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Chemotalk NewsletterChemotalk Newsletter, Vol. 70: February 1, 2014 Hello, 2014! Since I write January's "Chemotalk Newsletter" in December, this is the first newsletter of the year. The title of the newsletter is "Chemotalk", but as you know by now there's a lot more to the world of chemotherapy, than using it to cure something. It has side effects, and pain is one of the big ones. I asked for, and got more than the chemotherapy protocol approved for stage 4 breast cancer. But I had no pain whatsoever associated with any of my treatments. What I learned personally about pain came after knee surgery. Pain management is a hot-button issue. My mother was terminal but the doctors refused to prescribe more pain medication because "She'll get addicted." That's not just crazy-thinking, it's cruel. I believe that science can fix the problem of pain, and I think the longer we live, the more certain the odds that severe, intractable pain will be a horrific by-product of something that happens to us. On the medical pain scale graded from 1 to 10, I'm talking about 9-1/2 to OVER 10. Age is only one factor. Our lives provide many of them. So anyone who provides a new opportunity to explore pain management will get a hearing in this newsletter. When I update "Chemotherapy for Winners", I'm hoping Carl Hart give me an endorsement. To wit: TRACING ADDICTION OUTSIDE THE BRAIN From "Findings/John Tierney" in The New York Times Long before he brought people into his laboratory at Columbia University to smoke crack cocaine, Carl Hart saw its effect firsthand. Growing up in poverty, he watched relative become crack addicts, living in squalor and stealing fro their mothers. Childhood friends ended up in prisons and morgues. Those addicts seemed enslaved by crack, like the laboratory rats that couldn't stop pressing the lever for cocaine even as they were starving to death. The cocaine was providing such powerful dopamine stimulation to the brain's reward center that the addicts couldn't resist taking another hit. At least, that was how it looked to Dr. Hart when he started his research career in the 1990s. Like other scientists, he hoped to find a neurological cure to addiction, some mechanism for blocking that dopamine activity in the brain so that people wouldn't succumb to the otherwise irresistible craving for cocaine, heroin and other powerfully addictive drugs. But then, when he began studying addicts, he saw that drugs weren't so irresistible after all. "Eighty to 90% of people who use crack ad methamphetamine don't get addicted," said Dr. Hart, an associate professor of psychology. "And the small number who do become addicted are nothing like the popular caricatures." Dr. Hart recruited addicts by advertising in The Village Voice, offering them a chance to make $950 while smoking crack made from pharmaceutical-grade cocaine. Most of the respondents, like the addicts he knew growing up in Miami, were black men from low-income neighborhoods. To participate, they had to live in a hospital ward for several weeks during the experiment. At the start of each day, as researchers watched behind a one-way mirror, a nurse would place a certain amount of crack in a pipe -- the dose varied daily -- and light it. While smoking, the participant was blind-folded so he couldn't see the size of that day's dose. Then, after the sample of crack to start the day, each participant would be offered more opportunities during the day to smoke the same dose of crack. But each time the offer was made, the participants could also opt for a different reward that they could collect when they eventually left the hospital. Sometimes the reward was $5 in cash, and sometimes it was a $5 voucher for merchandise at a store. When the dose of crack was fairly high, the subject would typically choose to keep smoking crack during the day. But when the dose was smaller, he was more likely to pass it up for the $5 in cash or voucher. "They didn't fit the caricature of the drug addict who can't stop once he gets a taste," Dr. Hart said. "When they were given an alternative to crack, they made rational economic decisions." When methamphetamine replaced crack as the great drug scourge in the United States, Dr. Hart brought meth addicts into his laboratory for similar experiments -- and the results showed similarly rational decisions. He also found that when he raised the alternative reward to $20, every single addict of meth and crack alike, chose the cash. They knew they wouldn't receive it until the experiment ended weeks later, but they were still willing to pass up an immediate high. These findings made Dr. Hart rethink what he'd seen growing up, as he relates in his new book, "High Price." It's a fascinating combination of memoir and social science: wrenching scenes of deprivation and violence accompanied by calm analysis of historical data and laboratory results. He tells horrifying stories -- his mother attacked with a hammer, his father doused with a potful of boiling syrup - but then he looks for the statistically significant trend. Yes, he notes, some children were abandoned by crack-addicted parents, but many families in his neighborhood were torn apart before crack - including his own. (He was raised largely by his grandmother.) Yes, his cousins became destitute crack addicts living in a shed, but they'd dropped out of school and had been unemployed long before crack came along. "There seemed to be at least as many - if not more - cases in which illicit drugs played little or no role than were there situations in which their pharmacological effects seemed to matter," writes Dr. Hart, now 46. Crack and meth may be especially troublesome in some poor neighborhoods and rural areas, but not because the drugs themselves are so potent. "If you're living in a poor neighborhood deprived of options, there's a certain rationality to keep taking a drug that will give you some temporary pleasure," Dr. Hart said in an interview, arguing that the caricature of enslaved crack addicts comes from a misinterpretation of the famous rat experiments. "The key factor is the environment, whether you're talking about humans or rats," Dr. Hart said. "The rats that keep pressing the lever for cocaine are the ones who are stressed out because they've been raised in solitary conditions and have no other options. But when you enrich their environment, and give them access to sweets and let them play with other rats, they stop pressing the lever." Drug warriors may be skeptical of his work, but some other scientists are impressed. "Carl's overall argument is persuasive and driven by the data," said Craig R. Rush, a psychologist at the University of Kentucky who studies stimulant abuse. "He's not saying that drug abuse isn't harmful, but he's showing that drugs don't turn people into lunatics. They can stop using drugs when provided with alternative reinforcers." A similar assessment comes from Dr. David Nutt, a British expert on drug abuse. "I have a great deal of sympathy with Carl's views," said Dr. Nutt, a professor of neuropsychopharmacology at Imperial College London. "Addiction always has a social element, and this is magnified in societies with little in the way of work or other ways to find fulfillment." So why do we keep focusing so much on specific drugs? One reason is convenience: It's much simpler for politicians and journalists to focus on the evils of a drug than to grapple with the underlying social problems. But Dr. Hart also puts some of the blame on scientists. "Eighty to 90% of people are not negatively affected by drugs but in the scientific literature nearly 100% of the reports are negative," Dr. Hart said. "There's a skewed focus on pathology. We scientists know that we get more money if we keep telling Congress that we're solving this terrible problem. We've played a less than honorable role in the war on drugs." * * * RESEARCHERS DISCOVER BIOLOGICAL MECHANISM THAT ALLOWS BRAIN TUMORS TO ESCAPE FROM DRUGS Researchers from UCLA's Jonsson Comprehensive Cancer Center (JCCC) have discovered a biological mechanism that allows brain tumor cells to escape from the drugs designed to target them, resulting in drug resistance. The study was published in an issue of Science. Glioblastoma is the most common and deadliest form of BRAIN CANCER. Drugs have been designed to find and kill glioblastoma cells by targeting telltale mutations on the cell surface that accelerate tumor growth. The JCCC team, led by first author David Nathanson, assistant professor of Molecular and Medical Pharmacology, and former UCLA professor Paul Mischel, now at the Ludwig Institute for Cancer Research at UCSD, found that the tumor cells are able to eliminate the gene mutation, essentially removing the target while the drug is present and allowing the tumor to become drug resistant. Remarkably, Nathanson and Mischel's study, co-led by JCCC professors Harley Kornblum (UCLA), James Heath (UCLA and Caltech) in close collaboration with Dr. Timothy Cloughesy (UCLA), and Nagesh Rao (UCLA), also found that after the drug is removed, the tumor cells reacquire the gene mutation (called an oncogene) that helps the tumor cells grow more robustly. Thus, they discovered that tumor cells can eliminate the oncogene identified by drugs that specifically target them, and regain the oncogene after treatment is stopped. Importantly, the tumor cells' dynamic ability to reacquire this oncogene makes them vulnerable to the original therapy. "Now that we know that tumor cells have the surprising capacity to lose this oncogene during treatment and then reverse the process after drug removal, we may be able to exploit this phenomenon in the clinic." Nathanson said. Another exciting aspect of this discovery is that it is potentially applicable to other cancers that are susceptible to oncogene elimination. This is the first study to show reversible loss of an oncogene causing drug resistance, and could lead to different and more effective approaches to treat these cancers. * * * WEIGHING PREVENTITIVE SURGERIES By Jill Werman Harris When Tracy Dunbrook, a bioethicist in Sherman, Conn., tested positive for the BRCA gene mutation, she was told she had a 40 to 60% chance of developing OVARIAN CANCER in her lifetime. Doctors advised her to have her ovaries removed. She considered going further and having a hysterectomy, in which her uterus would be removed, but in the end opted for the standard of care: a procedure known as risk-reducing salpingo-oophorectomy (RRSO), removal of her ovaries and fallopian tubes. Five years later, she was given a diagnosis of Stage 3 uterine cancer. "I couldn't believe it," she said. "I thought, this is the dirtiest trick." Women when the BRCA mutations often opt for RRSO. But there is a debate among experts over whether this strategy is the best one for all women, and many patients are caught in the middle, struggling to balance conflicting information about hysterectomy as part of the risk-reducing surgery. "There definitely is an ongoing sense of confusion, and women do agonize over this," said Sue Friedman, executive director of the group Facing Our Risk of Cancer Empowered. "There are a lot of gynecologists and oncologists who have a strong opinion for or against removing the uterus." Dr. Nadeem Abu-Rustum, a gynecologic oncologist at Memorial Sloan-Kettering Cancer Center, agreed: "We struggle with this every day." About half of the carriers who undergo RRSO opt for removal of the uterus, according to timothy Rebbeck, a professor of epidemiology at the University of Pennsylvania who studies women with BRCA mutations. Yet "there are really no guidelines or data that help a woman to make a decision for or against hysterectomy," he said. Indeed, there is scant evidence that women with BRCA mutations are more likely to develop UTERINE CANCER, although small case studies have shown a weak link to a rare form of the disease, uterine serous cancer. Instead, the worries persist largely because of anecdotal reports of cases like Ms. Dunbrook's, and the fact that uterine cancer is the most commonly diagnosed gynecologic cancer. The lack of data leaves doctors and patients struggling to make these decisions. Some doctors have seen patients like Ms. Dunbrook come back with uterine cancer years after risk-reducing surgery. Dr. Kevin Holcomb, director of gynecologic oncology at NewYork-Presbyterian/Weill Cornell hospital, recently treated two women who had RRSO and later developed uterine cancer. "The debate is really still open,: he said. "But if there's any genetic predisposition to ovarian cancer, it makes sense that it could also affect any of the gynecologic organs with similar epithelium, including the uterus," But the evidence is just not there, he acknowledged. Uterine cancer is just one of the fears driving more women with BRCA mutations to consider hysterectomy. Doctors know that some ovarian cancers originate in the fallopian tubes. Following RRSO, a small tubal remnant is left within the uterus, and some women worry that this may become cancerous. Studies don't bear this out, but some BRCA carriers aren't taking any chances, Kate Berges discovered along with her three sisters that a BRCA mutation had been passed down to them through their father. All four women opted for RRSO. But following the surgery, when her younger sister's pathology report revealed that an ovarian cancer had already taken root in her fallopian tubes, Ms. Berges, 53, a photographer from Branford Conn., picked up the phone and called her doctor to schedule a hysterectomy. "I just wanted it all out. I didn't want any surprises." Women who have had RRSO with or without hysterectomy may choose hormone replacement therapy to counteract the effects of surgical menopause. But there are a dizzying array of options that come in varying delivery systems - patches, pills, and creams - and there is contradictory research on both the risks and the benefits. For women who have RRSO alone, hormone therapy means a combination of estrogen and, in order to prevent uterine cancer, progesterone. But studies suggest that progesterone increases BREAST CANCER risk among women taking hormone therapy. Some women also experience side effects, including irritability, headaches, bloating and breakthrough bleeding. Women with BRCA mutations who opt for a hysterectomy are able to take estrogen alone, in many ways a less complicated strategy, but at the cost of a more complicated surgery. The confusion over all of these variables is visible on the online message boards run by Ms. Friedman's group that are filled with comments from well-informed women immersed in making profoundly difficult choices to overcome their odds of cancer. The dilemma of whether to remove some, or all, gynecologic parts is ever-present. Reads one typical post: Struggling with ooph vs. hyst -- please help!" The frustration of these women in part stems from the fact there is no way to predict what each individual will face in the future, whatever her choice now. Dr. Michael G. Muto, a gynecologic oncologist at Dana-Farber Cancer Institute, suggests taking the time to discuss the risks, benefits and nuances with each patient. "Women should know what we know and what we don't know," he said. Dr. Susan Domchek of the Basser Research Center for BRCA said: "The biggest challenge is trying to make those risk-benefit decisions every day, every time and get it right. Some people you're over-treating and some you're undertreating." Ms. Dunbrook, diagnosed with uterine cancer, was one of the unlucky ones. "I just don't think it's worth taking the chance," she said. "If I had known, I would have absolutely taken it out." * * * Until March... * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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