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Nick Cave sideman and Grinderman multi-instrumentalist Warren Ellis may not seem like the most likely candidate for a signature axe—heck, he spends half his time playing fiddle. But anyone who witnessed Warren the Wizard conjure everything from sweet jangle to hellhound howls from his Eastwood tenor on the last Grinderman tour could will understand the massive potential of both Ellis and this cool, little guitar.
PG Gear Editor Charles Saufley foundthat "the string spacing makes fingerpickingthis thing a delight. And adapting clawham-mer banjo techniques to electric guitar tonesresulted in some very interesting approachesto both composition and cool-sounding ver-sions of old folk and country standards."And while it's two strings shy of what mostof us would consider a full house, he alsofound the Eastwood to be a guitar of "remark-able versatility—one that can lend thrillingnew flavors to roots music, Americana, andinternationally flavored jams, as well as worldsof texture to the music of boundary-obliter-ating experimentalists." Trust us, you'll neverthink of four strings the same!eastwoodguitars.com
At this point, we could probably call Strymon relentless. This mad scientists' club of tone-tweaking kooks keeps obliterating expectations about how analog digital signal processing can sound. But they're also happy to exploit digital's potential to explore more exotic sounds and analog emulations in the same unit. And that breadth of vision births wonders like the TimeLine, a studio-grade Delay that leaves few permutations of the effect unexplored in a package that's surprisingly easy to navigate.
Strymon's amazing tape delay emulation technology is just one of the delay options on a menu that runs from analog delay staples to super-out-there intergalactic textures. It's full of cool preset capabilities, filters, and modulation for coloring your repeats. It also has an all-around, can-do aura that we found "infinitely tweakable to suit a musical situation." This is one tough-to-top delay.
Chicago amp wiz Tim Schroeder is good enough to win the favor of noted gear junkies Jeff Tweedy and Wilco. And these days, that means you also have the ear of otherwordly axe genius Nels Cline. The DB7 is essentially the same amp that Schroeder built for Cline—one that's since become his main squeeze onstage because it satisfies the sonic alchemist's need for wide sonic spectrum and sky-high headroom in a mid-power amp.
Reviewer Adam Perlmutter found the 6L6-powered, 45-watt DB7 to be "a sustain machine, making the plainest of sonori-ties a thing of wonder." He remarked that the "simple act of hitting a first-position chord on the guitar summoned a tone that was uncommonly full-bodied, sweet, and complex." Perlmutter was also knocked out by it's beauty, quality, and brilliant design. And if we heard a nicer amp this year, quite honestly we can't remember anymore—we still hear the sweet chime of the DB7 ringing in our ears.


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We recently stayed at the Carpi and the service was wonderful there was someone always at the front desk. The rooms were clean and the breakfast was good. We will stay next time we visit. It was a nice hotel for the price.
- Also Known As:
- New Victorian Hotel Beatrice
- New Victorian Hotel
- Official Description (provided by the hotel):
- Welcome to the unbeatable combination of comfort, value and service you will enjoy while staying with the Capri Inn & Suites of Beatrice, NE. Conveniently located on the north side of Beatrice on Hwy 77, this Nebraska owned hotel provides a complimentary deluxe breakfast bar every day with extended hours. Guest rooms include a refrigerator, microwave, iron and ironing board, hair dryer, cable TV, complimentary local calls and high speed wireless internet. We look forward to having you be our guest at the Capri Inn & Suites of Beatrice, NE! ... more less
- Reservation Options:
- TripAdvisor is proud to partner with Expedia, Hotels.com, Priceline, Orbitz, Travelocity, Booking.com, EasyToBook, Cheap Tickets, Venere and Tingo so you can book your Capri Inn & Suites of Beatrice reservations with confidence. We help millions of travellers each month to find the perfect hotel for both holiday and business trips, always with the best discounts and special offers.

subset: commoncrawl


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Saints Tickets – New Orleans Saints Tickets
The New Orleans Saints pose a huge question for NFL football fans. Never in the history of the NFL has a talented team like the Saints entered a season with so many questions to be answered. New Orleans has been a top franchise for five years now, but with so much going on it's going to take a crystal ball to see what's ahead.
First of all the offensive mastermind of the team is going to be at home as Sean Payton takes the hit for the Bounty scandal. Joe Vitt will run things in the pre-season but he serves his own suspension during the year. Starting middle linebacker Jonathan Vilma is out all year and Will Smith must serve his own time.
Luckily, New Orleans can count on the playcalling of pete Carmichael Jr. to get them through the season. Carmichael took on the role last year when Payton was out with a broken leg and did well with it. The Vilma problem was solved by signing Curtis Lofton away from the Atlanta Falcons and the defense as a whole will be overhauled under new Defensive Coordinator Steve Spagnuolo.
Don't expect many changes on offense. Drew Brees should get signed, despite the doomsday calls. And Brees will still be throwing to Marques Colston, Jimmy Graham, and Darren Sproles so the passing game should remain relatively intact. We may see more running as mark Ingram comes into his sophomore season. The former #1 Draft Choice did well in the rotation last season should take a step up in 2012.
A look over the Saints 2012 schedule shows some excellent matchups. The Washington Redskins will be bringing RG3 to the Superdome in his NFL debut, and New Orleans will also welcome the Atlanta Falcons, San Diego Chargers, and San Francisco 49ers to the hostile confines of the Mercedes Benz Superdome. On the road, big games include trips to take on the Green Bay Packers and Dallas Cowboys.


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Easy Seared Scallops
I stopped by Fresh Farms International Market the the other day (that place is awesome!) and was enticed by a special deal on some beautiful scallops. I decided it was time to give my scallop cooking skills another try. I used a recipe for seared scallops from Alton Brown (slightly modified) that I saw on a episode of Good Eats years ago and I'm proud to say that I ended up with a really amazing dish. The scallops had a lovely caramel coating on the outside and were tender and buttery on the inside.
If you've never cooked scallops or you just want a simplistic way to prepare them that will really allow for the flavor of the scallops to shine, I highly recommend this easy recipe!
Seared Scallops
1 to 1 1/4 lbs dry sea scallops (approximately 16)
2 tsp unsalted butter
2 tsp olive oil
Truffle salt (the original recipe calls for Kosher salt, but the truffle salt gives it a really lovely flavor)
Freshly ground black pepper
1. Remove the small side muscle from the scallops, rinse with cold water and thoroughly pat dry (this is especially important - do not try to sear wet scallops or else they will burn!).
2. Add the butter and oil to a 12 to 14-inch sauté pan on high heat. Salt and pepper the scallops.
3. Once the pans begins to slightly smoke, gently add the scallops, making sure they are not touching each other. Sear the scallops for 1-2 minutes on each side. The scallops should have a 1/4 inch golden crust on each side while still being translucent in the center. Remember that the scallops will cook very quickly - keep a close eye on them and do not cook them for more than 2 minutes on each side or else you will end up with chewy hockey pucks!
13 comments:
- Stephanie said...
- August 8, 2012 at 11:45 AM
- Food Geek Diary said...
Love scallops! Looks yummy!
- August 8, 2012 at 11:46 AM
- Nathan Hale PTO said...
I cook mine the same way except I shred a garlic clove to put in with the butter/oil. :)
- August 8, 2012 at 1:15 PM
- Rob-bear said...
This looks so very "interesting." I have this love-hate relationship with seafood. Mostly, it hates me, and can make me violently ill.
That minor messiness aside, your blog is looking good! - August 8, 2012 at 4:16 PM
- Jeanne S said...
- August 8, 2012 at 5:49 PM
- Steph Jennings said...
Hello! Yes please!!!!!
- August 8, 2012 at 7:55 PM
- Seeking Solace said...
I LOVE seared sea scallops. Thanks for sharing!!!!
- August 9, 2012 at 8:47 AM
- Rachel said...
I love scallops. My husband won't eat them, and when I once asked him why, he said he couldn't bring himself to, because of their scary blue eyes. I thought he was insane, until I googled for images (scallops + blue + eyes). They do look pretty alien!
- August 10, 2012 at 10:58 PM
- chicago foodie girl said...
@Rachel: OMG, I know! They are sooo creepy! I feel the same way about calamari - I love it, but I cannot bring myself to eat the tentacles because they weird me out.
- August 10, 2012 at 10:59 PM
- Laurie Dominguez said...
I enjoy eating scallops but never really used them except in seafood stew or paella. Simple and light recipe - love it!
- August 12, 2012 at 4:38 AM
- Meg @ write meg! said...
Oooh -- mouth-watering. I'm addicted to scallops, no doubt about that, but I've never attempted to cook them at home. Thanks for the inspiration! Will definitely bookmark so I don't wind up with the hockey-puck version... ack.
- August 13, 2012 at 8:45 AM
- Spicie Foodie said...
Wow your scallops look perfect! I love them but have never cooked them myself. Your recipe looks easy enough for a scallop newbie like me. Thank for sharing!
- August 13, 2012 at 1:36 PM
- Sandi said...
Thanks for stopping by my blog. These scallops look great. I have noticed too that if I overcook them, they are very tough and rubbery. I love that grilled crust on yours...Yum!!
- September 25, 2012 at 8:45 PM


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Tag: Bittners
Club 1854: Original Makers Club
Club 1854, the city's newest hotspot, attracted a spectacular crowd on Friday, Sept. 9 for an evening of camraderie, cocktails and a few surprise touches, as evidenced in our gallery.
Lori Andriot Has A Passion for Design
As I enter Bittners, it is abuzz with new fall arrivals for the Showroom. Lori Andriot warmly greets me as we settle into a comfortable spot in the great room, by a magnificent, oversized Italian bookcase.
Dean Wilkinson, Historic Homes Foundation Derby Breakfast co-chair.
This year's 33rd annual Derby Breakfast will be the perfect toast to your morning. Whether it's a pre-party before heading to the track or your morning destination, one thing is certain: If you aren't there, you'll be green with envy.


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The Global Gallivanter Trunk
For the jet setting pet in your life! Your precious companion will never be away from home without his or her "essentials", with the Global Gallivanter Trunk! This luxurious collection contains a water bowl, a pet passport holder, a chew toy and your choice of either a bone or fish plush cushion. All of which are encased in a heavily padded handmade Napa leather trunk, (that doubles as a luxe dog bed) complete with collar and leash holders and a storage area to keep your k9's outfits neat and organized! My suitcase isn't even this nice! The Global Gallivanter Trunk retails for around $2,000 and is available online.


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Progrmatically capture from camera -possible?
Can you explain a bit more in details on what should be actually captured and when ? do you want to take an image with camera, if so, do you want to use the naitve UI, or your own. Or it is something else that you want to capture ?
you could check wiki for examples:
also see this one: http://wiki.forum.nokia.com/index.ph...feature_in_WRT


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My Current Coffee Table Decor: Pretty Shells on a Mirrored Tray
February 19, 2012 in Coastal, My Home and Paintings, Summer
Hi friends! Thought I'd share a few snaps of my coffee table this lovely Sunday. What do you think about my new shells? They come all the way from Thailand (thank you mom and dad!) along with many others. I'll stage a photoshoot with the rest next weekend =)


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- Products:
- 1-2 of 2
ScalextricDigital Race Line Set
This Digital Race Line Set is an awesome update on the classic design, allowing you to switch lanes and overtake for even more epic races.
This set comes with 2 cars, each with a digital chip installed inside so you can perform tricky manoeuvres and overtakes to steal first place from your opponent. The track can race up to 4 cars (available separately) at a time to add to the fun.
The track is over 6 metres long and with extended stretches you can really build up speed before pulling off a daring overtake to steal the top spot.
This set comes with 2 robust cars that are built for life in the fast lane.
Useful info:
- Race up to four cars
- Set comes with 2 cars
- Switch lanes and overtake
- Track length: 630 cm
- Age from 7 years
- Digital layout is compatible with standard Scalextric track pieces
- Scalextric Digital Race Line Set
Warning: Not suitable for children under 3 years.
- Weekly Price
- From £2.86 per week
- Price
- £285.00
- In Stock
- Next day delivery available
- Availability
- Available
ScalextricDigital Law Enforcer
Bring the city streets to vivid life with breathtaking police pursuits in the incredible Scalextric Digital Law Enforcer set!
You can perform amazing, realistic overtaking and braking manoeuvres and with only the touch of a button you can switch lanes to overtake or even block your opponent!
Packed with incredible features this fantastic set boasts more than 6 metres of track and cars installed with digital chips for even more realistic racing action.
Part of the Scalextric Digital range, the set gives you more power than ever before to create the kind of races you want, with up to 4 digital chip-installed cars now able to go head-to-head (3 cars are supplied with this set).
The super resistant Audi R8 Police Car's siren sounds and its lights flash as it races off in hot pursuit of the street racing Dodge Challenger and Chevrolet Corvette which have working front and rear lights.
Useful info:
- Scalextric Digital Law Enforcer
- Recreate realistic police chases
- Change lanes, overtake and brake to avoid the cops
- Police car's siren sounds
- More than 6 metres of track
- Comes with power base to race up to 4 cars
- 3 cars supplied
- Suitable for age 7 and above
- Weekly Price
- From £4.01 per week
- Price
- £400.00
- In Stock
- Next day delivery available
- Availability
- Available
- Products:
- 1-2 of 2


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Lively in style, this gemstone necklace frames garnet, amethyst, peridot and blue topaz gemstones set in open rings of sterling silver along a cable chain that is perfect worn long or layered.
The item you've selected is exceptional and deserves special attention. Please phone a diamond and jewellery expert and they will help you complete your order.
Usually ships within 1 working day.
Note: Prices and availability are subject to change without notice. View our terms and conditions for more information.


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Wolves live in family groups with complicated social structures. They are considerably light for their size as are most endurance athletes. Their jaws are twice the strength of a Police Dog.
Wolf Valley, Wolf Haven and on our Wolf Training Up-Close Tour.


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Submitted by FoxFirstatTen on November 7th
KENNEWICK, Wash. - The Northwest Cancer Clinic is teaming up with Tri City Radiology to remind you that November is Lung Cancer Awareness Month.
To help spread awareness, they'll be offering free lung cancer screenings, which include a free low dose screening CT scan.
Anyone who is 55 years of age and older, and have smoke a pack of cigarettes a day for 30 years or more is eligible for a screening. To schedule, just call the Northwest Cancer Clinic at (509) 987-1800.
Screenings are limited and the Northwest Cancer Clinic staff will check to ensure this is an appropriate test for each person. Screening for lung cancer patients is designed for people who don't have symptoms, but meet other qualifying criteria.


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News You Can Use Personally and in For Your Business
Posted in Legal Services, Social.
Our mission and values
Everyone deserves legal protection. And at LegalShield, our mission is to make sure everyone can access it. With the commitment of over 1.4 million LegalShield members, we are able to negotiate comprehensive legal services with dedicated law firms nationwide, at a fraction of what they traditionally cost.
By offering uncommonly accessible legal services at an uncommonly affordable price, our hope is that everyone can live their lives worry-free, every day, every night, now and forever.
Our brand and what we stand for The LegalShield brand is a vow. It is a promise of peace of mind, a commitment to our customers that no matter the situation, we will be there to help. With total access to unlimited, complete legal coverage, our members should fear nothing. The protection of our product is total, a shield that watches over them and their loved ones, protecting their rights, their freedom and their future.
Comments or questions are welcome.
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- Showing 2 posts filed under: Practice [–], Correspondent:Lisa Rea [–] published between Nov 01, 2009 and Nov 30, 2009 [Show all]
Law school student asks: would victims really want restorative justice?
by Lisa Rea
I recently gave a speech at UC Davis Law School. Before the class the professor shared a comment made to him by one of the students in his class. A number of students had already explored restorative justice, perhaps having heard of it previously since the law school had hosted a number of events on the subject including bringing in guest speakers like me to speak in a classroom setting.
The student said this: "Restorative justice might be a good concept for the person who committed the crime since they may be able to understand the pain they caused that they might not otherwise be unaware of. However, for victims I think this is a waste of time. It probably just stirs up emotions unnecessarily and the session may turn into a shouting and crying match. But it still doesn't change the victims' pain or the harm that was caused."
Nov 30, 2009 Practice, Victim, Correspondent:Lisa Rea
Lisa Rea interviews Stephen Watt
By Lisa Rea:
The following interview is with Stephen Watt, a former Wyoming state trooper and two term state legislator who was shot multiple times by a fleeing bank robber. Lisa Rea's interview focuses on how the impact of a severely violent crime continues 20 years later. Mr. Watt has met with the offender, forgiven him and a friendly relationship has grown up between them. Nevertheless, he continues to suffer. Can restorative justice open doors for further healing in a victim of violent crime who is suffering continuing, severe trauma?
Nov 05, 2009 Story, Correspondent:Lisa Rea, Support, Practice, Victim, Restitution


text: High Adventure CampingThere are numerous activities that the Arrowmen attending the NOAC 2000 can participate in. Some of the activities that the Arrowmen are attending have to do with Camping and High Adventure. These activities not only are fun but very educational teaching them new skills that they might not be able to get at home. We hope that by showing the Scouts these skills they will be able to take them back to their Lodges and share their newly learned skills, thus helping the scouting program overall. Here are a few of the High Adventure Areas Scouts have been visiting The Outdoor Adventure Place (TOAP) Revised 7/30/00. |


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Easier than I hoped it would be. Nothin fancy, just a few buffs, potions, and hacking away.
Fantastic game. The ending was a little ... anticlimactic. By giving us a boatload of chests to loot after killing the final boss, you make us think we've got more adventuring to do
Really looking forward to Book II!


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You're watching...
9/11 hit eyed in murder of US envoy
U.S. officials increasingly suspicious that Libya strike was coordinated
Sep 12, 2012
P.j. Crowley
You're watching...
U.S. officials increasingly suspicious that Libya strike was coordinated
Sep 12, 2012
P.j. Crowley
Also in this playlist...
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The former United States assistant secretary of state for public affairs PJ Crowley is with -- -- served as a special assistant to the president.
President Clinton for national security affairs.
PJ it it it feels as if this has this has just grown in importance.
And and and and over and overseas troubles.
Absolutely -- and I think we've recognized since the beginning of the Arab awakening that as countries go through.
Difficult transitions from.
Two two democracies that there might be opportunities for.
-- -- all tired out or sell -- -- elements that are sympathetic with al-Qaeda.
To take advantage of of this mayhem and it's certainly very plausible and that's what happened yesterday and in Gaza.
What we do know is that -- in the neighboring country there was what appeared to be of an almost completely on armed bunch.
They acted I heard one person described -- almost like school children in that the teacher would say you can't go past here.
One -- two of -- would try it they'd run under the grounds of the embassy and then they'd run back eventually one of them got the flag they did destroy anything and hurting thing and then just hours later.
A group of about twenty heavily armed what was described us as militants.
Go in and murder for people and those four people happen to -- just by happenstance.
Our ambassador in three security guards PJ if this was a targeted hit how would you.
Quantify such a thing if it were a targeted hit by a nation state.
That could be considered an act of war.
Well they say two things there's a difference between it Egypt and Libya Egypt went through -- relatively soft landing in terms of its transition.
-- went through a civil war.
Every political faction in Libya is heavily armed -- as as we know from the attack yesterday they had guns -- RPG's.
That's not necessarily what you see on the streets.
Of Cairo.
And we don't know all that we need to know about what happened yesterday but certainly.
This would be consistent with the struggle that we've been dealing with since 9/11.
A struggle against al-Qaeda either its formal affiliates.
Or sympathetic.
And we've recognized for a long time that Libby was more of those places where.
You know bin Laden had a number of -- of key lieutenants who came from Libya.
And that there was the potential that al-Qaeda or its sympathizers would take advantage of the transition from Qaddafi to a democratic government.
TJ this is from I believe this is from our correspondent Catherine Herridge.
Who is entered into our -- what we have our own wire service that -- there are journalists -- to serve each other.
So that we can put information and that our our -- journalists have gotten confirmed and this is.
Two intelligence officials not one source two source quote this looks -- very coordinated.
Like the big al-Qaeda attacks whereas we'd see in Iraq.
Catherine Herridge send -- out earlier about this wave of attacks the second wave of deadly force.
And they were prepared it appeared at least that in this instance where our envoy was murdered where ambassador was I don't know assassinated potentially.
That that those who were -- out this attack met with very little resistance.
Not to say that that the military which is control that country for decades is back in charge of the streets frankly it is it.
Yeah -- -- we certainly embassies have been attacked in the past al-Qaeda attacked our embassies in East Africa.
In 1998 so -- that they are very much are.
On al-Qaeda or other terrorists -- target lists.
I mean this is a post conflict society Libya everyone has weapons as I mentioned.
But also you have a new government we've been in power for weeks or a few months high and it does not yet have the strong -- two kids of government.
You -- was a police force.
Under Qaddafi in the police force was they are protected -- the now you have a police force that is being asked to protect civil society and got quite -- the -- even with the rings of security around the consulate.
-- did what Libby is a work in progress and it does not yet have all the capacity that it needs I think we we anticipated that these kinds of bad days.
It would happen in a place like Libyan tragically it took out our ambassador.
PJ Crowley formally -- the State Department with us from Capitol Hill --
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Melanoma | |
Classification and external resources | |
a melanoma
DiseasesDB | 7947 |
MedlinePlus | 000850 |
eMedicine | derm/257 med/1386 ent/27 plastic/456 |
MeSH | D008545 |
Melanoma i/ˌmɛləˈnoʊmə/ (from Greek μέλας — melas, "dark")[1] is a malignant tumor of melanocytes.[2] Melanocytes produce the dark pigment, melanin, which is responsible for the color of skin. These cells predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye (see uveal melanoma). Melanoma can originate in any part of the body that contains melanocytes.
Melanoma is less common than other skin cancers. However, it is much more dangerous if it is not found early. It causes the majority (75%) of deaths related to skin cancer.[3] Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. In women, the most common site is the legs and melanomas in men are most common on the back.[4] It is particularly common among Caucasians, especially northwestern Europeans living in sunny climates. There are high rates of incidence in Oceania, Northern America, Europe, Southern Africa, and Latin America,[5] with a paradoxical decrease in southern Italy and Sicily.[6] This geographic pattern reflects the primary cause, ultraviolet light (UV) exposure[7] crossed with the amount of skin pigmentation in the population.[8][9]
According to a WHO report, about 48,000 melanoma related deaths occur worldwide per year.[10]
The treatment includes surgical removal of the tumor. If melanoma is found early, while it is still small and thin, and if it is completely removed, then the chance of cure is high. The likelihood of the melanoma coming back or spreading depends on how deeply it has gone into the layers of the skin. For melanomas that come back or spread, treatments include chemo- and immunotherapy, or radiation therapy.
Signs and symptoms[edit]
Early signs of melanoma are changes to the shape or color of existing moles or, in the case of nodular melanoma, the appearance of a new lump anywhere on the skin (such lesions should be referred without delay to a dermatologist). At later stages, the mole may itch, ulcerate or bleed.[11] Early signs of melanoma are summarized by the mnemonic "ABCDE":
- Asymmetry
- Borders (irregular)
- Color (variegated)
- Diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser)
- Evolving over time
These classifications do not, however, apply to the most dangerous form of melanoma, nodular melanoma, which has its own classifications:
- Elevated above the skin surface
- Firm to the touch
- Growing
Metastatic melanoma may cause nonspecific paraneoplastic symptoms, including loss of appetite, nausea, vomiting and fatigue. Metastasis of early melanoma is possible, but relatively rare: less than a fifth of melanomas diagnosed early become metastatic. Brain metastases are particularly common in patients with metastatic melanoma.[12] It can also spread to the liver, bones, abdomen or distant lymph nodes.
All cancers are caused by damage to the DNA inside cells. This damage can be inherited in the form of genetic mutations, but in most cases, it builds up over a person's lifetime and is caused by factors in their environment. DNA damage causes the cell to grow out of control, leading to a tumor. Melanoma is usually caused by damage from UV light from the sun, but UV light from sunbeds can also contribute to the disease.[13]
A number of rare mutations, which often run in families, are known to greatly increase one's susceptibility to melanoma. Several different genes have been identified as increasing the risk of developing melanoma. Some rare genes have a relatively high risk of causing melanoma; some more common genes, such as a gene called MC1R that causes red hair, have a relatively lower elevated risk. Genetic testing can be used to determine whether a person has one of the currently known mutations.
One class of mutations affects the gene CDKN2A. An alternative reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis and in fifty percent of human cancers. Another mutation in the same gene results in a nonfunctional inhibitor of CDK4, a cyclin-dependent kinase that promotes cell division. Mutations that cause the skin condition xeroderma pigmentosum (XP) also seriously predispose one to melanoma. Scattered throughout the genome, these mutations reduce a cell's ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant (meaning that the chances of a person carrying the mutation to express the phenotype is very high).
Familial melanoma is genetically heterogeneous,[14] and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis (disease development) of melanoma.[15] The multiple tumor suppressor 1 (CDKN2A/MTS1) gene encodes p16INK4a – a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs) – which has been localised to the p21 region of human chromosome 9.[16]
Other mutations confer lower risk, but are more prevalent in the population. People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type (typical unaffected type) copies of the gene. MC1R mutations are very common; in fact, all people with red hair have a mutated copy of the gene. Mutation of the MDM2 SNP309 gene is associated with increased risk of melanoma in younger women.[17]
UV radiation[edit]
The UV radiation from tanning beds increases the risk of melanoma.[18] The International Agency for Research on Cancer finds that tanning beds are "carcinogenic to humans" with people who begin using tanning devices before age 30 are 75% more likely to develop melanoma.[19]
In a study scientists reveal that the dose of UV radiation is deciding factor and can lead to different pathway. The p16 pathway is favored at low doses of UV radiation and results in cell-cycle arrest, to the contrary; the p53 pathway is more responsive to higher doses and induces apoptosis depending on p53 mutation status.[20]
The earliest stage of melanoma starts when the melanocytes begin to grow out of control. Melanocytes are found between the outer layer of the skin (the epidermis) and the next layer (the dermis). This early stage of the disease is called the radial growth phase, and the tumor is less than 1 mm thick. Because the cancer cells have not yet reached the blood vessels lower down in the skin, it is very unlikely that this early-stage cancer will spread to other parts of the body. If the melanoma is detected at this stage, then it can usually be completely removed with surgery.
When the tumor cells start to move in a different direction — vertically up into the epidermis and into the papillary dermis — the behaviour of the cells changes dramatically.[21]
The next step in the evolution is the invasive radial growth phase, which is a confusing term; however, it explains the next step in the process of the radial growth, when individual cells start to acquire invasive potential. This step is important – from this point on the melanoma is capable of spreading. The Breslow's depth of the lesion is usually less than 1 mm (0.04 in), the Clark level is usually 2.
The following step in the process is the invasive melanoma — the vertical growth phase (VGP). The tumor attains invasive potential, meaning it can grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than 1 mm (0.04 in), and the tumor involves the deeper parts of the dermis.
The host elicits an immunological reaction against the tumor (during the VGP),[22] which is judged by the presence and activity of the tumor infiltrating lymphocytes (TILs). These cells sometimes completely destroy the primary tumor; this is called regression, which is the latest stage of the melanoma development. In certain cases, the primary tumor is completely destroyed and only the metastatic tumor is discovered. About 40% of human melanomas contain activating mutations affecting the structure of the B-Raf protein, resulting in constitutive signaling through the Raf to MAP kinase pathway.[23]
Visual diagnosis of melanomas is still the most common method employed by health professionals.[24] Moles that are irregular in color or shape are often treated as candidates of melanoma. The diagnosis of melanoma requires experience, as early stages may look identical to harmless moles or not have any color at all. People with a personal or family history of skin cancer or of dysplastic nevus syndrome (multiple atypical moles) should see a dermatologist at least once a year to be sure they are not developing melanoma. There is no blood test for detecting melanomas.
To detect melanomas (and increase survival rates), it is recommended to learn what they look like (see "ABCDE" mnemonic below), to be aware of moles and check for changes (shape, size, color, itching or bleeding) and to show any suspicious moles to a doctor with an interest and skills in skin malignancy.[25][26]
A popular method for remembering the signs and symptoms of melanoma is the mnemonic "ABCDE":
- Asymmetrical skin lesion.
- Border of the lesion is irregular.
- Color: melanomas usually have multiple colors.
- Diameter: moles greater than 6 mm are more likely to be melanomas than smaller moles.
- Enlarging: Enlarging or evolving
A weakness in this system is the diameter. Many melanomas present themselves as lesions smaller than 6 mm in diameter; and all melanomas were malignant on day 1 of growth, which is merely a dot. An astute physician will examine all abnormal moles, including ones less than 6 mm in diameter. Seborrheic keratosis may meet some or all of the ABCD criteria, and can lead to false alarms among laypeople and sometimes even physicians. An experienced doctor can generally distinguish seborrheic keratosis from melanoma upon examination, or with dermatoscopy.
Some advocate the system "ABCDE",[27] with E for evolution. Certainly moles that change and evolve will be a concern. Alternatively, some refer to E as elevation. Elevation can help identify a melanoma, but lack of elevation does not mean that the lesion is not a melanoma. Most melanomas are detected in the very early stage, or in-situ stage, before they become elevated. By the time elevation is visible, they may have progressed to the more dangerous invasive stage.
Nodular melanomas do not fulfill these criteria, having their own mnemonic, "EFG":
- Elevated: the lesion is raised above the surrounding skin.
- Firm: the nodule is solid to the touch.
- Growing: the nodule is increasing in size.
A recent and novel method of melanoma detection is the "ugly duckling sign".[28][29] It is simple, easy to teach, and highly effective in detecting melanoma. Simply, correlation of common characteristics of a person's skin lesion is made. Lesions which greatly deviate from the common characteristics are labeled as an "Ugly Duckling", and further professional exam is required. The "Little Red Riding Hood" sign[29] suggests that individuals with fair skin and light-colored hair might have difficult-to-diagnose amelanotic melanomas. Extra care and caution should be rendered when examining such individuals, as they might have multiple melanomas and severely dysplastic nevi. A dermatoscope must be used to detect "ugly ducklings", as many melanomas in these individuals resemble non-melanomas or are considered to be "wolves in sheep clothing".[30] These fair-skinned individuals often have lightly pigmented or amelanotic melanomas which will not present easy-to-observe color changes and variation in colors. The borders of these amelanotic melanomas are often indistinct, making visual identification without a dermatoscope very difficult.
Amelanotic melanomas and melanomas arising in fair-skinned individuals (see the "Little Red Riding Hood" sign) are very difficult to detect, as they fail to show many of the characteristics in the ABCD rule, break the "Ugly Duckling" sign, and are very hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines.
Following a visual examination and a dermatoscopic exam,[30] or in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. A skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining the severity of the melanoma. If the mole is malignant, the mole and an area around it need excision. Elliptical excisional biopsies may remove the tumor, followed by histological analysis and Breslow scoring. Punch biopsies are contraindicated in suspected melanomas, for fear of seeding tumor cells and hastening the spread of the malignant cells.
Total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up of high-risk patients. The technique has been reported to enable early detection and provides a cost-effective approach (being possible with the use of any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes.[24] The diagnosis method should be used in conjunction with (and not as a replacement for) dermoscopic imaging, with a combination of both methods appearing to give extremely high rates of detection.
Melanoma is divided into the following types:[31]
- Lentigo maligna
- Lentigo maligna melanoma
- Superficial spreading melanoma
- Acral lentiginous melanoma
- Mucosal melanoma
- Nodular melanoma
- Polypoid melanoma
- Desmoplastic melanoma
- Amelanotic melanoma
- Soft-tissue melanoma
See also:[32]
Lactate dehydrogenase (LDH) tests are often used to screen for metastases, although many patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates metastatic spread of the disease to the liver. It is common for patients diagnosed with melanoma to have chest X-rays and an LDH test, and in some cases CT, MRI, PET and/or PET/CT scans. Although controversial, sentinel lymph node biopsies and examination of the lymph nodes are also performed in patients to assess spread to the lymph nodes. A diagnosis of melanoma is supported by the presence of the S-100 protein marker. HMB-45 is a monoclonal antibody that reacts against an antigen present in melanocytic tumors such as melanomas, and stands for Human Melanoma Black. It is used in anatomic pathology as a marker for such tumors. The antibody was generated to an extract of melanoma. It reacts positively against melanocytic tumors but not other tumors, thus demonstrating specificity and sensitivity. The antibody also reacts positively against junctional nevus cells but not intradermal nevi, and against fetal melanocytes but not normal adult melanocytes. HMB-45 is nonreactive with almost all non-melanoma human malignancies, with the exception of rare tumors showing evidence of melanogenesis (e.g., pigmented schwannoma, clear cell sarcoma) or tumors associated with tuberous sclerosis complex (angiomyolipoma and lymphangiomyoma).
Further context on cancer staging is available at TNM.
Also of importance are the "Clark level" and "Breslow's depth", which refer to the microscopic depth of tumor invasion.[33]
Melanoma stages:[34] 5 year survival rates:
Stage 0: Melanoma in situ (Clark Level I), 99.9% survival
Stage I / II: Invasive melanoma, 89–95% survival
- T1a: Less than 1.0 mm primary tumor thickness, without ulceration, and mitosis < 1/mm2
- T1b: Less than 1.0 mm primary tumor thickness, with ulceration or mitoses ≥ 1/mm2
- T2a: 1.01–2.0 mm primary tumor thickness, without ulceration
Stage II: High risk melanoma, 45–79% survival
- T2b: 1.01–2.0 mm primary tumor thickness, with ulceration
- T3a: 2.01–4.0 mm primary tumor thickness, without ulceration
- T3b: 2.01–4.0 mm primary tumor thickness, with ulceration
- T4a: Greater than 4.0 mm primary tumor thickness, without ulceration
- T4b: Greater than 4.0 mm primary tumor thickness, with ulceration
Stage III: Regional metastasis, 24–70% survival
- N1: Single positive lymph node
- N2: Two to three positive lymph nodes or regional skin/in-transit metastasis
- N3: Four positive lymph nodes or one lymph node and regional skin/in-transit metastases
Stage IV: Distant metastasis, 7–19% survival
- M1a: Distant skin metastasis, normal LDH
- M1b: Lung metastasis, normal LDH
- M1c: Other distant metastasis or any distant metastasis with elevated LDH
Based upon AJCC five-year survival from initial melanoma diagnosis with proper treatment.
Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),[35] following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past, use of sunscreens with a sun protection factor (SPF) rating of 50 or higher on exposed areas were recommended; as older sunscreens more effectively blocked UVA with higher SPF.[36] Currently, newer sunscreen ingredients (avobenzone, zinc, and titanium) effectively block both UVA and UVB even at lower SPFs. However, there are questions about the ability of sunscreen to prevent melanoma.[37] This controversy is well discussed in numerous review articles, and is rejected by most dermatologists.[38] This correlation might be due to the confounding variable that individuals who used sunscreen to prevent burn might have a higher lifetime exposure to either UVA or UVB. See Sunscreen controversy for further references and discussions. Using artificial light for tanning was once believed to help prevent skin cancers, but it can actually lead to an increased incidence of melanomas.[39] Even though tanning beds emit mostly UVA, which causes tanning, it by itself might be enough to induce melanomas.
A good rule of thumb for decreasing ultraviolet light exposure is to avoid the sun between the hours of 9 a.m. and 3 p.m. or avoid the sun when one's shadow is shorter than one's height. These are rough rules, however, and can vary depending on locality and individual skin cancer risk.
Almost all melanomas start with altering the color and appearance of normal-looking skin. This area may be a dark spot or an abnormal new mole. Other melanomas form from a mole or freckle that is already present in the skin. It can be difficult to distinguish between a melanoma and a normal mole. When looking for danger signs in pigmented lesions of the skin, a few simple rules are often used.
Confirmation of the clinical diagnosis is done with a skin biopsy. This is usually followed up with a wider excision of the scar or tumor. Depending on the stage, a sentinel lymph node biopsy is done, as well, although controversy exists around trial evidence for this procedure.[40] Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.
Excisional biopsies may remove the tumor, but further surgery is often necessary to reduce the risk of recurrence. Complete surgical excision with adequate surgical margins and assessment for the presence of detectable metastatic disease along with short- and long-term followup is standard. Often this is done by a wide local excision (WLE) with 1 to 2 cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2 to 0.5 cm.[41] Many surgeons consider 0.5 cm the standard of care for standard excision of melanoma-in-situ,[42] but 0.2 cm margin might be acceptable for margin controlled surgery (Mohs surgery, or the double-bladed technique with margin control). The wide excision aims to reduce the rate of tumor recurrence at the site of the original lesion. This is a common pattern of treatment failure in melanoma. Considerable research has aimed to elucidate appropriate margins for excision with a general trend toward less aggressive treatment during the last decades.[43]
Mohs surgery has been reported with cure rate as low as 77%[44] and as high as 98.0% for melanoma-in-situ.[45] CCPDMA and the "double scalpel" peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this "intra-epithelial" type of melanoma.
Melanomas that spread usually do so to the lymph nodes in the area of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications, but no overall survival benefit. Recently, the technique of sentinel lymph node biopsy has been developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of nodes with tumor.[46]
Although controversial and without prolonging survival[citation needed], sentinel lymph node biopsy is often performed, especially for T1b/T2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs. A process called lymphoscintigraphy is performed in which a radioactive tracer is injected at the tumor site to localize the sentinel node(s). Further precision is provided using a blue tracer dye, and surgery is performed to biopsy the node(s). Routine hematoxylin and eosin (H&E) and immunoperoxidase staining will be adequate to rule out node involvement. Polymerase chain reaction (PCR) tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with a negative sentinel lymph node actually had a small number of positive cells in their nodes. Alternatively, a fine-needle aspiration biopsy may be performed and is often used to test masses.
If a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection will often be performed. If the disease is completely resected, the patient will be considered for adjuvant therapy. Excisional skin biopsy is the management of choice. Here, the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2 mm) ellipse of surrounding skin and tissue.[47] To avoid disruption of the local lymphatic drainage, the preferred surgical margin for the initial biopsy should be narrow (1 mm). The biopsy should include the epidermal, dermal, and subcutaneous layers of the skin. This enables the histopathologist to determine the thickness of the melanoma by microscopic examination. This is described by Breslow's thickness (measured in millimeters). However, for large lesions, such as suspected lentigo maligna, or for lesions in surgically difficult areas (face, toes, fingers, eyelids), a small punch biopsy in representative areas will give adequate information and will not disrupt the final staging or depth determination. In no circumstances should the initial biopsy include the final surgical margin (0.5 cm, 1.0 cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. A large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram-directed lymphnode dissection. A small punch biopsy can be used at any time where for logistical and personal reasons a patient refuses more invasive excisional biopsy. Small punch biopsies are minimally invasive and heal quickly, usually without noticeable scarring.
Adjuvant treatment[edit]
High-risk melanomas may require adjuvant treatment, although attitudes to this vary in different countries. In the United States, most patients in otherwise good health will begin up to a year of high-dose interferon treatment, which has severe side effects, but may improve the patient's prognosis slightly.[48] However British Association of Dermatologist guidelines on melanoma state that interferon is not recommended as a standard adjuvant treatment for melanoma.[49] A 2011 meta-analysis showed that interferon could lengthen the time before a melanoma comes back but increased survival by only 3% at 5 years. The unpleasant side effects also greatly decrease quality of life.[50]
In Europe, interferon is usually not used outside the scope of clinical trials.[51][52]
Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.[53]
Chemotherapy and immunotherapy[edit]
Various chemotherapy agents are used, including dacarbazine (also termed DTIC), immunotherapy (with interleukin-2 (IL-2) or interferon (IFN)), as well as local perfusion, are used by different centers. The overall success in metastatic melanoma is quite limited.[54] IL-2 (Proleukin) is the first new therapy approved for the treatment of metastatic melanoma in 20 years. Studies have demonstrated that IL-2 offers the possibility of a complete and long-lasting remission in this disease, although only in a small percentage of patients.[55] A number of new agents and novel approaches are under evaluation and show promise.[56] Clinical trial participation should be considered the standard of care for metastatic melanoma.[57]
Other chemotherapy options include ipilimumab, vemurafenib and temozolomide.
Lentigo maligna treatment[edit]
Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceedingly high (up to 50%). This is due to the ill-defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The narrow surgical margin used, combined with the limitation of the standard "bread-loafing" technique of fixed tissue histology — result in a high "false negative" error rate, and frequent recurrences. Margin control (peripheral margins) is necessary to eliminate the false negative errors. If bread loafing is used, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control.
Mohs surgery has been done with cure rate reported to be as low as 77%,[44] and as high as 95% by another author.[45] The "double scalpel" peripheral margin controlled excision method approximates the Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods.[58]
Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months.
Radiation therapy[edit]
Radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. It may reduce the rate of local recurrence but does not prolong survival.[59] Radioimmunotherapy of metastatic melanoma is currently under investigation. Radiotherapy has a role in the palliation of metastatic melanoma.[60]
Features that affect prognosis are tumor thickness in millimeters (Breslow's depth), depth related to skin structures (Clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion, presence of tumor-infiltrating lymphocytes (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant metastasis.[61] Certain types of melanoma have worse prognoses but this is explained by their thickness. Interestingly, less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging. Local recurrences tend to behave similarly to a primary unless they are at the site of a wide local excision (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion.
When melanomas have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy. Extent of malignancy within a node is also important; micrometastases in which malignancy is only microscopic have a more favorable prognosis than macrometastases. In some cases micrometastases may only be detected by special staining, and if malignancy is only detectable by a rarely employed test known as the polymerase chain reaction (PCR), the prognosis is better. Macrometastases in which malignancy is clinically apparent (in some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is extracapsular extension, the prognosis is worse still.
When there is distant metastasis, the cancer is generally considered incurable. The five year survival rate is less than 10%.[34] The median survival is 6 to 12 months. Treatment is palliative, focusing on life-extension and quality of life. In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment). Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis.
There is not enough definitive evidence to adequately stage, and thus give a prognosis for, ocular melanoma and melanoma of soft parts, or mucosal melanoma (e.g. rectal melanoma), although these tend to metastasize more easily. Even though regression may increase survival, when a melanoma has regressed, it is impossible to know its original size and thus the original tumor is often worse than a pathology report might indicate.
Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental.[64] "Intrinsic" factors are generally an individual's family history and inherited genotype, while the most relevant environmental factor is sun exposure.
Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA[65] and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of Activating Transcription Factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells;[66][67][68] studies from mice on skin cancer tend to confirm a role for Activating Transcription Factor-2 in cancer progression.[69][70] Occasional extreme sun exposure (resulting in "sunburn") is causally related to melanoma.[71] Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers.[72][73] Other factors are mutations in or total loss of tumor suppressor genes. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.[74]
Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia[75] where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult. Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that sunscreen — while preventing the sunburn — does not protect mice, injected with melanoma cells a day after UV exposure, from developing melanoma.[76]
Fair and red-headed people, persons with multiple atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk.[77]
A family history of melanoma greatly increases a person's risk because mutations in CDKN2A[disambiguation needed], CDK4 and several other genes have been found in melanoma-prone families.[78] Patients with a history of one melanoma are at increased risk of developing a second primary tumor.[79]
The incidence of melanoma has increased in the recent years, but it is not clear to what extent changes in behavior, in the environment, or in early detection are involved.[80]
To understand how sunscreen can reduce sunburn and at the same time cause melanoma it is necessary to distinguish between direct DNA damage and indirect DNA damage. Genetic analysis has shown that 92% of all melanoma are caused by the indirect DNA damage.[81] Although some people believe that dark-skinned people such as those of African descent cannot get sunburns, they are in fact susceptible, and should use sunscreen accordingly, as sunscreen has been proven to protect against other cancers such as squamous cell carcinoma and basal cell carcinoma.[82]
Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather scarce. However, one example lies in a 1960s examination of nine Peruvian mummies, radiocarbon dated to be approximately 2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases to the bones.[83]
John Hunter is reported to be the first to operate on metastatic melanoma in 1787. Although not knowing precisely what it was, he described it as a "cancerous fungous excrescence". The excised tumor was preserved in the Hunterian Museum of the Royal College of Surgeons of England. It was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma.[84]
The French physician René Laennec was the first to describe melanoma as a disease entity. His report was initially presented during a lecture for the Faculté de Médecine de Paris in 1804 and then published as a bulletin in 1806.[85] The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820.[86] In his later work in 1857 he remarked that there is a familial predisposition for development of melanoma (Eight Cases of Melanosis with Pathological and Therapeutical Remarks on That Disease). Norris was also a pioneer in suggesting a link between nevi and melanoma and the possibility of a relationship between melanoma and environmental exposures, by observing that most of his patients had pale complexions [87]. He also described that melanomas could be amelanotic and later showed the metastatic nature of melanoma by observing that they can disseminate to other visceral organs.
The first formal acknowledgment of advanced melanoma as untreatable came from Samuel Cooper in 1840. He stated that the only chance for a cure depends upon the early removal of the disease (i.e., early excision of the malignant mole) ...'[88] More than one and a half centuries later this situation remains largely unchanged.
Pharmacotherapy research for unresectable or metastatic malignant melanoma offers new treatment possibilities.[2] In addition to the advances with recently approved agents, ongoing research into combination therapy, such as dabrafenib and trametinib, may reveal a more effective and better-tolerated option for patients with metastatic melanoma. One important pathway in melanin synthesis involves the transcription factor MITF. The MITF gene is highly conserved and is found in people, mice, birds, and even fish. MITF production is regulated via a fairly straightforward pathway. UV radiation causes increased expression of transcription factor p53 in keratinocytes, and p53 causes these cells to produce melanocyte-stimulating hormone (MSH), which binds to melanocortin 1 receptors (MC1R) on melanocytes. Ligand-binding at MC1R receptors activates adenylate cyclases, which produce cAMP, which activates CREB, which promote MITF expression. The targets of MITF include p16 (a CDK inhibitor) and Bcl2, a gene essential to melanocyte survival. It is often difficult to design drugs that interfere with transcription factors, but perhaps new drugs will be discovered that can impede some reaction in the pathway upstream of MITF.
Studies of chromatin structure also promise to shed light on transcriptional regulation in melanoma cells. It has long been assumed that nucleosomes are positioned randomly on DNA, but murine studies of genes involved in melanin production now suggest that nucleosomes are stereotypically positioned on DNA. When a gene is undergoing transcription, its transcription start site is almost always nucleosome-free. When the gene is silent, however, nucleosomes often block the transcriptional start site, suggesting that nucleosome position may play a role in gene regulation.
Finally, given the fact that melanin helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce melanin synthesis in individuals who would otherwise get sunburns. Redheads, for example, do not tan because they have MC1R mutations. In mice, it has been shown that the melanin production pathway can be rescued downstream of MC1R.[citation needed]
A study published on January 27, 2011, by M. Raza Zaidi et al. shows that interferon-γ links ultraviolet radiation to melanomagenesis in mice. Using a mouse model that allowed the visual tracking and purification of melanocytes using a green fluorescent dye, data showed that UVB-induced, macrophage-enhanced interferon-γ release results in melanoma growth, proliferation and immunoevasion. Based on these results, the interferon-γ pathway can potentially serve as part of new therapeutic measures to treat patients suffering from malignant melanoma, as well as a potential preventive strategy against UV-induced radiation.[89]
About 60% of melanomas contain a mutation in the B-Raf gene. Early clinical trials suggested that B-Raf inhibitors including Plexxicon's vemurafenib could lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation.[90] In June 2011, a large clinical trial confirmed the positive findings from those earlier trials.[91][92]
In June 2012 a study reported that patients taking a different B-Raf inhibitor, Dabrafenib, did better than patients taking a chemotherapy agent. [93]
Some researchers believe that combination therapies that simultaneously block multiple pathways may improve efficacy by making it more difficult for the tumor cells to mutate before being destroyed. In October 2012 a study reported that combining Dabrafenib with a MEK inhibitor trametinib led to even better outcomes. Compared to Dabrafenib alone, progression-free survival was increased to 41% from 9%, and the median progression-free survival increased to 9.4 months versus 5.8 months. Some side effects were, however, increased in the combined study. [94][95]
At the American Society of Clinical Oncology Conference in June 2010, the Bristol-Myers Squibb pharmaceutical company reported the clinical findings of their drug ipilimumab. The study found an increase in median survival from 6.4 to 10 months in patients with advanced melanomas treated with the monoclonal ipilimumab, versus an experimental vaccine. It also found a one year survival rate of 25% in the control group using the vaccine, 44% in the vaccine and ipilimumab group, and 46% in the group treated with ipilimumab alone.[96] However, some have raised concerns about this study for its use of the unconventional control arm, rather than comparing the drug against a placebo or standard treatment.[97][98][99] The criticism was that although Ipilimumab performed better than the vaccine, the vaccine has not been tested before and may be causing toxicity, making the drug appear better by comparison.
In June 2011, a clinical trial of ipilimumab plus dacarbazine combined this immune system booster with the standard chemotherapy drug that targets cell division. It showed an increase in median survival for these late stage patients to 11 months instead of the 9 months normally seen. Researchers were also hopeful that perhaps 10–20% of patients could live a long time. Some serious side-effects of revving up the immune system were seen in some patients. A course of treatment costs $120,000. The drug's brandname is Yervoy.[91][100]
Targeted therapies[edit]
In clinical research setting other therapies, such as adoptive cell therapy or gene therapy, may be tested.[101] Two kinds of experimental treatments developed at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the US, have been used in advanced (metastatic) melanoma with high success rates in terms of melanoma treatments.[21] The first treatment involves adoptive cell therapy (ACT) using TILs immune cells (tumor infiltrating lymphocytes) isolated from a patient's own melanoma tumor. These cells are grown in large numbers in a laboratory and returned to the patient after a treatment that temporarily reduces normal T cells in the patient's body. TIL therapy following lymphodepletion can result in durable complete response in a variety of setups.[102][103] Up to date, the only medical center outside the USA that has managed to successfully implement this technology is Sheba Medical Center through "Ella Institute of Melanoma", found in Israel (objective response rates of 50%).[103] The second treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient's lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.[104]
A new treatment that trains the immune system to fight cancer has shown modest benefit in late-stage testing against melanoma.[105] Sutent may be effective for patients with metastatic melanoma.[106]
Surveillance methods[edit]
Advances in high resolution ultrasound scanning have enabled surveillance of metastatic burden to the sentinel lymph nodes.[107] The Screening and Surveillance of Ultrasound in Melanoma trial (SUNMEL) is evaluating ultrasound as an alternative to invasive surgical methods.[108]
Oncolytic virotherapy[edit]
In some countries oncolytic virotherapy methods are studied and used to treat melanoma. Oncolytic virotherapy is a promising branch of virotherapy, where oncolytic viruses are used to treat diseases; viruses can increase metabolism, reduce anti-tumor immunity and disorganize vasculature.[109]
See also[edit]
- Melanotropin receptor
- Uveal melanoma - melanoma of the eye
- Notes
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- ^ Cancer Research UK statistics team 2010.
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- ^ "Documento annuale 2009. I nuovi dati di incidenza e mortalità. Periodo 2003–2005. [Annual Document 2009. The new data of incidence and mortality. 2003–2005]". Associazione Italiana Registri Tumori.
- ^ Kanavy HE, Gerstenblith MR (December 2011). "Ultraviolet radiation and melanoma". Semin Cutan Med Surg 30 (4): 222–8. doi:10.1016/j.sder.2011.08.003. PMID 22123420.
- ^ Jemal A, Siegel R, Ward E, et al. (2008). "Cancer statistics, 2008". CA Cancer J Clin 58 (2): 71–96. doi:10.3322/CA.2007.0010. PMID 18287387.
- ^ Jost, L.M. (July 2003). "ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cutaneous malignant melanoma". Annals of Oncology 14 (7): 1012–1013. doi:10.1093/annonc/mdg294. PMID 12853340.
- ^ Lucas, Robyn; McMichael, Tony; Smith, Wayne; Armstrong, Bruce (2006). Solar Ultraviolet Radiation: Global burden of disease from solar ultraviolet radiation (PDF). Environmental Burden of Disease Series 13. World Health Organization. ISBN 92-4-159440-3.
- ^ MelanomaWarningSigns.com
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External links[edit]
Wikimedia Commons has media related to Melanoma. |
- Melanoma at the Open Directory Project
- Melanomas and melanocytic hyperplasias in: Atlas histopatologii guzów skóry (pl.wikibooks.org)
- EyeMelanoma.org


text:
UNION GAP, Wash.--Family and friends of the woman fatally shot outside a Union Gap movie theatre watched as her husband faced the judge.
43-year-old John Munzanreder is accused of devising a gruesome plan to have someone kill his wife, before ending up taking the shot himself.
NBC Right Now spoke with the victims son off camera. He says his mother, Cindy Kelly-Munzanreder, was a wonderful woman, and the family wants to thank the community for their overwhelming support.
"I just couldn't say enough good things about her," said Tom Sparling, Cindy's former boss at Valley Ford Nissan. "She was thoughtful, our customers loved her, our staff were her good friends. We are deeply saddened by the tragic death of Cindy."
According to court documents, John offered a co-worker at Valley Ford Nissan $20,000 to kill his wife.
22-year-old Juan Ibanez-Cortes told Union Gap Police he did not pull the trigger but did assist with the murder. Ibanez-Cortes said he heard gunshots, saw a handgun come flying through the bushes and took off with the weapon. Police later found the gun stashed at Valley Ford Nissan and quickly booked the two men for Cindy's murder.
"It's been a very difficult week," said Sparling. "Everybody thought the world of her. We're still in shock."
Court documents claim Munzanreder lacked "sincere emotion" during questioning. People who knew the couple, told police it was "common knowledge" that he had been having an affair for several months.
Both men face charges of first-degree murder. Bail has been set at $2 million each. Their next court appearance will be in two weeks.
UPDATE:UNION GAP, Wash. - According to court documents, the man accused of murdering Cynthia Kelly-Munzanreder is her husband.Union Gap Police arrested 43-year-old John Munzanreder and Juan Ibanez-Cortes Monday evening. Court papers show Munzanreder shot his wife outside the Majestic Theater and then threw the gun through some bushes to Ibanez-Cortes.Ibanez-Cortes then left in his vehicle and stashed the gun at Valley Ford, where both suspects work. Officers later found the gun at the dealership while serving a search warrant.Investigators say Munzanreder offered $20,000 to Ibanez-Cortes to shoot his wife but he refused. Munzanreder then asked him to at least help with the murder.According to people who knew the couple, the husband was having an affair for several months.Officers booked Munzanreder for 1st degree murder and booked Ibanez-Cortes for alien in possession of a firearm and 1st degree murder.UPDATE:UNION GAP, Wash. - Union Gap Police have arrested two men for the murder of Cynthia Kelly-Munzanreder. Both have been booked into the Yakima County Jail for 1st Degree Murder.Police say Kelly-Munzanreder was shot in the head Thursday night as she was walking out of the Majestic Theaters with her husband. Police say the shooting is not gang related.
Previous Coverage:
UNION GAP, Wash.-- Union Gap police say they have no new information in the murder of 45-year-old Cynthia Kelly-Munzanreder. Munzanreder was shot in the head in the parking lot of The Majestic Theatre on Thursday. She and her husband were walking to their car when the attack happened. Police are saying it was an isolated incident, but still have not released a possible motive or any information about suspects.


text:
(487 quotes found)
"The only difference between a genius and one of common capacity is that the former anticipates and explores what the latter accidentally hits upon; but even the man of genius himself more frequently employs the advantages that chance presents to him;"
Guillaume Thomas Raynal
"Treading the soil of the moon, palpitating its pebbles, tasting the panic and splendor of the event, feeling in the pit of one's stomach the separation from terra - these form the most romantic sensation an explorer has ever known"
Vladimir Nabokov
"To explore the unknown and the familiar, distant and near, and to record in details with the eyes of a child, any beauty, horror, irony, traces of utopia or Hell."
Dan Eldon
"Be an explorer...read, surf the internet, visit customers, enjoy arts, watch children play...do anything to prevent yourself from becoming a prisoner of your knowledge, experience, and current view of the world."
Charles Thompson
"That is the exploration that awaits you! Not mapping stars and studying nebula, but charting the unknown possibilities of existence"
Leonard Nimoy
"In any field, find the strangest thing and then explore it."
John Archibald Wheeler
"It's important for the explorer to be willing to be led astray."
Roger Von Oech
"I would like to explore some side roads in life while I am still in good health and good spirits."
Charles Kuralt
"We don't require our astronomers to explore the heavens with 19th century telescopes, and we don't require our geologists to study the Earth with a tape measure. If we are serious about realizing the promise of stem cell research, our biomedical researchers need access to the best stem cell lines available."
Tom Harkin
"I always wanted to be an explorer, but - it seemed I was doomed to be nothing more than a very silly person."
Michael Palin


text:
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What Makes it Mighty?
- Organic cotton mattresses to fit cribs, bassinets and porta-cribs
- Free from PVC, polyurethane and chemical flame retardants
Organic Cotton Bassinet/Cradle Mattress by Naturepedic
The Organic Bassinet/Cradle Mattress by Naturepedic is the most luxurious natural organic bassinet and cradle mattress available. It is firm, fire-safe, and eliminates harmful chemicals from your child's sleeping environment. It will provide your baby with a more natural, healthy and comfortable sleep.
Features Air-Core, a non-toxic environmentally friendly support layer made from 100% food-grade polyethylene. Air-Core is a network of closed cell air pockets that provide a firm and comfortable base without the toxic properties of polyurethane foam and the allergenic concerns of latex rubber.
Fire protection features a non-toxic and naturally derived fire barrier system that is safe and effective. It meets and exceeds all Federal and State flammability standards without the use of potentially harmful chemicals.
- Features a Waterproof Organic cotton cover with a 100% polyehtylene food-grade surface
- Free of: Vinyl, PVC and Phthalates, latex, wool and polyurethane foam
- Dimensions: 33" x 15" x 1.5"
Made in USA
This item ships directly from the manufacturer
About Naturepedic
Naturepedic was founded by Barry A Cik, a quarter century veteran in the field of environmental engineering. In anticipation of his first grandchild, Barry went searching for a suitable baby crib mattress. Sadly, he found all of the crib mattress offerings completely unacceptable and was in shock at the state of the industry. "I knew all about vinyl/PVC, polyurethane foam, and the various chemicals contained in them and there was no way I was going to put my grandchild to sleep within a few inches of these chemicals."
more »About MightyNest
We make it easy for families to create a healthy home. Each of our 1000+ products has been thoroughly researched to be free of concerning chemicals, and hand-picked for its quality and design. With products for the whole family, ranging from kitchenware to reusable lunch gear to skincare, it is truly better living made easy.