May’s MC2 contains a ballot for President and Regional Rep on page 20. There isn’t much time to vote, and – what’s more – Vicki Herd is a candidate for Regional Rep! We can’t ignore the election; it wouldn’t be fair. Scrawl, draw, or print your X right away and mail those ballots in. Beyond promoting democracy this month, we draw your attention to a bevy of Chinese Trojan horses making the email rounds. You may receive an email from a friend which consists only of a website. Don’t open it. Contact the friend separately and ask if the email is genuine. Or don’t trouble your friend; simply delete the email. Another example is the ungrammatical email recommending a company’s expedient service. Why would a friend burden you with wonky English or – for that matter – suggest you favour a particular firm with your business? Makes no sense. Delete on receipt.

Further this month, we present a couple of arithmetical puzzles; see how fast you can untangle them. In our Notes & Queries, we gather the names and background of the greatest con men in history. For Your Contemplation summarizes some difficulties in cancer research and decision-making, of which you’ll find the core in our first Article. Also in FYC, we direct you to a comment critical of the Greek bailout, or perhaps more gloomy than critical, and point out how we’re at the mercy of financial gnomes. In the Articles section, we see that there were prefabricated Greek buildings in Italy as early as the 6th century BC, and we might do better to acknowledge how little we know about the tide of future political and economic events, raising the question how we should pick politicians.

Click here to see the calendar of events for this month. Use it as a reference by rolling your mouse over the links or just as a reminder. Bookmark it today!

1) What is the smallest number that is divisible by 13, which – if divided by any of the numbers from 2 to 12 inclusive – leaves a remainder of 1? [from Jocoby and Benson’s Intriguing Mathematical Problems]

2) Two cyclists are headed directly towards each other at constant speed. At the beginning of Interval X, they are a quarter of a mile apart. One is traveling at 8 mph, the other at 12 mph. A mutant fly flits between the cyclists at a constant 30 mph, directly back and forth, reversing its direction each time without pause. At the beginning of Interval X, the mutant fly is just leaving the 8 mph cyclist, headed towards the other. The fly continues back and forth until it is crushed when the cyclists collide. Its death marks the end of Interval X. If we ignore the length of the bicycles, forward incline of the cyclists’ bodies and similar issues, how far did the fly travel during the period we are considering?

The answers to last month’s puzzles were supplied last month.

Here are the answers to this month’s puzzles:

1) We start by finding the smallest multiple of the numbers from 2 to 12. The answer is 27,720. The number we’re looking for must therefore be 27,720x + 1, where this total is divisible by 13 and where x is an integer. The number is therefore 2132x + (4x + 1)/13. If this total is divisible by 13, then (4x + 1) must be a multiple of 13. It is obvious that x = 3 provides the smallest integral value of x that satisfies the condition. The result is (27,720 x 3) + 1, which is 83,161.

2) There’s a lot of sleight of hand in this puzzle. All we have to know is that the riders are approaching each other at a combined 20 mph and are ¼ mile apart. Interval X will end when the cyclists meet, which will be in 1/80 of an hour. The fly moves at 30 mph. Distance = speed x time, so the fly travels (30 x 1/80) which is 3/8 of a mile during Interval X.

Dr. Linda Griffith was at a conference in Singapore in early January when she felt a lump in her breast. She assumed it was nothing — a cyst. And anyway, she had no time for it. She was returning on a Sunday night and the next Tuesday morning was leaving for a conference in Florida.

But she had a mammogram, ultrasound and biopsy within hours of getting off the plane. The news was not good: she had cancer.

Then the complications began. Dr. Griffith, director of the Center for Gynepathology Research at M.I.T., had a test to see whether her tumor had extra copies of a protein, HER2. If it did, it would respond to a drug, Herceptin, which blocks the protein and stymies the tumor’s growth.

Drugs aimed at disabling proteins that spur cancer are, many oncologists say, the future of cancer therapies. Only a few are available now but almost every new drug under study is designed to disable cancer-fueling proteins.

But these so-called targeted therapies are only as good as tests to find their protein targets. And while most patients do not yet know it, those tests can be surprisingly unreliable.

Acknowledging the problem, cancer specialists on Monday announced new testing guidelines for one protein target, but as new targets are identified, the problem continues to grow.

The test on Dr. Griffith’s tumor was negative. Or was it? One small area of her tumor stained chocolate brown, indicating lots of HER2. The rest was a cream color, indicating no extra HER2 protein.

Yet her treatment hinged on this result. A HER2 positive tumor has a bad prognosis. Herceptin can make that prognosis good, reducing the chances that the cancer will come back by 50 percent and reducing a woman’s risk of dying by 40 percent.

But Herceptin, costing $42,000 a year wholesale, causes flulike symptoms and also has a rare, serious side effect, severe heart damage that can even be fatal.

And if a tumor does not have high levels of HER2, Herceptin would be, as Dr. Antonio Wolff, a breast cancer specialist at Johns Hopkins put it, “a toxic and expensive placebo.”

Dr. Griffith had come face to face with an emerging, but rarely acknowledged, problem in today’s era of new cancer tests and therapies.

HER2 tests, for instance, can give false-positives up to 20 percent of the time, wrongly telling women they need the drug when they do not. Five percent to 10 percent of the time the tests can falsely tell a woman that she should not take the drug, when she should. And Herceptin testing for breast cancer is easy compared with what is coming next.

Genentech, Herceptin’s maker, is about to apply to the Food and Drug Administration to sell the drug to treat stomach cancer. But it is much more difficult to tell whether a stomach tumor has high levels of HER2, said Krysta Pellegrino, a company spokeswoman. Breast cancers usually are all positive or all negative. Not stomach cancers, which almost always have sections that are positive for HER2 and sections that are negative. The HER2 tests are the same, but “the interpretation and scoring are different,” Ms. Pellegrino said.

That sort of mosaic pattern is typical of cancers other than breast cancer, says Dr. Jeffrey Bloss, vice president, North America Medical Affairs at GlaxoSmithKline. And it raises questions of what a test result means.

“The science is still evolving,” Dr. Bloss said. “What was true last year may not be true this year.”

Like the HER2 tests, other molecular tests for breast cancer also have problems. Those tests, for estrogen receptors on breast cancer cells, determine whether cancer will be thwarted by drugs that deprive tumors of estrogen. They can be wrong at least 10 percent of the time. Some estrogen-depleting drugs, while generally safe, increase the risk of osteoporosis and, depending on the drug, can also cause joint pain and increase risks of stroke and cancer of the uterine lining.

Estrogen receptor tests are a muddle, noted Dr. Edith Perez, a breast cancer specialist at the Mayo Clinic in Jacksonville, Fla. Quite a few tests are being used, but Dr. Perez could not ascertain exactly how many or how good they were in predicting whether a tumor would respond to estrogen-depleting drugs.

And different labs may do tests in different ways; some even invent their own.

“How do you know they are the same?” Dr. Perez asked. “If you do the test in two different labs, you can get two different answers.”

Error rates for newer tests have not even been established.

“This is an issue that transcends breast cancer,” Dr. Wolff said. “A poorly developed test is potentially as dangerous as a poorly developed drug.”

The Food and Drug Administration says it is concerned about the quality of tests developed by clinical laboratories for their own use, said Alberto Gutierrez, who oversees diagnostic products for the agency. Some of the tests are increasingly complex, Mr. Gutierrez said, adding that there is a proliferation of laboratories offering tests without F.D.A. oversight. But, for now, the agency has no specific plan to regulate the tests, in part because of lack of money.

Meanwhile, Dr. Griffith’s doctor, Eric Winer at the Dana-Farber Cancer Institute, had a gradual awakening.

“In my naïve view, which wasn’t so many years ago,” Dr. Winer said, “I thought HER2 was a switch that turns on or off and it was pretty easy to tell when it’s on or off. It turns out that it is not nearly as straightforward for a large number of tumors.”

Now, recognizing the problem, Dr. Winer had Dr. Griffith’s tumor retested with a different method, hoping the result would help him and Dr. Griffith figure out whether she could benefit from Herceptin.

And Dr. Griffith was left facing the uncertainties of cancer medicine.

“Me as a scientist says it’s very interesting,” she said.

But, she said, as a patient she sees it differently.

“It’s really hard to know what to do,” Dr. Griffith said.

The two large national studies of Herceptin for women with HER2 positive early-stage breast cancer were just starting in 2001 when Dr. Perez, of the Mayo Clinic, a principal investigator, had a moment of truth. Women were having HER2 tests at a variety of places — community hospitals, major medical centers, national labs. Dr. Perez decided to retest tumors in a central lab to confirm the results.

The outcome stunned her and her colleagues. Twenty percent of the first 119 women whose initial tests indicated their tumors had excess HER2 turned out not to have it on retesting.

“We all felt, ‘Oh boy, we have a problem,’ ” said Dr. Wolff, a study investigator. “This was huge.”

So the studies were modified to require central labs to retest all the tumors.

Yet the discordance remained — one-sixth of women told by local labs that they were HER2 positive were not on retesting.

“We were all horrified,” said Dr. Elizabeth Hammond, a pathologist at Intermountain HealthCare in Utah.

The result of that moment of horror was HER2 testing guidelines by the College of American Pathology and the American Society of Clinical Oncology, dictating criteria for declaring a test positive or negative and requiring proficiency testing, among other things.

In a way, the effort was a huge success. About 900 of the nation’s estimated 1,500 labs agreed to follow the guidelines.

But even so, said Dr. Bloss of GlaxoSmithKline, there seemed to be approximately a 20 percent discordance between labs. GlaxoSmithKline makes Tykerb, which also focuses on HER2.

There are all sorts of reasons why different labs can get different results, said Dr. Mitch Dowsett of the Royal Marsden Hospital in London and a member of the United States committee that formulated HER2 testing guidelines.

In borderline cases, pathologists can disagree. Or stain can pool in areas where a tumor was crushed or damaged, making it look, to inexperienced eyes, like a positive stain.

Twelve years after Herceptin was approved for women with advanced breast cancer, “we’re still trying to refine the testing,” said Ms. Pellegrino of Genentech.

Then there is Dr. Griffith’s problem: what to do when part of a tumor is positive and the rest is negative.

The College of American Pathologists wants to develop testing guidelines for every molecular target for cancer drugs. On Monday, for example, ASCO and CAP released new guidelines for estrogen receptor testing.

And Dr. Hammond has become driven to make sure pathologists know about and follow the HER2 guidelines.

At pathology meetings, she asks her audience how many know about the guidelines and are following them.

“Almost everyone raises their hand,” Dr. Hammond said. “I am preaching to the choir. They chose to come to the meeting. It’s the ones who did not choose to come that I am worried about.”

But even the best labs can differ, as some women learned.

When Sheila Maloney had breast cancer surgery in October, her doctor wanted to test her tumor for HER2.

“I had never heard of it,” said Mrs. Maloney, a 64-year-old hostess at an Olive Garden restaurant in Lady Lake, Fla.

She is now seeing Dr. Perez, and ended up having her tumor tested four times with four different commonly used HER2 tests. The first test was positive, the second negative, the third positive, the fourth negative.

Dr. Perez recommended that Mrs. Maloney take Herceptin.

As for Dr. Griffith, the two tests for HER2 turned out to agree, but with that mixed result, it was hard to know what to do. Her tumor was on the fence — part negative, part weakly positive.

Medical experts say there are no easy answers. For now, their best advice is for women to ask that their breast cancer tissue be sent to experienced labs that follow accreditation procedures like those recommended by the College of American Pathologists.

But Dr. Griffith did all that. And Dr. Griffith, a scientist whose own research involves the HER2 protein, also read and examined the literature on HER2 to prepare for a discussion with Dr. Winer.

“Here I sit as a patient. My situation is ambiguous,” Dr. Griffith said.

In the end, the studies, along with Dr. Winer’s clinical perspective, did not convince her that the drug would help. The risk of serious heart damage and other side effects was scary. And, she said, she cannot ignore the drug’s price, even though her insurer would pay.

Dr. Griffith decided not to take Herceptin, but she is having standard chemotherapy.

“I am very comfortable with my decision,” she said.

(Gina Kolata, New York Times, 19April2010)

Italian archaeologists have found the ruins of a 6th-century BC Greek temple-like structure in southern Italy that came with detailed assembly instructions and is being called an “ancient IKEA building”.

Massimo Osanna, head of archaeology at Basilica University, said that the team working at Torre Satriano near Potenza in what was once Magna Graecia had unearthed a sloping roof with red and black decorations, with “masculine” and “feminine” components inscribed with detailed directions on how they slotted together.

Professor Christopher Smith, director of the British School at Rome, said that the discovery was “the clearest example yet found of mason’s marks of the time. It looks as if someone was instructing others how to mass-produce components and put them together in this way”” he told The Times.

Professor Osanna suggested that a “fashion for all things Greek” among the indigenous population had led an enterprising builder to produce “affordable DIY structures” modelled on classical Greek buildings. The terracotta roof filtered rainwater down the decorative panels, known as cymatiums, with projections to protect the wall below.

“All the cymatiums and several sections of frieze also have inscriptions relating to the roof assembly system,” Professor Osanna told Storica, the Italian magazine of the National Geographic Society.

He added: “So far around a hundred inscribed fragments have been recovered, with masculine ordinal numbers on the cymatiums and feminine ones on the friezes”. He said the result was “a kind of instruction booklet”.

“The characteristics of these inscriptions indicate they date back to around the 6th century BC, which tallies with the architectural evidence suggested by the decoration,” Professor Osanna said.

He said that the decorative features were remarkably similar to those on another structure unearthed at Braida di Vaglio nearby: “The similarity in the use of these decorations indicates the same origin” he said. “Possibly the same mould was used”.

Magna Graecia — Latin for “Greater Greece” — was a coastal area colonised by Greek settlers who traded with enclaves such as Lucania, of which modern Potenza was part.

Greek colonisation left much of southern Italy with an Hellenic inheritance, including architecture and culture and even language. A minority in Calabria and Apulia still speaks a dialect known as Griko.

(Richard Owen, The Times, 22April2010)

Change. That seems to be the holy grail of this [UK] election and of the television debates. David Cameron has been confidently promising it for some time, but suddenly Nick Clegg is trying to grab it from his hands and offer it to us himself. A nasty shock for Cameron, this is even more depressing for Gordon Brown, who cannot after 13 years pretend to offer change at all and has been forced to glower at the two younger, prettier men squabbling on air over who can, while sipping his own poisoned chalice.

Change is indeed in the air: the sudden rise without trace of Clegg, the emergence of a viable third party and the prospect of a hung parliament are all important. But the truth is that politicians are deluding themselves when they try to peddle this or that change and we are deluding ourselves if we believe them. Change will certainly come, both fast and hard, but it won’t necessarily have anything to do with the promises politicians make.

Tony Blair and Brown have discovered this the hard way (and at our expense). They promised enormous change in education, the National Health Service, employment and social equality. And they failed to deliver, despite 13 years of massive expenditure. Unemployment is up, social inequality hasn’t narrowed, education is worse and one hospital even turned away a woman in labour.

More important, the supposedly brilliant Brown failed in his unsophisticated promise to put an end to boom and bust: instead we have truly frightening debt, thanks to his splurge. He, of course, would blame every economic ill on a “global” crisis. But in so doing he only supports my point. Politicians may propose, but something entirely different usually disposes.

One of the biggest changes that has taken place is a sudden realisation of how little anyone knows about most things. The plume of volcanic ash that wafted above us was a perfect metaphor for our cloud of unknowing. We couldn’t predict it, we don’t understand the risks and we don’t know whether it will return. No one predicted the eruption of Clegg or knows whether he’ll just blow over like a puff of hot air. Few people saw the banking crisis coming. Now we are beginning to realise how difficult it is to understand complex economies and societies or to foresee the consequences of political intervention.

Many of Labour’s new social policies turned out to be just experimentation. Sure Start, for instance, was meant to offer directly to the poorest children some of what was lacking in their deprived backgrounds. Instead it developed into a system of pleasant nurseries for the better off, while independent academic research into its results showed that it was achieving almost nothing for the children it was designed for.

Other problems, such as the misery of children in care or the national illiteracy scandal, have defeated this government for reasons it cannot explain and despite all the early promises of change. The invasions of Iraq and Afghanistan also turned out to be an ill-considered mess, bedevilled by constant mission creep and doubt. What we’ve seen on every front is a mass failure of knowledge, understanding and anticipation and a disastrous, destructive lack of modesty in the face of life’s complexities and uncertainties.

What has been particularly shocking about the banking crisis is that most governments did not know about the risks the money men were taking; nor, apparently, did some of the money men themselves. Earlier this month it emerged that Fabrice “Fabulous Fab” Tourre, a Goldman Sachs banker and collateralised debt obligation expert, did not understand the highly risky debt packages he himself was creating: he confessed as much in a terrifying email of 2007 to his girlfriend about the imminent collapse of the “system”, describing himself as the “only potential survivor, the fabulous Fab Tourre … standing in the middle of all those complex, highly leveraged, exotic trades he created without necessarily understanding all of the implications of those monstruosities (sic)!!!”.

In the painful aftermath, the most brilliant and respectable economists are genuinely divided about whether to deal with debt now or later, how best to regulate banking, or what is the least worst trade-off between tax and public spending cuts — and this, of course, without necessarily allowing for the brute force of vested interests, human error and plain incompetence. The only point on which well informed people seem to agree is that huge numbers of people will probably lose their jobs as neither state sector nor private sector can afford to employ them any longer. The only certainty in public affairs seems to be uncertainty.

In these particularly uncertain times, it is character that matters. It’s impossible to say what will be thrown at the next government, so manifestos hardly matter, except insofar as they show any caution about excessive promises and excessive government. The voter can only really choose the man who seems most likely to show judgment, restraint and courage. So political beauty parades, normally something I hate, do for once have a certain value in this election. Three sessions of 90 minutes’ staring at Clegg and Cameron strutting their stuff — I exclude Brown as someone whose character defects are already as well known as his disastrous debts — do at least give some impression of what they are made of.

Clegg is tall, handsome and agreeable. Standing beside Vince Cable, he has sometimes looked ineffectual and lost, but on his own he has displayed a confident, boyish candour, with a beguiling optimism, possibly due to inexperience. Instinctively I remain unconvinced. Cameron has easy charm too, but he has chosen not to show it in the TV debates: he stands and speaks like a sadder, steelier person, prepared for difficulties. All this is in effect show business, but there’s some truth to be discovered in it. To judge purely from their manner, Clegg is the more appealing. To judge from their attitudes, Cameron seems to understand far more clearly the limitations of what the state can or should do. And that really is the big change we need in politics.

(by Minette Marrin, The Sunday Times, 25April2010)

The 10 greatest conmen of all time

1. George C Parker (1870-1936) made a career of “selling” New York landmarks, including the Metropolitan Museum of Art and the Statue of Liberty, to naive newcomers. His favourite was Brooklyn Bridge, which he flogged an average of twice a week for years – complete with impressive “title deeds” – before being sentenced to imprisonment for life at the notorious Sing Sing in 1928

2. Gregor MacGregor (1786-1845) invented the Central American state of Poyais, a fertile territory of 12,500 square miles rich in precious metals. He appointed himself its cazique, or prince, “sold” land and rights there to gullible British investors and raised a loan of £200,000 on behalf of the Poyais Government. When the scam was exposed here, he took it to France with some success

3. Victor Lustig (1890-1947) operated swindles across Europe and America before being sent to Alcatraz. His first success was the repeated sale of a “money-printing machine”. This cost the buyer $30,000 and produced two $100 bills, then blank paper. He is best known for posing as a corrupt offical to “sell” the Eiffel Tower to a scrap metal dealer for a large sum, plus bribe

4. Frank Abagnale (1948-) passed bad cheques for $2.5 million as a teenager during the 1960s. He also posed as a Pan Am pilot, doctor and attorney to milk various perks. As a “pilot”, for instance, he took advantage of free “deadheading” flights to 26 countries, complete with hotel stays. He served four years in prison, escaping once, and now advises businesses on fraud

5. Charles Ponzi (1882-1949), made millions from the pyramid scheme which now takes his name before it collapsed in 1920. After serving a jail term in Massachussets, and running a second scam selling swampland while out on bail, he was deported to Italy. There he advised Mussolini on finance before fleeing to retirement in Brazil with a chunk of the dictator’s treasury

6. Philip Arnold (1829-1878) perpetrated the Diamond Hoax of 1872 with his cousin John Slack. The pair bought cast-off stones and planted these across a field in Wyoming, which they showed to prospective investors, including Baron Rothschild and Charles Tiffany of Tiffany & Co. The latter bought the cousins’ interest for $660,000. He later sued, but the case was settled out of court

7. Howard Welsh (1953-) and his partner Lee Hope Thrasher reportedly made $31 million from a Ponzi scheme that targeted Christians with a “tax-free investment” marketed as “a divinely-inspired mission that behaves like a diocese, a church, a mission or assembly”. The couple were arrested in Shropshire in 2004 after a two-year FBI manhunt and later jailed in Virginia

8. Gerd Heidemann (1932-), a journalist on Germany’s Stern magazine, sold the rights to the “newly-discovered diaries of Adolf Hitler” to his employer for $6 million in 1983. These were a crude forgery by his friend Konrad Kujau but nevertheless fooled historian Hugh Trevor-Roper among others. Heidemann maintains that he was conned by Kujau but was convicted and jailed for three years

9. Shaun Greenhalgh (1961-) made a series of forgeries which duped leading art institutions in a garden shed in Bolton. These included a “Gauguin” sold to the Art Institute of Chicago and an “ancient Egyptian” statuette authenticated by the British Museum. Greenhalgh’s parents were convicted with him in 2007 for posing as the cash-strapped owners of his numerous creations

10. Bernie Madoff (1938-) perpertrated the largest swindle in Wall Street history with a £36 billion Ponzi scheme that fooled the financial world before its collapse last year. Victims included HSBC, charities and a plumber invited to participate after he saved the life of Madoff’s son. The sometime philanthropist pleaded guilty yesterday, but just $700 million of his haul has been traced

(Money Central of the Times Online, 13March2009)

Cancer Research

(http://www.nytimes.com/2010/04/20/health/research/20cancer.html?ref=todayspaper) focusses primarily on breast cancer and demonstrates a difficulty doctors and patients currently encounter. It is nigh impossible to determine exactly what kind of cancer is present and therefore what treatment regimes and risk factor profiles apply. Not only is there a high rate of false positives/negatives, but many tumours have a mosaic or composite nature. Research is too new for testing protocols to have firmed up, and there is a sore lack of professional/administrative supervision. Not a pretty picture. But intense work in a field may create this situation at the cutting edge. Better chaos at the frontier, I suppose, than no frontier at all. Good luck to all readers with cancer; our hearts are with you.

The Next Money Crisis

http://business.timesonline.co.uk/tol/business/columnists/article7107780.ece and http://www.timesonline.co.uk/tol/news/world/europe/article7107857.ece explain how the Greek financial crisis could trigger a global problem. Financial gnomes calculate how to stick it to countries. That’s what they do. It’s what they’re paid for. The gnomes will be hired as consultants by a country, misrepresent the country’s finances, bet against the state through the derivatives market (debt insurance etc), and rake it in.