November 2024 – artdiamondblog.com

“Common Practice of Excluding Former Cancer Patients From Clinical Trials”

Phase 3 randomized double-blind clinical trials (RCTs) are very expensive and often fail. When they do the drug company loses their investment in the new drug. As a result they have a big incentive to design the RCT to maximize the chances of success. One way is to exclude weak patients who are less likely to survive the new drug, for example in the passages quoted below, by excluding patients who have a past history of cancer. But the result is that the RCT does not provide evidence about the efficacy of the new drug in helping one of the groups we would like to help.

(p. D5) In a recent report in JAMA Oncology by researchers at the University of Texas Southwestern Medical Center in Dallas, approximately 25 percent of Americans 65 and older and 11 percent of younger adults who were previously treated for cancer were subsequently found to have one or more new cancers in a different site. Depending on the type of original cancer and the person’s age, the risk of developing a second unrelated cancer ranged from 3.5 percent to 36.9 percent. The study covered 765,843 new cancer diagnoses made between 2009 and 2013 and recorded in a population-based national registry, the Surveillance, Epidemiology and End Results (SEER) program.

. . .

The Texas researchers, led by Caitlin C. Murphy, an epidemiologist, undertook the study of new cancers in cancer survivors in hopes of changing the common practice of excluding former cancer patients from clinical trials when they develop another cancer.

“This exclusion is not evidence-based,” Dr. Murphy said in an interview. “Patients with a prior cancer do not necessarily have a worse prognosis than those without a cancer history. They should be allowed to participate in clinical trials, which may be one of their only treatment options. If they’re excluded, a lot of patients are left out from what may be the best available treatment.”

For the full story see:

Jane E. Brody. “When Cancer Strikes Twice.” The New York Times (Tuesday, December 26, 2017 [sic]): D5.

(Note: ellipsis added.)

(Note: the online version of the story has the date Dec. 25, 2017 [sic], and has the same title as the print version.)

The academic report mentioned above is:

Murphy, Caitlin C., David E. Gerber, and Sandi L. Pruitt. “Prevalence of Prior Cancer among Persons Newly Diagnosed with Cancer: An Initial Report from the Surveillance, Epidemiology, and End Results Program.” JAMA Oncology 4, no. 6 (June 2018): 832-36.ds

“I’m Sick of It, I’m Leaving” Are First Words of Children in Primitive Village Routinely Eating Grubs and Starch Tasting Like “Gummy Mucous”

(p. C9) As she tended soldiers during the Crimean War, a British nurse found herself appalled by the wretched, vermin-infested conditions at the army’s hospital in Istanbul. She began collecting figures showing the devastating effects of the filth and the dramatic benefits of the sanitary improvements she implemented. Her presentation on the need for cleaner care facilities, published in 1858, led to reforms that ultimately saved millions of lives and increased life expectancy in the U.K. Florence Nightingale, it turns out, was a pioneering data scientist.

Data, when used to reveal the value of hospital hygiene or the harm of tobacco smoke, can be a vital force for good, as Tim Harford reminds us in “The Data Detective.”

. . .

Imprecise and inconsistent definitions are one source of confusion. . . . . . . “infant mortality,” a key data point for public health, varies depending on the specific time in fetal development when the line is drawn between a miscarriage and a tragically premature birth.

. . .

To learn from data, it’s essential to present it well. For her analysis after the Crimean War, Florence Nightingale created one of the first infographics, using shrewdly designed diagrams to tell a memorable story. From the outset, she regarded visually compelling data displays as indispensable to making her arguments.

. . .

An authentically open mind can make a difference, Mr. Harford says, noting that the top forecasters tend to be not experts but earnest learners who constantly take in new data while challenging and refining their hypotheses. Data, Mr. Harford concludes, can illuminate and inform as well as distract and deceive. It’s often maddeningly hard to know the difference, but it would be unforgivable not to try.

For the full review see:

Wade Davis. “To Hear a Dying Tongue.” The Wall Street Journal (Saturday, Aug. 10, 2019 [sic]): C9.

(Note: ellipses added.)

(Note: the online version of the review has the date Aug. 9, 2019 [sic], and has the title “‘A Death in the Rainforest’ Review: To Hear a Dying Tongue.”)

The book under review is:

Kulick, Don. A Death in the Rainforest: How a Language and a Way of Life Came to an End in Papua New Guinea. Chapel Hill, NC: Algonquin Books, 2019.

Formal and Tacit Knowledge Are Located in Different Parts of the Brain

Brenda Milner turned 106 on July 15, 2024.

(p. D5) At 98, Dr. Milner is not letting up in a nearly 70-year career to clarify the function of many brain regions — frontal lobes, and temporal; vision centers and tactile; the left hemisphere and the right — usually by painstakingly testing people with brain lesions, often from surgery. Her prominence long ago transcended gender, and she is impatient with those who expect her to be a social activist. It’s science first with Dr. Milner, say close colleagues, in her lab and her life.

Perched recently on a chair in her small office, resplendent in a black satin dress and gold floral pin and banked by moldering towers of old files, she volleyed questions rather than answering them. “People think because I’m 98 years old I must be emerita,” she said. “Well, not at all. I’m still nosy, you know, curious.”

. . .

Dr. Milner changed the course of brain science for good as a newly minted Ph.D. in the 1950s by identifying the specific brain organ that is crucial to memory formation.

She did so by observing the behavior of a 29-year-old Connecticut man who had recently undergone an operation to relieve severe epileptic seizures. The operation was an experiment: On a hunch, the surgeon suctioned out two trenches of tissue from the man’s brain, one from each of his medial temporal lobes, located deep below the skull about level with the ears. The seizures subsided.

But the patient, an assembly line worker named Henry Molaison, was forever altered. He could no longer form new memories.

. . .

In a landmark 1957 paper Dr. Milner wrote with Mr. Molaison’s surgeon, she concluded that the medial temporal areas — including, importantly, an organ called the hippocampus — must be critical to memory formation. That finding, though slow to sink in, would upend the accepted teaching at the time, which held that no single area was critical to supporting memory.

Dr. Milner continued to work with Mr. Molaison and later showed that his motor memory was intact: He remembered how to perform certain physical drawing tests, even if he had no memory of learning them.

The finding, reported in 1962, demonstrated that there are at least two systems in the brain for processing memory: one that is explicit and handles names, faces and experiences; and another that is implicit and incorporates skills, like riding a bike or playing a guitar.

“I clearly remember to this day my excitement, sitting there with H. M. and watching this beautiful learning curve develop right there in front of me,” Dr. Milner said. “I knew very well I was witnessing something important.”

. . .

For Dr. Milner, after a lifetime exploring the brain, the motive for the work is personal as well as professional. “I live very close; it’s a 10-minute walk up the hill,” she said. “So it gives me a good reason to come in regularly.”

For the full story see:

Benedict Carey. “At 98, ‘Still Nosy’ About the Brain.” The New York Times (Tuesday, May 16, 2017 [sic]): D5.

(Note: ellipses added.)

(Note: the online version of the story has the date May 15, 2017 [sic], and has the title “Brenda Milner, Eminent Brain Scientist, Is ‘Still Nosy’ at 98.”)

The “landmark 1957 paper” mentioned above is:

Scoville, William Beecher, and Brenda Milner. “Loss of Recent Memory after Bilateral Hippocampal Lesions.” Journal of Neurology, Neurosurgery & Psychiatry 20, no. 1 (Feb. 1957): 11-21.

Allowing Entrepreneurial Physicians to Improvise Can Save Patient Lives, Especially for Rare Conditions

The article quoted below makes the case, by example, that drugs that would be rejected based on early randomized double-blind clinical trials, can be revived by clever trial-and-error adjustments. Such improvisations saved the life of Magglio Boscarino, whose body began to develop antibodies that attacked the medicine that had been successfully treating his rare Pompe disease. Emil Freireich used trial-and-error adjustments to develop the chemo cocktail that cured many of childhood leukemia. He mentored Vincent DeVita who used trial-and-error adjustments to develop the chemo cocktails that cured many of Hodgkin’s lymphoma. Another approach, advocated by Dr. Ridker in a passage below, is to learn which patients will be able to take the drug with developing resistance to it–a form of personalized medicine that does not seem easily compatible with the oft-claimed “gold standard” of randomized double blind clinical trials.

(p. D1) The miracle treatment that should have saved Becka Boscarino’s baby boy almost killed him.

Doctors diagnosed her newborn son, Magglio, with Pompe disease, a rare and deadly genetic disorder that leads to a buildup of glycogen in the body. Left untreated, the baby would probably die before his first birthday.

There is just one treatment: a series of infusions. But after the boy received his fifth dose, he turned blue, stopped breathing and slipped into anaphylactic shock.

The problem? Eventually doctors discovered that Magglio’s body was producing antibodies to the very drug saving his life.

. . .

In a paper published in March [2017] by The New England Journal of Medicine, Pfizer reported that in the final phase of testing a new drug to lower cholesterol, many of the 30,000 patients taking it had stopped re-(p. D6)sponding to it.

Their cholesterol levels, which had plunged when they began taking the drug, were rising again. As it turned out, the subjects had begun making antibodies to the drug.

Pfizer was forced to stop the trial and pull the drug after investing billions of dollars.

. . .

By the time Magglio was 6 months old, he was weak and lacked muscle tone. Then came the diagnosis of Pompe disease and the beginning of his treatments, infusions with an enzyme his body was failing to make.

At first, Magglio improved. Within a few months, he was learning to sit up and to use his arms. His enlarged heart was shrinking. But his fifth treatment was a disaster.

He fell into anaphylactic shock and stopped breathing.

. . .

Magglio was hardly alone: Most babies with Pompe disease who received the only available treatment soon produced antibodies that rendered it useless.

“We tried everything, but these babies did not make it,” said Dr. Priya Kishnani, a professor of pediatrics at Duke University.

Dr. Kishnani realized she had to find a way to trick the immune system so it would leave the infused protein alone. Her idea was to give the babies a chemotherapy drug, rituximab, that wipes out cells that develop into antibody producers.

Along with it, she tried giving the children methotrexate, which destroys many of the body’s white blood cells, and infusions of antibodies from pooled donors’ serum so the children would have a way to fight off infections.

And for babies like Magglio, who already were making antibodies that blocked the drug they need, she added another drug — bortezomib — to eliminate those antibody-producing cells.

As the children’s immune systems were brought under control, the treatments began to work again. “It was breathtaking,” Dr. Kishnani said. “We were able to rescue these babies.”

. . .

At Brigham and Women’s Hospital in Boston, cardiologist Dr. Paul Ridker, who directed the Pfizer study, is taking a different tack.

He wants to do a large genetic study to see if he can predict which patients will develop antibodies to the Pfizer drug and perhaps to other drugs that the immune system might see as foreign.

“We probably have the best opportunity ever afforded to understand the cause of these antibodies,” Dr. Ridker said. “That would be very valuable for the development of future drugs if you could say, ‘This one patient out of 20 should not take this drug.’”

It would mean, too, that drugs that might have been abandoned could be developed for the patients who can tolerate them.