they were grown in the pot. Another solution, which helps the drainage is to build raised beds, add compost, crushed decomposed granite, and plant your Black-eyed Susan and other flowers. They will love it!
Rudbeckia hirta var. pulcherrima
More Compost and Mulch Questions
Transplant shock in Mountain Laurel in San Antonio, TX
June 03, 2011 - I planted a 2 ft. tall Texas mountain laurel a month ago. Some of the leaves have turned very yellow and some of them are falling off. The plant doesn't look real healthy in general. I did add s...
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December 26, 2010 - Greetings, Is it a good idea to allow oak leaves to pile up at the base of our California live oak? Will that cause fungus, mold and rot that hurts the tree? Thanks for your advice.
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Holding bare soil before sowing native grasses in spring.
November 03, 2009 - I want to try your buffalo/bluegrama/curly mesquite. Right now my yard is ploughed. What should I do until spring? I assume I should add living compost to the top 3", plant bluegrass for now, and ...
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How to make a lawn into a prairie in Arlington, Texas
September 15, 2010 - I am removing lawn grasses in order to start a native prairie meadow. After grass removal, I'll put down 1/2" of compost. I will broadcast wildflower seeds on the compost. If I mulch after broadcas...
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Too late to begin planting in May in Austin?
April 30, 2008 - Is it too late to begin planting in May? I live in Austin Texas and have finally completed my plans for a native Texas landscaping (plants and grass) of my front yard. I'd like to get the landscapi...
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|Support the Wildflower Center by Donating Online or Becoming a Member today.


text:
The View from Amethyst Beach
- 104 views
- 43 clicks
- 6 admirers
Feb 8, 2012
Wow, pretty!
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Beautiful! Great job!!! Thank you.
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So pretty, thank you!
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Cream color, males and females available. Lakenormankennels.com
Vet checked, wormed and immunizations for age, checked for coccidia accompanied by vet records. F1B, which is the most hypoallergenic. I own the mothers, mother and grandmother age 13. The father is AKC poodle and also on...
Corvette Roadster
1971 Corvette roadster, E/C, original factory, numbers matching, 350 C.I., 4-speed, A/C, Tilt/Tele., electric windows, vintage look AM/FM w/inputs, 57K original miles, new T/A Radials, Red, W/ black top and Interior. $25,000.
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Brittany's AKC OFA
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Uptown: 901 W 1st St Saturday, 9am-1pm
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Art - Hermitage Masterpieces, Volumes 1-18 (3-DVD)
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Format: DVD (3 Discs)
sku: STA 21D
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DVD Details
- Number of Discs: 3
- Run Time: 9 hours
- Video: Color
- Encoding: Region 1 (USA & Canada)
- Originally Released: 1992
- Label: WLIW21 Public Television/Studio Quart
Description by OLDIES.com:
The Hermitage museum in St. Petersburg, Russia is home to more than 2.5 million masterpieces from every school of Western art. In this 18-part series, stunning images of rarely seen treasures are illuminated by fascinating narrative about the art, the artists and their times, and set to classical music for a unique and memorable viewing experience.
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Versus: Round 1916
Tom is back with a few players going head to head in fantasy.Read more ›
Milestones were everywhere in round 19 including Jimmy Bartel's 300th. What a legend. One of the first true premiums.
Discuss round 19 as it unfolds in the comments. Proudly brought to you by moneyball.com.au.
Jump inside for all our hard-researched Moneyball tips designed to help you win big DFS bucks! Don't forget to pump the Match Committee podcast for Round 19 while you craft those winning sides.
This is it,the final minor round for all those leagues that haven't started finals yet. So, if you aren't in the top 8, this is the time to shine and do bloody everything you can to to get in there.
No Late changes Cats vs Dogs, Lockout @7:50pm!
Tom is back with a few players going head to head in fantasy.Read more ›
Need a captain, or even just some information about super premiums and how they will go this week? Check out the pirates take on it all.Read more ›
The round 18 edition of the Fantasy Freako Wrap for the 2016 season is now ready for download thanks to our friends at Champion Data.Read more ›
Jeppa is back from holidays and ready to give us more rookie analysis. There are plenty of fresh faces to choose from this week so this is a must read. Enjoy.Read more ›
Pete is back and goes inside the Fantasy numbers.Read more ›
It's one week from finals and many people need to make the right moves in order to consolidate a spot in the top 8, as opposed to being relegated to the 'Tit Ed' Cup.Read more ›
Round 19 is the last round before the Fantasy Finals start. Join Roy, Calvin and Warnie as they help you win a premiership this year.Read more ›
Discuss your round 19 trades and bye round thoughts in My Team. Get involved in the DT Talk community to discuss trades, captains and everything to do with your team in My Team!Read more ›


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im looking for a good horsee.
Boarding Lessons and WERE FULL on BOARDING not LEssons
All Around Show Horses
Kaylee Stables is a new facility where you can enjoy horseback riding, camping, hiking, and fishing; we also offer riding lessons for all ages and…
small. have our own horses
Foxhunting, jumping, English pleasure
we give riding lessons to any level of riding and also exercise a wide variety of breeds.


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2014 Murano
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2014 Nissan Murano Specs
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2014 Murano Specifications
: 3.5L V 6 DOHC with Continuously Variable Valve Timing Control System (CVTCS) variable valve timing
: Unleaded fuel
Fuel economy
: Gasoline 18 MPG city, 23 MPG highway, 20 MPG combined and 433 mi. range
Fuel Injection
: Multi-point fuel injection
Fuel Capacity
: 21.7gallon fuel tank
Power (SAE)
: 260 hp @ 6,000 rpm; 240 ft lb of torque @ 4,400 rpm
5.173:1 axle ratio
Brake assist system
Center differential lock
Four-wheel disc brakes: four ventilated
Electronic brake distribution
Electronic traction control (via ABS & engine management)
Space-saver spare tire with steel rim
Vehicle Dynamic Control (VDC) stability control
Independent front strut suspension with stabilizer bar and coil springs, independent rear multi-link suspension with stabilizer bar and coil springs
Driver and passenger fixed 3rd row windows
Body-color front and rear bumpers
Body-color driver and passenger power door mirrors
External dimensions: overall length (inches): 189.9, overall width (inches): 74.1, overall height (inches): 67.0, ground clearance (inches): 7.3, wheelbase (inches): 111.2, front track (inches): 63.4, rear track (inches): 63.4 and curb to curb turning circle (feet): 38.1
Headlights: halogen with projector beam lenses
Alloy trim and none
Pearl paint
Rear side windows: wind-up on driver side and passenger side
Fixed rear window with defroster
Roof spoiler
Tinted glass
Weights: gross vehicle weight (lbs): 5,133, published curb weight (lbs): 3,971, gross trailer weight braked (lbs): 3,500, payload allowance (lbs): 1,162, Manufacturer's own, 2,328 and 1,588
Intermittent windshield wipers
Two 12V power outlet(s) in front, one 12V power outlet(s) in cargo area
Dual-zone climate control
Diversity antenna
Audio system with AM/FM radio, six CDs (reads MP3 format)
Cargo area dimensions: length (inches): 29.6, front width (inches): 54.7, height (inches): 32.5 and loading floor height (inches): 30.8
Cargo area light
Cargo capacity: rear seat down (cu ft): 64.5, all seats in place (cu ft): 31.8 and Manufacturer's own
Trip computer: includes average speed, average fuel economy and range for remaining fuel
Floor console, overhead console
Cruise control
Front cup holders
Outside air temperature indicator
Floor covering: carpet in passenger compartment, carpet in load area and none
Intelligent driver and passenger front airbag
Driver bucket front seat manual height and manual lumbar, front passenger seat bucket front seat
Height adjustable driver and passenger front seat belts with pre-tensioners
Front seat center armrest
Two active height-adjustable front seat head restraints, three height-adjustable rear seat head restraints
Internal dimensions: front headroom (inches): 40.1, rear headroom (inches): 39.4, front hip room (inches): 54.8, rear hip room (inches): 55.4, front leg room (inches): 43.6, rear leg room (inches): 36.3, front shoulder room (inches): 59.6, rear shoulder room (inches): 58.7 and interior volume (cu ft): 108.6
Low tire pressure indicator
Card key power locks : includes power windows ; automatic locking
Vehicle speed-proportional power steering
Front windows with one-touch on two windows, rear windows
Front and rear reading lights
Height adjustable rear seat belt, height adjustable passenger rear seat belt, 3-point center rear seat belt
Rear seat center armrest
Split-folding rear seats: manual recline and remote folding
Rear view mirror
Remote control trunk/hatch release
Front and rear curtain airbag
Seating: five passengers
Upholstery cloth
Service interval indicator
Front side airbag
Intelligent Key smart card/smart key with keyless entry includes keyless starter
Six speakers
Tilt telescoping steering wheel
Illuminated driver and passenger vanity mirror
Ventilation system with micro filter and automatic recirculation
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Panasonic has introduced the AJ-YBX200 codec board, which allows both the AJ-HPX2100 production camcorder and the AJ-HPM100 field edit and playback device to operate in the new AVC-I codec.
Since its debut, Panasonic has intended to incorporate AVC-I, an intra-frame-only, H.264 codec, into selected equipment alongside the DVCPRO HD format.
The AVC-I codec enables producers to create content in two bit rates, one offering greater economy in storage space, the other offering higher-resolution images. In 50m mode, the AJ-HPX2100 can record content close to DVCPRO HD quality at half the bit rate, effectively doubling storage capacity. In 100m mode, the AJ-HPX2100 can record images at near HDD5 quality.
The inclusion of the AVC-I codec provides the AJ-HPX2100 and the AJ-HPM100 field editor with a better compression scheme. It also offers DVCPRO HD quality at one-half the bandwidth. This means that a single 32GB P2 card can record more than one hour of HD content.
For more information, visit www.panasonic-broadcast.com.
Comic-Con: AMC Unveils 'Walking Dead' Season 7 Premiere Date, Trailer
Fans Binge on the Third Season of Netflix's 'BoJack Horseman'
Washington State Utility Commission Has BDS Issues With FCC
Sunbeam, Dish Extend Retrans Talks
Reports: Verizon Finalizes $4.8B Yahoo Deal
Comic Con: Rihanna To Appear In Final Season of 'Bates Motel'
Staff Writer – Music Week
German pay-TV revenue to hit €3 billion in 2016
Live HD and VR streaming for iPhones
Lance Acord Directs Spots for YouTube Music
Tips to Clip: August 2016
All the World's a Stage: But Let's Make It Look Like a Movie


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Role - Multi Drop Delivery Driver
Contract - On-going Temporary
Rate of Pay - £7.20 - £10.60 per hour
Location - Swansea, but will require knowledge of South West Wales area
Centric Recruitment are immediately recruiting Multi Drop Drivers for a well-established courier firm. This position may start on an ad-hoc basis.
Main responsibilities:
* Assisting in the morning sortation of parcels ... more about Multi Drop Deliver Driver
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Latest Weather Blog
BRAVE goes to school to talk to students
BATON ROUGE- Students at Capitol High got a first hand look at the major players in the fight against crime, including the top law enforcement officials involved in the BRAVE program.
The students held an open forum to discuss the best ways to escape street violence and lead a successful life.
During the talk, students didn't hold back on what they think leads young people into gangs.
"They want to have a sense of being loved and they want to belong to something, and sometimes they don't find that at home, because it's not easy to have two parents, they often have single moms or single dads that have to take care of them and that's not always easy," said Danielle Howard, a senior at Capitol High.
One student told the crowd a story about how he got respect from people in his neighborhood, because of his success in school.
"You can get street cred by going to college and getting out of the hood, because, generally people say, people don't want to see that, but I think people do, because when you're doing the right thing, I think people look up to you and think this person is doing all right, that's how you get street cred, that's the right way to get street cred," said Javonta Rogers, who plans on going to a junior college in Mississippi.
Students also learned about resources available to them and their families provided by BRAVE, the Family Youth Resource Center, and faith based programs.
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Donations sought to upgrade police ballistic vests
BRAF's First Responders Fund has netted $200k+ in donations
Eight-year-old boy makes $20K donation to first responders fund


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Ebony is a 11 y/o (in 2016) solidly built 16.1h TB/Percheron mare. Ebony has hunted with Beaver Meadow Foxhounds for 7 years in first and second field…SOLD
Trail Horse! Cash is a 4 year old, 15.3hh Registered Tennessee Walker Gelding walks, run walks, Canters Cash is a gorgeous Sorrel gelding with a Flax…SOLD
SALE PENDING - Nice blue roan quarter horse, certified by NFQHA at 84% foundation blood. Has had 60 days professional training but still a bit green. Great…SOLD
For Sale: Remember The Titan is a flashy 2007, 12.1HH Welsh pony. Show experience at the 'A' shows in the Short Stirrup; finished 5 overall in 2015. Top…SOLD
SPEED IS NOTHING WITHOUT CONTROL This old lady still can take you to town and back in a heartbeat - looking good doing it! This mare wants to work and…SOLD
This boy is a very settled and mature minded guy who will be the same wherever you take him. He has had several months professional training and is now…SOLD
There might not even be a dozen registered Quarter Horses with his color and if you also consider his excellent breeding, great conformation and his athletic…SOLD
For Sale: Zanna is a lovely 2011, 16.3HH registered Oldenburg mare by Harvard. She is currently broke w/t/c and started jumping courses. She is very willing…SOLD


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You have the power to end brain cancer.
Surgery is sometimes used to treat cancer of unknown primary (CUP). With CUP, the cancer has already spread beyond the place where it started, so surgery may not be helpful. However, surgery may be used to:
The type of surgery done depends mainly on the size and location of the cancer and other factors, such as a person's overall health. Side effects of surgery depend on the type of surgical procedure.
Radiation therapy, and possibly chemotherapy, is sometimes given after surgery to destroy any cancer cells that may have been left behind.
A clinical trial led by the Society's NCIC Clinical Trials group found that men with prostate cancer who are treated with intermittent courses of hormone therapy live as long as those receiving continuous therapy.


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From Our Editors
From household items to basic necessities, Lawn and Landscape Gardens in Circle Pines offers bulk items at a price you can't find anywhere else.
Perfect for the warmer months, the outdoor furniture here is just what you need to make your patio complete.
Here you can find a range of nearby parking spots, which helps make your commute less stressful. Lawn and Landscape Gardens in Circle Pines has everything you need to keep your life running smoothly, from essentials to home goodies, so head on over today.


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Malignant Melanoma Treatment & Management
- Author: Winston W Tan, MD, FACP; Chief Editor: Dirk M Elston, MD more...
Approach Considerations
Surgery is the definitive treatment for early-stage melanoma. Wide local excision with sentinel lymph node biopsy and/or elective lymph node dissection (LND) is considered the mainstay of treatment for patients with primary melanoma. In patients with solitary or acutely symptomatic brain metastases, surgical management may alleviate symptoms and provide local control of disease.[24]
Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy of patients with advanced melanoma. Less than one half of patients with deep primaries (>4 mm) or regional lymph node involvement have long-term disease-free survival; consequently, these patients are classified as high risk and should be considered for adjuvant therapy.
Interferon alfa is approved for adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence. Currently, there are no standard systemic therapeutic regimens that offer significant prolongation of survival for most patients with metastatic melanoma without significant risk of toxicities.In patients with BRAF V600 wild-type unresectable or metastatic melanoma, however, the introduction of immune-based therapy has resulted in improved survival.
Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck Mucosal Melanomas.
Adjuvant Therapy
Gould Rothberg et al developed and validated a multimarker prognostic assay for determining survival in stage II melanoma, which these researchers suggest might be beneficial in improving the selection of patients for adjuvant therapy.[25] Multiple iterations of a genetic algorithm using the automated quantitative analysis (AQUA) method for immunofluorescence-based immunohistochemistry on 246 serial primary melanomas yielded a consistent five-marker solution. A favorable prognosis was predicted by the following criteria:
ATF2 ln(non-nuclear/nuclear AQUA score ratio) greater than -0.052
p21(WAF1) nuclear compartment AQUA score greater than 12.98
p16(INK4A) ln(non-nuclear/nuclear AQUA score ratio) -0.083 or less
Beta-catenin total AQUA score greater than 38.68
Fibronectin total AQUA score 57.93 or less
Primary tumors that met at least four of these five conditions were considered low risk. Validation of the score showed that tumors in the high-risk group (those that met three or fewer conditions) were associated with significantly reduced survival (hazard ratio, 2.72; 95% confidence interval, 1.12-6.58; P = 0.027).
Interferon alfa
A large multicenter study using high-dose interferon (IFN) alfa-2b, Eastern Cooperative Group (ECOG) 1684, showed improvement in disease-free survival and survival benefit (time to progression improvement of 8 months, with a 1-year survival benefit).[26] On the basis of ECOG-1684, the US Food and Drug Administration (FDA) approved IFN as adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence.
A pooled analysis of 1016 patients and 716 observational controls from all ECOG trials showed a significant increase in relapse-free survival (P = 0.006) but not overall survival (P = 0.42).[27]
Concerns about toxicity associated with high-dose adjuvant interferon alfa have prompted several investigators to test lower doses of the drug. Lower-dose adjuvant interferon alfa has demonstrated less toxicity than high-dose interferon alfa but also less efficacy in delaying progression, with no survival advantage.
To investigate the possibility that the survival benefit seen in ECOG-1684 had to do with its incorporation of an induction phase of maximally tolerated dosages of IFN given intravenously for the initial 4 weeks, Pectasides et al conducted a prospective, randomized study in 364 patients with stage IIB, IIC, or III melanoma who had undergone curative surgery. Patients were randomly assigned to receive IFN-alpha-2b IV for 5/7 days weekly for 4 weeks (arm A) versus the same induction regimen followed by IFN-alpha-2b administered subcutaneously 3 times a week for 48 weeks (arm B). At a median follow-up of 63 months, there were no significant differences in overall survival and relapse-free survival between the 2 arms, and patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity.[28]
On the other hand, Hauschild et al found that the addition of a 4-week modified high-dose IFN-alpha induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome. In their prospective, randomized, multicenter trial in 674 lymph node–negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness, there was no significant difference in 5-year relapse-free survival and overall survival between patients who received an induction phase (IFN-alpha-2b 5 times weekly IV for 2 wk and 5 times weekly subcutaneously for another 2 wk) followed by 23 months of low-dose IFN-alpha-2b, and patients who received low-dose subcutaneous treatment 3 times a week for 24 months.[29]
Hauschild et al also studied optimal duration of treatment of malignant melanoma with low-dose IFN alfa-2a and concluded that prolonging treatment with conventional low-dose IFN alfa-2a from 18 to 60 months showed no clinical benefit in patients with intermediate- and high-risk primary melanoma. Patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness and lymph node negative were included in this prospective, randomized, multicenter trial (n=850). Patients were randomly assigned to receive 3 MU IFN alfa-2a SC 3 times/wk for either 18 or 60 months. Median follow-up was 4.3 years. Relapse-free survival and distant-metastasis-free survival did not differ between the 2 groups.[30]
Meta-analysis data shows that ulceration and tumor stage are important predictors of response to interferon alfa/pegylated-interferon.[31]
Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the FDA in March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy.
The drug's approval was based on a 5-year, open-label, multicenter trial in which cancer recurrence was delayed about 9 months longer in patients who took peginterferon alfa-2b than it was in patients who did not take the drug.[3]
Granulocyte-macrophage colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in the adjuvant setting to treat high-risk melanoma. In a study of 46 patients with resected stage III or IV melanoma treated with a subcutaneous dose of 125 mg/m2 for 2 weeks on and 2 weeks off for a year, progression-free survival was 37 months, vs 12 months in historical controls.[32]
However, a subsequent double-blind, placebo-controlled trial that compared the effect of GM-CSF and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in 815 patients with resected high-risk melanoma (locally advanced and/or stage 4) found that neither adjuvant GM-CSF nor PV significantly improved RFS or OS. Exploratory analyses did show a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases.[33]
Treatment of Advanced-Stage Melanoma (Stage IV)
Treatment of patients with advanced-stage melanoma (stage IV) has continued to improve despite the challenges.
No combination chemotherapy regimen has proven to be significantly better than single-agent dacarbazine (DTIC), which yields only a 10-15% response rate.[34]
Two combination regimens commonly are used in the treatment of patients with advanced-stage melanoma. The first regimen is the cisplatin, vinblastine, and DTIC (CVD) regimen. The second commonly used regimen is the Dartmouth regimen, which is a combination of cisplatin, DTIC, carmustine, and tamoxifen. However, a meta-analysis found that the strength of evidence does not support the addition of tamoxifen to combined chemotherapy regimens.[35]
Biologic therapies now are being used alone and with chemotherapy regimens in the treatment of patients with advanced-stage melanoma. To date, studies do not show that interferon and interleukin 2 (IL-2) added to DTIC is better than DTIC alone.
DTIC was the first drug approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma. In the initial studies with dacarbazine, the overall response rate was 22%, with no impact on survival. In a phase III study of dacarbazine compared with temozolomide, the response rate was 12% versus 13%.[36] On the basis of this trial, and the greater ease of administration of temozolomide versus dacarbazine (oral versus intravenous), most oncologists currently use temozolomide as their first-line drug for melanoma.
Interleukin 2
The second drug approved by the FDA for the treatment of metastatic melanoma was IL-2, a recombinant hormone of the immune system originally described as a T-cell derived growth factor and used as a lymphokine-activated cell killer therapy.
A pooled analysis of 270 patients treated with a high-dose IL-2 bolus (600,000-720,000 units/kg every 8 hours for 5 days) resulted in an objective response rate of 16% (complete response of 6%) with the best response in patients with soft tissue and lung metastases. The overall median survival was 11.4 months.[37]
The treatment was quite toxic, with some patients requiring intensive care unit support. The more common toxicities included hypotension (45%), vomiting (37%), diarrhea (32%), and oliguria (39%). Consequently, this therapy is offered only in centers that have adequately trained staff and facilities. To qualify for this type of treatment, patients must have normal results on pulmonary function testing, brain MRI, and cardiac stress testing, plus adequate renal and hepatic function.
Carboplatin and paclitaxel
Carboplatin and paclitaxel have been tested in two small phase II studies, and when used in combination with sorafenib, the response rate was 11-17%. This regimen sometimes is being used by clinicians in clinical practice because of lesser toxicity than dacarbazine and also as a second- or third-line regimen.
However, a randomized, placebo-controlled phase III study by Hauschild et al found that the addition of sorafenib to carboplatin and paclitaxel did not improve outcome in patients with unresectable stage III or IV melanoma; these investigators recommend against this combination in the second-line setting for patients with advanced melanoma.[38, 39]
Treatment of melanoma with BRAF mutations
BRAF mutations are present in 60% of melanomas. Detection of this mutation is important prior to starting treatment in any melanoma patient. In a multicenter, phase I, dose-escalation trial, 32 patients with metastatic melanoma who had a BRAF mutation were treated with vemurafenib (PLX4032).[40] Two patients had a complete response, and 24 had a partial response.
First-line treatment of patients with BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma is with nivolumab as a monotherapy or in combination with the immunotherapy ipilimumab.[73]
Vemurafenib (Zelboraf) was approved by the FDA in August 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF -V600E. This agent is indicated for the treatment of unresectable or metastatic melanoma with BRAF -V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.
In May 2013 the FDA approved dabrafenib (Taflinar), a BRAF inhibitor in the same class as vemurafenib, for patients with unresectable or metastatic melanoma with BRAF V600E mutation confirmed by the THxID BRAF mutation test.[41] In a multicenter, open-label, phase III randomized controlled trial, treatment with dabrafenib significantly improved progression-free survival in patients with BRAF-mutated metastatic melanoma, compared with dacarbazine (5.1 vs 2.7 mo).[42]
Phase III trial results for the investigational BRAF inhibitor vemurafenib included a 63% relative reduction in the risk of death as well as a 74% relative reduction in the risk of tumor progression in patients with previously untreated metastatic melanoma with the BRAF V600E mutation compared with dacarbazine, the only chemotherapeutic drug currently approved by the US Food and Drug Administration (FDA) for this disease.[43]
In addition, the overall survival rate at 6 months in the vemurafenib group was 84%, versus 64% in the dacarbazine group.[43] Despite the short follow-up period, these results have significant clinical implications, as, of the previously mentioned 40-60% of cutaneous melanomas with BRAF mutations, about 90% involve the BRAF V600E mutation. Moreover, a response to vemurafenib in four of 10 patients with the BRAF V600K mutation was noted, suggesting sensitivity of this mutation variant to vemurafenib.[43]
Vemurafenib was generally well tolerated, with cutaneous events (squamous cell carcinoma, keratoacanthoma, or both; all were treated with simple excision), arthralgia, fatigue, and photosensitivity the most common adverse events; such events led to dose modification or interruption in 38% of patients.[43] Adverse events seen with dacarbazine were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification or interruption in 16% of patients.
Dabrafenib was shown to significantly improve progression-free survival compared with dacarbazine (5.1 vs 2.7 mo) in patients with BRAF -mutated metastatic melanoma in a multicenter, open-label, phase III randomized controlled trial.[44]
Trametinib (Mekinist) is a mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that was approved by the FDA in May 2013 for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by the THxID BRAF mutation test.[41] Approval was based on a phase III open-label trial that compared trametinib with either dacarbazine or paclitaxel. Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group. At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% confidence interval [CI], 0.32 to 0.92).[45]
In January 2014, the FDA approved trametinib for use in combination with dabrafenib for treating patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Approval was based on the demonstration of response rate and median duration of response in a phase I/II study. Median progression-free survival in the combination full-dose 150 mg/2 mg group was 9.4 months compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio for progression or death, 0.39; 95% CI, 0.25 to 0.62). The rate of complete or partial response with combination therapy was 76% compared with 54% with monotherapy. Improvement in disease-related symptoms or overall survival has not been demonstrated for this combination.[46, 47, 48]
In November 2015, the FDA approved cobimetinib, an MEK1 and MEK2 inhibitor, for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib. Approval was based on results in 495 patients with advance melanoma from the phase 3 coBRIM study, in which median progression-free survival was longer with cobimetinib plua vemiurafenib than with vemurafenib monotherapy (12.3 vs 7.2 months; hazard ratio, 0.58; 95% confidence interval, 0.46 - 0.72). Additionally, the objective response rate was higher with the combination than with vemurafenib alone (70% vs 50%; P <0.0001).[49]
Treatment of BRAF V600 wild-type melanoma
First-line treatment of patients with BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma is with nivolumab as a monotherapy or in combination with the immunotherapy ipilimumab.
The November 2015 approval for nivolumab monotherapy is based on data from the randomized phase 3 CheckMate-066 trial, which compared nivolumab monotherapy with dacarbazine in the first-line treatment of 418 patients with advanced BRAF wild-type melanoma. In an interim analysis, nivolumab demonstrated superior overall survival, which was the primary outcome. The overall survival rate at 1 year was 72.9% (95% CI, 65.5 to 78.9) in the nivolumab group and 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group. A significant benefit with respect to overall survival was observed in the nivolumab group, as compared with the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). Median progression-free survival was also improved in the nivolumab-treated patients compared with dacarbazine (5.1 vs 2.2 months; HR, 0.43; P <0.001).[50]
The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma. Approval was based on results from the phase 2 CheckMate-069 study Of the 142 patients enrolled, 109 had both BRAF wild-type and BRAF mutation-positive melanoma. The primary endpoint was objective response rate (ORR) in patients. In patients with BRAF wild-type melanoma treated with the combination regimen, the overall response rate was 61% (95% CI: 48-71) compared to 11% (95% CI: 3-25) in patients given ipilimumab monotherapy (P <0.001).
Additional analysis showed that complete responses were seen in 22% of patients. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P <0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0, NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3).[51]
In January 2016, this indication was expanded to include mutation-positive melanoma, making nivolumab effective across BRAF status.[73]
Melanoma vaccines and gene therapy are two additional treatment options that may become available.[52]
A 2007 review found no clear evidence that the addition of immunotherapy to chemotherapy increases survival in metastatic melanoma and recommended that combined immunotherapy and chemotherapy be limited to clinical trials.[53] Because numerous protocols for patients with advanced-stage melanoma exist, eligible patients should be referred to an oncology center participating in these studies. Vaccines have not been successful as a treatment for metastatic melanoma but are still a reasonable area of research in the adjuvant setting.[33]
External-beam radiation
The brain is a common site of metastasis in malignant melanoma. Brain metastases are associated with a poor prognosis. Management of brain metastases can be difficult due to rapid progression of disease and resistance to conventional therapies. Stereotactic radiosurgery is used increasingly in patients with a limited number of metastases; it is less invasive than craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, although the combination of chemotherapy with external-beam radiation is being investigated.[24]
Future therapies
In a multicenter phase II trial, targeted therapy with imatinib was an effective treatment option in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene.[54, 55, 56] Of 50 patients with melanomas arising from acral, mucosal, or chronically sun-damaged sites with KIT alterations, 24 evaluable patients with KIT -mutant (n = 8), KIT -amplified melanoma (n = 11), or both (n = 5) were treated with imatinib. Seven of these 24 patients achieved a partial response to therapy, with five patients' responses confirmed on subsequent imaging studies, for an overall confirmed response rate of 21%.[54, 55]
These findings reinforce similar findings in two earlier studies.[1, 57]
Anti–cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a humanized antibody directed at a down-regulatory receptor on activated T-cells.[58] The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T-cells.
Ipilimumab, a CTLA-4 blocker, has demonstrated remarkable promise in patients with metastatic melanoma. Clinical trials for monotherapy and in combination with other immunotherapies and vaccines have been concluded or are currently under way.[59] Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma.
Hodi et al reported improved survival with ipilimumab in patients with metastatic melanoma. Ipilimumab blocks CTLA-4 to a potentiate T-cell response. In a phase 3 study, 676 patients with HLA2-positive patients with unresectable stage III or IV melanoma who disease progressed while receiving therapy for metastatic disease were randomly assigned in a 3:1:1 ratio to ipilimumab plus gp100, ipilimumab, or gp100 alone. Ipilimumab was given at a dose of 3 mg/kg and was administered with or without gp100 every 3 weeks for up to 4 treatments; subsequently, patients would receive reinduction therapy. The median overall survival was 10 months among patients receiving ipilimumab plus gp100, compared with 6.4 months in those receiving gp100 alone. There was no difference in survival in the other ipilimumab arm compared with the ipilimumab-plus-gp100 arm. Because of these findings, ipilimumab has been approved as a treatment for metastatic melanoma.[59]
In a phase 3 study of ipilimumab and dacarbazine compared with dacarbazine and placebo, survival among patients with metastatic melanoma was improved by 2 months (11 mo vs 9 mo) in the ipilimumab arm; however, they had more grade 3 and 4 toxicity.[60]
In the MDX010-20 trial, researchers evaluated immune-related adverse events (AEs) in 676 patients previously treated for metastatic melanoma who were randomly assigned to receive 1 of the following 3 treatment regimens (in a 3:1:1 ratio): (1) ipilimumab plus glycoprotein 100 melanoma antigen vaccine (gp100); (2) ipilimumab plus placebo; or (3) gp100 plus placebo.[61, 62] Most of the immune-related AEs developed within 12 weeks of initial dosing, typically resolving in 6-8 weeks. Fewer than 10% of patients receiving any ipilimumab treatment experienced an immune-related AE more than 70 days after their last drug dose, and all of these AEs were grade 1 or 2 in severity. Most immune-related AEs, even grade 3/4 events, were readily managed with monitoring and early corticosteroid therapy; only 5 patients needed infliximab for gastrointestinal AEs, and all 5 subsequently improved.[61, 62]
The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.[51] Additionally, it is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy.[63]
The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies to combination strategies. This combination approach results in response rates around 60% and superior progression-free survival compared with ipilimumab monotherapy (median 11.5 versus 2.9 months).[74]
Immune-Based Therapy
PD-1 inhibitors
Programmed cell death–1 protein (PD-1) and the related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. The PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.
In September 2014, the FDA granted accelerated approval for pembrolizumab (Keytruda). Pembrolizumab is the first monoclonal antibody for inhibition of PD-1.[64] It was initially indicated for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on data including a study in which approximately 24% of patients experienced tumor shrinkage.[2] In December 2015, the FDA approved pembrolizumab as first-line treatment for unresectable or metastatic melanoma. Approval was based on the phase 3 KEYNOTE-006 trial. Patients with advanced melanoma were randomized to receive either pembrolizumab 10 mg/kg every 2wk or every 3wk, or 4 doses of ipilimumab (3 mg/kg every 3wk). Progression-free survival for the pembrolizumab groups were 47.3% and 46.4% respectively and 26.5% for ipilimumab. Note that the trial used a higher dose of pembrolizumab than the dose that is approved by the FDA, which is 2 mg/kg every 3 wk.[72]
Nivolumab (Opdivo), another PD-1 inhibitor, was granted accelerated approval in December 2014 for unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on interim results of a randomized clinical trial in patients with unresectable or metastatic melanoma that had progressed after ipilimumab. Interim analysis confirmed objective responses in 38 of the first 120 patients treated with nivolumab (31.7%; 95% confidence interval [CI] 23.5-40.8) versus five of 47 patients who received investigator's choice of chemotherapy (10.6%; CI, 3.5-23.1).[4]
Nivolumab and ipilimumab combination
The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma. Approval was based on results from the phase 2 CheckMate-069 study Of the 142 patients enrolled, 109 had both BRAF wild-type and BRAF mutation-positive melanoma. In patients with BRAF wild-type melanoma, the overall response rate was 61% (95% CI: 48-71) with the combination regimen, compared with 11% (95% CI: 3-25) with ipilimumab monotherapy (P <0.001). Additional analysis showed that complete responses were seen in 22% of patients. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P <0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0, NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3).[51]
Talimogene laherparepvec
In October 2015, the FDA approved the oncolytic immunotherapeutic vaccine talimogene laherparepvec (Imlygic). It is a genetically modified, live attenuated herpes simplex type I virus programmed to replicate within tumors and produce the immune stimulatory protein granulocyte-macrophage colony-stimulating factor (GM-CSF). In this process, the gene ICP 34.5 is deleted and replaced with the coding sequence for GM-CSF. It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery. It is administer by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.[65]
The study enrolled 436 patients, of which 295 patients treated with talimogene laherparepvec were compared with 141 patients treated with GM-CSF. The primary endpoint was the durable response rate (DRR), defined as the rate of complete response plus partial response continuously lasting ≥6 months and beginning within the first 12 months. Secondary endpoints included overall survival (OR) and the overall response rate (ORR).
The DRR was significantly higher among patients who received talimogene laherparepvec compared with those given GM-CSF (16.3% vs 2.1%; odds ratio, 8.9; P < 0.001). Of the patients who experienced a durable response, 29.1% had a durable complete response and 70.8% had a durable partial response. The median time to response was 4.1 (range: 1.2 to 16.7) months in the arm receiving talimogene laherparepvec.
ORR rate was also higher with talimogene laherparepvec (26.4% vs 5.7%; P <0.001). In all, 32 (10.8%) patients receiving talimogene laherparepvec experienced a complete response, compared with just one (<1%) patient receiving GM-CSF. The median time to treatment failure was 8.2 months with talimogene laherparepvec and 2.9 months with GM-CSF (hazard ratio [HR], 0.42). Median OS was 23.3 months and 18.9 months, respectively (HR, 0.79; P = 0.051), which just missed being statistically significant.[66]
Prevention of Malignant Melanoma
The focus of melanoma prevention is avoidance of sun exposure. Everyone, especially those individuals at high risk of developing a melanoma, should wear protective clothing, avoid peak sun hours, protect children against exposure to ultraviolet radiation, avoid tanning booths, and wear sunscreen with a sun protection factor (SPF) of at least 15. This last recommendation is considered somewhat controversial, because no study has shown sunscreen to reduce the incidence of melanoma.[67] Moreover, a systematic review found that sunscreen use leads to longer duration of intentional sun exposure, and sunburns tend to be more frequent among sunscreen users.[68]
First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations.
A patient with a suggestive lesion should be referred to a dermatologist or surgical oncologist for excisional biopsy.
If the diagnosis of melanoma is made, the patient should be referred to an oncologist after definitive surgery is performed.
Long-Term Monitoring
Follow-up care of a patient with melanoma is based on the stage of the primary. The follow-up examination should be performed with the knowledge that the patient has an increased risk for a second primary and that, of all solitary sites of visceral recurrence, the lungs are the most frequent.
Follow-up guidelines from the National Comprehensive Cancer Network are listed below.[18]
Follow-up for stage 0 in situ is as follows:
At least annual skin examination for life
Educate patient in monthly self-examination of skin
Follow-up for stage IA is as follows:
History and physical examination (H&P) (with emphasis on nodes and skin) every 3-12 mo for 5 y, then annually as clinically indicated
At least annual skin examination for life
Educate patient in monthly self-examination of skin and lymph nodes
Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:
H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2 y, then annually as clinically indicated
Chest radiography, lactate dehydrogenase (LDH) level, and complete blood cell count (CBC) every 6-12 mo (optional)
Routine imaging is not recommended for stage IB or IIA disease
CT scans to follow up for specific signs and symptoms
Consider CT scans to screen stage IIB and higher for recurrent/metastatic disease
At least annual skin examination for life
Educate patient in monthly self-examination of skin and lymph nodes
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text: Trace Your Family Roots with GRAMPSKevin Purdy3/02/08 1:30pmFiled to: Featured Linux DownloadDownloadsFamilyLinux23EditInvite manuallyPromoteDismissUndismissHideShare to KinjaToggle Conversation toolsGo to permalink Linux only: Dig into your genealogy with GRAMPS, a free software package that offers an array of tools to build and store your family history. GRAMPS gives you a lot of choices as to how you'll build your tree, from standard database entries to multimedia diagrams, and offers a pretty convenient "calendar" view that lets you see birth (and death) dates for your extended clan. The real benefit of GRAMPS is that you can put as much or as little detail as you want into each entry, making it an amateur genealogist's dream. GRAMPS is a free download for Linux only, although "experimental" installers are available for Windows and Mac OS X. For a Windows-friendly approach, try a Microsoft Word family tree templateGRAMPS [via Sysad Linux Blog]Reply23 repliesLeave a reply