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Medscape
29-05-2025
- Health
- Medscape
Defying Grim Prognosis to Celebrate a 20th ‘Cancerversary'
In 2005, Roy Brosgole, then 38, was a busy working parent. He commuted about an hour each way to a teaching job in New York City and took care of his children — then 4 years and almost 2 years — in the evenings. His lifestyle then kept him sitting in the car for hours daily, so it didn't surprise him that his back often ached. One morning Brosgole got up, went to the bathroom, coughed, and then found himself lying flat on the floor in blinding pain. After he tried and failed to stand, his wife Lori called 9-1-1. In the emergency room, Brosgole was triaged and — without any imaging — diagnosed with back spasms. He recalled that the attending physician ordered a strong steroid and pain meds, but neither of these treatments helped relieve the intense discomfort. 'The doctor said, 'Wow that's really strange. You should be able to get up and walk around now.' I said, 'Well, I can't.' The doctor's exact words — I will never forget them: 'Don't worry about it. It's not like you have back cancer or anything,' Brosgole recalled, in an interview. A few days later, an MRI ordered by Brosgole's orthopedist would prove the emergency room physician's statement wrong. The imaging of Brosgole's back showed a plasmacytoma on his sacrum, which doctors told him could be a precursor to multiple myeloma or lymphoma. 'The tumor was growing into the sacrum like Swiss cheese,' Brosgole said. He then consulted Patrick Boland, MD, an orthopedic surgeon at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City. His appointment fell on a Tuesday, he was admitted immediately, and his tumor was removed the next day. Brosgole was diagnosed with IgG kappa multiple myeloma, International Staging System stage II. His myeloma carried two chromosomal abnormalities, deletion 13 and deletion 17p, both associated with aggressive disease and poorer long-term prognosis. Brosgole's condition was designated as high risk, so he was told he might have only a few years to live. Fast forward to 2025, as Brosgole is celebrating his 20-year 'cancerversary.' He credits his survival to clinical trials and new standards of care for myeloma. Chemotherapy and Stem Cell Transplants: Finding a Balance Multiple myeloma was fairly uncommon in 2005, when Brosgole was diagnosed. Today, the disease is more prevalent but still rare. About 36,000 people will be diagnosed with multiple myeloma in 2025— 20,030 men and 16,080 women. The disease currently has a 62% 5-year survival rate. When Brosgole was diagnosed, the 5-year survival rate was 56% for patients younger than 65 years and significantly lower for people with chromosomal deletions, like him. Once the tumor was excised, Brosgole was put on a regimen of dexamethasone and thalidomide, alternating 4 days on and 4 days off. The treatments brought his cancer markers down significantly, but his doctors, noting that he was young and otherwise healthy, offered him the chance to participate in a clinical trial of tandem stem cell transplants. The study would assess if such treatment could improve long-term survival as compared with a single autologous stem cell transplant. The first transplant took place in November 2005, with Brosgole's doctor harvesting his stem cells. Next, he underwent high-dose chemotherapy. Just 3 months later, in February 2006, he went through the entire process again. That treatment was successful for 18 months, he said. 'Then all of a sudden, my numbers — M spike protein levels, immunoglobulins, protein electrophoresis — started to climb,' Brosgole said. When his MSKCC oncologist agreed that he had relapsed, Brosgole was started on a new intravenous chemotherapy cocktail of Velcade (bortezomib) and Revlimid (lenalidomide) with dexamethasone. That treatment worked for a while, too. His tumor markers stayed stable for nearly a year, but his MSKCC care team wanted to add another treatment: Allogenic bone marrow transplant. That procedure took place in May 2011. In the years since then, Brosgole's cancer has often recurred, but donor lymphocyte infusions (DLIs) have brought him back into remission. 'I had 10 DLIs: December 2011, April 2012, September 2012, March 2013, November 2013, January 2014, August 2015, September 2015, and November 2015,' Brosgole noted. He was also given an immunomodulatory agent, lenalidomide, which he took until March 2021. Then he transitioned to a different immunotherapy drug, Pomalyst. Today Brosgole has no detectible levels of multiple myeloma in his body. 'If you do a blood test, there's no way you could tell that I ever had multiple myeloma,' he said. Treatment for Multiple Myeloma: 2025 When you look back at Brosgole's earlier treatments, they differ significantly from today's standard of care, said Hamza Hashmi, MD, a hematologist-oncologist at MSKCC. Hashmi, Brosgole's current doctor, said that allogenic bone marrow transplant comes with the risk for graph-vs-host disease. 'The mortality rate of allogeneic transplant procedures is somewhere around 30-40%,' Hashmi explained. 'Back in 2011, we were pursuing heroic measures for patients like Roy in their 40s, hoping to put myeloma into a deep and durable remission. Someone who is diagnosed today with multiple myeloma would start with a four-drug cocktail of chemotherapy — combinations of chemo and immunotherapies that target the cancer in a very intuitive way that can actually lead to very deep, durable remissions.' If patients relapse, they move on to chimeric antigen receptor (CAR) T-cell therapy, which was first FDA-approved in 2017 for treatment of acute childhood lymphoblastic leukemia. 'It has shown very promising efficacy, with very tolerable or minimal toxicity or side effects, in comparison to the allogenic transplant, which can be very difficult to go through, especially if a patient is elderly, frail, or has many different comorbidities,' Hashmi explained. Other drugs on the horizon may push the needle even further. One new drug, teclistamab, is already helping patients who have stopped responding to three previous therapies or treatments. A phase 2 clinical trial, published in The New England Journal of Medicine in June 2022, found that nearly 40% of study patients saw complete eradication of their disease. In addition, monoclonal antibodies such as daratumumab are added to the standard-of-care drug combinations. Finally, bispecific antibody drug treatments, which recognize antigens on both the patient's T-cells and the myeloma cells, are shrinking tumors for people who stop responding to other treatments. Unlike CAR T-cell therapy, which requires removal and manipulation of the patient's T cells, bispecific antibody treatments are available immediately. These innovative treatments have transformed life expectancy, Hashmi said. 'In 2025 we are saying that average survival for a myeloma patient is beyond 15-20 years. And when I say survival, I mean a 70-year-old man, so you can imagine if someone is 40 years old when they get diagnosed, they may actually be able to live another 30-plus years of their life with their cancer in control and remission,' he said.
Business Mayor
17-05-2025
- Science
- Business Mayor
Researchers find CRISPR is capable of even more than we thought
Every living creature on Earth needs to protect itself from things that would do it harm. Bacteria are no different. And despite their relative simplicity, they deploy remarkably savvy defensive strategies against viral invaders. The most well-known is CRISPR-Cas9, adapted for human use as the first FDA-approved genetic editing technique. In the past year, researchers at Rockefeller's Laboratory of Bacteriology, headed by Luciano Marraffini, and at the MSKCC's Structural Biology Laboratory, headed by Dinshaw Patel, have been studying key immune components of some CRISPR systems called CARF effectors. These newly discovered weapons take different approaches to achieving the same goal: arresting cellular activity, which prevents a virus from spreading through the rest of the bacterial population. In a recent publication in Science , the scientists announce the newest CARF effector they've discovered, which they coined Cat1. Thanks to an unusually complex molecular structure, this protein can deplete a metabolite essential for cellular function. Left without fuel, the viral invader's plans for a further onslaught are brought to a grinding halt. 'The collective work of our labs is revealing just how effective — and different — these CARF effectors are,' says Marraffini. 'The range of their molecular activities is quite amazing.' Multiple defense systems CRISPR is a mechanism in the adaptive immune systems of bacteria and other certain single-cell organisms that offers protection against viruses, called phages. The six types of CRISPR systems work roughly the same way: A CRISPR RNA identifies foreign genetic code, which triggers a cas enzyme to mediate an immune response, often snipping off the invader material. But an increasing body of evidence indicates that CRISPR systems deploy a wide variety of defensive strategies beyond genetic scissors. Marraffini's lab has led the way on much of this research. In particular, they have been studying a class of molecules in CRISPR-Cas10 systems called CARF effectors, which are proteins that are activated upon phage infection of a bacterium. CARF effector immunity is believed to work by creating an inhospitable environment for viral replication. For example, the Cam1 CARF effector causes membrane depolarization of an infected cell, while Cad1 triggers a sort of molecular fumigation, flooding an infected cell with toxic molecules. Metabolic freeze For the current study, the researchers wanted to try to identify additional CARF effectors. They used Foldseek, a powerful structural homology search tool, to find Cat1. They found that Cat1 is alerted to the presence of a virus by the binding of secondary messenger molecules called cyclic tetra-adenylate, or cA 4 , which stimulate the enzyme to cleave an essential metabolite in the cell called NAD+. 'Once a sufficient amount of NAD+ is cleaved, the cell enters a growth-arrest state,' says co-first author Christian Baca, a TPCB graduate student in the Marraffini lab. 'With cellular function on pause, the phage can no longer propagate and spread to the rest of the bacterial population. In this way, Cat1 is similar to Cam1 and Cad1 in that they all provide population-level bacterial immunity.' Unique complexity But while its immune strategy may be similar to these other CARF effectors, its form is not, as co-first author Puja Majumder, a postdoctoral research scholar in the Patel Lab, revealed through detailed structural analysis using cryo-EM. She found that the Cat1 protein has a surprisingly complex structure in which Cat1 dimers are glued by cA 4 signal molecule, forming long filaments upon viral infection, and trap the NAD+ metabolites within sticky molecular pockets. 'Once the NAD+ metabolite is cleaved by Cat1 filaments, it's not available for the cell to use,' Majumder explains. But the protein's singular structural complexity doesn't stop there, she adds. 'The filaments interact with each other to form trigonal spiral bundles, and these bundles can then expand to form pentagonal spiral bundles,' she says. The purpose of these structural components remains to be investigated. Also unusual is the fact Cat1 often seems to work alone. 'Normally in type III CRISPR systems, you have two activities that contribute to the immunity effect,' Baca says. 'However, most of the bacteria that encode Cat1 seem to primarily rely on Cat1 for their immunity effect.' Marraffini says these findings pose intriguing new questions. 'While I think we've proven the big picture — that CARF effectors are great at preventing phage replication — we still have a lot to learn about the details of how they do it. It will be fascinating to see where this work leads us next.'
Yahoo
28-04-2025
- Health
- Yahoo
Immunotherapy drug capable of eliminating tumors in some early-stage cancers: Study
A new study in the New England Journal of Medicine suggests that some people with early-stage cancers may be able to skip surgery after being treated with the immunotherapy drug dostarlimab. In the study, 82 out of 103 participants responded so well to the drug that they no longer needed an operation. While the results are promising, the study was conducted at a single hospital — Memorial Sloan Kettering Cancer Center in New York City — and some patients have not been followed long enough to know if their cancer might return over time. And because the study included many different types of cancer, there were relatively few patients with each specific cancer type, making it difficult to interpret the results for larger groups of patients. It also focused on a very select type of patient whose tumors had a "mismatch repair defect," a genetic problem that prevents cells from fixing DNA damage and makes it more likely they would respond to immunotherapy. "They kind of selected themselves, in that they had a specific genetic alteration, and that genetic alteration occurs about 2% to 3% of all cancer patients," said Dr. Luis Diaz, one of the study's authors and head of the Division of Solid Tumor Oncology at MSKCC. MORE: RFK Jr. is moving to phase out synthetic food dyes. Are they safe? When people are diagnosed with early-stage cancers that form a lump or mass, they often need major surgery to try to remove it — and despite surgery, they can also face aggressive treatments like chemotherapy or radiation. Because these cancers often affect organs in the belly or digestive system, surgery can have a major impact on a patient's life. Some people lose part or all of their esophagus or stomach, making it hard or impossible to eat normally. Others may need a bag to collect stool or lose the ability to get pregnant. All 49 patients with early-stage rectal cancer who received six months of immunotherapy were able to avoid surgery. "And it's after six months of treatment, their tumors were completely gone," said another one of the study's authors, Dr. Andrea Cercek, head of the Colorectal Section at MSKCC. "They didn't need any other treatment." Two years later, 92% remained cancer-free. Among the first group to reach the five-year mark, all four patients were still disease-free — and two of them had gone on to have two children each. "The amazing thing is they would not have been able to conceive or carry children had they gone through standard therapy," Diaz said. MORE: Supreme Court divided over Obamacare mandate for no-cost preventive health benefits As for patients with other early-stage cancers, 35 of 54 were cancer-free after undergoing immunotherapy and were able to avoid surgery. However, two patients still chose to proceed with surgery — one for peace of mind and the other to remove medical hardware related to the cancer. Of the five patients whose cancers came back, most were successfully treated again. Cercek explained that, while immunotherapy alone may not yet help most cancer patients avoid surgery, their work opens the door for the future. "Just close your eyes and just imagine that one day you're diagnosed with cancer and you don't have your esophagus or your stomach or your rectum or your bladder, and you can avoid that," Diaz said. "For these 3% we can completely eliminate the need for surgery. It's quite transformational." By combining different approaches with this type of immunotherapy, Cercek hoped they can replicate their success in more types of cancer. "So, we are continuing this trial and we are working on expanding the study outside of Memorial with more patients so that we can offer this therapy as a standard of care," Cercek said. Luis Gasca -- an internal medicine resident at the Mayo Clinic in Rochester, Michigan, and a member of the ABC News Medical Unit -- contributed to this report. Immunotherapy drug capable of eliminating tumors in some early-stage cancers: Study originally appeared on
