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Quarta-feira, 29.07.15

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


ASCO Releases Guideline Updates for the Use of 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.


  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 18:56

Quarta-feira, 29.07.15

Frequent, Actionable MET Gene Mutations Found in Pulmonary Sarcomatoid Carcinoma


Frequent, Actionable MET Gene Mutations Found in Pulmonary Sarcomatoid Carcinoma

Mutational events that lead to MET exon 14 skipping may be targetable events in pulmonary sarcomatoid carcinoma.
Mutational events that lead to MET exon 14 skipping may be targetable events in pulmonary sarcomatoid carcinoma.

Mutational events that lead to MET exon 14 skipping occur frequently and may be targetable events in patients with pulmonary sarcomatoid carcinoma (PSC), according to a recent study published online ahead of print in the Journal of Clinical Oncology.

Balazs Halmos, MD, of Columbia University Medical Center, in New York, NY, and fellow researchers conducted whole-exome sequencing as well as targeted METmutation screening in patients with PSC in order to further understand molecular pathogenesis of the disease.

With regard to MET exon 14 skipping,, which was validated through reverse transcriptase polymerase chain reaction and Western blotting , they also performed functional studies for validation of its oncogenic roles in lung adenosquamous cell line H596 as well as gastric adenocarcinoma cell line Hs746T.

The researchers found and validated several novel mutations in genes that had since been unknown to be cancer-associated, including RASA1, CDH4, CDH7, LAMB4, SCAF1, and LMTK2. They also confirmed mutations in genes that were previously known, such as TP53, KRAS, PIK3CA, MET,NOTCH, STK11, and RB1.


RELATED: Greatest EGFR Prevalence in Women with Adenocarcinoma with No Smoking History

Mutations that led to exon 14 skipping were identified in eight out of 36 patient cases.

Furthermore, RNA silencing of MET and MET inhibition with crizotinib demonstrated an effect on cell viability and a decrease in downstream AKT and mitogen-activated protein kinase activation inHs746T and Hh596.


  1. Liu X, Jia Y, Stoopler MB, et al. Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations. Journal of Clinical Oncology. 2015. [epub ahead of print]. doi: 10.1200/JCO.2015.62.0674.

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por cyto às 18:51

Quarta-feira, 29.07.15

Brain - Reaching the right size


Brain - Reaching the right size

Mutations in a protein involved in neuronal proliferation and survival cause extreme brain malformations and atrophy

Published online 29 July 2015

Magnetic resonance image of the brain of an individual with the brain formation disorder microlissencephaly.

Reprinted from Ref. 1, Copyright 2014, with permission from Elsevier.

A gene responsible for a severe form of the brain formation disorder microlissencephaly has been identified by A*STAR scientists through a collaboration with researchers in seven countries1.

Microlissencephaly is a neuronal development disorder characterized by smaller brains having fewer neurons than normally developed brains (see image). Researchers, including Bruno Reversade from the A*STAR Institute of Medical Biology, identified three Middle Eastern families with children affected by the disorder who did not have mutations in any of the genes already known to cause microlissencephaly. Because some of the families had a history of marriages between closely related individuals, such as first cousins, the causative gene was believed to be passed on by both parents. By sequencing regions that were identical in the affected individuals of a particular family, the researchers were able to home in on mutations in the KATNB1 gene, as these mutations were absent in unaffected individuals in other populations.

The protein encoded by KATNB1 is part of a complex responsible for severing structural proteins in the cell called microtubules. A structure called the centrosome is known to play a central role in organizing microtubules in the cell, and many centrosomal proteins have previously been linked to patients with microlissencephaly.

To determine the function of KATNB1 during development, Reversade and his colleagues generated mice and fish lacking the Katnb1 gene — the mouse and fish analogue of KATNB1. The animal models showed defective proliferation of neuronal progenitor cells, loss of many cell types that rely on normal cell division, enhanced cell death and thinner brains. Also, cells derived from humans with microlissencephaly showed many abnormalities in cell division, such as centromeres that were abnormally placed, chromosomes that did not line up properly and cells with too many chromosomes.

Centromeres are made up of paired structures called centrioles and play a key role in forming hair-like extensions of the cell called cilia. The researchers found that cells from mice lackingKatnb1 contained many more centrioles than normal cells and that these centrioles were often unpaired. Moreover, the cells lacking this gene contained many more cilia than normal, which the researchers argue could mean that signaling regulated by cilia is defective. These dysfunctional processes probably contribute to the abnormal neuronal development observed in organisms lacking KATNB1.

“Our discovery of the causative gene for this disease will benefit families as we are now able to provide premarital and prenatal diagnosis for parents,” explains Reversade.


The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology and the Institute of Molecular and Cellular Biology. More information about the group’s research can be found at theHuman Genetics and Embryology Group webpage.


Related Links

Developmental biology: How a protein collaboration builds the brain

Molecular biology: Fragile interactions and brain function

Cell biology: Taking advantage of defects in splicing




  1. Hu, W. F., Pomp, O., Ben-Omran, T., Kodani, A. & Henke, K. et al. Katanin p80 regulates human cortical development by limiting centriole and cilia number. Neuron 84, 1240–1257 (2014). | article

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por cyto às 11:41

Quarta-feira, 29.07.15

A speedy test for bladder cancer


A speedy test for bladder cancer

A novel assay for screening urinary biomarkers employs two advanced technologies

Published online 14 January 2015

Schematic representation of antigens (red) binding onto antibody-conjugated osmium carbonyl clusters (green and purple) on bimetallic film over nanoparticles (yellow).

© 2014 A*STAR Singapore Bioimaging Consortium

A fast and accurate urine test for bladder cancer developed by A*STAR researchers has the potential to replace the currently used invasive physical probe.

Cystoscopy — a clinical procedure that uses a narrow, tubular optical instrument called a cystoscope to view inside the bladder — is currently the gold standard for detecting cancer in this organ. However, the technique is not favored by most patients because it is invasive, expensive and time consuming.

Malini Olivo at the A*STAR Singapore Bioimaging Consortium and co-workers have now developed a rapid immunoassay to detect and quantify alpha-1 antitrypsin (A1AT)1, a recently discovered urinary antigen and a potential biomarker for bladder cancer. The new tool could be used as a high-throughput screening platform to identify patients at risk of developing the urologic condition.

The immunoassay employs two advanced technologies, namely surface-enhanced Raman scattering (SERS), a powerful spectroscopic technique for detecting analytes at low concentrations, and bimetallic film over nanoparticles, a planar substrate for enhancing SERS signals. Together these technologies help to overcome interfering signals from the matrix background such as proteins in urine. The bimetallic film over nanoparticles is also coated with osmium carbonyl clusters to which target-seeking antibodies can be conjugated for assaying A1AT (see image).

The researchers first tested the immunoassay on a series of standard solutions containing A1AT antigens at various concentrations in the range 10 to 1,000 nanograms per milliliter. They observed a ‘fingerprint’ of A1AT antigens — a spectral change in the 1,850 to 2,130 cm−1 region that increases with concentration.

The scientists then tried the immunoassay on urine samples from nine patients. They found significantly elevated levels of A1AT in bladder cancer patients. There was also a marked difference in the A1AT concentrations of cancer and non-cancer patients, which suggests that the technique is highly discriminative, specific and accurate. Importantly, only tiny amounts of sample were required: A1AT concentrations could be quantified using as little as ten microliters of urine.

Compared to conventional immunoassays, the SERS-based bioassay has two practical advantages: the low-volume sample requires no purification prior to testing and the device has a simple design.

With further developments, the device may help save the lives of millions of would-be patients.

“We have developed a smart SERS biosensor for the rapid screening of bladder cancer,” says Olivo. “Our device is extremely versatile because, in theory, the osmium carbonyl clusters can be swapped with other metal carbonyl species to account for different needs and purposes.”


The A*STAR-affiliated researchers contributing to this research are from the Singapore Bioimaging Consortium. More information about the group’s research can be found at the Bio-optical Imaging Group webpage.


Related Links 

Medical diagnostics: Sweet sensing

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  1. Kong, K. V., Leong, W. K., Lam, Z., Gong, T., Goh, D. et al. A rapid and label-free SERS detection method for biomarkers in clinical biofluids. Small 10, 5030–5034 (2014). | article

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por cyto às 11:37

Quarta-feira, 29.07.15

Imaging probe yields double insight


Imaging probe yields double insight

A probe enables tumors to be investigated using complementary imaging techniques

Published online 29 July 2015

A new probe enables multimodal imaging based on photoacoustic imaging and surface-enhanced Raman scattering for studying cancer in living mice.

© vitanovski/iStock/Thinkstock

An organic dye that can light up cancer cells for two powerful imaging techniques providing complementary diagnostic information has been developed and successfully tested in mice by A*STAR researchers1.

Imaging tumors is vitally important for cancer research, but each imaging technique has its own limitations for studying cancer in living organisms. To overcome the limitations of individual techniques, researchers typically employ a combination of various imaging methods — a practice known as multimodal imaging. In this way, they can obtain complementary information and hence a more complete picture of cancer.

Two very effective methods for imaging tumors are photoacoustic imaging and surface-enhanced Raman scattering (SERS). Photoacoustic imaging can image deep tissue with a good resolution, whereas SERS detects miniscule amounts of a target molecule. To simultaneously use both photoacoustic imaging and SERS, a probe must produce signals for both imaging modalities.

In multimodal imaging, researchers typically combine probes for each imaging modality into a single two-molecule probe. However, the teams of Malini Olivo at the A*STAR Singapore Bioimaging Consortium and Bin Liu at the A*STAR Institute of Materials Research and Engineering, along with overseas collaborator Ben Zhong Tang from the Hong Kong University of Science and Technology, adopted a different approach — they developed single-molecule probes that can be used for both photoacoustic imaging and SERS. The probes are based on organic cyanine dyes that absorb near-infrared light, which has the advantage of being able to deeply penetrate tissue, enabling tumors deep within the body to be imaged.

Once the team had verified that the probes worked for both imaging modalities, they optimized the performances of the probes by adding gold nanoparticles to them to amplify the SERS signal and by encapsulating them in the polymer polyethylene glycol to stabilize their structures.

The researchers then deployed these optimized probes in live mice. By functionalizing the probes with an antibody that recognizes a tumor cell-surface protein, they were able to use them to target tumors. The scientists found that, in photoacoustic imaging, the tumor-targeted probes produced signals that were roughly three times stronger than those of unmodified probes. Using SERS, the team was also able to monitor the concentrations of the probes in the tumor, spleen and liver in real time with a high degree of sensitivity.

U. S. Dinish, a senior scientist in Olivo’s group, recalls the team’s “surprise at the sensitivity and potential of the nanoconstruct.” He anticipates that the probe could be used to guide surgical removal of tumors.


The A*STAR-affiliated researchers contributing to this research are from the Singapore Bioimaging Consortium and the Institute of Materials Research and Engineering


Related Links

Bioimaging: Exposing breast cancer using nanoscale polymers

Bioassays: A speedy test for bladder cancer

Nanoparticles: Shaken, not stirred, is best for cancer imaging 



  1. Dinish, U. S., Song, Z., Ho, C. J. H., Balasundaram, G., Attia, A. B. E. et al. Single molecule with dual function on nanogold: Biofunctionalized construct for in vivo photoacoustic imaging and SERS biosensing. Advanced Functional Materials 25, 2316–2325 (2015). | article

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por cyto às 11:26

Quarta-feira, 29.07.15

Cannabis May Reduce Pain in Diabetic Peripheral Neuropathy


Inhaling Cannabis May Reduce Pain in Diabetic Peripheral Neuropathy


Patients diagnosed with diabetic peripheral neuropathy may have an alternative treatment to managing pain if dosages are examined more closely -- medical cannabis. 

About 50% of patients with diabetes are suffering from diabetic peripheral neuropathy, which can be present in a multiple forms.1 Some common symptoms include: hyperalgesia, numbness, paresthesia, sensitivity to touch, unsteadiness and weakness.

Published in the Journal of Pain, a new study revealed that inhaling cannabis relieves pain resulting from neuropathy — but there's a catch.2

Researchers found that there's a dose-dependant reduction in pain. Higher doses caused more sedation and euphoria in patients suffering from diabetic peripheral neuropathy pain.2

"There is some uncertainty regarding the dosing range that results in analgesia after administration of cannabis," the authors wrote in the study.

Study author Mark Steven Wallace, MD, told Clinical Pain Advisor that “there have been very few studies looking at different doses.”

"Most studies used single doses with inconsistencies between results," said Wallace, chair of the Division of Pain Medicine in the Department of Anesthesiology at UCSanDiego Health, an academic health system. "One study using experimental pain in healthy volunteers showed that medium doses of cannabis were effective in relieving pain whereas high doses actually increased pain."

In Wallace's randomized, double-blinded, placebo-controlled crossover study, researchers sampled 16 patients with  diabetic peripheral neuropathy to analyze both the tolerability and short-term efficacy of inhaled cannabis.

Each participant was exposed to placebo or cannabis in four sessions, separated by two weeks. Dosage amounts varied for those who were administered aerosolized cannabis. Researchers gave participants a low (1% THC), medium (4% THC), or high (7% THC) dose of cannabis. Pain intensity and subject "highness" scores were measured at various intervals. Researchers measured highness by asking participants to rank how "high" they felt on a 10-point scale (0 being "not high at all").

"It is unclear on the balance between the positive (pain relieving effects) and the negative," Wallace noted. "However, there was actually minimal effects on psychomotor testing."

His team measured psychomotor speed, attention and cognitive sequencing using what's known as the Trail Making Test, a neuropsychological test consisting of visual attention and task switching. Researchers, using the Paced Auditory Serial Attention Test (PASAT), also measured participant attention, working memory and information processing speed.

"Cannabis does not treat the underlying disease process of diabetic neuropathy,” he said. “It will not prevent the progression of the disease nor will it reverse the process. It only relieves the pain that results from the neuropathy.

As for pain specialists using medical marijuana for chronic pain, many questions still remain. What can this treatment be used for? Up until May of this year, about 15 trials of medical cannibinoids have been conducted worldwide. These findings indicated effectiveness in reducing pain in patients with cancer, diabetes, fibromyalgia and neuropathy.

One lingering question that hasn't been answered: Should physicians be allowed to prescribe medical cannabis to children? While nearly 65% of Americans approve of medical marijuana use for adults, only 36% agree that medical marijuana should be available for children, according to one report.3 The majority of survey respondents also noted that medical cannabis should not be used in front of children who are under the age of 18. When children do use the drug, however, it's typically not inhaled -- it's normally available in liquid, non-psychoactive form, such as the cannabinoid cannabidiol (CBD).

More recently, a recent study in JAMA concluded that there was moderate-quality evidence suggesting that cannabinoids could benefit those with chronic neuropathic or cancer pain. The study also revealed, however, that there was low-quality evidence for no effect on psychosis. There was very low-level evidence that cannabinoids affected depression.

"More studies are needed on chronic delivery," Wallace said. "And more studies are needed on cannabidiol (the non psychoactive component of marijuana). Our study used cannabis that had very low levels of cannabidiol."


  1. Tesfaye S, et al. Painful Diabetic Polyneuropathy. 2015; doi: 10.1007/978-1-4614-6299-6_13.
  2. Wallace M, et al. J. Pain. 2015; doi: 10.1016/j.jpain.2015.03.008.
  3. Most Americans say medical marijuana shouldn't be used by kids or in front of kids – legal or not | University of Michigan Health System. 2015. Accessed July 22, 2015.

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por cyto às 11:21

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Julho 2015