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Quinta-feira, 13.08.15

Telomere length may aid in predicting lung cancer risk

Telomere length may aid in predicting lung cancer risk


Individuals with long telomeres are at increased risk for lung adenocarcinoma but not other types of cancer.
Individuals with long telomeres are at increased risk for lung adenocarcinoma but not other types of cancer.

Individuals with long telomeres are at increased risk for lung adenocarcinoma but not other types of cancer, according to a study published in Human Molecular Genetics.

Researchers analyzed genetic data from 51,725 cancer patients and 62,035 people without cancer to learn more about the links between telomere length and the risk of five types of cancer: breast, lung, colorectal, ovarian, and prostate.

The team found an association between long telomeres and increased risk of lung adenocarcinoma (odds ratio of 2.78 per 1 kb increase in telomere length). No significant association was noted between telomere length and any of the other types of cancer.

"Our work provides compelling evidence of a relationship between long telomeres and increased risk for lung adenocarcinoma," lead author Brandon Pierce, Ph.D., an assistant professor of public health sciences at the University of Chicago, said in a university news release.

"The prevailing hypothesis has been that short telomeres are bad for health, but it appears that this does not necessarily translate to some types of cancer."

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por cyto às 20:38

Quinta-feira, 13.08.15

Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy

Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy; Muraro E, Comaro E, Talamini R, Turchet E, Miolo G, Scalone S, Militello L, Lombardi D, Spazzapan S, Perin T, Massarut S, Crivellari D, Dolcetti R, Martorelli D; Journal of Translational Medicine 13 204 (2015)


BACKGROUND Locally advanced HER2-overexpressing breast cancer (BC) patients achieve a high rate of pathological complete responses (pCR) after neoadjuvant chemotherapy (NC). The apparently unaltered immune proficiency of these patients together with the immune-modulating activities of NC drugs suggest a potential contribution of host immunity in mediating clinical responses. We thus performed an extensive immunomonitoring in locally advanced BC patients undergoing NC to identify immunological correlates of pCR induction.

METHODS The immune profile of 40 HER2-positive and 38 HER2-negative BC patients was characterized at diagnosis and throughout NC (Paclitaxel and Trastuzumab, or Docetaxel and Epirubicin, respectively). The percentages of circulating immune cell subsets including T and B lymphocytes, Natural Killer (NK) cells, regulatory T cells, T helper 17 lymphocytes, were quantified by multiparametric flow cytometry. NK cells functional activity was evaluated through the analysis of NF-kB nuclear translocation by Multispectral flow cytometry, and with the in vitro monitoring of Trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC). CD8(+) T cell responses against six different tumor-associated antigens (TAA) were characterized by IFN-γ ELISPOT and IFN-γ/IL-2 DualSpot assays.

RESULTS After NC, HER2-positive patients showed a significant increase in the number of NK cells and regulatory T cells irrespective of the pathological response, whereas patients undergoing a pCR disclosed higher percentages of T helper 17 cells. Notably, a significant increase in the number of activated NK cells was observed only in HER2-positive patients achieving a pCR. Characterization of anti-tumor T cell responses highlighted sustained levels of CD8(+) T cells specific for survivin and mammaglobin-A throughout NC in patients undergoing a pCR in both arms. Moreover, HER2-positive patients achieving a pCR were characterized by a multi-epitopic and polyfunctional anti-tumor T cell response, markedly reduced in case of partial response.

CONCLUSIONS These results indicate that maintenance of functional T cell responses against selected antigens and improvement of NK cell proficiency during NC are probably critical requirements for pCR induction, especially in HER2-positive BC patients. Trail registration:

TRIAL REGISTRATION NUMBER NCT02307227, registered on ( , November 26, 2014).

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por cyto às 20:32

Quinta-feira, 13.08.15

Advancements in Deep Brain Stimulation for Parkinson's

Advancements in Deep Brain Stimulation for Parkinson's

Advancements in Deep Brain Stimulation for Parkinson's
Advancements in Deep Brain Stimulation for Parkinson's

In the United States alone, there are approximately one million cases of Parkinson's disease (PD) — more than the number of people diagnosed with multiple sclerosis, muscular dystrophy, and Lou Gehrig's disease combined.1 There is currently no cure, and the number of people diagnosed with PD is only projected to rise as the Baby Boomer generation grows older and lives longer.2

PD is a chronic and progressive motor symptom disorder caused by the loss of dopamine-producing brain cells. The four primary symptoms observed among patients include tremor (particularly in the limbs), rigidity, slowness of movement, and posture instability or impaired balance and coordination.3 As a result of these symptoms, many patients find themselves having trouble walking, talking, or completing other simple activities.4 Understandably, this may result in a decrease in quality of life for patients and an increase in burden for their caregivers.5

As a physician who treats patients with PD, it is important to think of this condition as a very individualized disease. Each patient has a different journey, and as such, the goals of treatment may vary for each patient. Generally speaking, we aim to maintain overall quality of life, improve mobility and function, and also improve the cardinal motor symptoms of the disease, such as tremors, bradykinesia, and rigidity.

Fortunately, PD treatment has come a long way due to ongoing innovation and clinical research. While there is still no magic bullet or cure, it is encouraging to see the trajectory of advances in treatment. In the 1960s, the introduction of levodopa for PD was arguably one of the greatest success stories in modern medicine. Now, physicians are armed with a cadre of therapies and treatment options and are able to customize treatment regimens for each patient. Even so, there are still many people that continue to struggle to control their symptoms with medication alone.

The Promise of Deep Brain Stimulation

For these patients, deep brain stimulation (DBS) may be an option. DBS is an established yet innovative surgical treatment approach for movement disorders. First approved by the U.S. FDA for use in PD patients in 2002, it is now also approved for other indications.

When describing DBS to others, I often use the expression “pacemaker for the brain.” As with a pacemaker for the heart, a device goes under the skin that generates electrical pulses. In the case of PD, the device delivers electrical stimulation to specific areas of the brain that control movement, thus altering the abnormal nerve signals that cause motor symptoms.


Opportunity to Support Clinical Research

As lead investigator for the INTREPID clinical trial for DBS, I work with other physicians to help evaluate the safety and effectiveness of the Vercise™ DBS System for reducing symptoms associated with PD that are not adequately controlled with medication.

This is an innovative system designed for accurate targeting and precise control. The Vercise DBS System includes a stimulator which is similar in size and shape to a pacemaker.  The stimulator produces electrical pulses that travel along leads.  Once leads are placed in the brain (subthalmic nucleus) they will be firmly secured and connected to the lead extensions, which then will be attached to the stimulator. The stimulator is typically placed under the skin near the clavicle.

The INTREPID study began enrolling patients in the U.S. in mid-2013 and is being conducted at approximately 30 study sites. Physician referrals will be essential to successful recruitment for the INTREPID study.  Patients who wish to participate will receive only study-related care at the research site.  They will be advised to continue seeing their primary physician for routine care.

INTREPID Trial Eligibility

When deciding whether any of your patients may benefit from this type of clinical study, the most important point to consider is whether their symptoms are being adequately controlled with medications alone. If not, they may qualify. Patients must also be between 22 and 75 years old and have a diagnosis of bilateral idiopathic PD with duration equal to or greater than five years. Patients must be able to understand study requirements and provide informed consent. Referring physicians can rest assured that their patients will be required to go through screening procedures to further determine whether they are good candidates and whether the study would be appropriate for them.

More information about the Vercise DBS System and the INTREPID clinical trial can be found at


  1. Parkinson's Disease Foundation. Statistics on Parkinson's. Available at Accessed May 2, 2015.
  2. National Parkinson Foundation. Research Reports; Parkinson's Disease: A Global View. Available at Accessed May 2, 2015.
  3. Parkinson's Disease Foundation. What is Parkinson's Disease. Available at Accessed on May 11, 2015.
  4. NIH MedlinePlus. What are the symptoms of Parkinson's Disease? Available at Accessed on May 11, 2015.
  5. Schrag A et al. Parkinsonism Rel Disord. Caregiver-burden in Parkinson's disease is closely associated with psychiatric symptoms, falls, and disability. 2006; 12:35-41. Available at Accessed on May 11, 2015.

Jerrold Vitek, MD, PhD, is the head of the Neurology Department and the Director of the Neuromodulation Research Program at the University of Minnesota. He previously served as the Neuromodulation Research Center Director at the Lerner Research Institute of the Cleveland Clinic Foundation developing functional surgery and deep brain stimulation (DBS) techniques for the treatment of neurological disease. He has also held faculty positions at Emory University and The Johns Hopkins University.

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por cyto às 20:30

Quinta-feira, 13.08.15

Ponatinib May Be Considered for First-line Treatment of Chronic Phase CML

Ponatinib May Be Considered for First-line Treatment of Chronic Phase CML


Patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase respond well to treatment with ponatinib, but due to the risk of vascular thrombotic events and the availability of alternative options, other drugs should be considered before ponatinib in the frontline setting, a recent study published online ahead of print in the journal The Lancet Haematology has shown.

For the phase 2 study, researchers sought to assess the activity and safety of ponatinib, a multi-targeted tyrosine kinase inhibitor, as first-line treatment for patients with chronic phase CML.

Researchers enrolled 51 patients with early chronic phase CML. Of those, 43 patients received ponatinib 45 mg daily and eight patients were started on ponatinib 30 mg daily.

After a warning by the U.S. Food and Drug Administration (FDA) for vascular complications with ponatinib, all patients received aspirin 81 mg daily and were dose reduced to ponatinib 30 or 15 mg daily.

Results showed that 94% of evaluable patients achieved complete cytogenetic response at 6 months.


RELATED: Biomarkers in Hematological Malignancies: A Review of Molecular Testing in Hematopathology

In regard to safety, 69%, 63%, and 49% of patients experienced skin-related effects, elevated lipase, and cardiovascular events, respectively. Grade 3 to 4 myelosuppression was reported in 29% of patients.

Ultimately, the study was stopped early after the FDA warned of the increased risk for thromboembolism with ponatinib.


  1. Jain P, Kantarjian H, Jabbour E, et al. Ponatinib as first-line treatment for patients with chronic myeloid leukemia in chronic phase: a phase 2 study. Lancet Haematol. 2015. [epub ahead of print]. doi: 10.1016/S2352-3026(15)00127-1.

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por cyto às 20:22

Quinta-feira, 13.08.15

Activated T cell therapy developed for advanced melanoma


Activated T cell therapy developed for advanced melanoma


T cells from patients with melanoma can trigger a protective immune response against the disease according to data from an in vitro and animal study. The findings were published in the Journal of Immunotherapy (2015; doi:10.1097/CJI.0000000000000078).

The new findings demonstrate that T cells derived from lymph nodes of patients with melanoma can be expanded in number and activated in the laboratory for intravenous administration in the treatment of patients.

 The research team was led by Julian Kim, MD, Chief Medical Officer at University Hospitals Case Medical Center Seidman Cancer Center and at Case Western Reserve University School of Medicine in Cleveland, Ohio. 

They developed a novel technique to generate large numbers of activated T cells that can be transferred back into the same patient to stimulate the immune system to attack the cancer.

"This study is unique in that the source of T cells for therapy is derived from the lymph node, which is the natural site of the immune response against pathogens as well as cancer," said Kim. "These encouraging results provide the rationale to start testing the transfer of activated T cells in a human clinical trial."

Kim and his team developed a new method to grow and activate immune cells in a two-week culture. Immune cells are extracted from lymph nodes that have been exposed to growing melanoma in the patient's body.

Rather than trying to activate the T cells while in the body, the lymph nodes are surgically removed so that the activation process and growth of the T cells can be tightly regulated in a laboratory.

This novel approach to cancer treatment, termed adoptive immunotherapy, is only offered at a few institutions worldwide.

These promising findings have led to the recent launch of a new phase 1 human clinical trial at UH Seidman Cancer Center in patients with advanced melanoma.


RELATED: Mechanism discovered for BRAF inhibitor resistance in melanoma

The research leading to the clinical trial was funded by the National Institutes of Health and the Case Comprehensive Cancer Center.

The trial is being supported by University Hospitals as well as a significant philanthropic effort including the Immunogene Therapy Fund, the Paula and Ronald Raymond Fund, and the Kathryn and Paula Miller Family Fund.

"The infusion of activated T cells has demonstrated promising results and is an area of great potential for the treatment of patients with cancer," said Kim.

"We are really excited that our method of activating and expanding T cells is practical and may be ideal for widespread use. Our goal is to eventually combine these T cells with other immune therapies which will result in cures."

Additionally, the team has been researching the possibility of using lymph nodes from patients with pancreatic cancer to develop T cell therapy. Their goal is to expand the program and eventually study other tumor types including lung, colorectal, and breast cancers.

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por cyto às 20:17

Quinta-feira, 13.08.15

Biomarkers in Hematological Malignancies: A Review of Molecular Testing in Hematopathology (2)

Biomarkers in Hematological Malignancies: A Review of Molecular Testing in Hematopathology

the Cancer Therapy Advisor take:

Molecular markers are an integral part of determining the diagnosis, prognosis, and therapy of patients with hematologic malignancies and molecular testing has become widely used for the workup of myeloid and lymphoid neoplasms.

In this review, Mohammad Hussaini, MD, from the Department of Hematopathology and Laboratory Medicine at the Moffitt Cancer Center and Research Institute in Tampa, Florida, assessed current practices and trends for molecular testing in hematopathology by disease type, including chronic myelogenous leukemia, myelodysplastic syndrome, acute myeloid leukemia, and lymphoblastic leukemia/lymphoma.

In Philadelphia chromosome-positive chronic myelogenous leukemia, patients possess the BCR-ABL1 fusion gene, which can be detected by conventional cytogenetics the vast majority of the time. This fusion gene is a target for imatinib therapy, a tyrosine kinase inhibitor used to decrease BCR-ABL activity.

In patients with acute myeloid leukemia, genetic abnormalities affect survival rate and influence therapeutic decisions. For example, patients with favorable risk include those with t(15;17), t(8;21), inv(16/t[t16;16]), a normal karyotype and mutated NPM, or a normal karyotype with a biallelic CEBPA mutation, may receive consolidation therapy following 7+3 induction with chemotherapy, while those with adverse risk may undergo transplantation after standard induction.

In lymphoblastic leukemia/lymphoma, 25% of adult cases and 2% to 4% of pediatric cases possess t(9;22)(q34;q11).

These patients can receive adjuvant imatinib, which can improve complete remission rates despite carrying the worst prognosis of all types of lymphoblastic lymphoma. The presence of this translocation can also be used as a marker for minimum residual disease testing.

As technologies for genome sequencing become more affordable and powerful, they will become even more widely used to diagnose hematologic malignancies and play a larger role in therapeutic decisions. 


Background: Molecular interrogation of genetic information has transformed our understanding of disease and is now routinely integrated into the workup and monitoring of hematological malignancies. In this article, a brief but comprehensive review is presented of state-of-the-art testing in hematological disease.

Methods: The primary medical literature and standard textbooks in the field were queried and reviewed to assess current practices and trends for molecular testing in hematopathology by disease.

Results: Pertinent materials were summarized under appropriate disease categories.

Conclusion: Molecular testing is well entrenched in the diagnostic and therapeutic pathways for hematological malignancies, with rapid growth and insights emerging following the integration of next-generation sequencing into the clinical workflow.


Perhaps in no other field of oncology is the routine use of molecular markers more integrated into the diagnostic, prognostic, and therapeutic workup of disease as in the realm of hematological malignancies.

Molecular diagnostics is a burgeoning field in the era of personalized medicine, with high-volume laboratories running 10,000 molecular tests or more every year, many of which are for the workup of leukemia and lymphoma.1,2

Molecular testing has wide applicability in hematopathology, guiding diagnosis (eg, TCR gene rearrangement to establish T-cell clonality), subclassification (eg, recurrent cytogenetic translocations in acute myeloid leukemia [AML]), prognosis (eg, Philadelphia chromosome–positive [Ph+ ] in acute lymphoblastic leukemia [ALL]), and minimal residual disease testing (eg, BCR-ABL transcripts in chronic myelogenous leukemia [CML]).

Myeloproliferative Neoplasms

Chronic Myelogenous Leukemia: The Ph chromosome in CML was discovered in 1960.3,4 t(9;22) (q34;q11) juxtaposes most of ABL1 to 5' regions of BCR, resulting in constitutively increased kinase activity and neoplastic transformation.5

Although the breakpoint for ABL1 is mostly conserved, occurring in the intron preceding exon 2, the breakpoints in BCR are more variable and typically occur in either the major or minor breakpoint regions (M- or m-bpr). M-bpr fusions result in a p210 fusion protein, which is the form typically found in Ph+ CML.

A sizeable number of patients with Ph+ B-cell acute lymphoblastic leukemia (B-ALL; 40% of adults and 10% of children6 ) also harbor the p210 product. Conversely, m-bpr translocations result in a p190 fusion found in most Ph+ B-ALL cases but rarely in Ph+ CML.7

Uncommonly, BCR breakpoints fall in the microregion (µ-bcr), resulting in the p230 fusion product associated with chronic neutrophilic leukemia (CNL).6,8

Detection of t(9;22) is most commonly performed by either cytogenetics, fluorescence in situ hybridization (FISH), or reverse transcription–polymerase chain reaction (RT-PCR; amplification of the transcript product); the latter is used for minimal residual disease testing.

At diagnosis, conventional cytogenetics can detect t(9;22) in 95% of cases of CML; however, an additional 2.5% of cases with submicroscopic translocations can be recovered by applying molecular methods.6

If the results of both cytogenetics and FISH are negative, then an alternative diagnosis should be considered. Assaying for t(9;22) can be used to monitor the therapeutic response of imatinib mesylate and for relapse surveillance (using quantitative polymerase chain reaction [qPCR] methods, particularly screening for positive results 6–12 months after transplantation).6

However, the importance of the BCR-ABL1 fusion gene in CML is in its role as a paradigm for targeted cancer therapy; patients with CML may receive imatinib as first-line therapy as established by data from the International Randomized Study of Interferon and STI571 trial.9

Baseline values from this trial are also used as the basis of the international reporting scale (IS). The IS allows for the standardization and comparison between laboratories with regard to BCR-ABL levels.10

Response to therapy can be classified as complete hematological response, complete cytogenetic response, and molecular response based on levels of fusion transcripts by RT-qPCR.

A major molecular response is defined as a 3-log reduction compared with baseline (or ≤ 0.1% IS), and a complete molecular response is defined as a 4.5-log reduction or more from baseline.9,11

A lack of response may indicate acquired resistance. In such cases, Bcr-Abl kinase domain mutations (> 100 types documented) can be found in one-half of refractory cases and are an indication to adjust therapy by integrating a second-generation tyrosine kinase inhibitor into treatment.12

Atypical Chronic Myelogenous Leukemia and Chronic Neutrophilic Leukemia

CNL has been well established given the prior detections of 20q-, 11q-, and JAK2 V617F mutation in this disease, but they are not disease specific.13-15

Deep sequencing has identified CSF3R mutations in CNL and atypical CML in 59% of patients,16 and these findings were subsequently documented in all World Health Organization (WHO)–defined CNL cases, possibly prompting a future revision of the WHO diagnostic criteria.17

Polycythemia Vera, Essential Thrombocytosis, and Primary Myelofibrosis

JAK2 codes for an intracellular tyrosine kinase and provides signaling for growth factor receptors, including the erythropoietin receptor. The JAK2 V617F mutation was discovered in 2005 and was shown to be present in 95% of polycythemia vera cases and approximately 50% to 65% of cases of essential thrombocytosis (ET) and primary myelofibrosis (PMF).18

In addition, the JAK2 V617F mutation can also be seen in nearly one-half of cases of refractory anemia with ring sideroblasts associated with marked thrombocytosis.19,20 In cases of polycythemia vera in which the JAK2 V617F mutation is not detected, the remaining 5% of patients may harbor mutations in exon 12 of JAK2.20 

Similarly, in ET and PMF cases lacking the JAK2 V617F mutation, an assessment of MPL is indicated, given that 5% or more of patients with PMF and even fewer patients with ET (1%) will show an aberration in this gene (W515K/L).20-22 Exon 10 c-MPL mutations have also been reported in ET or PMF (5%).23

The JAK2 V617F mutation can be detected via targeted PCR followed by sequencing of the amplicon. Other methods include restriction digest of PCR-amplified products followed by separation by capillary electrophoresis, allele-specific PCR using probe-based gene expression analysis, real-time PCR, pyrosequencing, and melting curve analysis.24,25

Despite the discovery of JAK2 and MPL mutations, until recently many ET and PMF cases did not have a unique genetic basis (ie, JAK2, MPL) until 2 independent groups identified CALR mutations in this patient subset. CALR mutation, which comprises insertions (ins) and deletions (del) leading to a frameshift, are found in 20% to 25% of ET and PMF cases and tend to cluster in exon 9.26-28

Commercial testing utilizes sequencing and fragment length analysis. Recently, the Dynamic International Prognostic Scoring System Plus listed unfavorable karyotype as a risk factor for predicting survival in primary myelofibrosis.29


Activating point mutations in KIT are highly associated with mastocytosis and can be detected in more than 95% of cases of systemic mastocytosis using real-time qPCR, allele-specific oligonucleotide PCR, or direct sequencing.30,31

KIT mutations result in the ligand-independent activation of the c-kit tyrosine kinase. The most common mutation in systemic mastocytosis is the D816V variant seen in 68% of cases of mastocytosis; however, in certain subsets (eg, aggressive systemic mastocytosis), its incidence may exceed 80%.32

The presence of this variant constitutes a minor criterion for the diagnosis of systemic mastocytosis. Other KIT variants have been described (< 5%) and are more likely to be detected in the context of cutaneous mastocytosis rather than systemic mastocytosis.20 Patients with the D816V variant are resistant to imatinib


Myeloid and Lymphoid Neoplasms With Eosinophilia and Abnormalities of PDGFRA, PDGFRB, or FGFR1

A unique group of myeloid and lymphoid neoplasms are defined by aberrant tyrosine kinase activity due to translocations involving PDGFRA, PDGFRB, or FGFR1, all of which are characteristically associated with eosinophilia.

A workup for abnormalities in these genes should be considered in cases of eosinophilia with end-organ damage or in which secondary reactive eosinophilia has been excluded.

The cellular ontogeny of these disorders may originate from a pluripotent (lymphoid–myeloid) stem cell. PDGFRB or FGFR1 can be detected with conventional cytogenetic analysis (ie, karyotype); however, the FIP1LI-PDGFRA results in an 800-kb cryptic del(4q12) that houses CHIC2.

Typically, it is detected using FISH with a probe spanning CHIC2 or break-apart assay for either of the translocation partners. The translocation can also be detected using RT-PCR.20 FIP1LI–PDGFRA disease commonly manifests as chronic eosinophilic leukemia, and FIP1LI–PDGFRA is detected in 10% to 20% of those with idiopathic hypereosinophilia.34

Patients have a response to imatinib more than 100 times greater than that seen in BCR-ABL rearrangement.20,35 Neoplasms associated with PDGFRB commonly present as chronic myelomonocytic leukemia. ETV6 is the most common translocation partner, but more than 13 others have been described; patients will be responsive to imatinib.34

Neoplasms associated with FGFR1 can manifest as acute leukemias (myeloid or lymphoid) or as chronic eosinophilic leukemia. Translocation partners include ZNF198, CEP110, FGFR10P1, BCR, TRIM24, MYO18A, HERVK, and FGFR10P2.

By contrast to PDGFRA- and PDGFRB-associated neoplasms, these disorders are unresponsive to tyrosine kinase inhibitors.20,34

Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a clonal disorder of myeloid cells characterized by morphological dysplasia and ineffective hematopoiesis that manifests as peripheral cytopenia.36

Cytogenetic abnormalities are seen in one-half of MDS cases, and they most commonly involve del(5q/7q) or monosomies of the same.20,37 TP53 mutations are associated with therapy-related MDS and have a poor prognosis.38

Various cytogenetic abnormalities can be considered presumptive evidence of MDS even in the absence of sufficient dysplasia (ie, -5/del[5q], -7/del[7q], +8,-Y, del[20q], isochromosome [i][17q], -13/del[13q], del[11q], del[12p], del[9q], isodicentric [idic][Xq13], and certain balanced translocations involving chromosomes 1, 2, 3, 9, 11, 16, and 21).20

Various prognostic models are available for MDS. The most widely adopted is the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R), both of which integrate the percentage of blasts in the bone marrow, cytogenetic abnormalities, and number of cytopenias.39

In the latter scheme, cytogenetics are placed in 5 tiers: very good (-Y, del[11q]), good (normal, del[5q], del[12p], del[20q], and del[5q] + 1 more), intermediate (del[7q], +8, +19, i[17q], and others), poor (-7, inversion [inv][3/t3q/del{3q}], -7/del[7q] + 1 more, and 3 cytogenetic aberrations), and very poor (> 3 abnormalities).40

Although gene-expression profiling and single nucleotide polymorphism arrays are powerful tools, they are not routinely employed in the clinical setting. However, somatic mutation in 40 genes has been found in MDS and analysis for these genes can add prognostic value.41

By contrast to cytogenetic abnormalities, which are seen in one-half of cases, at least 1 of these “driver” mutations can be found in most cases of MDS.42,43 For example, patients with 1 or more mutations in TP53, EZH2, ETV6, RUNX1, or ASXL1 show survival patterns analogous to those in the next higher tier by subgrouping in the IPSS.44

Various epigenetic modifiers (DNA methylation regulators, spliceosome mutations, and histone modifiers TET2, IDH1/2, DNMT3A, EZH2, ASXL1, SF3B1, U2AF1, SRSF2, and ZRSR2), transcription factor genes, and kinase signaling genes have been implicated in MDS, providing a basis for approved therapies and those in development.45

However, these aberrations have limitations because their clinical significance is not always clear given their association with poor prognostic clinical features, our lack of knowledge of their interactions with other markers often concurrently detected, intratumoral clonal heterogeneity, and the wide gamut of mutations in any given gene.42

Next-generation sequencing (NGS) technologies, which garner the power of massively parallel sequence generation, enable laboratories to clinically sequence many genes simultaneously, which was previously untenable by traditional sequencing technologies.

Commercial testing is available for activated signaling genes (KIT, JAK2, NRAS, CBL, MPL), transcription factors (RUNX1, ETV6), epigenetic genes (IDH1/2, TET2, DNMT3A, EZH2, ASXL1, SETBP1), ribonucleic acid splicing genes (SF3B1, U2AF1, ZRSF2, SRSF2), and tumor suppressors (TP53, NPM1, PHF6), among others.

In cases of MDS or MDS/myeloproliferative neoplasms in which the diagnoses are unclear or dysplasia has yet to emerge, detecting a mutation in one of these key genes may be helpful in establishing the diagnosis of a clonal myeloid neoplasm.

Although they are not formally incorporated into prognostic stratification schemas, certain mutations may also carry prognostic implications.46

In addition, robust myeloid testing commercially available (FoundationOne Heme, Cambridge, Massachusetts) can interrogate 405 cancer-related genes, allowing — in theory — for the identification of targetable mutations and patient enrollment in clinical trials.47

Acute Myeloid Leukemia

AML is the most common type of acute leukemia occurring in adults.48 In 2015, an estimated 20,830 new cases of AML will occur in the United States, along with 10,460 deaths.48 AML is a lethal disease and has a 5-year relative survival rate of 24.2%.49

However, outcomes are heterogenous and overall survival rates range from approximately 5% to 70%.50 Thus, a need exists for prognostic markers to predict outcomes and guide therapeutic decision-making. Prognostic markers can be clinical, disease related, and molecular, although the strongest prognostic factor for predicting therapeutic response and survival is cytogenetic subgrouping.

The results of numerous clinical trials across several decades have indicated that overall survival rates can be as long as 11.5 years in favorable patient groups or shorter than 1 year in patients with adverse risk.51-53

Those with favorable risk (5-year survival rate of 50%–80%) include those with t(15;17), t(8;21), inv(16/t[16;16]), a normal karyotype and mutated NPM, or a normal karyotype with biallelic CEBPA mutation.54

These patients may receive consolidation therapy following induction 7 + 3 with chemotherapy (eg, high-dose cytarabine). Those with adverse risk (overall survival rate of 5%–20%), including those with MLL aberrations, inv(3), t(6;9), -7/del(7q), -5/del(5q), TP53 deletions, and a complex karyotype, may undergo transplantation after standard induction.55,56

Determining whether consolidation therapy is appropriate in those with intermediate risk (overall survival rate of 20%–40%55) is not as clear. In this cohort, molecular testing for FLT3, NPM, and CEBPA is informative and has therapeutic implications.

For example, detecting FLT3 internal tandem duplication by PCR in patients with normal karyotype AML may lead to consolidation therapy with hematopoietic stem cell transplantation, after which patients may have a 30% likelihood of cure.55

FLT3 codes for a transmembrane signal-transducing protein of the tyrosine receptor kinase family and reveals 2 major abnormalities in AML, ie, internal tandem duplication in the juxtamembrane portion resulting in constitutive activation and a point mutation in Asp835 (the activity loop portion of protein) resulting in dysregulation. FLT3 aberrations are seen in 5% to 10% of AMLs.57,58

NPM1 encodes nucleophosmin, a 37 kDa protein. NPM1 mutations involve 4 to 11 break-point insertions in exon 12 that lead to the mislocalization of normal nucleophosmin to the cytoplasm via dimerization.59,60

This can be detected by PCR followed by sizing via capillary electrophoresis. NPM1-mutated AML has been designated as a provisional entity in the 2008 WHO classification and is associated with unique morphological (blasts with “cup-like” nuclei) features and a favorable prognosis in normal karyotype AML.20 CCAAT/enhancer-binding protein α is a 42 kDa transcription factor whose loss is associated with the oncogenic transformation of myeloid cells due to a loss of differentiation.61

Patients with mutated CEBPA show outcomes similar to those in the favorable cytogenetic subgroup of AML (eg, t[8;21]+ AML).62 The prognostic value of CEBPA is in the double-mutated subset of patients lacking FLT3 and NPM1 mutations.63

Other single gene alterations that may carry important prognostic implications have been identified in AML — many were identified during whole genome sequencing studies — and include DNMT3A, IDH1/2, TET2, WT1, ERG expression, BAALC expression, and MN1 expression, among others. IDH2 is associated with a good prognosis and TET2, ASXL1, and PHF6 confer poor prognoses.

However, in the absence of prospective trials and the present controversy regarding them, many of these single genes have not been formally integrated into accepted risk-stratification models.64 In general, investigating the mutation status of these genes is simultaneously obtained using NGS technologies.

Biomarkers are important for subclassifying AML types, and several categories of AML are defined based on the presence or absence of recurrent genetic abnormalities alone, in particular t(8;21)(q22;q22), inv(16), t(15;17)(q22;q12), t(9;11)(p22;q23), t(6;9)(p23;q34), inv(3), and t(1;22)(p13;q13).13

In some cases, the detection of 1 of these aberrations alone is enough to diagnose AML, even in the absence of the conventional criteria of 20% blasts in the marrow or peripheral blood, such as in the case of t(15;17) and core-binding factor-related leukemias (eg, t[8;21][q22;q22], inv[16]) and possibly inv(3)/t(3;3).65-67

These translocations can be detected by conventional cytogenetics, FISH, and more novel technologies, including single molecule imaging and NGS. One such type of sequencing uses color-coded barcodes directly hybridized to individual target molecules and then digitally detects them in a multiplexed manner.68

A comprehensively targeted clinical panel currently on the market uses NGS to interrogate the exons of 405 genes and examines the intronic regions of 31 genes involved in rearrangements as well as complementary DNA (ribonucleic acid) to sequence 265 genes to detect translocations.69

In some cases, the detection of a translocation carries both diagnostic and therapeutic importance. Namely, t(15;17)(q22;q21), which is diagnostic for acute promyelocytic leukemia (AML M3), juxtaposes the 17(q21) retinoic acid receptor α (the receptor for vitamin A involved in cell proliferation and differentiation) to the 15(q22) promyelocytic leukemia zinc finger protein (involved in transcriptional regulation and apoptosis). The chimeric protein blocks differentiation beyond the promyelocytic stage, resulting in acute leukemia.

However, treatment with all transretinoic acid allows for differentiation and, in combination with cytotoxic chemotherapy, can result in complete remission. Variant translocations involving RARA are seen in fewer than 2% of cases, but they are important given that some patients may not respond to all transretinoic acid therapy.20,70

Another example of molecular testing informing therapeutic management involves KIT testing in AML. C-kit mutations are associated with core-binding factor AMLs and may abrogate the favorable prognosis generally associated with this group.

Autoria e outros dados (tags, etc)

por cyto às 20:00

Quinta-feira, 13.08.15

Biomarkers in Hematological Malignancies: A Review of Molecular Testing in Hematopathology (2)

Biomarkers in Hematological Malignancies: A Review of Molecular Testing in Hematopathology


Lymphoblastic Leukemia/Lymphoma

Similar to AML, the detection of certain characteristic translocations further subclassifies cases of B-ALL, including t(12;21)(p12,q22) TEL/AML-1, t(1;19)(q23;p13) PBX/E2A, t(9;22)(q34;q11) ABL/BCR, (5;14)(q31;q32) IL3-IGH, and (V;11)(V;q23) V/MLL. 20 t(9;22)(q34;q11) is seen in 25% of adult cases and 2% to 4% pediatric cases.72

Patients with this Ph+ translocation carry the worst prognosis of all types of lymphoblastic leukemia73; however, these patients can be treated with adjuvant imatinib, which improves complete remission rates.74 The presence of the translocation also serves as a useful marker for minimum residual disease testing.

Molecular methods for detecting the translocation are similar to those used for CML. Notably, when qRT-PCR testing is undertaken, the p190 protein product is typically associated with B-ALL, not the p210 protein typical of CML; in children with ALL, the break point occurs in m-bcr, which generates the p190 protein product in 90% of cases.6

If a p210 protein product is detected, then consideration should be given to a lymphoid blast crisis arising in CML. By contrast to t(9;22), the reverse demographic appears to be true for t(12;21)(p12,q22): It occurs in 25% of pediatric cases but is rare in adults and associated with a favorable prognosis and curative rates of higher than 90% in children.75 MLL can have various translocation partners, the most common of which is AF4 on chromosome 4.

MLL translocations carry a poor prognosis, and this is particularly true in infants.76 The unique characteristic of t(5;14)(q31;q32) IL3/IGH B-ALL, which is rare, is its association with eosinophilia due to the overexpression of IL3.77

t(1;19)+ B-ALL is historically associated with a poor prognosis, but this has changed through the use of intensive chemotherapy regimens.78 Immunophenotypically, the blasts lack CD34 but have aberrant CD9 positivity.79

Based on gene-expression profiling, BCR-ABL1–like B-ALL has been identified as being associated with deletions of IKZF1, CRLF2 rearrangements, and poor outcomes.80 JAK1/2-activating mutations are present in a subset of these patients and may benefit from Janus kinase inhibitor therapy.80

In all children with ALL, cytogenetic testing or flow cytometric analysis of ploidy should be undertaken. Hyperdiploidy (> 50 chromosomes) is associated with a better prognosis, whereas hypodiploidy (< 44 chromosomes) is associated with a poor prognosis.80,81 Translocations in T-cell ALL (T-ALL) commonly involve 1 of the TCR loci (A, B, G, D).

The most common translocation partner includes HOX11 on chromosome 10 (occurring in 10%–30% of cases) or various other transcription factors dysregulated by juxtaposition to 1 of the TCR genes.82 PICALM-MLLT10 and MLL rearrangements are seen in approximately 10% of cases.83

Both B-ALL and mature B-cell non-Hodgkin lymphomas (NHLs) show clonal immunoglobulin (Ig) gene rearrangements, which are helpful in residual disease testing as well as in establishing a malignant diagnosis. For follow-up specimens, screening for clonal peaks identical to those identified at diagnosis can be performed to assess for residual/relapsed minimal residual disease.

B-cell antigen receptors are encoded by IGH (14q32), IGLK (2p11), and IGLL (20q11), coding for the Ig heavy chain, κ light chain, and the λ light chain, respectively. Each contains variable (V), joining (J), and constant regions; IGH contains an additional diversity (D) region.

Multiplex PCR that uses primers to target highly conserved framework regions within the V segment are used to generate PCR products, which can then be separated using capillary electrophoresis, which is preferred to Southern blot analysis.84,85 Monoclonal peaks have heights 2 to 3 times that of the background and can be seen in clonal B-cell neoplasms.

Repeat peaks in duplicate wells raise confidence that clonal peaks do not represent a PCR artifact. Care must be taken because false-positive results can occur in cases of benign lymphoid hyperplasia, which may be present in the setting of immunodeficiency and autoimmune disease.86,87 Furthermore, lineage infidelity is present with BCR gene rearrangement and is similar to that seen in T-cell lymphoma.

Most precursor and 5% to 10% of mature B-cell neoplasms will harbor clonal T-cell gene rearrangements.6 Other various factors may result in false-negative results, including primer failure due to somatic hypermutation (which can occur at a rate of > 50% in certain lymphoid neoplasms [eg, follicular lymphoma]), complex IGH rearrangements, or DNA of poor quality.6,88

Mature B-Cell Neoplasms

Various translocations are associated with B-cell NHLs and their detection helps to establish a diagnosis in these entities. t(14;18) involves BCL2 on chromosome 18 and IGH on chromosome 14. BCL2 is juxtaposed to the J region of the heavy chain.

Given that the IGH enhancer element is highly active, bcl2 can become overexpressed. Because bcl2 has antiapoptotic properties, its overexpression will result in neoplasia.

This translocation is found in 85% to 90% of cases of follicular lymphoma (a lower percentage occurs in cases of high-grade follicular lymphoma) and 25% of cases of diffuse large B-cell lymphoma (DLBCL).20 Because follicular lymphomas may lack demonstrable Ig clonality due to ongoing somatic hypermutation, the use of FISH or PCR for the translocation offers alternative markers to assess for clonality, establish a diagnosis, or both; however, FISH is preferred to PCR as it is more sensitive and specific.89

DLBCL, in addition to BCL2, can have translocations of BCL6 and MYC (10% of cases).90 When a MYC translocation is detected along with other specific translocations (usually BCL2 and BCL6) in an intermediate to large B-cell lymphoma, its presence qualifies as a “double hit” lymphoma, which may be categorized under the rubric of large B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma.91

Typically, MYC gene rearrangements are associated with Burkitt lymphoma, but they can also be present in plasmablastic lymphomas (50% of the time) and, rarely, in follicular lymphoma and primary central nervous system DLBCL.92,93

Burkitt lymphoma is characterized by t(8;14) involving MYC and IGH and will less commonly show translocations involving light chain loci (κ or λ).94-96 BCL6 translocations can be seen in follicular lymphoma, DLBCL, and are frequently identified in primary cutaneous leg-type DLBCL.97

Nearly all cases of mantle cell lymphoma carry t(11;14)(q13;q32) CCND1-IGH, which can be assessed by FISH, and is preferred over PCR-based methodologies that demonstrate lower sensitivity rates (50%–60%); this is because of the large number of dispersed break points at 11q13.98 Translocation of CCND1 with light chain has also been reported; rarely, cyclin D2 may be translocated, which should be a consideration in cyclin D1– tumors otherwise characteristic of mantle cell lymphoma.99

Various translocations have also been described in lymphoma involving the mucosa-associated lymphoid tissue. Of these, MALT1 and BCL10 translocations are worthy of mention (t[14;18][q32;q21], t[11;18] [q21;q21], t[1;14][p22;q32]) because they represent mucosa-associated lymphoid tissue that usually does not respond to Helicobacter pylori eradication.100-102

Although multitudinous, single nucleotide variants and copy number changes have been found in B-cell NHL, sometimes even with reported prognostic significance (eg, NOTCH1 mutations in chronic lymphocytic leukemia [CLL]), in clinical practice testing for these in B-cell NHL has a limited role.103

A limited 7-gene CLL panel with targets that carry prognostic implications has been launched by Cancer Genetics (Rutherford, New Jersey).

Commonly, when molecular testing is indicated in B-NHL, the genetic aberrations are usually of diagnostic importance. BRAF V600E mutation was originally found in 100% patients with hairy cell leukemia compared with none of the 195 other peripheral B-cell lymphoma/leukemias.104-106 The results of subsequent studies have confirmed that the mutation is present in all cases of hairy cell leukemia and is rare in other chronic lymphoproliferative disorders.104-106

In lymphoplasmacytic lymphoma, MYD88 mutation has been detected with high frequency (> 90%),107 and detecting the mutation may be diagnostically useful given the overlap with lymphoplasmacytic lymphoma and other low-grade B-cell lymphomas that may be associated with plasmacytic differentiation, including marginal zone lymphoma, multiple myeloma, and CLL.

In these other conditions, the prevalence of the mutation is 3% to 9%.108 Of note, nearly one-third of activated B-cell-like DLBLC harbors the mutation, and its presence is not useful in the differential with IgM monoclonal gammopathy of undetermined significance.108 Thus, a correlation with morphology and other ancillary studies is needed.

In CLL, hypermutation status is assessed by comparing each IGH clonally rearranged gene sequence with a database of germline V-region sequences to determine the expressed V-region gene and the extent and position of somatic mutations. If a difference exists of more than 2%, then the tumor is considered hypermutated and confers a better prognosis.109

Mature T-Cell Lymphoproliferative Disorders

A total of 95% of T cells express the a-b receptor and a smaller proportion express the γ-δ receptor; both of these receptors contain heterodimer proteins encoded by TCR genes located on chromosomes 7 and 14.6,110 Early in development, the TCR genes undergo somatic rearrangement involving V, D, and J regions (TCRB and TCRD) or V–J rearrangements alone (TCRA and TCRG).

Unlike in B cells, in which Ig light chains (κ and λ) can be assessed for clonality by flow cytometry or immunohistochemistry, establishing the clonal nature of T cells using these techniques is difficult, thus making TCR gene rearrangement studies valuable.111

Each T cell bears a unique, rearranged sequence. Under normal circumstances, a range of gene products can be seen given the gamut of polyclonal T cells present.

However, if a clonal process is present, then a particular gene rearrangement product should predominate,112 and it can be detected using Southern blot analysis as a single clonal band. Although Southern blot analysis is considered the gold standard, it is inefficient and seldom used in modern clinical laboratories for T-cell clonality detection.

Drawbacks of Southern blot analysis include its high cost, increased time, large sample requirements, and low sensitivity rates compared with PCR (5%–10% vs 1%).112,113 PCR amplification of TCRG and TCRB gene products followed by gel separation or capillary electrophoresis is employed in the clinical laboratory.

PCR testing demonstrates a clonal peak 2 to 3 times larger than the background peaks in T-cell lymphomas. In certain cases, false-negative results may occur if the rearrangement involves the primer site or too few T cells are present for analysis. Positive cases of gene arrangements should not be taken to mean that T-cell lymphoma is present.

Such positivity can be seen in cases of B-cell lymphoblastic leukemia (approximately 50% of cases), mature B-cell lymphomas (5%–10%), AML (10%), and non-neoplastic conditions such as autoimmune disorders, certain infectious diseases (Epstein–Barr virus–induced oligoclonal processes), and certain cutaneous lesions (eg, lymphomatoid papulosis).6

In ALK-positive anaplastic large cell lymphoma, t(2;5)(p23;q35) juxtaposing ALK and NPM, respectively, is the most frequent genetic translocation (83% of pediatric and 31% of adult cases) present; however, various, less frequently seen partners have also been described, including TPM3 (13%), ATIC, TGS, CLTC, MSN, TPM4, MYH9, and ALO17 (all < 1%).20,114

The translocation can be assayed using RT-PCR or break-apart FISH probes.6,20,114,115 In T-cell prolymphocytic leukemia, the most common genetic aberration (80%) involves inv(14) juxtaposing the TRA locus at 14q11 to the TCL1A and TCL1B oncogenes.20

In a subset of cases, a reciprocal tandem t(14;14) is present; t(X;14)(q28;q11) has also been described but is less common. Both can be assayed using FISH. Cytogenetics can be used to detect chromosome 8 abnormalities (70%–80%), ATM deletions, as well as del(12p13), all of which can be seen in the setting of T-cell prolymphocytic leukemia.116,117

Hepatosplenic T-cell lymphoma is associated with numerical abnormalities of chromosome 7, and most cases will demonstrate i(7q). As the disease progresses, 2 to 5 copies of i(7)(q10) or derangements in the second chromosome 7 may be present. i(7)(q10) can be detected using FISH.118

In adult T-cell leukemia, clonal integration of the human T-lymphotropic virus type 1 viral DNA can be seen. Although it is conceivable to perform testing via Sanger sequencing, it is typically easier to perform serum studies for human T-lymphotropic virus type 1.119 In enteropathy-associated T-cell lymphoma, amplification of 19q31.3, del(16q12.1), or both have been reported.20


Molecular testing is well entrenched in the workup and management of hematological malignancies. As sequencing technologies become both more powerful and affordable, they will take on an even larger role in the molecular diagnostics of hematopathology and in the era of precision medicine.


  1. Memorial Sloan Kettering Cancer Center. Molecular pathology fellowship. fellowships/fellowship/molecular-diagnostics-fellowship. Accessed February 18, 2015.
  2. University of Texas MD Anderson Cancer Center. Molecular genetic pathology fellowship. education-and-training/schools-and-programs/graduate-medical-education/ residency-and-fellowship-programs/molecular-genetic-pathology-fellowship. html. Accessed February 18, 2015.
  3. Gonon-Demoulian R, Goldman JM, Nicolini FE. History of chronic myeloid leukemia: a paradigm in the treatment of cancer [in French]. Bull Cancer. 2014;101(1):56-67.
  4. Gahrton G. Historical note on the discovery of the Philadelphia chromosome. Cancer Genet. 2012;205(6):338-339.
  5. Zhen C, Wang YL. Molecular monitoring of chronic myeloid leukemia: international standardization of BCR-ABL1 quantitation. J Mol Diagn. 2013;15(5):556-564.
  6. Leonard DG, ed. Molecular Pathology in Clinical Practice: Genetics. New York: Springer; 2008.
  7. Nashed AL, Rao KW, Gulley ML. Clinical applications of BCR-ABL molecular testing in acute leukemia. J Mol Diagn. 2003;5(2):63-72.
  8. Pane F, Frigeri F, Sindona M, et al. Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/ A2 junction). Blood. 1996;88(7):2410-2414.
  9. O'Brien SG, Guilhot F, Larson RA, et al; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. 
  10. Branford S, Fletcher L, Cross NC, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood. 2008;112(8):3330-3338.
  11. Press RD. Major molecular response in CML patients treated with tyrosine kinase inhibitors: the paradigm for monitoring targeted cancer therapy. Oncologist. 2010;15(7):744-749.
  12. Frankfurt O, Licht JD. Ponatinib--a step forward in overcoming resistance in chronic myeloid leukemia. Clin Cancer Res. 2013;19(21):5828-5834.
  13. Gotlib J, Maxson JE, George TI, et al. The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood. 2013;122(10):1707-1711.
  14. Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes. Blood. 2005;106(4):1207-1209.
  15. Elliott MA, Hanson CA, Dewald GW, et al. WHO-defined chronic neutrophilic leukemia: a long-term analysis of 12 cases and a critical review of the literature. Leukemia. 2005;19(2):313-317.
  16. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368(19):1781-1790.
  17. Elliott MA, Tefferi A. Chronic neutrophilic leukemia 2014: update on diagnosis, molecular genetics, and management. Am J Hematol. 2014;89(6):651-658.
  18. Baxter EJ, Scott LM, Campbell PJ, et al; Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054-1061.
  19. Szpurka H, Jankowska AM, Makishima H, et al. Spectrum of mutations in RARS-T patients includes TET2 and ASXL1 mutations. Leuk Res. 2010;34(8):969-973.
  20. Swerdlow EA. WHO Classification of Tumours of the Heamatopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC; 2008.
  21. Pancrazzi A, Guglielmelli P, Ponziani V, et al. A sensitive detection method for MPLW515L or MPLW515K mutation in chronic myeloproliferative disorders with locked nucleic acid-modified probes and real-time polymerase chain reaction. J Mol Diagn. 2008;10(5):435-441.
  22. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270.
  23. Ding J, Komatsu H, Wakita A, et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood. 2004;103(11):4198-4200.
  24. Cankovic M, Whiteley L, Hawley RC, et al. Clinical performance of JAK2 V617F mutation detection assays in a molecular diagnostics laboratory: evaluation of screening and quantitation methods. Am J Clin Pathol. 2009;132(5):713-721.
  25. Steensma DP. JAK2 V617F in myeloid disorders: molecular diagnostic techniques and their clinical utility: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn. 2006;8(4):397-411.
  26. Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood. 2014;123(24):3714-3719.
  27. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390.
  28. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405.
  29. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392-397.
  30. Kristensen T, Vestergaard H, Møller MB. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagn. 2011;13(2):180-188.
  31. Tefferi A, Verstovsek S, Pardanani A. How we diagnose and treat WHO-defined systemic mastocytosis in adults. Haematologica. 2008;93(1):6-9.
  32. Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113(23):5727-5736.
  33. Pardanani A. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. Am J Hematol. 2013;88(7):612-624.
  34. Gotlib J. World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management. Am J Hematol. 2014;89(3):325-337.
  35. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201-1214.
  36. Bejar R, Tiu RV, Sekeres MA, et al. Myelodysplastic syndromes: recent advancements in risk stratification and unmet therapeutic challenges. Am Soc Clin Oncol Educ Book. 2013:e256-e270. sites/ EdBookAM201333e256.pdf. Accessed February 18, 2015.
  37. Jacoby MA, Walter MJ. Detection of copy number alterations in acute myeloid leukemia and myelodysplastic syndromes. Expert Rev Mol Diagn. 2012;12(3):253-264.
  38. Lai JL, Preudhomme C, Zandecki M, et al. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations. Leukemia. 1995;9(3):370-381.
  39. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079-2088.
  40. Schanz J, Tüchler H, Solé F, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30(8):820-829.
  41. Malcovati L, Hellström-Lindberg E, Bowen D, et al; European Leukemia Net. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964.
  42. Bejar R. Prognostic models in myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program. 2013;2013:504-510.
  43. Papaemmanuil E, Gerstung M, Malcovati L, et al; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616-3627.
  44. Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364(26):2496-2506.
  45. Bravo GM, Lee E, Merchan B, et al. Integrating genetics and epigenetics in myelodysplastic syndromes: advances in pathogenesis and disease evolution. Br J Haematol. 2014;166(5):646-659.
  46. Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241-247.
  47. Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023-1031.
  48. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015. editorial/documents/document/acspc-044552.pdf. Accessed February 17, 2015.
  49. Nestal de Moraes G, Castro CP, Salustiano EJ, et al. The pterocarpanquinone LQB-118 induces apoptosis in acute myeloid leukemia cells of distinct molecular subtypes and targets FoxO3a and FoxM1 transcription factors. Int J Oncol. 2014;45(5):1949-1958.
  50. Grimwade D, Walker H, Oliver F, et al; The Medical Research Council Adult and Children's Leukaemia Working Parties. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. Blood. 1998;92(7):2322-2333.
  51. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood. 2000;96(13):4075-4083.
  52. Mrózek K, Marcucci G, Nicolet D, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30(36):4515-4523.
  53. Döhner H, Estey EH, Amadori S, et al; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453-474.
  54. Dufour A, Schneider F, Metzeler KH, et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol. 2010;28(4):570-577.
  55. Zeisig BB, Kulasekararaj AG, Mufti GJ, et al. SnapShot: acute myeloid leukemia. Cancer Cell. 2012;22(5):698-698.e1.
  56. Estey EH. Acute myeloid leukemia: 2013 update on risk-stratification and management. Am J Hematol. 2013;88(4):318-327.
  57. Bullinger L, Döhner K, Kranz R, et al. An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML. Blood. 2008;111(9):4490-4495.
  58. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3(9):650-665.
  59. Tan AY, Westerman DA, Carney DA, et al. Detection of NPM1 exon 12 mutations and FLT3 - internal tandem duplications by high resolution melting analysis in normal karyotype acute myeloid leukemia. J Hematol Oncol. 2008;1:10.
  60. Thiede C, Creutzig E, Reinhardt D, et al. Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1-exon 12. Leukemia. 2007;21(2):366-367.
  61. Lin LI, Chen CY, Lin DT, et al. Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res. 2005;11(4):1372-1379.
  62. Leroy H, Roumier C, Huyghe P, et al. CEBPA point mutations in hematological malignancies. Leukemia. 2005;19(3):329-334.
  63. Green CL, Koo KK, Hills RK, et al. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol. 2010;28(16):2739-2747.
  64. Naoe T, Kiyoi H. Gene mutations of acute myeloid leukemia in the genome era. Int J Hematol. 2013;97(2):165-174.
  65. Sangle NA, Perkins SL. Core-binding factor acute myeloid leukemia. Arch Pathol Lab Med. 2011;135(11):1504-1509.
  66. Haferlach C, Bacher U, Haferlach T, et al. The inv(3)(q21q26)/t(3;3) (q21;q26) is frequently accompanied by alterations of the RUNX1, KRAS and NRAS and NF1 genes and mediates adverse prognosis both in MDS and in AML: a study in 39 cases of MDS or AML. Leukemia. 2011;25(5):874-877.
  67. Rogers HJ, Vardiman JW, Anastasi J, et al. Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3) (q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014;99(5):821-829.
  68. Reis PP, Waldron L, Goswami RS, et al. mRNA transcript quantification in archival samples using multiplexed, color-coded probes. BMC Biotechnol. 2011;11:46.
  69. Foundation One. Technical information and test overview. Accessed February 25, 2015.
  70. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111(5):2505-2515.
  71. Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood. 2006;107(9):3463-3468.
  72. Moorman AV, Chilton L, Wilkinson J, et al. A population-based cytogenetic study of adults with acute lymphoblastic leukemia [Erratum appears in Blood. 2010;116(5):1017]. Blood. 2010;115(2):206-214.
  73. Hoelzer D, Thiel E, Löffler H, et al. Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood. 1988;71(1):123-131.
  74. Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2010;116(18):3409-3417.
  75. Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the Children's Oncology Group. J Clin Oncol. 2012;30(14):1663-1669.
  76. Hilden JM, Dinndorf PA, Meerbaum SO, et al; Children's Oncology Group. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood. 2006;108(2):441-451.
  77. Grimaldi JC, Meeker TC. The t(5;14) chromosomal translocation in a case of acute lymphocytic leukemia joins the interleukin-3 gene to the immunoglobulin heavy chain gene. Blood. 1989;73(8):2081-2085.
  78. Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med. 2004;350(15):1535-1548. 
  79. Borowitz MJ, Hunger SP, Carroll AJ, et al. Predictability of the t(1;19) (q23;p13) from surface antigen phenotype: implications for screening cases of childhood acute lymphoblastic leukemia for molecular analysis: a Pediatric Oncology Group study. Blood. 1993;82(4):1086-1091.
  80. Mullighan CG. Genome sequencing of lymphoid malignancies. Blood. 2013;122(24):3899-3907.
  81. Nachman JB, Heerema NA, Sather H, et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood. 2007;110(4):1112-1115.
  82. Ferrando AA, Neuberg DS, Dodge RK, et al. Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia. Lancet. 2004;363(9408):535-536.
  83. Turkmen S, Timmermann B, Bartels G, et al. Involvement of the MLL gene in adult T-lymphoblastic leukemia. Genes Chromosomes Cancer. 2012;51(12):1114-1124.
  84. Bagg A. Immunoglobulin and T-cell receptor gene rearrangements: minding your B's and T's in assessing lineage and clonality in neoplastic lymphoproliferative disorders. J Mol Diagn. 2006;8(4):426-429.
  85. Sandberg Y, van Gastel-Mol EJ, Verhaaf B, et al. BIOMED-2 multiplex immunoglobulin/T-cell receptor polymerase chain reaction protocols can reliably replace Southern blot analysis in routine clonality diagnostics. J Mol Diagn. 2005;7(4):495-503.
  86. Elenitoba-Johnson KS, Bohling SD, Mitchell RS, et al. PCR analysis of the immunoglobulin heavy chain gene in polyclonal processes can yield pseudoclonal bands as an artifact of low B cell number. J Mol Diagn. 2000;2(2):92-96.
  87. Nihal M, Mikkola D, Wood GS. Detection of clonally restricted immunoglobulin heavy chain gene rearrangements in normal and lesional skin: analysis of the B cell component of the skin-associated lymphoid tissue and implications for the molecular diagnosis of cutaneous B cell lymphomas. J Mol Diagn. 2000;2(1):5-10.
  88. Grody WW, Nakamura RM, Kiechle FL, et al, eds. Molecular Diagnostics: Techniques and Applications for the Clinical Laboratory. San Diego, CA: Academic Press; 2010.
  89. Wang SA, Wang L, Hochberg EP, et al. Low histologic grade follicular lymphoma with high proliferation index: morphologic and clinical features. Am J Surg Pathol. 2005;29(11):1490-1496.
  90. Tomita N. BCL2 and MYC dual-hit lymphoma/leukemia. J Clin Exp Hematop. 2011;51(1):7-12.
  91. Swerdlow SH. Diagnosis of ‘double hit' diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC. ASH Education Handbook. 2014;(1):90-99.
  92. Valera A, Balague O, Colomo L, et al. IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas. Am J Surg Pathol. 2010;34(11):1686-1694.
  93. Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood. 2011;117(8):2319-2331. 
  94. Hummel M, Bentink S, Berger H, et al; Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe. A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006;354(23):2419-2430.
  95. Haralambieva E, Boerma EJ, van Imhoff GW, et al. Clinical, immunophenotypic, and genetic analysis of adult lymphomas with morphologic features of Burkitt lymphoma. Am J Surg Pathol. 2005;29(8):1086-1094.
  96. Ferry JA. Burkitt's lymphoma: clinicopathologic features and differential diagnosis. Oncologist. 2006;11(4):375-383.
  97. Crisan D, ed. Hematopathology: Genomic Mechanisms of Neoplastic Diseases. New York: Humana Press; 2010.
  98. Sun T, Nordberg ML, Cotelingam JD, et al. Fluorescence in situ hybridization: method of choice for a definitive diagnosis of mantle cell lymphoma. Am J Hematol. 2003;74(1):78-84.
  99. Seto M. Cyclin D1-negative mantle cell lymphoma. Blood. 2013;121(8):1249-1250.
  100.  Dierlamm J, Baens M, Wlodarska I, et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18) (q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood. 1999;93(11):3601-3609.
  101. Streubel B, Simonitsch-Klupp I, Müllauer L, et al. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia. 2004;18(10):1722-1726.
  102. Hamoudi RA, Appert A, Ye H, et al. Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism. Leukemia. 2010;24(8):1487-1497.
  103. Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208(7):1389-1401.
  104. Arcaini L, Zibellini S, Boveri E, et al. The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms. Blood. 2012;119(1):188-191.
  105. Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364(24):2305-2315.
  106. Tiacci E, Schiavoni G, Forconi F, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood. 2012;119(1):192-195.
  107. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. N Engl J Med. 2012;367(9):826-833.
  108. Treon SP, Hunter ZR. A new era for Waldenstrom macroglobulinemia: MYD88 L265P. Blood. 2013;121(22):4434-4436.
  109. Murray F, Darzentas N, Hadzidimitriou A, et al. Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood. 2008;111(3):1524-1533.
  110. Rådestad E, Wikell H, Engström M, et al. Alpha/beta T-cell depleted grafts as an immunological booster to treat graft failure after hematopoietic stem cell transplantation with HLA-matched related and unrelated donors. J Immunol Res. 2014;2014:578741.
  111. British Committee for Standards in Haematology; Royal College of Pathologists. Best Practice in Lymphoma Diagnosis and Reporting. London: British Society for Haemotology; 2010. Accessed February 18, 2015.
  112. Chitgopeker P, Sahni D. T-cell receptor gene rearrangement detection in suspected cases of cutaneous T-cell lymphoma. J Invest Dermatol. 2014;134(4):e19.
  113. Ioachim HL, Medeiros LJ, eds. Ioachim's Lymph Node Pathology. 4th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2009.
  114. Liang X, Meech SJ, Odom LF, et al. Assessment of t(2;5)(p23;q35) translocation and variants in pediatric ALK+ anaplastic large cell lymphoma. Am J Clin Pathol. 2004;121(4):496-506.
  115. Rudolph C, Bittner C, Feller AC, et al. Cytogenetic characteristics of a murine in vitro model for the human anaplastic large cell lymphoma (ALCL). Cytogenet Genome Res. 2006;114(3-4):292-295.
  116. Delgado P, Starshak P, Rao N, et al. A comprehensive update on molecular and cytogenetic abnormalities in T-cell prolymphocytic leukemia (T-pll). J Assoc Genet Technol. 2012;38(4):193-198.
  117. Dearden C. How I treat prolymphocytic leukemia. Blood. 2012;120(3): 538-551.
  118. Mandava S, Sonar R, Ahmad F, et al. Cytogenetic and molecular characterization of a hepatosplenic T-cell lymphoma: report of a novel chromosomal aberration. Cancer Genet. 2011;204(2):103-107.
  119. Tsukasaki K, Tsushima H, Yamamura M, et al. Integration patterns of HTLV-I provirus in relation to the clinical course of ATL: frequent clonal change at crisis from indolent disease. Blood. 1997;89(3):948-956.

Source: Moffitt Cancer Center

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por cyto às 19:50

Quinta-feira, 13.08.15

A Decade of Dramatic Change in the Treatment of Prostate Cancer

A Decade of Dramatic Change in the Treatment of Prostate Cancer

Major treatment strategies have been approved over the past decade, dramatically increasing survival rates and changing the treatment paradigm for prostate cancer. Greater improvements are expected within the next decade through precision medicine.

In 2005, there were only a handful of approved medications. However, today there are many more and they work by several different mechanisms, allowing them to extend life in novel ways.

In 2005, the relative 10-year survival rate for prostate cancer was 92% and the relative 15-year survival rate was 61%, according to the American Cancer Society.1

Today, the numbers are significantly higher: the relative 5-year survival rate for all stages of prostate cancer is almost 100%, the relative 10-year survival rate is 99%, and the 15-year relative survival rate is 94%.2

“The greatest advances in the management of prostate cancer in the last decade have come directly from our understanding of the biology of what causes prostate cancer cells to become resistant to treatments we had a decade ago,” said Anthony D'Amico, MD, PhD, of Brigham and Women's Hospital and Dana-Farber Cancer Institute, in Boston, MA.

He said the Prostate Cancer Foundation (PCF), which was formerly the Association for the Cure of Cancer of the Prostate (CaP CURE), helped usher in a new era in terms of research. It included leading scientific and clinical experts and it helped expedite new treatments.

In 2004, the U.S. Food and Drug Administration (FDA) approved docetaxel after the publication of two random controlled trials, one of which was led by a PCF clinical investigator.3

Over the past decade, the FDA has approved the pure luteinizing hormone–releasing hormone antagonist degarelix (Firmagon), the first immunotherapy for prostate cancer, sipuleucel-T (Provenge), and a taxane-based chemotherapy, cabazitaxel (Jevtana).

The FDA also approved denosumab (Prolia/Xgeva) as a treatment to increase bone mass in patients at high risk for fracture receiving androgen-deprivation therapy (ADT).

Enzalutamide (Xtandi) has been approved to treat men with metastatic castration-resistant prostate cancer that has spread or recurred, even with medical or surgical therapy to minimize testosterone. Enzalutamide was approved for patients who have previously been treated with docetaxel.

In May 2013, the FDA approved radium Ra 223 dichloride (Xofigo) to treat symptomatic late-stage metastatic castration-resistant prostate cancer that had spread to bones, but not to other organs.

“Provenge and radium 223 dichloride have helped a lot for patients in the late stages of the disease,” Dr. D'Amico told Cancer Therapy Advisor. “In the future, we hope to do more than just extend life more than several months in late stage disease.”

It is now estimated that one in seven men will be diagnosed with prostate cancer during his lifetime and approximately 220,800 new cases of prostate cancer will be diagnosed in 2015 alone.4 The American Cancer Society predicts in 2015 there will be approximately 27,540 deaths from prostate cancer.


RELATED: Post-diagnostic Dietary Changes Among Men with Prostate Cancer Beneficial

Yair Lotan, MD, who is a professor of urology and chief of urologic oncology at University of Texas Southwestern Medical Center, in Dallas, TX, said no one agent has been a home run, even though there have been significant advances in the past decade.

“The advancements of the past decade have been mostly small incremental changes. Each of the new therapies provides modest survival benefits, 3 to 4 months,” Dr. Lotan told Cancer Therapy Advisor. “There is still a desperate need for effective therapy for patients with castrate resistant prostate cancer and it is unclear whether this will be provided by novel targeted therapies.”

Tomasz Beer, MD, who is chair for prostate cancer research and the deputy director of the Oregon Health & Science University (OHSU) Knight Cancer Institute, in Portland, OR, said clinicians should be cautious when analyzing the 5- and 10-year survival numbers.

He said while treatment improvements are partly responsible for better outcomes, a part of this trend reflects early diagnosis and stage migration.

“Having said that, there have been major advances; the most notable of which is the development of two new drugs that target androgen receptor signaling, abiraterone and enzalutamide. But in total six agents that extend survival have been approved, approximately five in the last 5 years. That is real progress,” Dr. Beer told Cancer Therapy Advisor.

“Further, and importantly, we have learned that earlier use of chemotherapy in metastatic but hormone responsive disease substantially magnified the benefits of chemotherapy. Taken together, the early application of chemotherapy coupled with compelling new androgen receptor signaling inhibitors have transformed the management of advanced disease.”

Measuring circulating tumor cells (CTC) following first-line therapy is changing how patients are managed. This past year, researchers reported that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in CTC from men with advanced prostate cancer may be associated with resistance to enzalutamide and abiraterone.5

“The biggest changes in the landscape of advanced prostate cancer include discovery of CTC, genetic testing on them (AR-V7), improvement in overall survival from various drugs like abiraterone, enzalutamide, radium-223, sipuleucel-T, and cabazitaxel. The most striking data are from the ECOG-3805 trial, which changed the standard of care for de novo metastatic prostate cancer by adding six cycles of docetaxel to ADT. This significantly changed the overall survival,” said Saby George, MD, an assistant professor of oncology at Roswell Park Cancer Institute, in Buffalo, NY.

Novel agents that work by different mechanism and are matched to genetic signatures may soon significantly change the management of metastatic prostate cancer. Gerald Andriole, MD, chief of urologic surgery at Washington University School of Medicine in Saint Louis, MO, said experimental therapeutic vaccines and check-point inhibitors are showing promise and may soon be part of the armamentarium.

Recently, researchers discovered that cytotoxic T lymphocyte antigen 4 (CTLA-4) is a receptor on the surface of T cells that blocks the immune response by inhibiting T cell activation. Now, studies are looking at whether an antibody (anti–CTLA-4) can block the “immune checkpoint” protein.

"More complete obliteration of the androgenic pathways has played a major role for men with advanced prostate cancer. Going forward, efforts to better understand the role of immunotherapy with vaccines, checkpoint inhibitors, and other approaches, hold great promise, and may be applied to men with earlier stages of prostate cancer," Dr. Andriole told Cancer Therapy Advisor.


RELATED: No Link Between Shift Work, Prostate Cancer Incidence, Study Shows

Dr. George said there is a strong possibility that prostate cancer could become a manageable chronic disease. However, he said it is important that clinicians not give their patients false hope. Dr. George said many patients may mistakenly have too high of expectations based on recent reports about precision medicine and what it can and cannot do.

“Precision medicine is a loose term. The clinical development of second-line hormonal manipulation like enzalutamide and abiraterone are examples of how to optimize the targeting of the androgen receptor signaling axis. There needs to be a lot more development to make this disease a chronic disease. Cure is an elusive term in advanced prostate cancer as of today,” Dr. George told Cancer Therapy Advisor.


  1. American Cancer Society. Cancer facts & figures 2005. redpdf.pdf. Published 2005. Accessed July 30, 2015.
  2. American Cancer Society. Survival rates for prostate cancer. Revised March 12, 2015. Accessed July 30, 2015.
  3. D'Amico AV. US Food and Drug Administration approval of drugs for the treatment of prostate cancer: a new era has begun. J Clin Oncol. 2014;32(4):362-364.
  4. American Cancer Society. What are the key facts about prostate cancer?. Revised March 12, 2015. Accessed July 30, 2015.
  5. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028-1038.

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por cyto às 19:38

Quinta-feira, 13.08.15

New Brain Tumor Classification and Treatment Based on Genetic Analysis


Cancer Research Network Proposes New Brain Tumor Classification and Treatment Based on Genetic Analysis

A new study from The Cancer Genome Atlas Research Network recently revealed the added value of performing genetic analysis in brain tumors. The study is entitled “Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas” and was published in the New England Journal of Medicine. The study involved more than 300 researchers from 44 different institutions.

Gliomas are a type of cancer that develops in glial cells, which are non-neuronal cells that constitute up to 50% of the brain cells and that provide support and protection for neurons. As the tumor grows, it can compress normal brain tissue, often leading to disability or fatal consequences. It is estimated that 80% of all malignant brain tumors correspond to gliomas, which can be classified by grade according to their histopathological evaluation. The most common grading system from the World Health Organization (WHO) classifies gliomas from I (least advanced disease and a better prognosis) to IV (most advanced disease and a worst prognosis).

Diffuse low-grade (grade II) and intermediate-grade (grade III) gliomas, which together form the lower-grade gliomas, have a highly variable clinical behavior from indolent to highly aggressive that cannot be accurately predicted based on their histological class. In addition, the histologic classification of gliomas can differ between observers. Apart from the histological classification, mutations in the genes IDH, TP53 and ATRX, as well as co-deletion of chromosome arms 1p and 19q (1p/19q), have been reported as clinically relevant biomarkers of lower-grade gliomas.

In the study, researchers conducted genome-wide analyses of 293 lower-grade gliomas from adults in terms of specific genetic features including gene mutations and chromosomal anomalies.

Researchers found that the genetic makeup obtained from the brain tumors analyzed allowed the generation of three robust, non-overlapping and prognostically significant subtypes of lower-grade glioma. Patients with lower-grade gliomas, and an IDH mutation and 1p/19q co-deletion were found to have the most favorable clinical outcomes. The team also found that almost all lower-grade gliomas with IDH mutations and no 1p/19q co-deletion had mutations in the TP53 gene (94%) and ATRX inactivation (86%). The majority of the lower-grade gliomas without IDH mutations exhibited genomic aberrations and a clinical behavior similar to the one observed in aggressive glioblastomas.

“We found molecular signatures that better define clinical behavior based on our analysis,” said the study’s lead co-author Dr. W.K. Alfred Yung from The University of Texas MD Anderson Center in a news release. “We hope this will impact how physicians both diagnose and plan therapies for brain cancer.”

“We looked at the six most common forms of glioma and were able to deduce that these can be effectively grouped into three distinct molecular super clusters of lower-grade gliomas,” explained the study’s lead co-author Dr. Roeland Verhaak also from The University of Texas MD Anderson Center. “It is exciting that our findings are likely to provide a basis for the upcoming update to the WHO classification of tumors of the central nervous system.”

The research team concluded that lower-grade gliomas can be classified into three molecular classes that are more in agreement with IDH, 1p/19q, and TP53 status than with histologic classes. The team believes that their findings might change brain tumor diagnosis, classification and also treatment into a more accurate, consistent and precise manner based on the genetic makeup of the tumor and specific biomarkers. The authors propose that molecular tests combined with the current standard histopathological examination of brain tumors will allow the identification of the tumor aggressiveness and predict its response to certain therapies.

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por cyto às 19:26

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Agosto 2015