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Domingo, 25.10.15

immune cells

Immunology

A clear view of immune cells

A mouse strain gives the most detailed visualization yet of immune cells in the bone marrow

Published online Oct 21, 2015

A*STAR researchers have generated a new reporter mouse strain that can be used to examine the behavior of monocytes in the bone marrow over time. The fluorescent tagging of monocytes in the mice allows clear imaging of the cells using multiphoton intravital microscopy.

A*STAR researchers have generated a new reporter mouse strain that can be used to examine the behavior of monocytes in the bone marrow over time. The fluorescent tagging of monocytes in the mice allows clear imaging of the cells using multiphoton intravital microscopy.

© 2015 A*STAR Singapore Immunology Network

White blood cells called monocytes, that play a vital role in stable immune responses, can now be visualized over time inside the bone marrow using a new reporter mouse developed by A*STAR researchers1.

Monocytes mediate inflammation and trigger the body’s defense mechanism in response to injury and disease. From the bone marrow, monocytes are sent out into the bloodstream, where they differentiate into tissue macrophages — large cells that ‘consume’ pathogens. This process is accelerated during disease or infection, and its disruption is implicated in inflammatory diseases such as cancer.

Despite their critical role, little is known about how monocytes are recruited and mobilized in the body. The ability to view monocytes leaving the bone marrow over time would be invaluable (see image and video). To achieve this goal, A*STAR researcher Lai Guan Ng at the Singapore Immunology Network, and co-workers from institutions across Singapore, adopted multiphoton intravital microscopy, a deep-tissue imaging technique that picks up signals from the fluorescent tagging of specific cell types.

“Current approaches track monocyte recruitment using cell counting methods, and only provide static snapshots of what is happening,” explains Ng. “In contrast, multiphoton intravital microscopy can monitor individual cells over time, revealing critical details and providing a comprehensive picture of the entire biological process.”

Ng and his team tested three genetically-modified mice to determine the best reporter mouse for tracking monocytes. One of the mice, labeled Cx3cr1gfp/+, produced reasonable images of cell activity in the bone marrow. Dendritic cells — immunity messenger cells — were also tagged by the same fluorescent marker, leading to an unclear confused signal and difficulty in singling out individual monocytes.

“We realized we needed to create a new reporter mouse that labels fewer dendritic cells,” says Ng. “We crossed the Cx3cr1gfp/+ reporter mouse with another strain that produces less dendritic cells. Using this crossbred mouse, we could visualize the monocytes in greater detail than ever before.”

The team found that most monocytes mobilized in response to a trigger signal, such as molecules on the surface of bacteria. Some monocytes were unable to leave the bone marrow however, indicating a retention mechanism is at play. This mechanism may provide a pharmacological target that could mobilize cells from the bone marrow.

“Our approach could help us understand monocyte behavior in multiple diseases and metabolic conditions,” says Ng. “It may also prove a powerful tool to address the efficacy of drugs targeting monocyte mobilization, and may be applied to other cell types involved in immunity in the future.”

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network

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por cyto às 19:04

Domingo, 25.10.15

ASCO Releases Guideline Updates for the Use of Colony-stimulating Factors

ASCO Releases Guideline Updates for the Use of Colony-stimulating Factors

ASCO updates Clinical Practice Guidelines for the use of hematopoietic colony-stimulating factors.
ASCO updates Clinical Practice Guidelines for the use of hematopoietic colony-stimulating factors.

The American Society of Clinical Oncology (ASCO) has released an updated version of its Clinical Practice Guidelines on the use of hematopoietic colony-stimulating factors (CSFs), a treatment option for neutropenia, which is a major complication of myelosuppressive chemotherapy.

The updates were based on a systematic review of randomized clinical trials, meta-analyses, and systematic reviews conducted between October 2005 and September 2014 and are intended to address the limitations and strengths of using CSFs in clinical practice.1

Key guideline recommendations include:

• In patients with a greater than 20% risk of febrile neutropenia, primary prophylaxis with CSF with first and subsequent cycles of chemotherapy is recommended. The guidelines also note that regimens that do not require CSF and are equally effective should be considered as well.
• In patients with a neutropenic complication from a previous cycle of chemotherapy (without primary prophylaxis) and reduction or delay in treatment would alter outcome/survival, CSF is recommended for secondary prophylaxis. The authors note, however, that a reduction/delay may be reasonable in many situations.
• In patients with afebrile neutropenia, CSFs should not be used routinely.
• Adjunctive treatment of CSFs with antibiotics should not be routinely used for patients with febrile neutropenia. However, patients with febrile neutropenia who are considered at risk for poor outcomes or infection related-complications may be considered for adjunctive treatment with CSFs.
• The authors note that use of CSF with dose-dense regimens should only be considered when involved in a well-designed clinical trial or with support of convincing efficacy data.
• In order to mobilize peripheral-blood progenitor cells, CSFs may be used with plerixafor, after chemotherapy, or alone.
• To lessen the duration of severe neutropenia, CSFs should be given after autologous stem-cell transplants.
• To lessen the duration of severe neutropenia, CSFs may be given after allogeneic stem-cell transplants. Since the 2006 update, reports of increased risk of grade 2 to 4 graft-versus-host disease with CSF use after allogeneic transplantation have not been confirmed. The researchers note that the benefits seem to be modest with the limited amount of data.
• Patients age 65 or older, particularly those with comorbidities, with aggressive forms of diffuse lymphoma treated with curative chemotherapy should be considered for CSF prophylaxis.
• In pediatric patients, CSFs for primary prophylaxis is considered reasonable in patients at high risk for febrile neutropenia. Likewise, the guidelines note that secondary prophylaxis should be limited to patients who are high risk.
• CSFs should be used in pediatric patients to facilitate dose-intense chemotherapy regimens that are known to have survival benefits (Ewing sarcoma).
• The guidelines do not recommend using CSFs in nonrelapsed acute myeloid leukemia or nonrelapsed acute lymphocytic leukemia in pediatric patients without infection.
• There were no additional data to support a change in recommendation on treatment choice for treatment-related neutropenia. Patient's clinical situation, convenience, and cost are factors considered in the agent choice.
• The authors note a moderate recommendation for use of CSFs or pegylated granulocyte CSFs in patients exposed to lethal doses of total-body radiotherapy without evidence of impending death from organ injury.


The authors highlight the evidence that comorbid conditions increase the risk of febrile neutropenia in patients treated with chemotherapy.

 

RELATED: Consider Febrile Neutropenia Risk When Administering Standard Treatment in Prostate Cancer

Furthermore, when taking into account age and type of cancer, a patient's comorbidities continue to be an important predictor for febrile neutropenia.

Finally, the authors note that granulocyte-CSFs are expensive and questions remain to be answered on cost effectiveness. However, it is emphasized that choice of agent should be guided by the clinical scenario, not cost.

Reference

  1. Smith T, Bohlke K, Lyman G, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol.  July 13, 2015. [epub ahead of print] doi: 10.1200/JCO.2015.62.3488.

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por cyto às 19:03

Domingo, 25.10.15

BRCA1 Gene Expression May be Biomarker for Survival in Glioblastoma Multiforme

BRCA1 Gene Expression May be Biomarker for Survival in Glioblastoma Multiforme

BRCA1 protein expression may be an important predictive biomarker of overall survival in glioblastoma multiforme.
BRCA1 protein expression may be an important predictive biomarker of overall survival in glioblastoma multiforme.

Breast cancer type 1 susceptibility gene (BRCA1) protein expression may be an important predictive biomarker of overall survival in patients with glioblastoma multiforme (GBM), according to a study presented at the American Society for Radiation Oncology (ASTRO) 56th annual meeting in San Antonio, TX.

Researchers led by Maria Vasilakopoulou, MD, PhD, of the Pitié-Salpêtrière Hospital in Paris, France, analyzed tissue microarrays from archived GBM tumors from 66 patients who participated in the Radiation Therapy Oncology Group (RTOG) clinical trials in order to determine any association with the expression and prognostic significance of 4 molecular biomarkers.

Observed patients had similar overall survival and were treated with surgery, radiation, and non-temozolomide chemotherapy.

“Among the 4 biomarkers assessed, only BRCA1 protein expression had a statistically significant correlation with overall survival,” said Dr. Vasilakopoulou.

Patients with low tumor BRCA1 protein expression were found to have a median survival time of 18.9 months compared to those with high expression of the protein who had 4.8 months.

 

RELATED: Accelerated Partial Breast Not Inferior to Whole-breast Irradiation Following Surgery

“The study results suggest strongly that low BRCA1 protein expression in the GBM tumor, and the consequent low DNA repair, causes the cancer cells to be more susceptible to DNA-damaging cancer treatment,” said Dr. Vasilakopoulou.

She concluded that patients identified as high expressers could be treated with agents that downregulate BRCA1 in order to sensitize them to other cytotoxic therapies.

Reference

  1. BRCA1 expression in glioblastoma multiforme tumors predicts patient survival [press release]. NRG Oncology; October 21, 2015; http://www.eurekalert.org/pub_releases/2015-10/no-bei101615.php. Accessed October 23, 2015.

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por cyto às 18:56

Domingo, 18.10.15

Tumor Grade

Tumor Grade (Fact Sheet)

Tumor grade is the description of a tumor based on how abnormal the tumor cells and the tumor tissue look under a microscope. It is an indicator of how quickly a tumor is likely to grow and spread. If the cells of the tumor and the organization of the tumor's tissue are close to those of normal cells and tissue, the tumor is called “well-differentiated.” These tumors tend to grow and spread at a slower rate than tumors that are “undifferentiated” or “poorly differentiated,” which have abnormal-looking cells and may lack normal tissue structures. Based on these and other differences in microscopic appearance, doctors assign a numerical “grade” to most cancers. The factors used to determine tumor grade can vary between different types of cancer.

Tumor grade is not the same as the stage of a cancer. Cancer stage refers to the size and/or extent (reach) of the original (primary) tumor and whether or not cancer cells have spread in the body. Cancer stage is based on factors such as the location of the primary tumor, tumor size, regional lymph node involvement (the spread of cancer to nearby lymph nodes), and the number of tumors present. More information about staging is in the NCI fact sheet Cancer Staging.

How is tumor grade determined?

If a tumor is suspected to be malignant, a doctor removes all or part of it during a procedure called a biopsy. A pathologist (a doctor who identifies diseases by studying cells and tissues under a microscope) then examines the biopsied tissue to determine whether the tumor is benign or malignant. The pathologist also determines the tumor's grade and identifies other characteristics of the tumor. The NCI fact sheet Pathology Reports describes the type of information that can be found in a pathologist's report about the visual and microscopic examination of tissue removed during a biopsy or other surgery.

How are tumor grades classified?

Grading systems differ depending on the type of cancer. In general, tumors are graded as 1, 2, 3, or 4, depending on the amount of abnormality. In Grade 1 tumors, the tumor cells and the organization of the tumor tissue appear close to normal. These tumors tend to grow and spread slowly. In contrast, the cells and tissue of Grade 3 and Grade 4 tumors do not look like normal cells and tissue. Grade 3 and Grade 4 tumors tend to grow rapidly and spread faster than tumors with a lower grade.

If a grading system for a tumor type is not specified, the following system is generally used (1):

  • GX: Grade cannot be assessed (undetermined grade)
  • G1: Well differentiated (low grade)
  • G2: Moderately differentiated (intermediate grade)
  • G3: Poorly differentiated (high grade)
  • G4: Undifferentiated (high grade)  

What are some of the cancer type-specific grading systems?

Breast and prostate cancers are the most common types of cancer that have their own grading systems.

Breast cancer. Doctors most often use the Nottingham grading system (also called the Elston-Ellis modification of the Scarff-Bloom-Richardson grading system) for breast cancer (1). This system grades breast tumors based on the following features:

  • Tubule formation: how much of the tumor tissue has normal breast (milk) duct structures
  • Nuclear grade: an evaluation of the size and shape of the nucleus in the tumor cells
  • Mitotic rate: how many dividing cells are present, which is a measure of how fast the tumor cells are growing and dividing

Each of the categories gets a score between 1 and 3; a score of “1” means the cells and tumor tissue look the most like normal cells and tissue, and a score of “3” means the cells and tissue look the most abnormal. The scores for the three categories are then added, yielding a total score of 3 to 9. Three grades are possible:

  • Total score = 3–5: G1 (Low grade or well differentiated)
  • Total score = 6–7: G2 (Intermediate grade or moderately differentiated)
  • Total score = 8–9: G3 (High grade or poorly differentiated)

Prostate cancer. The Gleason scoring system is used to grade prostate cancer (1). The Gleason score is based on biopsy samples taken from the prostate. The pathologist checks the samples to see how similar the tumor tissue looks to normal prostate tissue. Both a primary and a secondary pattern of tissue organization are identified. The primary pattern represents the most common tissue pattern seen in the tumor, and the secondary pattern represents the next most common pattern. Each pattern is given a grade from 1 to 5, with 1 looking the most like normal prostate tissue and 5 looking the most abnormal. The two grades are then added to give a Gleason score. The American Joint Committee on Cancer recommends grouping Gleason scores into the following categories (1):

  • Gleason X: Gleason score cannot be determined
  • Gleason 2–6: The tumor tissue is well differentiated
  • Gleason 7: The tumor tissue is moderately differentiated
  • Gleason 8–10: The tumor tissue is poorly differentiated or undifferentiated

How does tumor grade affect a patient's treatment options?

Doctors use tumor grade and other factors, such as cancer stage and a patient's age and general health, to develop a treatment plan and to determine a patient's prognosis (the likely outcome or course of a disease; the chance of recovery or recurrence). Generally, a lower grade indicates a better prognosis. A higher-grade cancer may grow and spread more quickly and may require immediate or more aggressive treatment.

The importance of tumor grade in planning treatment and determining a patient's prognosis is greater for certain types of cancer, such as soft tissue sarcoma, primary brain tumors, and breast and prostate cancer. 

Patients should talk with their doctor for more information about tumor grade and how it relates to their treatment and prognosis.

Selected References

1. American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.

SOURCE: NCI

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por cyto às 11:48


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