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Hundreds of DotA fans submitted signs written on pieces of paper for the Dota 2 beta key contest. Steven Addison (San Antonio, Texas) had a bigger idea - he was going to show his love for Dota 2 to the world by getting his own sign on a billboard along a major highway.
We did a quick interview with Steven to document the task.
1) How long have you guys been playing DotA?
I have never actually played DotA. I know I know, "TAKE AWAY HIS PRIZE, BURN HIM AT THE STAKE". I didn't get into the Dota genre till about a year and a half ago and then I went hard. I participated in the LoL beta like twice, enough to say "I want to play the jester guy!" but that was about it.
My friend Clay (the other guy in the picture/video) did, however. He played the first incarnation of it before anyone knew much about it and had no idea what he was doing, and pretty much left it at that. Some time later, his friends started to get pretty big into it which drew him back in for another go, at that point, he still knew nothing, but gave it some attention here and there.
2) Why do you want to be in the Dota 2 beta?
I didn't get into the Dota genre until a mutual friend of ours, who played League of Legends, begged us to give it a try, being free, we did and both of us fell pretty hard for it. Clay had been playing Heroes of Newerth (HoN) by this time with some of his friends that he worked with at a Cyber Cafe and that propelled him to going pretty hard on HoN as well. He eventually broke me down and I ended up buying a HoN account. After some conditioning and getting rid of a lot of my LoL bad habits, we both started playing HoN pretty regularly.
We both were pretty big on wanting to try any DOTA genre games we could find (we even went back to try DotA, but the learning curve and the different content we had to learn was so steep we quickly abandoned that idea). However, when Dota 2 was announced we both were very attentive to any details that were released on it. Initially, we were skeptical as to whether or not we wanted to play it, after all, we had two games that we've spent a fair amount of money on - do we really want to get into another one that's "the same game"?
As we learned more and saw more, we talked more and more about it and started to discuss all the stuff in the original DotA as well comparing it to the other DOTAs out there and slowly became more and more excited about it. And then, there we are at 2:30 in the morning, watching 8 hours of stream for the Dota2 international competition when we both had work in the morning.
Needless to say, we are no longer concerned as to whether or not we'll give Dota2 a try. Clay can't get enough of the art style and the more he sees the re-imagining of the heroes, the more he wants to change who he wants to play. I spend more money on Valve than I feel I ever should have but they've never let me down. I'm looking forward to getting a hold of a DOTA that has a group like Valve backing it. I'm pretty excited to see what their team is going to be able to do (and the hats for TF2... lets be honest).
3) How did you come up with the idea of getting a Dota 2 billboard for the contest?
Clay heard about the competition first lurking on playdota.com and came to me to get a photoshop image made for him (before we knew shops would get you disqualified). I turned down the idea thinking anything that I could do, one of the other hordes of DotA fans could do MUCH better. But with the idea in mind, while I was driving down 1604 (the major highway that surrounds San Antonio), the billboard caught my eye as it changed it's advertisement. I suddenly wondered to myself how much something like that would cost since it's digital, maybe it wouldn't be so bad.
I went home and looked it up; $3000 for one board for a month. I almost abandoned the idea right then, but thinking better on it, decided to send of my contact info to the company. I mentioned it to Clay while I was looking it up and, while talking about it, he thought of the idea of implementing it into a film we're involved in, two birds one stone, so to speak. I sent the email Monday the 19th of Sept. That Friday, BJ from Clearchannel.com contacted me to learn more. I had explained in my initial email that we wondered if we would be able to rent some billboard time for MUCH less than the 1 month duration (like... a few minutes).
When he called, I explained that it was for a film project for a class and that we'd only need it briefly in a shot we would make involving it. Not only did he tell me that was very possible, but when I asked him how much that would run me, he said "I used to be a photography student, I tried to do the same thing once and got shot down, so I know what you're going through. For school? Don't worry about it then, man, I'll take care of you." I'm, at this point, trying not to scream into the phone from yelling and celebrating. He gave me a few extra details on the requirements for the graphic and I told him I'd get back in touch with him. I immediately called Clay (who immediately after called Jason, who was creating the film) to tell them it was on and plan accordingly. Jason set to work readjusting the film to include this scene, and I put together the simple graphics to be displayed. I contacted BJ Saturday after ironing out everything with the film aspect and we set 7 pm Sunday evening as the start time. BJ said he would put it in the rotation with 8 other advertisements, it would come up every 80 seconds for 10 seconds, and he would leave it in rotation for 30 minutes. The clip on my stream was us burning our first couple rotations admiring it and trying to get pictures for the contest, we filmed what we needed (several times) after we knocked that out of the way.
"3000 US Dollars for one board for a month - I almost abandoned the idea."
4) Overall, how much did the project cost you?
5) How long did it take for you guys to prepare for it?
Prep time really wasn't too bad. I thought and acted on the idea Monday, was responded to on Friday and had it done on Sunday. Creating the graphic took all of 30+ minutes (refining it, getting the colors of my name and the text I wrote to match the Dota 2 text and the symbol colors, asking and re asking if it looks good, and another 15 minutes trying to decide if Axe was the champ we wanted to showcase). We spent the full 30 minutes while the image was running using it to take pictures and record and tweet and Facebook and anything else we could think of to shoot it out to the world. I guess you could argue it was a weeks worth of work and the combined efforts of 5 people.
After all the hard work... the official entry.
6) Shoutouts to the people who helped you pull it off.
Shout outs DEFINITELY start with BJ Stewart who is the Clear Channel Outdoor Digital Media Specialist for the San Antonio, Texas area. It seriously COULD NOT have been done without his generosity. I also want to thank Bexar who made himself ever resourceful in getting us these shirts, I owe that guy a WHOLE lot, he always has to find someone to pile on that debt I have to him. I also want to thank Jason Crow for photographing the whole event and getting us some super high quality images and quality adjustments, you can see more of his work at www.youtube.com/shatteredskullprod.
I want to thank all my friends who saw us through this and gave all kinds of emotional support, most specifically - Katie, The Peter Tribe (Chase, Hutton and Evan), Alex, Rita, both my family and Clays. Finally, I definitely want to thank my best buddy Clay Beitel for bringing the competition to me and being as head over heals for the whole project as I was to make sure it went as best it could.
Steven Addison is a Dota genre fan who got a Dota 2 billboard in order to win a Dota 2 beta key. He hails from San Antonio, Texas.
Damn, this guy's in the next level.
I'll destroy this guy in pudge wars.

industry_corpus2: Gaming


text:
I worked with a student who once lamented to me that the police in his neighborhood were so "bored" that they'd given him three speeding tickets in one month.
What? You're blaming the police?
Then his parents told me, "Can you believe how unlucky he is? To get three speeding tickets in one month!"
One of the most important skills a person can have is the ability to admit fault. Take responsibility. Own up to your mistakes and apologize if you've hurt anybody.
It's so easy to do, and it will go so far towards making you more likeable, responsible, and trustworthy.
Excuses rarely make someone like and respect you more. And it's not likely to work on colleges, either.
Thanks for your advice! I happened upon your blog and it has a lot of good advice. I will surely tell my friends about this! Thanks again.

industry_corpus2: Subject Education


text:
Re: Any thoughts on updating the EFI system on a K75?
Bringing this post back from the dead. The Formula SAE competition in lincoln, ne this year has inspired me. As well as the 33mpg i get while cruising at midwest superslab speeds to get there.
I am thinking i will use VEMS, which is similar to megasquirt, but a more solid system, that is based on a similar architecture to the mpg guages i am making, facilitating my programming it. Also has a built in Wideband O2 sensor controller.
Some of the profit from the mpg guages will go to this.
33mpg? What do you get at say, 60 to 70? Should be almost 50 with a 75.
Something is amiss if you're only getting 33 mpg.
Some depends on the altitude plug. With it in at 5000 feet, get 42 or so at 70.
I may try bumping the timing up some more.
Although, i am still interested in doing this as a fun project. Will vastly improve throttle response as well. Rather than having the jetronic catch up to the throttle position, the throttle position (combined with manifold vacuum) will determine the fueling, calibrated by the wideband o2 sensor.
Some of my thoughts are that the bikes contemporary, the V65 sabre, gets better mileage with an 1100 cc, 150 horsepower, carburated monster.
Max, I get a solid 48 with my 1100 as long as I keep the RPMs under 5 or 6 K. Only time it dropped into the high 30's was when I was running on 3 cylinders.
Well, I pulled the trigger. Ordered a Megasquirt 1 kit. I will use the Airflow sensor for accurate fueling. Tunerstudio MS has a very good autotune feature. So I will be riding around with a laptop strapped to the back of the bike.
Basically, the initial setup will be Megasquirt 1, with a wideband O2 sensor controller. Stock AFM, actual throttle position sensor (rather than a switch).
Max, super excited to hear how that project goes. Besides just seeing if it works, what's the goal?
Some of the goal is that its interesting. But I will be able to improve power somewhat, improve throttle response greatly, and significantly improve fuel economy. The old ljet doesnt respond to changes, and runs super rich at high rpm. I will be able to control fuel mixxture accurately, with closed loop feedback. keep it at 15-16:1 while cruising, 14.7 in the middle, and 13.5 at wot.
Got most of the computer and related items set up. O2 sensor bung welded into the exhaust, and all the things needed to wire it up.
I am going to start out using the control method that the K1100's use, Alpha-N. This compares throttle opening, RPM, air temperature/pressure, and coolant temperature. Then it trims the fuel delivery with feedback from the oxygen sensor.
What will you be using for your TPS? The K75 uses just a switch whereas the K1100 unit outputs a signal proportional to the throttle opening. Are you adapting the K1100 TPS to your K75 throttle bodies ? I was toying once with the idea of fitting K1100 TBs to the K75 engine; never got past the contemplation stage though I think it could work. In your case, if you fitted the K1100 TBs, you'd get both larger throat opening and proportional TPS for your Megasquirt.
I just used a cheap proportional tps. Pretty much universal. Paired with a quick and easy adapter (prototype as of now).
Almost ready to install the Megasquirt unit.
I have a proportional TPS, and I have modified the circuit to provide inverse log response (for more accuracy) at the low end of the throttle.
All that is needed is to cut one wire on the air flow meter, and install.
I used a cheap volvo 740 L-Jetronic computer for its connector. I made a little circuit board with connectors for other circuits and sensors, as well as the main L-jet connector. This will all go into the old enclosure for the volvo ecu.
I have a wideband O2 sensor controller in a separate box, which feeds a 0-5 volt signal for the Air Fuel ratio (from 9:1 to 19:1 with gasoline).
TWB on the K100 forum put the K1100 TBs on his K100RS and it worked fine but he does not have a TPS working because the mounting is different . It goes well without the TPS.
Max How are you getting round the intergration of the megasquirt ECU and the K75 ignition and revlimiter?
The K100s also use a Air Flow Meter like the k75, which doesn't need the tps.
The K75 has the bosch ignition controller, which handles revlimits and ignition. It outputs a tach signal to the L-jet controller, which I am using with the Megasquirt.
I will enable a revlimiter on the megasquirt as a secondary safety.
The megasquirt and j-jet adapter board. Mounted on the stock ecu tray. The wideband o2 controller is in the box on the right.
Project is held up for a few days waiting for a $0.28 crystal. Those little buggers are delicate when installing. This time, I will glue it in place before soldering it.
Started right up. Needed to tweak a couple of settings, then it started on the first crank. Now to tune it.
I've been able to get a good idle vacuum signal (impressive with a Individual Throttle Body engine) at around 50kpa. This should make tuning much easier.
Hooked it up to a laptop, and drove around today. Got a functional tune working so far. Great (far better than stock) response and power at lower rpms, and equal or better at higher. Its easier to do the low rpm tuning around town and on the twisties above berkeley, so understandably this part is tuned better. I need some more open straight road to dial in the higher rpms and higher loads. With the lower gears, it shoots through the rpms too quick to get a good reading. So for now, I have the high rpm set rich to keep the engine safe, and then I will let the tuning software (Tunerstudio MS) dial it back.
Interestingly, it starts far easier now. Even without priming the fuel pump (which the megasquirt usually does). Touch the starter switch, and it fires up even more quickly than stock.
I have it set up taking the ignition signal from the middle coil, which is the same cylinder as I am taking the vacuum (load) signal from. I have it configured in the software as a 2 cylinder, with a single coil. Basically, that is to give the correct reading for the crank position, and to allow me to split the fuel injection into two events per cycle (720 degrees) for smoother idle. I would do three times per cycle, but the resolution of the fuel injector decreases as the pulsewidth decreases. At idle, I am at about 3.5 milliseconds, divided into two 1.75 ms squirts. As long as the pulswidth is around 2 ms, it is usually fine.
Will keep working on it and update here. Looks like this will be fairly useful. Thus far I have left the stock fuel injection wiring harness on the bike, and tapped into it for some connections. But based on the results of todays testing, I am thinking I will want to make this a permanent install, with a custom, high quality wiring harness, perhaps this winter.
Interesting project to follow you have going on here. Can't wait until it is finalized.
I will indeed. Most of it is very well documented in general (see megamanual.com and MSextra.com), but there are a few tricks I had to use.
Basically what is needed is to tap the Water temperature sensor wire that goes to pin 10 of the L-Jet connector, make an adapter plate for a volvo throttle position sensor, add a temperature sensor to the intake (I screwed a GM coolant sensor into the intake snorkel. If it was turbo or supercharged, this would be more critical, need to be in the plenum, and would need a faster response), weld a oxygen sensor bung to the header collector box, make a harness for the injectors (which taps from the fuel pump supply wire, and supplies the wideband oxygen sensor controller), and then finally tap the #2 coil (-) and the #2 cylinder's vacuum port (with a vacuum line to the built in air pressure sensor). A pre-assembled wideband oxygen sensor controller is attached as well. All of this is hooked into the controller box.
A laptop is used for tuning, most of which occurs with an automatic algorithm with Tunerstudio software(http://www.tunerstudio.com/). The base map had it running well enough to get going after a bit of fidgeting with the idle and off idle mixture.
From here, I will continue tuning the fuel maps, and then add acceleration enrichment (like a pumper carb/accelerator pump). I will also add exhaust gas oxygen control, which updates the mixture on the fly.
So far it has better response in the lower rpms than it ever has had. Huge increase in torque and smoothness. I haven't gotten the higher rpm as well tuned yet. I have it set super rich for the moment as a safety precaution, and it has pretty good power at full throttle.
In general, I have been starting with the autotune function set for around 13.5:1 air fuel ratio, richer at higher loads, leaner down with lower loads. From there, I will lean it out for better mpg and emissions at cruise and other speeds. Will aim for a stochiometric (14.7:1) ratio at cruise, 13:1 at wide open throttle for peak power and torque.
Will keep posting as I update it. I'll happily share the maps with anyone who is interested in doing this.
Well, did about 50 miles on it on friday. I changed the injection cycle to once per engine revolution. Much smoother response and idle, and better off idle performance, even without acceleration enrichment.
Was having some trouble tuning at higher speeds/rpm due to vibration/bumps causing read errors on my beater laptop. This will be resolved with a flash drive with linux running off of it, not using the hard drive.
Also had some issues with jiggling cables breaking the DB9 serial port on the megasquirt. I have made a new cable, which is a much lower profile, which prevents there from being leverage to damage the port. I have also added a 5 dollar bluetooth module. This allows me to use my phone (droid) as a datalogger and dashboard, and to change settings on the road, if I desire.
It is running great. Much more fun to ride: better performance down low in the rpms, and stays good throughout. I may be taking a trip next weekend, which will be a great trial run and tuning opportunity.
Well, more work has been done. The system is working well thus far, so I removed the old EFI harness and Air flow meter. Removing the AFM should give a bit better flow at peak torque (6000 rpm) where a lower manifold pressure at WOT suggests some restriction.
Well, more tuning completed. Its running well. However, I am hitting the maximum Duty Cycle for the Injectors at WOT in several spots. There are a few things I can do here. This basically means I am trying to inject more fuel than the injectors allow. I may switch the injectors to fire once every 720 degrees rather than every 360. I can also increase the fuel pressure, which I will probably do.

industry_corpus2: Automobiles


text: Our P/U (poly urethane synthetic leather) wallets will be a big hit with all men! These strong constructed wallets are water resistant (transfer area) makes it more durable than fabric front wallets and with so many slot all items can be safe and secure! This wallet has a separate slot for ID.

industry_corpus2: Manufacturing


text:
That moment, you know you have to cut, you've laid it out, measured, remeasured, scoured the web for any other alternative, checked the books, the magazines and the blogs. Faced with the terrifying prospect of completely and irrevocably butchering that very expensive piece of wood, when do you decide to cut?
Once scrambled, you can never get the yolk out of the whites.
Ah hell, it's just a piece of freaking wood!
Wait though, what if you made an error, how do you correct it at this point?
What if that joint isn't beefy enough?
What if the grain just isn't going in the right direction?
These thoughts are the cancer of woodworking, if you don't overcome these fears, face those demons, you'll never get a damn thing done!
pick me up and use me dammit!
both my favorite and most dreaded parts.
I just had the opportunity to meet an amazing supplier. At this point he'll remain anonymous until I ask if it's alright.
Urban trees, some hundreds of years old, felled by storms, cars, death, or construction, that would otherwise be trundled off to a mulch plant or bonfire. Trees with character and history, somehow managing to survive as long as they have. It's in the wood, there in the grain, its twists and turns and convolutions, its color and pattern and stain. It's in the sap that pumped through and the branches we can only imagine. And you can ask the story, he knows. He knows how to cut it and dry it and point out spots you may have missed. He used to mill bits of firewood on a band saw as a child. He earned a degree in forestry and now imparts his knowledge in the wood he sells.
Last year about this time I was waist deep in my own smoother, some folks have seen the pics, some very lucky few have had the chance to hold it, caress it, heft it, and even fewer still have made a shaving with it, no not a shaving really, a whisp..
So here's how it's done..
It is hands-down my favorite plane in the shop, it undoubtedly has its place, only used to put that final show finish on the surface, but damn does it feel good!
and Chicago , and actually miss being home. But a week spent in my girlfriend's parents' house, hearing the whine of the dust collector, snarl of radial arm saw, weed-wacker staccato of random orbital sander, made me miss my shop.
Ideas which I've approached, torn apart, reassembled, thrown out, recovered, seem to get lost in the perpetual separation of vacation. An understanding that drawings aren't always necessary.
Absence from your norm is therapy for your soul.
I learned a lot more about things other than woodworking.
I really picked up the value of other people. What some one else means to me. When that one shines that glimmer of one-ness.
I've decided the chairs will reflect this, four pieces, as a whole each reflecting one. I can't say they will be about another specific person, but each will include a bit of place, that centers each object through a physical artifact of being with another person.
Mysterious, huh? Just you wait.
Of course, I missed my cats too!


text:
Earth Day is here! This is the time of the year that we look back and reflect on some of the decisions we have made, and learn how to make simple changes that can make the world a more sustainable place in the future. We have gathered five great articles that can make it easy and fun to make your life greener, and why you don't need paper towels or plastic bags to clean or carry. Make a vow to do something different this year and tell us your #EDResolution on Twitter or Facebook! Additionally, the Nature Conservancy has given us their Top 5 Earth Day Action List: Eat Smart, Eat Local, Eat Sustainably, Eat Green, and how to Picnic for the Planet! Go green!
The ease of the paper towel can quickly overpower your eco-conscience until you unthinkingly grab for one after every little spill. Suddenly you're creating mini mountains of used paper towels in your trash can after every dusting session or bathroom cleaning. Read how to live without paper towels.
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Plastic bags are incredibly harmful to the environment: One plastic bag can take up to 1,000 years to degrade and remains toxic even after it breaks down, according to reuseit.com, a company that sells reusable bags and educates consumers on how to live plastic-free. Read more about how to really live without plastic bags. It can be done!

industry_corpus2: Others


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Corel has sold off its NetWinder thin client desktops to Hardware Computing Canada (HCC) less then a month after it officially launched the products. But Corel is far from abandoning the Linux-based desktops.
Corel has sold off its NetWinder thin client desktops to Hardware Computing Canada (HCC) less then a month after it officially launched the products. But Corel is far from abandoning the Linux-based desktops. The deal states that Corel will inherit a 25 percent stake in HCC, which is expected to float as a public company later this year.

industry_corpus2: Computing & Telecommunications


text:
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text:
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text:
A sunrise at the riverside, an enchanted chateau in the hills or a modern building in a globalized metropolis – our workshops offer various types of photography. We strongly emphasize on the symbiosis of classic theory and practical work.
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We will give you an insight in the major technical details of photography and show you how to use your DSLR or Compact system camera in full manual mode. Main focuses are camera functions, aperture, shutter speed, ISO, depth of field, white balance, image size, picture quality and composition.
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Feel the pulse of one of the most exciting cities in Germany and spent one day in Düsseldorf. The major carnival hotspot is also the capital of North Rhine-Westphalia.
With its famous Gehry buildings in the Media Harbour, State Parliament and the award-winning Kö-Arc, the city offers a medley of modern boulevards and buildings.
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The Museum District houses the famous Rijksmuseum. The Riverside is characterized by ocean liners and urban quarters. And Zuidas, the business district, is a mecca for photographers.
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The City of a Hundred Spires is home of the world famous medieval astronomical clock Orloj, a beautiful Vltava river side and the Charles Bridge, lined with statues of Catholic saints.
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The city is known for its historic and contemporary buildings, Imperial palaces, including Schönbrunn, the Habsburgs’ summer residence and the MuseumsQuartier.


text:
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Find any of our products cheaper somewhere else and we'll match the price.

industry_corpus2: Travel & Geography


text: We are dedicated to outputting the premium EVA foam products for customers. Continuous improvement is required for us to become better partners for our customers, improve our company and grow as individuals. This process requires that we actively listen and learn in order to improve.


text:
"The secret to managing is to keep the five guys who hate you away from the five guys who are undecided” is a quote that is frequently credited to New York Yankees and New York Mets baseball manager Casey Stengel (1890-1975), but this could possibly be incorrect. “Billy Martin, manager of the Texas Rangers: ‘The secret of managing is to keep the five guys who hate you away from the five guys who are undecided’” was cited in print in March 1974. Billy Martin (1928-1989) had played for the New York Yankees under Stengel.
“Casey Stengel once put it this way: ‘Keep the five guys who hate you away from the five who are undecided’” was cited in print in April 1974. Whatever Stengel said was usually printed in columns the next day by several sportswriters, and it’s probably notable that the quotation cannot be found during Stengel’s managerial career.
Charles Dillon “Casey” Stengel (30 July 1890 – 29 September 1975) was an American baseball player and manager from the early 1910s into the 1960s. In the 1950s, sportswriters dubbed him with yet another nickname, “The Old Perfessor”, for his sharp wit and his ability to talk at length on anything baseball-related. He is regarded as one of baseball’s more colourful personalities.
The key to good management is keeping the nine guys who hate your guts away from the nine guys who haven’t made up their minds.
Casey Stengel used to say, ‘’The secret to managing is to keep the five guys who hate you away from the five who are undecided.’’ These days the manager or coach has to keep the five who hate him away from reporters.
The secret of managing is to keep the five guys who hate you away from the guys who are undecided.

industry_corpus2: Sports


text:
The San Antonio Breast Cancer Symposium of 2006 brought together over 8,000 people from all corners of the globe for the unifying purpose of sharing the current state-of-the-art on all aspects of breast cancer. As usual, this year’s symposium devoted time to significant advances in the entire spectrum of the disease, including prevention, screening, prognostic factors, adjuvant chemotherapy, hormonal therapy and treatment of metastatic disease. Below is a discussion of results concerning adjuvant and neoadjuvant therapies.
Breast cancer is now clearly seen as several different diseases molecularly defined even within an apparent uniform histology. Increasing evidence suggests each of these diseases demands a different approach to treatment for greatest success: hormone receptor positive (ER+ PR+) tumors requiring predominantly endocrine therapy; HER2/neu + tumors requiring a HER2 targeted agent; and triple negative ER- PR – HER2 – or the so-called basal type requiring aggressive chemotherapy. The use of Herceptin® (trastuzumab) is now firmly established in the treatment of HER2 positive breast cancer, as is the use of dose-dense chemotherapy in high-risk patients. Neoadjuvant treatment is commonly used to downstage primary tumors and identify biomarkers predictive of benefit. Each of these therapeutic options had further exploration at this year’s SABCS.
Eagerly awaited was the second interim analysis of the BCIRG-006 study, a three arm trial comparing Adriamycin® (doxorubicin) and Cytoxan® (cyclophosphamide) followed by sequential Taxotere® (docetaxel) (AC-T) as a control arm, to two experimental arms: 1) AC and sequential Taxotere plus Herceptin for one year (AC-TH) and 2) a novel non-anthracycline regimen, Taxotere and carboplatinum plus Herceptin (TCH) followed by Herceptin for one year.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn1 "_ednref1") Patients with positive lymph nodes or who were high-risk, node-negative (29% of the population) were eligible, and over 3,000 patients were randomized. Median follow up is now 36 months. The disease-free survival at four years is 83% for AC-TH, 82% for TCH and 77% for AC-T. The hazard ratio for the addition of Herceptin is 0.61 (AC-TH) or 0.67 (TCH). No significant difference in the two Herceptin arms exist (p = 0.12). Overall survival is 92% for AC-TH, HR=0.59; 91% for TCH, HR=0.66; and 86% for ACT.
Interestingly, the authors reported data separately for the 900 women with lymph node negative (LN-) disease at entry. AC-TH had a hazard ratio of 0.32 (p = 0.007) and TCH, HR=0.47; p = 0.0096, demonstrating that the benefit of Herceptin in LN- patients is at least as proportionally good as in higher risk patients. In terms of safety, TCH was the least toxic regimen with significantly less anthracycline-related symptoms as hand-foot syndrome, stomatitis, vomiting, neuropathy, myalgia and nail changes than AC-TH. Importantly, the lesser degree of cardiac dysfunction seen with TCH in the first interim analysis persisted with only 4 patients experiencing Grade 3/4 LV dysfunction compared to 20 in the AC-TH arm (p = 0.005) and 4 in the AC-T arm.
Whereas in the first interim analysis the 35% of patients with coamplification of both topo-isomerase II and HER2 showed benefit of AC-TH compared to either TCH or AC-T, more complete and longer follow up now shows a coming together of the curves. However, for the two-thirds of patients with no co-amplification, there remains a marked improvement for patients in either of the two Herceptin arms. These interesting results suggest that topo-isomerase II coamplification in the presence of HER2 amplification promotes some form of resistance to Herceptin. Overall, given the equivalent efficacy and reduced toxicity of TCH, this study supports a practice changing paradigm: the use of a non-anthracycline regimen in the adjuvant treatment of HER2 positive breast cancer patients.
BCIRG-006, like most other adjuvant Herceptin trials, utilizes maintenance Herceptin to complete one year of therapy after chemotherapy. The choice of this schedule and duration remains entirely empirical. In contrast, the small Fin-HER study demonstrated that a 9-week course of Herceptin concurrently with chemotherapy could provide similar proportionally benefit as seen in the larger trials.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn2 "_ednref2") ECOG E-2918, another smaller pilot trial, randomized 227 HER2+ patients between short course TH-AC vs. long course TH-AC-H for 52 weeks in lymph-node positive patients.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn3 "_ednref3") The primary endpoint was the rate of congestive heart failure between arms. There was no difference in CHF: 3 in the short course and 4 in the long course arm. Six cardiac events occurred <2 years after treatment initiation. While the disease-free survival and overall survival were not primary endpoints of the study, at five years 76% of the short course H and 75% of long course H were disease-free, while 89% of short course H and 83% of long course H were alive. Results were even better in the approximately 80% of patients with 3+ IHC or positive FISH results. The study suggests that much of the benefit of Herceptin can be derived from a brief course in conjunction with chemotherapy; however, no benefit in terms of long-term CHF reduction was seen with an attenuation of the Herceptin schedule.
A meta-analysis of the effect of HER2 status in studies comparing an anthracycline containing-arm and a non-anthracycline arm was reported.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn4 "_ednref4") Overall, across seven studies, the use of anthracycline provided a 10% advantage in both DFS and OS. In the subset of HER2+ patients (generally obtained retrospectively), the HR for anthracycline in HER2+ was 0.71 for DFS, p=<0.001 and for overall survival HR=0.73; p=<0.001. In contrast, in HER2- patients in these trials, the HR was around unity for both DFS and OS. These results suggest that the majority of benefit from anthracyclines may be in the HER2+ patients, perhaps representing a surrogate marker for topo-II amplification. Furthermore, it supports the concept that anthracyclines do not necessarily benefit the 75% of patients who are HER2- with the possible exception of the small group with topo-II amplification but HER2 non-overexpressed.
Dose-dense chemotherapy (DDC), a concept in which total doses and cycle doses of drugs are the same but the cycle length is compressed, is based on a mathematical model predicting better cancer cell kill and outcome. This notion has been clinically proven in the landmark cooperative group study C9741, reported in final form at SABCS 2005.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn5 "_ednref5") Confirmatory studies have been highly anticipated and several were reported at this year’s meeting.
The German AGO group reported interim analysis of a randomized Phase III trial comparing standard epirubicin and cyclophosphamide followed by Taxol® (paclitaxel), (EC-T) at three-week intervals to sequential dose dense epirubicin, Taxol, and cyclophosphamide (DD ETC).[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn6 "_ednref6") This study was not a pure example of dose density as the individual doses in the sequential dose dense arms were also higher than in the standard dose arms, and the number of cycles were not equivalent between arms. Nevertheless, in this trial of high risk (> 4 positive lymph nodes, 25% HER2+) patients, there was a clear 5-year RFS advantage for the DD ETC arm: 70% compared to 62% for EC-T, HR-0.72, p=0.0079 and OS, 82% vs. 77%, HR 0.76, p=0.29. Toxicity, however, was greater for the DD ETC arm, including leukopenia, anemia, thrombocytopenia and febrile neutropenia. Moreover, nonhematologic toxicity was also greater for DD ETC, particularly in regard to infection, stomatitis and pain.
These results contrast with C-9741 where neutropenic events were actually less common in the dose-dense arm. It is likely that the use of cyclophosphamide 2500 mg/m2 and epirubicin at 150 mg/m2 in DD ETC caused most of the hematologic toxicity, while multiple previous trials have failed to show benefit of dose escalation of either anthracyclines or cyclophosphamide above standard doses. Therefore, the higher doses may have only increased toxicity but not efficacy. Despite greater toxicity in the AGO trial, the improvement in survival for the dose dense arm is impressive and supports the general concept of dose density in high risk women.
Another study addressing the use of dose-dense chemotherapy, NCIC MA.21, was the subject of an interim analysis.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn7 "_ednref7") This Phase III, three arm trial study randomized patients to CEF (with oral cyclophosphamide) on a day 1, 8 epirubicin and 5-FU schedule every 28 days, dose-dense EC followed by Taxol at 14 day intervals (DD EC-T), or standard AC-T every 21 days. High risk node-negative or LN+ patients under the age of 60 were eligible. About one-third of patients had > 4 positive lymph nodes. The primary finding was the inferiority of AC-T to either dose-dense EC-T or FEC with 3-year RFS, 90% for CEF; 89.5% for EC-T and 85% for AC-T (p=0.001). No significant difference in HR for CEF vs. DD EC-T was detected. The benefit for CEF or dose-dense EC-T was most pronounced in hormone receptor negative patients. Toxicity was generally higher for CEF, both in terms of febrile neutropenia and cardiac toxicity. Both epirubicin-containing regimens had higher acute venous thromboembolic events than AC-T and both Taxol-containing arms had much higher any grade sensory neuropathy. Interestingly, CEF was also associated with neuropathy (26.3% vs. approximately 70% for Taxol regimens). While final results for this trial will be available in the future, the head-to-head comparison of dose density clearly confirms the results of 9741.
Given the emerging benefit of dose-dense chemotherapy, investigators at Memorial Sloan-Kettering Cancer Center wondered about the safety of adding Herceptin to DDC as given in C9741. An interim analysis reported on 70 HER2+ patients with normal LVEF and no prior cardiac history received DDC with Neulasta® (pegfilgrastim) support and Herceptin for one year starting concurrently with Taxol.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn8 "_ednref8") Four patients discontinued treatment for cardiac events: one had clinical CHF and three for asymptomatic LVEF decline at six months after start of chemotherapy. All three patients with asymptomatic LVEF decline had recovery to normal levels. The authors concluded that Herceptin can be safely added to DDC without any increasing cardiac events.
Taken together, there is now abundant evidence of the benefit of dose density in improving outcome in the adjuvant treatment of early stage breast cancer. Many questions remain: are sequential single agents less toxic than combinations? Can dose density be increased further? How can short and long-term toxicity be lessened? What is the incremental benefit of dose-dense Taxol vs. weekly treatments?
Perhaps the most eagerly anticipated data at SABCS 2006 was the presentation of Tykerb® (lapatinib) and Taxol in newly diagnosed inflammatory breast cancer.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn9 "_ednref9") Tykerb is a novel, oral, small molecule inhibitor of both the EGFR receptor (ERbB1) and HER2/neu. Recently published results confirm the activity of Tykerb in Herceptin-refractory MBC.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn10 "_ednref10") Inflammatory breast cancer (IBC) often overexpresses HER2, and ERbB1 and is a very aggressive form of the disease. Thirty-five patients with IBC were treated with Tykerb 1500 mg/day for two weeks and then had Taxol weekly added for 12 additional weeks. After 14 weeks of therapy, patients underwent surgery. The primary endpoint was pathologic CR rate. Twenty-six percent of the women enrolled had Stage IV disease. Overall, 3/21 patients had a pCR in breast and lymph nodes, including 3/18 with HER2+ and 0/3 without overexpression of HER2. Thirty percent of patients responded to Tykerb alone by day 14, and, overall, 78% of patients responded to the combination therapy. Grade > 3 diarrhea was seen in 60% of patients, but other grade 3 toxicity was uncommon including nausea, vomiting, rash, fatigue and asthenia. Preliminary biomarker analysis suggested response to Tykerb correlated with expression of insulin-like growth factor I or deficiency in the PTEN pathway. Further studies with Tykerb in the neoadjuvant, adjuvant, and metastatic setting are well underway.
A novel approach to neoadjuvant therapy was presented by the Dana-Farber group.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn11 "_ednref11") Based on the observation that most patients with BRCA1 mutations have triple negative (ER-, PR-, HER2-), basal-like breast cancer and that BRCA1 is an enzyme which normally functions to repair double stranded DNA breaks, they reasoned that cisplatinum, of which the mechanism of action involves creating double strand breaks, would be effective in these tumors.
Twenty-eight patients with clinical Stage II/III triple negative breast cancer received cisplatinum as a single agent at 75 mg/m2 every 21 days for 4 cycles. Six (22%) achieved pCR and 3 had progressive disease. Both of the women with documented BRCA1 mutation achieved pCR. The toxicity of the single drug was modest. These results point towards a developmental strategy including platinum agents in the treatment of basal type breast cancer and perhaps particularly in those patients with BRCA1 mutations.
Final results of the German GEPAR-trio study were the subject of a presentation.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn12 "_ednref12") This complex neoadjuvant study assessed response to two cycles of TAC and then assigned patients to further therapy based on their clinical response. Those with “minimal” response were randomized to continue TAC to complete eight cycles vs. switching after four more cycles of TAC to a combination of Navelbine® (vinorelbine) and Xeloda (NX). Those with clinical partial response or better to two cycles of TAC were randomized to complete a total of six or eight cycles of the same regimen. This large study enrolled 2,000 women. Two-thirds were responders to two cycles of TAC. Interestingly, nonresponders were significantly more likely to have lower grade tumors, 72.6% vs. 61.3%; be HR positive, 68.5% vs. 58.3%; or have locally advanced tumors, 19.4% vs. 13.0%; while there was no difference in response by the HER2 status, age, tumor size or nodal involvement.
For clinical responders after two cycles of TAC, the pCR rate was 21-23.5% after further TAC with no significant benefit of prolonged therapy after six cycles. In contrast, nonresponders had a 5.7-6.0% pCR rate with no benefit to switching a putatively noncross-resistant regiment of NX. This large study allowed for multivariate analysis demonstrating that young age, high grade tumor, ductal histology, hormone receptor negativity and a complete clinical response after two cycles of TAC were all predictive of ultimate pathologic complete response. The lack of benefit from additional drugs in patients with suboptimal response to the three most active agents in breast cancer suggest the need for a different approach, perhaps with biological agents added, in future trials.
Two presentations derived from retrospective analyses of large databases give a glimpse of what can be expected in the future of breast cancer. Sir Richard Peto presented the first results of the Early Breast Cancer Trial 1st Collaborative Group latest five year analysis for 2005-2006.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn13 "_ednref13") The Oxford review, as it is known, now comprises over 660,000 patients enrolled in clinical trials since 1984 and provides a broad canvas meta-analysis of the effects of breast cancer treatment.
The group has demonstrated that the large decrease in breast cancer mortality that has occurred since 1990 in women under the age of 70 is due to the accumulated effect of multiple small to moderate improvements in treatment. Trends emerging from the most recent analysis include the benefit of adding radiation therapy to adjuvant chemotherapy for all lymph node positive patients and the benefit of anthracycline-based chemotherapy vs. CMF. The 15-year recurrence rate difference for patients <50 years of age who receive chemotherapy is about 12%, particularly prominent in ER-negative patients. The authors predict that the overall deaths from breast cancer in 2010 will be one-half of what they were in 1990 in the United Kingdom and the United States.
Ravdin and colleagues presented exciting and encouraging data from the most recent analysis from the SEER database utilizing incidence data in invasive breast cancer through 2004.[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_edn14 "_ednref14") There was a significant decrease in the number of breast cancer cases diagnosed in 2003 and 2004 compared to an essentially flat line incidence from 1998 to 2002. Virtually all of the decrease was in ER-positive cases. Overall, there was a 7% decrease in age adjusted breast cancer incidence in 2003 relative to 2002, which translated into almost 14,000 fewer patients diagnosed. Subgroup analyses demonstrated that almost all of the reduction was accounted for by women > 50 years of age.
What factors underlie this marked decrease? The authors postulated two leading possibilities: (1) change in mammographic screening levels or (2) change in the use of hormonal therapy. There was virtually no change in mammographic screening in 2003. However, the publication of the Women’s Health Initiative results in July 2002 led to a dramatic 50% reduction in hormonal therapy usage within 6 months with further decline in hormonal therapy usage by women through 2004. The prior use and reduction in use was mainly seen in women > 50 years of age. These trends support the concept that cessation of hormone replacement therapy may keep ER+ tumors from progressing from a pre-clinical state to a clinically apparent one. Obviously this potentially exciting result will require both more study and more time to assess if 2003 was merely an aberration or hopefully the beginning of a new era of reducing the burden of breast cancer.
Results from continued clinical studies evaluating Oncotype DX in different roles in the setting of adjuvant breast cancer continue to demonstrate its effectiveness in providing more individualized treatment options for patients with early breast cancer.
Oncotype DX is a CLIA-approved reverse-transcription polymerase chain reaction (RT-PCR) test that may be useful in determining which patients with newly diagnosed, Stage I or II, node-negative, estrogen receptor-positive breast cancer require adjuvant chemotherapy in addition to anti-estrogen therapy. Oncotype DX predicts the risk of a patient experiencing a recurrence 10 years following diagnosis utilizing formalin-fixed paraffin-embedded tumor tissue. Oncotype DX comprises a panel of 21 genes (16 cancer-related genes and 5 control genes), derived from 3 studies, to accomplish a recurrence-score algorithm. Oncotype DX also helps predict the likelihood of the benefit of adjuvant chemotherapy in these patients.
Results from previous trials have also demonstrated that Oncotype DX may help predict anti-cancer responses to neoadjuvant chemotherapy with Taxotere® (docetaxel) as well as changing treatment decisions in at least one-quarter of women with early breast cancer. Oncotype DX is already covered by Medicare for eligible patients and continues to be evaluated in clinical trials to further define its role.
Estrogen receptor status is an important component in determining optimal treatment for patients with breast cancer. However, the power of different testing methods for ER expression, such as IHC or LB testing varies considerably.
The first study presented at 2006 SABCS was conducted by researchers affiliated with the National Surgical Adjuvant Breast and Bowel Project (NSABP) to evaluate the effectiveness of results from Oncotype DX in accurately measuring ER expression. This trial included 297 node-negative, ER-positive breast cancer patients who had already received treatment with tamoxifen in the prior NSABP B-14 study. The NSABP B-14 trial had randomized node-negative, ER-positive breast cancer patients to tamoxifen or placebo.
To test for ER expression, study sites had performed LB testing for ER at the time of patient enrollment, the NSABP Foundation Laboratory performed IHC with the DakoCytomation ER/PR pharmDx, and one of the genes from the 21-gene panel of Oncotype DX was used. The time to a distant recurrence among patients was an endpoint used to measure the accuracy of ER expression among the 3 tests.
Higher ER expression with all three testing methods was associated with a greater time to a distant recurrence.
Quantitative measurement from Oncotype DX had the strongest association with time to cancer recurrence of all the three testing methods; p<0.0001 for Oncotype DX; p=0.003 for IHC; p=0.045 for LB testing.
A second study presented at the 2006 SABCS evaluated the prognostic and predictive associations between ER and PR analysis of Oncotype DX. This study included the examination of results from the NSABP-14 trial and the Kaiser Oncotype DX studies. The Kaiser study included node-negative breast cancer patients in which the association of gene expression and breast cancer death were evaluated.
In ER-positive patients in both the NSABP and Kaiser studies, the level of expression of ER is significantly predictive of benefit from tamoxifen, but is not significantly associated with the prognosis of untreated patients.
The level of PR expression is not significantly predictive of benefit from tamoxifen, but is significantly associated with the prognosis of patients.
The researchers from this study concluded that quantitative ER and PR expression as measured through Oncotype DX provide different and distinct associations with the prognosis and prediction of the benefit from tamoxifen among patients with node-negative breast cancer.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref1 "_edn1") Slamon D, Eiermann W, Robert N, et al. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) with docetaxel, carboplatin and trastuzumab (TC) in Her2neu positive early breast cancer patients. 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 52.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref2 "_edn2") Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. New Engl J Med 2006; 354:809-820.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref3 "_edn3") Sledge G, ONeill A, Thor A, et al. Adjuvant trastuzumab: long-term results of E2198. 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 2075.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref4 "_edn4") Gennari A, Sormani M, Puntoni M, et al. A Pooled analysis on the interaction between HER-2 expression and responsiveness of breast cancer to adjuvant chemotherapy. 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 41.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref5 "_edn5") Hudis C, Citron M, Berry D, et al. Five year follow-up of INT C9741: dose dense (DD) chemotherapy (CRx) is safe and effective. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium, San Antonio Texas. 2005; Abstract 41.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref6 "_edn6") Moebus V, Lueck H, Thomssen C, et al. Dose-dense sequential chemotherapy with epirubicin (E), paclitaxel (T) and cyclophosphamide (C) (ETC) in comparison to conventional schedule chemotherapy in high-risk breast cancer patients (> 4+ LN). Mature results of an AGO-trial). 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 43.
 Burnell M, Levine M, Chapman J, et al. A randomized trial of CEF versus dose dense EC followed by paclitaxel versus AC followed by paclitaxel in women with node positive or high risk node negative breast cancer, NCIC CTG MA.21: Results of interim analysis. 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 53.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref8 "_edn8") Dang C, Smith K, Fornier M, et al. Mature cardiac safety results of dose-dense (DD) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) with trastuzumab (H) in HER2/neu overexpressed/amplified breast cancer (BCA). 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 2101.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref9 "_edn9") Cristofanilli M,Boussen H, Baselga J, et al. A phase II combination study of lapatinib and paclitaxel as a neoadjuvant therapy in patients with newly diagnosed inflammatory breast cancer (IBC). 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 1.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref10 "_edn10") Geyer C, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006 Dec 28;355(26):2733-43.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref11 "_edn11") Garber J, Richardson A, Harris L, et al. Neoadjuvant cisplatin (CDDP) in “triple-negative” breast cancer (BC). 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 3074.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref12 "_edn12") v Minckwitz G, Kuemmel S, du Bois A, et al. Individualized treatment strategies according to in vivo chemosensitivity assessed by response after 2 cycles of neoadjuvant chemotherapy. Final results of the Gepartrio study of German breast group. 29th Annual San Antonio Breast Cancer Symposium. 2006; Abstract 42.
 EBCTCG Secretariat, on Behalf of EBCTCG, University of Oxford, Oxford, United Kingdom. Highlights from the early breast cancer trialists’ collaborative group (EBCTCG) 205-2006 worldwide overview. 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 40.
[](http://news.cancerconnect.com/developments-in-adjuvant-and-neoadjuvant-treatment-of-breast-cancer-a-report-from-the-29th-annual-san-antonio-breast-cancer-symposium/#_ednref14 "_edn14") Ravdin P, Cronin K, Howlander N, et al. A Sharp decrease in breast cancer incidence in the United States in 2003. 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 5.
[](http://professional.cancerconsultants.com/conference_sabcs_2006.aspx?id=38866#_ednref1_ednref1 "_edn1") Kim C, Tang G, Baehner F, et al. A Comparison of Estrogen Receptor (ER) Measurement by Three Methods in Node-Negative, Estrogen Receptor (ER)-Positive Breast Cancer: Ligand Binding (LB), Immunohistochemistry (IHC), and Quantitative RT-PCR. Proceedings from the 2006 annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006. Abstract #3116.
 Baehner F, Habel L, Quesenberry C, et al. Quantitative RT-PCR Analysis of ER and PR by Oncotype DX Indicates Distinct and Different Associations with Prognosis and Prediction of Tamoxifen Benefit. Proceedings from the 2006 annual San Antonio Breast Cancer Symposium. San Antonio, Texas. Oral presentation December 17, 2006. Abstract #45.

industry_corpus2: Health & Medicine


text:
Bright Horizons | ENV | Design. Innovation. Vision.
Bright Horizons at TriBeCa is a child care center and daycare located on two floors. The first floor consists of three toddler rooms and two infant rooms, and the basement level consists of five pre-school classrooms. The ENV team worked closely with Bright Horizons to provide a safe, nurturing, and engaging environment for children to learn and develop.
The "Movement Matters Zone" is equipped with ballet bars, mirrors, and a rock-climbing wall.


text:
Aside from the curse of typhoons scare every now and then, Mati also abounds with gifts for being situated facing the open Pacific Ocean. These gifts come in the form of wonderful beaches. In fact, these beaches are renowned tourist destinations and come as a more affordable substitute for other popular beaches like the ones in Boracay and in Palawan. One ofthe recommended places to go to is the Botona Beach Resort. Even if the resort is more budget friendly, it still gives you the best kind of summer and holiday experience.
The white sand, thecrystal clear beach, and the peaceful serenity of the place are more than you can ask for. Surely,this is something that you do not get anywhere else especially in more crowded resorts. Thus, if you are planning for a road trip adventure and very willing to spend some time away fromhome, the Botona Dahican Beach Resort in Mati is definitely a must-try for you.
how can i contact you for reservations? Can i have your cellphone number?
-the room is very expensive and you have to add an additional fee for additional mattress..
-the food is very very expensive.. what the!!!!
-we’ve wasted our 6 hour trip here..


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industry_corpus2: Hospitality & Catering


text: Mackamine LA is a vegetable derived grade of lauramine oxide that provides excellent foam boosting and foam stability. Mackamine LA is compatible with most surfactants, contains no amide or ester groups and will not hydrolyze in acid systems. Mackamine LA is also stable in highly alkaline products.

industry_corpus2: Petrochemicals


text:
World of Facades seminar on 26th April 2019, ITC Maratha, Mumbai.
World of Facades seminar on 21st June 2019, Park Hyatt, Hyderabad.
World of Facades seminar on 8th November 2019, TBC, Bangalore.
Window & Facade Magazine, 26th Edition out now !!!


text: ProSecure Locksmiths provide a full range of locksmith services across Torbay and South Devon for both Residential and Commercial properties. Our professional locksmiths are fully trained and experienced having served full apprenticeships and all have ‘Master Locksmith’ status. Whether you have been locked out of your home or business premises after losing or breaking your keys or if you require additional security for your home or business we are on hand to assist you with a fast response 24 hour emergency locksmith service across the whole of South Devon and beyond.

industry_corpus2: Real Estate & Construction


text:
In my last post, I described my first and only experience taking an actual philosophy course, how throughout that semester we took a quick journey through a good number of the major topics in philosophy, and how we were assigned a couple of short essays that semester apparently named after a marginalized demographic of the Harry Potter universe. I remember clearly that the first topic of the course was free will, and accordingly, this subject inspired the prompt for our first squib, which I displayed in the other post. Apparently one of the topics very soon to follow was the issue of personal (and perhaps also object) identity, as this prompted our second squib, which I’ve also found tucked away in the form of a Word document dated October 15th, 2007. It seems that either our main instructor was already getting tired of assigning squibs or the discussion leaders were getting tired of grading them, because as far as I can tell this was our last one even though the semester was only halfway over.
Again, I don’t know exactly what our prompt was. Clearly we were instructed to read an essay of John Locke and somewhat of a response essay by Thomas Reid, the first of which proposed a definition of personal identity and the second of which attempted to poke holes in that definition. It’s unfortunate that I didn’t include sources at the end of these essays. My best guesses for the Locke and Reid essays we read are (at least appropriate sections/excerpts from) this and this.
Unlike the problem of free will, the question of identity was not a favorite topic of mine going into writing this mini-essay; yet I clearly remember that I received an A on this squib, which didn’t happen with the free will squib. Moreover, having been asked to think critically on something that I hadn’t spent much time considering previously, I was able to form and articulate a position that was most likely fairly original among the group of students taking the course, and (perhaps unsurprisingly) it’s the position I still tend towards to this day.
Here’s the essay (once again, everything I originally wrote is in blue).
The papers of John Locke and Thomas Reid are a clear indication that the issue of defining personal identity is a very difficult one. In his paper on personal identity, Locke dismisses many candidates before finally settling on what he perceives as a satisfactory definition. Reid, in his turn, attacks Locke’s definition of personal identity from many angles by invoking thought experiments occurring in conceivable worlds. Both of these thinkers strive to come up with a single definition of personal identity which will apply in all situations for which personal identity is relevant, but both seem to have trouble with coming up with such a definition. In this paper, I suggest that it is not necessary to come up with a single definition of personal identity which applies to all situations, and I will use Reid’s Dreamless Sleeper thought experiment to demonstrate this claim. My object is not to argue that it is necessarily impossible to come up with a universal definition of personal identity, but to show that it suffices to use different definitions for different contexts.
In his paper, Locke creates a definition of personal identity which equates it to continuity of consciousness. A particularly powerful counterargument to Locke’s definition is formed by imagining a person who enters a dreamless sleep and later wakes up with memories from before the sleep but no memories of the sleep itself. We define P1 as being the person who goes to bed, P2 to be the person in the dreamless sleep, and P3 to be the person after waking up. By Locke’s criterion, it seems that P3 and P1 are the same person, but P2 cannot be said to be the same person as P1 and P3. Even if we modify Locke’s criterion to involve a chain of consciousness, we still cannot say that P2 is the same person as P1 or P3. This leads to such absurd conclusions as “No person can go to sleep.” Therefore, it seems that Locke’s conception of what it means to be the same person does not hold, not even for situations that may easily arise in our own universe. However, this does not imply that we cannot derive a definition of personal identity for the dreamless sleeper which will satisfy our practical needs for a particular circumstance, as I will now demonstrate.
First we must ask ourselves why we should care about personal identity. Several situations and contexts come to mind. One particularly important dilemma in which the issue of personal identity comes into play is in the appropriation of punishments. Other situations include the treatment of the dead and the comatose, and the treatment of a patient under anesthetic. Each of these situations can be applied to the Dreamless Sleeper thought experiment, and for each situation, one can arrive at an answer to the question of personal identity.
In every human civilization throughout history, there has been an instinct to punish those who violate the laws of that particular society. In order to carry out punishment, there clearly must be an intuitive notion of personal identity, so that one can ensure that the same person who committed the crime is punished. In order to decide on definition of personal identity that fits this circumstance, we should first ask ourselves what the purpose of punishment is. Let us assume that the purpose of punishment is 1) to deter a wrongdoer from continuing to break the law, and 2) to discourage all members of that society from committing the same crimes. (I will not argue in this paper that the above is indeed the purpose of punishment, but will assume it for the purposes of this example.) Now we imagine a human P1 who commits a crime and then falls into a dreamless sleep (P2). A punishment to fit the crime is agreed upon, and the remaining question concerns the manner in which the punishment should be inflicted.
After summing up the above, it is possible to conclude that P2 should not be considered the same person as P1 in the context of meting out a punishment for a crime that P1 committed. More generally, in the context of appropriating punishments, person A is the same person as person B who committed the crime if the punishment inflicted on A will be experienced consciously by A and remembered in connection to the crime.
Other circumstances in which personal identity becomes relevant may yield different definitions of personal identity. For instance, we examine the case where P1 makes an appointment to undergo surgery and then is put under anesthesia (becoming P2). In this case, it is clearly absurd for the surgeon to treat P2 as a different person from P1. The purpose of surgery is to remedy a physical problem so that the physical body that wakes up with P1’s memories may have an improved life. The conclusion that P2 is the same person as P1 relies on the notion that P1, P2, and P3 are connected by the continuity of the functions of a physical body. As long as the dreamless sleeper P2 shares the same body as P1 (body bits doing the same corpse-y dance), P2 is the same person as P1 in this context.
A somewhat altered context is the case where P1 expresses a wish to be cremated (“I want (myself) to be cremated following my death”) and then dies. In this scenario, P2 is the dead body (assuming no afterlife, which implies that no entity has the memories of P1 after P1’s death). Then the wishes of the living P1 should clearly be met as though P2 is the same person as P1 (the “myself” in P1’s quote above refers to the dead body, P2). A variation on this case is that of a permanently comatose person, such as the Terri Schiavo situation (assuming that Schiavo was indeed completely unconscious and had no hope of recovering).
The strategy used above for each analysis of the definition of personal identity in the Dreamless Sleeper thought experiment is different from that of both Locke and Reid. In their papers, Locke and Reid strive to come up with a definition of personal identity which will lend an answer to the issue of whether P2 is the same person as P1 and P3 that makes intuitive sense for every situation in which personal identity is relevant. My approach is different. First, I choose one particular situation in which a choice must be made which depends on whether or not P2 is the same person as P1. Then I examine the criteria necessary for the choice to be right or wrong. From this, I derive a definition of personal identity which suffices for that context. This method yields a definition of personal identity for any given situation that comes up and thus, gives us the same practical advantage that Locke and Reid hope to attain. Therefore, although all definitions proposed by Locke may fail as universal definitions, we can still come up with circumstantial definitions which serve equally well.
 While I was already being an advocate of singular they by 2007 (I know I mentioned it in a Facebook note, the closest thing I had to a blog, before that time), apparently I didn’t feel comfortable using it an essay for one of my college classes. Perhaps I chose male pronouns out of carelessness — it’s mostly but not completely consistent, since at only one point later in the paragraph I refer to the criminal as “he or she”.
 Nowadays my choice of phrase would be “commit more crimes”. I’m easily able to believe that I used singular “crime” in the collective sense in that context nearly 11 years ago, though. Funny the little things that jump out at you when looking at old writing.
 One of my few distinct memories of the main lecture content for that course, apart from the relentless use of terms like Thinker and Decider, was a theory proposed (I’m not sure it was credited to any particular philosopher) during our unit on identity that maybe a dog doesn’t exist as a single entity but rather, as “doggy bits just doing their doggy dance”. I’m not sure exactly what this is supposed to mean, and I’m not entirely sure I did back then either. I’d like to think that I coined the phrase “body bits doing the same corpse-y dance” in order to allude to the dog thing in the squib, and that’s entirely possible, but it seems more likely that this was also a phrase handed to us in lecture.
 Here I was referring to this tragedy, which at the time of writing the squib was a fairly recent national controversy.
I guess I look back on this assignment as a happy moment in my development as a thinking person, because I actually surprised myself with the position I wound up taking. I expected (and probably others expected of me) that after some thought I’d be able to come up with some global definition of personal identity that would be an improvement over what both Locke and Reid had to offer. Instead, my answer was more of a meta-answer: it is not necessary to find a global definition (note that I stopped just short of declaring that one doesn’t exist!), but we can make do with a set of local definitions that cover the space of all possible situations in which for practical purposes we care about personal identity. What I just said about global and local definitions is inspired by a common idea in theoretical math, where “global” things are often obtained by patching together “local things”, but I don’t know how securely ingrained in me such concepts were at the time of writing the squib. I am fairly certain I remember likening my solution to a metaphor used by Steven Hawking in The Universe in a Nutshell (which I believe I had a copy of then) where he suggests that there may not be a single model of the universe but that it can be patched together from “local” models that explain phenomena on different physical scales.
I don’t have much more to add on this topic, as I think I gave a fairly good answer in the above mini-essay and haven’t felt the need to seek a more satisfying one. The one additional point I could make about my squib is that it conveniently skates over the rather sticky question of why it’s important to respect the wishes of the dead as though their corpses embody the same person as when they were alive. The whole “respecting the dead’s wishes” thing seems like a weak spot in utilitarianism at least, and while it should be explored, I think the appropriate place for that would be neither in that squib nor in this blog post.
I was pleased to see a similar point of view (but expanded to greater sophistication) expressed in this essay by John Nerst (where the definition of “existence” is discussed), which played to a similar theme as in this other essay also by Nerst (where the meta-answer of “global definitions are not necessary” is proposed, with some object-level discussion of object identity as well). All in all, I would like to see philosophy take a more pragmatic approach in its use of specific terms and in its study of specific profound questions.


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The Business Owner’s Bookshelf: Who Moved My Cheese?
Today’s blog post was written by Chris Amori, Founding Partner of Network Depot and Virtual Administrator.
Our next book in our Business Owner’s Bookshelf series is a book called “Who Moved My Cheese?” by Spencer Johnson, M.D.
“Who Moved My Cheese?” is not just a business book, it is really a life lesson book. At less than 100 pages with big type, it is a quick read, and one that should be shared. I remember reading this out loud around the dinner table one night (not sure the kids appreciated it, but I thought it was an important lesson).
This book boils down to two words…CHANGE HAPPENS.
The book begins with Sniff, Scurry, Hem and Haw happily living in their maze, going about their daily lives in search of Cheese, until one day, you guessed it, the Cheese was no longer there! Then, of course, Sniff, Scurry, Hem and Haw have to deal with this, and that is the main struggle within the book.
By looking inside ourselves and realizing which character we relate to, it helps us understand how we deal with situations from an objective perspective. We can see how we would deal with not only their situation, but also how we deal with our own inevitable cheese-moving!
Folks, this is a simple parable, not a work of literary genius. We all KNOW change happens, so it is not like some big secret is going to be revealed by reading this book. But sometimes, we just need a little kick in the shorts to motivate us to look at change for what it is, and respond in-kind, and “Who Moved My Cheese?” is that kick.
I really do recommend reading this. Not only is it great for business owners, but it is really helpful for someone in any level of an organization. Using this book to be able to look objectively at how we handle situations thrown at us- and more importantly, how we want to handle the unexpected, helps prepare us and therefore our company as a whole to be able to adjust to the constant change that happens.
For that matter, it’s a really great book for all ages. When we are young we use stories to help us come to terms with the world around us- fairy tales help us grapple with good and evil, the Muppets on Sesame Street help us develop and learn life lessons, etc. As we get older, stories hold the same power. By using these types of books we can look at ourselves objectively, and use that knowledge to help us grow as people. Plus, let’s face it, they are pretty fun to read.
I was given this to read over 15 years ago, and I still think about it every so often, when some new obstacle gets in my way.


text:
Downton Abbey star Michelle Dockery's fiance has died aged just 34.
John Dineen passed away on Sunday morning in a hospice in Ireland after a long illness.
Dockery, who played Lady Mary Crawley on the hit ITV series, has appealed for privacy ahead of her fiance's funeral in County Cork on Wednesday.
The family is very grateful for the support and kindness they have received but would kindly request that they are left to grieve in private.
The couple met in September 2013 after being introduced by co-star Allen Leech, who starred as Tom Branson in the period drama.
Dockery and Dinnen are believed to have got engaged earlier this year.
The award-winning actress, who rarely spoke publicly about their relationship, said she had a "wonderful man in my life from Ireland" in an interview over a year ago.

industry_corpus2: Film & Entertainment


text:
STILLWATER � Oklahoma State had just been to the Final Four and a Sweet 16 when Byron Eaton came to campus in one of the most ballyhooed recruiting classes in school history.
Three straight years without reaching NCAA tournament wasn�t at all what he had in mind for his college career.
�We had a great recruiting class, they had been to the Final Four two years before that and then to the Sweet 16. When I came here, I�d seen all these banners that said NCAA,� Eaton said.
In his last chance, Eaton finally will get to play in the NCAA tournament when the Cowboys (22-11) face ninth-seeded Tennessee (21-12) in the first round Friday in Dayton, Ohio. It�s the culmination of a career in which he�s played for three coaches and seen the majority of his recruiting class disintegrate as Oklahoma State�s program took a brief step backward.
Before Eaton�s arrival, the Cowboys had been to the Final Four in 2003 and seemed to be on such solid ground that Sean Sutton, the son of longtime coach Eddie Sutton, was installed as the head coach in waiting.
He was to take over whenever his father decided to retire.
That process was sped up when Eddie Sutton was involved in a drunk-driving crash in February 2006, and he never returned to lead the Cowboys after taking a leave of absence. Sean Sutton finished out that season and guided Oklahoma State for the next two, resulting in a string of three straight first-round NIT losses before he resigned under pressure.
Travis Ford was hired away from Massachusetts to replace him, and the Cowboys rallied with a six-game winning streak toward the end of the regular season and then removed any doubt that they�d make the NCAAs by upsetting No. 6 Oklahoma in the Big 12 tournament.
�These guys have been through a lot since they�ve been here,� Ford said. �A lot�s been said about them, this and that, and I heard all the things when I took this job about how they hadn�t been to the NCAA tournament.
Aside from all the drama involving the Suttons, Eaton has been the focal point for the Cowboys. His weight, which fluctuated by dozens of pounds because of poor eating habits, became a regular topic of conversation and was often blamed when he played poorly.
But when he�s at the top of his game, Eaton has showed he can be one of the country�s most dynamic players. He guided Oklahoma State to an upset of Kansas last season that was the Jayhawks� final loss before their national championship run, and there�s no doubt who�ll have the ball in his hands when the game is on the line late for the Cowboys.
�My first year when I wasn�t able to do it, people were like, �Y�all are young.� And then the second year, they were like, �You almost had it.� And then last year, it was, �I guess y�all can�t do it.� To do it this year, it�s definitely a relief for me to go out making the tournament my last year,� Eaton said.
The fact that Eaton is even still on the team bucks a remarkable trend of attrition in the program. Of the nine players recruited to Oklahoma State four years ago, only three made it to the end of their college careers in Stillwater. Mario Boggan played two full seasons after transferring out of junior college, and Eaton and guard Terrel Harris were the only two of six high-school recruits to get to their senior seasons in Stillwater.
Gerald Green bolted for the NBA out of high school and Keith Brumbaugh, who considered making the same jump, never got to play after an issue with his ACT score. Roderick Flemings was kicked off the team late in his freshman year and junior-college transfers Torre Johnson and Jamaal Brown were dismissed after one season. Finally, Kenny Cooper decided to transfer after his sophomore season.
Looking back on all that�s happened, Eaton sees Oklahoma State reaching the pinnacle as his career draws to a close.
Now, he and Harris will finally get to play in the tournament they had envisioned when they came to Oklahoma State in the first place.


text:
This guide walks through the use cases for implementing your own unique playbooks into Dooly for your team to close more business.
 Take any relevant content from Guru, incorporate it into your Playbook, and push it to your team while they're in their meetings.
Have content pieces or SOP documents in GDrive you'd like to refer to and see when on your calls? Turn them into Dooly content!


text: Insurance Operations Attorney The candidate will perform factual due diligence gather all relevant facts and documents; collaborate with business partners and other Law & Regulation members. Perform legal research identify and apply to facts applicable laws, regulations, and other legal authority. Identify, define and resolve legal issues. Explain and counsel business partners on impact of legal requirements and collaborate with them on developing and implementing compliant processes. Collaborate with other areas of L&R. Drafting and Negotiation. Draft, review and negotiate basic matters, agreements, routine communications and forms. Business Knowledge and Acumen. Gather facts to understand goals and objectives client intends to achieve. Determine if/how business processes and practices need to be modified and work with business partners, other potentially impacted business units and L&R departments to implement change. Manage moderately-complex projects including development of meeting materials, and coordination and collaboration with senior management, legal teams and business clients. Retain and manage outside counsel representing the Company in Federal and state courts throughout the country to include development of trial and settlement strategy, and perform budget oversight. Oversee discovery, identifying relevant facts, materials, and witnesses, to include witness preparation. Assist business partners with responses to regulatory investigations, examinations and disputes. Participate in meetings with business partners at all levels of the Company. Participate in relevant external industry groups. Should have knowledge of insurance industry and regulation, to include regulatory and litigation environment. Must possesses a juris doctorate and license to practice law in Florida (or be eligible to provide in-house counsel under Florida Bar Rules). Should have 1+ years related experience.

industry_corpus2: Finance & Economics


text:
Lot 168 Nice lot in Woodlands-Closing 30 to 60 days. Paved Road. Extra oversized lot.
Lot 118 - Nice Lot in Woodlands. Closing 30 to 60 days, Oversized, Paved Street.


text:
Ever wanted to see John Cena as a bull? Ever wanted to see that bull try and make it through a china shop? Then your wishes are granted in the first trailer for the animated film “Ferdinand,” which Blue Sky Studios and 20th Century Fox released Tuesday.
The family pic is based on the classic children’s book “The Story of Ferdinand” by Munro Leaf and Robert Lawson. The book, published in 1936, tells the story of a bull who would rather smell flowers than fight in the ring.
Cena voices the titular bull, who’s taken from his town after he is mistaken for a dangerous beast. He then gathers a ragtag group of animals to help him get back.
“Set in Spain, Ferdinand proves you can’t judge a bull by its cover,” the official synopsis reads.
Other actors providing voices in the film include Kate McKinnon, Gina Rodriguez, Daveed Diggs, Anthony Anderson, Gabriel Iglesias, and David Tennant.
“Ferdinand” is set to hit theaters on Dec. 15, 2017.
Guess Who WWE Superstar John Cena Wants to Slime at Nickelodeon’s Kids Choice Awards?