Chemotalk Newsletter

Chemotalk Newsletter, Vol. 79: November 1, 2014

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What's that stuff hitting the roof?  No way!  It's raining in Southern California!!!  Happy November, Everybody!!!


Scientists have developed a highly accurate prototype technique which can produce a detailed 'molecular fingerprint' of breast tissues removed during surgery. This technique ­ which can produce detailed maps of the tissue - has the potential to improve the outcome for BREAST CANCER surgery and to reduce unnecessary secondary operations.

The new study, published in the journal Physics in Medicine and Biology, has been carried out by a group of researchers led by Dr Ioan Notingher in the School of Physics and Astronomy at The University of Nottingham, in collaboration with The Breast Pathology research Group, led by Professor Ian Ellis.

Breast-conserving surgery (BCS) aims to remover the tumor but at the same time conserve as much healthy breast tissue as possible. One of the main challenges during this type of surgery is the detection of tumor margins during surgery. Imaging techniques such as MRI or CT scans are not enough of a guide for a surgeon to ensure clear margins.

Dr Notingher said: "The main aim of breast-conserving surgery is to remove the cancer while ensuring a good cosmetic outcome for the patient. Currently, surgeons rely on information based on other imaging modalities (for example MRI) obtained several days before the operation to locate the cancer during surgery. However, such information is not sufficiently accurate, and during the operation, surgeons rely on their fingers and eyes to decide on how much tissue to cut out. Our new technique can detect the presence or absence of breast tumors at the surface of the tissue removed by the surgeon."

This new technique uses an integrated optical technique based on auto-fluorescence (natural fluorescence from the tissue) and Raman spectroscopy (a highly sensitive technique using laser to identify the molecules in a tissue sample).  Although Raman spectroscopy is known to be a very slow technique, fast auto-fluorescence imaging was used to guide the Raman measurements to sample only the suspicious tissue regions. By combining these two techniques, high-accuracy detection of breast tumors can be obtained in only few minutes.

"By optimizing our prototype instrument using cutting-edge optical components, diagnosis of the entire resection surface could be achieved in few minutes," adds Dr Notingher. "This technology has the potential to revolutionize the surgical treatment of breast cancers by providing accurate information to the surgeons on whether the entire tumor has been removed while at the same time preserving as much healthy tissue as possible."

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By Gina Kolata

Grace Silva has a horrible form of THYROID CANER that is considered untreatable -- usually, patients are sent to a hospice and die within months of learning they have the disease.  But she is still alive four years after her diagnosis.  She is what cancer doctors call an exceptional responder: someone who defies all expectations by responding dramatically to a drug tried not with a real rationale but more out of a doctor's desperate urge to do something.

The annals of medicine are full of stories of exceptional responders, but until recently, they were just that: stories.  Case histories that could not be generalized because there was no way to know why these patients got better when others did not.

But now, with the advent of rapid and inexpensive gene sequencing, the National Cancer Institute has started a nationwide search for people like Mrs. Silva to try to figure out the genetic changes that allowed them to respond.  And The New England Journal of Medicine published her story as a case history in the new genetic era.  It concludes with a lesson that may help doctors treat thousands of patients with more common cancers, like BREAST and BLADDER cancer, and even find an alternative when a drug stops working.

Dr. Barbara Conley a lead investigator for the new cancer institute study, said she and her colleagues had been inspired by a couple of published papers on exceptional responders and genetic analyses that revealed why they reacted the way they did.

One study at Memorial Sloan-Kettering Cancer Center tested a drug called everolimus that is approved for KIDNEY and breast cancer.  Researchers asked if it could treat bladder cancer.  Forty-five patients received the drug. Two responded.

"The verdict was, 'O.K., I guess everolimus does not work in bladder cancer," said Dr. David Solit, the principal investigator.  But then there were those two patients -- one, in particular.  Her cancer had spread to her abdomen.  She was expected to live less than a year, and there was no treatment for her.  But with everolimus, her tumors disappeared.

"I was at a clinical meeting, and everyone was saying this drug did not work," Dr. Solit said.  "I said, 'It worked for her.'"

The investigators found out why.  Her cancer had a mutation in a gene that made it dependent on a protein, mTOR, for growth.  Everolimus squelches the activity of mTOR.  The woman is still taking everolimus, and her cancer has not recurred.

Then the group found another exceptional responder, a patient taking an experimental drug for a cancer of the URETER, the tube that carries urine from the kidney to the bladder.  "She not only responded, but she was cured," Dr. Solit said.  When the company discontinued the drug because it was not working -- except for her -- she was forced to stop taking it.  But her cancer has not returned.

Dr. Conley and her colleagues at the cancer institute decided to look back at a variety of early-phase clinical trials of drugs that had been abandoned because, on average, they did not help patients.  Were there some participants who had been helped -- some exceptional responders?

"Yes, they were actually there," Dr. Conley said.  "Ten percent, maybe less, had this response."

Recently, the cancer institute announced that it was sending letters to cancer doctors seeking exceptional responders.  The researchers are hoping for tumor samples from 300 such patients, Dr. Conley said, and want to find 100 whose tumor samples contain enough tissue for analysis.  So far, they have examined the clinical data for three cases that were sent in.  Two of them really are exceptional responders, she said.  Now the challenge will be to figure out why.

That may not be easy, said Charles Perou, a professor of molecular oncology at the University of North Carolina at Chapel Hill.  Sometimes, he said, researchers will see hundreds of mutations in a cancer and none will explain a patient's response to a drug.  "You are left scratching your head," he said.

In that light Dr. Perou said he can certainly see why The New England Journal of Medicine decided to publish Mrs. Silva's story.

"It is a stunningly interesting example of molecular genetics and drug response and resistance," he said.

Mrs. Silva's symptoms started in 2010 with a badly swollen neck and throat.  She saw her doctor, who gave her antibiotics, but the condition recurred again and again.

"I went to my doctor and said, 'This isn't normal,'" she recalled. Finally, Mrs. Silva, who is 58 and lives in Dartmouth, Mass., ended up at the Dana-Farber Cancer Institute in Boston, where she got terrible news. She had ANAPLASTIC THYROID CANCER.  Anaplastic thyroid cancer, said Dr. Jochen Lorch, her oncologist at Dana-Farber, "is one of the worst cancers you can get."

Surgeons removed her thyroid gland and the tumor that was growing there and gave Mrs. Silva CHEMOTHERAPY and radiation, but the cancer almost immediately reappeared in her lungs and grew rapidly -- a typical scenario. "There is just a maximum amount of tumor the body can support," Dr. Lorch said.  "Tumors eat up all the nutrients around -- patients lose weight very, very quickly -- and poke holes in the surface of the lungs.  Patients die very quickly."

But Dana-Farber was starting a study of everolimus in thyroid cancer patients because mouse studies had indicated it might work.  The researchers decided to include seven patients with anaplastic thyroid cancer, reasoning that there were no other treatments for them.

To everyone's surprise, Mrs. Silva -- but none of the other patients with anaplastc cancer -- responded immediately.  Her tumors shrank to almost nothing and stayed that way for 18 months.  That, said Dr. Nikhil Wagle, another of Mrs. Silva's doctors at Dana-Farber, "is just unheard of."

The researchers sequenced her tumor's genes and figured out why.  Just as had happened with the bladder cancer patient at Memorial Sloan-Kettering, a mutation made Mrs. Silva's cancer dependent on mTOR, and the drug happens to squelch the production of that protein.

then her tumors started to grow again.  Mrs. Silva agree to have another biopsy and genetic analysis to find out why the drug had stopped working.

It turned out that a second mutation in the mTOR gene was letting her cancer evade the drug and grow.  That mutation had never been seen in a human being, even though by now researchers have determined the genetic sequences of tens of thousands of cancers.  But, 20 years ago, it had been seen in yeast.  An experimental drug, which Mrs. Silva will soon receive as part of a clinical trial, overcomes the mutation's effect and stops the cancer's growth, at least in laboratory studies.

Everolimus, though, is used by thousands of kidney and breast cancer patients.  Why, then, did no one see the mutation that can stop it from working?

The answer, Dr. Lorch said, is that the genetic analysis that revealed why the everolimus had stopped working for Mrs. Silva was "actually quite complex."  But, he said, now that the genetic change that leads to resistance is known, investigators can look just for that mutation.

"The resistance mechanism almost certainly does not just apply to our case," Dr. Lorch said.

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By Denise Grady

Mammography has become a fighting word in recent years, with some researchers questioning its value and others staunchly defending it.

One especially disturbing criticism is that screening mammography may lead to "overtreatment." in which some women go through grueling therapies -- surgery, radiation, CHEMOTHERAPY -- that they do not need.  Indeed, some studies estimate that 19% or more of women whose BREAST CANCERS are found by mammography wind up being overtreated.

This problem occurs, researchers say, because mammography can "overdiagnose" breast cancer, meaning that some of the tiny cancers it finds would probably never progress or threaten the patient's life.  But they are treated, anyway.

So where are these overtreated women?  Nobody knows.

They are out there somewhere, studies suggest.  But the figures on overtreatment are based on theory and calculations, not on counting the heads of actual patients known to have experienced it.  No one can point to a particular woman and say, "Here's a patient who went through the wringer for nothing."

Overdiagnosis is not the same as a false positive result, in which a test like a mammogram initially suggests a problem but is proved wrong. False positives are frightening and expensive, but overtreatment is the potential harm of mammography that worries doctors most, according to an article published in the Journal of the American Medical Association.

But the authors also say that estimates of how often overdiagnosis and overtreatment occur are among the least reliable and most controversial of all the data on mammography.

In the past, oerdiagnosis was thought to apply mainly to ductal carcinoma in situ, or D.C.I.S., a breast growth that may or may not turn cancerous.  Now, researchers think that invasive cancers are also being overdiagnosed and overtreated by mammography.

The concept of overtreatment is based on the belief that not all breast cancers are deadly.  Some never progress, researchers suspect, and some progress so slowly that the patient will probably die of something else, particularly if she is older or has other health problems.

But mammography can find all of these tumors, even those too small to feel.  And doctors and patients rarely watch and wait -- once a tumor is found, it is treated, because nobody knows how to tell the dangerous ones from those that could be safely left alone.

"Everyone has an anecdote of a small spot on mammography year after year that was finally biopsied and turned out to be positive -- invasive, low grade," said Dr. Constance Lehman, a radiologist at the Fred Hutchinson Caner Center and the director of breast imaging at the University of Washington in Seattle.

Where do the numerical estimates of overdiagnosis come from?  In several large studies of mammography screening, women judged to have the same risk of breast cancer were picked at random to have the test or to skip it. Early on, more cancers were expected in the mammogram group, because the test can find small tumors.

Over time, the groups should have equalized, because if small tumors in the unscreened group were really life-threatening, they would have grown big enough to be felt or caused other symptoms.

But in several studies, the number of cancers in the unscreened group never caught up with the number in the mammography group.  The reason for the difference, researchers assume, is that there must have been women in the unscreened group who had cancers that were never diagnosed an never progressed -- and therefore did not need treatment.

The next step is to subtract the number of cancers in the unscreened group from the number in the mammography group.  The result is the estimate of how many women in the mammography group were overtreated.

"We don't know which individual women those were," said Dr. Lydia E. Pace, of Brigham and Women's Hospital, an author of the new paper.  "All we know is the proportion, and a lot of people would argue that we don't really know the proportion."

this kind of calculation was used in a Canadian study of about 90,000 women, published in February in the journal BMJ.  The authors found that after 15 years there was a "residual excess" of 106 invasive cancers in the mammography group.  The authors attributed that to overdiagnosis, and said that it amounted to 225 of the 484 invasive cancers found by mammography. They concluded that for every 424 women who had mammography in the study, one was overdiagnosed.

Other studies have estimated overdiagnosis in different ways, with huge variations in the results, reported that 5% to 50% of cancers found on mammograms are overdiagnosed.  To make it clear that the numbers are uncertain, some offer ranges: For example, one says that if 10,000 50-year-old women have annual mammograms for 10 years, 30 to 137 women will be overdiagnosed.

It is frightening to consider the prospect that mammography could be leading some down a slippery slope to unneeded surgery, chemotherapy and radiation, with all their risks and side effects.  But the numbers on overdiagnosis are all over the map, a shaky foundation on which to base important decisions.

The best hope for resolving the confusion may lie in molecular tests that can tell the difference between dangerous tumors and those unlikely to progress -- but those tests are in the future.

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By Ronald Piana

Imagine watching a loved one moaning in pain, curled into a fetal ball, pleading for relief.  Then imagine that his or her pain could be relieved by an inexpensive drug, but the rug was unavailable.

Each day, about six million terminal CANCER patients around the world suffer that fate because they do not have access to morphine, the gold standard of cancer pain control.  The World Health Organization has stated that access to pain treatment, including morphine, is an essential human right.

Most suffering because of a lack of morphine is felt in the poorer regions of the globe.  About 90% of the world's morphine consumption is in countries in North America and Europe whereas all the globe's low- and middle-income Countries combined use a mere 6%.  In sub-Saharan Africa, which has the world's lowest consumption of morphine and other opioids, 32 of 53 countries have little, if any access to morphine.

However, this grossly lopsided use of morphine is not about the unequal distribution of wealth.  Morphine is easy to produce and costs pennies per dose.  But its per-dose profits are also low, which decreases a drug company's incentive to enter low-income markets in the developing world.

If it were just about money, the solution -- subsidized access -- would be obvious.  However, the issue is complicated by a dizzying array of bureaucratic hurdles, cultural biases and the chilling effect of the international war on drugs, which can be traced back to the 1961 United Nations Single Convention on Narcotic Drugs that standardized international regulation of narcotics.  Driven by its lopsided concern over the illicit use of opioids, a class of drugs that includes heroin, the Single Convention drove countless, onerous country-level restrictions on morphine use, for fear that it would be abused.

India offers a glaring example of how such restrictions can have devastating effects on human lives.  In a powerful documentary, "The Pain Project," India's leading palliative care specialist, Dr. M. R. Rajagopal, explains that India's narcotic regulatory agencies are so irrationally stringent that in 27 of the country's 28 states doctors simply avoid prescribing morphine for cancer pain, for fear of running afoul of the law.

In the documentary, you see an aged Indian woman with terminal breast cancer lying on a cot and wailing in pain.  It's agonizing to watch, but it illustrates the unrelenting soul-searing effects of untreated cancer pain.*

Under mounting pressure, India recently eased some restrictions on the medical use of morphine and consolidated the licensing process from four or five agencies into a single authority.  While a step forward, the new amendment doesn't address many harsh regulations that dissuade doctors from freely prescribing morphine.  Adding to the regulatory roadblocks, India's health care delivery system is woeful fragmented and understaffed.  And India is just one, albeit very large, country -- the same story can be found across the developing world.

Several organizations, such as Global Access to Pain Relief Initiative, Hospice Without Borders and Human Rights Watch, are devoted to easing the global crisis of untreated cancer pain, but it is a Sisyphean undertaking for a handful of cash-strapped nongovernmental organizations.  Still, by partnering with international organizations and developing innovative delivery systems, certain resource-challenged areas in the developing world have made progress.

The sparsely populated, war-ravaged country of Uganda has made strides in providing morphine to its cancer patents, thanks to the determination of public health advocates like Dr. Jack Jagwe, a former adviser to the Ugandan Health Ministry.  In the 1990s, Dr. Jagwe and others partnered with foreign doctors and members of the international community to write into the health code that every Ugandan citizen had the right to palliative care, which was the first in Africa.

Thanks in part to this initiative, Uganda amended its rigid narcotics laws, allowing nurses to prescribe morphine to cancer patients without having a doctor present, which proves essential in delivering morphine to patients in rural areas who are unable to trek long distances to city clinics.

That regulatory easing has opened the door for a nongovernmental entity, Hospice Africa Uganda, to produce its own morphine.  This process not only frees Hospice Africa Uganda from dealing with international suppliers; it makes the market more efficient by allowing it to manufacture morphine on demand -- indeed, per-patient pain-control costs are now estimated to be about $1 per week.  That experience, though still a work in progress, should be a model for other resource-challenged countries.

Untreated cancer pain is a human disaster not unlike famine; its victims are starving for relief.  But as the Ugandan experience shows, there are easy-to-implement, cost-effective health care models that could rapidly deploy morphine to cancer patients around the world.

As with all successful human rights movements, we need to put a face on the injustice of untreated cancer pain.  Witnessing a clinic full of poor children with advanced cancer, crying in agony, should convince anyone that access to morphine is a human right.


* When my mother was dying of breast cancer over 40 years ago and already declared terminal, she begged for more morphine.  It was refused because the doctor had determined that more morphine would turn her into an addict.  She died in agony.  The author of this piece has stayed away from the issue of pain relief in America, but the problem still exists today.

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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