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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY


Domingo, 16.08.15

Stem cell transplantation improves outcomes for children with rare form of leukemia

 

Stem cell transplantation improves outcomes for children with rare form of leukemia

Improved outcomes have seen treating JMML with stem cell transplantation.
Improved outcomes have seen treating JMML with stem cell transplantation.

Researchers have shown greatly improved outcomes in using stem cell transplantation to treat patients with juvenile myelomonocytic leukemia (JMML), a very rare form of chronic blood cancer. Their findings were published in a letter to Blood (2015; doi:10.1182/blood-2015-05-644161).

Allogeneic hematopoietic stem cell transplantation (HSCT) involves the transplantation of stem cells from a donor, which may be derived from bone marrow, peripheral blood, or umbilical cord blood. The recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation.

Allogeneic HSCT is the only reported cure for JMML; however, best outcomes of the therapy have shown that cure is achieved in only half of patients with the disease. According to the researchers, there is currently no standard conditioning regimen for children with JMML undergoing HSCT.

This study, conducted by researchers in the Division of Hematology, Oncology and Blood & Marrow Transplantation at Children's Hospital Los Angeles (CHLA) in California and led by Hisham Abdel-Azim, MD, looked at children with JMML who underwent HSCT at Children's Hospital Los Angeles. All of the seven patients were alive and in clinical remission at a median follow-up of 25.3 months. Their average age was 2.6 years.

"The lack of transplant-related mortality in the group of children we studied at the Children's Center for Cancer and Blood Diseases at CHLA suggests that BUMEL [intravenous busulfan and melphalan] may represent a successful HSCT high-dose chemotherapy regimen," said Abdel-Azim. "It is also possible that administering conventional dose chemotherapy, before HSCT, to patients with more progressive disease may have contributed to the improved outcomes."

He added that a follow up clinical trial is warranted to confirm these promising findings.

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por cyto às 14:15

Quinta-feira, 23.07.15

Dartmouth researchers perform first total syntheses of compounds involved in rapid cell death in leukemia

 

Dartmouth researchers perform first total syntheses of compounds involved in rapid cell death in leukemia

Published on July 22, 2015 at 5:18 AM 

Dartmouth researchers and their colleagues have carried out the first total syntheses of certain compounds involved in excessive cell death in leukemia.

The findings appear in the journal Angewandte Chemie International Edition. A PDF is available on request.

"We anticipate that these compounds will serve as useful tools for dissecting an important but as yet undefined step in the regulation of apoptosis," says senior author Jimmy Wu, an associate professor of chemistry at Dartmouth. "Studies to clarify the biological mechanism by which they operate are ongoing."

The researchers completed the total syntheses of several members of the family of dimeric nuphar alkaloids, which are compounds previously isolated from the yellow pond lily. These are structurally complex molecules that are capable of including apoptosis, or programmed cell death, in certain human leukemia cell lines faster than any other small molecule. The researchers also were able to synthesize some related structures that they predict might exist in nature but have not yet been found.

There have been only two reports that attempt to explain the biological mechanism of action of these molecules. But these are incomplete and more research is required to fully reveal how these compounds work. The Dartmouth-led team's synthetic efforts now provide a means to a steady supply of the active compounds for further study. Preliminary biological tests conducted by co-author Alan Eastman, a professor of pharmacology and toxicology at Dartmouth's Geisel School of Medicine, indicate that all the compounds, both naturally occurring and ones predicted to be exist in nature, are capable of inducing extremely rapid apoptosis in leukemia cells. The researchers are in the process of studying their biological mechanism of action.

"Insufficient apoptosis is strongly linked to cancer and autoimmune disorders," Wu says. "There are also numerous diseases associated with excessive cell death, such as AIDS, Alzheimer's, Huntington's, Parkingson's and ALS. A better understanding of the biological basis of how the dimeric nuphar alkaloids can so rapidly induce cell death may lead to novel points of intervention for the design of prospective therapeutics and other diseases attributed to abnormal apoptosis."

Source:

Dartmouth College

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por cyto às 22:57

Terça-feira, 21.07.15

Patients' own genetically engineered immune cells show significant success against multiple myeloma

 

Patients' own genetically engineered immune cells show significant success against multiple myeloma

Published on July 21, 2015 at 2:37 AM 

In recent years, immunotherapy has emerged as a promising treatment for certain cancers. Now this strategy, which uses patients' own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable. The results appeared in a study published online today in Nature Medicine.

Patients received an infusion of altered immune cells known as T-cells - roughly 2.4 billion of them - after undergoing a stem cell transplantation of their own stem cells. In 16 of 20 patients with advanced disease, there was a significant clinical response. The scientists found that the T-cell therapy was generally well-tolerated and that modified immune cells traveled to the bone marrow, where myeloma tumors typically are found, and showed a long-term ability to fight the tumors. Relapse was generally associated with a loss of the engineered T-cells.

"This study suggests that treatment with engineered T-cells is not only safe but of potential clinical benefit to patients with certain types of aggressive multiple myeloma," says first author Aaron P. Rapoport, MD, the Gary Jobson Professor in Medical Oncology at the University of Maryland School of Medicine. "Our findings provide a strong foundation for further research in the field of cellular immunotherapy for myeloma to help achieve even better results for our patients."

The trial is the first published use of genetically modified T-cells for treating patients with multiple myeloma. The approach has been used to treat leukemia as well as lymphoma, according to Dr. Rapoport, who is the Director of the Blood and Marrow Transplant Program at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.

More than 77,000 people in the United States have multiple myeloma, with about 24,000 new cases diagnosed each year. Patients are treated with chemotherapy and in many cases an autologous stem cell transplant, but long-term response rates are low, and median survival is three to five years.

"The majority of patients who participated in this trial had a meaningful degree of clinical benefit," Dr. Rapoport notes. "Even patients who later relapsed after achieving a complete response to treatment or didn't have a complete response had periods of disease control that I believe they would not have otherwise experienced. Some patients are still in remission after nearly three years."

The research is a collaboration between the University of Maryland School of Medicine, the Perelman School of Medicine at the University of Pennsylvania and Adaptimmune, a clinical stage biopharmaceutical company which owns the core T-cell receptor technology and funded the study. Dr. Rapoport and co-authors Edward A. Stadtmauer, MD, of the University of Pennsylvania Abramson Cancer Center, and Gwendolyn K. Binder-Scholl, PhD, of Adaptimmune, contributed equally to the research. Dr. Rapoport is the study's principal investigator.

In the clinical study, patients' T-cells were engineered to express an affinity-enhanced T-cell receptor (TCR) specific for a type of tumor antigen, or protein, known as a cancer-testis antigen (CT antigen). The target CT antigens were NY-ESO-1 and LAGE-1. Up to 60 percent of advanced myelomas have been reported to express NY-ESO-1 and/or LAGE-1, which correlates to tumor proliferation and poorer outcomes. According to Adaptimmune, the trial is the first published study of lentiviral vector mediated TCR gene expression in humans.

Of the 20 patients treated, 14 (70 percent) had a near complete or complete response three months after treatment. Median progression-free survival was 19.1 months and overall survival was 32.1 months. Two patients had a very good partial response three months post treatment. Half the patients were treated at the University of Maryland Greenebaum Cancer Center and half at the University of Pennsylvania Abramson Cancer Center. Researchers note that the response rate was better than would be expected for a standard autologous stem cell transplant. In addition, patients did not experience side effects which have been associated with another type of genetically engineered T-cells (chimeric antigen receptors, or CARS) used to treat other cancers.

The study was originally developed by Carl H. June, MD, of the University of Pennsylvania Abramson Cancer Center, and Dr. Rapoport, who have been research collaborators for 18 years.

"Multiple myeloma is a treatable but largely incurable cancer. This study reveals the promise that immunotherapy with genetically engineered T-cells holds for boosting the body's ability to attack the cancer and provide patients with better treatments and control of their disease," says E. Albert Reece, MD., PhD, MBA, vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine. "This trial is also an excellent example of significant scientific advances that result from collaborations between academic medical institutions and private industry."

Source:

University of Maryland Medical Center

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por cyto às 18:10

Quinta-feira, 25.06.15

Acute Lymphoblastic Leukemia, Blood, Blood Cancer, Blood Disorder, Bone, Bone Marrow, Cancer, Cardiology, Cell, DNA, Education, Gene, Genetic, Genetics, Hematology, Hospital, Leukemia, Neurology, Neurosurgery, Oncology, Pediatrics, Platelets, Thrombocytop

Researchers track down key gene mutation responsible for causing acute lymphoblastic leukemia

Published on June 18, 2015 at 8:52 AM ·

After collecting data on a leukemia-affected family for nearly a decade, Children's Hospital of Michigan, Detroit Medical Center (DMC), Hematologist and Wayne State University School of Medicine Professor of Pediatrics Madhvi Rajpurkar, M.D., joined an international team of genetic researchers in an effort to track down a mutation partly responsible for causing the disease. Their findings, recently published in one of the world's leading science journals, have "major implications" for better understanding the genetic basis of several types of cancer, including leukemia.

Says Children's Hospital of Michigan Hematology/Oncology Researcher and Wayne State University Assistant Professor of Pediatrics Michael Callaghan, M.D., an investigator who co-authored the recently published study in Nature Genetics: "This is a very exciting new finding in cancer research - and I think a lot of the credit has to go to Dr. Rajpurkar for identifying the family (with the genetic mutation). This is a great example of how an astute clinician can help accomplish a breakthrough in research by paying careful attention to patients and then thinking long and hard about what she is seeing in the treatment room."

Two medical researchers from the Children's Hospital of Michigan and the Wayne State University School of Medicine have published the results of a nearly 10-year investigation that identified a key gene mutation that can trigger acute lymphoblastic leukemia, or ALL, and several other types of cancer.

Recently published in Nature Genetics, the findings assembled by the Children's Hospital of Michigan and Wayne State University School of Medicine duo and a team of international investigators have for the first time pinpointed a mutation that allows a lymphoblastic leukemia "precursor" to set the biochemical stage for the blood disorder.

ALL is a blood cancer that attacks an early version of white blood cells manufactured in bone marrow. Investigators have long suspected that it is caused in part by a mutation in a gene that is supposed to "turn off" excessive blood-cell growth. When the mutation suppresses the controlling mechanism that regulates the runaway growth, leukemia is often the result.

The study, "Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia," began nearly a decade ago when Dr. Rajpurkar treated a child at the Children's Hospital of Michigan for low blood platelets, known medically as "congenital thrombocytopenia." When both the child and an aunt later developed ALL - even as several other family members were diagnosed with thrombocytopenia - Dr. Rajpurkar began to suspect that there might be a genetic mutation at work in the family.

What followed was a 10-year journey through the labyrinth of the Human Genome, as the researchers worked with a growing number of genetic investigators to isolate and identify the mutation in a gene (ETV6) that regulates growth rates in bone marrow.

A key breakthrough in the quest for the genetic culprit took place when a nationally recognized expert in gene mutation - University of Colorado physician-researcher Jorge DiPaola, M.D. - joined Drs. Rajpurkar and Callaghan, and other investigators from Italy and Canada, in the effort to solve the DNA puzzle by uncovering the flaw in ETV6. The mutation discovery occurred in a core facility where the gene-sequencing took place.

While noting that "our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition," the study's authors concluded that the mutation occurs through "aberrant cellular localization" of the gene, which can result in "decreased transcriptional repression" during white blood cell formation.

"What we think that means," Dr. Callaghan said, "is that ETV6's job is to 'turn off' growth, but when you have this mutation, it can't turn it off because it's in the wrong place. It's usually supposed to sit on the DNA and keep things (including cancer) from getting made, but when you have this mutation, instead of sitting on the DNA it's sitting in a different part of the cell.... And that predisposes you to getting a (blood) cancer."

Dr. Rajpurkar, who is also the division chief of Hematology at the Children's Hospital of Michigan and an associate professor of Pediatrics at the Wayne State University School of Medicine, said she was "greatly pleased" that her decade of treating the Detroit family with the mutation eventually led to the breakthrough. "I told them that I didn't know what the family had," she said, "but that I would do my best to find out. Sometimes one has to accept uncertainty in the field of medicine, but (persistence in clinical research) pays off!"

The Children's Hospital of Michigan Pediatrician-in-Chief and chair of the Wayne State University School of Medicine Department of Pediatrics Steven E. Lipshultz, M.D., said the breakthrough was "hugely important" because it resulted in "a new association (between a genetic mutation and leukemia) that can now be scanned for.

"Because of this finding," he added, "families will eventually be counseled regarding their risk for some kinds of cancer and targeted interventions will be devised and tested."

Dr. Lipshultz also noted that the new findings in "what many physicians and researchers regard as the leading journal in the world on the molecular genetic basis of human disease" also provide "an exciting and extremely encouraging example of how research that takes place in the clinical setting can greatly improve care for patients.

"Our goal at the Children's Hospital of Michigan is to do everything we can to help achieve better outcomes for the patients we serve. This latest publication by two CHM physician-researchers and their colleagues underlines the vitally important links between treatment and research, and to see them demonstrated so compellingly inNature Genetics is quite thrilling for all of us who spend our days trying to help kids at the Children's Hospital of Michigan!"

Source:

Wayne State University - Office of the Vice President for Research

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por cyto às 11:49


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